Datasets:

alon-albalak

/

licensed_pubmed

like 0

PMC3051893

Introduction ============ The A.M. Dogliotti College of Medicine of Liberia, West Africa, was established in 1968 through a tripartite arrangement involving the Vatican, the Government of Liberia and the Dogliotti Foundation of Italy. The college had a maximum capacity of 125 students and currently has two schools, the College of Medicine and the School of Pharmacy on the College of Medicine campus. This is the only recognized school of medicine in Liberia and has been the major source of Liberia\'s qualified physicians. Length of training is 5 years plus a 2-year internship. There is no accredited specialty residency training available in Liberia. From 1980 to 2003, Liberia entered into a period of conflict and civil wars. During this time Liberia\'s health and educational services were severely disrupted. Many health care workers, university and college faculty, medical school and hospital administrators fled the country. During the war, buildings were badly damaged by armed forces or shell fire, and the contents either stolen or totally destroyed \[[@B1]\]. The war ended, and now the best interventions to help re-build Liberia\'s medical educational structure needed to be identified and targeted. Our main focus was to obtain as much information as possible on the current status of the Medical School and the barriers to physician training. Methods ======= To evaluate the impact of Liberia\'s multiple wars on medical education both past and present, we compiled data from three sources. First we evaluated the data from a survey of participants of a symposium on emergency medicine and trauma care organized at the A.M. Dogliotti College of Medicine of the University of Liberia in Monrovia, Liberia, in September 2007. The symposium was advertised by announcement and posters at the A.M. Dogliotti School of Medicine and JFK Government Hospital in Monrovia. Attendance was recommended to the medical students but was optional as many health care providers could not be given time off from their duties. The participants in the symposium were requested to voluntarily complete an anonymous survey inquiring about (1) demographic information, (2) educational experience to date and (3) the current length of training. They also (4) answered the question, \"Has your training been delayed?\" If the training had been interrupted or delayed, the respondents were asked to explain using free text answers. Responses were recorded and tabulated (numbers and ranges) on an Excel database. Second, we collected the collated answers regarding the perceived barriers to academic and clinical training from open afternoon discussion groups with the symposium participants. The format was open discussion while a senior medical student with IRB training on the visiting team took notes and collated the responses. Third, we summarized information volunteered in interviews by the Dean of the A.M. Dogliotti School of Medicine in 2002, 2007 and 2009, and published online in 2002 and 2006. Limitations of these Methods ---------------------------- The symposium was open and free to anyone who could come. Participants therefore consisted of a mix of medical students, physician assistants and nurses, with only a few graduate physicians being available to attend sporadically as staffing at the hospitals was so critical. Attendance also varied from day to day, with some participants only being able to attend part of the symposium\'s didactic sessions, and consequently these participants did not complete surveys. The survey was optional, and so a convenience sample resulted of participants who stayed for the full symposium and chose to fill out the survey. Results ======= Surveys ------- Thirty registered full-time participants at the symposium responded, completed and returned the questionnaire. Only 1 intern and 12 medical students submitted completed surveys, while the rest of the surveys were from nurses, physician assistants and a pharmacist. We primarily focused on the situation of the Medical School and so are reporting the responses of the intern and medical students below, but all the surveys demonstrated that these expressed concerns could be extrapolated to other institutions of higher learning as well. The average age of the medical students was 36.5 years, and 80% were men. The medical students and intern all reported a delay in training with 83.3% citing the civil war as a cause and 75% citing the lack of Basic Science and Clinical faculty as the major delaying factors. Discussion groups ----------------- There were six open discussion groups voluntarily attended by 50 Liberian health care professionals including physicians and medical students. The groups targeted the lack of basic science and clinical faculty as both past and current impediments to their training in the Medical School and the teaching hospitals. They also referenced the extensive damage to the laboratories, library and classrooms of the Medical School during the war and the lack of books, teaching equipment, laboratory equipment and materials needed in training. They mentioned the need for safe nearby dormitory rooms with reliable electricity and water, and the need for a peripheral security fence around the Medical School campus. They discussed the disrepair of the teaching hospitals, closure of other medical facilities, the lack of essential equipment and medication, and the need for improved finances and resources as critical to delivering future medical care to the people of Liberia. Supporting documents -------------------- In 2002, Tabeh L. Freeman, RN, MD, MPH, Dean of the AM Dogliotti College of Medicine, published a \"Situational Analysis\" \[[@B2]\] summarizing the current state of the college and its needs. In this document he highlighted the impact of the civil war: \"The seven-year civil conflict has caused considerable destruction of the infrastructure of the college, that is, the buildings, library and laboratory facilities, and flight of members of the teaching staff.\" Most importantly, he stressed that \"the shortage of teaching staff was particularly dire.\" Indeed, with six pre-clinical departments (public health and preventive medicine, anatomy, physiology, biochemistry, pharmacology, and microbiology and parasitology) and seven clinical departments (internal medicine, surgery, radiology, pediatrics, obstetrics and gynecology, pathology and psychiatry), there were four full-time faculty members in the Pre-Clinical Divisions and two full-time faculty in the Clinical Divisions. In the preclinical years, one of the full-time public health teaching staff was the Dean of the Medical School. The Dean wrote that there should be a minimum of one full-time faculty member per department. By those standards, the college needed at least eight more full-time faculty members. In 2006, Dr. Freeman published an update titled \"An Appeal for Assistance\" \[[@B3]\]. Per Dr. Freeman\'s report in 1990, there were over 500 practicing physicians in the country, including the public and private sectors. In 2006 there were fewer than 75, with 26 of those in the public sector \[[@B3]\]. At that time, Dr Freeman reported 34 faculty members at the College\--10 full time and 24 part time. He stated that the need for teachers especially in the basic sciences division was the most acute. In an interview in 2008, Dr. Freeman stated that only 51 Liberian physicians remained practicing in Liberia. Most of A.M. Dogliotti\'s alumni had fled the country. In 2007 only 4 medical students had graduated (as compared to the usual 40 graduates/year before the civil war), and the average course length had jumped from 5 to 9 years \[[@B4]\]. In 2009, Dean Freeman shared the statistics shown in Table [1](#T1){ref-type="table"} in an interview. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Teaching faculty at the A.M. Dogliotti School of Medicine in 2009 ::: [Pre-Clinical]{.underline} Full-time teaching staff Part-time teaching staff Total --------------------------------------- --------------------------------------------- -------------------------- ------- Public Health and Preventive Medicine 5 0 5 Anatomy/Embryology 1 Occasional 1 Histopathology 1 Occasional 1 Physiology 1 0 1 Microbiology and Parasitology 0 - but position filled, professor expected 0 0 Pharmacology 1 0 1 Biochemistry 1 0 1 Total pre-clinical 10 \-\-\-\-\-- 10 [Clinical]{.underline} Full-time teaching staff Part-time teaching staff Total Internal Medicine 2 0 2 Surgery 0 0 0 Ob-Gyn 0 0 0 Pediatrics 0 0 0 Psychiatry 0 0 0 Radiology 0 0 0 ENT 1 0 1 Orthopedics 1 1 2 Neurology \* 1 on contract 0 1 Anesthesiology \* 1 on contract 0 1 Emergency medicine at JFK \*\* Global Health Alliance -1 0 1 Total clinical 7 1 8 \*The Government of Liberia is hiring full-time faculty and staff from other countries on salaried contracts of 1 or more years. The contract of the anesthesiologist from Nigeria will expire in September 2010. \*\* The Global Health Alliance, partnering with the NGO HEARTT (Health Education and Relief through Teaching), is a consortium of universities dedicated to placing senior residents, fellows and faculty in the Emergency Area of JFK in rotating blocks throughout the year. ::: The data shows that by 2009, Dean Freeman had recruited at least one basic science faculty member to every department. However, there still remained a clear need for more full-time clinical faculty in every department of the Medical School and teaching hospitals. Part-time and visiting professors are also critical in supplementing the gaps when full-time professors are on needed leave. The Dean also stressed that just when there was a compelling need to graduate more and more qualified physicians, the institution qualified to do so was reporting an on-going lack of teaching faculty. Discussion ========== The prolonged civil conflict caused major damage to the health care system of Liberia \[[@B5]\]. The medical students were severely impacted, with 100% reporting a delay in training, and 83.3% of them citing the civil war and 75% citing a lack of clinical and basic science faculty as delaying factors in the surveys. In the discussion groups the students further defined the impact of the civil war on training delays due to loss of laboratory, library, teaching and residential facilities, destruction of the infrastructure and lack of personal security. However, since 2007, because of a grant from the World Bank and other generous donations, a security fence for the Medical School has been built, and laboratories, classrooms and administrative offices are being constructed. The country is now at peace. The greatest need both past and present is for new faculty members-especially Clinical, but also Basic Science-to allow the A.M. Dogliotti Medical School to graduate the number of qualified physicians necessary to re-build Liberia\'s medical delivery system. Conclusion ========== An identified and important targeted intervention includes volunteer or subsidized Basic Science and Clinical faculty members for the Medical School and teaching hospitals from a coalition of concerned partnering institutions to assist in re-building the medical educational capacity of Liberia. The long-term rewards of this would be immeasurable-a country\'s health-care infrastructure restored and Liberian physicians trained to deliver health care in a West Africa country recovering from a horrible and crippling civil war. Competing interests =================== KC has no competing interests. NF has no competing interests. Authors\' contributions ======================= NF compiled and summarized the data and references, and wrote the methods and results sections. NF has read and approved the final manuscript. KC did the literature search and the interviews and wrote the abstract, introduction, discussion and conclusions sections of the paper. KC has read and approved the final manuscript. Acknowledgements ================ The authors would like to recognize and thank Dr. Mare Tom for her assistance in helping collate and organize the survey data, and Dr. Tabeh Freeman for the generous distribution of the \"2002: A Situational Analysis\" and his generous sharing of information. We also thank the medical students (Drs. Olaes, Ladine and Martindale) and all the team members of the 2007 Emergency Medicine Team who came and taught and volunteered on their own time and at their own expense. One author currently works with Health Education and Relief Through Teaching (HEARTT) a regional non-governmental organization dedicated to re-building the health care system of Liberia. HEARTT and its consortium of academic medical centers and leaders partner with the JFK Medical Center in Monrovia and the Ministry of Health in its support of clinical operations (Emergency Medicine, Pediatrics, General Surgery) and educational platforms. This article is dedicated in profound admiration to the health care professionals and educators of Liberia who risked their lives during the civil war to provide health care and training to their people.

PubMed Central

2024-06-05T04:04:17.192776

2011-2-16

PMC3051894

Introduction ============ Burn injuries can be encountered in all ages. The most common burn injuries among the Turkish population are caused by a variety of causes: fires, scalding substances (i.e., traditional Turkish tea, hot milk, etc.), electricity and chemical agents. When taking into account the mechanisms of chemical burns, it was observed that 4% of cases were caused by the application of herbs used as traditional medication \[[@B1]\]. Despite the advances in medicine, a tendency towards using alternative treatments can be seen in every population, including the Turkish one, and plant application is among the most common methods used in folk medicine. *Ranunculus arvensis*(a member of the *Ranunculaceae*family) is a wild plant traditionally used in the Far East to treat arthritis, asthma, gout, high fever and psoriasis, and is highly allergenic in spring during the flowering period. In Turkey, the plant is frequently seen in the high mountains of the Mediterranean region and the southeastern and eastern regions of Anatolia, which are agricultural areas with plant production \[[@B2]-[@B11]\]. Herein, we present three patients with chemical burns caused by *Ranunculus arvensis*used as poultice around the knees and the thumb for the treatment of rheumatic symptoms. Case reports ============ Case 1 ------ A 48-year-old man was admitted to our emergency department because of an open wound on his right thumb (Figure [1](#F1){ref-type="fig"}). Following a neighbor\'s advice, the patient had applied bruised plant material as a poultice to his right thumb, covering it with an occlusive bandage for 1 h to treat arthralgia. This procedure had resulted in pain and bullous and erythematous lesions on the treated area. The patient did not apply any other substance to the wound and left it open. One day later, as there was no improvement, the patient presented to our clinic and was hospitalized. The lesion healed within 3 weeks with appropriate topical fusidic acid therapy and daily dressing changes. The plant specimens provided by the patient were identified in the Department of Pharmaceutical Botany, Faculty of Pharmacy, at Marmara University as *Ranunculus arvensis*, a member of the *Ranunculaceae*family. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Phytocontact dermatitis on right thumb (case 1)**. :::  ::: Case 2 ------ A 59-year-old female patient presented to our burn unit with complaints of vesiculo-bullous lesions that were circumferential around both knees (Figure [2](#F2){ref-type="fig"}). Three days before, at the recommendation of a neighbor, she had applied plant paste on her both knees, covering them overnight for osteoarthritis-related pain. When unfurling the bandages, the patient had noticed wounds over the treated areas. As no improvement had occurred after 3 days, the patient presented to our clinic. Routine laboratory investigations revealed values within normal ranges, and radiological examination showed no pathological findings. On physical examination, all vital signs were stable. Because the patient had diabetes mellitus managed by diet alone, cefazolin sodium was started as antibiotic prophylaxis. The patient was hospitalized in the burn unit, and the wounds were washed with chlorhexidine scrub. When the debris and bullous lesions were removed, second-third degree skin injuries were observed. The lesion healed within 2 weeks with appropriate topical silver sulfadiazine cream and daily dressing changes. No contracture developed during the 4-month follow-up period. The plant specimens provided by the patient were identified as *Ranunculus arvensis*. ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Phytocontact dermatitis on both knees mimicking burn injury (case 2)**. :::  ::: Case 3 ------ A 70-year-old woman living in a rural area of Diyarbakir presented to our emergency outpatient unit with marked burns on both knees (Figure [3](#F3){ref-type="fig"}). According to the history, the patient, suffering from bilateral knee pain not responding to analgesics, had followed the recommendation of a neighbor; she ground a plant found growing in the mountains and applied it to both knees. Despite the pain, she had not unfurled the bandages for 2 days, and after removing the poultices, she had noticed burn wounds. On the same day, the patient presented to our emergency unit. Her medical history revealed no chronic disease except hypertension. On physical examination, second-degree burns on the anterior aspect of both knees were observed. After performing debridement on the first day of admission, the injuries were cleaned with chlorhexidine scrub and topical silver sulfadiazine cream. By the end of the 10th day, the patient had recovered completely. The plant specimens were identical with those in the first two cases. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Phytocontact dermatitis on both knees mimicking burn injury (case 3)**. :::  ::: Discussion ========== The plants of the genus *Ranunculus*contain the toxic glycoside ranunculin. In case of dermal contact, ranunculin is broken down to protoanemonin, which leads to dermal-epidermal separation and formation of bullous lesions. This clinical condition is called phytodermatitis \[[@B4],[@B8],[@B10]\]. Protoanemonin is a volatile and highly vesicant oil, whose toxicity may be explained by the increase in free oxygen radicals resulting in the inhibition of DNA polymerase. The irritant effect of protoanemonin is highest during spring when the plant is blooming and has fresh leaves, and decreases to a minimum as the plant dries up \[[@B3]\]. All three patients reported in this study presented to our clinic in spring. Members of the *Ranunculaceae*family are widely used as traditional treatment in the form of poultices for various medical conditions, such as abscess drainage, bullous lesions, hemorrhoids, burns and lacerations, and in the form of herbal remedies for rheumatic and myalgic pain, common colds, etc. \[[@B2],[@B8]-[@B10]\]. In the literature, the terms \"plant burn\" and \"phytodermatitis\" have been frequently used interchangeably. Metin et al. \[[@B8]\] proposed the name \'phytodermatitis\' to designate this medical condition; however, in our opinion, the important point is not the name, but how it is treated. After all, the above-mentioned two terms interpret alterations in the anatomic integrity of the skin with pathogenic mechanisms resembling those of burn injury. Therefore, treatment plans should be made in accordance with the methods for treating burns. Eskitascioglu et al. \[[@B4]\] noted in their study that the severity of chemical burns caused by plant poultices depends on the application method and duration. Reviewing the literature, we found that most patients used the plant as a poultice that was applied to the painful extremity and was covered with a cloth for a period ranging from 25 min to 48 h. We assume that this covering method increases the rate of contact and the degree of damage. When scanning the literature using PubMed and the Google scholar database, we accessed ten articles on phytocontact dermatitis caused by plants from the *Ranunculaceae*family. A total of 25 patients\--18 females and 7 males\--aged between 17 and 76 years (mean age: 53.4 ± 14.1 years) were presented in these studies. Twenty-one patients were living in the eastern and southeastern regions, and four in the western regions of Turkey. Age, gender and clinical data for the patients are summarized in Table [1](#T1){ref-type="table"}. As shown in the table, women are two times more likely to use alternative medicine than men. Our experience supports this observation, and we postulate that it might be due to the fact that women are more prone to follow the advice of their neighbors and to trust folk medicine. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Age, gender and clinical characteristics for 25 cases of phytocontact dermatitis caused by plants of the Ranunculaceae family and mimicking burn injuries (25 reported in the literature and our 3 cases) ::: Ref. Age Sex Implementation period Admission to hospital Location Type of plant Approach to lesions Healing time ------------- ------- --------- ----------------------- ----------------------- -------------------------------------- --------------------------- ------------------------------------------------- -------------- 2 64 M 12 h Immediately Left distal thigh *R. arvensis* Debridement, topical nitrofurantoin 3 weeks 3 17 M 48 h 2 days Back, scrotum, penis, chest *R. arvensis* Wet dressing, silver sulfadiazine, collogenase 4 weeks 4 42 M 8 h 1 week Left foot dorsum and ankle *C. testiculatus* Clorhexidine scrub + split thickness skin graft 7 days 40 F 4 h 3 weeks Right foot dorsum and ankle *C. testiculatus* Clorhexidine scrub + paraffin gauze 10 days 60 F 2 h 10 days Right foot dosrum and left knee *C. testiculatus* Clorhexidine scrub + paraffin gauze 7 days 65 F 2 h 1 week Left knee *C. testiculatus* Clorhexidine scrub+ paraffin gauze 15 days 48 F 4 h 14 days Right leg *C. falcatus* Clorhexidine scrub + paraffin gauze 2 weeks 5 52-76 F:6 M:3 12 h NA Both knees: 7 One knee: 2 *R. constantinopolitanus* Topical antibacterial treatment 10 d 6 55 F 1 day 2 days Right knee R. illyricus Wet dressing and topical antibiotics 4 days 7 58 F 2 days 5 days Left knee *R. illyricus* Topical antibacterial cream A few days 54 F 1 days 3 days Right knee *R. illyricus* Wet dressing and topical antibiotic 1 week 8 69 M 2.5 h 2 days Left knee *C. falcatus* Wet dressing and topical fusidic acid 2 weeks 33 F 1.5 h 2 days Right distal leg, ankle, dorsal foot C. falcatus Wet dressing and topical antibiotic 3 weeks 18 F 1 h 1 week Left ankle, dorsal foot *C. falcatus* Wet dressing and topical antibiotic 2 weeks 9 47 F 25 min NA Right knee *C. falcatus* Wet dressing and topical mometasone cream 10 days 10 45 F Overnight 2 days Abdomen, right leg *R. damascenus* Wet dressing and topical fusidic acid 10 days 11 NA F NA NA Right ankle *C. falcatus* Wet dressing 2 weeks **Current** 48 M 1 h 1 days Right thumb *R. arvensis* Dressing with fusidic acid 3 weeks 59 F Overnight 3 days Bilateral knee *R. arvensis* Clorhexidine scrub + silver sulfadiazine cream 2 weeks 70 F 2 days Immediately Bilateral knee *R. arvensis* Clorhexidine scrub + silver sulfadiazine cream 10 days ::: In addition, the results of this literature scan revealed that people living in socio-culturally and economically underdeveloped regions are more enthusiastic about using alternative treatment methods. All of the patients presented in this study were living in a culturally backward area located in a mountainous and rural region of southeastern Turkey. As we have often observed, herbal products are frequently used for the purpose of treating psoriasis, hemorrhoids, back/lower back pain and arthralgia. This may be explained by the fact that folk medicine is an easily accessible, affordable and natural form of treatment; also, there is still a lack of reliance on pharmaceuticals as well as a desire to avoid long waiting times in the hospital. Burn injuries are still a major cause of mortality and morbidity in most of the developing world, with burn wound infections being the most important complication. Loss of the normal skin barrier, as well as impairment of many systemic host-defense mechanisms, makes burn wounds susceptible to colonization and infection by multiple endogenous microorganisms. The patient remains vulnerable to invasive infection until the wound is completely epithelialized \[[@B12]\]. Therefore, the areas with disrupted skin integrity should be covered as soon as possible, and, for this purpose, grafting and topical antibacterial dressing are most commonly used in the early stages. Reviewing the literature, we observed that in most of the reported cases, antimicrobial dressings were applied, and the predominantly used agents in burn wound care were: silver sulfadiazine, fusidic acid, mafenide, nitrofurazone, chlorhexidine, povidone-iodine, mupirocin, etc. In our burn unit, we frequently prefer dressings containing an antimicrobial agent to cover the burn wound. In conclusion, although plant poultices applied to the skin show positive effects on many dermatological and rheumatic diseases, they also have many adverse effects. We believe that benefiting from modern medicine is the correct approach rather than attempting alternative treatment methods, whose therapeutic effects have not been proven yet by scientific studies. Consent ======= Written informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= AS, KO,CM and BM made the daily dressings; AS, YY, OA and SH contributed to writing the article and reviewing the literature as well as undertaking a comprehensive literature search; AS, BM, KO, SH and CM contributed to the design of the study and manuscript preparation.

PubMed Central

2024-06-05T04:04:17.194509

2011-2-21

PMC3051895

Introduction ============ Prolongation of air leakage and bleeding after lung operations are among the important causes of morbidity. Prolongation of air leakage is the second leading cause of delay in the time of discharge from the hospital \[[@B1]\]. Prolonged parenchymal air leakage is commonly seen after lung resections and has been reported at a rate of 15-18%. Thus, chest tubes are needed for a longer time and consequently, this causes pain, decreased mobility and possible complications \[[@B2]\]. The standard method for prevention of air leakage and bleeding developing following lung resection is surgical suturing or stapler application. Tissue adhesives and supported stapler use are the other methods \[[@B3]-[@B10]\]. Ankaferd Blood Stopper (ABS) is a herbal product used as a hemostatic agent in traditional Turkish medicine. It is a topical agent, the safety and efficacy of which have been proven in dermal, external traumatic, postoperative and dental bleedings \[[@B8]\]. Clinical and experimental studies on its blood stopping effect are available. Its effect on stopping bleeding and preventing air leakage in the lungs is not known. In this study, we experimentally investigated the effect of Ankaferd Blood Stopper on stopping bleeding and preventing air leakage in the lungs. Methods ======= This study was carried out in the animal experiment laboratory of our institution. All rats were treated in a humane manner according to the Guide for the Care and Use of Laboratory Animals. The study was commenced after having obtained approval from the ethical committee for experimental animals. A total of 21 adult male Wistar Albino rats weighing 240 ± 20 grams were used in our study. Three groups were constituted with seven rats in each. An equal extent of injury was created in all groups by performing left thoracotomies. No interventions were made on the tissue injury in the first group (control group), suturing was performed in the second group (standard surgery group), and Ankaferd Blood Stopper was applied in the third group (Ankaferd group). Air leakage and duration of bleeding were recorded in all groups. The rats were sacrificed after the procedure had been completed and histopathological assessment was performed. Anesthesia Technique -------------------- General anesthesia was applied on all test subjects. A combination of 60 mg/kg ketamin hydrochloride (Ketalar, Parke Davis-Eczacıbası, İstanbul, Turkey) and 10 mg/kg xylacine hydrochloride (Rompun, Bayer, Toronto, Canada) were used as anesthetic agents. The rats were fixed in the supine position. The operation sites were cleaned and sterilization was provided. Tracheotomies were performed with neck incisions and intubation was performed. Surgical Technique ------------------ All the rats underwent left anterior thoracotomy. An injury 5 mm in length and 2mm in depth was created in the left lung parenchyma using a scalpel. In the control group (Group I), no interventions were made for parenchymal injury and a compress was applied and continuation of the air leakage and bleeding was monitored every 5 seconds. These durations were recorded. The procedure was terminated at the 100. second. In the standard surgery group (Group II), after having created an equal injury, the injury was sutured using 6-0 polyglactin (vicryl). Then the air leakage and bleeding were controlled and the times of cessation of the leakage and bleeding were recorded. In the Ankaferd group (Group III), a spray form of the Ankaferd Blood Stopper was applied 4 times onto the identical injury. It was controlled at every 5 seconds and cessation times of the air leakage and bleeding were recorded. Statistical Analysis -------------------- All statistical analyses and calculations were performed using the SPSS for Windows Version 16.0 (SPSS Inc, Chicogo, IL, USA) package program. The Kruskal Wallis test was used to find whether or not there was a difference between the three groups in terms of air leakage time and bleeding time. Paired assessments were made using the Mann Whitney U test to find the group where the difference originated from. The level of significance was set at p \< 0.05. Histopathological Analysis -------------------------- Some of the rats (n = 11) were sacrificed intraoperatively after the procedure had been completed and the specimens were obtained from the lung. The remaining rats (n = 10) were sacrificed after monitorization for five days and the lung was analyzed patologically on the fifth day. The sampled lung tissue was fixed with formalin solution (10%). Paraffin cross sections were obtained after routine follow-up and analyzed after staining with hematoxylin-eosin. Results ======= While the mean air leakage time was 95.7 ± 6.07 sec, the bleeding time was measured as 75.00 ± 15.00 sec in the control group. While the mean time of air leakage was 27.14 ± 21.76 sec, the bleeding time was measured as 9.28 ± 7.31 sec in the standard surgery group, whereas both the air leakage time and the bleeding time were measured as 7.14 ± 2.68 sec in the Ankaferd group (Table [1](#T1){ref-type="table"}) (Figure [1](#F1){ref-type="fig"}). Bleeding and air leakage were found to have stopped in the shortest mean duration in the Ankaferd group. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Mean air leakage and bleeding times of the groups ::: Groups Mean air leakage time (sec) Mean bleeding time (sec) ----------------------------------- ----------------------------- -------------------------- Group I (control group) 95.7 ± 6.07 75.00 ± 15.00 Group II (standard surgery group) 27.14 ± 21.76 9.28 ± 7.31 Group III (Ankaferd group) 7.14 ± 2.67 7.14 ± 2.68 ::: ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Distribution of air leakage and bleeding times in the control group (Group 1, n = 7), standard surgery group (Group 2, n = 7) and Ankaferd Blood Stopper group (Group 3, n = 7)**. :::  ::: A statistically significant difference was found between the three groups in terms of duration of air leakage (p = 0,0001) and bleeding (p = 0,001). There was a statistically significant difference between the control group and the standard surgery group in terms of duration of leakage (p = 0,002) and bleeding time (p = 0,001). A statistically significant difference was found between the standard surgery group and the Ankaferd group in terms of air leakage (p = 0,017). No statistically significant difference was found between the standard surgery group and the Ankaferd group in terms of bleeding time (p = 0,827). A statistically significant difference was detected between the control group and the Ankaferd group in terms of air leakage time (p = 0,001) and bleeding time (p = 0,001). Normal lung regions (Figure [2](#F2){ref-type="fig"}) and the lungs of rats sacrificed intraoperatively and on the fifth day were analyzed in the histopathological evaluation. Masses of hemolyzed clot (blood-fibrin masses) were observed in the areas in which Ankaferd had been applied in the lungs of intraoperatively sacrificed rats (Figure [3](#F3){ref-type="fig"}). Newly organized fibrin plugs were observed in the alveoli of the lungs of rats that had been sacrificed on the fifth, in which Ankaferd had been applied (Figure [4](#F4){ref-type="fig"}). ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Appearance of lung tissue of the normal rats ( H&E, X200)**. :::  ::: ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Changes in the early period (intraoperative) in the lung in which Ankaferd was applied**. Hemolyzed clot masses (blood-fibrin masses) are observed in the areas exposed to Ankaferd ( H&E, X200) :::  ::: ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Histopathological changes on the 5. day in the lung in which Ankaferd was applied**. Newly organized fibrin plugs are observed in the alveoli of the lung of Ankaferd-applied rats( H&E, X200) :::  ::: Discussion ========== The incidence of leakage from the lung parenchyma is still vey high despite the use of many surgical techniques and biological agents to reduce it. Leakage is observed at a rate between 48% and 70% intraoperatively, and the rate of air leakages continuing for longer than the 7. postoperative day is between 15% and 18%. The ideal method for preventing this has yet not been determined \[[@B2]\]. Prolongation of air leakage is the second leading cause of delay in the time of discharge from the hospital following pain \[[@B1]\]. Prolongation of air leakage following lung resections is among the important causes of morbidity. It is the second leading complication following arrhythmias. Cause of morbidity is air leakage exceeding five days after segmentectomy (5.9%), lobectomy (9.6%) and pneumectomy (0.4%) \[[@B11]\]. In the study of Varela et al. \[[@B12]\] air leakage exceeding five days was found to be related to significant pulmonary complications and atelectasis, pneumonia, and empyema. Air lekage is a common condition seen after lung operations. The standard method for prevention of air leakages developing following lung operations is surgical suturing or stapler application. The other methods are fibrin glue, synthetic polyethylene glucose-based hydrogel adhesives, tachocomb, covered adhesives or stapler use supported with various materials \[[@B3]-[@B10]\]. Fibrin glue application is a commonly used approach. There are different opinions about the utilization of fibrin glue. In the prospective study carried out by Fabian et al. \[[@B4]\] fibrin glue was applied to one group in 100 lung resections. Both groups were compared in terms of air leakage, amount of pleural drainage, time of chest tube removal and duration of hospitalization. Utilization of fibrin glue was shown to significantly decrease the incidence of air leakage, the air leakage cessation time, chest tube removal time, and the rate of prolonged air leakage. No difference was found in terms of the amount of chest tube drainage and duration of hospitalization. No complications related to fibrin glue were found. In conclusion, fibrin glue utilization was reported to be effective and safe. In a study carried out with fibrin glue comprising 360 patients, it was shown to decrease only the chest tube removal time and not to affect the prolongation of air leakage (\>7 days) and duration of hospitalization \[[@B5]\]. Ankaferd Blood Stopper (ABS) is a herbal product used as a hemostatic agent. It contains a standardized mixture of Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum and Urtica dioica. All of these plants are effective on the endothelium, blood cells, angiogenesis, cellular proliferation, vascular dynamics and mediators. The mechanism of action of this drug which is being used clinically and found to be safe is not fully understood \[[@B13]\]. There have been no studies investigating the effect of Ankaferd Blood Stopper on air leakage in the lung. In our study, we investigated the air leakage repressive effect of ABS. It prevents air leakage significantly compared to the control group and the standard surgery group. Postoperative hemorrhage is among the important causes of morbidity in thoracic surgery practice. The incidence of at least 4 units of blood transfusion requirement after lung resections is 2.9% in lobectomy, 3% in pneumonectomy \[[@B11]\]. The focus of hemorrhage cannot be determined in most of the cases. In the study of Sirbu et al. analyzing 1960 patients who underwent thoracotomy, they detected that the most common cause of re-thoracotomy was bleeding (52%). In this study, while the source of bleeding was found to be mediastinal and bronchial vessels (23%), intercostal vessels (17%) or pulmonary vessels (17%), no sources of bleeding could be detected in most of the cases (41%) \[[@B14]\]. The blood stopping effect of Ankaferd Blood Stopper has been demonstrated in many clinical and experimental studies. It was found to be successful in the treatment of rectal ulcers in the study of Ibis et al. \[[@B15]\] which was carried out in gastrointestinal hemorrhages. It was shown to reduce hemorrhage considerably in bladder hemorrhages and partial nephrectomies \[[@B16]\]. Ankaferd Blood Stopper was shown to decrease the operation time and warm ischemia time in the partial nephrectomy model in rats. In the pathological anaysis, erythrocyte aggregation was found to develop, but glomerular necrosis and calcifications were not observed \[[@B16]\]. ABS was reported to reduce hemorrhage effectively in the study on its clinical use in tonsillectomies \[[@B17]\]. It was emphasized that it could be beneficial clinically when used endoscopically in gastrointestinal hemorrhages related to tumor \[[@B18]\]. Similarly, it was stated to be effective in hemorrhages related to endobronchial tumor when used endoscopically \[[@B19]\]. In our study, when we evaluated the blood stopping effect of ABS, we found that this property was prominent compared to the control group; however, there was no statistically significant difference compared to the standard surgery group. Ankaferd Blood Stopper prevents air leakage in the lung effectively. It has an effect on stopping bleeding, but the effect is similar to that in standard surgery. Further experimental and clinical studies are needed to investigate the effect of this plant extract in the lung. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= AK, NGS, TK and GB conceived of the study, and participated in its design and coordination and helped to draft and performed the statistical analysis. ÇB carried out the macroscopic and microscopic studies. ÖS, AK, and TK participated in the design of the study. AK and ÖS participated in the sequence alignment and drafted the manuscript. All authors read and approved the final manuscript.

PubMed Central

2024-06-05T04:04:17.197205

2011-2-27

PMC3051896

Background ========== Chronic Kidney Disease (CKD) a serious long term illness affecting more than two million Canadians, is a major public health problem\[[@B1]\]. Patients with CKD stage 5 D - also referred to as end-stage kidney failure - require renal replacement therapy (RRT). Diabetes is the leading cause of Stage 5 CKD and 54% of patients requiring RRT in 2007 were over the age of 65. Between 1998 and 2007, there has been a 51% increase in the number of patients with CKD stage 5 D receiving hemodialysis (HD)\[[@B2]\]. The estimated annual cost of hospital based HD (inpatient or outpatient clinic) in Canada per patient in 2002 was \$59,476.00 \[[@B3]\]. Adults living with Stage 5 CKD face numerous decision points \[[@B4]\]. These patients often experience uncertainty when considering the best course of action among different options for treatment and care. This uncertainty is called decisional conflict \[[@B5]\]. The RNAO nursing BPG *Decision Support for Adults Living with Chronic Kidney Disease*\[[@B6]\] outlines the importance of screening for decisional conflict and applying decision support strategies to address unmet decision making needs in this high risk population. A major decision for patients, with Stage 5 CKD receiving or who are planning to initiate HD therapy is about dialysis vascular access. Evidence-based standards of care recommend an arteriovenous fistula (AVF) as the optimal access due to its longevity and lower complication rates compared to central venous catheters (CVC)\[[@B7]\]. Many CKD patients are followed by an interprofessional team, and education related to RRT modality options and vascular access planning are key components of the care provided. Despite this, patients often defer modality choice during pre-dialysis stages, or may not receive pre-dialysis care, leading to acute HD initiation with an obligatory CVC as the vascular access in an urgent or emergent situation. This contributes to a CVC rate in Canada that is well above international standards for best CKD care with a corresponding increased risk of morbidity and mortality for patients \[[@B8]\]. Current estimates suggest that CVCs are used for initial HD access in 70% of cases\[[@B9]\]. Once a CVC has been inserted as a vascular access, about 33% of Canadian patients continue to use a CVC as their permanent vascular access putting them at increased risk for morbidity and mortality\[[@B9]\]. Reported reasons for the high incidence and prevalence of CVCs in Canada include late referral to nephrologists and fewer vascular surgeons per capita (who arrange for and perform AVF surgery) as compared with the USA and Europe \[[@B9]\]. Efforts to optimize the timeliness of patient decisions about access through patient and staff education and resource allocation strategies have been unsuccessful in addressing the high CVC rates in Canadian HD units \[[@B8]\]. Reports from systematic reviews confirm that concerns about impact of decisions on others and on quality of life; wish to maintain normalcy; influence of others; and personal assessments of perceived risk/benefits affect patients\' decisions about CKD treatment options \[[@B4],[@B10]\]. Added to this is the difficulty in translating population based probabilities of risks and benefits to the individual level which also contributes to uncertainty when making health decisions. Consequently, patients can experience decisional conflict due to knowledge gaps, lack of clarity about what matters most to avoid or achieve among the possible outcomes of options under consideration or have support needs which in turn affects their readiness to participate in decision making. A process that helps patients explicitly consider their choices, information needs, values and preferences when making decisions about HD access could help to address these unmet decision making needs. Decision support interventions help patients a) prepare for decision making and b) to arrive at a quality decision informed by both evidence and patient values \[[@B11]\]. In practice areas other than CKD, decision support interventions have been found to be effective in reducing decisional conflict. The RNAO BPG for *Decision Support for Adults with CKD*\[[@B6]\]suggests several evidence based approaches to help mediate patients\' decisional conflict. However, to our knowledge these recommendations have not been tested in clinical practice. As well, the impact of a targeted decision support intervention on patient and health service outcomes is unknown. Purpose & Objectives ==================== The purpose of this study is to determine the impact of implementing selected recommendations from the *RNAO Decision Support for Adults with Chronic Kidney Disease*(CKD) best practice guideline (BPG) \[[@B1]\]on priority provincial targets for hemodialysis (HD) access sites in patients with Stage 5 CKD requiring dialysis (Stage 5D) who currently use central venous catheters (CVC) as their HD access. Specific research objectives will be to: 1\) Identify the prevalence of decisional conflict in a cohort of patients with CKD Stage 5 D who receive HD via CVC access; 2\) Identify the most frequently reported sources of decisional conflict identified by patients with CKD Stage 5 D who receive HD via CVC access; 3\) Determine the impact of tailored decision support interventions identified from decisional conflict screening on HD access decisions among a cohort of patients with CKD Stage 5 D who receive HD via CVC access; and 4\) Identify the acceptability, feasibility of such an approach from the perspective of patients with CKD Stage 5 D who receive HD via CVC access and providers. Guiding Theoretical Framework ----------------------------- The Ottawa Decision Support Framework (ODSF), which underpins the Decision Support Guideline for CKD\[[@B12]\], guides study measures and outcomes. The ODSF proposes that decisional needs \[uncertainty, knowledge, values clarity, support, personal characteristics\] strongly influence the quality of decisions patients make and that providers can improve the quality of those decisions by providing decision support to address decisional needs \[clarify decisional needs, provide facts, probabilities, clarify values, support/guide deliberation, monitor/facilitate progress\]. Methods/Design ============== Design ------ A prospective quasi-experimental intervention study with repeated measures (baseline and post decision support intervention) over an 18 month period will be conducted). This study incorporates quantitative and qualitative approaches to triangulate findings and provide a fuller perspective\[[@B13]\]. The use of qualitative and quantitative data will contribute to our understanding of decisional conflict and potential modifiers in the context of HD access decisions for patients with Stage 5 CKD \[[@B14]\]. Intervention ------------ Decisional conflict can be screened with the 4 item SURE tool. Based on core concepts of the validated Ottawa Decisional Conflict Scale\[[@B15]\] the SURE tool has been found suitable for screening decisional conflict in French and English-speaking patients with a variety of health conditions\[[@B16]\]. Four questions target sources of decisional conflict (feeling uncertain, feeling informed, feeling clear about values and feeling supported in decision making). Responses are scored as yes (score = 1) or no (score = 0). Scores of less than 3 indicate decisional conflict. Coupling the SURE tool with a decision support system structured so that a positive test result (scores of 3 or less) triggers providers to help patients through the decision-making process through a collaborative effort involving the interprofessional health care team and/or refer patients to appropriate resources could benefit patients and ensure patients have the opportunity to make informed HD access choices. Setting ------- The study will take place at Toronto\'s St. Michael\'s Hospital. St Michael\'s is a tertiary care teaching and research hospital with more than 5,000 staff, 600 physicians and 1,100 students, which is affiliated with the University of Toronto. With more than 450 inpatient beds and extensive outpatient clinics, the Hospital has a large kidney disease program including an in-centre hemodialysis unit providing outpatient and inpatient hemodialysis unit where 235 patients with Stage 5 D CKD receive care. Participants ------------ A purposive sampling strategy will be used to ensure that the study sample will be representative of the level of care within the renal patient population. Participants will be recruited from the following categories: a) patients (n = 40) receiving HD; b) professionals from the interprofessional team (n = 10-12) providing direct patient care within and/or directly associated with HD delivery; and c) managers and educators (n = 4-6) with varying levels of influence in the renal program practice environment (e.g., managers, educators, senior leaders influencing practice). Eligible patient participants include Stage 5 CKD HD patients with CVCs who would be candidates for AVF who are receiving maintenance HD in the hemodialysis unit and who are able to communicate in English and who are judged mentally and physically able to participate by the HD care team. Eligible health professional participants include nurses, physicians, dieticians, pharmacists, and social workers. Eligible managers and educators include nurse practitioners, nurse educators, vascular access coordinators, clinical leader managers, and the program director. Data Collection and Procedures ------------------------------ Sessions outlining study information and procedures will be held in staff meetings and rounds. Education based on the RNAO BPG for Decision Support in CKD\[[@B1]\] recommendations will be provided to HD clinic nurses by the HD Nurse Practitioner (a member of the CKD BPG development team). Table 2 summarizes the relationship between research objectives, data collection and analysis. In line with our research objectives, study procedures include three main phases: **Phase 1: Identify the prevalence of decisional conflict***(research objective 1&2: BPG recommendation 1,2, 3,4,5)*. Nurses in the HD clinic will provide information about the study to eligible patients. The research coordinator will obtain informed consent from patients indicating an interest in participating. The HD nurse will then screen for decisional conflict using the SURE tool. Results of the screening (presence or absence of decisional conflict and source(s)) will be verbally communicated to the interprofessional team and will be recorded in the patient health record. After the source(s) of decisional conflict has been pinpointed, a decision support intervention will be developed using the Decision Support for Adults Living with Chronic Kidney Disease BPG. This intervention will be tailored to meet the identified need and will be led by an Advanced Practice Nurse who specializes in CKD Stage 5 D care. For instance, the nurse will help the patients through a decision-making process (i.e.: provide facts; discuss with patient what is personally important for them to achieve or avoid; clarify what resources patient needs to make a decision) and/or refer patients to appropriate resources or members of the interprofessional team (i.e.: facilitate team conference/family meeting; refer to social worker). The SURE tool will be repeated following the decision support intervention to evaluate the intervention and plan next steps. Intervention details, outcomes and planned next steps will be documented in the patient health record. **Phase 2: Determine the impact of tailored decision support interventions***(research objective 3: BPG recommendation 4,7,8)*. We will aggregate and compare the pre and postintervention SURE scores. Using chart review and our Program\'s HD Vascular Access Database, congruence between identified preferred choice following the intervention and actual HD access will be assessed. Interviews based on previous research related to patient decision making needs will be conducted with patient participants \[[@B17]\]. **Phase 3: Identify the acceptability, feasibility of such an approach**(research objective 4: BPG recommendation 7,8). We will conduct focus groups with members of the interprofessional team who have been directly or indirectly involved with patient participants. A focus group will also be held with the renal program management and educator group. Focus group guides will be adapted from our previous research about barriers, facilitators and implementation strategies for decision support interventions \[[@B18]\]. Data Analysis ------------- Quantitative data will be analyzed using descriptive and inferential statistics. Statistical significance of difference between means over time for aggregated SURE scores will be assessed using a paired t-test. The estimated sample size for the t-test is based on a test for differences in mean scores of decision conflict (SURE scores) pre and post intervention. An effect size of .70 requires n = 32/group, when alpha error = 0.05 and beta error = 0.20\[[@B19]\]. To accommodate attrition we plan to recruit 40 patients. Congruence between identified preferred HD access choice following intervention and actual HD access will be analyzed using Pearson r correlation. Qualitative analysis with content coding and identification of themes will be conducted for the focus group and patient interview data using well established criteria to maintain trustworthiness and credibility of analysis processes and findings \[[@B20]\]. Ethical Considerations ---------------------- Ethics approval has been obtained from St Michaels Research Ethics Board. All participants will receive study information letters and informed consent forms. Dissemination ------------- Patients and providers will be directly involved in providing feedback about the feasibility and acceptability of the SURE tool and decision support intervention on the process of care thereby making the findings from this study more relevant to the organization\'s processes of care. Intended users of our research results include kidney health teams, educators, organizational managers and senior leaders and health policy makers interested in addressing barriers to HD access in clinical practice. As well, members of the research team have extensive and relevant experience and connections with the intended users. End of grant activities will include dissemination of study results: a) at conferences (scientific and professional) with themes related to shared decision making, interprofessionalism and renal policy; and b) on the website of institutions where team members are located. The research protocol and study results will be published in peer reviewed open-accessed journals. Discussion ========== Patient uncertainty related to renal treatments and particularly for vascular access is well known \[[@B21],[@B22]\]. This will be the first study to evaluate the impact of a patient decision support intervention designed to help providers identify sources of decisional conflict patients are experiencing. Tailored decision support tailored to address decision making needs can then be provided. This reproducible, portable intervention addresses a key policy mandate regarding patient involvement in care planning set out by health providers such as the Ontario Ministry of Health in Canada. This is a pragmatic study with relatively inclusive entry criteria. There are three identified benefits of the proposed research study: 1) improved clinical practice through standardized assessment for decisional conflict for adults living with chronic kidney disease; 2) provision of a practical approach to engage patients in decisions about vascular access and enhance the quality of their decision making and; 3) improved communication among health care team members. Moreover, the SURE assessment tool and other tools tested will provide health care practitioners with common inter-professional measures to identify decisional conflict with those living with chronic kidney disease. The SURE assessment tool will facilitate the communication of the patient\'s decisional conflict among the health care team members. With a standardized, repeatable measure of decisional conflict, the patient and the health care team members will be able to determine appropriate interventions, the effectiveness of those interventions and enhance communication among team members in regards to decisional conflict and appropriate care modalities. Participation of clinicians in the research process will foster a sense of inquiry and engagement and will ensure clinical relevance of the measure\'s content, which will facilitate its future use in the practice setting. Should this approach show promise this initial step will provide the foundation for large scale future testing and generalizability of the assessment tools and interventions. The success of this study and future studies will lead to improved patient care. Further, this study will provide corroboration of current RNAO best practice guidelines and lead to future recommendations for guideline implementation. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= MAM and AT conceived of the study and drafted the manuscript. LJ participated in its design and coordination and helped to draft the manuscript. SD, RW and RM are providing support during the implementation of the study and analysis of study data and have contributed to manuscript preparation. All authors read and approved the final manuscript. Pre-publication history ======================= The pre-publication history for this paper can be accessed here: <http://www.biomedcentral.com/1471-2369/12/7/prepub> Acknowledgements ================ Murray received post doctoral fellowship from the Canadian Health Services Research Fund. The study has received funding from the Canadian Nurses Foundation and St Michaels Hospital in Toronto.

PubMed Central

2024-06-05T04:04:17.198404

2011-2-3

PMC3051897

Background ========== Coeliac disease (CD) is a common and complex inflammatory disorder of the small intestine that affects genetically susceptible individuals carrying HLA-DQ2 or -DQ8 haplotypes. Symptoms develop after ingestion of gluten storage proteins (prolamins) from wheat (gliadins), barley (hordeins), rye (secalins), and their crossbred varieties \[[@B1],[@B2]\]. CD can be diagnosed at any age. It can either be asymptomatic or present with a broad spectrum of clinical manifestations. The classical (typical) form of CD is usually characterized by gastrointestinal symptoms like flatulence, vomiting, constipation or persistent diarrhoea, general failure to thrive, mineral and vitamin deficiencies, and weight loss due to malabsorption. Atypical forms, on the other hand, present predominantly with extra-intestinal manifestations that include a blistering skin disease (Dermatitis herpetiformis), iron-deficiency anaemia, osteoporosis, fatigue and neurological complaints \[[@B3]-[@B6]\]. The prevalence of CD is estimated to be about 1% in the Western populations \[[@B7],[@B8]\]. Moreover, in recent years the total disease prevalence has increased. The reason for the observed raise is currently unknown and cannot be explained by the increase of CD diagnosis that occurred after introduction of antibody screening \[[@B9],[@B10]\]. In CD patients, peptides that originate from incomplete digestion of gluten prolamins, either in their native form or deamidated by tissue transglutaminase (tTG), bind to HLA-DQ2 or -DQ8 receptors of antigen presenting cells that activate the lamina propria infiltrating CD4^+^T cells. As a response the CD4^+^T cells release pro-inflammatory cytokines, in particular γ-interferon. Ultimately, this leads to profound tissue remodelling characterised by the atrophy of the small intestinal villi and hyperplasia of crypts \[[@B2],[@B11]-[@B14]\]. Active CD is also characterised by high levels of antibodies against tTG and gliadin in the patients\' sera. The role of anti-tTG IgA class antibodies is still unclear. However, it has been proposed that they may be involved in the development of mucosal damage \[[@B15]\]. Also IgG class anti-gliadin antibodies have been shown to contribute to the pathogenesis by activating the complement system or inducing antibody-mediated cytotoxicity \[[@B16]\]. T cell epitopes in wheat gluten proteins have been characterised within both gliadins and glutenins. A hierarchy exists within these epitopes. The majority of CD patient-derived intestinal T cell clones recognise α-gliadins, and less frequently γ-gliadins and glutenins \[[@B17]-[@B20]\]. The most prominent peptide is a 33-mer of α-gliadins (residues 57-89) that contains six T-cell epitopes. Another fragments, also found in α-gliadins (residues 31-43 and 44-55), seem to be important for the activation of the innate immunity system \[[@B18],[@B21]-[@B23]\]. In a recent study gluten-specific T cells from peripheral blood of CD patients challenged either with wheat, barley, rye or a combination of the three cereals were used to identify the immunostimulatory sequences in these grains \[[@B24]\]. The α-gliadin 33-mer was found immunogenic only after the wheat challenge while sequences from ω-gliadin (wheat) and C-hordein (barley) were found to be immunodominant despite the grain consumed. Currently there is no cure for CD. The only existing therapy is a life-long adherence to a gluten-free (GF) diet \[[@B3]\]. However, several strategies that may in the future serve as alternatives to the GF diet have been proposed. T cell activation may be inhibited by molecules that block peptide binding to HLA-DQ2. Alternatively, inhibition of tissue transglutaminase may prevent gluten deamidation \[[@B25]\]. Supplementation with prolyl endopeptidases (PEPs), enzymes derived from moulds and bacterial strains, or with a mixture of PEP and cysteine endoprotease from germinating barley, which aid in digestion of immunostimulatory gluten peptides into harmless molecules, is under investigation \[[@B26]-[@B29]\]. Another possible therapeutic alternative that is currently pursued is a vaccine that contains a mixture of immunodominant peptides that trigger the immune response and are supposed to retrain the immune system of HLA-DQ2 positive CD subjects to tolerate gluten \[[@B24],[@B30]\]. Furthermore, an inhibitor of paracellular permeability (AT-1001, larazotide acetate) has been shown to reduce the intestinal barrier dysfunction, production of pro-inflammatory cytokines, and GI symptoms in CD individuals after gluten exposure \[[@B31],[@B32]\]. Moreover, attempts have been made to degrade toxic gluten sequences during sourdough fermentation with selected lactobacilli strains \[[@B33]\]. Finally, the potential of a linear polymeric binder P(HEMA-*co*-SS) to neutralise gliadin *in vitro*and *in vivo*in mice models have been described \[[@B34]\]. Another alternative could be blocking gliadin domains with synthetic peptides and thus preventing tTG modification and formation of immunostimulatory epitopes. In the present study we have selected *in vitro*gliadin-binding peptides with the help of phage display. Phage display refers to a molecular method where gene libraries are constructed in filamentous bacteriophage in a way that each individual phage in the population will display a unique peptide or protein on its surface \[[@B35]\]. From such a population, phage that interact with in principle any *a priori*chosen molecule can be isolated and amplified. The concept has been used in many different variations to select and produce novel peptides that bind to target molecules of interest \[[@B36]-[@B38]\]. The aim of this work was to identify phage that express peptides specifically binding to different gliadin domains and to identify and characterise the gliadin-binding properties of the chosen individual peptides. Results ======= Purification and immobilisation of gliadin proteins --------------------------------------------------- Gliadin was semi-purified from commercially obtained gluten (Sigma) and from whole wheat grains as a comparison. Several proteins of varying molecular weights were obtained from both sources (Figure [1](#F1){ref-type="fig"}). Using a commercial gliadin ELISA kit it was confirmed that the included anti-gliadin antibodies reacted with the semi-purified gliadin fractions. As a control, gliadin-like proteins (avenins) were extracted from oat grains but the commercial antibodies did not, as expected, react with the oat proteins (data not shown). The gliadin preparation was finally dissolved in either 0.1 M NaHCO~3~or in 2 M urea, added to microtiter plate wells and allowed to bind to plastic. After washing, bound gliadin molecules were quantified with an ELISA assay using the commercial human anti-gliadin IgG antibodies. This confirmed that gliadins indeed had been immobilised to the wells and that the antibodies used recognised both the gliadin NaHCO~3~- and urea-treated molecules. However, the detection limit was reduced about 5 times when gliadins were dissolved in urea indicating that the 3D structure of the antibody-binding sites of gliadin were affected by the buffer used (Figure [2](#F2){ref-type="fig"}). ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **SDS-PAGE separation of gliadin and gliadin-like proteins**. Lane 1: molecular weight standard; lane 2: gliadin purified from gluten (Sigma) in 40% ethanol; lane 3: gliadin purified from *Triticum aestivum*cv. Surco in 40% ethanol; lane 4: gliadin purified from *Triticum aestivum*cv. Surco in 2 M urea; lane 5: gliadin-like (avenins) proteins purified from *Avena sativa*cv. Leon in 40% ethanol; lane 6: avenins purified from *Avena sativa*cv. Leon in 2 M urea. :::  ::: ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Quantification of immobilised semi-purified gliadin (Sigma)**. Microtiter wells were coated with increasing amounts of gliadin (ng) as indicated on X-axis. Commercial anti-gliadin antibodies bound to the coated gliadin were quantified by adding a secondary AP-tagged goat anti-human IgG antibody and measured as absorbance at 405 nm (Y-axis). A. Gliadin dissolved in 100 μl 0.1 M NaHCO~3~(pH 8.6). B. Gliadin dissolved in 100 μl 2 M urea. Error bars indicate variation between two different experiments :::  ::: Selection of peptides specifically binding to gliadin peptides by biopanning ---------------------------------------------------------------------------- Two different phage display libraries, one displaying 12-mer and one displaying 7-mer random peptides, were panned to the immobilised gliadin. In each panning round unbound phage were removed by washing. Remaining bound phage were eluted and allowed to infect *E. coli*cells. After single plaque amplification and phage purification a new round of panning was performed with the obtained phage population. Panning was done both with gliadin dissolved in urea and in NaHCO~3.~Since electrostatic binding of the phage to the target protein weakens with increasing ionic strength, which in turn influences the specificity of the interaction \[[@B39]\], different buffers with different ionic strengths were tested prior the actual panning experiments. After optimising parameters like binding, washing, and elution conditions, a protocol was developed in which the phage recovery increased after each round of panning. Typically five rounds of panning were done. After the final plating, 100 plaques were randomly picked and amplified separately. Phage DNA was then isolated from each isolate, the oligonucleotide inserts sequenced and the deduced amino acid sequence of the displayed peptide determined. In total, inserted individual oligomer sequences from approximately 1000 phage, selected under a number of different panning conditions, were obtained. Although identical sequences were frequently picked up in independent experiments, altogether more than 160 unique sequences encoding peptides with potential gliadin binding activities were identified (data not shown). All obtained sequences originated from the 12-mer library. Many of the peptides could be crudely divided into subgroups based on sequence similarities. However, more than a half of the peptides showed no obvious sequence similarities to each other. This indicates that the peptide-targeted surfaces in the used gliadin preparations are much diversified. As a control, panning against microtiter plates coated with BSA was performed. Peptides identified in this way were denoted *control peptides*(CP). Altogether, five different CP sequences were identified. There were no sequence similarities between these control sequences and any of the gliadin binding sequences. Rescuing selected phage clones ------------------------------ In order to confirm that the selected phage clones interacted with gliadin proteins, nine different phage populations that had repeatedly been picked up in different panning experiments were chosen. Together, these nine sequences represent 89% of all identified gliadin-binding sequences (Table [1](#T1){ref-type="table"}). The remaining approximately 150 sequences thus were found in only 11% of the cases. From each of the nine populations 1 × 10^11^pfu were incubated with the gliadin-coated microtiter wells. In addition, a phage population representing a non gliadin-binding control sequence (CP31) was incubated with the gliadin-coated microtiter wells. After extensive washing, remaining phage were eluted and counted. This showed that phage carrying the CP31 control peptide were very poor binders, as only 1 × 10^4^pfu were rescued from this population under the conditions used. From the phage that carry specific peptides, on the other hand more than 1 × 10^8^pfu were rescued (Figure [3](#F3){ref-type="fig"}). Phage P61, which was the was most frequently picked up in the panning experiments, displayed the highest relative binding affinity, while phage carrying peptides P21, P22, P62, P64, P65 and P67 showed intermediate affinities (Figure [3](#F3){ref-type="fig"}). ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Most frequently identified phages and peptides in this study ::: Peptide Sequence Frequency (%) ---------------- ------------------------- --------------- P61 W H W R N P D F W Y L K 22.5 P64 W H W T W L S E Y P P P 21.5 P22 L E T S K L P P P A F L 12.5 P62 W H W S Q W L S G S P P 8.5 P63 W H R T P Q F W A F P W 7 P21 S V S V G M K P S P R P 5 P66 W H K T P W F W P T N L 5 P67 W H W S W Q P Q R H S P 4 P65 W H W Q Y T P W W R G S 3 **Sum** **89** CP31 (control) A Y Y P Q N H K S N A E NA ::: ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Phage recovery experiment**. Different phage (1 × 10^11^pfu), as indicated on the X-axis, were incubated in gliadin (10 ng) coated microtiter wells. After washing, bound phage were eluted and counted. The Y-axis shows the number of recovered phage given as plaque forming units (pfu). The experiment was replicated three times. Error bars indicate the variation between the experiments. :::  ::: Selected phage clones hinder anti-gliadin antibody binding to gliadin --------------------------------------------------------------------- To investigate if the selected, gliadin-interacting phage could hinder antibody binding to gliadin, 1 × 10^11^pfu of the same nine phage populations as in the previous experiment (Figure [3](#F3){ref-type="fig"}) were added to wells coated with 10 ng gliadin. The CP31 phage population as well as a buffer solution without phage were used as controls. To investigate if the peptides not only interfered with commercial anti-gliadin antibody binding but also interfered with the interaction between gliadin and antibodies present in serum from individuals with suspected CD, after extensive washing, pooled sera from 20 individuals was added. Again, the amount of bound antibody was quantified by adding an AP-labelled secondary anti-human IgG antibody. This showed that the greatest signals i.e. most antibodies bound were from the controls where no gliadin-blocking peptides were present (Figure [4](#F4){ref-type="fig"}). On the other hand, all the selected phage populations blocked the signal to various extents, indicating that the peptides displayed on the phage interfered with the anti-gliadin antibody-gliadin interaction. Wells incubated with phage populations P61 and P64 gave the lowest signal indicating, in agreement with the previous experiment (Figure [3](#F3){ref-type="fig"}), that these were the most efficient gliadin binders. ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Gliadin-anti-gliadin antibody interaction in the presence of peptide-displaying phage**. The Y-axis shows different phage displaying peptides tested. Phage (10^11^pfu/ml) were added to microtiter wells coated with 10 ng gliadin. After incubation and extensive washing, pooled sera from patients with suspected CD were added. The amount of bound antibody was determined by adding a secondary AP-tagged goat anti-human IgG antibody, and measured as absorbance at 405 nm (Y-axis). :::  ::: Gliadin binding of synthetic peptides ------------------------------------- Since all selections were based on phage-displayed peptides, we investigated whether synthetic peptides, with the same sequence as those in the selected phage, maintained the gliadin-binding ability also when removed from the steric context of the phage surface. Peptides based on the most frequently identified sequences, P64, P61 and P22 (Table [1](#T1){ref-type="table"}) as well as the non-specifically binding control peptide CP31, were synthesised. A biotin label was added at the N-terminus of all the peptides to facilitate detection. To test peptide-gliadin binding, different concentrations of gliadin proteins (110 ng) were immobilised in microtiter wells and 10^15^molecules (1.67 nmoles) of the synthetic peptides were added to the wells. After incubation and extensive washing to remove unbound peptides the biotin signals from the remaining peptides were quantified. The results showed that P61 had the highest binding activity, P64 somewhat weaker, and P22 the weakest binding activity (Figure [5](#F5){ref-type="fig"}), corroborating the experiments with the phage carrying peptides (Figure [3](#F3){ref-type="fig"} and [4](#F4){ref-type="fig"}). No activity at all could be detected from the incubations with the control peptide. As expected, the number of bound peptides increased with increasing gliadin concentrations (Figure [5](#F5){ref-type="fig"}). ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **Binding of synthetic peptides to gliadin proteins**. Microtiter wells were coated with increasing amounts of gliadin (ng) as indicated on the X-axis. Afterwards 10^15^molecules (1.67 nmoles) of biotinylated peptides, P61, P64, or P22 were added to the wells. Bound peptides were quantified as absorbance units at 405 nm (OD units) by means of the biotin adduct as described in Methods. P61/64 is a 1:1 mixture of peptides P61 and P64. :::  ::: Gliadin-blocking activity of selected synthetic peptides -------------------------------------------------------- To confirm that the free peptides could block anti-gliadin antibody-gliadin interactions with similar efficiency as the phage-displayed peptide, 1.67 nmoles (10^15^molecules) of the synthetic peptides were mixed with increasing concentrations of gliadin (0.25-100 ng), followed by an incubation of the peptide/gliadin mixture in anti-gliadin antibody coated wells. After incubation and washing away unbound gliadin and peptides, a secondary antibody binding to the solid phase antibody-antigen complex was added, and the amount of complex quantified by means of the tag on the secondary antibody. This showed that the P64 and P61 peptides interfered with or blocked antigenic sites on the gliadin molecules, since fewer signals were obtained with these peptides than with P22, CP31 and the *no peptide*control (Figure [6](#F6){ref-type="fig"}). Furthermore, the blocking effect was visible in the whole concentration range (0.5-100 ng) of gliadin tested (Figure [6](#F6){ref-type="fig"}). ::: {#F6 .fig} Figure 6 ::: {.caption} ###### **Inhibition of gliadin/anti-gliadin antibody binding by selected synthetic peptides**. Increasing amounts of gliadin in ng (as indicated on the X-axis) were incubated with 1.67 nmoles of biotin-labelled synthetic peptides (10^15^molecules) for 1 h at room temperature. Buffer (0.1 M NaHCO~3~) without peptides was used as a control. The mixes were then added to anti-gliadin monoclonal antibody-coated wells provided with the Immunotech gliadin ELISA kit. After incubation for 1 h at room temperature, gliadin-antibody complexes immobilised in the wells were quantified as described (see Methods) and given as absorbance units at 450 nm (Y-axis). Error bars show the variation in three different experiments. :::  ::: To further test the binding efficiencies of the peptides, two best peptides P61 and P64 and the control peptide CP31 were diluted in several steps and incubated with 1 ng of gliadin followed the incubation in the antibody-coated microtiter wells. This showed that as little as 10^9^peptide molecules (0.167 pmoles) could interfere with the anti-gliadin antibody-gliadin interactions to a level detectable in the experiment (Figure [7](#F7){ref-type="fig"}). ::: {#F7 .fig} Figure 7 ::: {.caption} ###### **Concentration dependency of peptide gliadin/anti-gliadin antibody binding inhibition**. Gliadin was diluted to 1 ng/ml and mixed with 1.67 nmoles, 0.167 pmoles, and 0.0167 fmoles (10^15^, 10^9^, and 10^5^molecules respectively) of peptides P61, P64, and CP31. Afterwards the gliadin/peptides mixes were added to anti-gliadin, monoclonal antibody-coated wells and incubated for 1 h. The formed gliadin/antibody complexes immobilised in the wells were quantified as described (see Methods) and given as absorbance units at 450 nm (Y-axis). :::  ::: Dot blot and western blot analysis ---------------------------------- To further verify the physical interaction of the peptides and gliadin, and to elucidate if the peptides preferentially bind to specific proteins in the semi-purified gliadin fraction used here, dot blot and western blot experiments were performed. In the dot blot experiments, increasing concentrations (25 ng/μg) of the gliadin preparation were spotted on filters. The filters were then incubated with either of the P22, P61, P64 or CP31 peptides, and subsequently washed. Bound peptides were quantified with an anti-biotin AP-labelled antibody recognising the biotin tag on the peptides. The results from these analyses again confirmed that the peptides physically interacted with gliadin and as previously, the P61 peptide had the highest binding activity, followed by the P64 peptide. No binding could be detected with the P22 and the CP31 peptides (Figure [8](#F8){ref-type="fig"}). ::: {#F8 .fig} Figure 8 ::: {.caption} ###### **Dot blot analysis of peptide-gliadin binding**. Different amounts of gliadin proteins, as indicated on the Y-axis, were spotted onto nitrocellulose strips. Each strip was incubated with 1.67 nmoles (10^15^molecules) of the peptide indicated on the top of the figure. After washing the biotin signal from the bound peptide was developed as described. :::  ::: In the western blot experiments, gliadin proteins were separated on SDS-PAGE gels and blotted to nitrocellulose membranes. By using the P61, P64, P22 or CP31 peptides as probes and again detecting peptides bound to the filter by means of the secondary AP-labelled anti-biotin antibody it became clear that, as in the dot blot experiments, P61 and P64 showed the strongest binding (Figure [9](#F9){ref-type="fig"}). Both these peptides interacted with proteins in the 29-30 kDa range, and in addition P61 also bound to proteins between 49-70 kDa. Thus, the two peptides have overlapping but distinct binding specificities. A similar pattern was obtained both when analysing the gliadin extracted from Sigma gluten and gliadin extracted from wheat (Figure [9](#F9){ref-type="fig"}). ::: {#F9 .fig} Figure 9 ::: {.caption} ###### **Western blot analysis of peptide-gliadin binding**. 10 μg of gliadin extracted from Sigma gluten (A) or 10 μg of gliadin extracted from Surco wheat (B) was loaded on a polyacrylamide gel. Separated proteins were transferred to a nitrocellulose membrane. Each membrane was incubated with 1.67 nmoles (10^15^molecules) of the peptide indicated at the bottom of the figure. After washing the biotin signal from the bound peptide was developed as described. :::  ::: Discussion ========== Wheat gluten consists of a complex mixture of proteins that based on their common structures can be divided into three groups: a high molecular weight (HMW) group that contains HMW-glutenin subunits with Mr \~67-88 kDa; a medium molecular weight (MMW) group containing ω-gliadin proteins with Mr \~34-55 kDa; and a low molecular weight (LMW) group with α/β-, γ-gliadins and LMW-glutenin subunits with Mr \~28-39 kDa \[[@B40]-[@B43]\]. Several of the glutenin and gliadin proteins contain repeated proline and glutamine residues, especially QQPFP and PQQPF motifs, which are resistant to complete digestion by gastric and pancreatic enzymes \[[@B18]\]. The repeats can trigger immune response and appear to be especially important for the specific gluten peptide recognition by CD4^+^T cells \[[@B17],[@B44]\]. Previously, it was shown that phage display might be a useful technology to identify peptides that bind to gliadin residues, although no sequences were shown \[[@B38]\]. Here, we extended this work to include several different gliadin proteins to increase the probability of identifying phage that bound to reactive surfaces (Figure [1](#F1){ref-type="fig"}). Glutamine residues within gliadin can be deamidated by tissue transglutaminase (tTG), which will further enhance the pathologic immune response \[[@B45]\]. If blocking peptides efficiently inhibit recognition of gliadin by tTG they will most probably aid in limiting the development of T cell epitopes. In a recently published study we have shown that when in complexes with the selected blocking peptides, the *in vitro*enzymatic modification of gliadin by tTG was reduced by \~one-third \[[@B46]\]. There is no cure for CD. The only available therapy is a life-long exclusion of gluten from a diet. The variety of bakery and pastry gluten-free products is limited and the price is higher than their gluten containing equivalents \[[@B47]\]. Moreover, these products often do not meet the dietary requirements, as they tend to be high in fat and low in fibre as compared to gluten-containing equivalents \[[@B47],[@B48]\]. Furthermore, naturally gluten-free grains and flours can be contaminated with gluten during fieldwork, transport, processing or in a store if grains are kept in open containers \[[@B49],[@B50]\]. One alternative strategy would be to neutralise minor contaminations in e.g. oat, rice or maize products by mixing in molecules that block or digest the harmful motifs in gluten molecules \[[@B25]\]. Gluten-blocking peptides, like the ones described in this work, could perhaps be one way to detoxify disease-inducing gluten peptides in the future. By using a number of different panning conditions and gliadin proteins dissolved in either urea or NaHCO~3~a large number of phage displaying different peptide sequences has been identified. To investigate if the identified peptides could interfere with the human anti-gliadin antibody and gliadin interaction, we mixed peptide-carrying phage with gliadin and pooled sera originating from patients with suspected CD. In that way we demonstrated that the phage indeed inhibited interactions between gliadin and human anti-gliadin antibody (Figure [4](#F4){ref-type="fig"}). For these analyses we used patient sera from a biobank. The sera were selected for having high titers of anti-gliadin antibodies (≤100 U/ml) and positive or high titers of anti-transglutaminase IgA antibodies, although we had no specific information regarding the patients\' clinical diagnosis. The production of anti-gliadin antibodies is not specific to coeliac disease since slightly elevated serum concentrations are also found in other gastrointestinal disorders and even in normal individuals \[[@B51],[@B52]\]. However, the levels of anti-gliadin antibodies in patients without coeliac disease seem to be much lower compared to our selected serum samples \[[@B53]\]. As our patients had high levels of both anti-gliadin and anti-transglutaminase antibodies it is likely that they had CD. To verify whether the peptides, also when removed from the context of the phage, could interact with gliadin, we synthesised three peptides that were repeatedly identified in independent panning experiments and one control peptide that only interacted with BSA. We could then show that two of the peptides, P61 and P64 indeed interfered with the gliadin anti-gliadin antibody binding (Figure [6](#F6){ref-type="fig"} and [7](#F7){ref-type="fig"}). In this case, two different monoclonal anti-gliadin antibodies provided by a commercial kit were used. In addition, by means of the biotin label attached to the peptides, we also showed in western blot experiments that P61 and P64 could bind to several of the separated and immobilised gliadin proteins (Figure [9](#F9){ref-type="fig"}). Since we have so far only studied the nine gliadin-binding peptides that were most often picked up, we still have more than 150 additional peptides to test. Most likely, several of these peptides will also bind to gliadin. Since all individual peptides will bind to different sites on the gliadin complex, pooling of several different peptides could generate synergistic effects, and it should be possible to develop this concept in the direction of a drug against CD. However, many more experiments have to be performed, addressing issues like the stability of the peptide-gliadin interaction in chemical conditions likely to be encountered in the gut or in food preparation, the characterization of the actual binding sites in more detail, and the interaction with digestive enzymes and tissue transglutaminase etc. before any conclusions about the usefulness of these peptides in a therapeutic situation can be drawn. Conclusions =========== Finally, there are still several unanswered questions on the role of gliadin in the development of CD. Some of the gliadin-binding peptides presented here, labelled in different ways, could provide valuable tools for researchers in the field of CD to study localisation and uptake of various gliadin peptides in the small intestine. Methods ======= Gliadin preparation ------------------- Gliadin was extracted from gluten (Sigma Aldrich, Stockholm, Sweden) as described \[[@B41]\] with some modifications. Essentially, 1.5 g gluten was dissolved in 20 ml 25 mM Na~2~SO~3~, vortexed 15 min at room temperature (RT) and centrifuged at 5000 *g*for 5 min. The pellet was washed in 20 ml 25 mM Na~2~SO~3~and suspended in 70% ethanol by incubating at 70°C for 30 min with vortexing every 5 min. Undissolved material was eliminated by centrifugation, and the supernatant was incubated on ice for 2 h to precipitate the high molecular weight glutenin, which was eliminated by centrifugation for 10 min at 4°C. Subsequently the supernatant was mixed with 6 M NaCl in 70% ethanol to a final concentration of 256.67 mM NaCl and centrifuged for 10 min at 4°C. The supernatant that contained the gliadin-LMW-glutenin enriched fraction (in 70% ethanol and 256.67 mM NaCl) was stored at -80°C until further use. In addition, seeds (*ca*1 g) from *Surco*(wheat) and *Leon*(oat) varieties were ground and dissolved in 1 ml of 40% ethanol. The samples were centrifuged at 5000 *g*for 10 min and the supernatant stored at -20°C. Immobilisation of gliadin proteins ---------------------------------- Gliadin (1-100 ng) prepared as above and diluted in 0.1 M NaHCO~3~(pH 8.6) was incubated in 96-well microtiter (EIA/RIA) plates (Corning Inc. Corning, NY) at 4°C for 16 h. The amount of immobilized gliadin was quantified using the Anti-Gliadin IgG Kit (Biohit Oyi, Helsinki, Finland) according to the producer\'s protocol where the \"positive control\" patient serum provided in the kit was used as the primary anti-gliadin antibody, and labelled polyclonal anti-human IgG (goat) antibody was used as the secondary antibody. The positive signal was developed using the p-nitrophenyl phosphate solution (NPP) reagent and measured as absorbance at 405 nm. In vitro panning of phage display peptide library ------------------------------------------------- The Ph.D. -12™ Phage Display Peptide Library kit, including *E. coli*ER 2738 host strain, was purchased from New England BioLabs (Beverly, MA). Selection of peptides was carried out according to the manufacturer\'s instructions. 25 μg of gliadin in 0.1 M sodium bicarbonate (pH 8.6) was coated onto 96-well microtiter plates (EIA plates) at 4°C overnight. Remaining surfaces in the wells were then blocked for 2 h at 4°C with 5% BSA diluted in 0.1 M sodium bicarbonate (pH 8.6) with 0.02% NaN~3~. Afterwards, approximately 1 × 10^11^plaque forming units (pfu) of phage were diluted in 100 μl of 1 × LIB (Low Ionic Strength buffer, 10 mM sodium phosphate, pH 6.0) with 0.5% BSA and 0.1% Tween-20, and incubated with gliadin for 1 h at RT with gentle shaking. The same procedure was used in negative control pannings but in this case the wells were just coated with BSA (no gliadin present). After phage incubation, the wells were washed ten times with LIB with 0.5% Tween-20. Unbound phage were discarded. Bound phage were eluted with 0.2 M glycine-HCl, 1% BSA (pH 2.2) and amplified by infecting *E. coli*ER2738 host cells. After 4.5 h of growth at 37°C phage were removed from bacterial cells by centrifugation. The phage present in the supernatant were precipitated by adding 1/6 volume of PEG/NaCl solution (20% w/v polyethylene glycol-8000; 2.5 M NaCl), and incubated for 16 h at 4°C. The precipitate was resuspended in a small volume of LIB, and amplified elutes were titrated to determine phage concentration. Typically, the panning procedure was repeated five times after which phage were plated and random plaques were picked. After amplification, phage were purified by precipitation in PEG/NaCl followed by resuspension in 1/50 volume of the original volume in 1 × LIB with 0.02% NaN~3~and stored in aliquots at 4°C. These phage were then used in the binding specificity and affinity experiments and for DNA extraction. DNA sequencing -------------- Single-stranded phage DNA was isolated by incubation in iodide buffer (4 M NaI, 1 mM EDTA in 10 mM Tris-HCl, pH 8.0) to denature the phage coat protein. Released DNA was then precipitated in 70% ethanol. Purified DNA was sequenced by Microgen Inc. (Seoul, Korea) and MWG Biotech AG (Martinsried, Germany). Phage recovery experiment ------------------------- Coated and blocked (as described above) microtiter plate wells were washed three times with 0.1% LIBT (LIB buffer with 0.1% Tween-20). Selected phage were serially diluted in 0.1% LIBT buffer and 100 μl was added to the wells. After addition of 1% BSA the wells were incubated for 1 h at 37°C. Control wells were incubated in the same buffer but without phage. Next, the wells were washed six times with 0.5% LIBT to remove the unbound phage. The remaining phage were eluted with glycine-HCl (pH 2.2) in 1% BSA and phage titers were determined. Patient antisera ---------------- The serum samples were obtained from a biobank at the immunological laboratory, Sahlgrenska University hospital, Gothenburg, Sweden. The samples were selected for high titers (≤100 U/ml) of anti-gliadin IgA antibodies and for positive or high titers of anti-transglutaminase IgA antibodies. The serum samples were prepared according to standard procedure, i.e. blood was drawn into unprepped tubes and serum was collected by centrifugation at 3000 *g*. Serum was diluted (1:500) with dilute buffer (same as dilute buffer from Anti-Gliadin IgG kit). The serum used here was a pool from 20 different anonymous patients. Phage ELISA ----------- Since the phage display was done on a mixture of different gliadin proteins, potentially a lot of different peptides could bind to the coated proteins. To block out as many peptides as possible in the same experiment pooled polyclonal patient sera isolated from 20 different patients with suspected CD were used. Microtiter plate wells were coated with 100 μl of gliadin proteins (0-100 μg/ml) dissolved in 0.1 M NaHCO~3~(pH 8.6) and incubated overnight at 4°C. Subsequently, the wells were blocked with 200 μl of blocking buffer (5% BSA in 0.1 M NaHCO~3~, pH 8.6; with 0.02% NaN~3~) for 2 h at 4°C and washed three times with 0.1% LIBT (LIB with 0.1% Tween-20). Phage (1 × 10^11^) carrying different peptide sequences in 100 μl blocking buffer were transferred to the coated wells and incubated at 37°C for 1 h. Unbound phage were removed by washing six times with 0.5% LIBT (1 × LIB buffer with 0.5% Tween-20). After this, 100 μl pooled patient antiserum (diluted 1:500 with dilution buffer from the Anti-Gliadin IgG kit, Biohit Oyi, Helsinki, Finland) was added. After the 30 min incubation at RT the wells were washed four times with 1 × ELISA washing buffer (Phosphate Buffered Saline, pH 7.2, 0.05% Tween-20, Biolegend, San Diego, CA). For detection, 100 μl of AP-linked, goat anti-human IgG (Invitro/Biolabs, Beverly, MA) diluted (1:4500) with dilution buffer from the Anti-Gliadin IgG kit was added to the wells and incubated for 30 min at RT. After washing four times with 1 × ELISA washing buffer, 100 μl of Nitrophenyl Phosphate Disodium substrate solution (NPP) (Invitrogen, Madison, WI) was added and incubated for 30 min at RT. Finally, the signal was detected by measuring absorbance at 405 nm in a microplate reader. Peptide synthesis ----------------- Four peptides, denoted P61, P64, P22 and CP31 were synthesized at \>95% purity by Bio-Synthesis Inc. (Lewisville, TX), with biotin added to the N terminus. Peptides were dissolved in 150 μl DMF (dimethylformamide) and diluted to 1 ml with 0.05 M phosphate buffer containing 0.15 M NaCl, pH 7.4 (Peptide Dilution Buffer, PDB) to a final concentration of 16.7 μM. Aliquots were stored at -20°C until further use. Binding of synthetic peptides to gliadin proteins ------------------------------------------------- 100 μl, corresponding to 1.67 nmoles (10^15^molecules) of the synthesized peptides were added to gliadin-coated microtiter wells (1-100 ng) and was incubated in 0.1 M NaHCO~3~(pH 8.6) for 1 h at 37C. The wells were washed four times with 1 × ELISA buffer (diluted from 20 x ELISA washing buffer, Biolegend, San Diego, CA) after which 100 μl anti-biotin AP-linked antibody (<http://www.cellsignal.com>) diluted 1:3000 was added. After the 30 min incubation at RT, and washing (four times) with 1 × ELISA buffer, 200 μl of 1 × NPP substrate (Invitrogen, Carlsbad, CA) was added to the wells. After the 30 min incubation at RT in the dark 100 μl of stop solution was added, the plates were shaken, and the signal was read at 405 nm. Inhibition of gliadin-anti-gliadin antibody binding by selected synthetic peptides ---------------------------------------------------------------------------------- Gliadin was prepared as described and diluted to a final concentration of 100, 50, 30, 10, 5, 3, 1 and 0.5 ng/ml in 200 μl dilution buffer provided in the Immunotech ELISA kit (Radiová 1, Prague, Czech Republic). Each gliadin dilution was incubated with 1.67 nmoles (10^15^molecules) of the synthetic peptides P64, P61, P22, CP31 and a control with only 0.1 M NaHCO~3~buffer at RT for 1 h. The gliadin/peptide mixtures were then added to microtiter wells coated with two different anti-gliadin monoclonal antibodies provided with the Immunotech Gliadin ELISA kit. As internal calibrators, 0 and 9 ng gliadin solutions were added to separate wells. Wells with the different mixes were incubated for another hour at RT. Afterwards bound gliadins were quantified using a polyclonal antibody (horseradish peroxidase conjugate) that binds to the solid phase antibody-antigen complex. Bound secondary antibody was quantified using TMB substrate (tetramethylbenzidine) as described in the kit. Positive signals were given as absorbance units at 450 nm. Concentration dependency of peptide gliadin-anti-gliadin antibody binding inhibition ------------------------------------------------------------------------------------ Gliadin was diluted to a final concentration of 1 ng/ml in 200 μl 0.1 M NaHCO~3~dilution buffer as described and mixed with 1.67 nmoles, 0.167 pmoles, and 0.0167 fmoles (10^15^, 10^9^, 10^5^molecules) respectively of the biotin-labelled synthetic peptides P61, P64, and CP31, dissolved in 0.1 M NaHCO~3~buffer. After incubation for 1 h at RT the gliadin/peptide mixtures were then added to the anti-gliadin antibody coated microtiter wells and incubated for another hour. Secondary antibody was thereafter added and quantified as absorbance units at 450 nm as described above. Dot blot assay -------------- 4 μl of serial dilutions of gliadin proteins in 0.1 M NaHCO~3~(pH 8.6) were spotted onto 0.45 μm nitrocellulose membranes, air dried, and subsequently quenched by soaking into 5% non-fat milk in PBS overnight at 4°C. Blocking solution was removed by washing the membranes with PBST (137.9 mM NaCl, 1.47 mM KH~2~PO~4~, 8.1 mM Na~2~HPO~4~, 2.68 mM KCl, 0.05% Tween-20, pH 7.4). Biotinylated blocking peptides were diluted in PBS and incubated with the membranes for 3 h at RT with gentle shaking. After subsequent washing with PBST (four times), anti-biotin AP-linked antibody (diluted 1:3000 with dilute buffer, 50 mM PBS, pH 7.2, 0.05% Tween-20) was incubated with the membranes for 2 h with gentle shaking. Finally, the membranes were washed four times with PBST-0.05%, once with PBS and the AP-substrate was added. The images were developed with immune-star™ AP chemiluminescent protein detection system (Bio-Rad Laboratories, Sundbyberg, Sweden). Western blot analysis --------------------- Gliadin proteins were separated during SDS-PAGE on 12% Tris-glycine gels. The separated proteins were transferred in transfer buffer (48 mM Tris, 38.6 mM glycine, 1.6 mM SDS, 20% methanol) to nitrocellulose membranes (Amersham/Biosciences, Sweden) for 2.5 h at 90 mA in a semi-dry electroblotting unit (Z34050-2, Sigma, Stockholm, Sweden). After the protein transfer the membranes were washed with washing buffer (PBS, 0.05% Tween-20) and blocked with 3% BSA in PBS overnight at 4°C. For development of the biotin signal, the same protocol as in the Dot blot assay was used. The study was approved by the Human Research Ethics Committee of the Medical Faculty, Gothenburg University, Gothenburg, Sweden with the permission number 144-06. The serum samples were obtained from a biobank at the immunological laboratory, Sahlgrenska University hospital, Gothenburg. Biobank samples were selected for high titers of gliadin-specific IgA antibodies and for positive or high titers of anti-tTG antibodies. According to the Swedish biobank law, the serum samples were completely impersonalized, which means that the samples cannot be linked to any patient, his or her personal data, or to the clinical evaluation. Authors\' contributions ======================= TC developed and optimised the phage display technology and performed most of the experiments to test the peptides. KH participated in the gluten purification and gave suggestions during method development. SÖ provided the human antibodies and helped with ELISA experiments. OO and ASS planned the project. OO supervised the work and wrote the manuscript together with TC and KH. All authors read and approved the final manuscript. Acknowledgements ================ This work was supported by a grant from the Swedish Council for Environment, Agricultural Sciences and Spatial Planning no: 222-2004-2705 given to ASS. We also thank Bruce Downie, University of Kentucky and Britt Gabrielsson from Chalmers University of Technology for critical reading of the manuscript.

PubMed Central

2024-06-05T04:04:17.200462

2011-2-17

PMC3051898

Background ========== The *ssrA*gene which encodes the tmRNA molecule has been identified in all known bacterial phyla \[[@B1],[@B2]\]. The term tmRNA describes the dual \"transfer\" and \"messenger\" properties of this RNA molecule. In bacteria, the function of the tmRNA molecules is to release ribosomes that have become stalled during protein synthesis and to tag incomplete and unnecessary peptides for proteolysis. A typical tmRNA is between 300-400 nucleotides in size and is present in cells in relatively high copy number around 1000 copies per cell \[[@B3]\]. tmRNA molecules contain both conserved as well as variable regions between different species; complementary 3\' and 5\' ends fold together into a tRNA like structure that permits the entry to the ribosome when needed. Proteolysis-coding mRNA part and structural domains usually make up for the rest of the molecule. All those characteristics make the tmRNA transcript (and its *ssrA*gene) a suitable tool as a target marker molecule for phylogenetical analysis and species identification in microbial diagnostics. Over the last 10 years tmRNA and its corresponding gene have been used for species identification in several methods including fluorescence in situ hybridization (FISH) detection of specific bacteria \[[@B4]\], real-time PCR \[[@B5]\] and real-time NASBA \[[@B6]\] analysis of food and dairy contaminants and pathogen detection using biosensors \[[@B7]\]. Combining the capabilities of tmRNA for species identification with DNA microarray technology offers the potential to investigate samples simultaneously for large numbers of different target tmRNA molecules. DNA microarrays have found several practical applications in microbial diagnostics such as composition analysis and species identification of different environmental and medical samples as well as in microbial diversity investigation \[[@B8]-[@B10]\]. Depending on the experiment setup and specific probe design, precise detection of one specific microbe \[[@B11]\] or more complex analysis of microbial taxa can be performed \[[@B12]\]. The design of microarray probes for the detection of bacterial RNA poses unique challenges, because certain RNA/DNA or RNA/RNA mismatches have almost as strong binding affinity as matches \[[@B13]\]. The nearest-neighbor thermodynamic modeling (NN) approach should therefore be used to calculate the hybridization affinities (ΔG) of probes \[[@B14]-[@B16]\]. The hybridization on microarray surface is more complex then hybridization in solution and the NN model should include surface and positional parameters for more accurate modeling \[[@B17],[@B18]\]. Although there are many recent studies of surface hybridization thermodynamics \[[@B19]\], the exact hybridization properties of microarray probes cannot be precisely modelled and experimental verification is still needed \[[@B20],[@B21]\]. A common feature of many microarray analysis protocols is that the nucleic acid sequences of interest are amplified and labeled prior to the hybridization experiment. Hybridization protocols may involve labeled cDNA \[[@B22]\], cRNA \[[@B23]\] or (RT-)PCR products \[[@B24]\]. RNA molecules can also be amplified by Nucleic Acid Sequence Based Amplification (NASBA) \[[@B25]\]. Although not as common as RT-PCR, NASBA is less prone to genomic DNA contamination and therefore more suitable for applications where the testing of microbial viability is important \[[@B26]\]. Several methods have recently been published that describe different NASBA product labeling methods for the purpose of microarray hybridization. These methods include the dendrimer-based system NAIMA \[[@B27]\], biotin-streptavidin binding assisted labeling \[[@B28]\] and aminoreactive dye coupling to aminoallyl-UTP (aa-UTP) molecules in NASBA products \[[@B29]\]. In this report we present a complete technological solution for detection of low amounts of bacterial tmRNA molecules. We describe a new software program, SLICSel, for designing specific oligonucleotide probes for microbial diagnostics using nearest-neighbor thermodynamic modeling and evaluate SLICSel by testing the specificity of the designed tmRNA specific probes. Finally we demonstrate the sensitivity of these probes using a molecular diagnostics method that combines tmRNA amplification by NASBA with microarray-based detection \[[@B29]\]. Using this approach we were able to specifically detect *S.pneumoniae*tmRNA in the amount that corresponds to a single bacterium or less in the presence of 4000-fold excess of other bacterial tmRNA. Methods ======= SLICSel program for probe design -------------------------------- The nearest-neighbor thermodynamic (NN) modeling of probe hybridization strength with target (specific hybridization) and control (nonspecific hybridization) nucleotide sequences at exact annealing temperature is used as design criterion of the SLICSel program. The previously published empirical formula was used to adjust the calculated thermodynamic values to the actual annealing temperature and salt concentration \[[@B15]\]. No surface and positional effects were added to the model to keep it universal and not bound to specific technology. We also expect that NN parameters on surface, although slightly different, are in correlation with the ones in solution \[[@B19]\]. Bacterial strains ----------------- *Streptococcus pneumoniae*ATCC 33400 (*S.pneumoniae*), *Streptococcus pyogenes*ATCC 12344 (*S.pyogenes)*, *Klebsiella pneumoniae*ATCC 13883 (*K.pneumoniae*), *Moraxella catarrhalis*ATCC 25238 (*M.catarrhalis*) were obtained from DSMZ (Braunschweig, Germany); *Streptococcus agalactiae*(*S.agalactiae*) and Group C/G streptococcus (GrC/G) from University College Hospital (Galway, Ireland). Bacterial strains were grown in Brain Heart Infusion Broth (Oxoid, Hampshire, UK). Total RNA extraction and CFU counting is further described in the Additional file [1](#S1){ref-type="supplementary-material"}. Microarray design ----------------- We used the *S.pneumoniae*tmRNA molecule as the main specific target molecule, while tmRNAs from other bacteria were used as non-specific controls. The custom made microarray for SLICSel validation experiments contained 97 probes covering the whole *S.pneumoniae*tmRNA sequence. For NASBA-microarray experiment, the 25 best performing probes were selected and additional control probes specific to *S.pyogenes*, *S.agalactiae*, *M.catarrhalis*and *K.pneumoniae*(three for each) were also added. The precise probe list and microarray manufacturing have been described previously \[[@B30]\] and customization for the current article is described in the Additional file [1](#S1){ref-type="supplementary-material"}. *In vitro*tmRNA synthesis for validation experiment --------------------------------------------------- For *in vitro*transcription of tmRNA *ssrA*genes of *S.pneumoniae*, *S.agalactiae*, *S.pyogenes*, Group C/G streptococcus, *M.catarrhalis*and *K.pneumoniae*were inserted in the pCR^®^II-TOPO vector (Invitrogen, Carlsbad, CA, USA) under the transcriptional control of either T7 or SP6 promoter sequence. tmRNA molecules were transcribed from vector as described previously \[[@B30]\] with minor alterations. The complete protocol is available in the Additional file [1](#S1){ref-type="supplementary-material"}. NASBA amplification experiment ------------------------------ A series of experiments were performed to determine the detection capability of NASBA in combination with microarray hybridization. A NASBA primer pair (see the Additional file [1](#S1){ref-type="supplementary-material"}) was designed to amplify a 307 nucleotide tmRNA product using *S.pneumoniae*total RNA as a template. The T7 promoter was added to the forward primer in order to generate a sense strand of the RNA molecule. Three different amounts of *S. pneumoniae*total RNA were added to the NASBA reactions: 1 pg, 100 fg and 10 fg, corresponding to 10, 1 and 0.1 CFU, respectively. An equal volume of NASBA water (included in EasyQ kit) was added to control experiment without any *S. pneumoniae*total RNA. NASBA reactions were performed with NucliSENS EasyQ Basic kit v2 (bioMerieux bv, Boxtel, NL) according to manufacturer\'s instructions but with addition of aminoallyl-UTP (aa-UTP) as described previously \[[@B29]\]. Final concentration of aa-UTP (Epicentre, Madison, WI, USA) used in the reaction was 1 mM. EasyQ kit was used for 96 NASBA amplifications instead of the original 48 by halving all of the manufacturer suggested reagent volumes. In experiments with background RNA 10 pg of *S.pyogenes, S.agalactiae, M.cattarhalis*and *K.pneumoniae*total RNA were added, making the RNA excess ratios of each control to target RNA 10:1, 100:1 and 1000:1, respectively. Following amplification, tmRNA was purified using a NucleoSpin^®^RNA CleanUp Kit and vacuum dried using RVC 2-25 CD rotational vacuum concentrator (Martin Christ GmbH, Osterode am Harz, Germany). Labeling of aa-UTP modified RNA and microarray hybridization ------------------------------------------------------------ Extra amine groups of aa-UTP modified tmRNA molecules were labeled with the monoreactive fluorescent dye Cyanine™ 3-NHS (Cy3) (Enzo, Farmingdale, NY, USA) as described previously \[[@B30]\]. For the SLICSel validation experiments, 300 ng of *in vitro*synthesized target or control RNA was hybridized onto microarray. In NASBA experiments all of the amplified material was used in the subsequent microarray hybridization. In both cases vacuum dried RNA was resuspended in 80 μl of hybridization buffer and hybridized for 4 hours on the microarray in an automated HS-400 hybridization station (Tecan Austria, Grödig, Austria) at 55 C°. Complete hybridization protocol and reagents are shown in the Additional file [1](#S1){ref-type="supplementary-material"}. After hybridization, the slides were scanned using an Affymetrix 428 scanner (Affymetrix, Santa Clara, CA, USA), λ = 532 nm. Raw signal intensity data was analyzed using Genorama™ BaseCaller software (Asper Biotech, Estonia). Results ======= Probe design software --------------------- SLICSel was used to design hybridization probes for all bacterial species in the experiment. It uses a brute-force algorithm that finds all theoretically acceptable probe sequences. All designed probes are guaranteed to have at least specified minimum difference (ΔΔG~control~) between the binding energies (ΔG) of specific and nonspecific hybridization and at most specified maximum binding energy difference (ΔΔG~target~) between the binding energies of the hybridization with different target sequences. The algorithm also accepts degenerate nucleotides in sequences; in which situation the worst-case variant is used (strongest binding for control set and weakest binding for target set). The program uses well-established thermodynamic models of hybridization in solution, as the more complex surface effects are still under active study and are also dependant on the microarray technology used. The program code can be easily extended to take account of more specific models, if needed. The tables for both DNA-DNA and DNA-RNA nearest-neighbor hybridization thermodynamics are included with the program. It is also possible to use a custom table of thermodynamic parameters, necessary if very specific experimental conditions are used. SLICSel is available from web interface at <http://bioinfo.ut.ee/slicsel/> SLICSel validation ------------------ A series of hybridization experiments were conducted to validate the SLICSel program by testing the specificity of the SLICSel designed oligonucleotide probes and their suitability for the use in development of diagnostical technology. In total 97 oligonucleotide probes were designed complementary to the different regions of *S.pneumoniae*\'s tmRNA (the main target molecule). Control tmRNA molecules were from five other bacteria: *S.pyogenes, S.agalactiae*, GrC/G streptococcus, *K.pneumoniae*and *M.catarrhalis*. All tmRNA sequences were synthesized i*n vitro*and then hybridized individually to the panel of *S.pneumoniae*tmRNA specific probes on microarray. Figure [1](#F1){ref-type="fig"} shows the scatter plot of relative signal intensities of control tmRNA hybridizations onto microarray probes according to their binding energy difference ΔΔG between target and control RNA. From a total of 463 hybridization events only 20 (\~4.3%) gave relative signal intensities higher than preset 10% false positive signal threshold condition. For the remaining 443 hybridizations (95.7%) the control signals remained under the threshold level. As shown in the Figure [1](#F1){ref-type="fig"}, designing probes with higher binding energy difference (ΔΔG) decreases the possibility of a false positive signal. For example, choosing the probes with the minimum ΔG difference of 4 kcal/mol was sufficient to avoid all the false-positive bindings over the threshold while in the case of ΔG difference 2 kcal/mol 6 signals remained over the 10% signal threshold (\~1.5% of hybridizations). The average hybridization signal intensities of target and control tmRNAs (all five together and individually) are shown on a bar chart and complementary table in Figure [2](#F2){ref-type="fig"}. Nearly fivefold increase of the probe specificity was achieved with ΔΔG condition 4 kcal/mol as the average false-positive control tmRNA signal intensity dropped from 2.46% to 0.55%. All of the average false-positive hybridization signals of individual tmRNAs were lower with higher minimum ΔΔG criteria. In general, control tmRNAs from bacteria belonging to the Streptococcus genus showed stronger than/or near average false-positive hybridization signals while signals of more distant *K.pneumoniae*and *M.catarrhalis*remained under the overall average. *K.pneumoniae*tmRNA produced lowest average false-positive signals in all three different minimum ΔΔG conditions and had no signals over the 10% threshold. All of the false-positive signals greater than 10% were contributed by 10 single microarray probes. After removal of those problematic probes the average hybridization signal intensities were under 1% for all the different control tmRNAs. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Non-specific microarray signal intensities from hybridization experiments with target and five control tmRNAs**. Non-specific tmRNA signal intensities are divided by the corresponding probe-specific signal intensity. Target hybridization signal intensity is given on a y-axis as a 100% signal baseline. A maximum false-positive signal threshold is shown as horizontal 10% dotted line. Microarray signals are distributed along x-axis according to the calculated binding energy difference between the specific and non-specific binding (ΔG~target~- ΔG~control~(ΔΔG) 0.2\...10.7 kcal/mol). Dotted vertical lines separate the probes with binding energy difference smaller then 2 and 4 kcal/mol, respectively. :::  ::: ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Average microarray signal intensities with target *Streptococcus pneumoniae*and five different control tmRNAs**. The probe-specific target tmRNA hybridization signal average is shown as a 100% bar. Control signal averages of five different tmRNAs (*Streptococcus pyogenes (S.pyo), Streptococcus agalactiae (S.aga)*, GrC/G streptococcus (GrC/G)*, Klebsiella pneumoniae (K.pne)*and *Moraxella catarrhalis (M.cat))*are given as a percentage of the target signal. Three different average bars for control tmRNAs represent the average hybridization signal intensities with probes\' minimum ΔG differences 0.2; 2 and 4 kcal/mol compared to the hybridization with target molecule (ΔΔG = 0). Error bars show SD of control signal averages. All of the average signal values of the control tmRNA hybridization reactions are shown on the table added onto the graph. :::  ::: NASBA-microarray technology --------------------------- To test the SLICel designed probes for their potential use in microbial diagnostics; a new microarray was designed that consisted of the 25 best performing probes out of 97 according to their specificity and the sensitivity in the validation experiments. For control purposes oligonucleotide probes specific to *S.pyogenes, S.agalactiae*, *K.pneumoniae*and *M.catarrhalis*were also added to the microarray. tmRNA molecules of *S.pneumoniae*were amplified from three different total RNA dilutions (equaling to 0.1, 1 and 10 CFU, respectively) and labeled for microarray hybridization. Microarray signals were obtained with all three total RNA dilutions in all of the three parallel experiments including the 10 fg of total RNA sample equivalent to 0.1 CFU. According to the total RNA input into the NASBA reaction, microarray signals increased correspondingly with 0.1 CFU being the lowest and 10 CFU the highest in three replicate experiments (figure [3](#F3){ref-type="fig"}). Hybridization experiments with NASBA amplified negative control solution provided no significant signals over the background level on microarray. NASBA control experiments with excess amounts of total RNA mix from 4 control species (*S.pyogenes, S.agalactiae*, *K.pneumoniae*and *M.catarrhalis*) were performed to verify the specificity of the NASBA-microarray based detection method. 10 pg of total RNA from each of the control species were added, making the background RNA ratio to target RNA 4 × 10:1, 4 × 100:1 and 4 × 1000:1, respectively. Addition of control total RNA-s to NASBA reaction did not cause any changes to the microarray signal intensities; all of the *S.pneumoniae*target dilutions were amplified and detected on the microarray while the negative control remained blank. The capability of the described NASBA-microarray method to detect tmRNA from low amounts of bacteria was also confirmed experimentally when the total RNA was prepared from dilutions of *S.pneumoniae*cultures (0.1 to10 CFU) instead of using total RNA dilutions, making the experiment setup closer to real-world diagnostic situations where only small amounts of target bacteria may be present. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Microarray signal intensities of NASBA amplified tmRNA from *Streptococcus pneumoniae*total RNA dilutions**. The microarray signal intensity of NASBA amplified 1 CFU total RNA was set as a 100% in all three parallel experiments. Rest of the RNA dilution hybridization signals from 0 CFU (equal volume of NASBA water as negative control), 0.1 and 10 CFU represent their relation to 1 CFU signal as a percentage. Error bars show ± 1 SD of signal averages over three parallel experiments. 1 CFU equivalent of total RNA stands for 100 fg of RNA from *S.pneumoniae*. :::  ::: Discussion ========== We selected tmRNA as a marker molecule for technological tool development in bacterial diagnostics because they are present in all bacteria \[[@B1],[@B2]\] in high copy number and they contain both conserved as well as highly divergent regions \[[@B3]\]. Presence of intact RNA molecules can additionally indicate the viability of the bacterial population in the analyte solution \[[@B26]\]. These characteristics make tmRNA a suitable marker molecule in microbial diagnostics. Although the aforementioned properties also apply to16S rRNA (and its corresponding gene), possibly the best known and most used marker in diagnostic and phylogeny studies, the need for investigation of novel alternative marker molecules like tmRNA remains as 16S rRNA often cannot be used to detect and distinguish closely related species \[[@B4],[@B31]\]. For microarray-based detection technologies, the signal strength is determined by the number of target molecules hybridized to probes, i.e. by the equilibrium point of hybridization, and can thus be theoretically predicted using the nearest-neighbor thermodynamic model. The same model, incorporating mismatches, can also be used to predict the signal strength of nonspecific hybridizations - i.e. false-positive signals. In our approach the goal was not to design probes with maximum affinity, but instead maximize the difference of affinity between specific and nonspecific hybridization at annealing temperature. The microarray hybridization experiments conducted with tmRNA specific probes gave information about the concept of designing probes using NN thermodynamic modeling in SLICSel and whether the tested probes are suitable for further species detection and identification. In general the hybridization experiments with *in vitro*synthesized target and control tmRNA molecules proved that SLICSel designed probes are highly capable of specific bacterial identification. By implementing stringent binding energy difference criteria during probe design SLICSel can minimize the possibility of designing probes that would result in false-positive signals. In our validation experiment the hybridization binding energy difference ΔΔG 4 kcal/mol between control and target tmRNA was sufficient to eliminate all the false-positive control signals over the needed threshold level (Figure [1](#F1){ref-type="fig"}). We achieved an almost fivefold increase in average probe specificity by using stringent ΔΔG criteria 4 kcal/mol (Figure [2](#F2){ref-type="fig"}). Although, the efficiency of average SLICSel designed probe is high, there is no 100% guaranteed approach for the *in silico*oligonucleotide probe design for hybridization based experiments with surface-immobilized probes. Additional probe specificity evaluation *in vitro*and low quality probe removal still remain as necessary steps in any microarray experiment \[[@B20]\]. In our case the removal of 10 probes was needed to assure that hybridization signals with control tmRNAs remain safely under the determined 10% threshold level. We designed a new microarray incorporating only the optimum *S.pneumoniae*specific probe sequences for the detection of labeled tmRNA products amplified using NASBA. A key characteristic of the NASBA-microarray technology, especially in microbial diagnostics, is that the detection and the identification of the correct target can be optimized at two different points in the experimental protocol. The selection of oligonucleotide primer set determines the specificity of the NASBA amplification phase while a second level of specificity is provided by the SLICSel designed immobilized microarray probes. Specific amplification of a single RNA molecule or wider selection of various RNAs in case of multiplex-NASBA is possible. Certain rules have been described for the NASBA primer pair design \[[@B32]\], but as no convenient software has yet been developed it remains somewhat a trial-and-error approach. In our case the primer set was designed according to the aforementioned rules to amplify a near full length tmRNA molecule from *S.pneumoniae*. We included additional control probes specific to *S.pyogenes, S.agalactiae*, *K.pneumoniae*and *M.catarrhalist*in the microarray to determine the specificity of NASBA amplification step conducted in the presence of a non-*S.pneumoniae*total RNA background. The composition of capture probes on the microarray depends on the overall goal of the experiment. In our case the objective was to specifically detect tmRNA molecules from *S.pneumoniae*total RNA and test the sensitivity of the method previously described by us \[[@B29]\]. Our intention was to investigate whether the method is capable of detecting 1 CFU by using tmRNA as a target molecule. Previous works have shown that detection of 1 CFU by using NASBA amplification of rRNA \[[@B33]\] or tmRNA \[[@B6]\] is possible. The addition of highly parallel microarray based detection to this amplification technology could represent a significant advance in microbial diagnostics; particularly in situations where high number of different bacterial species may be present (such as environmental samples) or in clinical settings where it is necessary to identify one particular infection causing species from a large panel of potential pathogens. We successfully detected and identified *S.pneumoniae*tmRNA molecules from all three different dilutions of total RNA used in experiments (Figure [3](#F3){ref-type="fig"}). Our experiments proved that 0.1 CFU equivalent total RNA was sufficient to produce strong reproducible hybridization signals on our microarray. Addition of background total RNAs to the NASBA reaction mix provided no signals on control probes on microarray, confirming the high specificity of NASBA-microarray technology and also its components: NASBA primers and microarray probes. In case of the specific tmRNA detection from 0.1 CFU equivalent of *S.pneumoniae*total RNA, the amount of non-specific RNA exceeded the target 4000 times. The described high level of achieved specificity and sensitivity demonstrates the potential and suitability of NASBA-microarray technology for the purpose of pathogen detection in microbial diagnostics or more complex analysis of microbial taxa in environment. Conclusions =========== We have presented a novel technological procedure for bacterial diagnostics and microbial analysis. The nearest-neighbor thermodynamics based SLICSel tool is not exclusive for tmRNA and microarray probe design, but can be used for any other hybridization based technology where DNA or RNA oligonucleotide probe design is necessary. The combination of NASBA amplification technology with microarray based fluorescently labeled RNA detection enabled us to detect tmRNA molecules from as low as 0.1 to 10 CFU of *S.pneumoniae*total RNA. Using the described approach different patient samples, food products or any analyte solution can be tested and screened in a highly parallel approach for several live pathogens or contaminants. SLICSel and NASBA-microarray technology can be used separately for different areas of microbial diagnostics including environmental monitoring, bio threat detection, industrial process monitoring and clinical microbiology. Authors\' contributions ======================= OS conducted NASBA and microarray experiments, performed microarray analysis and drafted the manuscript. LK designed SLICSel and microarray probes, helped with microarray data analysis and drafted the manuscript. BG carried out the microbiological experiments and RNA extraction and helped to draft and review the manuscript. PP helped designing SLICSel and the microarray probes, helped in data analysis and drafted the manuscript. SP participated in NASBA and microarray experiments and data analysis. KT participated in NASBA and microarray experiments and helped in manuscript review. MM and TB conceived of the study, participated in its design and coordinated microbiological experiments. MR conceived of the study and participated in its design, conducted SLICSel design, helped to draft and review the manuscript. AK conceived of the study, participated in its design, coordinated NASBA and microarray experiments and helped to draft and review the manuscript. All authors read and approved the final manuscript. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **Methods supplementary file**. Additional file describing thoroughly all of the necessary data and reagents needed for the methods section ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ This work was funded by the SLIC-513771 EU grant and by targeted financing from Estonian Government SF0180027s10. This work was also funded by grant SF0180026s09 from the Estonian Ministry of Education and Research and by the EU through the European Regional Development Fund through the Estonian Centre of Excellence in Genomics. Authors would like to thank Indrek Valvas and Asper Biotech for microarray manufacturing

PubMed Central

2024-06-05T04:04:17.204041

2011-2-28

PMC3051899

Background ========== The recalcitrance of lignocellulose to enzymatic degradation and the high cost of hydrolytic enzymes required for depolymerization of polysaccharides found in the plant cell wall are significant barriers to the large-scale production and commercialization of biofuels and bioproducts derived from plant biomass \[[@B1]\]. In order to rapidly increase production of cellulosic biofuels and bioproducts there is a need to develop more efficient and cost effective enzyme mixtures for the conversion of biomass to fermentable sugars \[[@B2]\]. In order to address this challenge, a better understanding of the interactions between plant cell wall polysaccharides and the diversity of cell wall degrading enzymes (CWDE) needed for efficient hydrolysis is essential. The complexity of cell wall polysaccharides is one factor which contributes to the resistance of biomass to efficient hydrolysis for bioenergy production. Plant cell walls are heterogeneous and dynamic structures, composed of polysaccharides, proteins and aromatic polymers. Cell wall composition and structures differ among plant lineages \[[@B3]\]. The cell walls of Angiosperms (flowering plants) and Gymnosperms (including conifers) all contain cellulose microfibrils embedded in a matrix of pectin, hemicellulose, lignin and structural proteins, but the types and relative amounts of these structural polymers differ among groups of plants and also change as the wall matures. For example, the walls of the Poales (grasses) and other commelinoid monocots differ from dicots and non-commelinoid monocots in several ways. Type I cell walls found in non-commelinoid monocots and dicots are generally rich in xyloglucan and pectin. In contrast, the type II cell walls of commelinoid monocots contain glucuronoarabinoxylan as the major non-cellulosic polysaccharide. Commelinoid monocots are also unique in having mixed-linkage β-1,3(1,4)-glucans \[[@B3]-[@B5]\]. There are additional differences in the types of lignin and ferulic acid esterification found in grasses and dicots \[[@B3],[@B6]\]. In addition to the physical complexity of the cell wall, it is a dynamic structure that changes as the plant grows and ages. During cell wall maturation from a primary to secondary wall in both monocots and dicots, the amounts of xyloglucans, pectins and structural proteins decrease while the amount of xylans and lignin increase. The major constituents of typical secondary cell walls are cellulose (35%-45% dry weight in grasses, 45%-50% in dicots), xylans (40%-50% in grasses, 20%-30% in dicots) and lignin (20% in grasses, 7%-10% in dicots) \[[@B4]\]. Thus the sugars found in cellulose and xylans are the major carbon source for fermentation of biofuels and other bioproducts. The complexity of the plant cell wall is mirrored by the diverse arsenal of CWDE produced by lignocellulose-degrading microbes. Each type of structural polysaccharide-degrading enzyme is represented in multiple families determined by sequence and structural similarities \[[@B7]-[@B10]\]. The Carbohydrate-Active Enzymes Database (CAZy) categorizes cellulases (EC 3.2.1.4 and 3.2.1.91) in at least 12 different glycosyl hydrolase (GH) families, and xylanases (EC 3.2.1.8 and 3.2.1.37) in 12 GH families \[[@B11]\]. Some GH families contain both cellulases and xylanases (such as GH5) while others contain cellulases but no xylanases (GH7) or vice versa (GH11). Genomic analysis of lignocellulose-degrading fungi shows that a single species can have the genetic capacity to produce many different enzymes with similar functional designations (cellulase, xylanase and others). For example, the genome of the phytopathogen *Magnaporthe grisea*is predicted to encode at least 30 enzymes in six GH families for the degradation of cellulose and 44 enzymes in 11 families for the degradation of hemicellulose (Fungal Genome Initiative, Broad Institute, <http://www.broadinstitute.org/science/projects/fungal-genome-initiative>). When compared to six other filamentous Ascomycete fungal genomes, the industrial cellulase-producing fungus *Trichoderma reesei*has a similar number of GH families for cellulose degradation and slightly fewer GH families for hemicellulose degradation \[[@B12]\]. However, *T. reesei*contains the smallest total number of genes encoding cellulases and xylanases compared to six fungal genomes. The genome of the phytopathogen *Fusarium graminearum*has twice the number of genes encoding cellulases and xylanases as *T. reesei*, and the genome of *M. grisea*contains three times as many \[[@B12]\]. Despite having relatively few genes coding for CWDE, engineered strains of *T. reesei*, such as RUT-C30, produce large quantities of extracellular enzymes, and culture broths are highly effective at the depolymerization of cellulose because of the abundance of cellulases produced \[[@B13]-[@B15]\]. As a result of the complexity of lignocellulosic biomass, there is potential to supplement the limited repertoire of commercial CWDE by complementation with enzymatic diversity from other sources \[[@B12],[@B16]\]. For example, the supplementation of a blend of commercial enzymes \[Celluclast (from *T. reesei*) and Novozyme 188 (from *Aspergillus niger*); Novozymes A/S (Bagsvaerd, Denmark)\] with culture broths from several fungal species at a level of only 10% of the total protein in the reaction was sufficient to stimulate cellulose hydrolysis to twice the benchmark activity of the commercial enzymes alone \[[@B17]\]. Proteins in family GH61 have recently been identified as factors that enhance the hydrolysis of lignocellulose while being weakly or non-hydrolytic by themselves \[[@B1],[@B18]\]. The precise mechanism of GH61 stimulation of lignocellulose hydrolysis remains elusive, but insights from the related CBP21 that acts on insoluble chitin suggest both an oxidative and a hydrolytic step, which may result in the disruption of substrate crystallinity and increased accessibility to recalcitrant polysaccharides \[[@B19]\]. The genome of *T. reesei*appears to encode very few GH61 proteins compared to other filamentous Ascomycetes, including the phytopathogens *F. graminearum*and *M. grisea*\[[@B12]\]. Interestingly, even the genome of *Blumeria graminis*(a biotrophic phytopathogen that lacks canonical lignocellulolytic enzymes) encodes several GH61 enzymes, raising questions about the biological roles of these proteins in addition to their biotechnological applications \[[@B20]\]. Most plant-associated microbes (both pathogenic and saprophytic) that break down plant cell walls have the genetic capacity to produce enzymes for the degradation of the major structural polysaccharides found in the cell wall, namely cellulose, xylan and pectin \[[@B21],[@B22]\]. In particular, plant pathogens have intimate relationships with their hosts, requiring penetration of the cell wall and colonization of living host tissue. Many pathogenic fungi actively kill and degrade plant tissue and utilize liberated carbohydrates for growth and reproduction. Plants produce proteins to inhibit microbial CWDE as one mechanism of disease resistance, and this interaction may drive evolution of unique enzymes in phytopathogens. For example, inhibitors of pectin-degrading enzymes are common in dicots and the pectin-rich non-commelinoid monocots \[[@B23]\]. These proteins have also been reported in wheat \[[@B24]\] and rice \[[@B25]\] and may be involved in control of growth and development. More commonly found in grasses are inhibitors of xylan-degrading enzymes \[[@B26]-[@B28]\]. Following plant senescence, pathogenic fungi may continue to colonize and overwinter on dead tissue, and many plant pathogens are also competitive saprophytes \[[@B29]\]. Although it is unlikely that the differences in cell wall composition between monocots and dicots are sufficient to determine host specificity, there is some evidence that plant pathogens may produce different amounts of specific CWDE depending on whether the plant host is a monocot or dicot and whether fungi are grown on cell walls from monocots or dicots \[[@B30],[@B31]\]. Both plant pathogenic and non-pathogenic fungi could provide a rich source of CWDE to complement *T. reesei*and other industrial enzyme sources for biofuel and bioproduct production. In order to identify promising taxa with high hydrolytic activities for more detailed characterization and to evaluate whether the suite of CWDE produced by plant pathogens reflects host specificity, we have analysed the hydrolytic enzyme profiles of 156 species of fungi and oomycetes using multiple polysaccharide substrates. These substrates included purified cellulose and hemicellulose, pretreated biomass similar to materials for bio-refineries and untreated plant cell walls representing agricultural by-products and dedicated biofuel crops. Results and discussion ====================== Effect of carbohydrate source in growth media --------------------------------------------- An initial sampling of 12 phytopathogenic fungi was used to test the effect on CWDE production for three growth media with switchgrass (SG), soybean stem (SS) or Avicel as the primary carbon source. Data were collected for hydrolysis of nine different polysaccharide or biomass substrates. A full-factorial mixed-effect model was built with host (monocot or dicot), substrate and medium treated as fixed effects and isolate as a random effect. The third order interaction of host\*substrate\*medium was significant (*P*= 0.0135), as was the second order interaction of medium\*substrate (*P*= 0.0184) and the primary effect of substrate (*P*= 0.0009). For all assay substrates, extracts from fungi grown on the Avicel-based medium released either comparable amounts or fewer reducing sugars than cultures grown on SG- or SS-based media, as determined by pairwise *t*-tests of fitted data from the model (see Additional File [1](#S1){ref-type="supplementary-material"}, Figure S1). The only example where extracts from Avicel medium were noticeably more active than the SG or SS media was the case of dicot pathogens hydrolyzing filter paper (FP). However, this difference was not significant as determined by pairwise *t*-tests (*P*= 0.0822 for dicot pathogens grown on Avicel compared to SG and *P*= 0.1097 for Avicel compared to SS). When data from cultures grown on Avicel were removed and a mixed-effect model was fitted using standardized data from only biomass-based media (SG and SS), the second order interactions of substrate\*host (*P*\< 0.0001) and substrate\*medium (*P*= 0.0091) were significant. The primary effects of host (*P*= 0.1319) and medium (*P*= 0.7287) were non-significant and the effect of substrate was barely non-significant (*P*= 0.0506). Extracts from cultures grown on SG medium released more sugar than cultures grown on SS medium when tested on the two xylans \[arabinoxylan from oat (AXO) and xylan from birch (XY)\] and the two grasses \[corn stalk (CS) and SG\]. The opposite trend was seen for hydrolysis of xyloglucan (XG) and the two legumes \[alfalfa (AL) and SS\] with cultures grown on SS-based medium releasing more sugar than cultures grown on SG-based medium. Although the model found this substrate\*medium effect to be significant, pairwise *t*-tests of both standardized data and values fitted from the model were found to be non-significant. For the host\*substrate interaction, extracts from dicot pathogens were significantly more active than monocot pathogens when tested for hydrolysis of the dicot substrates XG (*P*= 0.0385), SS (*P*= 0.0017) and AL (*P*= 0.0008). Other substrate\*host interactions were not significant. The significant interaction between plant host and dicot substrates indicated preferential hydrolysis of monocot and dicot cell walls and host-specific cell wall polysaccharides depending on the host range of pathogens. This preferential hydrolysis of monocot and dicot cell walls prompted us to look at host preference using a much larger data set capturing a greater diversity of fungi. Recent proteomic studies of *F. graminearum*showed that supplementation of minimal medium with pectin resulted in a total of 13 pectinases and pectate lyases being expressed, while induction with xylan induced seven pectin-degrading enzymes and of these six were induced in both cases. For xylan-degrading enzymes, supplementation with xylan induced 14 xylanases or arabinofuranosidases. Supplementation with pectin only induced seven xylan-degrading enzymes; of these, five were also induced by xylan. When the researchers supplemented minimal medium with either dicot (carrot) or monocot (maize) cell walls, the induction of pectin and xylan degrading enzymes was much more similar. When supplemented with either dicot or monocot cell walls, 12 common pectin-degrading enzymes were detected while only two additional unique enzymes were induced by dicot cell walls and only one unique pectin-degrading enzyme by maize cell walls. Similarly, both dicot and monocot cell walls induced a common set of 22 xylan-degrading enzymes, with an additional two unique enzymes induced by monocot cell walls and only a single unique enzyme induced by dicot cell walls \[[@B32]\]. As microbial CWDE synthesis is primarily induced by low levels of simple monosaccharides, and because these sugars are found in the majority of both monocot and dicot cell walls, it is expected that both monocot and dicot cell walls will induce similar types of enzymes by microbes \[[@B22]\]. This does not rule out a minor, quantitative difference in CWDE induction profiles for monocot- or dicot-based growth media, but because we observed the effect of growth medium to be subtle and not statistically significant when SS- and SG-based media were compared, cultures for the large-scale screening were grown solely on SG-based medium. Screening of culture collections -------------------------------- A total of 348 unique isolates was tested for hydrolysis of FP, three types of hemicellulose (arabinoxylan from wheat (AXW), XY and XG), biomass from two grasses (CS and SG) and biomass from two legumes (AL and SS; see Additional File [2](#S2){ref-type="supplementary-material"}, Table S1). Most isolates were from the kingdom Fungi (344, 98.9%). Only four (1.1%) isolates were Oomycetes in the kingdom Chromista. The majority of isolates (317, 91.1%) were in the division Ascomycota, with fewer isolates from the Basidiomycota (22, 6.3%) and the Zygomycota (5, 1.4%). At the class level, most isolates were in the Sordariomycetes (190, 54.6%) and the Dothideomycetes (91, 26.1%). The most highly represented subclasses were the Hypocreomycetidae (129, 37.1%), the Pleosporomycetidae (70, 20.1%) and the Sordariomycetidae (58, 16.7%). On the order level, the Hypocreales (121, 34.8%) and the Pleosporales (70, 20.1%) were most highly represented. The families Nectriaceae (103, 29.6%), Glomerellaceae (41, 11.8%), and Pleosporaceae (37, 10.6%) contained the greatest number of isolates. The two most sampled genera were *Fusarium*(101, 29.0%) and *Colletotrichum*(41, 11.8%). Negative controls of extracts in the absence of substrate did not react with 3,5-dinitrosalicylic acid (DNS). Negative controls of substrates and buffer in the absence of hydrolytic enzymes detected small amounts of reducing sugar (less than 0.12 mg/mL) from the reaction of DNS with soluble compounds present in the mostly insoluble substrates, small amounts of contamination by fine particulate matter and decreased sensitivity of the DNS reaction at very low sugar concentrations. This background was subtracted from measured sugar values and negative values were adjusted to zero. The fungi tested showed a broad range of activity on eight substrates (see Additional File [3](#S3){ref-type="supplementary-material"}, Figure S2). *T. reesei*RUT-C30 was roughly twice as active as the top natural isolates when tested for hydrolysis of FP and SS. *T. reesei*RUT-C30 also stood out as being highly hydrolytic on the other substrates with the exception of the two xylans. Although many species were weakly or non-hydrolytic, some species exhibited activity greater or equal to *T. reesei*when assayed on either untreated biomass or xylans. Many species were represented by multiple isolates, and we observed that some isolates within a species were highly active, while others showed weaker activities. Although these studies were conducted with dried plant biomass or purified cell wall components, there have been some indications that the production of CWDE is related to fungal lifestyle, either pathogenic or saprophytic \[[@B33]\]. One possibility is that variability in CWDE activity might be related to isolate virulence. In a study of eight isolates of *Mycosphaerella graminicola*, several pathogenicity components were positively correlated with production of xylanase and pectinase *in vitro*, implying that CWDE may be key determinants of pathogenicity \[[@B34]\]. The ability of the fungus to successfully colonize plant mesophyll tissues was also strongly correlated with the production of endo-beta-1,4 xylanase activity *in planta*in a study of 26 isolates of *M. graminicola*\[[@B35]\]. Hierarchical clustering ----------------------- Ranking and ordering of species based on hydrolysis of diverse substrates is challenging since the activity on one substrate may be very different than on another. For example, *Sclerotinia sclerotiorum*was ranked third for hydrolysis of FP but 39th for hydrolysis of XY. Hierarchical clustering was used to provide a useful way to organize the moderately large dataset into meaningful groups and to identify coherent patterns. Clustering of the complete dataset (excluding *T. reesei*) identified two major groups of species (see Additional File [4](#S3){ref-type="supplementary-material"}, Figure S3). The top tier of 86 (55%) species showed moderate or strong hydrolysis of most substrates tested. A bottom tier contained 69 (45%) inactive or very weakly active species. All species tested from the genera *Bipolaris*(4), *Colletotrichum*(7), *Penicillium*(3), *Rhizoctonia*(4), *Sclerotinia*(4) and *Trichoderma*(5) were in the top tier of active isolates. The genus *Fusarium*was represented by 20 species, the greatest number of any genus. Most species of *Fusarium*(17) fell in the top tier of active species. However, three species (*F. decemcellulare*, *F. lateritium*and *F. merismoides*) were average or below average and fell in the bottom tier. Of the nine species tested within the genus *Aspergillus*, four species (*A. lineolatus*, *A. awamori*, *A. fumigatus*and *A. niger*) clustered in the active group, while five species (*A. candidus*, *A. janus*, *A. penicilloides*, *A. peyronelii*and *A. proliferans*) fell in the bottom tier. Data from the weakly active tier of species was excluded, and the top tier containing 86 species with moderate or strong hydrolytic activities was used for further analysis, revealing a cluster of 27 very highly active species (Figure [1](#F1){ref-type="fig"}). In particular, the species *F. proliferatum*, *F. oxysporum*, *A. fumigatus*, *Penicillium expansum*, *Mucor hiemalis*, *Rhizoctonia cerealis*, *S. homeocarpa*, *Cylindrocarpon didymum*, *T. viride*, *Macrophoma phaseolina*and *Penicillium*sp. had activities greater than two standard deviations from the mean for at least one of the eight substrates tested and also had high activity on most other substrates. In addition to these broadly active species, *Sclerotium rolfsii*and *Rhizopus*sp. had activity greater than two standard deviations from the mean for hydrolysis of XG and *S. sclerotiorum*had activity greater than two standard deviations from the mean for hydrolysis of FP. However, these three isolates were not extremely active across a broad range of substrates. Several species of *Fusarium*(*Fusarium*sp., *F. acuminatum*, *F. avenaceum*, *F. incarnatum*, *F. graminearum*, *F. crookwellense*, *F. moniliforme*, *F. culmorum*, *F. compactum*, *F. proliferatum*and *F. oxysporum*) clustered together and were highly active on grass cell walls and xylans, as well as being higher than average on most other substrates. Three species of *Trichoderma*(*T. viride*, *T. koningii*, and *T. harzianum*) clustered together and had very high activity on XG and good activity on other substrates. Some species, such as all four species of *Bipolaris*, had activities near or above the mean for AXW and XY, but were average or below average for other substrates. All isolates showed growth on quarter strength potato dextrose agar (PDA), but it is possible that the use of a minimal medium, based on SG where biomass is the major carbon source, may have been sub-optimal for growth of some fungi. Negative results from this study do not rule out a species as producing active CWDE. Nevertheless, these data identify numerous species that are very capable of hydrolyzing cellulose, hemicellulose and lignocellulosic biomass. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Hierarchical clustering of active species**. Heatmap showing the mean activities and clustering of 86 species of plant pathogenic and non-pathogenic fungi when assayed for hydrolysis of eight polysaccharide substrates \[XG, xyloglucan (from tamarind); FP, filter paper; AL, alfalfa; SS, soybean stems; SG, switchgrass; CS, corn stalks; AXW, arabinoxylan (from wheat); XY, xylan (from birch)\]. Weakly and inactive species were excluded. *Trichoderma reesei*RUT-C30 was excluded because of its unusual hydrolytic activities. Negative estimations of reducing sugars were adjusted to zero and data were standardized within substrates by subtracting the substrate mean and dividing by the standard deviation. Dendrogram and ordering was determined using the distance matrix computation (dist) and hierarchical clustering (hclust) functions in R. Red colors indicate values greater than the substrate mean, while blue colors indicate values less than the mean. Column Z-score and color intensity indicate how many standard deviations the species mean is from the substrate mean. :::  ::: In addition to identifying clusters of species with similar activities, the substrates also clustered showing biological significance. The two grass substrates (CS and SG) clustered together as did the two legume substrates (AL and SS). These two groups of cell walls \[grass (monocot) and legume (dicot)\] are clearly distinct from each other as reflected in hydrolysis by diverse microbes. This also indicates that some suites of enzymes produced by microbes are more suited for breaking down grass cell walls, while other suites of enzymes are more suited for breaking down legume cell walls. Both xylans tested (XY and AXW) clustered together. FP and XG did not cluster closely with any other substrates. A smaller set of top isolates was recultured and tested using a greater number of substrates and hydrolysis times. Data from a subset of isolates with the highest activity for each substrate and time were standardized within each substrate and time. The standardized values were averaged for the two timepoints, and organized using hierarchical clustering (Figure [2](#F2){ref-type="fig"}). Among the top plant pathogenic isolates, *S. homeocarpa*86-190 showed very good activity on isolated cellulose and xylans, as well as most types of grass cell wall biomass. *F. oxysporum*85-031 was above average on both untreated and pretreated grasses. The hypercellulolytic mutant, *T. reesei*RUT-C30, shows an unusual pattern of hydrolytic activity. It was highly active on the two pure cellulosic substrates tested \[FP and bacterial microcrystalline cellulose (BMCC)\] as well as the three pretreated biomass samples \[acid pretreated corn stover (PCS), acid pretreated switchgrass (PTSGA) and base pretreated switchgrass (PTSGB)\]. However, when compared with the other top isolates, *T. reesei*was the weakest isolate for hydrolysis of the three xylans (AXW, AXO, XY) and five of six types of untreated grass cell walls \[SG, eastern gammagrass/switchgrass mix (EGG/SG), big bluestem/switchgrass mix (BBS/SG), tall fescue (TF) and reed canarygrass (RC)\]. This clearly illustrates the skewed hydrolytic profile of *T. reesei*, which emphasizes cellulase production that is essential for hydrolysis of pretreated grasses where cellulose is the major component. However, high production of cellulases may result in relatively ineffective hydrolysis of the more complex and heterogeneous untreated plant cell walls in which lignin and hemicellulose may limit cellulose accessibility. For hydrolysis of untreated biomass, high xylanase activity could directly increase the amount of five carbon sugars (mainly xylose and arabinose) as well as stimulate cellulose hydrolysis, perhaps by improving cellulose accessibility. Increased hydrolysis of glucans in pretreated grass cell walls has been reported by supplementing *T. reesei*cellulases with endoxylanase, arabinofuranosidase, α-glucuronidase, acetyl xylan esterase, ferulic acid esterase and other activities \[[@B36]-[@B38]\]. Accessory enzymes that facilitate more complete utilization of plant biomass could be used to develop less energetically and chemically intensive pretreatments and allow for greater fermentable sugar recovery, especially for five carbon sugars derived from hemicellulose. ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Hierarchical clustering of top isolates and *Trichoderma reesei***. Heatmap showing mean activities and clustering of the top isolates on each substrate and *T. reesei*when assayed for hydrolysis of 14 polysaccharide substrates \[SG, switchgrass; CS, corn stalk; EGG/SG, eastern gammagrass/switchgrass mix; BBS/SG, big bluestem/SG mix; TF, tall fescue; AXW, arabinoxylan (wheat); AXO, arabinoxylan (oat), XY, xylan (birch); RC, reed canary grass; BMCC, bacterial microcrystalline cellulose; FP, filter paper; PTSGB, base pretreated SG; PTSGA, acid pretreated SG; PCS, acid pretreated corn stover\]. Each substrate was hydrolyzed for two lengths of time and the mean of those two timepoints was used for clustering. Selected isolates showed the highest activity on at least one substrate and at least one timepoint. Measured reducing sugars were standardized within substrates by subtracting the substrate mean and dividing by the standard deviation. Dendrogram and ordering was determined using the distance matrix computation (dist) and hierarchical clustering (hclust) functions in R. Red colors indicate values greater than the substrate mean, while blue colors indicate values less than the mean. Column Z-score and color intensity indicate how many standard deviations the isolate mean is from the substrate mean. :::  ::: Mixed-effect modelling for lifestyle and host specificity --------------------------------------------------------- Species identified as being weakly active when tested on most substrates in the initial clustering of all 155 species were excluded from further statistical testing (see Additional File [4](#S4){ref-type="supplementary-material"}, Figure S3). As some taxa were sampled more frequently than others (for example, *Fusarium*), a mixed-effect model was used to compare groups of fungi for lifestyle (pathogenic/non-pathogenic) and host specificity (monocot/dicot) where genus, species and isolate are treated as random effects. By treating taxonomic ranks as random, increased sampling within a taxonomic group will not affect the mean of the larger grouping (lifestyle and host specificity) but will give a more accurate estimation of variance for the group. In the top tier of 86 active species, 17 species could confidently be identified as pathogens primarily of dicots, 28 as pathogens of monocots and 16 as non-pathogenic (Table [1](#T1){ref-type="table"}). Among these, several genera (*Colletotrichum*, *Fusarium*, *Phoma*and *Sclerotinia*) included some species pathogenic on monocots and others pathogenic on dicots. The large number of pathogenic species with known host specificity and the number of species classified as non-pathogenic provides a robust data set to use mixed-effect modelling to test whether hydrolysis of plant cell walls and cell wall polysaccharides reflects a difference between pathogenic and non-pathogenic lifestyles and for pathogenic species if hydrolysis reflects host preference. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Species used for comparison of lifestyle (pathogenic or non-pathogenic) and host specificity (monocot or dicot). ::: Dicot Monocot Non-pathogenic ------------------------------- --------------------------- ------------------------- *Botrytis cinerea* *Bipolaris maydis* *Aspergillus fumigatus* *B. fuckeliana* *B. oryzae* *A. niger* *Colletotrichum destructivum* *B.sorokiniana* *Clonostachys rosea* *C. orbiculare* *B. zeicola* *Epicoccum sp.* *C. trifolii* *Colletotrichum caudatum* *Humicola fuscoatra* *Diaporthe phaseolorum* *C. graminicola* *Lentinula edodes* *Fusarium incarnatum* *C. navitas* *Mucor hiemalis* *F. oxysporum* *C. sp.* *Neurospora crassa* *F. sambucinum* *Cyathus stercoreus* *Nigrospora sp.* *F. solani* *Drechslera biseptata* *Penicillium vulpinum* *Phoma sp.* *Fusarium acuminatum* *Trichocladium asperum* *Phytophthora sojae* *F. avenaceum* *T. hamatum* *Sclerotinia minor* *F. crookwellense* *T. harzianum* *S. sclerotiorum* *F. culmorum* *T. koningii* *S. trifoliorum* *F. equiseti* *T. sp.* *Stemphylium botryosum* *F. graminearum* *T. viride* *Ulocladium cucurbitae* *F. heterosporum* *F. moniliforme* *F. proliferatum* *Fusarium sp.* *F. subglutinans* *F. tricinctum* *Phoma sp.* *Phoma zeae-maydis* *Pyricularia grisea* *Rhizoctonia cerealis* *R. zeae* *Sclerotinia homeocarpa* All species were in the top tier of 86 active isolates as determined by clustering analysis using the complete data set. This subset of species was used to test the effect of lifestyle (pathogenic/non-pathogenic) and host specificity (monocot/dicot) on hydrolysis of eight polysaccharides and plant cell walls. For testing lifestyle, three additional pathogens of woody species were also included, *Cylindrocarpon didymum*, *Fusicoccum aesculi*and *Schizophyllum commune*. ::: A mixed-effect model was fitted using lifestyle (pathogen or non-pathogen), substrate (FP, XG, XY, AXW, AL, SS, CS, SG) and the lifestyle\*substrate interaction as fixed effects. Genus, species and isolate were treated as nested random effects. Lifestyle by itself was not significant (*P*= 0.5346), but substrate (*P*\< 0.0001) and the lifestyle\*substrate interaction (*P*\< 0.0001) were highly significant, indicating that on at least one substrate there was a significant difference between activities of pathogens and non-pathogens. Pairwise *t*-tests comparing pathogens and non-pathogens for each substrate found that pathogens were more hydrolytic on six of eight substrates (*P*\< 0.005, Figure [3](#F3){ref-type="fig"}). There was no significant difference between pathogens and non-pathogens when tested on XG (*P*= 0.059) or XY (*P*= 0.08). Although more isolates of pathogenic fungi than non-pathogens were tested, treating genus, species and isolate as random effects reduced the sampling bias; these results indicate a significant trend and highlight the powerful suite of CWDE produced by many plant pathogenic fungi. Not only do pathogens often rely on CWDE for breaching the physical barrier presented by plant cell walls and rapid colonization of plant tissue, many pathogens are also capable of saprophytic growth on senesced plant tissue. Efficient CWDE may allow plant pathogens to quickly colonize dead plant material and outcompete environmental saprophytes and also provide a carbon source required for growth and reproduction. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Interactions between lifestyle (pathogenic or non-pathogenic) and substrates**. Fitted values from mixed-effect model on activity standardized within substrates. Lifestyle \[non-pathogenic (NP) or pathogenic (P)\], substrate (FP, XG, XY, AXW, AL, SS, CS, SG) and the lifestyle\*substrate interaction were treated as fixed effects; genus/species/isolate were nested random effects. Data used for this analysis included 47 species of pathogens and 16 species of non-pathogens. Non-pathogenic and pathogenic species are the same as presented in Table 1 with the addition of three pathogens of woody species, *Cylindrocarpon didymum*, *Fusicoccum aesculi*and *Schizophyllum commune*. Pathogenic species had significantly higher activity on the substrates FP, AXW, AL, SS, CS and SG as determined by pairwise *t*-tests on fitted values from the model (*P*\< 0.005). There was no significant difference on XG (*P*= 0.059) and XY (*P*= 0.08). The middle black bar at the center of the notch indicates the median value, edges of boxes indicate the interquartile range and whiskers indicate minimum and maximum values. :::  ::: A similar model to the pathogenic/non-pathogenic lifestyle model was fitted using host preference (monocot or dicot) in place of lifestyle. Both fixed effects of host (*P*= 0.0071) and substrate (*P*\< 0.0001) were significant, as was the host\*substrate interaction (*P*\< 0.0001). When pairwise *t*-tests were performed comparing pathogens of monocots and dicots on each substrate, there were significant differences in all cases (*P*\< 0.001, Figure [4](#F4){ref-type="fig"}). Pathogens of dicots showed slightly greater hydrolysis of FP, and although the difference was significant, the median value of monocot pathogens was greater than the median value for dicot pathogens. Similarly, monocot pathogens showed significantly greater hydrolysis of XY than dicot pathogens, but the interquartile ranges for the two host groups were nearly the same. However, for dicot cell walls (AL and SS) and dicot-specific hemicellulose (XG), pathogens of dicots clearly showed greater hydrolytic activity than pathogens of monocots. In contrast, for monocot cell walls (CS and SG) and monocot-specific hemicellulose (AXW), pathogens of monocots clearly showed greater hydrolytic activity than pathogens of dicots. These results provide strong evidence that among plant pathogens with the capacity to degrade plant cell walls, pathogens of monocots are better adapted for degradation of monocot cell walls while pathogens of dicots are better adapted for degradation of dicot cell walls, reflecting host preferences. ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Interactions between hosts (monocot or dicot) and substrates**. Fitted values from mixed-effect model on activity standardized within substrates. Host preference of pathogenic fungi \[dicot (D) or monocot (M)\], substrate (FP, XG, XY, AXW, AL, SS, CS, SG) and the host\*substrate interaction were treated as fixed effects; genus/species/isolate were nested random effects. Data used for this analysis included 17 species of dicot pathogens and 28 species of monocot pathogens. Dicot pathogens had significantly higher activity on the substrates FP, XG, AL and SS as determined by pairwise *t*-tests on fitted values from the model (*P*\< 0.0005). Monocot pathogens had significantly higher activity on the substrates XY, AXW, CS and SG (*P*\< 0.001). The middle black bar at the center of the notch indicates the median value, edges of boxes indicate the interquartile range and whiskers indicate minimum and maximum values. :::  ::: The observation that pathogens of monocots are better adapted for degradation of monocot cell walls may have industrial applications for the processing of mixed biomass containing a variety of plant types, including grasses and legumes. By tailoring industrial enzyme mixtures similarly to the way in which plant pathogens have evolved specialized CWDE systems for monocots and dicots, it may be possible to achieve more efficient hydrolysis of diverse biomass feedstocks. Although most lignocellulolytic fungi have the capacity to degrade most plant cell wall polysaccharides, these results provide compelling evidence for the adaptation of phytopathogens for degradation of cell walls and hemicellulose from their host of preference. A few genera were well represented with multiple species and isolates, allowing a comparison among species within a genus with multiple hosts. The genera *Colletotrichum*and *Fusarium*contain some species pathogenic on monocots and other species pathogenic on dicots. In the genus *Bipolaris*, all species tested were pathogens of monocots. When hydrolytic preferences were examined at the species level within these genera, similar results were observed when all data were considered suggesting that host specificity is reflected in hydrolytic activity at the species level within a genus. One challenge when screening an unknown pool of organisms for biological activity is capturing the greatest variation in a reasonable number of samples. In order to assess the contribution of taxonomic rank on variance in the data, a mixed-effect model was fitted for the response of standardized activity with family as a fixed effect. Genus, species and isolate were treated as nested random effects. *T. reesei*and the bottom tier of 69 weakly active species were excluded from the dataset. Based on hydrolysis of eight substrates by 248 isolates of plant pathogenic and non-pathogenic fungi from 86 species and 45 genera, taxonomic hierarchy (genus, species, isolate) accounted for roughly 42% of the total observed variance. Genus-to-genus variance contributed 5.3% to the total variance, species-to-species variance accounted for 17.8% of the total variance and isolate-to-isolate variance accounted for 18.5% of the total variance. This indicates that greater variation is seen at the species and isolate level and further screening at the sub-generic level will probably reveal significant variation. Therefore, after the identification of promising genera, further screening within the genus will probably detect a wide range in activity. Similarly, after the identification of promising species, there is still significant variation among isolates which may reveal superior candidates. This approach is warranted, particularly if a genus or species is suspected of being hyper-variable. Such variability is commonly seen when phytopathogenic isolates are examined for virulence traits \[[@B39],[@B40]\]. In *Cochliobolus carbonum*, a targeted gene knockout of a regulatory gene resulted in mutants with low levels of pectinases and other CWDE and with reduced virulence on maize, supporting that these enzymes play an important role in pathogenicity \[[@B41]\]. Virulence may be a useful selection criterion with which to identify the most promising isolates as is suggested by the relationship between the positive correlation of CWDE and measures of pathogenicity, such as lesion size and disease development \[[@B33]-[@B35]\]. This study itself does not directly explore sources of variance, however it could be due to many factors including multiple isoforms or copies of similar enzymes, variation in total production or secretion of hydrolytic enzymes and different suites of CWDE diversity. Earlier work to identify virulence factors in plant pathogens pointed to the presence of multiple forms of enzymes with similar functions, such as pectinases \[[@B33],[@B42]\], that were associated with infection of living plant tissues. Recent surveys of fungal genomes clearly indicate that these organisms are replete with many types of CWDE classes and genes \[[@B12]\]. Most pathogenic isolates tested were isolated directly from the field, and many of these isolates had comparable or higher hydrolytic activity than the engineered strain *T. reesei*RUT-C30 when tested on untreated biomass and hemicellulose. This natural diversity of CWDE could provide a large reservoir that can be further improved by engineering enzymes and strains for increased performance. Conclusions =========== The results presented here clearly illustrate that plant pathogens are promising sources in which to discover highly active CWDE that would be useful for more efficient lignocellulosic digestion. Genomic analysis of several plant pathogens indicates an abundance of CWDE, particularly when compared with *T. reesei*\[[@B12]\]. While *T. reesei*produces a CWDE system that results in efficient hydrolysis of pure cellulose and pretreated biomass, this high cellulase activity does not confer exceptional hydrolysis of untreated plant biomass. Several plant pathogens were identified as highly competent degraders of untreated biomass. Compared to *T. reesei*, many plant pathogens had higher xylanase activity and some highly active isolates had greater activity than *T. reesei*when tested on grass cell walls. Specifically, the species *F. avenaceum*, *F. incarnatum*, *F. graminearum*, *F. crookwellense*, *F. moniliforme*, *F. culmorum*, *F. compactum*, *F. proliferatum*, *F. oxysporum*, *Phytophthora sojae*, *A. fumigatus*, *P. expansum*, *M. hiemalis*, *R. cerealis*, *S. homeocarpa*, *S. sclerotiorum*, *S. trifoliorum*, *C. didymum*, *T. viride*, *T. koningii*, *T. harzianum*, *Chaetomium funicola*, *M. phaseolina*, *S. rolfsii*, *Leptodontium elatius*, as well as the unidentified species *Fusarium*sp., *Penicillium*sp. and *Rhizopus*sp. are promising candidates in which to discover highly active enzymes in one or more classes of CWDE. Although we did not test synergism directly, enhancement of *T. reesei*cellulases with crude enzyme preparations from other fungi has been documented and may lead to the identification of novel accessory enzymes for biomass hydrolysis \[[@B1],[@B17],[@B18],[@B43]\]. Any of the top candidates identified in this study would be good candidates for closely controlled synergy experiments in future work. Some of these taxa may contain novel enzymes with unique activity, such as GH61. In addition, a closer examination of the CWDE systems employed by these naturally highly active taxa may provide insights to guide the engineering of multi-enzyme cocktails based on established enzymatic activities and synergies. Pathogenic species showed greater hydrolysis than non-pathogenic species for all substrates tested except xyloglucan from tamarind and xylan from birch, on which there was no significant difference between the groups. Among pathogenic species, pathogens of monocots had relatively higher hydrolysis of monocot hemicellulose (arabinoxylan) and cell walls (corn stalk and switchgrass), while pathogens of dicots preferentially hydrolyzed dicot hemicellulose (xyloglucan) and cell walls (alfalfa and soybean stem). Together, these results show that many plant pathogenic fungi are highly competent producers of lignocellulolytic enzymes, specialized on their preferred hosts, and a promising source from which to find accessory enzymes that may complement the highly cellulolytic CWDE system of *T. reesei*. Methods ======= Cultures and growing conditions ------------------------------- A total of 348 isolates from 156 species in 93 genera were used in this study (see Additional File [2](#S2){ref-type="supplementary-material"}, Table S1). Unless noted otherwise, isolates were obtained from the New York Field Crop Pathogen Culture Collection (NYFC, Gary Bergstrom, Cornell University, Ithaca, NY, USA) or the Cornell Plant Pathology Teaching Culture Collection (CPP, David Kalb, Cornell University, Ithaca, NY, USA). Frozen stocks of spores and/or mycelium were stored in 20% glycerol at -80°C. Isolates were plated on quarter strength potato dextrose agar (PDA; 6 g potato dextrose broth (Beckton Dickinson, Franklin Lakes, NJ, USA), 16 g agarose, 1L H~2~O) and grown for seven days at 25°C. Five subcultures of each isolate were made by transferring 6 mm plugs from PDA cultures to biomass- or cellulose-based agar media modified from the ATCC cellulose medium 907 (0.5 g (NH~4~)~2~SO~4~, 0.5 g L-asparagine, 1 g KH~2~PO~4~, 0.5 g KCl, 0.2 g MgSO~4~, 0.1 g CaCl~2~, 0.5 g yeast extract, 16 g agarose, 5 g cellulose or biomass, 1 L H~2~O) in 50 mm Petri dishes. For use as the carbon source in the cellulose-based agar medium, Avicel (FMC BioPolymer, type PH-101, 50 mm, Philadelphia, PA, USA) was used. For biomass-based media, dry switchgrass (SG; *Panicum virgatum*cv. \'Blackwell\', 15 + 4 year stands, Pawling, NY, USA) and soybean stems (SS; *Glycine max*from Phil Atkins, Cornell University Department of Crop and Soil Sciences, Ithaca, NY, USA) were milled to pass through a 20 mesh screen. Cultures were grown on these media for an additional 10 days before freezing at -80°C. Cultures were then thawed and chopped into roughly 1 cm^2^pieces and extracted in 11 mL of buffer (0.1 M Na acetate, 0.02 M NaCl, 0.02% Na azide, pH 5.5) for 2 h at room temperature: 1.5 mL aliquots of extracts were placed into individual wells of 2 mL 96-deepwell plates (Eppendorf AG, Deepwell Plate 96, 2000 μL, Hamburg, Germany) and frozen at -80°C until assayed. Enzyme assays ------------- Hydrolysis of various polysaccharide substrates was conducted in 96 well microplates \[[@B44]\]. Two cellulosic substrates were used: FP (7 mm discs of Whatman No. 1 1001070, Maidstone, UK) and BMCC (CPKelco Cellulon Press Cake, K5C486-SC3 010133A, Atlanta, GA, USA). Four hemicellulosic substrates were used: XY (Sigma X0502, St. Louis, MO, USA), AXO (Sigma X0627, MO, USA), AXW (Megazyme P-WAXYI, Wicklow, Ireland) and XG (Megazyme P-XYGLN, Wicklow, Ireland). Several types of untreated biomass milled to 0.5 mm were tested: CS (*Zeae mays*from Gary Bergstrom, Cornell University Department of Plant Pathology and Plant-Microbe Biology, Ithaca, NY, USA), SG (see previous description), SS (see previous description), as well as AL (*Medicago sativa*cv. \'Oneida VR\'), RC (*Phalaris arundinacea*cv. \'Bellevue\'), TF (*Festuca arundinacea*cv. \'Bull\'), biomass from a mixed BBS/SG stand (*Andropogon gerardii*cv. \'Bonanza\'/*P. virgatum*cv. \'Cave-in-Rock\'), and from a mixed EGG/SG stand (*Tripsacum dactyloides*cv. \'Pete\'/*P. virgatum*cv. \'Cave-in-Rock\'), all of which were provided by Hilary Mayton (Cornell University Department of Plant Breeding and Genetics, Ithaca, NY, USA) unless otherwise noted. Three types of pretreated biomass were tested: dilute base pretreated SG (PTSGB; same batch of SG as previously described), dilute acid pretreated SG (PTSGA; same batch of SG as previously described) and dilute acid pretreated CS (PCS; from Daniel Schell, National Renewable Energy Laboratory, CO, USA). SG pretreatment was performed in 10 g batches. For dilute base pretreatment, a 5% SG (w/w) suspension in 1% NaOH (w/w) was incubated at 25°C and shaken at 200 rpm for 24 h. For dilute acid pretreatment of SG, a 7% SG suspension in 0.75% H~2~SO~4~was autoclaved at 121°C for 1 h. Pretreatments were neutralized afterwards. All biomass samples and BMCC were washed at least five times by centrifugation in three volumes of distilled water to remove background simple sugars prior to use in assays. Hydrolysis reactions were conducted by mixing fungal extracts in a 1:1 (v/v) ratio with 2% substrate (dry weight substrate/total volume of suspension or solution). For insoluble substrates, the total reaction volume was 180 μL and was conducted in flat-bottom microplates (Corning Life Sciences, Costar flat bottom 3370, Corning, NY, USA). Insoluble slurries were prepared in small beakers and kept under constant agitation with magnetic stir bars while pipetted by hand into microplates using truncated pipette tips (Laboratory Product Sales Inc, L111806, Rochester, NY, USA). For soluble substrates, the total reaction volume was 50 μL and was conducted in conical-bottom microplates (Eppendorf AG, 96-well twin.tec, Hamburg, Germany). Plates were sealed with aluminum sealing film (Axygen, PCR-AS-200, Union City, CA, USA) and incubated at 37°C for various times depending on the substrate and experiment, then frozen. In order to test the effect of growth medium, nine substrates were used (FP, CMC, XY, AXO, XG, SG, CS, SS, AL). Hydrolysis of AXO and XY was conducted for 1 h, XG for 2 h, CMC for 6 h, FP for 24 h and SG, CS, SS and AL for 72 h. The major screening of all 348 isolates was conducted by culturing five replicates of each isolate on SG agar. Extracts were tested for hydrolysis of eight substrates (AL, AXW, CS, FP, SG, SS, XG, XY). XY was hydrolyzed for 1 h, XG for 2 h, AXW for 10 h, FP for 24 h and SG, CS, SS and AL for 72 h. Fresh extracts from the top isolates were re-cultured and re-tested. Extracts from these cultures were tested on a broad range of substrates (AXW, AXO, XY, FP, BMCC, SG, CS, RC, TF, BBS, EGG, SGA, SGB, PCS). For each substrate, hydrolysis was stopped at two time points. AXO and XY were hydrolyzed for 1 h and 3 h, AXW for 3 h and 11 h, BMCC for 18 h and 72 h, and all other substrates for 72 h and 168 h. Carbohydrate analysis --------------------- The colorimetric assay based on 3,5-dinitrosalicylic acid (DNS) for estimating total reducing sugars was employed in a microplate format \[[@B44]-[@B47]\]. The DNS reagent was prepared by dissolving 10.6 g of DNS and 19.8 g NaOH in 1416 mL ddH~2~O, then adding 306 g Rochelle salts (NaK tartrate), 7.6 mL phenol, and 8.3 g Na metabisulphite \[[@B48]\]. DNS reagent was allowed to sit for one week prior to use. Following completion of enzymatic reactions, 50 μL of hydrolysate was carefully removed in order to avoid disturbing and pipetting any insoluble undigested substrate, and added to 100 μL of DNS solution in 96 conical-well plates (Eppendorf AG, 96-well twin.tec, Hamburg, Germany). For BMCC, plates were centrifuged to compress the non-hydrolyzed substrate prior to removal of hydrolysate. In order to minimize plate-to-plate variation, each plate contained three replicates of sugar standards in buffer for the linear range of the DNS assay (0, 0.5, 1.0, 1.5, 2.0 and 3.0 mg/mL glucose or 0, 0.5, 1.0, 1.5, 2.0 and 2.5 mg/mL xylose). Plates were sealed with silicone compression mats (Axygen, CM-FLAT, Union City, CA, USA) and heated in a thermocycler (MJResearch Inc, PTC-100, Waltham, MA, USA) for 5 min at 95°C followed by cooling and holding at 20°C. If the initial analysis of hydrolysate contained more sugar than the linear range of the DNS assay, samples were retested by a double dilution before adding DNS reagent. For analysis, 36 μL of the completed DNS reaction were diluted in 160 μL ddH~2~O in a flat-bottom microplate. Absorbencies were measured at 540 nm and sugar concentrations were calculated from a linear regression of the standards. Pipetting was either done manually using a multichannel pipettor, or was automated using an epMotion 5075 liquid handling system (Eppendorf, Hamburg, Germany). Statistical analysis -------------------- Data were analysed using the software package R (R Development Core Team, Vienna, Austria, 2009). An initial group of 12 monocot pathogens and 12 dicot pathogens were arbitrarily selected from the NYFC culture collection to represent a diversity of fungal species. Each isolate was replicated three times on each of the three media based on Avicel, SG and SS. Extracts were assayed for hydrolysis of nine substrates (AL, AXO, CMC, CS, FP, SG, SS, XG, XY). Of the initial 24 isolates selected, the 12 showing the greatest hydrolysis were selected for further analysis. These included six pathogens of grasses and six pathogens of legumes (see Additional File [2](#S2){ref-type="supplementary-material"}, Table S1). Raw data were corrected by subtracting background reducing sugars from each substrate as determined by an enzyme-free buffer blank. In order to facilitate direct comparisons among substrates, sugar concentrations were standardized within substrates by centering and scaling the data (subtracting the mean and dividing by the standard deviation). A linear mixed-effects model was fit for the response standardized activity starting with a full factorial model using the effects host (monocot or dicot), medium (Avicel, SG, SS), and substrate (FP, CMC, XY, AXO, XG, AL, SS, CS, SG) as fixed effects and isolate as a random effect. The analysis was repeated excluding data from Avicel-grown cultures. For the large-scale screening of 348 unique isolates, five cultures were extracted for each isolate. Extracts were assayed for hydrolysis of eight substrates (AL, AXW, CS, FP, SG, SS, XG, XY). The mean background sugars were subtracted from the data for each substrate and data were again centered and scaled. Data from all isolates except *T. reesei*RUT-C30 were ordered and grouped using the distance matrix computation (dist) and hierarchical clustering (hclust) functions in R. Heatmaps were generated using the function heatmap.2 in the gplots package. The package RColorBrewer was used for colorizing the heatmaps. The hypercellulolytic mutant *T. reesei*RUT-C30 was excluded from this analysis because of its unusual hydrolytic activity on cellulosic materials compared to natural isolates. In order to test the interaction of lifestyle (pathogen or non-pathogen) and host preference (monocot or dicot) with substrates, a subset of isolates was created for species in the top tier identified by clustering analysis and those which could be confidently assigned a host (monocot, dicot or non-pathogen). All pathogens of monocots were pathogens of commelinoid monocots with the exception of *F. oxysporum*f. sp. *tulipae*that is a pathogen of tulip, a non-commelinoid monocot with cell walls resembling dicots. This isolate was treated as a dicot pathogen for statistical analysis. Data were standardized by centering and scaling. A mixed-effect model was built for the response of standardized activity using the fixed effects of lifestyle or host, substrate and the interaction lifestyle\*substrate or host\*substrate. Genus, species and isolate were treated as nested random effects. The linear mixed-effects model (lme) function in the package nlme was used for all modelling. A mixed-effect model was fitted in order to test the effect of taxonomic hierarchy as a source of variation in hydrolytic activity. Data from all isolates in the top tier (excluding *T. reesei*RUT-C30) were standardized by centering and scaling. Family was treated as a fixed effect, while genus, species and isolate were treated as nested random effects. Variance components were calculated as a percentage of total variance by squaring the standard deviations of each random effect, and dividing by the total variance. Abbreviations ============= AL: alfalfa; AXO: arabinoxylan from oat; AXW: arabinoxylan from wheat; BBS/SG: big bluestem/switchgrass mix; BMCC: bacterial microcrystalline cellulose; CAZy: carbohydrate active enzyme database; CS: corn stalk; CWDE: cell wall degrading enzyme(s); DNS: 3,5- dinitrosalicylic acid; EGG/SG: eastern gammagrass/switchgrass mix; FP: filter paper; GH: glycosyl hydrolase; PCS: acid pretreated corn stover; PTSGA: acid pretreated switchgrass; PTSGB: base pretreated switchgrass; RC: reed canarygrass; SG: switchgrass; SS: soybean stem; TF: tall fescue; XG: xyloglucan from tamarind; XY: xylan from birch. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= KDW, NVN and BCK cultured the organisms for enzyme extraction and KDW isolated some of the organisms used in the study. BCK and NN performed the screening assays. BCK carried out the statistical analysis and drafted the manuscript. LPW, GCB and DMG conceived the study and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **Supplemental Figure 1**. Interactions among hosts, growth media, and substrates. Fitted values from mixed-effect model on activity standardized within substrates. Data are from six dicot (d) pathogens and six monocot (m) pathogens grown on Avicel (A), switchgrass (SG) and soybean-stem (SS) supplemented minimal media. The lower case letter on the *x*-axis label indicates pathogen host (d, m) and the upper case letters indicate growth media (A, SG, SS). Each set of plots is for nine different substrates (FP, CMC, XY, AXW, XG, AL, SS, CS, SG). The effects of host, media and substrate, as well as their interactions, were treated as fixed effects and isolate was treated as a random effect. The third order interaction of host\*substrate\*medium was significant (*P*= 0.0135), as was the second order interaction of medium\*substrate (*P*= 0.0184) and the primary effect of substrate (*P*= 0.0009). For all assay substrates, extracts from fungi grown on the Avicel-based medium released either comparable amounts or fewer reducing sugars than cultures grown on SG- or SS-based medium, as determined by pairwise *t*-tests of fitted data from the model The middle black bar at the center of the box indicates the median value, edges of boxes indicate the interquartile range and whiskers indicate minimum and maximum values. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 2 **Supplemental Table 1**. Complete list of isolates tested in this study. All isolates were tested on filter paper, xylan, arabinoxylan, xyloglucan, switchgrass, corn stalk, alfalfa and soybean stem. NYFC, New York Field Crop Pathogen Collection (Gary Bergstrom, Cornell University, Ithaca, NY, USA); CPP, Cornell Department of Plant Pathology and Plant-Microbe Biology Culture Collection (David Kalb, Cornell University, Ithaca, NY, USA); KO, Kerry O\'Donnell (USDA-ARS, Peoria, IL, USA); DG, David Geiser (Penn State University, State College, PA, USA); TZ, Tom Zitter (Cornell University, Ithaca, NY, USA); GH, Gary Harman (Cornell University, Geneva, NY, USA). A single asterisk indicates isolates used to determine effect of growth media. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 3 **Supplemental Figure 2**. Ranking of 156 species for hydrolysis of eight polysaccharides and plant cell walls. Response is presented in μM reducing sugar present in hydrolysate. Species are ranked by median values, indicated by center black bars. The edges of each box indicate the interquartile range. Whiskers indicate minimum and maximum values or 1.5 times the interquartile range of the data in the case of outliers which are represented by \'\*\'. Vertical dashed grey lines indicate minimum and maximum species medians for each substrate. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 4 **Supplemental Figure 3**. Hierarchical clustering of complete dataset, excluding *Trichodermareesei*. Heatmap showing mean activities and clustering of 155 species of plant pathogenic and non-pathogenic fungi when assayed for hydrolysis of eight polysaccharide substrates \[XG, xyloglucan (from tamarind); FP, filter paper; AL, alfalfa; SS, soybean stems; SG, switchgrass; CS, corn stalks; AXW, arabinoxylan (from wheat); XY, xylan (from birch)\]. *T. reesei*RUT-C30 was excluded from this analysis because of its unusual hydrolytic activities. Negative estimations of reducing sugars were adjusted to zero and data were standardized within substrates by subtracting the substrate mean and dividing by the standard deviation. Dendrogram and ordering was determined using the distance matrix computation (dist) and hierarchical clustering (hclust) functions in R. Red colors indicate values greater than the substrate mean, while blue colors indicate values less than the mean. Column *Z*-score and color intensity indicate how many standard deviations the species mean is from the substrate mean. ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ This work was supported by grants from the US Department of Energy and the Northeast Sun Grant. Additional support for BCK was provided by a Chemistry-Biology Interface training grant from the National Institutes of Health (NIGMS). The authors would like to thank Francoise Vermeylen and Shamil Sadigov at the Cornell Statistical Consulting Unit as well as Patrick Brown, Sean Myles and Haruo Suzuki for advice on how to analyse the data using R. Mention of a trademark, proprietary product, or vendor does not constitute a guarantee or warranty of the product by the US Department of Agriculture and does not imply its approval to the exclusion of other products or vendors that may also be suitable.

PubMed Central

2024-06-05T04:04:17.206363

2011-2-16

PMC3051900

Background ========== Epigenetic changes are one of the most common molecular modifications in cells \[[@B1]-[@B4]\]. Among different epigenetic changes, DNA methylation, the addition of a methyl group (CH~3~) to the 5\'s cytosine (C) at a CpG site, plays an important role in gene expression regulation, transposons silencing, and transcription factor binding inhibition \[[@B5]-[@B13]\]. Therefore, DNA methylation has significant implications in both normal biology and complex diseases, such as cancer. In fact, DNA methylation patterns change during tumor growth. These changes may include regional or genome-wide gain or loss of methylation \[[@B14]\]. The gain of methylation in cancer is called hypermethylation, that is, there are more methylation signals in cancerous cells than in normal cells. On the other hand, the loss of methylation in cancer is called hypomethylation, that is, there are fewer methylation signals in cancerous cells than in normal cells. Numerous studies have reported that DNA hypermethylation may cause tumor suppressor gene silencing \[[@B15],[@B16]\]. These abnormal DNA methylations usually occur at CGIs, genomic regions rich in CpG sites. In order to gain an understanding of how genome-wide (especially CGI) methylation changes affect tumor growth, numerous microarray protocols have been developed to simultaneously assay the methylation status of all or partial regions in the whole genome. Most of these microarray protocols are developed based upon one of the following three methods of methylation-dependent treatment of DNA, each with its advantages and disadvantages \[[@B16]\]: (1) using methylation sensitive enzymes (such as HpaII and HinpI) to digest DNA, (2) using specific antibodies or methyl-binding proteins to obtain DNA fragments enriched with methylation signals, and (3) using sodium bisulfite to treat denatured DNA to convert unmethylated cytosine (C) to thymine (T). In our group, the DMH protocol has been developed to simultaneously assay the methylation status of all known CGIs \[[@B17],[@B18]\] using methylation sensitive enzymes HpaII and HinpI to digest DNA. As opposed to the earlier DMH protocol in which interrogated samples were hybridized onto CGI clone arrays with printed probes averaging 870 bp in length, the current DMH method assays the sample using CGI tiling arrays with much shorter probes (45 - 60 bp). Probe affinity, PCR effects, and many other measurable and unmeasurable confounding factors due to shorter probe length affect the observed methylation signals \[[@B19]\]. Previous DMH methylation microarray data analysis methods either propose an arbitrary log ratio cut off of 1.5 to detect differential methylation \[[@B20]\] or focus on modeling differential methylation at the probe level \[[@B21]\]. Due to the large impact of probe affinity and many confounding factors, a single high log ratio probe may not represent true biological signals. Furthermore, it can be misleading to select differentially methylated promoter regions based on independent probe signals. In addition, we are more interested in identifying hypermethylated regions as opposed to local changes detected by a difference in a single probe. To meet these biological interests and needs, we propose the use of a quantile regression model \[[@B22]\] in order to aggregate CGI probe signals for the identification of hypermethylated regions. Probe effects are directly incorporated into this proposed model. Genes with hypermethylated promoters can be easily selected according to their associated CGIs. The idea of using a quantile regression model to identify methylated CGIs was originally presented by our group as a poster at the 4th International Symposium on Bioinformatics Research and Applications. In that poster, we used a quantile regression model at 75% quantile. Although known methylated and unmethylated genes can be identified, we were unsure whether 75% would turn out to be the best quantile level. In the following sections, we first give a brief introduction to our breast cancer cell line and ovarian cancer microarray data. We then explain how to use a quantile regression model to identify hypermethylated CGIs. Finally, we implement quantile regression models at different quantile levels and compare the performance of these models using three statistical measurements. Methods ======= We use two DMH microarray datasets generated from 40 breast cancer cell lines and 26 ovarian cancer patients. In particular, we use the 2-color 244K Agilent arrays hybridized with the test samples (e.g. the breast cancer cell lines) dye coupled with Cy5 (red) and a common normal reference dye coupled with Cy3 (green). The base two log ratio of red over green intensity, log~2~(Cy5/Cy3), is used as the observed methylation signal at each probe. For each array, dye effects are corrected using the standard within array LOESS normalization in the Bioconductor package \"limma\" \[[@B23]\]. We have explored several normalization methods and found that the standard LOESS normalization produces more consistent and reliable results than the others (data not shown). In a common DMH experiment, it is desirable to identify CGIs that are hypermethylated in a large percentage of the total N samples (e.g., N cancer patients or N cancer cell lines). Therefore, one important goal of our DMH microarray study is to identify the CGIs that are commonly methylated in N samples (N = 40 for breast cancer data and N = 26 for ovarian cancer data). In order to control the noise due to measured and unmeasured factors such as GC content, scanner effects, and PCR effects that may affect the signals, we apply the following quantile regression model to each CGI: $$Q_{\text{Ysp}}\,(\tau|sample_{s},\, probe_{p}) = sample_{s}(\tau) + probe_{p}(\tau)$$ where Q~Ysp~(τ\|*sample~s~, probe~p~*) is the τ-th conditional quantile of the observed probe log ratio of sample *s*at probe *p*, *sample~s~*represents the expected signal from the sample, and *probe~p~*denotes the probe effect. In the above quantile regression model, error terms are assumed to be independent and distribution-free. The regression coefficients, especially *sample~s~*and *probe~p~*, are estimated by formulating the quantile regression problem as a linear program \[[@B22]\]. In fact, both parameter estimation and inference are conducted using the R package \"quantreg\" \[[@B22]\]. An example of using this package to fit a quantile regression model for one CpG island has been provided (see Additional file [1](#S1){ref-type="supplementary-material"}). In the above regression model, we let τ = 95%, 90%, 85%, 80%, 75%, 70%, 65% and 60%. We choose quantile levels over 50% because we are interested in identifying hypermethylated regions. In particular, for each sample (or cell line) effect from the quantile regression output, there is a p-value indicating whether a sample (or cell line) shows significant methylation signals at one particular CGI under the null hypothesis that *sample~s~(τ) =*0. The methylation level at each CGI is taken as the number of samples for which their associated p-values are less than a certain cutoff value p~0~where we let p~0~= 0.05, 0.04, 0.03, 0.02, and 0.01. For example, if a CGI has p-values less than 0.01 in 38 out of 40 breast cancer arrays, this indicates that this CGI may have very strong methylation signals across many samples. In order to verify that our quantile regression model can identify the real methylation signals and to compare the results of our regression models at different quantile levels, we use known methylated and housekeeping genes as \"positive\" and \"negative\" controls respectively. In fact, 30 known hypermethylated genes \[[@B24]-[@B27]\] have been reported for breast cancer, and 32 known hypermethylated genes have been reported for ovarian cancer \[[@B28]\]. For both breast and ovarian cancer, 47 housekeeping genes \[[@B29]\] are selected as \"negative\" control (i.e., known unmethylated genes) due to their low methylation signals. Recall that the methylation score given to each CGI is the count of samples with p-value less than a cutoff point. At each p-value cutoff point p~0~, we have a methylation score for each CGI. Then, there are N~m~and N~HK~methylation scores with N~m~= 30 for breast cancer data, N~m~= 32 for ovarian cancer data, and N~HK~= 47 for unmethylated housekeeping genes. We choose these N~m~and N~HK~genes because each of them is associated with at least one CGI. Therefore, this paper will refer to these genes as N~m~methylated and N~HK~unmethylated CGIs. In order to determine if known methylated and unmethylated CGIs are identified correctly, we use three different statistical measurements for known methylated and unmethylated CGIs. The first measurement is the area under a Receiver Operating Characteristic (ROC) curve, which we call \"AUC\" (Area Under Curve). A ROC is a graphical plot of the sensitivity vs. (1 - specificity) for a binary classifier system as its discrimination threshold varies. The ROC can also be represented equivalently by plotting true positive rates (TPR) vs. false positive rates (FPR). In this paper, the TPR is the fraction of known methylated CGIs that are correctly classified as methylated CGIs at a specific methylation score level C~0~(0 ≤ C~0~≤ N). The FPR is the fraction of known unmethylated housekeeping CGIs that are incorrectly classified as methylated CGIs at a specific methylation score level C~0~. The second measurement is the mean difference of methylation scores of two groups. We call this measurement mean.diff, that is ${\overline{x}}_{m} - {\overline{x}}_{HK}$, where ${\overline{x}}_{m}$ and ${\overline{x}}_{HK}$ are mean methylation scores for known methylated and unmethylated housekeeping CGIs. The third measurement is the mean difference of methylation scores of two groups of CGIs divided by their standard deviation. That is,$\frac{{\overline{x}}_{m} - {\overline{x}}_{HK}}{\sqrt{s_{m}^{2}/N_{m}^{} + s_{HK}^{2}/N_{HK}^{}}}$, where ${\overline{x}}_{m}$, ${\overline{x}}_{HK}$, $s_{m}^{2}$ and $s_{Hk}^{2}$ are the mean and variance of methylation scores for known methylated and housekeeping CGIs respectively, we call this measurement \"T.stat\". At each quantile level τ, the larger a statistical measurement is, the more evident that this quantile level is better at identifying methylated and unmethylated CGIs. Results ======= Using both breast and ovarian cancer data sets, we compare the performance of the proposed quantile regressions using three different measurements: AUC, mean.diff and T.stat. All comparison results are listed in Tables [1](#T1){ref-type="table"}, [2](#T2){ref-type="table"}, [3](#T3){ref-type="table"}, [4](#T4){ref-type="table"}, [5](#T5){ref-type="table"} and [6](#T6){ref-type="table"} with Tables [1](#T1){ref-type="table"}, [2](#T2){ref-type="table"} and [3](#T3){ref-type="table"} for breast cancer data and Tables [4](#T4){ref-type="table"}, [5](#T5){ref-type="table"} and [6](#T6){ref-type="table"} for ovarian cancer data. To have a clear view of these tables, we have plotted the summary result for each table in Figure [1](#F1){ref-type="fig"}, where the top three plots are for the three measurement results based on breast cancer data, and the bottom three plots are for the three measurements based on ovarian cancer data. For all three measurements, the larger a statistical measurement is, the better that a quantile regression model is at identifying the two different groups of CGIs (methylated and unmethylated). In Figure [1](#F1){ref-type="fig"}, we can see consistent patterns in all three measurements for both breast and ovarian cancer data. That is, 90% (cyan), the 85% (dark green), and 80% (red) are the top 3 lines and these three lines have relatively small variations across different p-values. Therefore, we can conclude that any τ between 80% and 90% could serve well to identify two different groups of CGIs (methylated and unmethylated). We recommend 85% for convenience. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Breast cancer AUC measurement table ::: ------- ------------ ------------ ------------ ------------ ------------ `τ` `P < 0.01` `p < 0.02` `p < 0.03` `p < 0.04` `p < 0.05` `95%` `0.865` `0.843` `0.839` `0.839` `0.845` `90%` `0.846` `0.843` `0.840` `0.849` `0.850` `85%` `0.849` `0.847` `0.846` `0.848` `0.855` `80%` `0.868` `0.851` `0.849` `0.849` `0.849` `75%` `0.837` `0.825` `0.832` `0.833` `0.843` `70%` `0.797` `0.779` `0.788` `0.821` `0.835` `65%` `0.753` `0.747` `0.746` `0.754` `0.762` `60%` `0.645` `0.669` `0.670` `0.676` `0.681` ------- ------------ ------------ ------------ ------------ ------------ The first column contains the quantile levels. The second column contains a sub-table with each sub-column corresponding to the AUC measurement based on a specific p value and each sub-row corresponding to one quantile level. Bold numbers are the five largest AUC values in this table. ::: ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### Breast cancer mean.diff measurement table ::: ------- ------------ ------------ ------------ ------------ ------------ `τ` `P < 0.01` `p < 0.02` `p < 0.03` `p < 0.04` `p < 0.05` `95%` `13.550` `11.197` `10.187` `9.277` `8.788` `90%` `17.497` `16.955` `15.899` `15.312` `14.515` `85%` `16.030` `16.936` `17.191` `17.357` `17.309` `80%` `13.114` `14.165` `14.837` `15.312` `15.694` `75%` `9.386` `10.770` `11.798` `12.317` `13.143` `70%` `5.732` `6.981` `7.860` `9.204` `9.818` `65%` `3.548` `4.589` `5.187` `5.528` `5.765` `60%` `1.682` `2.156` `2.618` `2.972` `3.395` ------- ------------ ------------ ------------ ------------ ------------ The first column contains the quantile levels. The second column contains a sub-table with each sub-column corresponding to the mean.diff measurement based on a specific p value and each sub-row corresponding to one quantile level. Bold numbers are the five largest mean.diff values in this table. ::: ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### Breast cancer T.stat measurement table ::: ------- ------------ ------------ ------------ ------------ ------------ `τ` `P < 0.01` `p < 0.02` `p < 0.03` `p < 0.04` `p < 0.05` `95%` `6.939` `5.946` `5.549` `5.311` `5.213` `90%` `6.680` `6.816` `6.786` `6.869` `6.790` `85%` `6.110` `6.443` `6.586` `6.826` `7.097` `80%` `5.463` `5.749` `5.982` `6.172` `6.241` `75%` `4.810` `5.037` `5.259` `5.482` `5.740` `70%` `4.254` `4.313` `4.472` `4.938` `5.147` `65%` `3.780` `3.637` `3.796` `3.938` `4.005` `60%` `2.686` `2.774` `2.787` `2.872` `2.941` ------- ------------ ------------ ------------ ------------ ------------ The first column contains the quantile levels. The second column contains a sub-table with each sub-column corresponding to the T.stat measurement based on a specific p value and each sub-row corresponding to one quantile level. Bold numbers are the five largest T.stat values in this table. ::: ::: {#T4 .table-wrap} Table 4 ::: {.caption} ###### Ovarian cancer AUC measurement table ::: ------- ------------ ------------ ------------ ------------ ------------ `τ` `P < 0.01` `p < 0.02` `p < 0.03` `p < 0.04` `p < 0.05` `95%` `0.808` `0.800` `0.807` `0.808` `0.796` `90%` `0.822` `0.821` `0.815` `0.815` `0.809` `85%` `0.823` `0.821` `0.824` `0.823` `0.820` `80%` `0.826` `0.846` `0.836` `0.819` `0.812` `75%` `0.815` `0.818` `0.802` `0.791` `0.796` `70%` `0.774` `0.769` `0.784` `0.780` `0.774` `65%` `0.754` `0.759` `0.749` `0.754` `0.766` `60%` `0.712` `0.714` `0.672` `0.687` `0.671` ------- ------------ ------------ ------------ ------------ ------------ The first column contains the quantile levels. The second column contains a sub-table with each sub-column corresponding to the AUC measurement based on a specific p value and each sub-row corresponding to one quantile level. Bold numbers are the five largest AUC values in this table. ::: ::: {#T5 .table-wrap} Table 5 ::: {.caption} ###### Ovarian cancer mean.diff measurement table ::: ------- ------------ ------------ ------------ ------------ ------------ `τ` `P < 0.01` `p < 0.02` `p < 0.03` `p < 0.04` `p < 0.05` `95%` `8.122` `7.071` `6.564` `5.870` `5.414` `90%` `11.339` `10.331` `9.459` `8.942` `8.229` `85%` `11.022` `11.119` `11.099` `10.734` `10.453` `80%` `9.226` `9.966` `10.166` `9.909` `9.969` `75%` `6.922` `8.138` `8.270` `8.589` `8.878` `70%` `5.320` `6.301` `6.908` `7.119` `7.310` `65%` `2.991` `3.579` `4.092` `4.326` `4.745` `60%` `1.745` `2.407` `2.369` `2.521` `2.682` ------- ------------ ------------ ------------ ------------ ------------ The first column contains the quantile levels. The second column contains a sub-table with each sub-column corresponding to the mean.diff measurement based on a specific p value and each sub-row corresponding to one quantile level. Bold numbers are the five largest mean.diff values in this table. ::: ::: {#T6 .table-wrap} Table 6 ::: {.caption} ###### Ovarian cancer T.stat measurement table ::: ------- ------------ ------------ ------------ ------------ ------------ `τ` `P < 0.01` `p < 0.02` `p < 0.03` `p < 0.04` `p < 0.05` `95%` `5.673` `5.295` `5.177` `4.889` `4.758` `90%` `6.378` `6.134` `5.953` `5.958` `5.656` `85%` `6.253` `6.258` `6.290` `6.293` `6.308` `80%` `5.772` `6.194` `6.272` `6.044` `6.010` `75%` `4.906` `5.451` `5.523` `5.616` `5.699` `70%` `4.400` `4.671` `4.962` `5.002` `5.132` `65%` `3.712` `3.949` `4.134` `4.075` `4.307` `60%` `3.302` `3.395` `2.967` `3.065` `3.024` ------- ------------ ------------ ------------ ------------ ------------ The first column contains the quantile levels. The second column contains a sub-table with each sub-column corresponding to the T.stat measurement based on a specific p value and each sub-row corresponding to one quantile level. Bold numbers are the five largest T.stat values in this table. ::: ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Comparisons of quantile regression models at different quantile levels**. We compare results of different quantiles by studying their performances on identifying two different groups of CGIs (methylated and unmethylated). The legend is: \"brown\" for τ = 95%, \"cyan\" for τ = 90%, \"dark green\" for τ = 85%, \"red\" for τ = 80%, \"green\" for τ = 75%, \"blue\" for τ = 70%, \"black\" for τ = 65%, and \"purple\" for τ = 60%. The top panel contains three plots for breast cancer data while the bottom panel contains three plots for ovarian cancer data. :::  ::: In order to determine if our quantile regression model is better than other available methods, we compare our method with the previous one that uses a 1.5 cutoff value at a probe level \[[@B20]\] using our breast cancer data. A single probe with a large log ratio is not reliable, so we consider the following cases in each CGI: (1) at least 30% of probes with log ratios greater than 1.5, (2) at least 50% of probes with log ratios greater than 1.5, and (3) 100% probes (that is, all probes) with log ratios greater than 1.5. For the above three cases, the AUC is 0.51, 0.52, and 0.50. These small AUCs are mainly due to the fact that some methylated CGIs or genes do not necessarily have many probes with log ratios greater than 1.5. In fact, they are more likely to have several probes with relatively large but less than 1.5 log ratios. We see this pattern very often in our data. As for the first case, only 3 out of 30 known methylated genes and 4 out of 47 HK genes have at least one cell line with more than 30% probes that have log ratios greater than 1.5. As for the second case, only 2 out of 30 known methylated genes and 1 out of 47 HK genes have at least one cell line with more than 50% probes that have log ratios greater than 1.5. As for the third case, 0 out of 30 known methylated genes and 0 out of 47 HK genes have at least one cell line with 100% (i.e., all) probes that have log ratios larger than 1.5. Therefore, our quantile regression method is certainly much better than the one that uses 1.5 as a cutoff. In addition, the 1.5 cutoff method may work well for our previous version DMH protocol that has longer printed probes (about 870 bp). However, this arbitrary cutoff method does not work for the current protocol that uses much shorter probes (45 \~60 bp). Discussion ========== The three measurement plots of breast and ovarian cancer data have slightly different patterns. This may be due to the sample differences between the two datasets. Breast cancer data are generated from cell lines while ovarian cancer data are generated from patients. The breast cancer cell line samples are more homogeneous than ovarian patient samples. In addition, cancer cell lines appear to have more methylation than cancer patients. Furthermore, breast cancer data have 40 arrays and ovarian cancer data have 26 arrays. This sample size difference may also explain some inconsistencies between breast and ovarian cancer data at different quantile levels due to random variability. We also observe that the results of the three proposed measurements show slightly inconsistent patterns. This may be due to the definition of the three measurements. AUC and T.stat both consider the variations of methylation scores. However, mean.diff only considers the difference of mean methylation scores between methylated CGIs and unmethylated housekeeping CGIs. Therefore, the result of AUC and T.stat may be more reliable. Conclusions =========== In this paper, we have proposed to use a quantile regression model to identify hypermethylated CGIs. In particular, we have incorporated probe effects to take into consideration the noises from unmeasurable factors. In order to find out at which quantile levels (95%, 90%, 85%, 80%, 75%, 70%, 65%, and 60%) the proposed quantile regression model is better at identifying known methylated and unmethylated CGIs, we have introduced three statistical measurements: AUC, mean.diff, and T.stat. These measurements show that the quantile level between 80% and 90% might serve well for identifying methylated and unmethylated CGIs. Although this paper has only demonstrated how to identify hypermethylated CGIs by setting quantiles larger than 50%, our quantile regression model can also be used to identify hypomethylated CGIs with quantiles smaller than 50%, if desired. Authors\' contributions ======================= SS and ZC developed and implemented the models, performed all statistical analyses, and drafted and revised the manuscript. PSY and YWH were involved in the data collection and helped in preparation of the manuscript. THMH oversaw the project and revised the manuscript. SL provided suggestions on the project and revised the manuscript. All authors have read and approved the final document. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **R code for fitting a quantile regression model**. This file gives an example of using the R package \"quantreg\" to fit a quantile regression model to identify methylation signals in one CpG island. ::: ::: {.caption} ###### Click here for file ::: Acknowledgements and Funding ============================ This work was supported by the National Science Foundation 0112050 while SS was a postdoctoral researcher at the Mathematical Biosciences Institute, The Ohio State University. The authors thank Drs. Terry Speed and Dustin Potter for valuable suggestions and discussions.

PubMed Central

2024-06-05T04:04:17.211397

2011-2-15

PMC3051901

Background ========== Alternative splicing -------------------- Alternative splicing (AS) is an important mechanism implicated in eukaryotic gene expression, whereby exon segments of precursor-mRNA transcripts are joined together in different arrangements. In contrast to constitutive splicing, where all exons of a gene are joined together in a single fixed composition, AS is thus a mechanism which generates distinct mature mRNA transcripts from the same gene by variable use of splice sites. Many different types of AS events are known so far. The most common types are exon skipping, intron retention and the alternative usage of 5\' or 3\' splice sites. Exon skips have been shown to be the most prevalent type in mammals, whereas intron retentions account for most AS events in plant systems, such as *A. thaliana*\[[@B1]-[@B3]\]. Accumulating evidence suggests that in many instances the generation of alternative isoforms of a gene is not just transcriptional noise, but a specifically regulated process of physiological importance, as it, for instance, substantially contributes to the structural and functional diversification of cell types \[[@B4]\]. Consistent with this view, several studies of AS in different organisms reported that AS events may undergo differential regulation between tissues, i.e., the ratios of alternative transcript isoforms were observed to vary across tissues \[[@B5],[@B6]\]. This suggests that tissue-specific differential splicing plays a major role in the evolution of specialized cell and tissue types \[[@B7],[@B8]\]. Moreover, misregulation of AS may give rise to pathophysiological processes and has been associated with human diseases, such as cancer \[[@B9]\], cystic fibrosis \[[@B10]\], and many others \[[@B11]\]. Since AS has been extensively studied in mammals, but to a notably lesser extent in plants, we focused on the well-established model organism *A. thaliana*for investigating the regulation and prevalence of AS in plants. Environmental stresses have been found to impact AS in plants, and novel transcript isoforms appearing under biotic or abiotic stresses have been reported \[[@B3],[@B12]-[@B14]\]. Stress-induced AS is supposed to be mediated by altered levels, localization, or phosphorylation status of splicing factors \[[@B3]\]. Consequently, levels of mRNA isoforms change or new splice variants appear. This regulatory mechanism enables sessile plants to adapt their transcriptome in response to substantial environmental changes. Cold and heat stress, for instance, have been shown to result in altered splicing of SR protein pre-mRNAs \[[@B15],[@B16]\], which are known to act as splicing factors that in turn affect alternative splicing of pre-mRNAs at a more global level. However, the whole complexity of the interaction network underlying stress-regulated AS events still remains to be elucidated by experimental and computational in-depth studies of AS in plants. Large-scale studies of AS are either based on sequencing mRNA transcripts or on the inference of AS events from splicing sensitive microarrays. Sequencing approaches are typically based on a mapping of expressed transcripts (e.g. ESTs, cDNAs or deep sequencing reads) to the genomic sequence of the studied organism using a spliced alignment algorithm, such as BLAT \[[@B17]\]. Array-based approaches utilize microarray platforms which are purpose-built for the highly parallel quantitative profiling of alternative transcript isoforms on a genome-wide level. Unless very deep sequencing of transcriptomes becomes a routine and affordable, splicing-sensitive microarrays are still a viable alternative for detecting and profiling transcript isoforms\[[@B18]\]. Splicing-sensitive microarray platforms --------------------------------------- Since microarrays commonly used for gene expression profiling do not generally allow to accurately detect AS events, special array platforms have been developed for the characterization of transcript isoform variation. Most of them can be assigned to one of the following categories: tiling arrays, exon arrays and exon junction arrays \[[@B19]\], each of which comes with its own advantages and limitations. Exon or exon junction arrays as well as tiling arrays enable *de novo*discovery of new transcript isoforms. One distinguishing feature of tiling arrays is that they are unbiased, as the tiling probes are designed independently of genome annotations. To measure the expression of individual isoforms relative to the overall expression of a gene, microarrays comprising both exon body as well as isoform-specific exon junction probes, have been widely used \[[@B6],[@B8]\]. The design of these arrays is often focused on a particular gene set of interest. In contrast to that, tiling arrays typically interrogate the whole non-repetitive portion of a genome with equally spaced probes, a design which is particularly suited for compact genomes, such as that of *A. thaliana*. Moreover, in contrast to exon arrays, which are mostly limited to monitoring exon skips and alternative 5\' and 3\' splicing owing to their probe design, tiling probes complementary to intronic regions enable the discovery of intron retention events, which account for more than 50% of the known AS events in *A. thaliana*\[[@B2]\]. Theoretically, all types of AS are detectable from tiling arrays, but in practice, probe density is a limiting factor. For instance the detection of alternative 3\' or 5\' splice site selection is very difficult with the Arabidopsis Tiling Array 1.0R by Affymetrix, because a substantial fraction of these events can only be detected from changes in a single probe set (44% of the ones annotated in TAIR7). Methods for the analysis of splicing microarray data ---------------------------------------------------- Previous array-based approaches aiming at global analysis of AS in diverse organisms are mostly unsupervised and typically based on statistical testing. The widely used method MIDAS <http://www.affymetrix.com/support/technical/whitepapers/exon_alt_transcript_analysis_whitepaper.pdf>, which is part of the freely available R/Bioconductor package exonmap, \[[@B20]\] is based on the assumption that the signal level of an exon relative to the overall gene signal level is constant over samples for constitutively spliced exons. However, in the presence of AS significant differences in the logarithmized ratio of normalized exon and gene levels, which is referred to as splicing index, can be detected over samples using an ANOVA test. MADS is an algorithmically similar approach which is also based on splicing indices \[[@B21]\]. The main difference to MIDAS, which computes p-values on probeset-level, is that MADS performs the statistical test for the detection of differential splicing indices across samples on the probe-level and performs the summarization over probes afterwards. Purdom *et al*. developed another unsupervised method for the detection of AS from exon arrays, which is called FIRMA \[[@B22]\]. FIRMA extends the very popular robust multi-chip analysis (RMA) model. AS events are in essence inferred from high residuals of individual exon probe sets in the base RMA gene-expression model, since these indicate a high deviation of the observed from the expected signal level of an exon. All of the above-mentioned methods are based on the assumption that the expression level of single exons is equal to the overall gene expression level in the absence of alternative splicing, and consequently exon skips are inferred based on deviations from this behavior. However, a recent study reported that in practice a technical bias of exon array platforms leads to a dramatic overestimation of AS in the presence of differential gene expression. To correct for this bias, the authors developed the method COSIE, which adjusts splicing indices using a non-linear model that incorporates probeset-specific response characteristics and saturation effects \[[@B23]\]. All of these computational methods were developed for the analysis of data from exon (junction) arrays, and in practice they cannot easily be applied to tiling array platforms. Conceptually, however, many of their modeling approaches are applicable to tiling arrays as well. Most notably, the concept of relating the hybridization pattern of an exon or intron, for which AS is to be tested, to those of surrounding exons and introns in the same gene can be transferred to tiling arrays. One of the first approaches for tiling array-based inference of AS was developed by Ner-Gaon *et al*. \[[@B24]\]. It discovers retained introns based on untypically high hybridization signals. Specifically, hybridization intensities measured for individual introns of a gene are related to each other and to the mean exonic signal level by means of a one-way ANOVA test. Building on the key concept common to many of the above-mentioned methods that the hybridization pattern of a putatively skipped exon is expected to be dissimilar to those of surrounding exons (and likewise that retained introns deviate from the typical intron hybridization pattern), we developed a method for tiling array data which uses a new principle of inference. Instead of employing a statistical test, our method is based on supervised learning, and specifically makes use of well-studied Support Vector Machine (SVM) classifiers (see \[[@B25],[@B26]\] and references therein). In contrast to the unsupervised testing approaches, our method is trained on known AS events obtained from EST/cDNA databases or genome annotations. It proceeds in two steps: First, we predict single-sample confidence scores measuring the inclusion level of an exon or intron in the mature mRNA transcripts of a gene. In a second step, we integrate these confidences across samples to predict all-sample confidence scores for alternative splicing. Results ======= We focused on two types of alternative splicing (AS) events, namely exon skips (ES) and intron retentions (IR), which can be detected sufficiently accurately with the given tiling array resolution. A supervised machine learning approach for the identification of IR and ES requires a set of \"labeled data\", i.e., exons and introns which are known to be subject to AS or not. Such labeled data are needed for the training of classifiers, and provide a reference for the evaluation of the prediction accuracy and comparisons of different detection methods. Owing to extensive previous work, several thousand AS events have been annotated and confirmed by EST and cDNA sequences \[[@B27],[@B28]\]. As the SVM classifiers had to distinguish alternative from constitutive splicing, we also collected examples which are unlikely to be alternatively spliced. However, despite the existence of several AS databases and continuous improvements of gene annotations \[[@B29],[@B2],[@B27]\], it remains a challenging task to assess for exons and introns which are not annotated as alternatively spliced, whether alternative isoforms may exist, but have not yet been sequenced. Arguably, exons or introns which are confirmed by many sequenced transcripts, none of which reveals an alternative isoform, are the best candidates for true constitutive splicing events \[[@B30]\]. AS confirmed by EST and cDNA sequences -------------------------------------- After aligning ESTs and cDNAs to the genome and inferring exon-intron structures (see Methods), we obtained confirmation counts for each exon and intron as the number of sequenced transcripts confirming both adjacent splice sites. To account for the higher quality of full-length cDNAs, we counted them twice. Based on these confirmation counts, we compiled a high-confidence sequence-confirmed splicing (SCS) data set as follows. As positive examples, it contains 762 IR and 173 ES events for which each isoform was found in at least two sequenced transcripts. To obtain a ratio between alternative and constitutive splicing that reflects current knowledge about the prevalence of AS in the *A. thaliana*genome \[[@B2],[@B31]\], we included 14,492 constitutive exons and 13,132 constitutively spliced introns. These negative examples were sampled from exons and introns with confirmation counts greater or equal to 5, for which no alternative transcript had been sequenced. On average, constitutive exons and introns in the SCS set are confirmed by 15 and 19 sequenced transcripts, respectively. The composition of the exon and intron SCS data sets is available as supplemental material from Additional File [1](#S1){ref-type="supplementary-material"} and [2](#S2){ref-type="supplementary-material"}, respectively. A supervised two-stage approach for the identification of AS ------------------------------------------------------------ In this work, we developed a supervised two-stage approach for the detection of IR and ES events from tiling array data (Figure [1](#F1){ref-type="fig"}). At the core of the first stage, a set of support vector machine (SVM) classifiers distinguish exons from introns, based on features derived from their hybridization patterns and their relative position in the spliced transcript. We employed these exon-intron classifiers to decide for each tissue or stress treatment in isolation whether a given mRNA segment (i.e., an exon or intron) is included or excluded in a mature mRNA transcript under this condition. This step is based on the assumption, that all included mRNA segments (i.e., constitutive exons and retained introns) show similar hybridization patterns, which can accurately be distinguished from those of excluded mRNA segments (i.e., constitutive introns and skipped exons). Subsequently, the resultant SVM scores were transformed into probabilistic confidences indicating the inclusion probability of a given exon or intron in the mature mRNA transcripts of a gene for a given condition. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Workflow of the AS detection method and exemplary gene with observed hybridization profile**. (A) Workflow of the supervised two-stage AS detection method. In the first stage, SVMs are employed to classify a given gene segment as an exon or intron, based on the hybridization signal observed in a single sample. The resulting SVM scores are transformed to probabilistic confidences to estimate the probability that this segment is included in mature mRNA transcripts. In the second stage, these inclusion probabilities are combined across samples by another SVM classifier to detect alternative splicing. (B) Example gene with hybridization data. The figure illustrates the annotated structure and measured hybridization data for the anti-fungal resistance gene RLM3 (AT4G16990), which was among the top 1% in our genome-wide screen. The logarithmized probe intensities for different samples are plotted against the relative genomic positions of the probes. The highlighted intron shows a characteristic hybridization pattern for differential alternative splicing. :::  ::: Clearly, the difficulty of the exon-intron classification task, solved in the first stage, varies from gene to gene depending on the expression level, as the difference between the hybridization signals of intronic and exonic probes increases with gene expression. To alleviate the expression-dependent differences of exonic and intronic signal levels, we employed a meta-classifier, consisting of *M*= 10 SVM classifiers, each of them specialized to a certain range of expression values. These ten SVM classifiers were independently trained on hybridization patterns corresponding to exons and introns not included in the SCS data set and posterior class probabilities estimated (see Methods). We verified that this meta-classifier consisting of several expression-specific SVM classifiers indeed achieved higher accuracy than a single SVM classifier (Additional File [3](#S3){ref-type="supplementary-material"}). In the second stage, another layer of classifiers integrates these single-sample inclusion probabilities across multiple hybridization samples to predict alternatively spliced segments. We trained different SVM classifiers for the prediction of different types of AS. One of these classifiers learned to infer ES events from untypically low exon inclusion probabilities; another one was trained to detect IR events from untypically high inclusion probabilities of introns. In addition to the sample-specific inclusion probabilities, we provided these predictors of AS with sample-matched gene expression values allowing them to re-weight the inclusion probabilities in an expression-dependent manner. The proposed two-layer architecture allows to optimally use the existing labeled data: abundant constitutive splicing events are used to train the model dealing with highly variable the hybridization intensities to obtain stable exon/intron inclusion rates, while the much fewer AS events are used to predict AS based on the inclusion estimates. Prediction accuracy assessed in comparison to genome annotation and sequence data --------------------------------------------------------------------------------- In order to assess the prediction accuracy of the exon-intron classifiers, applied in the first stage of our method, we performed a 5-fold cross-validation on a large set of 71,928 constitutive exons and 47,952 constitutive introns, obtained from the TAIR annotation \[[@B27]\]. For this purpose, we employed receiver operating characteristic (ROC) as well as precision-recall analysis. Depending on gene expression levels, exon-intron classifiers achieved values for the area under the ROC curve (auROC) ranging from 0.85 to 0.99 indicating very high accuracy (Figure [2A](#F2){ref-type="fig"}). Precision-recall plots further confirmed that exons can be distinguished from introns with very high recall rates at a low false discovery rate (Figure [2B](#F2){ref-type="fig"}). In addition to gene expression level, as measured on tiling arrays, two more factors were identified to influence classification accuracy. Sequence confirmation had a positive effect, partly, because it is also strongly correlated with gene expression level, but probably also because label uncertainty decreases as sequence confirmation increases (Figure [2D](#F2){ref-type="fig"}). Furthermore, the number of tiling probes interrogating an exon or intron also impacts prediction performance. Accuracy was found to increase with the number of informative probes, especially for genes expressed at low levels (Figure [2C](#F2){ref-type="fig"}). The accuracy values shown here are the result of carefully selecting features on the basis of their discriminatory power (see Additional File [4](#S4){ref-type="supplementary-material"}). Whereas a reliable benchmark set for exon/intron classification could readily be obtained from the annotation, assessing the accuracy of AS predictions resulting from the second-stage classifiers was more challenging. Here we used the EST/cDNA-based SCS data set (see above) to evaluate our predictions of AS in a 5-fold cross-validation. ROC plots show a large overlap between our predictions and the SCS data (Figure [3](#F3){ref-type="fig"}), notwithstanding the fact that there are caveats to the direct comparison between array-based and sequence-confirmed AS events. Importantly, tissues and conditions analyzed with tiling arrays are not matched to those sampled by ESTs and cDNA sequencing, and due to inconsistent labeling of EST origin, it is hardly feasible to filter EST data for a more direct comparison to tiling array data. The lack of deep EST and cDNA data for some of the conditions represented in the tiling array data sets analyzed here implies that cases which are labeled as constitutively spliced in the SCS data set, may potentially be true examples of alternative splicing if a broader set of conditions is considered. Effectively, this can result in exaggerated estimates of the false-discovery rate of tiling array-based predictions of AS as benchmarked on the SCS data set. Similarly, such a comparison likely underestimates the true recall rate of our AS predictions. Nonetheless, the strong enrichment of our predictions with known cases of AS directly confirms the validity of many of these predictions and allows us to estimate an upper bound of the false discovery rate. ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Performance of the exon-intron classifier**. (A) Accuracy as measured by the area under the ROC curve for different gene expression quantiles. (B) Classification accuracy assessed with precision-recall curves. (C) Prediction accuracy as a function of gene expression levels and the number of probes interrogating an exon/intron. (D) Histogram showing correlation between sequence confirmation and expression level of mRNA transcripts. :::  ::: ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Performance of predictors for alternative and differential splicing**. The classification accuracy of the SVM-based predictor was compared to unsupervised predictors for the detection of tissue-specific and stress-dependent differential AS events, respectively. (A) Depicted are ROC curves assessed on the unified exon and intron SCS sets. The area under the curve was computed for the x-axis interval corresponding to a false positive rate between 0 and 0.3. (B) Shown is the corresponding Precision-recall curve. :::  ::: A comparison of supervised and unsupervised AS detection methods ---------------------------------------------------------------- Although it is difficult to estimate absolute values for the accuracy of tiling array-based predictions of AS using the SCS data set as a benchmark, it is, however, useful to compare the predictions of different methods to each other in terms of their relative enrichment with known cases of AS contained in the SCS data set. Since most of the previous array-based approaches for profiling or discovery of AS events \[[@B21],[@B22],[@B32]\] are restricted to other types of microarray platforms, such as exon and/or exon junction arrays, it was not possible to directly compare our method to these approaches. Here, we selected two representative tiling array-based approaches for the method comparison; an approach by Ner-Gaon *et al*. \[[@B24]\], which had to be modified to enable a direct comparison to our method, and another ANOVA-based test, similar to MIDAS <http://www.affymetrix.com/support/technical/whitepapers/exon_alt_transcript_analysis_whitepaper.pdf>. Both methods are unsupervised, relying on statistical testing. In essence, the former approach identifies potentially retained introns for which the mean probe signal is significantly higher than the mean signal of other introns of the same gene and statistically similar to the mean exonic signal. Similarly, the naive ANOVA-based approach directly takes the hybridization signals as input. First the overall gene expression levels are normalized to correct for expression differences across experimental conditions. Subsequently, the statistical test identifies differentially spliced introns, based on the assumption that their normalized probe signal levels significantly differ between the analyzed samples. We compared the three different array-based methods for the identification of IR events relative to the SCS data set by means of ROC analysis. We found that IRs predicted by our supervised learning approach are significantly stronger enriched for sequence-confirmed AS events than the results of the two other AS detection methods that are based on statistical tests (Figure [4A](#F4){ref-type="fig"}). Particularly, precision-recall curves show that both statistical testing methods achieve considerably lower agreement with known AS events (Figure [4B](#F4){ref-type="fig"}). ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Performance of supervised SVM-based method vs. unsupervised statistical methods**. The SVM-based approach was compared to unsupervised methods based on statistical tests. The prediction accuracy was assessed on the SCS data set of constitutively and alternatively spliced introns confirmed by EST/cDNA data (see main text). (A) ROC curves. (B) Precision-recall curves. :::  ::: Moreover, we evaluated to what extent different design choices (i.e., different SVM kernels) and tiling array-derived features contributed to the accuracy of our method and how it compares to simpler ad-hoc procedures for the inference AS events (Additional File [5](#S5){ref-type="supplementary-material"}). Genome-wide identification of AS -------------------------------- Using the SVM-based predictors of AS, we conducted a whole-genome analysis of all introns contained in the top 50% of TAIR annotated genes with highest expression level. We tested a total of 53,669 internal exons and 68,006 introns, contained in 9,745 and 11,528 TAIR annotated genes, respectively. To quantify the uncertainty associated with each prediction, SVM outputs were transformed to probabilistic confidences using the SCS data sets as a reference (see Figure [5](#F5){ref-type="fig"}). Taking a stringent cutoff, conservative genome-wide predictions included 1,355 IR events. ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **Cumulative performance of the whole-genome screen**. Number of genome-wide array-based ES and IR predictions as a function of (A) false positive rate (FPR) and (B) precision (PPV). FPR and PPV were assessed on the SCS set (see main text), depending on the prediction score cutoff used for class discrimination. :::  ::: We also performed a whole-genome screen for exon skips, which resulted in the prediction of 1,839 candidates that are expected to be enriched with exon skipping events. However, the predicted ES events are considered as unreliable, as the observed overlap with the SCS data set is substantially lower. The IR and ES events predicted genome-wide are available as supplemental material in Additional Files [6](#S6){ref-type="supplementary-material"} and [7](#S7){ref-type="supplementary-material"}. The confidence scores computed for all introns and exons considered in our genome-wide study of AS can be found in Additional File [8](#S8){ref-type="supplementary-material"}. External validation against AS events derived from RNA-seq data --------------------------------------------------------------- We performed an additional external validation of our genome-wide predictions of IR by comparing them to a recently published RNA-seq data set \[[@B14]\]. From the RNA-seq read data, which covers diverse abiotic stress conditions, we derived IR events (see Methods) and determined the overlap with tiling array-based predictions. More than 25% of our predictions are also supported by the RNA-seq data - a \> 9-fold enrichment over random (Figure [6A](#F6){ref-type="fig"}). We note, however, that annotated AS events are more strongly overrepresented among our predictions (13-fold enrichment) (Figure [6B](#F6){ref-type="fig"}) and furthermore that the overrepresentation of annotated AS events among those derived from RNA-seq data is weaker (7.5-fold) (Figure [6C](#F6){ref-type="fig"}). Thus, tiling array-based inference of AS recovered annotated IR events more accurately than could be achieved with a comprehensive RNA-seq data set \[[@B14]\]. This result can in part be explained by the fact that the tiling array data set covers a richer set of experimental conditions than the RNA-seq data set. In total, 525 out of our 1,355 genome-wide predictions of IR (almost 40%) are supported by either annotation or RNA-seq data with 124 events being present in all three sets. We expect that many more of our predicted AS events will be confirmed by more comprehensive sequence experiments. ::: {#F6 .fig} Figure 6 ::: {.caption} ###### **Overlap of array-based predictions with RNA-seq data and the TAIR annotation**. Overlaps between tiling array-based IR predictions, and IR events derived from RNA-seq data and present in the TAIR annotation illustrated as Venn diagrams. Values in brackets indicate overrepresentation compared to random. Overlap significance was assessed using a hypergeometric test. (A) Overlap between tiling array-based IR predictions and TAIR annotation. (B) Overlap between RNA-seq-derived IR events and TAIR annotation. (C) Overlap between tiling array-based predictions and RNA-seq-derived IR events. :::  ::: Tissue-regulated and stress-induced AS -------------------------------------- Inferring AS based on tiling arrays rather than EST and cDNA sequences has the advantage that complete information for all analyzed samples is available. We thus investigated splicing profiles across tissues and stress conditions for the set of genome-wide predicted AS events. To detect tissue-specific and stress-induced AS events, respectively, we implemented two scores integrating multiple samples on top of the single-sample inclusion probabilities, which were estimated in the first stage of our method. Tissue-regulated AS was inferred from high differences of tissue-specific inclusion levels. Stress-regulated events were identified based on varying inclusion levels between stress treatments and controls. Accordingly, we defined tissue and stress scores (see Methods section for details) and selected differentially spliced introns using a stringent cutoff. We identified 478 IR events showing tissue-specific regulation. 244 IR events were found to be differentially included in mRNA transcripts between stress treatments and the corresponding controls. For 139 IR events we observed both tissue-specific and stress-dependent AS. The predicted AS events listed in Additional Files [6](#S6){ref-type="supplementary-material"} and [7](#S7){ref-type="supplementary-material"} are specifically marked to indicate tissue-specificity and/or stress-dependency. Discussion ========== Tiling arrays are well-suited to study AS in a plant model ---------------------------------------------------------- Many of the commonly known biases and limitations inherent in sequence-based approaches for the study of AS are ameliorated by tiling arrays. EST coverage usually increases toward the 3\' and 5\' ends of transcripts as a consequence of over-representation of end-sequence reads in the respective libraries, and similar biases resulting from oligo(dT)-based priming are commonly known for cDNAs \[[@B24]\]. Furthermore, traditional sequence-based approaches with limited sequencing depth inevitably result in a poor coverage of genes with low expression. Consequently, AS events occurring in genes with expression restricted temporally, spatially, or to certain environmental conditions are often missing or underrepresented in current databases. However, tiling array data exist and are publicly available for a large variety of tissues, developmental stages, and environmental conditions for many model organisms including *A. thaliana*\[[@B33]\]. Tiling arrays provide a well-suited platform for profiling AS in plants, not least because in contrast to other AS-sensitive arrays, only tiling arrays allow for the discovery of novel intron retention events. A better understanding of this most prevalent type of AS in plants will also contribute to the elucidation of the mechanistic differences in splicing between plant and animal systems. Accuracy of the proposed method ------------------------------- With the amount of training data available for *A. thaliana*, SVMs were found to more accurately recover known IR events than the unsupervised statistical methods considered in our comparison. A possible explanation for this is the robustness of SVMs against high levels of noise as observed in the microarray data. Furthermore, statistical tests often rely on modeling assumptions (e.g., Gaussian distributions) which might not necessarily be true for real microarray data. In contrast to statistical methods which are normally exclusively based on normalized probe intensities, our SVM-based classifiers incorporate additional features, which were found to increase the classification accuracy (Additional File [4](#S4){ref-type="supplementary-material"}). We observed much lower accuracy for the ES classifier compared to IR predictions. This may be a consequence of ES events being less frequent in *A. thaliana*than IR events (173 confirmed ES events vs. 762 confirmed IR events in the SCS data set). Hence also the class distribution, i.e., the ratio between constitutively and alternatively spliced exons/introns, is much more imbalanced for ES events than for IR events (1 : 84 and 1 : 17 respectively), which makes the ES classification task more difficult. Applicability of the proposed method ------------------------------------ The supervised AS detection method proposed here is applicable to other organisms, provided that sufficient training data, i.e., EST/cDNA sequences, are available from genome annotations and sequence databases. Already at moderate sequencing depth, ESTs and cDNAs typically confirm sufficiently many exons and introns to derive ample training data for the exon-intron classification in the first step of the algorithm, and hence this should be applicable to a wide range of non-model organisms. The second step of our algorithm, which involves the training of SVM classifiers on known AS events, depends much more on comprehensive annotations. However, a statistical test could replace the supervised approach here, and this slightly modified strategy would also be applicable to species that are poorly annotated with respect to AS. Conceptually, our method could also be applied to focused array designs provided that intron probe sets are available. If exon-exon junction probes were integrated on the employed array platform, the respective hybridization signals could be incorporated as additional connectivity features supporting the condition-dependent inclusion or exclusion of an exon in mature mRNA transcripts. Analogously, exon-intron junction probes could be utilized for the detection of retained introns. However, the analysis of exon arrays is not directly possible, because our method requires intronic signal levels for the estimation of single-sample inclusion probabilities. Validation of tiling array-based AS predictions relative to EST/cDNA sequences, RNA-seq data, and the genome annotation ----------------------------------------------------------------------------------------------------------------------- As most studies of AS have the goal to discover new AS events for which by definition no sequence-evidence exists, it has become a common practice to independently validate predictions by reverse-transcriptase PCR (RT-PCR) experiments \[[@B24],[@B34]\]. This validation method provides an accurate means for assessing the confidence in predicted, as yet unknown AS events, but is typically only used to confirm a few dozen cases. Instead of performing biological validation experiments, we adopted an alternative strategy of evaluating our predictions on a set of known, sequence-confirmed AS events, derived from large collections of publicly available transcript sequences. Such a comparison can easily be based on thousands of cases, but there are caveats to the interpretation of the results. First, the number of AS events contained in our SCS test set is constrained by the number of available EST and cDNA sequences, which mostly cover highly expressed genes. Therefore, our evaluation set is biased toward high expression levels, which limits the generalizability of the results for genes expressed at low levels. Second, as the TAIR annotation as well as sequence databases are incomplete with respect to AS at present, an unknown number of constitutively labeled segments in our test set may actually undergo AS, and these mislabelings may distort evaluation results, particularly the estimation of false positives. To partially overcome these limitations, we complemented this first evaluation strategy by a comparison against ultra-high throughput sequencing data. These data were generated by Filichkin *et al*., who recently published a study of AS, for which they profiled several *A. thaliana*tissues and diverse stress conditions \[[@B14]\] using RNA-seq. The comparison of AS events inferred from tiling arrays to those independently derived from RNA-seq data showed a highly significant overlap between both sets of results (9.2-fold overrepresentation, p-value \< 10^-221^) (Figure [6](#F6){ref-type="fig"}). Interestingly, even though RNA-seq is already replacing splicing-sensitive microarrays as the method of choice for studying AS \[[@B35],[@B36],[@B14]\], the RNA-seq data presently available for *A. thaliana*does not appear to more accurately reflect annotated cases of AS (Figure [6](#F6){ref-type="fig"}). Although these data set comparisons do not allow us to accurately estimate the performance of our tiling array-based inference, the large number of predictions supported by either RNA-seq-derived or annotated IR events (almost 40%) and the considerably smaller relative overlap between these two sets makes it plausible that many more of our predictions are valid (Figure [6](#F6){ref-type="fig"}) and that the extent of AS is still likely to be underestimated. A catalog of newly identified AS events will enable future research ------------------------------------------------------------------- The compilation of array-based predictions generated in this study adds to our current knowledge of the prevalence of AS in *A. thaliana*\[[@B27],[@B2],[@B37]\] and provides new insights into tissue- and stress-specific regulation of AS. The fact that our predictions were made with respect to a large, but well-defined panel of plant organs, developmental stages, and stress treatments is an advantage over sequence-based AS databases, for which sample origin information is typically difficult to map. Since we studied the tissue-dependent occurrence of isoforms, our work constitutes a starting point for functional characterization as well as for studying regulation of differential alternative splicing. The latter task could be approached based on correlation of expression patterns of known splicing regulators with the putatively targeted, \"co-spliced\" exons and introns, showing consistent splicing profiles across tissues. Furthermore, putative splicing factor binding sites could be detected, based on a search for overrepresented motives in the flanking sequences of co-spliced exons or introns. \[[@B8],[@B38]\]. Finally, a splicing-regulatory network integrating the predicted relationships between splicing factors and target exons and introns could be inferred for *A. thaliana*. To provide a basis for studying the mechanisms governing AS regulation and its physiological implications on a systems level, future research focusing on the elucidation of the regulatory interactions between *trans*-acting splicing factors and their *cis*-acting pre-mRNA motives appears promising. Conclusions =========== In this paper we describe a supervised machine learning-based method for large-scale detection and profiling of alternative splicing from a quantitative tiling array platform. While limited amounts of known AS events are available, which serve as labeled training data for supervised AS detection methods, the number of reliably annotated constitutive exons and introns is very large. We therefore designed a two-stage classification procedure which first learned to discriminate constitutive exons and introns in single samples and subsequently integrated scores across samples to obtain predictions of AS. Specifically, we trained ten SVMs in the first stage, which were specialized to appropriate ranges of gene expression, and discriminated exons from introns, based on diverse features derived from the corresponding hybridization pattern and position in the transcript. The predicted SVM scores were in turn transformed to probabilistic confidences which served as an estimator for the probability that a given exon or intron is contained in the mRNA of a gene expressed under a particular environmental condition. In the second step the single-sample inclusion probabilities were combined across samples for each exon and intron. The resulting all-sample score proved to be an appropriate means for the discrimination of constitutively and alternatively spliced segments and was found to be more accurate than the outcome of statistical tests when benchmarked against known AS events. We thus applied the all-sample SVM-based prediction score in a genome-wide screen to discover novel IR events. Comparisons to a recently published comprehensive RNA-seq data set \[[@B14]\] and the latest genome annotation directly validated almost 40% of our genome-wide predictions and suggest that our method re-discovered AS events present in these benchmarking sets with an accuracy that is comparable to that of the presently available RNA-seq data. Methods ======= Definition of ES and IR ----------------------- As skipped exons we considered exons which are present in at least one transcript, while in at least one other transcript the same region is entirely contained in an intron. Additionally, we required that these two transcripts have at least one upstream exon and one downstream exon in common. As retained introns we treated introns which are spliced out from at least one isoform, while at least one additional isoform exists in which an exon spans the same region. Inferring AS events from EST/cDNA sequences ------------------------------------------- The gene models used in this computational analyses of AS incorporate TAIR annotated transcripts, as well as EST/cDNA sequence information. We obtained full-length cDNA sequences from RIKEN \[[@B28]\] and additionally collected EST sequences from dbEST \[[@B39]\] (as of November, 15, 2007). At first we built a cDNA/EST-based gene structure using BLAT \[[@B17]\] to align EST/cDNA sequences to the genome of *A. thaliana*. For detailed information about the pipeline used for generating the EST/cDNA-based gene structure we refer to Sonnenburg *et al*. \[[@B40]\]. We generated a second gene structure, which was parsed from a gff3-file containing the TAIR7 annotation \[[@B27]\]. The annotation-based gene structure was in turn combined with the EST/cDNA-based gene structure by merging overlapping transcripts located on the same strand. Finally, we built splicing graphs for each gene in which exons correspond to nodes with genomic coordinates and introns to joining edges between exons. AS was then inferred based on splicing graphs according to the definitions given above. Generation of the SCS data set ------------------------------ In order to collect positive examples for the SCS set (see Table [1](#T1){ref-type="table"}), we detected IR or ES events based on splicing graphs and included them in the SCS set, if both isoforms were confirmed by at least two EST/cDNA sequences. For the negative examples in the SCS set, which correspond to constitutive exons and introns, respectively, we required at least 5-fold EST/cDNA confirmation for each of the two adjacent splice sites. Since the high-quality cDNAs provide more reliable evidence for the existence of splice sites than EST sequences, we counted them twice. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Data sets used for SVM training and performance evaluation. ::: Data set Positive examples Negative examples ----------------------------------- ------------------------------------------------------------ ----------------------------------------------- Constitutive types of segment set 71928 annotated constitutive exons 47952 annotated constitutive introns intron SCS set 762 IR events with EST/cDNA evidence for both splice forms 13132 sequence-confirmed constitutive introns exon SCS set 173 ES events with EST/cDNA evidence for both splice forms 14492 sequence-confirmed constitutive exons The table itemizes all data sets on which the classification performance of our methods was assessed, and specifies the positive and negative examples used for SVM training and evaluation. ::: In order to evaluate our method we compiled a representative SCS set, adapting the class distribution to the ratio *r~AS~*of alternatively spliced genes we would expect for the whole genome, based on published surveys of AS. We set *r~AS~*= 30%, using an overestimation of an EST/cDNA-based estimate by Wang *et al*. \[[@B2]\] who found that 22% of the genes in the *A. thaliana*genome undergo alternative splicing. Due to the limited amount of sequence data used in this study, the estimate reported by Wang *et al*. is likely to be an underestimation of the true ratio \[[@B3]\]. This view is also supported by the work of Simpson et al., who reported that AS is estimated to occur in a third of the genes in *Arabidopsis*\[[@B31]\]. We thus increased the ratio computed by Wang and Brendel to 30%, which is closer to current expectations about the prevalence of AS in *A. thaliana*. Based on a list of genes undergoing sequence-confirmed AS events taken from the ASIP database <http://www.plantgdb.org/ASIP/Download/>, we determined the proportion of genes undergoing IR or ES events among all alternatively spliced genes which is *r~IE~*= 70; 9%. Combining the two estimated ratios, we computed the proportion of genes undergoing IR or ES events among all genes: *r*= *r~IE~r~AS~*= 21; 3%. The number of genes with a single isoform was chosen, such that this ratio *r*is reflected by the SCS set. Since we evaluated the considered AS detection methods on a set of introns and exons, respectively, we had to infer the class distribution on the segment level from the ratio *r*determined on the gene level. To this end, we first determined the number intron retentions *i~a~*= 996 and exon skips *e~a~*= 259, which occurred in *g~a~*= 964 alternatively spliced genes, based on splicing graphs built from the EST/cDNA data. Given the number of alternatively spliced genes *g~a~*= (*g~a~*+ *g~c~*) ·*r*, we computed the number of single-isoform genes $g_{c} = g_{a} \cdot \frac{1 - r}{r} = 3,568$. Based on a statistical analysis by Reddy, who observed that the average gene of *A. thaliana*is composed of 5 exons and 4 introns \[[@B3]\], we calculated the number of constitutively spliced exons *e~c~*= 5 · *g~c~*+ 4 · *g~a~*= 21, 696 and the number of constitutively spliced introns *i~c~*= 4 · *g~c~*+ 3 · *g~a~*= 17, 164 under the simplifying assumption, that there is only one AS event per alternatively spliced gene. Our approximation resulted in a class distribution of *i~a~*: *i~c~*= 1 : 17 for the intron SCS set and *e~a~*: *e~c~*= 1 : 84 for the exon SCS set (see Table [1](#T1){ref-type="table"}). As the number of available constitutive introns and exons with high EST/cDNA evidence was insufficient for adjusting the respective SCS sets to the predetermined class distributions, the corresponding segments were sampled with replacement from a basic population. Array design ------------ The expression data was measured by the Affymetrix GeneChip Arabidopsis Tiling 1.0R Array, which comprises more than 3.2 million perfect match and as many mismatch probes tiled throughout the whole non-repetitive portion of the *A. thaliana*genome. The central positions of adjacent 25-mer probes are spaced 35 base pairs on average, leaving a gap of approximately ten base pairs between the probes. Experimental conditions of the hybridization samples ---------------------------------------------------- The analyzed dataset comprises signal levels measured in 11 tissues and developmental stages of the *A. thaliana*Col-0 referenced strain \[[@B41]\], as well as hybridization data of 13 abiotic stress treatments \[[@B13]\]. The environmental stress response data were derived from plant seedlings, which were exposed to diverse stress conditions at preassigned time points. As three biological replicates were available for each hybridization sample, the whole dataset comprehends 72 tiling array experiments. For detailed information about the plant material, growth conditions, probe preparation, and array hybridization, the reader is referred to \[[@B41],[@B13]\]. Normalization of the tiling array data -------------------------------------- In order to compensate for background noise, cross-hybridization, and probe-specific effects, we used diverse normalization techniques. We corrected for the uneven hybridization background of individual microarrays using a mean image subtraction technique \[[@B42]\]. To correct for the inherent variation of the laboratory experiments, which causes differing intensity distributions between arrays, the distributions of probe intensities were mapped to the mean of the empirical intensity distributions of all arrays by quantile normalization \[[@B43]\]. Since the whole sequence of the Arabidopsis genome was known a priori \[[@B44]\], we could address the problem of cross-hybridization by identifying repetitive k-mers in the genome and by excluding all repetitive probes from further analysis as described previously \[[@B45]\]. Probe-specific effects were alleviated by using a transcript normalization technique \[[@B46]\]. SVM-based approach for the detection of AS ------------------------------------------ We formulated the problem of identifying IR and ES events as a supervised learning task and designed a two-stage classification procedure. First, we trained SVMs to discriminate constitutive exons and introns in single samples. In a second step, the single-sample scores computed in the first step were integrated across samples to predict of IR and ES events. ### Expression-dependent partitioning of the training data As gene expression may differ dramatically between genes and experimental conditions, it is difficult to accurately define a global threshold, separating the likewise differing intronic and exonic probe signal levels. Intuitively, it would be more appropriate to choose such a threshold depending on gene expression. This could be achieved by discretizing the complete range of gene expression levels into a fixed number of intervals and defining a local threshold for each such interval. Based on these considerations, we split the training data of the SVMs applied in Stage 1 (*see constitutive segment set*in Table [1](#T1){ref-type="table"}) into ten disjoint *expression bins*and then trained ten SVM classifiers, each applicable for a well-defined range of gene expression. The limits of the ten expression bins were defined as the percentiles (*P*~10,~*P*~20,~\..., *P*~90~) calculated from the distribution of the median exonic probe intensities measured under each condition for each gene. ### Extraction of hybridization-based features for exon/intron classification We trained SVMs on three types of features extracted from the signal levels and positions of the probes, complementary to a given exon/intron *s*and measured in sample *t*: absolute intensity features, *F~abs~*(*s*, *t*), relative intensity features *F~rel~*(*s*, *t*) and positional features *F~pos~*(*s*). The absolute intensity features are given by the vector *F~abs~*(*s*, *t*) = (*P*~20~, *P*~40~, *P*~50~, *P*~60~, *P*~80~) composed of five local intensity percentiles. These percentiles provide a compact representation of the intensity distribution measured in sample *t*by the probes complementary to segment *s*. As each experiment was performed in triplicate, three measurements per probe were included in the calculation. The relative intensity features *F~rel~*(*s*, *t*) measure the relative expression level of an exon/intron *s*under the experimental condition *t*compared to the whole spectrum of observed probe intensities. These features are not correlated to the absolute expression features and correspond to histograms, built from the probe intensities measured for a certain exon/intron. The discrete intervals, i.e., bins, are defined based on *N*= 5 global percentiles *L*= (*P*~20~, *P*~40~, *P*~50~, *P*~60~, *P*~80~) computed from the intensity distribution of all genic probes in all samples combined. As done for the local percentiles, probe intensities were pooled across replicates. Given the intensity vector representation *I*(*s*, *t*) = (*I*~*t*1~(*p*~1~),\..., *I*~*t*3~(*p*~*n*~)) of a segment/sample pair (*s*, *t*), which is measured in triplicate by the complementary probes *p*~1~,\..., *p*~*n*~, we calculated the components of *F*~*re*l~(*s*, *t*) by linear interpolation between the global percentiles *L*~1~,\..., *L*~*N*~. We first initialized *F*~*re*l~(*s*, *t*) = (0,\..., 0), where each component corresponds to one of the *N*= 5 global percentiles. Next, we iteratively assigned each intensity value, i.e., component of *I*(*s*, *t*), to an interval, limited by either the first, the last, or two neighboring global percentiles. If the intensity value was outlying one of the outer global percentiles *L*~1~= *P*~20~and *L*~*N*~= *P*~80~, either the first or the last component of *F*~*re*l~(*s*, *t*) was increased by 1. Otherwise, if the intensity value was assigned to an interval limited by two global percentiles, the two corresponding components of *F*~*re*l~(*s*, *t*)*~i~*were increased in a weighted manner. We defined this increase as the reciprocal of the relative distance of the intensity value to the corresponding distance limit. Formally, the *i*-th component *F*~*re*l~(*s*, *t*)*~i~*of the feature vector *F*~*re*l~(*s*, *t*) is defined as: $$F_{rel}\left( {s,t} \right)_{i} = {\sum\limits_{j = 1}^{n}{\sum\limits_{r = 1}^{3}{f(I_{tr}(p_{j}),i)}}}$$ $$f(I,i) = \begin{cases} 1 & {\text{if}\,(I \leq L_{1} \land i = 1) \vee (I > L_{N} \land i = N)} \\ \alpha & {\text{if}\, L_{k} \leq I < L_{k + 1} \land i = k} \\ {1 - \alpha} & {\text{if}\, L_{k} \leq I < L_{k + 1} \land i = k + 1} \\ 0 & \text{otherwise} \\ \end{cases}$$ $$\text{where}\,\alpha = \frac{L_{k + 1} - I}{L_{k + 1} - L_{k}}$$ Since exonic probe signal levels were found to unevenly run across transcripts and often tend to decrease with increasing distance to the 3\' transcript end \[[@B46]\], we additionally provided the SVM classifiers with positional features *F~pos~*(*s*) in order to compensate for this bias. These features measure the distances of the probes *p*~1~,\..., *p~n~*, complementary to an exon/intron *s*, from the 3\' end of a spliced transcript. First, we arbitrarily defined distance limits *L*= (100, 300, 500,\..., 1900), each corresponding to a certain number of nucleotides between a probe and the 3\' transcript end. Then, we determined these distances for each probe *p*~1~,\..., *p~n~*and computed the positional feature vector *F~pos~*(*s*) by linear interpolation of the probe distances between the distance limits *L*, using the same procedure as for the relative intensity features. ### Training and evaluation of exon/intron classifiers For the exon/intron classification SVM models with linear kernel were trained for each of the ten expression bins and a 5-fold cross-validation was performed on the *constitutive segment set*(see Table [1](#T1){ref-type="table"}) to assess the prediction accuracy. The data were partitioned such that 60% were used for training and 20% for model selection and testing, respectively. In each iteration the optimal value of the soft margin parameter *C*was determined on the validation set by grid search (*C*∈ {0.001, 0.01, 0.1, 1, 10, 100, 1000}). The prediction accuracy was estimated on the test set in terms of auROC and averaged across the 5 folds to produce a single score. For SVM training and classification we used an efficient CPLEX-based implementation <http://www.ilog.com/products/cplex/>\[[@B47]\]. ### Estimation of single-sample inclusion probabilities To obtain a score measuring the sample-specific inclusion of exons/introns in mRNA transcripts, we transformed the predicted SVM scores to probabilistic confidences, which are comparable between variably parametrized SVMs trained on different datasets. In essence, the algorithm used for this purpose estimates the conditional likelihood *P*(*y*= 1 \| *f~svm~*(*s*, *t*)) that segment *s*is an exon, given the SVM score of segment/sample pair (*s*, *t*) and learns a mapping from SVM outputs to confidences, which is based on monotonically increasing piecewise linear functions. For a detailed description of the algorithm the reader is referred to Sonnenburg *et al*. \[[@B40]\]. ### Detection of AS by integration of single-sample predictions In the second stage of our classification procedure the single-sample inclusion probabilities were used as features for a second SVM-based model which was in turn applied to produce all-sample scores allowing for the detection of unspecifically regulated AS as well as tissue-regulated or stress-induced differential splicing. Since the array-based prediction of AS requires sufficiently high differences between intronic and exonic probe intensities, we restricted further analyses to the 50% genes with highest expression level. These genes were selected, based on the median signal level of the exonic probes, pooled across conditions and replicates. The SVM classifiers of Stage 2 were provided with the single-sample inclusion probabilities from Stage 1 and additional expression features. First, each exon/intron was represented by a vector, composed of the inclusion probabilities predicted for each sample. The single-sample scores were sorted in descending order, such that the first and last component correspond to the sample with maximum and minimum inclusion probability, respectively. In a second step, this sorted single-sample score vector was concatenated with an expression feature vector of equal length, which captured the expression level of the flanking exons, given as the median signal level of the complementary probes. The expression feature vector was sorted in consistent order, such that dependencies between inclusion probabilities and gene expression levels could be learned. In order to distinguish retained from constitutive introns, linear SVMs were were trained and evaluated on the intron SCS set (see Table [1](#T1){ref-type="table"}) using a 5-fold cross-validation. Analogously, we separately trained SVMs for the detection of ES. To extract the IR and ES events predicted with highest confidence, we introduced a threshold for the Stage 2 SVM output values, corresponding to an estimated FDR of 0.5 and 0.7 on the intron and exon SCS set, respectively. ### Detection of tissue-regulated and stress-dependent differential splicing To further analyze the sets of predicted IR and ES events with respect to tissue-specific and stress-dependent regulation, we implemented a tissue and a stress score on top of the Stage 2 SVM outputs. The scores are based on the assumption that the inclusion of exons/introns is expected to differ across samples in the presence of differential splicing, whereas less variation is expected for basal AS events, characterized by similar isoform ratios in all samples. $$S_{tissue}(s) = \max_{t}(p(s,t)) - \min_{t}(p(s,t))$$ where *p*(*s*, *t*) denotes the inclusion probability of segment *s*in tissue *t*. $$S_{stress}(s) = \max_{(t,c)}|p(s,t) - p(s,c)|$$ where *p*(*s*, *t*) and *p*(*s*, *c*) denotes the inclusion probability of segment *s*for stress treatment *t*and the corresponding control *c*, respectively. The final set of predictions was obtained by imposing a cutoff corresponding to a recall of 0.1. ANOVA-based IR detection method ------------------------------- The first test method is based on the assumption that retained introns exhibit hybridization intensities which differ across samples, whereas constitutively spliced introns are expected to consistently show low intensities in all samples. We represented each tested segment *s*with complementary probes *p*~1~,\..., *p*~*n*~by \|*T*\| = 24 single-sample intensity vectors *I*~*t*~(*s*) = (*I*~*t*1~(*p*~1~),\..., *I*~*t*3~(*p*~*n*~)) where *I*~*tr*~(*p*~*i*~) denotes the signal level of probe *i*in replicate *r*of sample *t*. To account for differential overall gene expression, we computed the median intensity $m_{t}(g(s)) = median(I_{t1}(p_{1}^{c}),...,I_{t3}(p_{k}^{c}))$ of the constitutive exonic probes $p_{1}^{c},...,p_{k}^{c}$ covering the gene *g*(*s*) that contains segment *s*for each sample *t*∈ *T*. We alleviated the effects of differential expression by calculating splicing index vectors $S_{t}(s) = \frac{I_{t}(s)}{m_{t}(g(s))}$ for all samples which correspond to groups in the subsequently performed ANOVA test. Based on the p-value *p*(*s*) resulting from the ANOVA test, we distinguished retained introns from constitutive ones. IR detection method by Ner-Gaon et al ------------------------------------- The approach by \[[@B24]\] applies statistical tests to identify retained introns from tiling arrays, based on untypically high hybridization signals. The main idea of the authors is that retained introns can be discovered based on a comparison of the probe intensities measured in individual introns to the mean exonic signal level of the respective gene. We reimplemented the method proposed by Ner-Gaon *et al*. in Matlab, maintaining the main concepts of the algorithm, but modifying it in some aspects to enable a comparison to our method. In contrast to Ner-Gaon, we did not require that each tested intron is covered by at least 3 probes, as 60% of the introns in our SCS set do not fulfill this condition. Furthermore, we disregarded the cutoff for the minimal mean exonic and maximal mean intronic transcript signal level proposed by Ner-Gaon, since we observed highly overlapping intensity distributions of exon and intron probes. Since the assignment of a prediction score to all introns in our SCS set was a necessary prerequisite for the subsequent ROC analysis, we omitted the Benjamini-Hochberg correction for multiple testing, which would have excluded genes with insufficient significance from further analysis. As the transcript classes defined by Ner-Gaon *et al*. do not capture all transcripts, we introduced an additional class for the *undifferentiated*transcripts not inclusive to one of the original classes by Ner-Gaon. Furthermore, for the computation of ROC curves, we had to change the numbering of the transcript classes, such that the predicted class index increases with higher confidence of AS. Subsequently, we mapped transcript classes to equivalent intron classes, since the classification performance was assessed on a set of *introns*. To obtain additional points in ROC space, we increased the number of discrete class labels, i.e. intron classes 1-4, by varying the significance level *α*used for the pairwise comparison of group means from 0.01 to 0.5 in 5 logarithmically spaced steps. For each significance level *α*∈ \[0.01, 0.5\] and intron *s*assigned to intron class *c*(*s*) ∈ {1, 2, 3, 4}, we computed a significance score *N~α~*(*s*) = *c*(*s*) + (1 - *α*). The final intron score $N(s) = \max\limits_{\alpha}S_{\alpha}(s)$ results from the significance level *α*with maximal score *N~α~*(*s*). Detection of IR from deep RNA sequencing (RNA-seq) -------------------------------------------------- For this analysis we used the read data published in \[[@B14]\] (Short Read Archive accessions SRX006192, SRX006681, SRX006682, SRX006692, SRX006704, SRX006690, SRX006688) obtained with an Illumina Genome Analyzer 1G. We aligned the total of 210 million reads with Palmapper \[[@B48]\] against the *A. thaliana*genome (TAIR 9). In total we were able to align 75 million reads, out of which 4.2 million reads lead to a spliced alignment for the best hit. We merged the alignments of all libraries and to increase specificity of the alignments we filtered out those which had more than 1 mismatch or a minimal segment length in spliced alignments that was shorter than 8nt. We then considered every annotated intron in the TAIR 9 annotation and checked whether all of the following conditions were satisfied: (a) the median read coverage in the intron was larger than 2, (b) at least 75% of the intronic positions were covered by at least one read, (c) the mean intron coverage of the intron was at least 10% and at most 120% of the average coverage of the two flanking exons and the average coverage of the two flanking exons differed at most 4-fold. This led to a total of 3, 691 detected IR events out of 125, 921 annotated introns. After removing redundancy, we finally obtained 3, 450 IR events. We have also derived AS events using more stringent filtering settings, but did not observe a significantly increased enrichment when compared with the annotation (data not shown). Overlap between tiling array-based, RNA-seq-derived, and annotated IR events ---------------------------------------------------------------------------- All segments were mapped to the TAIR9 genome release. Comparisons were conducted with respect of all introns annotated in TAIR9 and mapped to the nuclear chromosomes. Statistical significance based on the Hypergeometric test as well as representation factors were calculated using an implementation by Jim Lund <http://nemates.org/MA/progs/overlap_stats.html> with 125, 921 as the total number of introns. Authors\' contributions ======================= JE and GZ conceived the method and wrote the manuscript. JE implemented the method in Matlab and performed validation and predictions. SL helped with interpreting the data. GR initiated and supervised the project, implemented the detection of intron retention events from the RNA-seq data and helped writing the manuscript. All authors have read and approved the manuscript. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **Exon SCS set**. This file lists all constitutively and alternatively spliced exons inferred from EST and cDNA sequences, forming the test set which was used for the validation of our predictions. Along with gene/transcript identifiers, the exon boundary coordinates and the number of sequences confirming adjacent splice sites are stated for each exon. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 2 **Intron SCS set**. Analogous to Additional file [1](#S1){ref-type="supplementary-material"}, this file contains the list of constitutively and alternatively spliced introns, used for the evaluation of our method. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 3 **Classification performance of 1-Bin vs. 10-Bin exon-intron classifier**. We compared the prediction accuracy of two SVM-based classifiers which were trained to distinguish exons from introns: a single SVM classifier, and a meta-classifier which incorporates 10 SVMs, each specialized to a certain range of gene expression levels. The prediction accuracy was assessed on a large evaluation set of annotated constitutive exons and introns. (A) ROC curves. (B) Precision-recall curves. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 4 **Prediction accuracy achieved by different features for exon-intron classification**. This file contains a supplementary table which shows the ROC and precision recall scores achieved by first stage classifiers provided with different combinations of expression features and positional features. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 5 **Classification accuracy of different IR and ES predictors**. This file contains a supplementary table which shows the prediction accuracy assessed for different variants of our AS detection method in terms of ROC and precision-recall scores. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 6 **List of predicted exon skips**. The list itemizes all exons which have been predicted to be differentially included in transcript isoforms with high confidence. For each listed exon the respective ID from the TAIR annotation, as well as the genomic location, and confidence scores for AS are specified. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 7 **List of predicted intron retentions**. This file contains a list of the intron retention events predicted with highest confidence. The corresponding table is structured in the same way as Additional File [6](#S6){ref-type="supplementary-material"}. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 8 **Genome-wide predictions of AS**. This file contains a list of all exons and introns which were analyzed in our genome-wide study of AS. For each listed exon and intron we provide the respective TAIR ID, genomic coordinates, and confidence scores for general AS, as well as tissue-specific, and stress-dependent differential splicing. ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ We are grateful to Wolfgang Busch, Jonas Behr, Kay Nieselt-Struwe, and Detlef Weigel for inspiring discussions. We wish to thank Cheng Soon Ong for providing us with his source code for the detection of alternative splicing from splicing graphs. We thank Andreas Zell for critically reading the manuscript and helpful suggestions for improving it.

PubMed Central

2024-06-05T04:04:17.213543

2011-2-16

PMC3051902

pmc Background ========== Workflows are a natural model of how researchers process data \[[@B1]\], and will therefore only gain in relevance and importance as science continues becoming more data- and information-intensive. Unlike business workflows, which emphasize process modeling, automation and management, and are *control-flow*oriented \[[@B2],[@B3]\], scientific pipelines emphasize *data-flow*, and fundamentally consist of chained transformations of collections of data items. This is particularly true in bioinformatics (see, *e.g*., \[[@B4]\] and references therein), spurring the recent development of workflow managment systems (WMS) to standardize, modularize, and execute *in silico*protocols. Such systems generally enable the construction, automation, deployment, exchange, re-use, and reproducibility of data-processing/analysis tasks \[[@B5]\]; catalogs of bioinformatically-capable WMS and web service (WS)-related systems can be found in relatively recent reviews \[[@B6],[@B7]\]. The feature sets of existing WMS solutions vary in terms of monitoring, debugging, workflow validation, provenance capture, data management and scalability. While some WMS suites (*e.g*., [BIO]{.smallcaps}WMS \[[@B8]\], [ERGATIS]{.smallcaps}\[[@B9]\]) and pipelining solutions (*e.g*., [CYRILLE]{.smallcaps}2 \[[@B10]\]) are tailored to the bioinformatics domain, many serve as either general-purpose, domain-independent tools (*e.g*., [KEPLER]{.smallcaps}\[[@B3]\] and its underlying [PTOLEMY]{.smallcaps}II system \[[@B11]\], [TAVERNA]{.smallcaps}\[[@B12]\], [KNIME]{.smallcaps}\[[@B13]\]), frameworks for creating abstracted workflows suitable for enactment in grid environments (*e.g*., [PEGASUS]{.smallcaps}\[[@B14]\]), high-level \"enactment portals\" that require less programming effort by users (*e.g*., [BIOWEP]{.smallcaps}\[[@B15]\]), or flower-level software libraries (*e.g*., the Perl-based [BIOPIPE]{.smallcaps}\[[@B16]\]). Indeed, the recent proliferation of WMS technologies and implementations led Deelman *et al.*\[[@B5]\] to systematically study a taxonomy of features\", particularly as regards the four stages of a typical workflow\'s lifecycle - creation, mapping to resources, execution, and provenance capture. The division into *task-based*versus *service-based*systems appears to be fundamental \[[@B5]\]. Systems of the first kind emphasize the orchestration and execution of a workflow, while the latter focus on service discovery and integration. With its emphasis on enabling facile creation of Python-based workflows for data processing (rather than, *e.g*., WS discovery or resource brokerage), PaPy is a *task-based*tool. Traditional, non-WMS solutions for designing, editing, and deploying workflows are often idiosyncratic, and require some form of scripting to create input files for either a Make-like software build tool or a compute cluster task scheduler. Such approaches are, in some regards, simpler and more customizable, but they lack the aforementioned benefits of workflow systems; most importantly, manual approaches are brittle and in flexible (not easily sustainable, reconfigurable, or reusable), because the data-processing logic is hardwired into \'one-off \' scripts. At the other extreme, a common draw-back of integrated WMS suites is that, for transformations outside the standard repertoire of the particular WMS, a user may need to program custom tasks with numerous (and extraneous) adaptor functions (\'shims\' \[[@B17],[@B18]\]) to finesse otherwise in-compatible data to the WMS-specific data-exchange format. This, then, limits the general capability of a WMS in utilizing (\'wrapping\') available codes to perform various, custom analyses. PaPy is a Python programming library that balances these two extremes, making it easy to create data-processing pipelines. It provides many of the benefits of a WMS (modular workflow composition, ability to distribute computations, monitoring execution), but preserves the simplicity of the Make-style approach and the flexibility of a general-purpose programming language. (PaPy-based workflows are written in Python.) The application programming interface (API) of PaPy reflects the underlying flow-based programming paradigm \[[@B19]\], and therefore avoids any impedance mismatch\" \[[@B20]\] in expressing workflows. This enables PaPy to expose a compact, yet flexible and readily extensible, user interface. Flow-based programming (FBP) and related approaches, such as dataflow programming languages \[[@B2]\], define software systems as networks of message-passing components. Discrete data items pass (as \'tokens\') between components, as specified by a connection/wiring diagram; the runtime behavior (concurrency, deadlocks, *etc*.) of such systems may be analyzed via formal techniques such as Petri nets \[[@B21]\]. Most importantly for bioinformatics and related scientific domains, the individual pipeline components are coupled only by virtue of the pattern of data traversal across the graph and, therefore, the functions are highly modular, are insulated from one another, and are re-usable. The connections are defined independently of the processing components. Thus, flow-based programs can be considered as (possibly branched) data-processing assembly lines. Dataflow programming lends itself as a model for pipelining because the goal of modular data-processing protocols maps naturally onto the concept of components and connections. The input stream to a component consists of self-contained (atomic) data items; this, together with loose coupling between processing tasks, all flows for relatively easy parallelism and, consequently, feasible processing of large-scale datasets. In PaPy, workflows are built from ordinary, user-definable Python functions with specific, well-defined signatures (call/return semantics). These functions define the operations of an individual PaPy processing node, and can be written in pure Python or may \'wrap\' entirely non-Python binaries/executables. Thus, there are literally no arbitrary constrains on these functions or on a PaPy pipeline, in terms of functional complexity, utilized libraries or wrapped third-party programs. In this respect, PaPy is agnostic of specific application domains (astronomy, bioinformatics, cheminformatics, *etc*.). An auxiliary, independent module (\'NuBio\') is also included, to provide data-containers and functions for the most common tasks involving biological sequences and structures. Implementation ============== Overview -------- PaPy has been implemented as a standard, cross-platform Python (CPython 2.6) package; the Additional File [1](#S1){ref-type="supplementary-material"} (§3.1) provides further details on PaPy\'s platform independence, in terms of software implementation and installation. PaPy\'s dataflow execution model can be described, in the sense of Johnston *et al.*\[[@B2]\], as a *demand-driven*approach to processing of data streams. It uses the multiprocessing package \[[@B22]\] for local parallelism (*e.g*., multi-core or multi-CPU workstations), and a Python library for remote procedure calls (RPyC \[[@B23]\]) to distribute computations across networked computers. PaPy was written using the dataflow and object-oriented programming paradigms, the primary design goal being to enable the logical construction and deployment of workflows, optionally using existing tools and code-bases. The resulting architecture is based on well-established concepts from functional programming (such as higher-order \'map\' functions) and workflow design (such as directed acyclic graphs), and naturally features parallelism, arbitrary topologies, robustness to exceptions, and execution monitoring. The exposed interface all flows one to define what the data-processing components do (workflow functionality), how they are connected (workflow structure) and where (upon what compute resources) to execute the workflow. These three aspects of PaPy\'s functionality are orthogonal, and therefore cleanly separated in the API. This construction promotes code re-use, clean workflow design, and alllows de-ployment in a variety of heterogenous computational environments. Modular design -------------- The PaPy toolkit consists of three separate packages (Table [1](#T1){ref-type="table"}) - PaPy, NuMap, NuBio - that provide Python modules (papy, numap, nubio) with non-overlapping functionality, and which can be utilized independently. The \'papy\' module provides just four classes (Worker, Piper, Plumber, Dagger) to enable one to construct, launch, monitor and interact with workflows (Table [2](#T2){ref-type="table"} and Additional File [1](#S1){ref-type="supplementary-material"} §3.2). To facilitate the construction of bioinformatics workflows with only minimal external dependencies, a \'nubio\' module provides general data structures to store and manipulate biological data and entities (*e.g*., sequences, alignments, molecular structures), together with parsers and writers for common file formats. (This functionality is further described below.) ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Overview of the PaPy package ::: Package Purpose --------- --------------------------------------------------------------------------------------------------------------------------------------------------------- papy Provides the core objects and methods for workflow construction and deployment, including the Worker, Piper, Dagger, and Plumber classes (see Table 2). numap Supplies an extension of Python\'s \'imap\' facility, enabling parallel/distributed execution of tasks, locally or remotely (see Fig. 1B). nubio Provides data-structures and methods specific to bioinformatic data (molecular sequences, alignments, phylogenetic trees, 3 D structures) PaPy is comprised of three packages, independently providing the set of functionalities described in this table. ::: ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### PaPy\'s core components (classes) and their roles ::: Component Description & function --------------- -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Piper, Worker The core components (processing nodes) of a pipeline. User-defined functions (or external programs) are wrapped as Worker instances; a Piper wraps a Worker and, in conjunction with numap, further species the mode of evaluation (serial/parallel, local/remote, *etc*.); these key pipeline elements also provide exception-handling, logging, and produce/spawn/consume functionality. Dagger Defines the data-flow pipeline in the form of a DAG; allows one to add, remove, connect pipers, and validate topology. Coordinates the starting/stopping of NuMaps. Plumber High-level interface to run & monitor a pipeline: Provides methods to save/load pipeline code, alter and monitor state (initiate/run/pause/stop/*etc*.), and save results. (See Additional file [1](#S1){ref-type="supplementary-material"} §3.2 for more information on the subtle differences between the Plumber and Dagger classes.) NuMap Implements a process/thread worker-pool. Allows pipers to evaluate multiple, nested map functions in parallel, using a mixture of threads or processes (locally) and, optionally, remote RPyC servers. ::: The \'numap\' module supplies a parallel execution engine, using a flexible worker-pool \[[@B24]\] to evaluate multiple map functions in parallel. Used together with papy, these maps comprise some (or all) of the processing nodes of a pipeline. Like a standard Python \'imap\', numap applies a function over the elements of a sequence or iterable object, and it does so lazily. Laziness can be adjusted via \'stride\' and \'buffer\' arguments (see below). Unlike imap, numap supports *multiple pairs*of functions and iterable *tasks*. The tasks are not queued, but rather are *interwoven*and share a pool of *worker*\'processes\' or \'threads\', and a memory \'buffer\'. Thus, numap\'s parallel (thread- or process-based, local or remote), buffered, multi-task functionality extends standard Python\'s built-in \'itertools.imap\' and \'multiprocessing.Pool.imap\' facilities. Workflow construction --------------------- A generic pipeline (Figure [1A](#F1){ref-type="fig"}) consists of *components*and *connections*. Components define data-processing tasks, while the topology of inter-connections coordinates the dataflow. Basic workflow patterns that have emerged \[[@B4]\] include those which are sequential (linear/unbranched or branched) or parallel (scatter/gather, MapReduce), those which incorporate decision logic (conditional branching), intricate loops or cyclic patterns, and so on. In PaPy, a workflow is a directed acyclic graph (DAG), with data-processing *nodes*and data-flow *edges*. The components are instances of a \'Piper\' class, which are nodes of a \'Dagger\' graph instance. A Dagger, in turn, is the DAG that literally defines the workflow connectivity. Processing nodes are constructed by wrapping user-provided functions into Worker instances. Together with a NuMap, the Worker is then wrapped to define a Piper (Figure [1C](#F1){ref-type="fig"}), instances of which are added as the nodes when composing a workflow graph. A function can be used within multiple nodes, and multiple functions can be chained or nested into higher-order functions within a single node ($\mathcal{P}$($\mathcal{W}$(*f, g*,\...)) in Figure [1A](#F1){ref-type="fig"}). Functions are easily shared between pipelines, and can be executed by remote processes because dependencies (import statements) are effectively \'attached\' to the source-code specifying the function *via*Python decorators \[[@B25]\]. Execution engines are represented by NuMap objects (Figure [1B](#F1){ref-type="fig"}). Piper instances are optionally assigned to (possibly shared) NuMap instances that enable parallel execution. In terms of cloud computing, abstraction of compute resources in this manner should make PaPy workflows cloud-compatible (see Additional File [1](#S1){ref-type="supplementary-material"} §3.3). ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **A generic PaPy workflow**. Any generic workflow that is expressible as a directed graph can be implemented as a PaPy pipeline (A). As indicated by the pipes linking separate processing streams in (A), workflow construction in PaPy is flexible, not restrictive. Because of the methods that PaPy\'s NuMap objects can use to parallelize or distribute calculations (text, Table 3), a workflow can utilize a variety of available computational resources, such as threads, multi-processor architectures, and remote resources (B). PaPy\'s Dagger objects, representing the entire pipeline, are comprised of Piper nodes (colored squares) inter-connected via pipes (black arrows); \'pipes\' can, equivalently, be considered as edges that represent data-flow dependencies (gray arrows \'pulling\' data through the left branch of (A)). Colors are used to match sample Pipers (A) with their NuMap instances (B), and the conceptual relationship between Piper, Worker, and NuMap concepts is shown in (C). Parallelism is achieved by pulling data through the pipeline in adjustable batches, and overall performance may be improved by collapsing unbranched linear segments into a single node (D). :::  ::: Bioinformatics workflows ------------------------ Because the architecture of PaPy is generalized, it is more of a software library than a single, domain-specific program, and it is therefore able to drive arbitrary workflows (bioinformatic or not). To enable rapid, consistent development, and facile deployment, of bioinformatics workflows, a lightweight package (\'NuBio\') is provided. NuBio consists of data structures to store and manipulate biological entities such as molecular sequences, alignments, 3 D structures, and trees. The data containers are based on a hierarchical, multi-dimensional array concept. Raw data are stored in at arrays, but the operational (context-dependent) meaning of a data-item is defined at usage, in a manner akin to NumPy\'s view casting\" approach to subclassing *n*-dimensional arrays (see \[[@B26]\] and Example 2 below). For example, the string object \'ATGGCG\' can act as a \'NtSeq\' (sequence of six nucleotides) or as a \'CodonSeq\' (sequence of two codons) in NuBio. This alllows one to customize the behaviour of objects traversing the workflow and the storage of metadata at multiple hierarchical levels. Functions to read and write common file formats are also bundled in PaPy (PDB for structural data, FASTA for sequences, Stockholm for sequence alignments, *etc*.). Parallelism ----------- Parallel data-processing is an important aspect of workflows that either (*i*) deal with large datasets, (*ii*) involve CPU-intensive methods, or *(iii*) perform iterated, loosely-coupled tasks, such as in \"parameter sweeps\" or replicated simulations. Examples in computational biology include processing of raw, \'omics\'-scale volumes of data (*e.g*. \[[@B27]\]), analysis/post-processing of large-scale datasets (*e.g*. molecular dynamics simulations in \[[@B28]\]), and computational approaches that themselves generate large volumes of data (*e.g*. repetitive methods such as replica-exchange MD simulations \[[@B29],[@B30]\]). PaPy enables parallelism at the processing node and data-item levels. The former (node-level) corresponds to processing independent data items concurrently, and the latter (item level) to running parallel, independent jobs for a single data item. PaPy\'s parallelism is achieved using the worker-pool \[[@B24]\] design pattern, which is essentially an abstraction of the lower-level producer/consumer paradigm (see, *e.g*., \[[@B31],[@B32]\]). Originally devised to address issues such as concurrency and synchronization in multi-programming, the produce/spawn/-consume idiom is useful at higher levels (such as dataflow pipelines), involving generation/processing of streams of data items (Figure [2](#F2){ref-type="fig"}). As schematized in Figure [1B](#F1){ref-type="fig"}, a NuMap instance uses a collection of local or remote computational resources (*i.e*., it abstracts a worker-pool) to evaluate, in parallel, one or several map functions. (A Piper instance becomes parallel if associated with a NuMap instance specifying parallel evaluation, or Python\'s itertools.i map.) Multiple pipers within a workflow can share a single worker-pool, and multiple worker-pools can be used within a workflow. This, together with the possibility of mixing serial and parallel processing nodes, allows for performance tuning and load-balancing. To benefit from parallel execution, the data-processing function should have a high granularity *i.e*., the amount of time spent per calculation is large compared to periods of communication. Note that this general approach bears similarity to the MapReduce model of distributed computing \[[@B33]\], and could be suitable for replicated, loosely-coupled tasks, such as in Monte Carlo sampling, replica-exchange MD simulations, or genome-wide motif searches (*e.g*. \[[@B34]\]). ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **The produce/spawn/consume idiom**. This workflow design pattern, used to process a single input node in parallel, arises in many contexts, such as in replica exchange simulations (see text). In this and remaining workflow diagrams (Figs. 3, 4), the sequence of Piper nodes is shown on the left (A), while the discrete data transformations that will implicitly occur (at the data-item level) are schematized on the right (B). :::  ::: Dataflow -------- The flow of data through a pipeline is intimately linked to the issue of parallelism. In PaPy, data traverse a pipeline in batches of a certain size, as defined by an adjustable \'*stride\'*parameter (Figure [3](#F3){ref-type="fig"}). The *stride*is the number of data items processed in parallel by a node in the workflow. The larger the stride the higher the scalability, as this results in fewer idle processes and greater speed-ups. However, memory requirements increase with batch size, as potentially more temporary results will have to be held in memory. Thus, the adjustable memory/speedup trade-off allows PaPy to deal with datasets too large to fit into resident memory and to cope with highly variable processing times for individual input items. Note that the order in which data items are submitted to the pool for evaluation is not the same as the order in which results become available; because of synchronization of processing nodes, this may cause a pipeline to incur idle CPU cycles. PaPy circumvents this potential inefficiency by (optionally) relaxing any requirement of ordered dataflow within a pipeline, as further described in the software documentation. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **The \'stride\' as a control parameter**. PaPy\'s adjustable *stride*modulates the trade-off between high memory consumption and parallelism (high stride) versus less aggressive paralellism and lower memory consumption (lower stride). This diagram un-winds PaPy\'s parallelism to show the interplay between the *stride*and item-level processing as pipeline execution proceeds (main blue arrow directed rightward). The relevent pipers are shown to the left (A), and traversal of the workflow graph by data-batches is shown in (B). Execution progress is also indicated by broken arrows progressing to the right, each arc representing equal incremenets of time (*t*~0~, *t*~1~,\.... assuming a uniform processing time per data-item) for strides of 3 (orange) or 5 (green). :::  ::: Data-handling and serialization issues -------------------------------------- Pipers must communicate the results computed by their wrapped functions. In PaPy\'s execution model, synchronization and message passing within a workflow are achieved by means of queues and locked pipes in the form of serialized Python objects. (*Serialization*refers to a robust, built-in means of storing a native Python object as a byte-string, thereby achieving object persistence.) Unlike heavyweight WMS suites such as [KNIME]{.smallcaps} (see the Additional File [1](#S1){ref-type="supplementary-material"} §4), PaPy does not enforce a specific rigorous data exchange scheme or file format. This intentional design decision is based on the *type system*\[[@B35]\] of the Python programming language, whereby the valid semantics of an object are determined by its dynamic, user-modifiable properties and methods (\"duck typing\"). Such potentially polymorphic data structures cannot be described by, *e.g*., XML schema \[[@B36]\], but serialization offers a method of losslessly preserving this flexible nature of Python objects. In PaPy, component interoperability is achieved by adhering to duck-typing programming patterns. By default, no intermediate pipeline results are stored. This behavior can be easily changed by explicitly adding Piper nodes for data serialization (*e.g*. JSON) and archiving (*e.g*. files) anywhere within a workflow. Inter-process communication (IPC) --------------------------------- IPC may occur between a single local manager process (Figure [4](#F4){ref-type="fig"}), local pool processes/threads and, potentially, any remote processes (if operating in distributed mode, across networked machines). Data serialization and transmission is an important aspect, and often bottleneck, in parallel computing \[[@B37]\], because of the involved computational cost and utilized bandwidth. PaPy provides functionality for direct connections between processing nodes in order to mostly bypass the manager process (Figure [4](#F4){ref-type="fig"}). In essence, the mechanism is that the source component makes data available (*e.g*. by storing it as a file or opening a network socket) and communicates only the information needed to locate and access it by the destination component. PaPy provides a few mechanisms of direct IPC (files, Unix pipes, network sockets) as described in Table [3](#T3){ref-type="table"}; an earlier implementation of PaPy, utilizing the posix\_ipc shared memory library for direct IPC, was found to be no faster than Unix pipes. It is also possible to avoid IPC altogether, by grouping data-processing functions: A PaPy processing node is guaranteed to evaluate a single data item within the same process, meaning that no IPC occurs between functions within a single Piper instance. Thus, any linear, non-branching segment of a workflow can be easily collapsed into a single Piper node, as illustrated in Figure [1D](#F1){ref-type="fig"}. Default automation of this locality-enforcing behavior (*i.e*., automatically collapsing consecutive nodes in a linear segment of a pipeline) may be implemented in future versions of PaPy. ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Inter-process communication in PaPy**. The possible means of IPC between two linked pipers ($\mathcal{P}_{1}$, $\mathcal{P}_{2}$) in a PaPy graph are indicated (A), and the dashed allow (B) denotes the possibility of direct IPC via sockets, pipes, shared memory, *etc*. (Table 3). Communication between local and remote processes utilizes RPyC, as described in the text. :::  ::: ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### PaPy\'s interprocess communication (IPC) methods ::: Method OS Remarks -------- ----------- ----------------------------------------------------------------------------------------------------- socket all Communication, *via*TCP sockets, between hosts connected within a computer network pipes Unix like Communication between processes on a single host files all The file storage location must be accessible by all processes (*e.g*., over an NFS or Samba share). PaPy provides the following direct IPC methods (see also Fig. 4), valid on operating systems as indicated. ::: Monitoring ---------- Interactive, real-time viewing of execution progress is valuable for parallel programs in general (*e.g*. for purposes of debugging), and it is particularly useful in workflow execution and editing to be able to log component invocations during the workflow lifecycle \[[@B5]\]. The information should be detailed enough to allow troubleshooting of errors and performance issues or auditing, and is a key aspect of the general issue of data provenance (data and metadata recording, management, workflow reproducibility). The process of capturing information about the operation of an application is often called \'logging\'. For this purpose, PaPy utilizes the Python standard library\'s \'logging\' facility, and automatically records logging statements emitted at various (user-specifiable) levels of detail or severity - *e.g*., DEBUG, INFO, WARNING, ERROR can be logged by the papy and numap modules. Python supplies rich exception-handling capabilities, and user-written functions need only raise meaningful exceptions on errors in order to be properly monitored. Robustness ---------- Sooner or later in the life-cycle of a workflow, an error or exception will occur. This will most likely happen within a Worker-wrapped function as a result of bogus or unforseen input data, timeouts, or bugs triggered in external libraries. PaPy is resilient to such errors, insofar as exceptions raised within functions are caught, recorded and wrapped into \'placeholders\' that traverse the workflow down-stream without disrupting its execution. The execution log will contain information about the error and the data involved. Results & Discussion ==================== While a thorough description of PaPy\'s usage, from novice to intermediate to advanced levels, lies beyond the scope of this article, the following sections *(i)*illustrate some of the basic features of PaPy and its accompanying NuBio package (Examples 1, 2, 3), (*ii*) provide heavily-annotated, generic pipeline templates (see also Additional File [1](#S1){ref-type="supplementary-material"}), *(iii)*outline a more intricate PaPy workflow (simulation-based loop refinement, the details of which are in the Additional File [1](#S1){ref-type="supplementary-material"}), and (*iv*) briefly consider issues of computational efficiency. Example 1: PaPy\'s Workers and Pipers ------------------------------------- The basic functionality of a node (Piper) in a PaPy pipeline is literally defined by the node\'s Worker object (Table [2](#T2){ref-type="table"} and the *\'W*\' in Figure [1A](#F1){ref-type="fig"}). Instances of the core Worker class are constructed by wrapping functions (user-created or external), and this can be done in a highly general and flexible manner: A Worker instance can be constructed *de novo*(as a single, user-defined Python function), from multiple pre-defined functions (as a tuple of functions and positional or keyworded arguments), from another Worker instance, or as a composition of multiple Worker instances. To demonstrate these concepts, consider the following block of code: `from papy import Worker` `from math import radians, degrees, pi` `def papy_radians(input): return radians(input[0])` `def papy_degrees(input): return degrees(input[0])` `worker_instance1 = Worker(papy_radians)` `worker_instance1([90.]) # returns 1.57 (i.e., pi/2)` `worker_instance2 = Worker(papy_degrees)` `worker_instance2([pi]) # returns 180.0` `# Note double parentheses (tuple!) in the following:` `worker_instance_f1f2 = Worker((papy_radians, papy_degrees)) worker_instance_f1f2([90.]) # returns 90. (rad/deg invert!)` `# Another way, compose from Worker instances:` `worker_instance_w1w2 = Worker((worker_instance1,\worker_instance2))` `# Yields same result as worker_instance_f1f2([90.]): worker_instance_w1w2([90.])` In summary, Worker objects fulfill several key roles in a pipeline: They (*i*) standardize the input/output of nodes (pipers); (*ii*) allow one to re-use and re-combine functions into custom nodes; (*iii)*provide a pipeline with graceful fault-tolerance, as they catch and wrap exceptions raised within their functions; and (*iv*) wrap functions in order to enable them to be evaluated on remote hosts. The following block of Python illustrates the next \'higher\' level in PaPy\'s operation - Encapsulating Worker-wrapped functions into Piper instances. In addition to what is done (Workers), the Piper level wraps NuMap objects to define the mode of execution (serial/parallel, processes/threads, local/remote, ordered/unordered output, *etc*.); therefore, a Piper can be considered as the minimal logical processing unit in a pipeline (squares in Figure [1](#F1){ref-type="fig"}, [2A](#F2){ref-type="fig"}, [3A](#F3){ref-type="fig"}, [4A](#F4){ref-type="fig"}). `from papy import Worker, Piper from numap import NuMap` `from math import sqrt` `# Square-root worker:` `def papy_sqrt(input): return sqrt(input[0])` `sqrt_worker = Worker(papy_sqrt)` `my_local_numap = NuMap() # Simple (default) NuMap instance` `# Fancier NuMap worker-pool:` `# my_local_numap = NuMap(worker_type ="thread",\` `# worker_num = 4, stride = 4)` `my_piper_instance = Piper(worker = sqrt_worker, \ parallel = my_local_numap)` `my_piper_instance([1,2,3]).start() list(my_piper_instance)` `# returns [1.0, 1.414..., 1.732...]` `# following will not work, as piper hasn't been stopped:` `my_piper_instance.disconnect()` `# ...but nflow the call to disconnect will work:` `my_piper_instance.stop() my_piper_instance.disconnect()` The middle portion (lines 7-12) of the above block of code illustrates two examples of NuMap construction, which, in turn, defines the mode of execution of a PaPy workflow - Either a default NuMap (line 7), or one that specifies multi-threaded parallel execution using four workers (lines 9-12). Example 2: Basic sequence objects in NuBio ------------------------------------------ As outlined in the earlier *Bioinformatics workflows*section, the NuBio package was written to extend PaPy\'s feature set by including basic support for handling biomolecular data, in as flexible and generalized a manner as possible. To this end, NuBio represents all biomolecular data as hierarchical, multidimensional entities, and uses standard programming concepts (such as \'slices\') to access and manipulate these entities. For instance, in this frame-work, a single nucleotide is a scalar object comprised of potentially *n*-dimensional entities (*i.e.*, a character), a DNA sequence or other nucleotide string is a vector of rank-1 objects (nucleotides), a multiple sequence alignment of *n*sequences is analogous to a rank-3 tensor (an (*n*-dim) array of (1-dim) strings, each composed of characters), and so on. The following blocks of code tangibly illustrate these concepts (output is denoted by \'- \> \'): `from nubio import NtSeq, CodonSeq` `from string import upper, lower` `# A sequence of eight codons:` `my_codons_1 = CodonSeq('GUUAUUAGGGGUAUCAAUAUAGCU')` `# ...and the third one in it, using the 'get_child' method:` `my_codons_1_3 = my_codons_1.get_child(2)` `# ...and its raw (internal) representation as a byte string` `# (ASCII char codes):` `print my_codons_1_3` `-> Codon('b', [65, 71, 71])` `# Use the 'tobytes' method to dump as a char string: print my_codons_1_3.tobytes()` `-> AGG` `# 'get_items' returns the codon as a Python tuple: print my_codons_1.get_item(2)` `-> ('A', 'G', 'G')` `# The string 'UGUGCUAUGA' isn't a multiple of 3 (rejected` `# as codon object), but is a valid NT sequence object:` `my_nts_1 = NtSeq('UGUGCUAUGA')` `# To make its (DNA) complement:` `my_nts_1_comp = my_nts_http://1.complement() print my_nts_1_complement ()` `-> ACACGATACT` `# Sample application of a string method, rendering the` `# original sequence lowercase (in-place modification):` `my_nts_1.str(method="lower")` `print my_nts_1.tobytes() -> ugugcuauga` `# Use NuBio's hierarchical representations and data conta-` `# iners to perform simple sequence(/string) manipulation:` `# grab nucleotides 3-7 (inclusive) from the above NT string:` `my_nts_1_3to7 = my_nts_1.get_chunk((slice(2, 7), slice(0,1))) print my_nts_1_3to7.tobytes()` `-> ugcua` `# Get all but the first and last (-1) NTs from the above NT` `# string:` `my_nts_1_NoEnds = my_nts_1.get_chunk((slice(1, -1), \ slice(0,1)))` `print my_nts_1_NoEnds.tobytes()-> gugcuaug` `# Get codons 2 and 3 (as a flat string) from the codon string:` `my_codons_1_2to3 = my_codons_1.get_chunk((slice(1,3,1), \` `slice(0,3,1)))` `print my_codons_1_2to3.tobytes() -> AUUAGG` `# Grab just the 3rd (wobble) position NT from each codon:` `my_codons_1_wobble = my_codons_1.get_chunk((slice(0,10,1), n` `slice(2,10,1)))` `print my_codons_1_wobble.tobytes() -> UUGUCUAU` For general convenience and utility, NuBio\'s data structures can access built-in dictionaries provided by this package (*e.g*., the genetic code). In the following example, a sequence of codons is translated: `# Simple: Methionine codon, followed by the opal stop codon:` `nt_start_stop = NtSeq("ATGTGA")` `# Instantiate a (translate-able) CodonSeq object from this:` `codon_start_stop = CodonSeq(nt_start_stop.data)` `# ...and translate it:` `print(codon_start_stop.translate()) ->` `-> AaSeq(M*)` `print(codon_start_stop.translate(strict = True))` `-> AaSeq(M)` The follflowing block illustrates manipulations with protein sequences: `from nubio import AaSeq, AaAln` `# Define two protein sequences. Associate some metadata (pI,` `# MW, whatever) with the second one, as key/value pairs:` `seq1 = AaSeq('MSTAP')` `seq2 = AaSeq('M-TAP', meta='my_key':'my_data')` `# Create an 'alignment' object, and print its sequences:` `aln = AaAln((seq1, seq2))` `for seq in aln: print seq` `-> AaSeq(MSTAP)` `-> AaSeq(M-TAP)` `# Print the last 'seq' ("M-TAP"), sans gapped residues` `# (i.e., restrict to just the amino acid ALPHABET):` `print seq.keep(seq.meta['ALPHABET'])` `-> AaSeq(MTAP)` `# Retrieve metadata associated with 'my_key': aln[1].meta['my_key']` `-> 'my_data'` Example 3: Produce/spawn/consume parallelism -------------------------------------------- Loosely-coupled data can be parallelized at the data item-level *via*the produce/consume/spawn idiom (Figure [2](#F2){ref-type="fig"}). To illustrate how readily this workflow pattern can be implemented in PaPy, the source code includes a generic example in `doc/examples/hello_produce_spawn_consume.py`. The \'`hello_*`\' files in the `doc/examples/` directory provide numerous other samples too, including creation of parallel pipers, local grids as the target execution environment, and a highly generic workflow template. Generic pipeline templates -------------------------- To assist one in getting started with bioinformatic pipelines, PaPy also includes a generic pipeline template (Additional File [1](#S1){ref-type="supplementary-material"} §1.1; \'`doc/workflows/pipeline.py`\') and a sample workflow that illustrates papy/nubio integration (Additional File [1](#S1){ref-type="supplementary-material"} §1.2; \'`doc/examples/hello_workflow.py`\'). The prototype pipeline includes commonly encountered workflow features, such as the branch/merge topology. Most importantly, the example code is annotated with descriptive comments, and is written in a highly modular manner (consisting of six discrete stages, as described in Additional File [1](#S1){ref-type="supplementary-material"}). The latter feature contributes to clean workflow design, aiming to decouple those types of tasks which are logically independent of one another *(e.g*, definitions of worker functions, workflow topology, and compute resources need not be linked). Advanced example: An intricate PaPy workflow -------------------------------------------- In protein homology modelling, potentially flexible loop regions that link more rigid secondary structural elements are often difficult to model accurately (*e.g*. \[[@B38]\]). A possible strategy to improve the predicted 3 D structures of loops involves better sampling the accessible conformational states of loop backbones, often using simulation-based approaches (*e.g*. \[[@B39]\]). Though a complete, PaPy-based implementation of loop refinement is beyond the scientific scope of this work, we include a use-case inspired by this problem for two primary reasons: (1) The workflow solution demonstrates how to integrate third-party software packages into PaPy (*e.g*., Stride \[[@B40]\] to compute loop boundaries as regions between secondary structural elements, MMTK \[[@B41]\] for energy calculations and simulations); (2) Loop-refinement illustrates how an intricate structural bioinformatics workflow can be expressed as a PaPy pipeline. This advanced workflow demonstrates constructs such as nested functions, forked pipelines, the produce/s-pawn/consume idiom, iterative loops, and conditional logic. The workflow is schematized in Figure [5](#F5){ref-type="fig"} and a complete description of this case study, including source code, can be found in Additional File [1](#S1){ref-type="supplementary-material"} (§2 and Fig. S1, showing parallelization over loops and bounding spheres). ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **MD-based loop refinement**. This pipeline illustrates a series of steps to perform MD simulation-based refinement of homology model loops, using the workflow paradigm. Piper nodes are numbered in this figure (for ease of reference), and can be classified into *(i*) those that handle input/output (grey; 1, 10); (*ii*) those that execute calculations serially (light blue; 2, 4, 5, 6, 8, 9); and (*iii)*more compute-intensive nodes, which utilize a parallel NuMap (orange; 3, 7). A detailed description of this use-case is available in the *Additional File*(§2). :::  ::: Computational efficiency ------------------------ Achieving speed-ups of workflow execution is non-trivial, as process-based parallelism involves *(i)*computational overhead from serialization; (*ii*) data transmission over potentially low-bandwidth/high-latency communication channels; (*iii)*process synchronization, and the associated waiting periods; and (*iv*) a potential bottelneck from the sole manager process (Figure [4](#F4){ref-type="fig"}). PaPy allows one to address these issues. Performance optimization is an activity that is mostly independent of workflow construction, and may include collapsing multiple processing nodes that preserves locality and increase granularity (Figure [1](#F1){ref-type="fig"}), employing direct IPC (Figure [4](#F4){ref-type="fig"} Table [3](#T3){ref-type="table"}), adjustments of speedup/memory trade-off parameter (Figure [3](#F3){ref-type="fig"}), allowing for unordered flow of data and, finally, balanced distribution of computational resources among segments of the pipeline. The PaPy documentation further addresses these intricacies, and suggests possible optimization solutions for common usage scenarios. Further information ------------------- In addition to full descriptions of the generic PaPy pipeline template and the sample loop-refinement workflow (Additional File [1](#S1){ref-type="supplementary-material"}), further information is available. In particular, the documentation distributed with the source-code provides extensive descriptions of both conceptual and practical aspects of workflow design and execution. Along with overviews and introductory descriptions, this thorough (≈50-page) manual includes *(i)*complete, step-by-step installation instructions for the Unix/Linux platform; (*ii*) a *Quick Introduction*describing PaPy\'s basic design, object-oriented architecture, and core components (classes), in addition to hands-on illustrations of most concepts *via*code snippets; *(iii*) an extensive presentation of parallelism-related concepts, such as maps, iterated maps, NuMap, and so on; (*iv*) a glossary of PaPy-related terms; and (*v*) because PaPy is more of a library than a program, a complete description of its application programming interface (API). Although a thorough analysis of PaPy\'s relationship to existing workflow-related software solutions lies beyond the scope of this report, Additional File [1](#S1){ref-type="supplementary-material"} (§4) also includes a comparative overview of PaPy, in terms of its similarities and differences to an example of a higher-level/heavyweight WMS suite ([KNIME]{.smallcaps}). Conclusions =========== PaPy is a Python-based library for the creation and execution of cross-platform scientific workflows. Augmented with a \'NuMap\' parallel execution engine and a \'NuBio\' package for generalized biomolecular data structures, PaPy also provides a lightweight tool for data-processing pipelines that are specific to bioinformatics. PaPy\'s programming interface reflects its underlying dataflow and object-oriented programming paradigms, and it enables parallel execution through modern concepts such as the worker-pool and producer/consumer programming patterns. While PaPy is suitable for pipelines concerned with data-processing and analysis (data *reduction*), it also could be useful for replicated simulations and other types of workflows which involve computationally-expensive components that generate large volumes of data. List of abbreviations ===================== API: application programming interface; DAG: directed acyclic graph; FBP: flow-based programming; IPC: inter-process communication; MD: molecular dynamics; RPyC: remote Python calls; shm: shared memory; WMS: workflow management system Authors\' contributions ======================= MC wrote PaPy; MC and CM tested the code and wrote the paper. All authors read and approved the final manuscript. Availability and requirements ============================= • **Project name**: PaPy • **Project homepage**: <http://muralab.org/PaPy> • **Operating system**: GNU/Linux • **Programming language**: Python • **Other requirements**: A modern release of Python (≥2.5) is advised; the standard, freely-available Python package RPyC is an optional dependency (for distributed computing). • **License**: New BSD License • **Any restrictions to use by non-academics**: None; the software is readily available to anyone wishing to use it. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **This supplementary file provides the following material, along with complete and fully annotated source-code for each example: (§1)**. Two simple examples of workflows (useful as pipeline templates), one showing a generic *forked*pipeline and the other focusing on the usage of NuBio; (§2) A detailed description of our more complicated case-study (simulation-based refinement of homology model loops); (§3) Further notes on PaPy\'s platform independence, as well as the relationship between the Dagger and Plumber classes; (§4) A brief overview of PaPy\'s scope and implementation, in relation to a fully-integrated WMS suite([KNIME]{.smallcaps}). ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ The Univ of Virginia and the Jeffress Memorial Trust (J-971) are gratefully acknowledged for funding this work.

PubMed Central

2024-06-05T04:04:17.219109

2011-2-25

PMC3051903

Background ========== Rasagiline (N-propargyl-1-(R)-aminoindan) and selegiline are drugs prescribed for the treatment of Parkinson\'s disease. Both are believed to act by inhibition of monoamine oxidase B (MAO B). However, both are metabolized in a different way: rasagiline gives rise to aminoindan, a compound reported to have neuroprotective capabilities of its own, whereas selegiline gives rise to the neurotoxic metabolite methamphetamine \[[@B1],[@B2]\]. Similar electropharmacograms obtained by quantitative brain field potential analysis were obtained from freely moving rats in the presence of rasagiline and its metabolite aminoindan (not inhibiting monoamine oxidase B). Selegiline-on the other hand-produced a time dependent biphasic action presumably due to the action of its active metabolites \[[@B3]\]. Available evidence suggests an additional mechanism of action for these drugs independently from MAO B inhibition. For example, a neuroprotective action unrelated to MAO inhibition has been reported by \[[@B4]\] for rasagiline as well as for its major metabolite 1-(R)-aminoindan \[[@B5]\]. For review of neuroprotective effects of rasagiline and aminoindan see \[[@B6]\]. But again, no [final]{.underline} mechanism has been reported to explain the proposed neuroprotective action. There is solid evidence of an involvement of glutamatergic transmission in neuroprotection. This calls for an experimental setup to dissect the possible interference of these compounds within the glutamatergic system. To our knowledge, no neurophysiological techniques have been applied up to now to characterize the effects of these compounds on glutamatergic transmission in the hippocampus. This model should be suitable since the communication between Schaffer-Collaterals and the hippocampal pyramidal cells takes place by using glutamate as transmitter. The hippocampus slice preparation is a validated model for direct analysis of interaction of substances with living neuronal tissue \[[@B7],[@B8]\]. Due to the preservation of the three dimensional structure of the hippocampus, drug effects on the excitability of pyramidal cells can be studied in a unique manner. Electric stimulation of Schaffer Collaterals leads to release of glutamate resulting in excitation of the postsynaptic pyramidal cells. The result of the electrical stimulation can be recorded as a so-called population spike (pop-spike). The amplitude of the resulting population spike represents the number of recruited pyramidal cells and relates to the extent of glutamatergic transmission. The advantage of the model not only consists in the possibility of physiological recording in vitro during 8 hours but also to modify the excitability of the system in order to create pathophysiological conditions like transient oxygen and glucose deprivation (OGD) \[[@B9]\]. The first part of the present investigation aimed at the characterization of the effects of rasagiline and its metabolite aminoindan in comparison to selegiline on glutamatergic transmission within a physiological environment and under pathophysiological conditions. The principle of the second part of the investigation was to use the enhancement of the pyramidal cell response (increased amplitudes of population spike) in the presence of highly specific and selective agonists of different glutamate receptors as a challenge. Accordingly, these responses were followed in the presence of several concentrations of rasagiline, aminoindan and selegiline. This approach should reveal great similarities between rasagiline and aminoindan on one side and a great difference to the action of selegiline on the other side. Methods ======= Hippocampus slices were obtained from 43 adult male Sprague-Dawley rats (Charles River Wiga, Sulzbach, Germany). Rats were kept under a reversed day/night cycle for 2 weeks prior start of the experiments, to allow recording of in vitro activity from slices during the active phase of their circadian rhythm \[[@B10],[@B11]\]. Animals were exsanguinated under ether anaesthesia, the brain was removed and the hippocampal formation was isolated under microstereoscopic sight. The midsection of the hippocampus was fixed to the table of a vibrating microtome (Rhema Labortechnik, Hofheim, Germany) using a cyanoacrylate adhesive, submerged in chilled bicarbonate-buffered saline (artificial cerebrospinal fluid (ACSF): NaCl: 124 mM, KCl: 5 mM, CaCl2: 2 mM, MgSO4: 2 mM, NaHCO3: 26 mM, glucose: 10 mM, and cut into slices of 400 μm thickness. All slices were pre-incubated for at least 1 h in Carbogen saturated ACSF (pH 7.4) in a pre-chamber before use \[[@B12]\]. During the experiment the slices were held and treated in a special superfusion chamber (List Electronics, Darmstadt, Germany) according to \[[@B13]\] at 35°C \[[@B14]\]. Five slices per rat were used. The preparation was superfused ACSF at 220 ml/h. Electrical stimulation (200 μA constant current pulses of 200 μs pulse width) of the Schaffer Collaterals within the CA2 area and recording of extracellular field potentials from the pyramidal cell layer of CA1 \[[@B12]\] was performed according to conventional electrophysiological methods using the \"Labteam\" Computer system \"NeuroTool\" software package (MediSyst GmbH, Linden, Germany). Measurements were performed at 10 min intervals in order to avoid potentiation mechanisms after single stimuli (first recording at 10 min is discarded for stability purposes). Four stimulations-each 20 s apart-were averaged for each time point. After averaging the last three of four responses to single stimuli (SS) to give one value, potentiation was induced by applying a theta burst type pattern (TBS; \[[@B7]\]). The mean amplitude of three signals 20 seconds apart were averaged to give the mean of absolute voltage values (microvolt) ± standard error of the mean for each experimental condition (single stimulus or theta burst stimulation). Electrical stimulation of the Schaffer Collaterals within the C2 area with single stimuli resulted in stable responses of the pyramidal cells in form of population spikes with an amplitude of about 1 mV and about 2 mV after theta burst stimulation (TBS) (representative example is given in Figure [1](#F1){ref-type="fig"}). Oxygen and Glucose deprivation (OGD) was performed in analogy to \[[@B15]\] by shutting off oxygen and glucose for 10 minutes. In this case glucose was replaced by sucrose. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Documentation of original signals showing the effects of using single stimuli (SS) or theta burst stimulation (TBS) in control slices (left panel) or in the presence of rasagiline (right panel) diluted in artificial cerebro-spinal fluid (ASCF)**. The amplitude is calculated from baseline to the down reflection of the signal (shadowed). Stimulus artefacts are omitted for the sake of clarity. Scales: Time is given in milliseconds (ms), amplitude in millivolt (mV). :::  ::: For stimulation of glutamate receptors (NMDA, AMPA, Kainate and metabotropic receptor) four agonists were used, respectively: *trans*-1-Aminocyclobutan-1,3-dicarboxylic acid (ACBD; \[[@B16]\]), (S)-(-)-α-Amino-5-fluoro-3,4-dihydro-2,4-dioxo-1(2*H*)-pyrimidinepropanoic acid (S-Fluorowillardiine; \[[@B17]-[@B19]\]), (RS)-2-Amino-3-(3-hydroxy-5-tert-butyliosxazol-4-yl)propanoic acid (ATPA; \[[@B20]-[@B23]\]) and (±)-1-Aminocyclopentane-*trans*-1,3-dicarboxylic acid (t-ACPD; \[[@B24]-[@B26]\]). All agonists were tested in pilot experiments in order to detect a concentration leading to strong increases of population spike amplitude in the presence of single stimuli (SS) and theta burst stimulation (TBS). Origin of the chemicals is given in Table [1](#T1){ref-type="table"}. The allowance to keep animals for this purpose was obtained from governmental authorities, dated 2009-09-01 under the document Nr. 0200052529. Experiments were performed in accordance with the German Animal Protection Law. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Compounds used ::: ----------------------------- ------------------ --------------------------- rasagiline CH.B: 255400204 TEVA Pharma GmbH selegiline CH.B: 0405BG/01 BIO TREND aminoindan CH.B:087K4619 Sigma-Aldrich Chemie GmbH trans-ACBD CH.B: 0048BN/01 BIO TREND trans-ACPD CH.B: 0053BN/01 BIO TREND (S)-(-) S-Fluorowillardiine CH.B: 9A/36714 BIO TREND (RS)-ATPA CH.B: 0096 BN/01 BIO TREND ----------------------------- ------------------ --------------------------- Origin of chemical compounds used for this experimental series. ::: Results ======= a) Neurophysiological evidence for neuroprotective effects ---------------------------------------------------------- Using single stimulus administration rasagiline and - to a lesser degree-selegiline attenuated the pyramidal cells response significantly at a concentration of 30 μM. In the presence of aminoindan, however, significant attenuation was observed already at 15 μM. At a concentration of 50 μM rasagiline and aminoindan reduced the amplitude by about 60%, selegiline by about 40%. The course of the concentration dependence is given in Figure [2](#F2){ref-type="fig"} for all three compounds. Under the condition of theta burst stimuli, rasagiline was able to reduce the signal amplitude significantly at 10 μM, whereas the effect of selegiline reached statistical significance at a concentration of 15 μM. The effects of aminoindan became statistically significant already at a concentration of 7.5 μM. Thus, in the presence of rasagiline, aminoindan and selegiline a concentration dependent decrease of the amplitudes of the population spike could be observed during single shock stimulation as well as during theta burst stimulation. Effects of selegiline were weakest (Figure [2](#F2){ref-type="fig"}). ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Concentration dependent effects of rasagiline, aminoindan and selegiline on pyramidal cell activity in terms of changes of population spike amplitude**. Results from single slices as obtained after single stimuli (SS) and after theta burst stimuli (TBS). Data are given in microvolt for a mean of four slices and standard error of the mean. Stars indicate statistical significance of p \< 0.05 in comparison to control. :::  ::: In order to proof, that this attenuation of glutamatergic transmission could be related to neuroprotective features of the compounds, a pathophysiological situation was created in slices by turning off oxygen and glucose for 10 minutes. This procedure succeeded in a breakdown of the signal amplitudes after electrical single stimuli by about 75%. This breakdown was nearly totally prevented (p \< 0.05) by the presence of a concentration of 5 μM rasagiline or aminoindan in the superfusion medium but rarely by selegiline (p \< 0.1). Time courses of the experiments are depicted in Figure [3](#F3){ref-type="fig"}. This effect was still visible but not statistically significant from control at time period 60 and 70 minutes after start of the experiment. Thus, rasagiline and aminoindan showed a clearly better neuroprotective effect than selegiline in this model. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Complete time course of experiments**. Bar indicates 10 min of oxygen and glucose deprivation (OGD) before measurement. Nearly complete prevention of OGD-induced break down of population spike amplitude (s. control) by rasagiline and aminoindan but only to a minor degree by selegiline (p \< 0.1). Stars indicate statistical significance of p \< 0.05 in comparison to control. :::  ::: b) Functional interference with NMDA receptor activation -------------------------------------------------------- In order to test a possible interference of rasagiline, aminoindan or selegiline with NMDA receptor activation, glutamatergic neurotransmission was modulated by ACBD, a very potent and selective NMDA receptor agonist. A concentration of 50 nM induced a significant enhancement of the population spike amplitude. Under the condition of single stimuli increase of the amplitude from 1106 to 1940 μV (176% of control value) could be observed (Figure [4](#F4){ref-type="fig"}). In the presence of rasagiline the amplitude remained at control value (changing from 1102 to 1185 μV). Statistically significant differences to the ACBD induced increase were already observed with a concentration of 1 μM of rasagiline (p \< 0.01). ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Concentration dependent effects of rasagiline, aminoindan and selegiline in the presence of single stimuli (SS) or theta burst stimuli (TBS) after stimulation of the NMDA glutamate receptor by ACBD (n = 4 slices +- SEM)**. Statistically significant attenuation of pop-spike amplitude in comparison to ACBD-induced increases were obtained in the presence of 1 μM of rasagiline or aminoindan following single stimuli (SS). During theta burst stimulation (TBS) already a concentration of 0.3 μM of rasagiline or aminoindan became statistically significant. Stars indicate statistical significance of p \< 0.05 in comparison to control. :::  ::: Similar results were obtained in the presence of theta burst stimulation. Presence of ACBD in the superfusion medium increased the amplitude to 3173 μV. Rasagiline at a concentration of 5 μM attenuated the ACBD-induced signal down to 2074 μV (about control value). A statistically significant difference to ACBD-induced values was obtained at the very low concentration of 300 nM of rasagiline and aminoindan (p \< 0.01). Thus, a concentration dependent attenuation of NMDA receptor induced increases of population spike amplitudes was recognized. Nearly identical results were seen in the presence of aminoindan (s. Figure [4](#F4){ref-type="fig"}). On the opposite, virtually no effect could be seen in the presence of selegiline up to a concentration of 5 μM. Thus, a clear difference could be observed between rasagiline and aminoindan on one site and selegiline on the other side with respect to functional antagonism of NMDA glutamate receptor stimulation. c) Functional interference with AMPA receptor activation -------------------------------------------------------- In order to test a possible interference of rasagiline, aminoindan or selegiline with AMPA receptor activation, the glutamatergic neurotransmission was stimulated by fluorowillardiine, a very potent and selective AMPA receptor agonist. A concentration of 100 nM induced a significant enhancement of the population spike amplitude. Under the condition of single stimuli increase of the amplitude from 1135 to 1692 μV (151% of control value) could be observed (Figure [5](#F5){ref-type="fig"}). In the presence of 5 μM of rasagiline the amplitude remained at control value (changing from 1089 to 1137 μV). ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **Concentration dependent effects of rasagiline, aminoindan and selegiline in the presence of single stimuli (SS) or theta burst stimuli (TBS) after stimulation of the AMPA glutamate receptor by fluorowillardiine (n = 4 slices +- SEM)**. Statistically significant attenuation of pop-spike amplitude in comparison to fluorowillardiine-induced increases were obtained in the presence of 1 μM of rasagiline or aminoindan following single stimuli (SS). During theta burst stimulation (TBS) already a concentration of 1 μM of rasagiline or aminoindan became statistically significant. Stars indicate statistical significance of p \< 0.05 in comparison to control. :::  ::: Statistically significant differences to the effect of fluorowillardiine were observed with 2.5 μM of rasagiline (p \< 0.02) and aminoindan (p \< 0.01). Similar results were obtained in the presence of theta burst stimulation. Fluorowillardiine increased the amplitude to 2873 μV. Rasagiline at a concentration of 5 μV attenuated the fluorowillardiine-induced signal to a control value of 1950 μV. A statistically significant difference to fluorowillardiine-induced values was obtained at the very low concentration of 1 μM of rasagiline (p \< 0.05). Even stronger effects were seen in the presence of aminoindan (s. Figure [2](#F2){ref-type="fig"}). Aminoindan attenuated the amplitude of the population spike from 2888 μV down to 1152 μV, which is far beyond the control values. Statistical significance in comparison to AMPA receptor stimulation was obtained already at 1 μM of aminoindan. Thus, a concentration dependent attenuation of AMPA receptor induced increases of population spike amplitudes was recognized for rasagiline and even more for its metabolite aminoindan. On the opposite, virtually no effect could be seen in the presence of selegiline up to a concentration of 5 μM. Thus, a clear difference could be observed between rasagiline and aminoindan on one site and selegiline on the other side with respect to functional antagonism also of AMPA glutamate receptor stimulation. d) Functional interference with Kainate receptor activation ----------------------------------------------------------- In order to test a possible interference of rasagiline, aminoindane or selegiline with Kainate receptor activation, glutamatergic neurotransmission was stimulated by ATPA, a very potent and selective Kainate receptor agonist. A concentration of 50 nM induced a significant enhancement of the populations spike amplitude. Under the condition of single stimuli increase of the amplitude from 1097 to 1904 μV (174% of control value) could be observed (Table [2](#T2){ref-type="table"}). Virtually no effect on this signal could be seen in the presence of rasagiline or aminoindan up to a concentration of 5 μM. However, in the presence of selegiline the amplitude remained at control values (changing from 1083 to 1257 μV). Statistically significant differences to the ATPA induced increase were observed already with 2.5 μM of selegiline (p \< 0.01). Similar results were obtained in the presence of theta burst stimulation. ATPA increased the amplitude to 3055 μV. Selegiline at a concentration of 5 μV attenuated the ATPA-induced signal down to 2134 μV. Thus, a concentration dependent attenuation of Kainate receptor induced increases of population spike amplitudes was recognized only for selegiline but not for rasagiline or aminoindan. Again a clear difference could be observed between the effects of rasagiline and aminoindan on one site and selegiline on the other side, but in a reversed manner. ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### Amplitudes of population spike ::: Single Stimulus Theta Burst Stimulus -------------------------- -------------------------- --------------------------- **RS-ATPA 0.05 μM** -1904.2 ± 55.4 -3054.5 ± 42.2 **+ Rasagiline 5.00 μM** -1789.0 ± 54.6 n.s -2998.5 ± 108.3 n.s **+ Aminoindan 5.00 μM** -1946.1 ± 58.8 n.s -2850.8 ± 92.1 n.s **+ Selegiline 2.50 μM** -1616.1 ± 37.8 p \< 0.01 -2531.3 ± 136.4 p \< 0.01 **+ Selegiline 5.00 μM** -1256.7 ± 53.2 p \< 0.01 -2133.6 ± 48.4 p \< 0.01 Effect of selegiline on Kainate receptor dependent increase of population spike amplitude, but lack of effect by rasagiline or aminoindan. Values are given as mean of n = 4 slices +- S.E.M. Statistical significance to ATPA signal is given as p-value. ::: e) Functional interference with metabotropic glutamate receptor activation -------------------------------------------------------------------------- In order to test a possible interference of rasagiline, aminoindan or selegiline with metabotropic glutamate receptor activation, ACPD, a very potent and selective metabotropic glutamate receptor agonist, was used to enhance pyramidal cell responses. A concentration of 25 nM induced a significant enhancement of the population spike amplitude. Under the condition of single stimuli increase of the amplitude from 1068 to 2003 μV (188% of control value) was observed (Figure [6](#F6){ref-type="fig"}). In the presence of rasagiline and SS conditions the amplitude remained at control value (changing from 1111 to 1134 μV). Statistically significant differences to the ACPD induced increase were observed with 1 μM of rasagiline (p \< 0.01). Similar results were obtained in the presence of theta burst stimulation. ACPD increased the amplitude to 3027 μV. Rasagiline at a concentration of 5 μV attenuated the ACBD-induced signal down to control value (2050 μV). Thus, a concentration dependent attenuation of the metabotropic glutamate receptor induced increases of population spike amplitudes was recognized. Nearly identical results were seen in the presence of aminoindan (s. Figure [6](#F6){ref-type="fig"}). On the opposite, virtually no effect could be seen in the presence of selegiline with a concentration of 5 μM. Thus, a clear difference could be observed between rasagiline and aminoindan on one site and selegiline on the other side with respect to functional antagonism of metabotropic glutamate receptor stimulation. ::: {#F6 .fig} Figure 6 ::: {.caption} ###### **Concentration dependent effect of rasagiline, aminoindan or selegiline in the presence of single stimuli (SS) or theta burst stimuli (TBS) after stimulation of the metabotropic glutamate receptor by ACPD**. Data are presented for the mean of n = 4 slices +- SEM. Statistically significant attenuation of pop-spike amplitude in comparison to ACPD-induced increases were obtained in the presence of 2.5 μM of rasagiline and aminoindan following single stimuli (SS) or theta burst stimulation. No effect was observed with selegiline. Stars indicate statistical significance of p \< 0.05 in comparison to control. :::  ::: Discussion ========== The rat hippocampal in vitro slice preparation has been used under physiological and pathophysiological conditions. Two monoamine oxidase B inhibitors (rasagiline and selegiline) and one compound lacking monoamine oxidase B inhibition (aminoindan) have been compared with respect to their ability to attenuate glutamatergic transmission represented by decreasing responses of pyramidal cells to electric stimulation. This result is interpreted to represent functional neuroprotection against massive glutamatergic excitation. Since simulation of ischemic conditions by oxygen-glucose deprivation (OGD) likewise resulted in showing that rasagiline and aminoindan prevented the breakdown of excitability, these effects probably also relate to neuroprotection (for selegiline this could be shown only to a minor degree). The term neuroprotection usually is taken to describe effects of drugs which might result in disease modifying actions during the course of Alzheimer\'s or Parkinson\'s illness. With respect to the latter, better neuroprotective and neurorestorative actions have been described for rasagiline in comparison to selegiline against lactacystin-induced nigrostriatal dopaminergic degeneration \[[@B27]\]. Also in a tissue culture model using PC12 cells under oxygen-glucose deprivation, rasagiline was clearly more effective than selegiline \[[@B28]\]. In addition, these authors could show that the neuroprotective effects of selegiline were blocked by its metabolite l-methamphetamine whereas aminoindan added to the effects of rasagiline. Taken together, all these findings suggest that the aminoindan moiety might be more important for neuroprotection than the propargyl moiety as suspected earlier \[[@B29]\]. Our results are therefore in line with earlier preclinical evidence for a neuroprotective action of rasagiline and its metabolite aminoindan. The functional impairment of glutamate dependent transmission obviously is not dependent on inhibition of monoamine oxidase B. However, a link between indirect inhibition of monoamine oxidase B and blockade of glyceraldehyde-3-phosphate dehydrogenase has recently been reported, which could also serve as an explanation for neuroprotective effects of rasagiline, selegiline and aminoindan \[[@B30]\]. The second part of the present investigation provides solid evidence that both rasagiline and selegiline interact functionally with glutamatergic receptor mediated transmission in addition to their known effects on MAO B, but by a different mechanism of action. The effects must be independent of the enzyme inhibition for the following reasons: firstly, aminoindan does not inhibit MAO B; secondly, both MAO inhibitors-rasagiline and selegiline-develop different receptor-mediated functional consequences within the glutamatergic system. This implicates that rasagiline and its metabolite aminoindan probably develop clinical properties different from that of selegiline. A hypothesis exists that particular glutamate receptors of the N-methyl-D-aspartate type are over-activated in a tonic rather than a phasic manner, which under chronic conditions leads to neuronal damage \[[@B31]\]. Another clinical implication could be suspected from the combined attenuation of NMDA and AMPA receptor dependent effects: simultaneous administration of sub-threshold dosages of NMDA and AMPA antagonists had a positive influence on the development of L-dopa induced dyskinesias in rats and monkeys \[[@B32]\]. These data are corroborated by earlier findings showing glutamate super sensitivity in the putamen of Parkinson patients treated chronically with L-dopa \[[@B33]\]. A common disadvantage of currently available rather unselective NMDA receptor antagonists is the occurrence of adverse effects like hallucinations \[[@B34]\]. Therefore, rasagiline and its metabolite aminoindan, which do not induce such side effects, but not selegiline with methamphetamine as its metabolite, should have a positive effect on motor fluctuations in Parkinson patients. With respect to the involvement of metabotropic glutamate receptors in Parkinson\'s disease there is evidence that they are involved in the pathologically altered circuitry in the basal ganglia. Several antagonists at this receptor alleviated L-dopa induced dyskinesia in 6-OH DA-lesioned rats \[[@B35]\]. Spontaneous firing of neurons in primate pallidum was increased by metabotropic glutamate receptor agonist DHPG and decreased by selective antagonists \[[@B36]\], which is in line with our results. Since glutamatergic input from the subthalamic nucleus shows over-activity during the disease, antagonists very well could compensate for this. Conclusions =========== Taking the effects of rasagiline and aminoindan together, not only neuroprotective effects could be measured but attenuation of NMDA, AMPA and metabotropic receptor mediated over-excitability of the glutamatergic system, also motor complications in Parkinson\'s disease-induced by imbalance of the glutamatergic system-should be ameliorated by a monotherapy with rasagiline. In addition, the newly discovered mechanism of action of rasagiline and aminoindan should be considered in the light of an extension of the clinical indication i.e. to treat Alzheimer\'s disease (for relation between Alzheimer\'s disease and glutamatergic system \[[@B37],[@B38]\]. Last not least, over-activation of the glutamatergic system also is one of the consequences during stroke, amyotropic lateral sclerosis, Huntington\'s disease and neuropathic pain \[[@B39]\]. It remains to be tested if pharmacological intervention by rasagiline and its metabolite aminoindan provides a valuable therapeutic strategy for treatment of these diseases in addition to treatment of Parkinson\'s disease. Authors\' contributions ======================= WD provided the electrophysiological technology, supervised the performance of the experiments, gave interpretation of the results and wrote the manuscript. JAH initiated the study and made major contributions to the design. He also provided important information on the pharmacology of the preparation. All authors read and approved the final manuscript. Acknowledgements ================ We greatly appreciate the experimental work as well as the data documentation performed by Mrs. Leoni Schombert. Mrs. Ingrid K. Keplinger-Dimpfel is acknowledged for her engagement in quality control.

PubMed Central

2024-06-05T04:04:17.222957

2011-2-21

PMC3051904

Background ========== Cancer is a complex genetic disease that exhibits remarkable complexity at the molecular level with multiple genes, proteins and pathways and regulatory interconnections being affected. Treating cancer is equally complex and depends on a number of factors, including environmental factors, early detection, chemotherapy and surgery. Cancer is being recognized as a systems biology disease \[[@B1],[@B2]\], as illustrated by multiple studies that include molecular data integration and network and pathway analyses in a genome-wide fashion. Such studies have advanced cancer research by providing a global view of cancer biology as molecular circuitry rather than the dysregulation of a single gene or pathway. For instance, reverse-engineering of gene networks derived from expression profiles was used to study prostate cancer \[[@B3]\], from which the androgen-receptor (AR) emerged as the top candidate marker to detect the aggressiveness of prostate cancers. Similarly, sub-networks were proposed as potential markers rather than individual genes to distinguish metastatic from non-metastatic tumors in a breast cancer study \[[@B4]\]. The authors in this study argue that sub-network markers are more reproducible than individual marker genes selected without network information and that they achieve higher accuracy in the classification of metastatic versus non-metastatic tumor signaling. Using genome-wide dysregulated interaction data in B-cell lymphomas, novel oncogenes have been predicted *in-silico*\[[@B5]\]. Finally, taking a signaling-pathway approach, a map of a human cancer signaling network was built \[[@B6]\] by integrating cancer signaling pathways with cancer-associated, genetically and epigenetically altered genes. Gene expression profiling has been widely used to investigate the molecular circuitry of cancer. In particular, DNA microarrays have been used in almost all of the main cancers and promise to change the way cancer is diagnosed, classified and treated \[[@B1]\]. However, expression analyses often result in hundreds of outliers, or differentially expressed genes between normal and cancer cells or across time points \[[@B2]\]. Owing to the large number of candidate genes, several different hypotheses can be generated to explain the variation in the expression patterns for a given study. In addition, the preferential expressions of some tissue-specific genes present additional challenges in expression data analyses. Nevertheless, recent systems approaches have attempted to prioritize differentially expressed genes by overlaying expression data with molecular data, such as interaction data \[[@B3]\], metabolic data \[[@B4]\] and phenotypic data \[[@B5]\]. Human malignancies are not just confined to genes and gene products, but also include epigenetic modifications such as DNA methylation and chromosomal aberrations. However, in order to effectively capture the properties that emerge in a complex disease, we need analytical methods that provide a robust framework to formally integrate prior knowledge of the biological attributes with the experimental data. The simplest heuristic will search for novel genes with a profile, in terms of differential expression and/or network connectivity, similar to those for which an association to disease has been well established (see, for instance, the approaches of \[[@B7],[@B8]\]). Boolean logic has been found to be optimal for such tasks. Within the context of cancer, Mukherjee and Speed \[[@B9]\] show how a series of biological attributes including ligands, receptors and cytosolic proteins, can be included in the network inference. More recently, Mukherjee and co-workers \[[@B10]\] introduced an approach based on sparse Boolean functions and applied it to the responsiveness of breast cancer cell lines to an anti-cancer agent. In addition, large scale literature-based Boolean models have been used to study apoptosis pathways as well as pathways connected with them. In this study, we propose a systems biology approach to predict disease-associated genes that are either not previously reported (novel) or poorly characterized and using colorectal cancer as a case study. To achieve this goal, we first implemented a Boolean logic schema derived from cancer-associated genes and developed a guilt-by-association (GBA) algorithm, which is subsequently applied in a genome-wide fashion. Although gene expression data are central to this approach, other biologically relevant functional attributes, such as tissue specificity, are treated as equally important in the Boolean logic informing the GBA algorithm. Finally, novel cancer-associated genes are interlaced with the known cancer-related genes in a weighted network circuitry aimed at identifying highly conserved gene interactions that impact cancer outcome. Results and Discussion ====================== Overview of the systems biology approach ---------------------------------------- Figure [1](#F1){ref-type="fig"} shows the schema of the proposed analytical approach. The first phase deals with the analysis of gene expression data to obtain a list of differentially expressed and condition specific genes. Conceptually, differentially expression differs from condition specificity in that the former requires the postulation of a contrast of interest while the latter enriches for genes that are preferentially expressed in one of the (potentially many) experimental conditions being considered. Nevertheless, the expectation is for a substantial overlap in the genes identified between either criterion. In the second phase, public databases are mined to compile a list of cancer-associated genes, non cancer-associated genes and functional attributes that are of relevance in the context of cancer. We considered a total of six functional attributes as follows: tissue specificity (TS), transcription factors (TF), post-translational modifications (PTM), kinases (KIN), secreted proteins (SEC) and CpG island methylation (MET)(see Additional File [1](#S1){ref-type="supplementary-material"} for rationale behind choosing these attributes). Table [1](#T1){ref-type="table"} summarizes the general characteristics of the functional attributes with a few prototypic examples of representative genes. Additional File [2](#S2){ref-type="supplementary-material"} provides the list of 749 cancer-associated genes that we compiled within each attribute. These features were selected based also on the fact that there is a strong functional interconnection among them and therefore we see the overlapping of these genes across attributes. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **The schema for the identification of novel genes associated with complex diseases**. The expression profiles from the cancer data are analyzed to predict differentially expressed and condition-specific genes. The functional attributes over-represented in cancer are selected and representative datasets from public resources mined. The common cancer fingerprints from cancer-associated genes are processed through Boolean logic to develop a guilt-by-association classifier which, applied to non-cancer-associated genes, predicts novel candidate cancer-associated genes. Finally, novel candidate genes are further analyzed using network theory approaches. :::  ::: ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Overview of the genetic, epigenetic and molecular information used in this study ::: -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Functional Attribute Role in Cancer Potential application Examples Data source Reference ---------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------- ----------------------------------------------------------------------------------------------------------------------------------------------------------- --------------------------------------------------------------------------------- ------------------------ Cancer associated genes Genes with at least 2 mutations in causally implicated in cancer. Includes oncogenes, tumor suppressor genes Potential drug targets and diagnostic or prognostic markers Oncogenes: *BCL2, c-Jun, ERG, ERBB2, RAS, c-MYC, c-SRC*\ <http://www.sanger.ac.uk/genetics/CGP/Census/>\ NA Tumor Suppressor Genes:\ <http://hprd.org/>\ *RB1, P53, APC, BRCA-1*,\ Reviews:\ *BRCA-2* (Futreal et al, 2004; Hahn et al, 2002; Mitelman, 2000; Vogelstein et al, 2004) Non-cancer associated genes There is no previous report of any causal mutation. If cancer association is established, these genes are either potential drug targets and diagnostic or prognostic markers *AMN, B3GNTL1, CDC42BPB*\ NCBI - Human Genome\ NA *S100A9, TRPM6, VNN1, ZIC2* <http://www.ncbi.nlm.nih.gov/projects/genome/guide/human/> Kinases More than 30% of cancer related genes are kinases and the most common domain that is encoded by cancer genes is the protein kinase domain Drug targets through inhibitors *c-Src, c-Abl, RAS*, mitogen activated protein (MAP) kinase, phosphotidylinositol-3-kinase (PI3K), *AKT*, and the epidermal growth factor receptor (EGFR) Human Kinome Consortium <http://kinase.com/human/kinome/> \[[@B15]\]\ \[[@B17],[@B51]\]\ Excretory - Secretory proteins Malignant tumors secrete increased levels of ES proteins non-invasive diagnostic or prognostic markers for early detection alpha-fetoprotein, *CD44*, kallikrein 6, kallikrein 10, *MIC-1* Secreted Protein Database (SPD)\ \[[@B52],[@B53]\]\ <http://spd.cbi.pku.edu.cn/> \[[@B54]\]\ \[[@B55]\] Transcription factors Overactivity of TFs at different stages of cancer is well documented and novel treatment strategies have been suggested for targeted inhibition of oncogenic TFs Alternative therapeutic strategy, potential drug targets *C-MYB, NF-kappaB, AP-1, STAT*and *ETS*transcription factors Genomatix\ \[[@B15],[@B56]\]\ <http://www.genomatix.de/> \[[@B57]\]\ \[[@B58]\] DNA Methylation Methylation patterns are altered in cancer cells as shown in hypomethylation of oncogenes and hypermethylation of tumor suppressor resulting in gene silencing or gene inactivation CpG island methylation could be used as a biomarker of malignant cells *hMLH1, BRCA1, MGMT, p16(INK4a), p14(ARF), p15(INK4b, DAPK, APAF-1* Human Colon Methylome from \[[@B29]\] \[[@B27],[@B59]\]\ \[[@B28]\]\ \[[@B60],[@B61]\] Post-translational modifications Key proteins driving oncogenesis, Can undergo PTM Although Phosphoryltion is partially covered in kinases section, other PTMs such as glycosylation and ubiquitination reported to play a role in malignancies, are included separate functional gene attributes. *BRCA1, EGFR, c-Src, c-Abl, RAS, TP53* HPRD <http://hprd.org/> \[[@B18]\]\ Burger and Seth, 2004) -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: The resulting set of variables (differentially expression, condition specificity, and the six functional attributed) are each binarized and used in a Boolean logic framework. The Boolean logic is then applied to cancer-associated genes to develop a GBA algorithm. When applied to non cancer-associated genes, the GBA algorithm preferentially ranks those genes whose behavior across all variables most mimics that of cancer-associated genes. Finally, in order to gain a global understanding of the novel candidate genes, we generate a series of gene co-expression networks. The resulting networks are surveyed with a focus on the interacting partners of candidate genes and within the context of the original functional attributes. Differentially expressed and condition specific genes ----------------------------------------------------- We explored three measures of differential expression (DE1 = Carcinoma - Normal; DE2 = Carcinoma - Adenoma; and DE3 = Carcinoma - Inflammation) and identified 444, 658 and 179 differentially expressed genes for DE1, DE2, and DE3, respectively. We observed several overlaps among the three differentially expressed gene categories, and 15 genes were found to be differentially expressed in all three categories (Figure [2](#F2){ref-type="fig"}). Among them, we highlight *CLCA4, CRNDE, DEFA5, DUOXA2, GCG, KLK10*, and *UGT2A3*. In particular, *CRNDE*(colorectal neoplasia differentially expressed) was the most differentially expressed (up-regulated) gene with a 16-fold change in expression. *CRNDE*gene is localized to chromosome 16 (16q12.2) and is poorly characterized with no functional information on its role in colorectal cancer except its differential expression from the EST data (UniGene Id: 167645). Another differentially expressed gene *KLK10*is a member of the kallikrein gene family which is well documented biomarker for the detection of colon, ovarian and pancreatic cancers \[[@B8],[@B11]\]. ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **The classification of differentially expressed genes resulting from the expression data analysis**. The top 15 DE genes in all of the three categories are tabulated with their expression values in normal, adenoma, carcinoma and inflammation. :::  ::: In addition, we identified 83, 61, 23, and 48 condition specific genes for Normal, Adenoma, Carcinoma and Inflammation, respectively. Among these genes, 23 were found to be specific to carcinoma (CS3) (see Additional File [1](#S1){ref-type="supplementary-material"} Table S1). Notably, *CCDC3, EREG, IL6, PAPPA*, *SERPINE1, TFPI2*and *THBS2*are a few examples of the condition specific genes that appeared as top candidates. In particular, *CCDC3*(coiled-coil domain containing 3) and *TFPI2*(tissue factor pathway inhibitor 2) genes were the most carcinoma-specific genes.*TFPI2*has been proposed to be a tumor suppressor gene as it\'s frequently methylated in colorectal cancer \[[@B7]\]. The *CCDC3*encoded protein is predicted to be localized to extracellular matrix \[[@B12]\] with no previous association with colorectal cancer. Higher IL-6 levels might be prognostic indicator in colorectal cancer as they are associated with increasing tumor stages and tumor size, with metastasis and decreased survival \[[@B13]\]. Expression-profiling analyses often result in hundreds of candidate genes. The challenge is exacerbated when the expression data are gathered at different time points or in multiple conditions, as in the current study with a number of differentially expressed and condition specific genes. Nevertheless, it is a common practice to stop the *in-silico*expression analysis with the list of outliers and select one or more genes for experimental characterization based on the underlying biology. Often, expression data analyses are accompanied by downstream bioinformatics investigations such as Gene Ontology (GO) enrichment, pathway mapping and network reconstruction. It is also believed that expression data are not sufficient to accurately reconstruct biological networks \[[@B14]\] and that the incorporation of additional biological data is required to constrain the number of plausible hypotheses. We approached this challenge by first identifying the most relevant functional attributes that has been well documented in cancer and then extracting this information to build a Boolean logic. Boolean logic to develop a guilt-by-association (GBA) algorithm --------------------------------------------------------------- We developed a model to infer a gene\'s association to cancer. The model accommodates biologically motivated semantics into a Boolean logic schema, but is of a probabilistic nature, allowing it to efficiently and effectively accommodate noise in biological concepts and data when ranking candidate genes (see Methods). We trained the model from data based on the behavior of the cancer-associated genes across 13 binarized Boolean variables: the three measures of differential expression (whether or not a gene was differentially expressed in each of the three contrasts), the four measures of condition specificity (similarly binarized), and the six cancer-biology attributes as previously described. At least one of the 13 variables was assigned to 530 of the 749 cancer-associated genes. These were used to construct a probabilistic Boolean truth table (Additional File [3](#S3){ref-type="supplementary-material"}) with 70 combinations (out of a total of 2^13^= 8192 possible combinations). The trained model is efficient in weighing each attribute based on firmly established principles in cancer biology. For instance, more than 30% of the cancer-associated genes encode protein kinases \[[@B15]\] and this information is implemented \'as is\'. In addition the proportion of kinases that undergo a PTM is also stored in the model and applied to non cancer-associated genes to capture similar kinases that harbor PTM but are strongly controlled by differential expression or condition specific properties in a given expression study. Furthermore, the flexibility of this method lies in its ability to simultaneously address different aspects of cancer. For example, the model predicts novel biomarkers by analyzing the genome-wide expression profiles and exclusively selecting secreted proteins as functional attributes. This will identify differentially expressed or condition specific secreted proteins expressed in blood/serum/urine. Next, we sought to obtain an overview of the representation of the 13 binarized Boolean variables across different gene classes which might provide additional insights into features of cancer genes in comparison to other genes. We selected the following four categories of genes: i. All the genes included in the analyses (n = 21 892); ii. The cancer-associated genes (n = 749), iii. The candidate genes processed by the GBA algorithm (n = 1017); and iv. The top candidate genes (n = 134, 13.2% of the genes processed by the GBA). Figure [3](#F3){ref-type="fig"} shows the distribution of the four gene categories across the 13 variables. We observed enrichment for PTM and secreted proteins in both cancer-associated and top candidate genes. For instance, 40% of cancer-associated genes encoding protein had a PTM and 98% among the top candidate genes. Similarly, 8% and 47% of genes encoded for secreted proteins in cancer-associated genes and top candidate genes respectively. These results lead us to inspect the coverage for PTM and secreted protein both in cancer-associated genes as well as other genes as they contributed significantly in ranking the candidate genes. Additional File [1](#S1){ref-type="supplementary-material"} Table S2 Shows exclusive and combined distribution of secreted proteins and PTM. Using chi-square test of independence, we examined the association of these two functional attributes and obtained a significant p-value of 3.713 E-06. This indicates that the association of PTM and secreted proteins either in combination or individually in cancer associated genes are significantly different compared to other genes. Finally, we note that the Boolean logic that gives rise to the GBA algorithm operates by exploiting the combinatorial nature of the 13 variables. Although, PTM are over-represented in both cancer-associated genes and hence candidate genes, their inclusion as one among five attributes was necessary as aberrant activation of signaling pathways drives cancer progression. For example, phosphorylation \[[@B16],[@B17]\], glycosylation \[[@B18]\] and ubiquitination \[[@B19]\] have been documented to play key role in cancer progression. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Trends showing the distribution of genes across 13 binarized Boolean variables**. Four classes of genes were used for the comparison; i. all the genes in the human genome (21 892), ii. cancer-associated genes (749), iii. GBA ranked candidate genes candidate genes (1017) and iv. top candidate genes (134, 13.2%of the GBA ranked candidate genes). PTM and SEC classes are enriched in cancer-associated genes as well as in candidate genes category. :::  ::: Computational validation of the analytical approach --------------------------------------------------- We designed a two-step approach to ascertain the inferential validity of the proposed GBA. In the first step, we processed all genes through the Boolean logic using the previously developed probabilistic truth table. We found that known cancer genes received an average Boolean score of 0.219 (range: 0.002 to 0.687), compared to an average score of 0.081 (range: 0.000 to 0.589) for the other genes. This indicates that our Boolean logic yields a score to cancer genes that is on average 2.71-fold higher than that of candidate genes. This odds ratio was used as the threshold to be applied for the calibration in the second step of the validation. The second step of the validation consisted of a standard cross-validation schema by which a random 4/5 of the cancer genes comprised the training sample used to build the GBA to be tested against the remaining 1/5 of the cancer genes (testing sample). After repeating this process 1000 times, each with a different 4/5 training/1/5 testing random samples, we found that a ranked list of candidate genes comprising the top 13.2% of genes guarantees a 2.71-fold over-representation of cancer genes (Figure [4A](#F4){ref-type="fig"}). We also found that selecting the 50% most extreme genes, captures 90% of all cancer genes (Figure [4B](#F4){ref-type="fig"}). ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Two-step computational validation approach to ascertain the inferential validity of the proposed GBA**. **4A**shows the ratio of the average Boolean score given to cancer genes over the average score given to the other genes. Candidate genes comprising the top 13.2% of genes guarantee a 2.71-fold over-representation of cancer genes. **4B**. Standard cross-validation in which the proportion of cancer-associated genes are compared to genes with extreme Boolean scores. By selecting the 50% most extreme genes captures 90% of all cancer genes. :::  ::: When the subject is concerned with the identification of differentially expressed genes after normalising the data, one can invoke the Gaussian distribution to produce p-values. Similarly, when the issue is to ascertain enrichment of a particular biological process, one could invoke the hypergeometric distribution to produce p-values. However and quite importantly, no parametric distribution functions were invoked in the development of the Boolean logic and the subsequent guilt-by-association algorithm. Instead, the sensitivity of the proposed approach in terms of its power to detect cancer genes was explored using a two-step procedures comprised of first assessing its efficiency when applied to cancer-associated genes, and then developing a cross-validation schema to identify the threshold beyond which the power to detect candidate genes is higher than the one obtained with known cancer-associated genes. The emergence of ranked candidate genes from the GBA algorithm -------------------------------------------------------------- Table [2](#T2){ref-type="table"} lists the top 20 candidate genes and Additional File [4](#S4){ref-type="supplementary-material"} contains the entire ranked list of 134 candidate genes (or 13.2% of the 1017 genes processed through the GBA). While a detailed description of the individual genes is beyond the scope of this study, we focus on candidates that also figure in the network analysis section described later, based on their connectivity to cancer-related genes and their position in the co-expression network. ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### The top candidates identified by the GBA algorithm (genes with similar functional attributes are clustered together) ::: Candidate Genes Normal Adenoma Carcinoma Inflammation Condition Specificity Colon tissue specificity Secreted Proteins Transcription Factors Protein kinases PTMs DNA Methylation ----------------- -------- --------- ----------- -------------- ----------------------- -------------------------- ------------------- ----------------------- ----------------- ------ ----------------- *GUCA2B* 11.01 5.66 7.52 8.05 ✓ ✓ ✓ ✓ *MMP1* 6.35 9.2 10.28 10.48 ✓ ✓ ✓ *PAPPA* 6.51 5.88 7.71 7.12 ✓ ✓ ✓ ✓ ✓ *PYY* 10.14 4.76 6.87 8.21 ✓ ✓ ✓ ✓ ✓ *REG1A* 5.71 10.87 10.8 12.17 ✓ ✓ ✓ ✓ *MEF2C* 8.66 7.36 8.43 9.04 ✓ *SOX2* 4.18 3.39 4.61 3.89 ✓ ✓ ✓ *SPIB* 9.11 6.15 6.76 8.26 ✓ ✓ ✓ ✓ *WWTR1* 8.31 7.22 8.69 8.78 ✓ ✓ ✓ *ZIC2* 2.22 4.8 3.53 2.55 ✓ ✓ ✓ *CDK8* 8.62 8.75 8.96 8.29 ✓ ✓ *EPHB3* 8.58 9.97 8.63 8.12 ✓ ✓ ✓ ✓ *ROR2* 5.16 4.4 5.47 5.56 ✓ ✓ *NPR1* 5.02 3.36 4.42 4.71 ✓ ✓ ✓ *TRIB3* 6.93 8.76 9.01 7.84 ✓ *TRPM6* 10.54 6.27 8.04 7.08 ✓ ✓ ✓ *GCG* 10.42 6.24 7.69 9.55 ✓ ✓ ✓ ✓ *REG3A* 4.95 10.34 10.1 11.19 ✓ ✓ ✓ ✓ *SERPING1* 8.9 8.11 9.28 10.21 ✓ ✓ *SLC4A4* 11.76 8.76 9.57 9.81 ✓ ✓ ✓ ::: ### Excretory-Secretory proteins as diagnostic or prognostic biomarkers ES proteins are particularly relevant in colorectal cancer because most colorectal cancers develop slowly; beginning as small benign colorectal adenomas that progress over several years to larger dysplastic lesions that eventually become malignant. A total of 178 genes encoding ES proteins were found using this approach, of which 51 genes were tissue-specific to the colon. 64 entries had evidence for a PTM and 25 genes showed methylation in colon cell lines. Among these, we highlight *PYY*and *GUCA2B. PYY*(peptide YY) is a gut hormone highly expressed in the colon \[[@B20]\] and down regulated eight-fold in adenomas compared with the normal colon (Table [2](#T2){ref-type="table"}). Its distinct variation in expression levels in the colon and gut region (gastric mucosa and rectum) compared with the cancerous colon makes it an important candidate gene for detailed biochemical characterization. As *PYY*is down regulated in carcinoma, it is unlikely candidate for early detection as decreased levels of protein in the cancer would not alter levels in the peripheral blood. *GUCA2B*(Uroguanylin) is a physiological regulator of intestinal fluid and electrolyte transport, 8-fold down regulated in adenoma, and its expression is observed in blood and urine \[[@B21]\]. Therefore, *GUCA2B*could be exploited as a non-invasive biomarker for the early detection of colorectal cancer. ### Transcription factors as novel oncogenic regulators for the treatment for colorectal cancer The altered activity of a few key TFs results in aberrant expression of their target genes, which can eventually lead to tumor development. The combination of the GBA and regulatory impact factor (RIF) analyses yielded 58 TF genes. Thirty-eight of these TFs showed colon-specific expression, 19 genes had DNA methylation and 6 proteins encoded by TFs had evidence for at least one PTM (Table [2](#T2){ref-type="table"}). Here, we highlight the biological relevance of the top two candidates: *SPIB*and *MEF2C. SPIB*is an adenoma condition-specific down regulated gene. The DNA-binding ETS domain of *SPIB*is highly homologous to the ETS domain from the oncoprotein Spi-1/PU.1 \[[@B22]\] and may be an oncogenic TF awaiting experimental characterization. In addition, *SPIB*interacts with the promoter region of the c-JUN oncogene and *MAPK3*gene \[[@B23]\] that are implicated in several cancers, including ovarian cancer. Similarly, *MEF2C*has been proven to play a role in angiogenesis \[[@B24]\], and shown to be over-expressed in hepatocellular carcinoma \[[@B25]\]. ### Genes encoding protein kinases A total of 11 genes encoding protein kinases were identified of which 2 were tissue-specific and 3 genes were DNA methylated: *EPHB3, NPR1*and *TRPM6. EPHB3*is a receptor tyrosine kinase that mediates several developmental processes \[[@B26]\]. Importantly, *EPHB3*interacts with the *Fyn*oncogene in vivo, and *EPHB3*has a suggested role in tumor suppression. Other kinases predicted by the GBA include *NPR1*, a novel guanylate cyclase that catalyzes the production of cGMP from GTP and *TRPM6*, also called channel kinase 2, which is significantly down regulated in adenomas. ### Post-Translational Modifications PTMs such as glycosylation also go awry in cancer cells. This is seen as a result of the initial oncogenic transformation and a key event in the induction of invasion and metastasis in cancer \[[@B18]\]. By treating PTMs of proteins as a separate functional attribute in the Boolean logic, we found a total of 158 genes whose protein product harbors at least one PTM. A total of 32 entries with a PTM were tissue-specific with four overlapping the kinase set and 64 being secreted proteins, some of which had already been described in the previous sections. *REG3A*, a secreted protein that undergoes a proteolytic cleavage (a form of PTM) is up-regulated in adenomas, and could be a potential biomarker for the early detection of colorectal cancer. ### DNA methylation as an epigenetic modification DNA methylation (DNAm) patterns are altered in cancer cells, as shown by the hypomethylation of oncogenes and hypermethylation of tumor suppressor genes resulting in gene silencing and gene inactivation respectively \[[@B27],[@B28]\]. Using genome-wide DNA methylome data for colon, we obtained 99 genes from the GBA algorithm as methylated genes. 17 of these genes have a preference for colon tissue expression and 19 of them were transcription factors, 23 proteins with a PTM and 22 secreted proteins. The *ADAMTS16, GUCA2B, PYY*and *THBS2*genes were hypomethylated, whereas *FXYD1*and *WWTR1*were hypermethylated \[[@B29]\]. DNAm information can serve as additional evidence for these genes as potential candidate genes and should be further investigated. Gene co-expression networks reveal novel associations between cancer and candidate genes ---------------------------------------------------------------------------------------- It is thought that co-expressed genes are co-regulated by similar regulatory mechanisms; hence, possible functional collaborations between co-expressed genes have been proposed. To obtain a holistic view of the relationship between known and novel genes identified by the GBA algorithm, we constructed a series of gene co-expression networks using highly correlated differentially expressed and condition specific genes. Each network contained 1347 genes including the 530 cancer-associated genes and the 817 candidate genes that were captured by at least one of the seven expression-based variables (differentially expression or condition specificity). Of the 1 617 503 correlations evaluated in each network, the proportion found to be significant (referred to as clustering coefficient) according to PCIT algorithm and varied from 4.6% for the Adenoma network to 11.7% for the Carcinoma network (Table [3](#T3){ref-type="table"}). The nodes (genes) and edges (connections) which were conserved in three or more network were retained to build what we referred to as the \'always-conserved network\'. ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### The properties of network connectivity: ::: Normal Adenoma Carcinoma Inflammation -------------- -------- --------- ----------- -------------- Normal 5.18 2.28 3.31 4.25 Adenoma 1.20 4.63 8.26 5.25 Carcinoma 2.01 3.89 11.67 11.07 Inflammation 2.30 1.96 4.01 11.10 Clustering coefficients (%, on diagonals) and percent overlap computed from the ratio of common links divided by the total number of unique links for positive (above diagonal) and negative (below diagonal) links across each pair-wise network comparison. ::: The always-conserved network shown in Figure [5](#F5){ref-type="fig"} was further dissected into eight different networks and investigated for their properties. The first four networks were built in such a way that all the functional attributes were included. In essence, the first network (Figure [5A](#F5){ref-type="fig"}) represents pairs of genes connected in (i) all four networks, (ii) all four networks except Normal or (iii) all four networks except Carcinoma. The second network (Figure [5B](#F5){ref-type="fig"}) retains only those connections involving at least one top candidate gene. In the third network (Figure [5C](#F5){ref-type="fig"}), connections involving at least one top candidate gene where both genes have more than two connections are retained. Finally, the fourth network (Figure [5D](#F5){ref-type="fig"}) contains the least number of nodes among those connections involving at least one top candidate gene with a significant connection in all the four networks. The remaining four networks were constructed based on similar functional attributes. For instance, the TF-TF only (nodes: 49, edges: 37) network was built, in which only those connections where a transcription factor is connected to another transcription factor are retained. Similarly, other networks based on the post-translational modifications (nodes: 216, edges: 372), secreted proteins (nodes: 135, edges: 346) and kinases (nodes: 7, edges: 4) were built. The always-conserved networks are scale-free networks and the connectivity of the network follows a power-law distribution (Additional File [1](#S1){ref-type="supplementary-material"} Figure S1). We addressed four key questions in the network analysis section: (i) which of the top candidate genes are hub genes? (ii) are there novel functional links between cancer and non-cancer-associated genes? (iii) are there any highly connected gene modules functionally relevant to cancer? and (iv) what is the nature of the attribute networks (TF-TF, SEC-SEC etc)? ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **The Always Conserved network visualized using the Cytoscape software at our levels of resolution**: (A) Connections involving at least one top candidate gene; (B) derived from A where only genes with more than two connections are displayed; (C) derived from B where only connections that were deemed to be significant across the four original networks (Adenoma, Carcinoma, Inflammation and Normal) are displayed; and (D) only those connections involving at least one top candidate gene in the four networks. The specific nature of edges, nodes and other features such as shape and color along with the Cytoscape file is provided in our website <http://www.livestockgenomics.csiro.au/courses/crc.html> :::  ::: Our network analysis identified a number of hub genes including several top candidate genes (Figure [5D](#F5){ref-type="fig"}). A notable, high impact module with *GUCA2B*as a hub gene with 41 connections is significant (Figure [5A](#F5){ref-type="fig"}). *GUCA2B*was connected to other top candidates such as *GUCA2A, CHGA*and importantly the nuclear receptor *NR3C2*, which is highly implicated in leukemia \[[@B30]\], colorectal carcinoma \[[@B31]\], and other carcinomas. Interestingly, *CHGA*was found to be the central link between two modules, one with *GUCA2B*as a hub and another module where *PYY, GCG*and *CHGB*, all candidate genes, were connected. Because these connections are based on significant correlations between gene pairs, they provide the first insights towards functional collaborations among the candidate genes found in this study. A number of network relationships were found among cancer-associated and non-cancer-associated genes. The MMP2 gene product which promotes tumor progression and metastasis by the degradation of the extra-cellular matrix \[[@B32]\] was connected to genes encoding candidate secreted proteins, *C1 S*and *COL5A1*. We further explored functional relationships between cancer-associated and non-cancer associated genes by conducting enrichment analysis of GO categories using the BiNGO plug-in \[[@B33]\]. Among the top ten over-represented GO terms were anatomical structure development, immune response, response to stress and negative regulation of biological process. Notably, over-representation of GO category of importance from the colorectal cancer viewpoint is the inflammatory response, as chronic inflammation is widely believed to be a predisposing factor for colorectal cancer particularly in individuals with inflammatory bowel diseases; however the underlying molecular links between these two conditions have remained elusive. The only documented example is the role of STAT3 that links inflammation to tumor development in colorectal cancer \[[@B34]\]. Therefore, our list of candidate genes (*C1 S, CXCL11*, and *REG3A*) where inflammatory response is over-represented can be considered as potential candidates for elucidating unresolved cellular mechanisms mediating this relationship in colorectal cancer. Next, we applied a combination of the BiNGO and MCODE plug-ins to study over-represented GO categories in the sub-networks \[[@B35]\]. Overall, we found 23 sub-networks of which the scores of five sub-networks were significant (Additional File [1](#S1){ref-type="supplementary-material"}). The first sub-network comprised of 44 highly connected nodes and 78 edges (4 cancer-associated genes and 40 non-cancer associated genes). This cluster was over-represented by GO terms, phosphate transport and response to external stimulus (that includes candidate genes *FPR2*and *S100A8*). The cluster also contains several collagen sub-unit genes (*COL4A1, COL3A1*, *COL1A2*, and *COL5A2*). Again, over-representation of cell adhesion was evident in the second cluster with membership from five cancer-associated genes including *MMP2*. These cell adhesion molecules bind to components of the extracellular matrix and up-regulation and down-regulation of candidate genes identified in this study may play a role in cancer invasion and metastasis by altering the ability of cells to adhere to surrounding cells and the extracellular matrix \[[@B36]\]. Finally, network analysis of similar functional attributes such as the transcription factors only network and the secreted proteins only network captured additional regulatory hot spots and secreted protein modules that were not predicted with significant scores previously (Additional File [5](#S5){ref-type="supplementary-material"}). These four networks are of great relevance, since they are correlated by similar expression patterns, have interrelated functional attributes and are candidate non-cancer associated genes. For instance, in the TF-TF network (Additional File [5](#S5){ref-type="supplementary-material"} Figure S1C), the hub genes (*NR5A2, MEF2C*) could be seen as regulatory hot spots that control gene expression via regulation of transcription. The RIF (Regulatory Impact Factor) analysis ------------------------------------------- We have recently introduced a novel metric called RIF or \'regulatory impact factors\' to measure the regulatory capacity of transcription factors from gene expression data alone \[[@B37]\]. RIF uses two different measures, RIF1 and RIF2, to predict key regulators (TF) in driving the phenotypically relevant component of a given co-expression network. The highest impact regulators (extreme RIF \|z-score\| \> 2) resulting from the RIF1 and RIF2 analysis are documented in Additional File [1](#S1){ref-type="supplementary-material"} Table S3. A few notable regulators with extreme scores include *SAP18, CDK8, NR3C1, NFYC, CEBPB, PHF19*and *TEAD4*. Of particular interest was the accurate prediction of CDK8 as the second-most significant regulator, recently identified as a colorectal cancer oncogene that regulates beta-catenin activity \[[@B38]\]. Second, *CEBPB*was established as a target gene for regulation in myeloid cells transformed by the *BCR/ABL*oncogene and also has a suggested role in promoting tumor invasiveness. Other potential regulators predicted by RIF such as *EPC1, SAP18*and *ZNHIT3*have no previous link with cancer and therefore provide an opportunity for further investigation. Conclusions =========== The method introduced here is highly flexible and can be implemented for any cancer type in a rather straightforward manner. Tissue specificity is one of the variables in the Boolean combinatorial logic that will require updating with every cancer type. For instance, one could study breast or pancreas-specific genes and their association with cancer by applying this method. Nuclear receptors are considered to be ideal drug candidates for treating breast cancer. We also believe that this approach could be applied to study other hereditary diseases such as Alzeimer\'s and Down\'s syndrome, provided sufficient molecular attributes are available for the respective diseases. Importantly, the candidate genes described here are classified based on individual attributes. Hence, those genes that share a number of attributes could be ranked as more promising candidates than their counterparts. For instance, *PYY*is a differentially expressed, condition-specific, tissue-specific to the colon, encoded product is a secreted protein that harbors a PTM and the gene is DNA hypomethylated in a colon cancer cell line. Therefore, *PYY*could be considered as a \'master candidate\' awaiting further biochemical characterization. Finally, we argue that this is a holistic approach that faithfully mimics cancer characteristics, systematically predicts plausible cancer-associated candidate genes and has universal applicability to the study and advancement of cancer research. Methods ======= Gene expression data: Identification of differentially expressed and condition-specific genes --------------------------------------------------------------------------------------------- We used the gene expression data from the colorectal cancer study of Galamb et al. (2008) profiling the gene expression from tissue samples classified as one of the following four conditions: normal (n = 8 samples), adenoma (15), carcinoma (15) and inflammation (15). Using the MAS5 detection call utility, probes yielding an absent signal in all 53 hybridizations were removed. As a result, we retained a total of 2 897 775 expression intensity signals across 34 844 probes that were annotated to 21 892 unique human genes were available for further analysis. For the identification of differentially expressed genes we explored three contrasts: 1. Carcinoma vs. Normal; 2. Carcinoma vs. Adenoma; and 3. Carcinoma vs. Inflammation. For each contrast and following previously described approaches \[[@B39]\], a combination of ANOVA models and mixtures of distributions were employed to normalize expression signals and to identify differentially expressed genes, respectively. In brief, for each of the four datasets, data normalization was achieved by fitting a parsimonious mixed-effect ANOVA model containing the main fixed effect of the hybridization and the random effects of gene, gene × experimental condition interaction, and residual error. After building and solving the ANOVA model, the difference between the normalized expression of a gene in the two conditions of the given contrast was computed as the measure of (possible) differential expression. Finally, differentially expressed genes were identified using a two-component normal mixture model with an estimated experiment-wise false discovery rate (FDR) of \< 1%. For the identification of condition specific genes, a measure of the condition specificity of each gene was obtained from the ratio of its expression in the *j*-th condition (*j*= 1 to 4 for normal, adenoma, carcinoma and inflammation) over its expression summed across all four conditions as follows: $$CS_{ij} = \frac{x_{ij}}{\sum\limits_{j = 1}^{4}x_{ij}}$$ Following the above expression, four measures of condition specificity were computed for each gene, and a gene was set to be condition-specific for the *j*-th condition if its expression in the *j*-th condition was (1) above the average expression of all genes in the *j*-th condition; (2) greater than its expression in any of the other three conditions; and (3) such that CS*~ij~*was greater than three standard deviations of all other CS*~ij~*\'s. Cancer-associated genes ----------------------- We compiled a list of cancer-associated genes by manual curation of literature and web-based resources. More than 1% of all human genes are implicated in cancer via mutations, and these genes collectively form the basis of cancer biology \[[@B15]\]. These genes form the basis of our \"cancer-associated genes\" dataset. First, we obtained 437 representative cancer-associated genes from the Cancer Gene Census at the Sanger Centre <http://www.sanger.ac.uk/genetics/CGP/Census/>. Next, we retrieved a second list of cancer related genes from the Atlas of Genetics and Cytogenetics in Oncology \[[@B40]\]. A third list was collated from the disease association data of HPRD database \[[@B41]\] and based on high confidence protein expression entries in multiple cancer tissues. In addition, we surveyed the lists of genes reported in the following research and review articles: \[[@B15]\]; \[[@B42]\]; \[[@B43]\]; and \[[@B44]\]. Finally, we collated these datasets to a master list of 749 cancer-associated genes Additional File [2](#S2){ref-type="supplementary-material"}. Functional attributes --------------------- We retrieved expression data from massively parallel signature sequencing (MPSS) covering 182 719 tag signatures across 32 tissues \[[@B45]\]. The complete list of TFs was retrieved from BiblioSphere \[[@B46]\] in the Genomatix web site <http://genomatix.de>. The post-translational modification (PTM) data were downloaded from the most recent version of the Human Protein Reference Database (HPRD - Release 9). A list of 1 764 high-confidence secreted proteins was obtained from the secreted protein database \[[@B47]\]. A catalogue of 518 protein kinase genes was downloaded from \[[@B48],[@B49]\]. A list of alterations in DNA methylation specific for colorectal cancer using DNAm was obtained from the human colon cancer methylome \[[@B29]\]. Datasets for functional attributes are provided in Additional File [2](#S2){ref-type="supplementary-material"}. The Boolean Logic and the Guilt-by-Association Algorithm -------------------------------------------------------- As detailed in Mukherjee *et al.*\[[@B10]\], a k-ary Boolean function is a function f: {0,1}^k^{0,1} which maps each of the 2^k^possible states of its binary arguments X = (X~1~⋯ X~k~) to a binary state Y. Such a function can also be represented as a truth table. In our case, we considered a total of k = 13 variables in the Boolean logic: Three measures of differentially expression, four measures of condition specificity, and the six functional attributes (TS, TF, PTM, KIN, SEC, and MET). These were binarized (prototypically 0 and 1) and used to compute what it\'s known as the probabilistic truth table, where the probabilities were obtained from the proportion of cancer-associated genes presenting a particular profile of 0\'s and 1\'s across the 13 variables. Therefore, the probabilistic Boolean truth table assigns a probability value to each existing combination of Boolean variables. In our case, this probability was derived from the proportion of cancer-associated genes exhibiting that combination. This trained model was then used as a GBA algorithm applied to non-cancer related genes in the human genome. The GBA algorithm proceeded as follows: • The particular combination across the 13 Boolean variables observed for a given non-cancer gene of interest was decomposed into its roots. • The probability associated with each root was captured from the probabilistic Boolean truth table. • These probabilities were added to rank the importance of the non-cancer gene of interest as a novel candidate. We illustrate this concept with an example. Let\'s consider a gene, *MEF2C*, being differentially expressed for the second contrast, TF, PTM and MET. Across the 13 variables, this is equivalent to the Boolean profile\"0100000011001\" which can be decomposed in the following 14 roots each associated with a probability value corresponding to the probabilistic Boolean truth table (Table [4](#T4){ref-type="table"}). Probability values on the third column add to 0.58868 and this value is the Boolean score used in the ranking of *MEF2C*as a novel cancer-related gene. ::: {#T4 .table-wrap} Table 4 ::: {.caption} ###### The Boolean probabilistic truth table for *MEF2C*gene ::: No Binarized Boolean profile Probability values ---- --------------------------- -------------------- 1 0000000000001 0.05094 2 0000000001000 0.23019 3 0000000001001 0.02453 4 0000000010000 0.10755 5 0000000010001 0.03396 6 0000000011000 0.07925 7 0000000011001 0.03019 8 0100000000000 0.01509 9 0100000000001 0.00377 10 0100000001000 0.00377 11 0100000001001 0.00189 12 0100000010000 0.00377 13 0100000010001 0.00189 14 0100000011000 0.00189 ::: Computational Validation of the analytical approach --------------------------------------------------- We designed a two-step approach to ascertain the inferential validity of the proposed GBA. In the first step, we processed all genes through the Boolean logic using the previously developed probabilistic truth table and recorded how extreme the cancer genes were ranked relative to the other genes. The ratio of the average Boolean score given to cancer genes over the average score given to the other genes was used as the threshold to be applied for the calibration in the second step of the validation. The second step of the validation consisted of a standard cross-validation schema by which a random 4/5 of the cancer genes comprised the training sample used to build the GBA to be tested against the remaining 1/5 of the cancer genes (testing sample). We repeated this process 1000 times, each with a different 4/5 training/1/5 testing random samples. In each iteration, the number of cancer genes captured in the top *x*-percentile (for *x*= 1,2\....,100) was recorded and used as the measure of sampling distribution upon which to infer the size of the ranked list of candidate genes that guarantees the threshold obtained in the step one of the validation is met. Reconstruction of Gene Co-Expression Networks --------------------------------------------- The PCIT algorithm \[[@B50]\] was used to reverse-engineer four gene networks, one for each condition: Normal, Adenoma, Carcinoma and Inflammation. The networks were constructed in such a way that a gene pair was allowed in the network only if it was conserved in at least three out of four conditions. Therefore, we refer to these networks as the \'Always conserved networks\' A network for each of the four conditions, Normal, Adenoma, Carcinoma and Inflammation, was constructed and integrated (intersect) to create four levels of resolution. The first network (1255 nodes, 5122 edges) was built to include the pairwise connections of the genes that were connected in all four networks. It addition, we also produced pair-wise connections of all genes except the Normal and Carcinoma genes, which enabled us to investigate exclusive interactions in Normal and Carcinoma sets. The second network (534 nodes, 5122 edges) retained only those connections involving at least one top candidate gene. The third network consisted of those connections involving at least one top candidate gene and where both genes had more than two connections (146 nodes, 367 edges). Finally, the fourth network contained those connections involving at least one top candidate gene found to be significant in the four networks (99 nodes, 79 edges). The remaining four networks were specific to the functional attributes. They were the transcription factors only, the secreted proteins only and so on where all of the nodes belonged to one functional attribute. Functional enrichment using GO was carried out using BiNGO plug-in \[[@B33]\] in Cytoscape. In this study, hypergeometric test was used to assess the statistical significance (p \< 0.05) and the Benjamini & Hochberg False Discovery Rate (FDR) correction. Identification of key transcription factors ------------------------------------------- Once the gene networks were obtained we applied the regulatory impact factor (RIF) algorithm of \[[@B37]\] to identity the key regulators, with emphasis in those not previously described as related to cancer. RIF assigns an extreme score to those transcription factors that are consistently most differentially co-expressed with the highly abundant and highly differentially expressed genes (case of RIF1 score), and to those transcription factors with the most altered ability to predict the abundance of differentially expressed genes (case of RIF2 score). Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= AR conceived and supervised the project. SHN and AR carried out the analyses and drafted the manuscript. Both SHN and AR read and approved the final manuscript. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **Additional text, tables and figures that describe the rationale behind choosing the functional gene attributes, cancer pathway analysis and gene co-expression network analysis**. The file contains additional text on rationale behind choosing the functional gene attributes, text on cancer pathway analysis, figures and tables on network connectivity and network analysis using MCODE, BINGO plug-ins and RIF analysis. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 2 **The list of cancer associated genes and publicly available datasets on functional attributes used in this study**. The list includes cancer associated genes, kinases, transcription factors, secreted proteins, proteins that undergo post-translational modifications and genes with CpG island methylation. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 3 **Probabilistic Boolean truth table**. The truth table constructed from 749 cancer associated genes. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 4 **The list of genes ranked by guilt-by-association algorithm**. The list comprises of 138 ranked list of candidate genes. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 5 **Additional network analysis figures**. Network analysis of similar functional attributes (the TF only network, the SEC only network, TF only network and PTM only network). ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ We thank Brian Dalrymple for the valuable suggestions and proof reading the manuscript. We thank Rob Dunne and Bill Wilson for their support in the early phases of the project. The authors are grateful to Victor Jongeneel and Christian Haudenschild for providing the gene-centric and tag-centric annotated MPSS data files. SHN is grateful to CSIRO for the award of an OCE Post-Doctoral Fellowship. The financial support of the CSIRO Transformational Biology Capability Platform is gratefully acknowledged.

PubMed Central

2024-06-05T04:04:17.225350

2011-2-26

PMC3051905

Introduction ============ The pathogenesis of chronic obstructive pulmonary disease (COPD) is characterized by persistent neutrophilic inflammation of the airways and lung parenchyma \[[@B1],[@B2]\]. They release cytokines, leukotrienes, reactive oxygen species (ROS), elastases and other proinflammatory mediators which correlate broadly with disease severity \[[@B3]-[@B5]\]. Neutrophils are attracted from the capillary bed into the airways through chemotactic mechanisms which are intensified during exacerbation \[[@B6],[@B7]\]. With increasing disease severity activated mononuclear cells and monocytes/macrophages contribute more and more to the complex inflammatory process in the airways and in the bronchial submucosa of those patients \[[@B8]\]. Chemotaxis is a biological phenomenon whereby a cell type migrates through barriers (e.g. vessel walls, epithelial layers or tissue) toward the site of inflammation. These cells will initiate and maintain the inflammatory process through a variety of mechanisms including ROS release. In COPD, chemotaxis is not only regarded as an important pathologic feature of prolonged inflammation due to cigarette smoke inhalation, but may also be an appealing target for anti-inflammatory therapy. By reducing the neutrophil influx into the airways one should be able to reduce the burden of airway inflammation and, thus, change the natural history of the disease \[[@B9],[@B10]\]. Unfortunately, inhaled corticosteroids have been shown to reduce neutrophilic inflammation in COPD patients just poorly at best \[[@B11]-[@B13]\]. Long-acting β2-agonists do not have intrinsic anti-inflammatory properties per se. In contrast, the long-acting muscarinic receptor antagonist tiotropium bromide has been shown a) to regulate release of chemotactic factors from human epithelial cells and macrophages in vitro \[[@B14]\], b) to inhibit airway remodelling and increase in smooth muscle mass in ovalbumin-sensitised guinea pigs \[[@B15],[@B16]\], and c) to inhibit acetylcholine mediated proliferation of fibroblasts and myofibroblasts in vitro \[[@B17],[@B18]\]. These observations may be based on induced mitogenesis by stimulated muscarinic receptors and mediator release, which can be lessened by muscarinic receptor antagonists \[[@B19]\]. We hypothesize that tiotropium may have potential antiinflammatory properties helping to explain its good clinical efficacy e.g. the reduction of exacerbation rate which can hardly be related to its bronchodilative function alone. Through reducing chemotaxis of neutrophils via inhibition pro-chemotactic properties of alveolar macrophages anticholinergic drugs and tiotropium in particular may impact the neutrophil and macrophage driven inflammation in COPD in a considerable way. This would be a new perspective how those compounds affect those patients. The rationale for this study was therefore to test tiotropium having anti-chemotatic properties in a macrophage and neutrophil containing cell system. Methods ======= In this study alveolar macrophages and neutrophils from COPD patients (n = 71) were used. They were recruited during out-patient or in-patient visits in our institution. Main inclusion criteria were a smoking history of ≥20 pack-years, COPD regardless of severity according GOLD -criteria (global initiative for lung disease \[[@B20]\]). Main exclusion criteria were an acute infection of the airways or the lung, other chronic lung diseases (except COPD), cancer or extra-pulmonary chronic diseases causing clinical instability. All patients gave written, informed consent. All of them had a clinical history, a physical examination and an X-ray from the chest prior to bronchoscopy and bronchoalveolar lavage (BAL). Appropriate investigations relating to the clinical presentation together with history including smoking history, spirometric and radiologic data as well as blood gas analysis were obtained from the records. The study was approved by the ethics committee of the Saxonian Chamber of Physicians, Dresden, Germany (approval No.: EK-BR-27/05-2). Patients referred for bronchoscopy for various clinical reasons were invited to participate in the study. Prior to bronchoscopy short acting anticholinergic drugs (ipratropium bromide) were stopped for at least 12 h and the long acting tiotropium bromide for at least 48 h. Prednisolone was limited to 7,5 mg/day. Inhaled short- and long-acting β2-agonists, inhaled corticosteroids, further, antibiotics and theophylline were allowed. BAL was performed according to standard procedure as recommended \[[@B21],[@B22]\]. The bronchoscope was wedged in the right middle lobe or lingula and up to 140 ml of normal warmed (37°C) saline was instilled in 20-ml aliquots. Lavage fluid was immediately rinsed through gauze in order to remove surplus mucus. The fluid was centrifuged at 800 rpm for 10 minutes, 1 × 10^6^/ml isolated macrophages were plated on 24-well tissue culture plates in RPMI (Biochrom AG)/10%FCS/L-glutamine (2 mM, GIBCO/Invitrogen)/antibiotics (penicillin 100 IU/ml, streptomycin 100 μg/ml, amphotericin 0,25 mg/ml, Biochrom AG) and cultured up to 2 h at 37°C/5%CO2. After washing to remove unattached AM and other cells, cells were further cultured over night. For estimation of cell viability/cytotoxicity we used trypan blue and neutral red uptake assay as described elsewhere \[[@B23]\]. Viability had to be ≥90%, macrophage content of BAL cell differential ≥85%, and at least 5 million cells were all required for further analysis. Cell vitality and cellular purity (microscopic examination of 300 cells at magnification ×100) was always ≥95%. For all experiments a cellular concentration of 2 × 10^6^cells/ml was used. All experiments were run in triplicates. Polymorphonuclear leukocytes were isolated from the blood of these patients according to standard procedure as described elsewhere \[[@B24]\]. They were labelled with Calcein AM (5 μg/ml, Molecular Probes) in a 30 min incubation step at 37°C/5% CO2 for later detection using a flourescence based detection system. Neutrophils were than washed twice with PBS, counted and resuspended in RPMI/FCS/L-glutamine/penicillin/strepto-mycin/amphotericin \[[@B25],[@B26]\]. AM were washed and incubated at 37°C/5% CO~2~for different time periods with RPMI/1%FCS/L-glutamine/penicillin/strepto-mycin/amphotericin with or without increasing concentrations of either acetylcholine (ACh: 1000; 100; 10; 1; 0.1 μM), carbachol, muscarin, oxotremorin (100, 10 and 1 μM) or LPS (10, 1 and 0.1 μg/ml; all reagents from Sigma Chemicals). In addition co-stimulation was done with LPS (0.1-1 μg/ml) and carbachol or muscarin (10-100 μM). After designated time periods, supernatants were strip off, centrifuged to remove remaining cells and cell detritus and frozen (-80°C) for cytokine quantification. AM and neutrophils from these patients were prospectively distributed to the different assays. Due to large assay number and control experiments, as well as depending on the usefulness of the material and the cell number obtained from each patient, assays were run only with a certain proportion of patient samples: n = 20 for chemotaxis with tiotropium, n = 10 for LPS/carbachol/muscarin/tiotropium co-stimulation, n = 9 for controls with acetylcholin-esterase, n = 15 for RT-PCR experiments, n = 17 for ROS release experiments. Cytotoxicity ------------ After AM-stimulation with LPS with or without tiotropium (3 nM, 30 nM, 300 nM) for 4 and 20 h, supernatants were stripped off. Remaining cells were washed three times with PBS and cytotoxicity was quantified. For the estimation of cell cytotoxicity we used neutral red uptake assay as described elsewhere \[[@B23]\]. Control cells (cultured with RPMI/1%FCS/antibiotics/glutamine) were set to 100% and used for normalisation. Proper staining with 2\',7\'-dihydrodichlorofluorescein diacetate (H~2~DCFDA) a fluorescent dye used in the cytotoxicity assay was confirmed by Fluorescence microscopy (Nikon). Chemotaxis ---------- Cell migration of neutrophils was assayed using a 96-well Transwell chamber (pore diameter 3 μm, Corning). The bottom chamber was filled with culture supernatants generated from AM culture supernatant as described above. Isolated neutrophils (75 μl, 2 × 10^6^cells) were placed in the upper chamber. Spontaneous migration during incubation in 37°C/5% CO2 for 60 min. was determined using RPMI alone. RPMI/1%FCS/L-glutamine/penicillin/strepto-mycin/amphotericin in the bottom chamber functioned as positive control (= FCS induced migration). Migrated cells were quantified in a multi-well fluorescent plate reader (Fluostar, BMG), whereas the intensity of the calcein fluorescence signal detected at excitation 485 nm and emission 535 nm in the bottom chamber corresponds to neutrophil cells found there. The values of the spontaneous migration were set to 100% and used for normalisation of different experiments. Different muscarinic receptor antagonists were tested to elucidate the role of specific M-receptors and their inhibitors on chemotactic activity in AM cultured in RPMI/FCS/L-glutamine/penicillin/streptomycin/amphotericin: telenzepine (M1R inhibitor, 0.01 μM), gallamine (M2R inhibitor, 100 μM), 4-DAMP (M3R inhibitor, 100 nM), tubocurarine (nicotinic receptor inhibitor, 100 μM), ipratropium (30 nM, Sigma Chemicals) and tiotropium (3 nM, 30 nM, 300 nM, provided by Boehringer Ingelheim). Cytokine measurements --------------------- Commercially available ELISA kits were used for the detection of human IL-8, IL6, TNF alfa, GM-CSF (IBL, Hamburg, Germany), LTB 4 (Cayman, USA), MIPα/β (Biosource Int., USA) in AM supernatants with minor modifications of the manufacturer\'s protocol. Reactive oxygen species (ROS) ----------------------------- Intracellular ROS formation was measured by the oxidant sensitive dye 2\',7\'-dichlorofluorescein diacetate (DCFH-DA \[[@B27]\]). The amount of fluorescence correlates with ROS released by the cells. AM were cultured under the above culture conditions (with or without the compounds to be tested), washed in PBS and then incubated with 1 μl DCFH-DA/1 ml PBS for 1 h at 37°C/5%CO2. Fluorescence was quantified with FLUOstar OPTIMA (BMG Labtech). Negative controls consisted of a) AM cultured without DCFH-DA, and b) AM preincubated with prednisolone (10 μM). LPS activated AM and PMA 0.1 μg/ml were used as positive controls. RT-PCR ------ For quantitative mRNA expression of muscarinic receptors of AM RT-PCR (Rotorgene 3000, Corbett Research) was used. Total RNA was isolated using Trizol (Invitrogen), quantified spectrophotometrically and 1 μg was reverse transcribed to produce cDNA (Superspcript III Platinum, Invitrogen). The cDNA was then used to determine gene expression levels of the muscarinic receptors M1R-M3 relative to β-actin. The PCR reaction was performed with primers described by Pieper et al. \[[@B17]\]. The specificity of PCR reactions was verified by melting curve analyses and electrophoresis (date not shown). The primers used had the following sequences: M1R for (5\'-GGCACGCTGGCTTGTGA-3\'), M1R rev (5\'-TTCATGACGGAGGCATTGC-3\'), M1R-Probe (FAM-5\'-CTGGCCCTGGACTATGTGGCC-3-TAMRA\'), M2R-for (5\'- CCTGGAGCACAACAAAATCCA -3\'), M2R-rev (5\'- TCCCTGAACACAGTTTTCAGTCA-3\'), M2R-Probe (FAM-5\'-ATGGCAAAGCCCCCAGGGATCC-3-TAMRA\'), M3R-for (5\'-ACAGCCCCTCCGATGCA -3\'), M3R-rev (5\'-AACATTGTAGCTGCCGAAATGA -3\'), M3R-Probe (FAM-5\'-CTGCCCCCGGGAACCGTC -3-TAMRA\'), β-actin for (5\'-TGACGCCGGCTACAGCTT -3\'), β-actin rev (5\'-TCCTTAATGTCACGCACGATTT -3\'), β-actin-Probe (FAM-5\'-ACCACCACGGCCGAGCGG -3-TAMRA\'). In order to exclude that our results were influenced by different muscarinic receptor expression due to varying culture conditions, RT-PCR was performed in AM-RNA a) without over night incubation (2 h after isolation from BAL), b) with overnight incubation in RPMI/10%FCS/L-glutamine/penicillin/streptomycin/amphotericin (for 20 h), c) in control cells (see above), and d) in AM stimulated with LPS (1 μg/ml) or e) carbachol (100 μM). Statistical analysis -------------------- Values were expressed as mean value ± SD (or ± SEM when indicated) of *n*experiments. For statistical analysis to compare the response of AM/neutrophils to tiotropium bromide with and without carbachol acetylcholine, muscarin and oxotremorin we used the Kruskall-Wallis test, the Mann-Whitney rank-sum test and the Wilcoxon signed-rank test respectably, if appropriate. Statistical significance was accepted at the level of p \< 0.05. All statistical tests were performed using the SigmaStat software version (SPSS Science). Results ======= Patient characteristics are shown in table [1](#T1){ref-type="table"}. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Baseline parameters of patients (mean ± SD). ::: Parameter Value --------------------------------------------------- ---------------- N 71 Women n = 46 (64.8%) Men n = 25 (35.2%) ***Lung function and blood gas analysis*** FEV1 (%predicted) 80.3 ± 23.1 FEV/FVC (%) 69.1 ± 7.6 pO2 (mmHg) 72.5 ± 12.1 pCO2 (mmHG) 37.0 ± 3.4 pH 7.4 ± 0.01 ***Cell differential of bronchoalveolar lavage*** Alveolar macrophage \[%\] 91.1 ± 7,2 Neutrophils \[%\] 5.2 ± 3,1 Lymphocyte \[%\] 1.9 ± 0,7 Eosinophils \[%\] 0.7 ± 0,4 Mast cells \[%\] 0.1 ± 0,3 Total cells \[10^6^\] 8.9 ± 5,5 ::: Chemotaxis ---------- Supernatant from AM stimulated with LPS (0.1, 1 and 10 μg/ml) caused a concentration-dependent increase in the neutrophilic migration. A LPS concentration of 1 μg/ml resulted in an optimal chemotaxis, and was used in all consecutive experiments. Involvement of muscarinic receptors in LPS-mediated effects ----------------------------------------------------------- Supernatant from AM cultured with LPS and the anticholinergic drug tiotropium (30 nM) resulted in a significant (p \< 0.001) reduction of neutrophil migration compared with supernatant from AM cultured with LPS alone (figure [1](#F1){ref-type="fig"}). Tiotropium had no effect on migration rates in the absence of LPS (data not shown). Taken together, these data suggest that activation of muscarinic receptors was involved in the LPS-mediated release of chemotactic factors. To further investigate this point, co-incubation experiments with AChE (acetylcholinesterase) added to LPS stimulated AM cell medium (n = 9) resulted in reduced migration rates of neutrophils: 154% ± 33% of control (LPS alone), 113% ± 17% (LPS+AChE, p value \< 0.001), suggesting that acetylcholine release and consequent activation of muscarinic receptors are part of the signalling cascade activated by LPS. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Tiotropium inhibited chemotactic activity from LPS activated AM (test runs from left to right: n = 4, n = 9, n = 20 patients)**. Mean ± SD (standard deviation). \* p \< 0.001 compared with LPS activation without inhibition. Concentrations according to expected values in the airways after tiotropium inhalation <http://www.rxlist.com/cgi/generic3/spiriva_cp.htm>. :::  ::: To further explore this aspect, AM were stimulated with different muscarinic agonists, i.e. acetylcholine, carbachol, muscarin and oxotremorine. However, neither of these agonists induced neutrophilic migration alone, nor potentiated LPS-mediated effect \[+45.5 ± 39.1% (LPS+ acetylcholine), +12.3 ± 12.7% (LPS+carbachol), +15.2 ± 19.8% (LPS+muscarin), +21.2 ± 17.1% (LPS+oxotremorine), +41.5 ± 23.2% (LPS)\]. Taken together, these data suggest that ACH release and muscarinic receptor activation are a necessary component in LPS mediated effect, but not sufficient. Detection of which muscarinic receptor subtype is involved in LPS effects ------------------------------------------------------------------------- The analysis of muscarinic M1R, M2R and M3R mRNAs by RT-PCR showed that all the subtypes are present in AM, with muscarinic M3R mRNA transcripts dominating over M2R, and M1R (figure [2](#F2){ref-type="fig"}). 20 h after isolation from BAL, M-receptor expression increased compared with 2 h incubation (p \< 0.001). At the 20 h time point M-receptor expressions did not vary regardless of stimulants added to the cell medium (figure [3](#F3){ref-type="fig"}). ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Cellular mRNA levels of muscarinic M1R (MRC1), M2R (MRC2), M3R (MRC3) subreceptors in alveolar macrophages from COPD patients (n = 11)**. Mean+SD. :::  ::: ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Differences in muscarinic receptor (MRC1-3) expression profile in AM from n = 19 COPD patients depending on culture conditions**. X-axis represents comparisons always after an incubation time of 20 h: carbachol vs. control, LPS vs. control, 20 h vs. 2 h, LPS+ACh vs. LPS. Mean ± SD. \* p = \< 0.001 (repeated measures One Way ANOVA). :::  ::: The muscarinic M3R antagonist 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and tiotropium (p \< 0.01 vs. LPS stimulation alone) reduced neutrophilic migration rate in our chemotaxis system, whereas the muscarinic M1R-receptor antagonist pirenzepine and M2R antagonist gallamine did not (figure [4](#F4){ref-type="fig"}). ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Inhibition of AM induced chemotactic activity from tiotropium on neutrophils is predominantly driven by M3R-blockage (n = 10): Tiotropium 30 nM, 4-DAMP 100 nM (each: p \< 0.01 vs. LPS stimulation alone), Ipratropium 30 nM, Gallamine 100 μM, Tubocurarine 100 μM, Telenzepine 10 nM**. Doses were adapted from earlier studies and customized to our assay conditions \[[@B43],[@B63],[@B64]\]. :::  ::: Taken together, these data suggest that, in this model, ACh exerts its activity through the activation of the human M3R, which is also the most expressed subtype in AM. Anticholinergic effects in reducing mediator release ---------------------------------------------------- As expected, LPS exposure of AM resulted in an increase of many pro inflammatory mediators, as TNF-a, IL-8, IL-6, LTB4, GM-CSF and MIPα/β (data not shown). Coincubation with tiotropium (30 nM) resulted in a significant reduction of elevated TNFα secretion from LPS stimulated AM, which correlated fairly with the reduction of neutrophil migration rates (R^2^=0.335, p \< 0.001, figure [5](#F5){ref-type="fig"}). Concerning the other cytokines, tiotropium had no significant effect (date not shown). ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **Correlation of TNFα release of pre-cultured and LPS activated alveolar macrophages (AM) to the migration rate of neutrophils cultured with AM cell medium (Tiotropium 30 nM)**. :::  ::: Release of reactive oxygen species in AM ---------------------------------------- ROS are another important pro-inflammatory stimulus in COPD which is known to be a chemotactic factor. We therefore tested tiotropium bromide also to reduce ROS in order to further elucidate anti-inflammatory efficacy of this compound. Among the different stimuli tested, PMA (0.1 μg/ml) generated the highest ROS release in cultured AM, followed by LPS, which in turn is a stronger stimulus than carbachol. As expected, dexametasone (10 μM), which was used as positive control, substantially reduced LPS mediated ROS (figure [6](#F6){ref-type="fig"}). In 11 out of 16 patients tiotropium (30 nM) reduced ROS production from LPS stimulated AM by 36.1%. After stimulation with carbachol (100 μM), tiotropium induced a 46.2% reduction in ROS release; (p \< 0.001 vs. LPS or carbachol alone; figure [7](#F7){ref-type="fig"}). ::: {#F6 .fig} Figure 6 ::: {.caption} ###### **ROS (reactive oxygen species) release from LPS, PMA or carbachol activated alveolar macrophages (AM) from 16 patients**. ROS production in unstimulated cells was defined as 100%, ROS in cell free medium was 0. LPS 1 μg/ml; Carb = carbachol in various concentrations; Dexam = Dexametasone 10^-7^M in LPS activated AM; PMA 0.1 μg/ml. Data expressed as mean ± SD. \*p \< 0.001 vs. LPS. :::  ::: ::: {#F7 .fig} Figure 7 ::: {.caption} ###### **Inhibition of ROS release by tiotropium (3 × 10^9^M) in LPS (1 μg/ml) or carbachol (10^-4^M) activated alveolar macrophages**. \*p \< 0.001, both comparisons with LPS or carbachol alone. Mean ± SD. :::  ::: Discussion ========== Clinical studies in COPD patients using inhaled anticholinergic tiotropium 18 μg once daily revealed reduced exacerbation rates as well as an improvement of lung function and the natural course of COPD \[[@B28],[@B29]\]. The underlying mechanism how long-term treatment with tiotropium prevents exacerbations in these patients is unclear since the drug is regarded as a bronchodilator apparently lacking antiinflammatory capabilities in vivo \[[@B30],[@B31]\]. COPD exacerbations are at the cellular level characterized by increasing systemic and bronchial inflammation which can be at least in part influenced by long-term treatment of inhaled corticosteroids \[[@B32]-[@B36]\]. It is unlikely that pure bronchodilation may cause this phenomenon because long-acting β2-agonist therapy alone is unable to reduce exacerbation rates and exacerbation severity to a clinically meaningful extent \[[@B37]-[@B39]\]. COPD has a high driving force to recruit inflammatory cells from the capillary bed into the airways \[[@B40]\] which is at least in part regulated by the muscarinic cholinergic system \[[@B41],[@B42]\]. The ACh promoting effect on neutrophilic migration rate is dose dependent as Sato et al were able to demonstrate in ACh (1-100 μM) activated bovine alveolar macrophages \[[@B43]\]. In concordance with other studies, our data demonstrate a) that ACh drives chemotaxis since AChE reduces LPS-induced neutrophilc migration rates by about 40%, and b) that long-acting muscarinic receptor antagonist tiotropium bromide has additional anti-inflammatory capabilities due to reducing chemotactic activity of cultured AM in vitro. In regard to chemotaxis induction, ACh proved to be a much weaker driving force than LPS, suggesting that its role in LPS-mediated effects is necessary, but not sufficient to induce migration. Also, exogenously added ACh did not further enhance LPS efficacy, suggesting that LPS is per se already very efficacious and maximal chemotaxis was already reached (ceiling effect). Because of that, we run our experiments solely with LPS. In our experimental setup tiotropium bromide reduced LPS-mediated chemotaxis, possibly through an antiinflammatory effect as indicated by the reduction of TNFα release. Anti-inflammatory drugs, such as phosphodiesterase 4 inhibitors, have been shown to reduce TNFα and chemotaxis in sputum of COPD patients \[[@B44]\] which is at least in part mediated by mitogen activated protein (MAP) kinase pathway \[[@B45]\]. Our data may point to a similar effect of tiotropium bromide. However, TNFα reduction correlated weakly with the drop of chemotaxis, hinting that other mechanisms may be involved in tiotropium bromide influence in human alveolar macrophage/neutrophil chemotaxis. Because the supernatant used in the chemotaxis chamber contained tiotropium it might have exerted an additional effect on neutrophils which also express muscarinic receptors \[[@B14]\]. Surprisingly, tiotropium bromide failed to have any impact on the chemotactic mediators IL8, IL6, LTB4 and GM-CSF but not on cellular ROS release. Various other studies in myocytes also emphasize the stimulating effect of ACh on ROS production which is caused by activation of PI3K, Src-kinases or the ERK pathway at last leading to opening of mitochondrial K^ATP^channels and ROS release \[[@B46],[@B47]\]. ROS by themselves trigger chemokine production in inflammatory cells thus enhancing the inflammatory process \[[@B48],[@B49]\]. The involvement of the cholinergic system in ROS and ROS-mediated cytotoxicity make it an ideal system to test muscarinic receptor inhibitors for their cell protective function. In this context we were able to demonstrate that nanomolar concentrations of tiotropium protect cells by reducing the oxidant load produced by alveolar macrophages and LPS-mediated cytotoxicity. The concentration needed to obtain the cell protective effect in our cytotoxicity assay is in a physiologic range which can be achieved in human airways after inhalation. However, best protection was seen at high concentrations (300 nmolar). Possibly, reduction of ROS release is another mechanism by which tiotropium bromide limits chemotaxis. Our data are in good concordance with Wollin and Pieper describing a dose-dependent reduction of pulmonary neutrophilic inflammation of inhaled tiotropium (0.01 - 0.3 mg/ml) in smoke exposed mice \[[@B50]\], but they seem to defy Perng et al. \[[@B31]\], who didn\'t detect any antiinflammatory effect of tiotropium in humans. The difference between the three studies may be due to the lack of a placebo arm in the COPD trial in which all 3 treatment arms (fluticasone/sameterol, fluticasone/tiotropium, tiotropium alone) failed to show differences in the cellular component in sputum although differences in some inflammatory mediators were observed. Profita et al. (2008) demonstrated in 16HBE cells that acetylcholine-mediated IL-8 release significantly increased chemotaxis of neutrophils. This effect was inhibited by tiotropium bromide \[[@B51]\]. In the A549 and MonoMac6 cell line as well as in alveolar macrophages derived from non-smoking patients without a pulmonary disease tiotropium bromide decreased the release of chemotactic mediators after stimulation with high doses of ACh (100 μM) by about 70% \[[@B14]\]. Because ACh did not influence cellular release of IL-8 and monocyte chemotactic protein-1 (MCP-1) the authors suggested that leukotriene B4 (LTB4) was the driving force of chemotactic activity. However, the authors failed to clearly demonstrate that the reducing effects of tiotropium bromide correlate with inhibition of cellular LTB4 release. Nevertheless there is clear relationship between ACh mediated LTB4 release and chemotaxis of inflammatory cells in COPD patients, who have higher LTB4 amounts in induced sputum, which correlates with number of sputum neutrophils, than healthy volunteers. ACh (100 μM) stimulated sputum cells from COPD patients but not from non-smokers release LTB4. Also in blood monocytes LTB4-production was ACh sensitive. These effects could be blocked by an inhibitor of extra cellular signal-regulated kinase, but also by the anticholinergic compound oxitropium bromide at a concentration of 10 μM \[[@B52]\]. However, this drug concentration is high when taking into account that by inhalation only nanomolar concentrations can be achieved locally <http://www.rxlist.com/cgi/generic3/spiriva_cp.htm>. The reason why we failed to demonstrate an inhibitory effect of tiotropium bromide on IL8 or LTB4 release from AM may be dependent on the chosen cells, since we evaluated human AM and human neutrophils instead of using a cell line. Because of working with primary cells, we think that our model is more representative of the situation in the airways of COPD patients. It seems reasonable that M-receptor blockage inhibits chemotaxis, reduces anti-proliferative effects and ROS release, since activation of the cholinergic system has been shown a) to induce proliferative processes in airway tissue in vitro \[[@B53]\] as well as in vivo \[[@B16],[@B19]\], b) to induce eosinophilic chemotactic activity \[[@B43],[@B54]\], and c) ACh potentates the release of pro-inflammatory 15-HETE and prostaglandin E2 \[[@B55]\]. Further, cell proliferation of fibroblasts and myofibroblasts could be blocked by the nicotinic antagonist *n*-tubocurarine and antimuscarinic compounds \[[@B17],[@B53]\], and progression of airway smooth muscle remodeling in a allergen challenge asthma model could be minimized using tiotropium bromide \[[@B16]\]. M1R, M2R and M3R mRNAs were all present in AM. M3R mRNA transcripts dominate over M2R, and M1R and expression increased 20 h compared with the beginning. We could confirm previous studies also showing muscarinic receptor expression in cell cultures. Differences in the extent of mRNA transcript levels are most likely related to different cell types \[[@B51]\] or different experimental set up and patient characteristics \[[@B52]\]. Our study has some shortcomings. First, although 71 patients were recruited, the number of single measurements of each assay block was low, which was due to the numerous controls and limited cell number per patient. However, due to strict selection criteria, data from the different experimental settings still are comparable. Second, due to numerous controls, number of single measurements seems low, and would have otherwise resulted in better statistics. This relates in particular to the weak TNFα/chemotaxis correlation. Third, in only about 50% of the cytotoxicity and ROS experiments in which the various inhibitors were tested, tiotropium bromide revealed inhibitory efficacy. This observation is not unique for our work since it has been found also in other studies on this subject. Blaas et al stimulated primary epithelial lung cells with carbachol (100 μg/ml) and found only in 5 out of 12 patients enhanced IL-8 release. In their experiments neutrophilic migration could be induced by carbachol in about 40% of their patients \[[@B56]\]. Subject variability \[[@B57],[@B58]\], health status, varying nicotine consumption \[[@B59]\], cell type \[[@B60]\] and species differences \[[@B61],[@B62]\] may be confounding factors contributing to this phenomenon. Forth, the number of migrated cells in our chemotaxis chamber system seems low in comparison to other publications. To detect more objectively migrated neutrophils and in order to enable high output measurements we used a fairly new chemotaxis chamber detecting fluorescence as the cellular marker for leukocyte migration. Other papers simply count the cells by light microscopy in the adjacent chamber as well as the filter whereas our system only detects truly migrated cells disregarding those cells sticking in the filter. Our assay has been described to comprise significant advances quantifying leukocyte chemotaxis and explains the differences to previous publications \[[@B26]\]. Conclusion ========== Our results show that tiotropium bromide inhibits AM mediated chemotaxis of neutrophils. This effect correlates at least in part by concomitant TNFα reduction. Further, it reduces cellular proinflammatory activities such as the generation of ROS. Experiments with selective M -receptor inhibitors indicate that the M3R subtype is responsible for tiotropium bromide inhibition of chemotaxis. Competing interests =================== GV declares that she has no competing interests. WG and AG have received consulting fees, speaking fees, and grant support from Boehringer Ingelheim Pharma Germany. Authors\' contributions ======================= All authors have made substantial contributions. GV established the assays, and coordinated the work in the laboratory. She carried out the molecular genetic studies as well the immunoassays GV wrote the first version of the manuscript. WR helped in revising the manuscript critically for important intellectual content. AG planed the conception and design of the study and applied for the funding. He recruited the patients, collected the clinical data, wrote the final version of the manuscript and gave final approval of the version to be published. All authors read and approved the final manuscript. Funding ======= This study was funded by Boehringer Ingelheim GmbH, Germany Acknowledgements ================ The authors appreciate the help of Katharina Dück and Ramona Dück who supported us regarding the set up of the experiments, the collection of clinical data and general assistance.

PubMed Central

2024-06-05T04:04:17.231852

2011-2-27

PMC3051906

Background ========== Atopic diseases including allergic rhinitis and asthma are inflammatory conditions that have increased in prevalence over the past two decades \[[@B1]\]. The inflammatory response to common environmental allergens during allergy and asthma has been extensively studied in the past years, and has clearly determined the pivotal role of T cell activation, with a predominant Th2 cytokine production \[[@B2],[@B3]\]. T regulatory (Treg) cells, characterized by the production of anti-inflammatory cytokines such as IL-10 and TGF-β \[[@B4],[@B5]\] are considered as responsible for the normal tolerance against auto-antigens and external antigens such as allergens \[[@B6]\]. Accordingly, a deficiency in Treg counts and activation was found in autoimmune diseases and allergic conditions, notably during allergen exposure \[[@B7],[@B8]\] and exacerbations of severe asthma \[[@B9]\]. However although this Th2/Treg imbalance applies both for allergic rhinitis and asthma, it is remarkable that despite a same atopic background and allergen exposure, some subjects will develop both rhinitis and asthma whereas other will display rhinitis only. We hypothesize since several years that T cell activation is different between both conditions and with others we previously described a Th1 activation in asthma that was absent in non asthmatic allergy in blood, induced sputum and broncho-alveolar lavages \[[@B10]-[@B12]\]. However, the role of allergen in the tuning of T cell activation in allergic rhinitics with and without asthma was not explored yet. Allergen-induced T cell activation depends on signals delivered from antigen presenting cells (APCs) through the antigen-specific T cell receptor as well as additional co-stimulatory signals provided by engagement of so-called co-receptors on APCs and T cells \[[@B13]\]. Major T cell co-receptors are CD28, inducible costimulatory molecule (ICOS) and cytotoxic T lymphocyte antigen (CTLA)-4. They belong to the immunoglobulin gene superfamily and display various kinetics of expression. CD28 is a constitutive co-stimulatory receptor binding CD80 and CD86 on APCs, delivering important signals for T cell activation and survival. Ligation of CD28 promotes the production of IL-4 and IL-5 and provides resistance to apoptosis and long-term expansion of T-cells. As CD28, ICOS is a positive regulator of T cell activation which is up-regulated on activated T-cells. ICOS was initially shown to selectively induce high levels of IL-10 and IL-4, but is also able to stimulate both Th1 and Th2 cytokine production *in vivo*\[[@B14]\]. CTLA-4 is also a CD80/CD86-binding protein. It is up-regulated on activated T cells and delivers mainly an inhibitory signal, playing an important role in maintenance of peripheral tolerance \[[@B15]\]. Indeed, it was shown in murine Treg cells, that CTLA-4 controlled homeostasis and suppressive capacity of regulatory T cells \[[@B16]\]. Co-receptors thus represent important potential targets for therapeutic immunomodulation. Indeed the blockade of CD28 and CTLA-4 agonists are tested for their ability to prevent graft rejection \[[@B17]\], and in animal models, ICOS inhibition prevented allergic inflammation \[[@B18]\]. However, the actual role of co-receptors in the context of asthma and allergy in humans is still unexplored. The objective of this study was therefore to compare the pattern of T cell activation between allergic rhinitics and asthmatics upon allergen stimulation and to assess the role of co-receptors CD28, ICOS and CTLA-4 in this process. Methods ======= Study population ---------------- Four groups of patients were recruited: allergic rhinitics (R), allergic rhinitics and asthmatics (AR), non allergic asthmatics (A), and controls (C). All allergic patients were selected to display house dust mite (HDM) allergy. As rBetv1 birch pollen allergen was used as control antigen for *in vitro*stimulation of T cells, patients were selected to be not sensitized to birch pollen. The diagnosis of HDM allergy was determined by positive skin prick test to *Dermatophagoides pteronyssinus*extract (Stallergenes, France). Allergic rhinitis was defined by the presence of perennial nasal symptoms out of viral infection such as nasal obstruction, sneezing, rhinorrhea and nasal pruritus. The diagnosis of asthma was done on the basis of a history of dyspnea and wheezes with a reversible obstructive ventilatory defect or a positive methacholine challenge. The distinction between mild and moderate asthma was done according to GINA classification \[[@B19]\]. In patients, any inhaled corticosteroids and anti-histamines were discontinued 15 days before sampling. As controls, healthy non smoker individuals with normal lung function, negative methacholine challenge and negative skin prick test were included. In controls, absence of allergy was established by the negativity of 35 skin prick tests to common environmental aeroallergens, and absence of asthma was stated on negative methacholine challenge and induced sputum eosinophil count below 3% (see additional file [1](#S1){ref-type="supplementary-material"}: Skin testing, methacholine challenge and induced sputum procedures). The positive methacholine test was defined by a drop of at least 20% of FEV1(forced expiratory volume in 1 second) in response to 200 μg or less of metacholine. This project was approved by the local Ethic Committee and written informed consent was obtained from each patient. Isolation of PBMC ----------------- Peripheral blood mononuclear cells (PBMC) were isolated from peripheral venous blood by Ficoll-Hypaque plus (GE Healthcare, Uppsala, Sweden) density gradient centrifugation. Cells were then washed three times and resuspended in complete medium RPMI-1640 supplemented with 10% (v/v) foetal calf serum (FCS), 2 mM L-glutamine, 1 mM sodium pyruvate, 1 μM 2-mercapto-ethanol (Sigma Chemical, Saint-Louis, Missouri), 1000 U/ml Penicillin and Streptomycin. All culture reagents, except 2-mercapto-ethanol, were purchased from GIBCO^®^. Antigens -------- Recombinant (r) Betv 1 of birch pollen (*Betula verrucosa*) and purified (p) Derp 1 of house dust mite (*Dermatophagoides pteronyssinus*) were provided by Stallergènes (Antony, France). None of the allergens contained detectable amounts of LPS. Specific stimulation of T cells ------------------------------- Optimal dose of stimulatory pDerp1 and kinetics of T cell cytokine secretion and proliferation were determined in an independent pilot study on 5 house dust mite allergics and 5 healthy volunteers. PBMC (5 × 10^5^) were cultured in 96 wells plates (Falcon) in 100 μl medium containing 1 μg/ml pDerp1 at 37°C in 5%CO~2~and cells were harvested after 8 days culture. 50 μl of fresh complete medium was added every 2 days in each well. rBetv1 was used as control antigen at a concentration of 1 μg/ml. Surface staining ---------------- After 8 days of culture with pDerp 1, PBMC (5 × 10^5^) were harvested and stained with anti-CD4-PE-Cy5, anti-CD25-FITC, (Beckman Coulter, Marseille, France); anti-CD3-FITC (Dako, Trappes, France), anti-CD3-PE-Cy5 (Immunotools, Friesoythe, Germany), anti-CD28-FITC, anti-ICOS-PE, or anti-CTLA-4-PE-Cy5 (BD Pharmingen, le Pont de Claix, France) mAbs at recommended concentrations. To detect Foxp3 intracellular transcription factor, T cells were then fixed, permeabilized, and stained with anti-Foxp3-PE mAb (eBiosciences, San Diego, California). The Treg population was identified as CD4+CD25^Hi^+Fox p 3+ cells. Fluorescence was detected with a 15 mW argon ion laser on a three colors FACSCan^®^(Becton Dickinson, Franklin Lakes, NJ, USA). Standard acquisition and analysis software were obtained through Cellquest^®^Software (Becton Dickinson). Intracellular T cell cytokine staining -------------------------------------- PBMC (5 × 10^5^) were cultured for 8 days with pDerp 1. PMA (Sigma Chemical, Saint-Louis, Missouri, 50 ng/ml), Ionomycin (Euromedex, 2 μg/ml) and Monensin (Sigma Chemical, 2 μM) were added during the last 6 hours of culture. These culture conditions allow the detection of cytokines already engaged in a synthesis process in vivo \[[@B20]\]. Cells were harvested and stained with CD3-PE-Cy5 (Immunotools, Friesoythe, Germany). Cells were then fixed, permeabilized, and stained with antibodies to detect intracellular cytokines (anti-IFNγ-FITC, anti-IL-4-FITC, BD Pharmingen, le Pont de Claix, France; anti-IL13-PE, anti-IL-10-PE, R&D system, Lille, France). IL-4+ and IL-13+ cells were considered as Th2 cells, IFN-γ + cells as Th1 cells. IL-10+ cells were considered as belonging to Treg cell population. Co-receptor study ----------------- To determine the role of co-receptors in T cell activation, PBMC cultures were performed with or without anti-CTLA-4 (clone 14D3, 12 μg/ml), anti-ICOS (clone ISA-3, 12 μg/ml) or anti-CD28 (clone CD28.6, 3 μg/ml) monoclonal antibodies (mAb). These mAb were purchased from eBioscience. Statistical Analysis -------------------- Analysis was performed using the Statview^®^Software. Normal distributions of the variables were checked with a Kolmogorov-Smirnof\'s test. Average percentages of positive cells and cytokine concentrations were then compared between groups (controls, non allergic asthmatics, allergic rhinitics and allergic asthmatics) using the analysis of variance (ANOVA). When the ANOVA showed statistical difference between groups, a multiple linear regression analysis was done to identify if allergy, asthma, or both could explain the variable studied. Between-groups comparisons were performed using a Student\'s t-test. A paired t test was used to compare differences between paired groups. A p value \< 0.05 was considered as statistically significant for all statistical tests. Results are expressed as mean ± standard error (SE). Results ======= Study population ---------------- Sixty-nine subjects (33 males, 36 females, mean age 37.20 ± 1.90) were included. Blood samples from 20 healthy individuals with no history of allergy or asthma, 18 allergic asthmatics (AR), 18 allergic rhinitics (R), and 13 non allergic asthmatics (A) were collected. Characteristics of the patients are shown in table [1](#T1){ref-type="table"}. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Characteristics of the patients ::: Controls (n = 20) R (n = 18) AR (n = 18) A (n = 13) ------------------------------------ ------------------- -------------- ------------------ --------------- **Clinical Data** Gender, (M/F) 5/15 12/6 10/8 6/7 Age\* 32.38 ± 4.49 33.68 ± 3.23 40.56 ± 3.59 50.61 ± 4.36 Body Mass Index 24 ± 0.5 22.5 ± 1.5 25 ± 4 24.5 ± 2 mild/moderate asthma \- \- 9/9 6/7 **Lung function** FEV~1~, (% of theoretical value\*) 100 ± 2.26 97.4 ± 4.30 89.5 ± 3.91 83.8 ± 6.64 Sputum eosinophils (%)\* 0.5 ± 0.31 0.75 ± 0.75 14.78 ± 5.98\*\* 29 ± 9.99\*\* FEV~1~= Forced expiratory volume in 1 second \* Values are mean ± standard error (SE), \*\* = p \< 0.01. R = allergic rhinitis; A R = allergic asthma and rhinitis; A = non allergic asthmatics. ::: None of the subjects was a smoker. Patients interrupted their local or systemic steroids or antihistamines 15 days before sampling. Asthmatics were mild asthmatics for one half and moderate asthmatics for the other half. All allergic patients displayed symptoms compatible with allergic rhinitis. All non allergic asthmatics also complained from nasal symptoms. Healthy volunteers did not report any symptom. Sputum eosinophil counts were significantly higher in asthmatics than in control subjects or allergic rhinitis, with no significant difference between allergic and non allergic asthmatics. None of the subjects was sensitized to birch. The age difference between the A+R group and other groups (A, R and C) was not significant statistically. T cell activation and co-receptor expression before specific stimulation ------------------------------------------------------------------------ Treg cells proportion, Th1 and Th2 cytokines production and co-receptors expression (CTLA-4, ICOS, CD28) in each group were first assessed by flow cytometry, prior to any specific stimulation. In non-stimulated conditions, CTLA-4+ T cells were decreased in asthmatics (p \< 0.05 vs controls, figure [1A](#F1){ref-type="fig"}), whatever their allergic status. In keeping with this result, a reduced Treg population (p \< 0.025, figure [1B](#F1){ref-type="fig"}) was found in these patients. Relevantly, Treg cell proportions were higher in mild asthmatics than in moderate counterparts (p \< 0.012, figure [1C](#F1){ref-type="fig"}). IFN-γ + cells were increased (p \< 0.022 vs controls, figure [1D](#F1){ref-type="fig"}) in asthmatics. No significant difference in Th2 cytokines or IL-10 production was found (table [2](#T2){ref-type="table"}) between groups. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **T cell activation and co-receptor expression before specific stimulation**. CTLA-4 expression (A), Treg cells (CD4+CD25+^Hi^Foxp3+, B), IFN-γ producing T cells (D) and ICOS expression (E) were assessed by flow cytometry in PBMC from HDM allergic rhinitics (R) (triangle, n = 18), allergic asthmatics and rhinitics (AR) (square, n = 18), non allergic asthmatics (A) (lozenge, n = 13), and controls (circle, n = 20). Treg cells were also evaluated in non allergic asthma and allergic asthma between mild and moderate asthmatics (C). Results are expressed as percentage of total T cell and compared versus controls. \_ : mean of each group. \* = p \< 0.05; \*\* = p \< 0.01 :::  ::: ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### Baseline T-cell co-receptor and cytokine expression ::: Controls (n = 20) R (n = 18) AR (n = 18) A (n = 13) ---------------- ------------------- -------------- -------------- -------------- CD3+IL-4+ (%) 2.38 ± 0.26 2.88 ± 0.29 2.35 ± 0.22 3.25 ± 0.60 CD3+IL-13+ (%) 3.02 ± 0.31 4.17 ± 0.48 3.54 ± 0.34 4.18 ± 0.54 CD3+IL-10+ (%) 5.01 ± 0.47 4.06 ± 0.33 4.38 ± 0.37 4.37 ± 0.46 CD3+CD28+ (%) 87.75 ± 2.50 89.04 ± 1.71 89.50 ± 1.31 84.85 ± 3.45 PBMC from each patient were cultured in complete medium during 8 days. ICOS, CD28, IL-4, IL-13, and IL-10 expression by T-cells were assessed by flow cytometry. Results are expressed as mean of total T-cells ± SE and compared versus controls. \* = p \< 0.05, \*\* = p \< 0,01. R = allergic rhinitis; A R = allergic asthma and rhinitis; A = non allergic asthmatics. ::: ICOS expression was higher in R compared to controls (p = 0.029, figure [1E](#F1){ref-type="fig"}), but similar in AR and controls. No significant variation was found at the level of CD28 expression between groups (table [2](#T2){ref-type="table"}). The multiple linear regression analysis showed that asthma (A + AR) was associated to lower ICOS and CTLA-4 expression and Treg cell proportions, but to higher IFN-γ+ T cells (table [3](#T3){ref-type="table"}). By contrast, allergic rhinitis (with or without asthma) was positively linked to ICOS expression. ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### Multiple linear regression analysis between asthma, allergy and allergy after specific stimulation ::: Asthma (A+AR) Allergy (R+AR) Allergy + specific stimulation (R+AR+Derp1 stimulation) ------------------------- ----------------------------------- ------------------------------- --------------------------------------------------------- CD3+ICOS+ (%) **-1.502**± **0.75 (p = 0.0485)** **1.675 ± 0.75 (p = 0.0292)** **2.929 ± 0.81 (p = 0.0006)** CD3+CTLA-4+ (%) **-1.649 ± 0.61 (p = 0.0087)** 0.508 ± 0.61 (p = 0.4088) **-1.406 ± 0.60 (p = 0.0223)** CD3+IL-4+ (%) 0.188 ± 0.34 (p = 0.585) -0.066 ± 0.34 (p = 0.848) **1.12 ± 0.37 (p = 0.034)** CD3+IL-13+ (%) 0.287 ± 0.43 (p = 0.508) 0.429 ± 0.43 (p = 0.325) **2.209 ± 0.43 (p \< 0.0001)** CD3+IFN-γ+ (%) **3.3643 ± 1.63 (p = 0.0283)** 1.44 ± 1.62 (p = 0.378) 0.884 ± 1.42 (p = 0.535) CD4+CD25^Hi^+Foxp3+ (%) **-1.647 ± 0.54 (p = 0.0033)** -0.371 ± 0.54 (p = 0.494) -0.774 ± 0.52 (p = 0.142) CD3+IL-10+ (%) -0.146 ± 0.42 (p = 0.729) -0.549 ± 0.42 (p = 0.196) **-1.896 ± 0.44 (p \< 0.0001)** Values are expressed as coefficient of regression ± SE ::: T cell activation and co-receptor expression after specific stimulation by allergens ------------------------------------------------------------------------------------ PBMCs were cultured in the presence or not of pDerp1 during 8 days. T cell activation and co-receptors expression were then studied by flow cytometry. In AR, Der p 1 up-regulated CD28 (89.78 ± 1.33 vs 91.01 ± 1.48; p = 0.0016) and ICOS expression, and decreased CTLA-4 (figure [2A](#F2){ref-type="fig"}). Furthermore, Derp1 stimulation induced an increase in IL-4+ and IL-13+ cells (figure [2A](#F2){ref-type="fig"}), without significant variation in IFN-γ+ cells (not shown). This increase in Th2 cells was associated to a decrease in IL-10+ cells and Treg cells (figure [2A](#F2){ref-type="fig"}). ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **T cell activation and co-receptor expression after specific stimulation**. ICOS, CTLA-4 expression, IL-4, IL-13, IL-10 producing T cells and Treg cells (CD4+CD25+^Hi^Foxp3+) were assessed by flow cytometry in PBMC from HDM allergic asthmatics and rhinitics (AR) (A, n = 18), HDM allergic rhinitics (R) (B, n = 18), non allergic asthmatics (A) (C, n = 13), and controls (D, n = 20) stimulated or not with Derp1 allergen (1 μg/ml) during 8 days. Results are expressed as percentage of total T cells. \_ : mean of each group. \* = p \< 0.05; \*\* = p \< 0.01 :::  ::: In R, Derp1 also increased CD28 (89.03 ± 1.71 vs 91.00 ± 1.48; p = 0.0025) but not ICOS expression (figure [2B](#F2){ref-type="fig"}). It decreased CTLA-4+ cell proportions. Allergen stimulation induced an increase in Th2 cells without variation of IFN-γ + cells (not shown), and a decrease in IL10+ and Treg cells (figure [2B](#F2){ref-type="fig"}). Therefore at the exception of ICOS, that was already increased at baseline in R and thus could not increase upon stimulation, the profile of T cell activation and co-receptor expression induced by Derp1 was similar in AR and R subjects. After specific stimulation (figure [2C-D](#F2){ref-type="fig"}), T cells from asthmatic and non asthmatic allergics displayed higher expression of ICOS (p \< 0.02) and lower expression of CTLA-4 compared to controls (p \< 0.007). In addition Th2 cell proportions were higher in allergics whereas Treg cells were decreased (IL-4, p \< 0.0022; IL-13, p \< 0.0001; Treg, p \< 0.008). CD28+ cell percentages were not different between groups after allergen-specific stimulation (not shown). In non allergic subjects (figure [2C-D](#F2){ref-type="fig"}) no significant variation was found in any of the parameters studied The multiple linear regression analysis showed that after Derp 1 specific stimulation, allergy (R + AR) correlated positively with percentages of ICOS, IL-13 and IL-4-expressing T cells and negatively with CTLA-4 and IL-10-expressing T cells (table [3](#T3){ref-type="table"}). No variation was found in any subject for any co-receptor or cytokine expression after stimulation with irrelevant rBetv1 (not shown). Role of co-receptor engagement ------------------------------ In order to study the respective role of CD28, ICOS and CTLA-4 in T cell activation patterns in the context of allergen presentation, PBMC were stimulated with Derp1 in the absence or presence of anti-ICOS, anti-CTLA-4 or anti-CD28 mAb. In allergics, whatever the asthmatic status (R + AR), anti-ICOS and anti-CD28 mAb specifically decreased IL-4+ and IL-13+ cells (figure [3A](#F3){ref-type="fig"} and table [4](#T4){ref-type="table"}), but had no influence on IFN-γ+ cells (table [4](#T4){ref-type="table"}). Anti-CTLA-4 mAb had no effect on IL-4+ cells, but unexpectedly decreased IL-13+ cell proportions (table [4](#T4){ref-type="table"}). ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Effect of anti-co-receptors antibodies on IL-13 production by T cells**. PBMC from allergic rhinitics (R) (triangle, n = 12), allergic rhinitic and asthmatics (AR) (square, n = 10) and non allergic asthmatics (A) (lozenge, n = 11) were stimulated with Derp 1 and cultured in the presence or absence of anti-ICOS, anti-CTLA-4 or anti-CD28 antibodies. IL-13 expressing T cells were then compared in each group versus baseline. Results are expressed as percentage of total T cells. Black line : mean of each group. \* = p \< 0.05; \*\* = p \< 0.01; \*\*\* = p \< 0.001 :::  ::: ::: {#T4 .table-wrap} Table 4 ::: {.caption} ###### Effect of anti-co-receptors antibodies on Treg cells, IL-10 and IFN-γ production ::: R (n = 12) AR (n = 10) A (n = 11) -------------------------- ------------- ---------------------- ----------------------- ---------------------- -------------- ---------------------- ----------------------- ---------------------- -------------- ---------------------- ----------------------- ---------------------- **Derp1** **Derp1+ anti-ICOS** **Derp1+ anti-CTLA4** **Derp1+ anti-CD28** **Derp1** **Derp1+ anti-ICOS** **Derp1+ anti-CTLA4** **Derp1+ anti-CD28** **Derp1** **Derp1+ anti-ICOS** **Derp1+ anti-CTLA4** **Derp1+ anti-CD28** CD3+IL-10+(%) 3.82 ± 0.49 3.79 ± 0.30 4.66 ± 1.05 3.31 ± 0.32 3.80 ± 0.41 3.54 ± 0.46 3.96 ± 0.50 3.60 ± 0.52 5.03 ± 0.68 4.42 ± 0.56 4.42 ± 0.64 4.37 ± 0.64 CD4+CD25^Hi^+ Foxp3+ (%) 4.25 ± 0.45 4.49 ± 0.65 4.24 ± 0.57 3.57 ± 0.65 3.61 ± 0.70 4.21 ± 1.13 3.87 ± 0.83 2.78 ± 0.83 2.65 ± 0.47 2.47 ± 0.38 2.55 ± 0.40 1.75 ± 0.29 CD3+IFN-γ+ (%) 7.48 ± 1.15 6.13 ± 0.75 7.24 ± 1.11 7.63 ± 0.98 12.26 ± 1.35 11.86 ± 1.01 13.99 ± 1.84 13.64 ± 1.36 11.90 ± 1.89 10.43 ± 1.78 12.35 ± 1.74 12.32 ± 1.98 CD3+IL-4+ (%) 4.22 ± 0.55 2.01 ± 0.26\* 3.67 ± 0.94 2.33 ± 0.40\* 3.29 ± 0.49 2.21 ± 0.15\*\*\* 2.85 ± 0.34 2.41 ± 0.22\*\* 3.53 ± 0.50 2.56 ± 0.54 2.92 ± 0.51 3.11 ± 0.95 PBMC from allergic non asthmatics (R, n = 12), allergic asthmatics (AR, n = 10) and non allergic asthmatics (A, n = 11), were stimulated with Derp 1 and cultured in the presence or absence of anti-ICOS, anti-CTLA4 or anti-CD28 antibodies. Treg cells, IL-10 and IFN-γ production by T-cells were assessed by flow cytometry. Results are expressed as mean of total T-cells ± SE and compared versus absence of anti-co-receptors antibodies conditions. R = allergic rhinitis; A R = allergic asthma and rhinitis. \* = p \< 0.05, \*\* = p \< 0,01, \*\*\* = p \< 0,001. ::: In non allergic subjects (A + controls), anti-co-receptor antibodies did not affect Th1 or Th2 cytokine production (figure [3](#F3){ref-type="fig"} and table [4](#T4){ref-type="table"}). Discussion ========== The results of our *ex vivo*study strongly suggest a contrasted picture of T cell activation in allergic rhinitis and asthma, with distinct patterns of Th1, Th2 and Treg profiles and expression of ICOS, CD28 and CTLA-4 co-receptors. Indeed, we showed that in asthma, IFN-γ production was constitutive, did not increase upon allergen stimulation, and was not blocked by any of the anti-co-receptor antibodies. Similarly, the constitutive defect of Treg and CTLA-4 expression seen in asthmatics and not enhanced in non allergic asthmatics after allergen stimulation was not modified after co-receptors blockade. The Th1/Treg imbalance in asthma is therefore constitutive and independent of allergen presentation. The constitutive Th1 activation in asthma was demonstrated before \[[@B10],[@B12],[@B21]\]. It could result from the intrinsic defect in the CTLA-4+ and Treg populations as CTLA-4, known to be involved in tolerance induction \[[@B22]\], could prevent the asthmatic inflammation by inducing T cells to differentiate in T regulatory cells. Recently, we have showed during *in vivo*studies a lower proportion of Treg cells in blood from severe refractory asthmatics compared to controls, which was even deeper during exacerbations, both in blood and induced sputum \[[@B9]\]. Herein we show that this lower proportion of Treg is present in milder stages of asthma. Relevantly, Treg cells were higher in mild than in moderate asthma whatever the allergic status. This results are concordant with the primary Treg cell deficiency suggested in asthma and allergy \[[@B23]\]. That the Th1/Treg imbalance is similar in allergic and non allergic asthma suggests that it is a characteristic of asthma independent of allergy, possibly triggered by infectious agents or non specific substances such as pollutants but it must be precised that asthmatics included in the present study were controlled and did not experienced any recent exacerbation. Another hypothesis would be that the Th1/Treg imbalance in asthma is really intrinsic and independent of any external aggression. In allergic groups, we demonstrated a Th2/Treg imbalance inducible upon allergen stimulation. That Th2 activation was not seen in non allergic patients and could be broken by CD28 and ICOS blockade indicates that it is really the cognate allergen presentation by antigen presenting cells that was responsible for it. IL-13 secretion was suppressed also by blocking CTLA-4, indicating that in peripheral cells (1) Th2 activation cannot be considered globally, Th2 cytokines being regulated distinctly, and (2) CTLA-4 being not only involved in tolerance but also in inflammation. This result is concordant with Lordan and al., who showed that allergen-induced production of IL-5 and IL-13 by PBMC from allergic asthmatics could be inhibited by blocking CTLA-4 receptor with CTLA-4-Ig \[[@B24]\]. Regarding the allergen-induced Treg defect in allergics, other co-receptors than these tested are likely involved, among which PD1 is a candidate \[[@B25]\]. Indeed, Meiler et al. recently demonstrated in PBMC from allergic patients that the suppressive effect of IL-10 secreting T cells was partially inhibited by blocking CTLA-4 or PD-1 co-receptors, whereas blocking both receptors simultaneously had an additive effect \[[@B26]\]. The association of allergy with ICOS over-expression before any allergen stimulation suggests a non specific priming of T cells towards the Th2 pathway in allergic subjects. Indeed ICOS was clearly related to Th2 activation, as shown by anti-ICOS stimulation results. Numerous studies using animal models of airways inflammation have showed that ICOS-mediated signalling was essential for induction of Th2 cytokines \[[@B27],[@B28]\]. Indeed inhibition of ICOS suppresses allergic lung inflammation and Th2 cytokines production in mice models \[[@B29]\]. However in other models ICOS engagement induces tolerance and inhibits the allergic inflammation. These distinct actions of ICOS seem related to the density of ICOS molecules per cell, with inflammation being related to a high density of co-receptors and tolerance induction to a lower number of ICOS molecules per cell \[[@B30]\]. That in R ICOS expression does not increase after allergen stimulation by contrast with the AR group could result from a maximal expression of ICOS in R whereas it is still inducible in AR. Indeed the basal level of ICOS expression is lower in the latter group than in the former. This relative defect in ICOS expression in AR patients could result from the constitutive Th1/Treg imbalance of asthmatics that by a Th1-driven \"anti-Th2\" effect would decrease ICOS expression. Under allergen stimulation, CD28 expression increased significantly in R and AR, and blockade of CD28 decreased the Th2 cytokine production, indicating the involvement of CD28 in Th2 cell activation in allergy. It is noteworthy that although significant statistically, the proportion of CD28+ cells could not increase in high proportion, as most T cells constitutively expressed CD28 in all groups. CD28 is a crucial co-receptor for inducing T cell cytokine production \[[@B31]\], and was showed to be involved both in Th1 and Th2 activation. CD28 blockade is proposed as an immunosuppressive strategy to prevent graft rejection, and is experimented in various inflammatory diseases. However the practical use of CD28 blockade was refrained by the agonist action of some anti-CD28 antibodies encountered in clinical trials \[[@B32]\]. Our study provides new insights into the hypothesis of Treg cell deficiency as a paradigm for allergic diseases, by showing a constitutive Treg cell deficit in asthma whatever the allergic status and an inducible Treg deficit in allergy, whatever the presence of asthma. As a consequence, the Treg cell deficiency is the highest in asthmatic allergics after allergen stimulation. This distinction between allergy and asthma contradicts our previous hypothesis of a gradient of Treg cell deficiency from allergy to asthma \[[@B23]\], and better suggests that the abnormalities seen in both diseases could be juxtaposed and independent, as showed by the multiple linear regression analysis. Recently an *in vivo*study showed no difference in the number of Treg cells between asthmatics and controls, whereas FOXP3 protein expression within Treg cells was significantly decreased in asthmatic patients \[[@B33]\]. Our study was performed in blood *ex vivo*and therefore might not fully reflect the *in vivo*and in situ reality. However many studies showed that blood compartment was relevant to the in situ inflammation as far as T cells and allergy were concerned \[[@B21]\], and the mechanistic studies proposed here cannot be assessed in situ in humans. They can be performed *in vivo*in animals, but the relevance to real asthma would also be uncertain. In conclusion, allergy is associated to a constitutive ICOS over-expression and inducible CTLA-4 under-expression with Th2/Treg imbalance, when a constitutive CTLA-4 under-expression and Th1/Treg disequilibrium appears as a hallmark of asthma. Both profiles are mixed in allergic asthma, and one can argue that asthma would occur in allergic subjects only if the unknown conditions leading to the constitutive Th1 activation are present. Still missing in the puzzle is the stimulus inducing the Th2 activation present in non allergic asthma \[[@B3]\]. Lastly, our results demonstrate that although targeting one type of T cell activation only would be a pitfall in allergic asthma, there is a rationale to develop strategies based on targeting co-receptors in allergy. Conclusion ========== In conclusion, our work adds significant insights into the immune mechanism involved in allergy and asthma and states the rationale for new diagnosis and/or therapeutic strategies in these pathologies. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= All the authors have contributed significantly to the research and preparation of the manuscript, and they approve its submission. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **Skin testing, methacholine challenge and induced sputum procedures**. ::: ::: {.caption} ###### Click here for file ::: Aknowledgements =============== We kindly acknowledge Stallergènes for providing the Der p 1 purified protein and Betv1 recombinant protein.

PubMed Central

2024-06-05T04:04:17.235055

2011-2-28

PMC3051907

Background ========== Cardiovascular disease is the main cause of premature death in industrialized countries, and its incidence is increasing worldwide \[[@B1]\]. In Switzerland, between 1970 and 2004, mortality rates from ischemic heart and cerebrovascular disease have decreased by circa 50% in men, and by a third by women \[[@B2]\]. Whether those decreases are due to a decrease in cardiovascular risk factors prevalence and/or management is currently unknown. There are few data regarding trends of cardiovascular risk factors in the Swiss population. The MONICA study showed an increase between 1984 and 1993 in the prevalence of hypertension in men and a decrease in women. For the same time period, a decrease in the prevalence of hypercholesterolemia (defined as a total cholesterol level \> 6.5 mmol/L) was also reported for both genders \[[@B3]\]. More recently, data from Geneva showed a decrease in the prevalence of hypertension for both genders between 1993 and 2000. For the same period, an increase in the prevalence of hypercholesterolemia was reported \[[@B4]\]. Still, it is not known if the results of this study also apply to the whole country. Thus, we used the data from the National Health Surveys conducted in representative samples of the Swiss population to assess the trends in self-reported prevalence, treatment and control of hypertension, hypercholesterolemia and diabetes in Switzerland, as well as to identify the groups at higher risk. Methods ======= Swiss Health Survey ------------------- Data from the Swiss Health Surveys (SHS) were obtained from the Swiss Federal Statistical Office (<http://www.bfs.admin.ch>). The SHS is a cross-sectional, nationwide, population-based telephone survey conducted every 5 years since 1992 (1992, 1997, 2002 and 2007) \[[@B5]\]. The SHS aims to track public health trends in a representative sample of the resident population of Switzerland aged 15 and over. The study population was chosen by stratified random sampling of a database of all private Swiss households with fixed line telephones. It is currently estimated that over 90% of the Swiss households have fixed telephones. The first sampling stratum consisted of the seven main regions: West \"Léman\", West-Central \"Mittelland\", Northwest, Zurich, North-Eastern, Central and South. The second stratum consisted of the cantons, and the number of households drawn was proportional to the population of the canton. In some cantons, oversampling of the households was made to obtain accurate cantonal estimates. Extra strata were used for two large cantons of Zurich and Bern. Within these strata, households were randomly drawn and, within the household, one member was randomly selected within all members aged 15 years and over. A letter inviting this household member to participate in the survey was sent, then contacted by phone and interviewed using computer-assisted software managing both dialling and data collection. The interviews were carried out in German, French or Italian, as appropriate. People who did not speak any of these three languages were excluded from the survey. Other criteria for exclusion were: asylum seeker status, households without a fixed line telephone, very poor health status and living in a nursing home \[[@B6]\]. Four sampling waves were performed (Winter, Spring, Summer and Autumn). Participation rate was 71% in 1992, 85% in 1997, 64% in 2002, and 66% in 2007. More details available at <http://www.bfs.admin.ch/bfs/portal/fr/index/infothek/erhebungen__quellen/blank/blank/ess/04.html>. As too many data were missing in 1992 (no information on hypertension and diabetes), only data for the three last surveys (1997, 2002 and 2007) was used. Data collected -------------- Three age categories were considered: 18 to 44, 45 to 64, and ≥ 65 years. Education was categorized as follows: 1) no education completed, 2) first level (primary school), 3) lower secondary level, 4) upper secondary level and 5) tertiary level, which included university and other forms of education after the secondary level. We defined \"low education\" (categories 1 and 2), \"middle education\" (categories 3 and 4), and \"high education\" (category 5) groups. Self reported height and weight allowed the calculation of Body Mass Index (BMI). Three BMI categories were considered: normal (\< 25 kg/m^2^), overweight (≥ 25 to \< 30 kg/m^2^) and obese (≥ 30 kg/m^2^). Citizenship was defined as Swiss (having a Swiss passport) or foreigner. The self-reported prevalence of hypertension, hypercholesterolemia or diabetes was assessed by the questions: \"Did a doctor or a health professional tell you that you have high blood pressure/a high cholesterol level/diabetes?\", respectively. Subjects were considered as treated for hypertension, hypercholesterolemia or diabetes if they answered positively to the questions \"Are you treated for blood pressure/to decrease your cholesterol levels/for diabetes?\" respectively. Self-reported prevalence of antihypertensive, hypolipidaemic or antidiabetic treatment was calculated as the ratio of subjects reporting being treated by the number of subjects reporting the disease (i.e. number of subjects reported being treated for hypertension divided by the number of subjects reporting being hypertensive). A further question on doctor-prescribed medicines was asked. All subjects being treated were considered irrespective of the answer to the latter question. Adequate treatment of hypertension, hypercholesterolemia or diabetes was considered if the subjects answered \"normal or too low\" to the questions: \"Currently, how is your blood pressure/cholesterol level/glycaemia?\" respectively. Self-reported prevalence of adequate CV RF management was calculated as the ratio of subjects reporting being treated and answering \"normal or too low\" divided by the overall number of subjects reporting being treated. Missing answers were considered as negative (i.e. high levels). As the questionnaires changed slightly between surveys, some questions were missing, i.e., the question on control of hypertension was not asked in 2002. All subjects, irrespective of their status, were asked when they last had their blood pressure, cholesterol or glucose levels measured. Adequate screening was considered if the measurement had been performed during the last 12 months. Statistical analysis -------------------- Statistical analysis was conducted using Stata version 10 (Statacorp, College Station, TX, USA) and SAS Enterprise Guide version 4.1 (SAS Inc, Cary, NC; USA). Results were expressed as number of subjects and (percentage) or mean ± standard deviation. Comparisons were performed using chi-square for categorical data or analysis of variance (ANOVA) for continuous data. A first analysis was conducted using the original data. A second analysis was conducted after probability weighting each subject according to the formula $$w_{i}^{h} = H_{i} \cdot \frac{N_{h}}{n_{h}^{n}}$$ Where N~*h*~is the average number of telephone numbers in stratum *h*(h = 29), H~*i*~is the household size, i.e. the number of subjects aged 15 and over living in household *i*, and n~h~^n^is the number of telephone numbers in the sample S~*h*~corresponding to stratum *h*to the power *n*(*n*= sample size in stratum *h*). Weights were further corrected taking into account the percentage of nonresponders by raking ratio estimation \[[@B7]\]. Weighting partly allowed the correction for bias, i.e. subjects with given characteristics who are under-represented in the original sample were attributed a higher weight \[[@B8]\]. The sum of weights thus corresponds to the Swiss adult population for the period considered. For simplicity, the weighted results will be presented and commented, as the conclusions arising from the unweighted data are similar (see Additional file [1](#S1){ref-type="supplementary-material"}). A third analysis using multivariate logistic regression adjusting for age group, sex, nationality, education and BMI classes was conducted to assess trends during the study period, using either the original (see Additional file [1](#S1){ref-type="supplementary-material"}) or the weighted data (presented here). The results were expressed as Odds ratio and \[95% confidence interval\]. Statistical significance was considered for p \< 0.05. Results ======= Characteristics of the subjects ------------------------------- The characteristics of subjects according to survey are summarized in table [1](#T1){ref-type="table"}. Between 1997 and 2007 mean age increased and the percentage of subjects with low or middle education decreased while the percentage of subjects with high education increased. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### characteristics of the samples ::: 1997 2002 2007 ----------------------- ------------- ------------- ------------- **Sum of weights** 5,564,776 5,647,472 5,784,057 Women (%) 51.7 51.6 51.2 Age classes (%)  18-44 years 51.5 49.9 49.5  45-64 years 29.8 30.9 31.9  ≥ 65 years 18.7 19.2 18.7 Swiss nationality (%) 81.7 80.5 79.5 Educational level (%)  Low ^§^ 22.6 20.4 12.8  Middle ^§§^ 60.0 63.2 59.6  High ^§§§^ 17.4 16.4 27.6 BMI classes (%)  Normal 63.8 61.3 61.0  Overweight 29.1 30.7 30.4  Obese 7.1 8.0 8.6 BMI \[kg/m^2^\] 24.2 ± 3.9 24.3 ± 4.0 24.4 ± 4.1 Age \[years\] 46.5 ± 17.6 47.2 ± 17.5 47.3 ± 17.6 Results are expressed as weighted percentage and average ± standard deviation. ^**§**^no education completed + first level (primary school). ^**§§**^lower + upper secondary level. ^**§§§**^tertiary level + other education after secondary level. ::: Hypertension ------------ The trends in self-reported prevalence of hypertension are shown in table [2](#T2){ref-type="table"}. Between 1997 and 2007, self-reported hypertension in the Swiss general population increased, and this was further confirmed after multivariate adjustment (table [3](#T3){ref-type="table"}). Subjects aged over 65 years or obese had a higher odds ratio, while subjects with university level or foreigners had a lower odds ratio of reporting being hypertensive (table [3](#T3){ref-type="table"}). Self-reported treatment increased (table [2](#T2){ref-type="table"}); on multivariate analysis, subjects aged over 45 or obese had a higher odds ratio, while women and foreigners had a lower odds ratio of reporting being treated (table [3](#T3){ref-type="table"}). Self-reported prevalence of treatment prescribed by the doctor was 96.0%, 99.4% and 99.6% while the daily taking of an antihypertensive drug was 89.6%, 95.3% and 97.1% in 1997, 2002 and 2007, respectively. The self-reported prevalence of controlled hypertension increased and the self-reported prevalence of uncontrolled and untreated hypertension decreased (table [2](#T2){ref-type="table"}); on multivariate adjustment, subjects over 65 presented a higher odds ratio of reporting being controlled (table [3](#T3){ref-type="table"}). Hypertension screening also increased (table [2](#T2){ref-type="table"}), and on multivariate analysis, men, foreigners, subjects aged over 45, overweight or obese had a higher odds ratio of being screened (table [3](#T3){ref-type="table"}). ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### trends in self-reported prevalence and management of hypertension in the Swiss population, 1997 - 2007 ::: 1997 2002 2007 ------------------ ----------- ----------- ----------- Sum of weights 5,564,776 5,647,472 5,784,057 Hypertension (%)  Screening 87.7 95.1 95.1  Prevalence 22.1 22.4 24.2  Treatment \* 52.1 53.8 60.4  Control \*\* 56.4 80.6 Results are expressed as weighted percentage. \*, among subjects reporting being hypertensive; \*\*, among treated subjects. -, data not available. ::: ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### multivariate analysis of the trends in self-reported prevalence and management of hypertension in the Swiss population, 1997 - 2007 ::: Prevalence **Treatment**\* **Control**\*\* Screening ------------- ---------------------- ---------------------- ---------------------- ---------------------- Surveys  1997 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  2002 0.98 \[0.97 - 0.99\] 1.01 \[1.01 - 1.02\] \- 2.73 \[2.71 - 2.74\]  2007 1.10 \[1.09 - 1.11\] 1.32 \[1.31 - 1.33\] 3.16 \[3.13 - 3.18\] 2.71 \[2.70 - 2.72\] Gender  Woman 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Man 1.01 \[1.00 - 1.02\] 1.17 \[1.16 - 1.18\] 0.96 \[0.95 - 0.96\] 0.78 \[0.77 - 0.79\] Age groups  18-44 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  45-64 2.79 \[2.78 - 2.80\] 4.96 \[4.93 - 5.00\] 1.89 \[1.86 - 1.92\] 1.36 \[1.35 - 1.37\]  ≥ 65 7.36 \[7.34 - 7.38\] 15.1 \[15.0 - 15.2\] 1.68 \[1.66 - 1.71\] 2.39 \[2.38 - 2.41\] Nationality  Swiss 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Other 0.90 \[0.89 - 0.91\] 0.91 \[0.90 - 0.92\] 0.56 \[0.55 - 0.57\] 1.25 \[1.24 - 1.26\] Education  Low 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Medium 0.93 \[0.93 - 0.94\] 0.98 \[0.97 - 0.99\] 1.22 \[1.21 - 1.23\] 0.95 \[0.95 - 0.96\]  High 0.90 \[0.89 - 0.91\] 1.03 \[1.02 - 1.04\] 1.60 \[1.58 - 1.62\] 0.83 \[0.82 - 0.84\] BMI classes  Normal 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Overweight 1.94 \[1.93 - 1.95\] 1.42 \[1.41 - 1.43\] 1.12 \[1.11 - 1.13\] 1.20 \[1.19 - 1.21\]  Obesity 4.23 \[4.22 - 4.25\] 1.98 \[1.96 - 1.99\] 1.07 \[1.06 - 1.08\] 1.57 \[1.56 - 1.59\] Results are expressed as multivariate-adjusted odds ratio and \[95% confidence interval\]. \*, among subjects with reported hypertension; \*\*, among treated subjects. -, data not available. ::: Hypercholesterolemia -------------------- Self-reported prevalence of hypercholesterolemia increased considerably between 1997 and 2007 (table [4](#T4){ref-type="table"}) and this increase was further confirmed by multivariate analysis (table [5](#T5){ref-type="table"}). Women, subjects over 45 years, with higher education or presenting with overweight or obesity had higher odds of reporting being hypercholesterolemic (table [5](#T5){ref-type="table"}). ::: {#T4 .table-wrap} Table 4 ::: {.caption} ###### trends in self-reported prevalence and management of hypercholesterolemia in the Swiss population, 1997 - 2007 ::: 1997 2002 2007 ---------------- ----------- ----------- ----------- Sum of weights 5,564,776 5,647,472 5,784,057  Screening 86.5 94.6 93.8  Prevalence 11.9 14.7 17.4  Treatment \* 18.5 32.2 38.8  Control \*\* 52.9 \- 75.1 Results are expressed as weighted percentage. \*, among subjects reporting being hypercholesterolemic; \*\*, among treated subjects. -, data not available. ::: ::: {#T5 .table-wrap} Table 5 ::: {.caption} ###### multivariate analysis of the trends in self-reported prevalence and management of hypercholesterolemia in the Swiss population, 1997 - 2007 ::: Prevalence **Treatment**\* Control\*\* Screening ------------- ---------------------- ---------------------- ---------------------- ---------------------- Surveys  1997 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  2002 1.26 \[1.25 - 1.27\] 2.21 \[2.19 - 2.22\] \- 2.77 \[2.75 - 2.78\]  2007 1.52 \[1.51 - 1.53\] 2.80 \[2.78 - 2.82\] 2.59 \[2.55 - 2.63\] 2.48 \[2.47 - 2.49\] Gender  Woman 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Man 0.77 \[0.76 - 0.78\] 0.68 \[0.67 - 0.69\] 1.19 \[1.18 - 1.21\] 0.95 \[0.95 - 0.96\] Age groups  18-44 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  45-64 3.53 \[3.52 - 3.55\] 4.11 \[4.07 - 4.15\] 0.96 \[0.93 - 0.98\] 0.74 \[0.74 - 0.75\]  ≥ 65 5.11 \[5.09 - 5.13\] 10.3 \[10.2 - 10.4\] 1.17 \[1.14 - 1.20\] 1.03 \[1.02 - 1.04\] Nationality  Swiss 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Other 1.02 \[1.01 - 1.03\] 1.02 \[1.01 - 1.03\] 0.74 \[0.72 - 0.75\] 1.01 \[1.01 - 1.01\] Education  Low 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Medium 1.09 \[1.08 - 1.10\] 0.96 \[0.95 - 0.97\] 1.15 \[1.13 - 1.17\] 0.85 \[0.84 - 0.85\]  High 1.24 \[1.23 - 1.25\] 0.86 \[0.85 - 0.87\] 1.58 \[1.54 - 1.61\] 0.69 \[0.68 - 0.69\] BMI classes  Normal 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Overweight 1.46 \[1.45 - 1.47\] 1.41 \[1.40 - 1.42\] 1.09 \[1.08 - 1.10\] 0.95 \[0.95 - 0.96\]  Obesity 1.67 \[1.66 - 1.68\] 1.82 \[1.80 - 1.83\] 1.04 \[1.02 - 1.06\] 1.03 \[1.02 - 1.03\] Results are expressed as multivariate-adjusted odds ratio and \[95% confidence interval\]. \*, among subjects with reported hypercholesterolemia; \*\*, among treated subjects.-, data not available. ::: Self-reported hypolipidemic drug treatment increased between 1997 and 2007 (table [4](#T4){ref-type="table"}); multivariate analysis showed women, older subjects, subjects with a higher education or presenting with overweight or obesity to have higher odds of being treated (table [5](#T5){ref-type="table"}). In 2007, 99.1% of hypolipidemic drug treatment was prescribed by the doctor and daily medication use was reported by 94.8% of treated subjects. The self-reported prevalence of controlled hypercholesterolemia increased (table [4](#T4){ref-type="table"}); on multivariate analysis, women, subjects over 45 years, subjects with a medium and high education had a higher odds ratio, while foreigners had a lower odds ratio of reporting being adequately controlled (table [5](#T5){ref-type="table"}). Conversely, the self-reported prevalence of uncontrolled and untreated hypercholesterolemia remained stable (table [4](#T4){ref-type="table"}). Hypercholesterolemia screening increased (table [4](#T4){ref-type="table"}); on multivariate analysis, a higher odds ratio of being screened was found for foreigners, subjects aged over 45, and in overweight or obese subjects, while women, subjects with a medium and a high education had a lower odds ratio of being screened (table [5](#T5){ref-type="table"}). Diabetes -------- Self-reported prevalence of diabetes increased between 1997 and 2007 (table [6](#T6){ref-type="table"}), a finding confirmed by multivariate analysis (table [7](#T7){ref-type="table"}) which also showed men and subjects with increasing age or BMI to have a higher odds ratio, while subjects with middle or high education had a lower odds ratio of reporting being diabetic. Self-reported prevalence of diabetes treatment increased (table [6](#T6){ref-type="table"}); multivariate analysis showed men, subjects aged over 45 or presenting with overweight or obesity to have a higher odds ratio, while foreigners had a lower odds ratio of being treated (table [7](#T7){ref-type="table"}). Self-reported diabetes control also increased and the self-reported prevalence of uncontrolled and untreated diabetes decreased (table [6](#T6){ref-type="table"}); multivariate analysis showed subjects aged 45-64 years, presenting with overweight or obesity or foreigners to have a lower odds ratio, while high educated subjects had a higher odds ratio of being controlled (table [7](#T7){ref-type="table"}). Finally, diabetes screening increased during the study period (table [6](#T6){ref-type="table"}) and multivariate analysis showed foreigners, subjects aged over 45, overweight or obese to have a higher odds ratio, while men and subjects with medium or high education to have a lower odds ratio of being screened (table [7](#T7){ref-type="table"}). ::: {#T6 .table-wrap} Table 6 ::: {.caption} ###### trends in self-reported prevalence and management of diabetes in the Swiss population, 1997 - 2007 ::: 1997 2002 2007 ---------------------- ----------- ----------- ----------- Sum of weights 5,564,776 5,647,472 5,784,057 Diabetes (%)  Screening 87.4 94.9 94.1  Prevalence 3.3 3.7 4.8  Treatment (drug) \* 50.0 \- 53.3  Control \*\* 50.5 \- 65.5 Results are expressed as weighted percentage. \*, among subjects reporting being diabetic; \*\*, among treated subjects. -, data not available. ::: ::: {#T7 .table-wrap} Table 7 ::: {.caption} ###### multivariate analysis of the trends in self-reported prevalence and management of diabetes in the Swiss population, 1997 - 2007 ::: Prevalence Treatment \* Control \*\* Screening ------------- ---------------------- ---------------------- ---------------------- ---------------------- Surveys  1997 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  2002 1.10 \[1.09 - 1.10\] \- \- 2.68 \[2.67 - 2.69\]  2007 1.49 \[1.48 - 1.50\] 1.16 \[1.15 - 1.18\] 1.92 \[1.88 - 1.95\] 2.43 \[2.42 - 2.45\] Gender  Woman 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Man 1.20 \[1.19 - 1.20\] 1.24 \[1.23 - 1.26\] 0.91 \[0.90 - 0.93\] 1.04 \[1.04 - 1.04\] Age groups  18-44 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  45-64 2.96 \[2.94 - 2.98\] 2.78 \[2.73 - 2.84\] 0.62 \[0.60 - 0.65\] 0.86 \[0.86 - 0.87\]  ≥ 65 6.78 \[6.73 - 6.83\] 5.23 \[5.13 - 5.34\] 0.79 \[0.76 - 0.82\] 1.19 \[1.19 - 1.20\] Nationality  Swiss 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Other 0.95 \[0.95 - 0.96\] 0.74 \[0.73 - 0.76\] 0.51 \[0.50 - 0.52\] 1.01 \[1.00 - 1.01\] Education  Low 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Medium 0.79 \[0.79 - 0.80\] 1.46 \[1.43 - 1.48\] 1.13 \[1.10 - 1.15\] 0.87 \[0.87 - 0.88\]  High 0.75 \[0.75 - 0.76\] 1.00 \[0.98 - 1.02\] 1.86 \[1.81 - 1.92\] 0.64 \[0.64 - 0.65\] BMI classes  Normal 1 (ref.) 1 (ref.) 1 (ref.) 1 (ref.)  Overweight 1.64 \[1.63 - 1.65\] 1.63 \[1.61 - 1.66\] 1.15 \[1.12 - 1.17\] 0.95 \[0.94 - 0.95\]  Obesity 3.71 \[3.68 - 3.73\] 2.24 \[2.20 - 2.27\] 0.84 \[0.82 - 0.86\] 1.02 \[1.01 - 1.03\] Results are expressed as multivariate-adjusted odds ratio and \[95% confidence interval\]. \*, among subjects with reported diabetes; \*\*, among treated subjects. -, data not available. ::: Discussion ========== Since the MONICA study in the nineties \[[@B3]\] and the Bus Santé study in Geneva \[[@B4]\], there has been little information on trends of hypertension, hypercholesterolemia and diabetes in Switzerland. The data from the Swiss National Health Surveys thus provide important information regarding the self-reported prevalence and management of those cardiovascular risk factors in the Swiss population. As the sampling frame covers about 90% of Swiss households and the participation rate was relatively high for all studies, this study is a good reflect of the Swiss situation. The fact that the weighted and unweighted results were quite similar also suggests the absence of important bias. Hypertension ------------ Prevalence of self-reported hypertension increased between 1997 and 2007 and was comparable to those reported using measured data by US \[[@B9]\] and German \[[@B10]\] studies and with other studies using self-reported data (table [8](#T8){ref-type="table"}). This increase could be due either to an increase in the true prevalence of hypertension, to a more widespread screening, or both. The second hypothesis might be more likely, as the prevalence of subjects reporting having their blood pressure measured during the previous 12 months also increased during this period, a finding already reported in the literature \[[@B11]\]. Another likely determinant is decrease in the thresholds to define hypertension from ≥ 160/95 mmHg in 1993 \[[@B3]\] to ≥ 140/90 mmHg afterwards. Still, self-reported prevalence rates are probably underestimated, as a recent study conducted in Lausanne has shown that less than two thirds of hypertensive subjects are actually aware of their condition \[[@B12]\]. ::: {#T8 .table-wrap} Table 8 ::: {.caption} ###### trends in self-reported prevalence of cardiovascular risk factors in Switzerland and in other countries ::: Switzerland Spain Greece USA France --------------- ------------- ------- -------- ------ -------- Hypertension  1997 22.1 11.4 24.4  1999 25.4  2001 14.5  2002 22.4 20.1  2003 14.5  2006 25.7  2007 24.2 Dyslipidaemia  1997 11.9 8.2 26.6  1999 27.7  2001 11.0  2002 14.7 17.5  2003 10.5  2006 22.3  2007 17.4 Diabetes  1997 3.3 5.0 6.5 8.5  1999 7.1  2001 5.6  2002 3.7 8.7  2003 5.9  2006 10.3  2007 4.8 References: Switzerland 1, current study; Spain, \[[@B21]\]; Greece, \[[@B28]\]; USA, \[[@B29]\]; France, \[[@B18]\]. ::: A higher prevalence of reported hypertension was found among subjects aged over 45 years or presenting with overweight or obesity. Those findings are in agreement with the literature \[[@B9],[@B13],[@B14]\] and might be due to an increased screening with age or because of the presence of other risk factors \[[@B15]\]. Conversely, foreigners had a lower self-reported prevalence of hypertension, and this could not be attributed to a lower screening frequency or to differences in age or BMI status. Possible explanations include differences in dietary or genetic background, but further studies are needed to better assess this point. The self-reported prevalence of hypertension was also inversely related with educational level, a finding in agreement with the literature \[[@B16]\]. This finding might be related to a better lifestyle, namely regarding dietary salt intake, although data from the Geneva study showed no improvement in salt intake in the general population \[[@B17]\]. Self-reported treatment of hypertension increased during the study period, suggesting an improvement in the management of this risk factor. Still, in 2007, only six out of ten hypertensive subjects indicated they were on antihypertensive treatment. Although the remaining 40% might be under nonpharmacological antihypertensive measures such as diet or specific lifestyle modifications, our findings suggest that there is still room for improvement regarding pharmacological management of hypertension, a finding reported previously \[[@B12]\]. In agreement with objectively measured data from the US \[[@B9],[@B13]\] and France \[[@B18]\], an increase in self-reported control of hypertension was found for the period 1997-2007. This increase might be related to an improvement in antihypertensive treatment, namely the appearance of more potent and new antihypertensive drugs, and/or an improvement of subject\'s compliance. Still, our results are probably overestimated because some treated subjects might report being controlled just because they are taking antihypertensive drugs. Indeed, a previous study conducted in Lausanne showed that a consistent fraction of treated hypertensive subjects actually presented with high blood pressure levels \[[@B12]\]. Hence, it is likely that the true prevalence of controlled hypertension in Switzerland might actually be lower. Nevertheless, the fact that the self-reported prevalence of uncontrolled and untreated hypertension also decreased suggests that the overall management of hypertension in the Swiss population is improving. Hypercholesterolemia -------------------- Self-reported prevalence of hypercholesterolemia was within values published for other countries which used self-reported data (table [8](#T8){ref-type="table"}), but lower than the values obtained in a smaller Swiss population-based study using objectively measured data (table [9](#T9){ref-type="table"}). Still, and in agreement with previous Swiss \[[@B4]\], French \[[@B18]\] and German \[[@B10]\] studies based on objectively measured data and with studies using self-reported data, the self-reported prevalence of hypercholesterolemia increased between 1997 and 2007. As for hypertension, possible explanations include a true increase in the prevalence of hypercholesterolemia, an increase in screening, a decrease in the threshold values to define hypercholesterolemia \[[@B19]\] or a mixture of them. Interestingly, cholesterol screening increased considerably during the study period, and the prevalence of subjects reporting having their blood cholesterol levels assessed during the previous 12 months was actually higher than other studies \[[@B11]\]. Still, in 2007, the self-reported prevalence of hypercholesterolemia in Switzerland was lower than the USA \[[@B11]\] or France \[[@B18]\]. Two explanations are possible, i.e. the prevalence of hypercholesterolemia being indeed lower in Switzerland, or a lower screening by Swiss GPs. Indeed, it has been shown that only 75% of Swiss physicians consider that screening for high cholesterol is very important, versus 93% for blood pressure \[[@B20]\]. Those differences could partly explain the lower percentage of self-reported hypercholesterolemia relative to hypertension. ::: {#T9 .table-wrap} Table 9 ::: {.caption} ###### comparison of prevalences or hypertension and hypercholesterolaemia based on self-reported and measured data for subjects aged 35-75, Switzerland ::: Switzerland 2002 Switzerland 2007 CoLaus 2003-6 ----------------------- ------------------ ------------------ --------------- Hypertension  Prevalence 26.2 27.5 36.0  Treatment \* 54.7 62.4 78.0  Control \*\* \- 83.0 48.0 Hypercholesterolaemia  Prevalence 18.6 22.4 29.0  Treatment \* 32.7 40.4 40.0  Control \*\* \- 77.1 58.0 Results are expressed as percentage. \*, among subjects with the selected risk factor; \*\*, among treated subjects. CoLaus data from \[[@B12]\] for hypertension and from \[[@B23]\] for hypercholesterolemia. ::: A higher self-reported prevalence of hypercholesterolemia was found among subjects aged over 45 years, with high education or presenting with overweight or obesity in agreement with other studies \[[@B16],[@B18]\] but not with others \[[@B21]\]. Still, our results suggest that, contrary to hypertension, a higher education is related to a higher self-reported prevalence of hypercholesterolemia. This higher self-reported prevalence is not due to higher screening rates among highly educated subjects, as their odds of being screened were significantly lower (table [4](#T4){ref-type="table"}). A possible explanation is the fact that highly educated subjects know better their medical situation \[[@B22]\], but again further studies are needed to better assess this point. The self reported hypolipidemic treatment doubled during the study period, in line with other French \[[@B18]\] and German \[[@B10]\] studies. Nevertheless, in 2007, only four out of ten Swiss patients who had been told they presented with hypercholesterolemia reported being treated, a value similar to the one reported in the CoLaus study \[[@B23]\] (table [9](#T9){ref-type="table"}). Although diet has been shown to lower cholesterol levels \[[@B24]\], it is unlikely that 60% of patients diagnosed with hypercholesterolemia are on a diet alone. Hence, and as for hypertension, our findings suggest that there is room for improvement regarding pharmacological management of hypercholesterolemia. An increase in self-reported control of hypercholesterolemia was found, a finding also found in other countries \[[@B18],[@B25]\]. Two hypotheses are possible, i.e. an improvement in hypolipidemic drugs and/or subject\'s compliance. Again, these results are certainly overestimated, either because the subjects believed they were controlled just because they were treated, or because their GP considered them as treated despite borderline high values \[[@B26]\]. Diabetes -------- The self-reported prevalence of diabetes increased during period 1997-2007. Still, in 2007, the self-reported prevalence was lower than reported for France \[[@B18]\] or the US \[[@B27]\], probably due to the self-reported (instead of objectively measured) diabetic status. Still, comparing our data with self-reported data from other countries \[[@B18],[@B21],[@B28],[@B29]\] led to similar conclusions (table [8](#T8){ref-type="table"}). Possible explanations include the relatively low prevalence of obesity in Switzerland \[[@B30],[@B31]\] albeit other factors might be at play. Interestingly, the increase in the self-reported prevalence of diabetes persisted after adjustment for overweight and obesity, suggesting that other factors might intervene \[[@B32]\], namely a better screening. Indeed, the prevalence of subjects reporting having their blood glucose assessed the previous 12 months increased between 1997 and 2007, a finding in agreement with other studies \[[@B33],[@B34]\]. Also in agreement with the literature \[[@B32]\], a higher self-reported prevalence of diabetes was found among men, subjects aged over 45 years or presenting with overweight or obesity. Similarly, and as reported previously \[[@B16],[@B32]\], a lower prevalence of self-reported diabetes was found among subjects with high educational level. High educated subjects could have more financial means to adapt their lifestyle, e.g., to buy higher quality food \[[@B35]\] or exercise more, thus preventing the occurrence of diabetes. They could better know their health state despite less screened, but further studies are needed to better assess this point. Self reported antidiabetic treatment increased, a trend also reported for France \[[@B18]\] and Italy \[[@B36]\]. Still and again, in 2007, only half of the subjects diagnosed with diabetes reported being treated, and, as for hypercholesterolemia, it is rather unlikely that the remaining half was only on diet. Overall, our data indicate that, in Switzerland, many diabetic subjects are probably undertreated, and that further efforts should be made to implement (non) pharmacological treatment. The increase in self-reported diabetic control found in this study has also been reported elsewhere \[[@B25]\]. This improvement is probably due to a change in therapies and/or an improvement of the subject\'s compliance. Still, in 2007, one third of treated diabetic subjects reported having high glycaemia, and again this figure is certainly underestimated because many treated subjects believed they are controlled simply due to the fact they receive a drug. Nevertheless, the fact that the prevalence of uncontrolled and untreated diabetes also decreased suggests that the overall management of diabetes in the Swiss population is improving. Limitations ----------- First, and as indicated previously, the self-reporting of the cardiovascular risk factors might underestimate the real prevalence in the population, as it can be inferred from the results of table [9](#T9){ref-type="table"}. Still, it represents the result of the screening done by doctors and health professionals and has been used in other studies for the assessment of trends \[[@B21],[@B28],[@B29],[@B37]\]. Further, it has been shown that self-reported data on cardiovascular risk factors is valid and can be used to assess prevalence rates in most cases \[[@B38],[@B39]\]. Second, increasing rates occurred mainly between 2002 and 2007, when the sample becomes much more educated, raising the issue of a possible selection bias, more educated participants tending to respond more easily. The presence of other unmeasured confounders such as changes in dietary intake could also influence results. Since other unmeasured predictors of disease treatment and control were likely to change along with education, the trends in treatment and control are thus likely to be biased away from the null. Still, in the absence of another nationally representative sample, this study provides the best estimates regarding self-reported prevalence and management of cardiovascular risk factors. Third, the fact that the unweighted and weighted estimates are similar does not remove the potential for response bias. Still, the weighting procedure gives some strata which are less represented in the sample (i.e. young males) a higher weight, thus partially reducing this bias. It should be noted that some studies only standardized on age \[[@B29]\] or even made no adjustment \[[@B28]\], while in this study weighting included gender, age, geographical location and nationality \[[@B8]\]. Forth, although several studies conducted in the USA \[[@B40],[@B41]\] indicate a high level of undiagnosed hypertension and hypercholesterolemia among uninsured subjects, this is rather unlikely to occur in Switzerland as all subjects living in Switzerland have a health insurance (federal law 832.10 of march 18^th^, 1994, available at <http://www.admin.ch/ch/f/rs/c832_10.html>). Still, as a nontrivial percentage of subjects with hypertension, dyslipidemia or diabetes might be unaware of their status \[[@B12],[@B42]\], our prevalence estimates might be underestimated. Finally, no information was available regarding nonpharmacological treatment of cardiovascular risk factors, so it was not possible to assess the percentage of subjects not treated with drugs but with other nonpharmacological measures. Conclusion ========== In Switzerland, self-reported prevalence of hypertension, hypercholesterolemia and diabetes have increased between 1997 and 2007. Management and screening have improved, but further improvements can still be achieved as over one third of subjects with reported CV RFs are not treated. Conflict of Interest Statement ============================== The authors hereby indicate no conflict of interest Authors\' contributions ======================= DE performed the statistical analysis and wrote most of the manuscript. PMV designed the study (data analysis), obtained the data, performed some statistical analyses and wrote part of the manuscript. FP and PV participated in the study design and coordination and revised the manuscript. All authors read and approved the final manuscript. Pre-publication history ======================= The pre-publication history for this paper can be accessed here: <http://www.biomedcentral.com/1471-2458/11/114/prepub> Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **Supplementary tables**. ::: ::: {.caption} ###### Click here for file :::

PubMed Central

2024-06-05T04:04:17.237961

2011-2-18

PMC3051908

Background ========== Evidence indicates that most smokers initiate the habit before attaining adulthood\[[@B1]\]. In addition, young smokers and adolescents are more likely to develop nicotine dependence\[[@B2]\]. This acquires particular significance in developing countries with demographic patterns similar to Pakistan\'s, where the median age of the population is only 21 years\[[@B3]\]. Here, future trends of tobacco attributable mortality are likely to be influenced by current tobacco consumption and perceptions amongst the youth. This school-going age group comprises the largest segment of the population and is also the most susceptible towards experimentation with tobacco. Therefore, achieving tobacco control amongst this age group is critical for mitigating the public health consequences of this emerging epidemic. Various surveys have provided evidence that tobacco use is widely prevalent amongst students and adolescents in the urban areas of Pakistan. The results of the Global Youth Tobacco Survey (GYTS) showed that tobacco use prevalence was 12.8% in males and 8.0% in females aged 13-15\[[@B4]\]. A study in Karachi evaluating smoking in males showed that prevalence increases to 19.2% in ages 15-17, 26.5% in ages 18-20 and reaches 65% in 21 years and above\[[@B5]\]. A survey in Karachi targeting adolescent female smoking showed a prevalence of 16.3% in the above 15 age group\[[@B6]\]. In addition shisha use is becoming increasingly popular in the student age group\[[@B7]\]. Whilst several reviews have evaluated the effectiveness of various tobacco control programs, few have taken into account the perceptions of students themselves regarding these measures. It is important to discover the factors that the youth considers as significant in either encouraging them to cease the habit or from initiating smoking in the first place. The current cigarettes pack warnings in the country that consist only of text, for example, may be less effective than pictorial warnings, as has been demonstrated elsewhere\[[@B8]\]. In addition, students that have already initiated smoking may be more resistant to anti-smoking messages. Such data is essential for review before effective health promotion advertisements, curricular material in textbooks and appropriate legislation can be introduced. Although a majority of anti-tobacco modalities are not specifically designed for the youth, there is evidence to suggest that such targeted interventions are highly effective ways of curtailing the tobacco epidemic \[[@B9],[@B10]\]. Therefore, the aim of this study was to determine the most effective anti-smoking messages that can be delivered in order to reduce tobacco consumption amongst high-school students in Pakistan based on their own, self-rated perceptions and to highlight which risk-factors related to tobacco consumption did the students consider most significant in deterring them from smoking. We also aimed to test the hypothesis that pictorial/multi-media warnings will be more effective than text-only warnings and to discover whether there was any difference in the perceptions of smokers to those of non-smokers to these health messages. Methods ======= Study Setting ------------- This study was carried out in five cities of Pakistan, including Islamabad, Rawalpindi, Lahore, Faisalabad and Karachi, from January to February, 2010. These cities represent the major urban centers of Pakistan where the youth has access to tobacco products and is influenced by advertising. A minimum of two high schools from each city were identified for carrying out this study. These schools allowed convenient access to adolescents and were an appropriate setting to conduct the study. Study Design and Procedure -------------------------- A Microsoft PowerPoint presentation was developed that highlighted some of the most important and well-established health consequences of smoking. These were derived and adapted from the US Surgeon General\'s report published in collaboration with the Centre for Disease Control\[[@B11]\]. The presentation consisted of slides that provided details and written warnings of each tobacco related illness. Following the health warnings of each specific illness, a slide utilizing different pictorial/multi-media aids was used to show the health outcome of the disease. These included a picture of smokers\' lungs, pictures of oral cancer, a video of a person using an electronic voice box, a video of a patient on a ventilator and a video of a person paralyzed due to stroke. The pictures and multi-media aids were obtained from open-access websites such as *YouTube*. In addition, other harmful effects of tobacco such as addiction, social implications and dangers posed by secondhand smoke exposure were also highlighted in the presentation. The presentation was delivered at each of the schools selected for the study. At the end of the presentation, the students were asked to fill out a graded questionnaire form, using which they rated the risk-factors and messages that they thought were most effective in stopping or preventing them from smoking (Table [1](#T1){ref-type="table"}). The questionnaire form consisted of a total of 20 questions related to the anti-smoking messages with responses ranging from 1 to 5 (1 = Not at all, 2 = Unlikely, 3 = Unsure, 4 = Likely, 5 = Definitely). The demographics of the participants including age and gender were noted along with smoking status. Tobacco usage greater than once in the month preceding the administration of the questionnaire was taken as positive for both cigarette smoking and water-pipe smoking. This figure was adapted from the criteria used in the GYTS\[[@B4]\]. Prior ethical clearance was sought at the Aga Khan University. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Mean rank scores of responses using the Friedman test ::: ---------------------------------------------------------------------------------------------------------------- --------------------- **Question** **Mean Rank Score** Did watching a picture of an oral cavity cancer convince you of the harmful effects of smoking? 11.04 Did watching a video of a person on a ventilator convince of you the harmful effects of smoking? 10.91 Did watching a video of a person using an electronic voice box convince you of the harmful effects of smoking? 10.77 Did watching a picture of cancerous lungs convince you of the harmful effects of smoking? 10.43 Did watching a video of a person recovering from stroke convince you of the harmful effects of smoking? 10.19 Smoking causes stroke, does knowing this risk stop you from smoking? 9.99 Smoking causes heart attacks, does knowing this risk stop you from smoking? 9.89 Smoking causes oral cancer, does knowing this risk stop you from smoking? 9.89 Smoking causes throat cancer, does knowing this risk stop you from smoking? 9.77 Smoking causes severe lung disease, does knowing this risk stop you from smoking? 9.57 Religious scholars consider smoking unlawful, does this stop you from smoking? 9.48 Smoking causes lung cancer, does knowing this risk stop you from smoking? 9.17 Does a ban on smoking in public areas stop you from smoking? 8.91 Passive smoking causes harm to others, does knowing this risk stop you from smoking? 8.61 Smoking leads to the use of other more dangerous drugs, does knowing this risk stop you from smoking? 8.16 Smoking is addictive, does knowing this risk stop you from smoking? 7.94 Smoking addiction adversely affects disposable incomes-Does knowing this risk stop you from smoking? 7.74 ---------------------------------------------------------------------------------------------------------------- --------------------- Friedman\'s p value \< 0.001 ::: Sample ------ All of the schools enrolled in the study were private schools where the medium of instruction was in English. This was due to certain logistical and financial constraints of conducting the study in government-run schools such as, availability of multi-media projectors and back-up generators in case of power failures. A recent survey showed that a third of Pakistanis are educated in English-medium private schools and a further 15% are in English-medium government schools\[[@B12]\]. This sample may therefore not be representative of the remaining students belonging from a lower socio-economic group that are currently enrolled in other government schools or *madrassahs*. However, efforts are being made to convert these into English-medium facilities in the future\[[@B13]\]. The presentation was delivered to students in small groups consisting of approximately 40 students each. Both male and female students as well as current smokers and non-smokers were included. Approval from the faculty and the administration of the schools where the study was conducted was sought before delivering the presentation. The responsible faculty members were approached, briefed on the purpose of the study and were shown the details of the presentation for their approval. Student groups were then arranged by the schools\' administration prior to the delivery of the presentation. The students were asked to sign a consent form that was included with the questionnaire for participating in the study. Data Analysis ------------- The data was analyzed using Statistical Package for Social Sciences (SPSS v16.0). To compare responses to questions across the data set, the Friedman test for non-parametric data was utilized. This test was used to generate ranks between individual questions in the dataset. These were utilized to show which risk factors and multi-media aids adolescents considered as the most effective anti-smoking messages. To assess the impact of pictorial/multi-media health warnings, five questions pertaining to these were each paired with questions of their associated written text warnings (Table [2](#T2){ref-type="table"}). The Wilcoxon Signed Ranks Test was utilized to assess whether there was any statistically significant difference in the responses to the questions within these pairs. The Mann Whitney U test was utilized to compare the responses of smokers to those of non-smokers. A p value of \< 0.05 was taken as significant for each of the tests. ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### Comparison of text warnings with multi-media warnings as deterrents from smoking ::: -------- ------------------------------------ ------------------------------------------------- ------------- **Text Warning** **Multi-Media Warning** **p-value** **1**. Smoking causes oral cancer Picture of an oral cavity cancer p \< 0.001 **2**. Smoking causes lung cancer Picture of cancerous lungs p \< 0.001 **3**. Smoking causes throat cancer Video of a person using an electronic voice box p \< 0.001 **4**. Smoking causes stroke Video of a person recovering from stroke p = 0.760 **5**. Smoking causes severe lung disease Video of a person a ventilator p \< 0.001 -------- ------------------------------------ ------------------------------------------------- ------------- ::: Results ======= A total of 388 high school students were included in the study out which 245 were males and 142 were females. The mean age of the sample population was 17 with a standard deviation of 1.51. Out of the sample, a total of 97 (25.5%) identified themselves to be smokers out of which 70 were males (28.5% of males) and 27 were females (19% of females). A total of 150 (38.7%) participants answered positively for shisha smoking out of which 104 were males (42.5% of males) and 46 were females (32.4% of females). Table [1](#T1){ref-type="table"} shows the mean rank scores generated using the Friedman test for the responses of each of the questions. \"*Did watching a picture of an oral cavity cancer convince you of the harmful effects of smoking*,\" had the highest rank. *\"Smoking addiction adversely affects disposable incomes-Does knowing this risk stop you from smoking,\"*ranked the lowest. The Friedman\'s p-value was \< 0.001. Table [2](#T2){ref-type="table"} shows the comparison of responses to questions regarding written health warnings with their associated multi-media messages. Responses were significantly greater for the pictorial/multi-media messages in each of the pairs except for *\"Video of a person recovering from stroke,\"*which was not significantly different from the written statement. The comparison of responses given by smokers to those of non-smokers yielded significantly lower scores (p \< 0.01) by the former group across the question set. Overall an encouraging response was received from the faculty and from the students to both the presentation and to the study in the schools that were visited. All of the students that were attending the presentations consented to be a part of the study. One of the schools approached, which was only for girls however, did not consent to the documentation of smoking prevalence of the students. The survey was not carried out at this school and only the presentation was delivered. An alternative school was subsequently selected for inclusion in the study. Discussion ========== Pakistan has taken a number of tangible steps towards reducing adolescent tobacco consumption in the country such as enforcing bans on tobacco advertising and underage sales. A recent decision by the Ministry of Health to introduce pictorial warnings on cigarette packs could also have a major impact\[[@B14]\]. However, for comprehensive enforcement of the Framework Convention for Tobacco Control (FCTC), the government will need to ensure that the warnings are rotated, are of appropriate size and are present on all packaging and labeling\[[@B15]\]. In addition, current tobacco control legislation is not directed against shisha smoking that is acquiring increasingly popularity amongst the youth\[[@B16]\]. Our results suggest that the effectiveness of the health messages could also be determined by the type of warning that is delivered. Graphic visual images, such as, pictures of oral cavity cancers were perceived to have the greatest impact in deterring students from smoking. Multi-media aids that conveyed messages students could relate to, both anatomically and functionally, ranked higher than the more commonly used pictures of a \'smoker\'s lungs,\' that could perhaps not convey the health warning with a similar impact. Amongst these multi-media aids also included videos of a patient using an electronic larynx and a patient on a ventilator. These findings suggest that such multi-media aids may be effective advertisements for health promotion campaigns. Our findings give further support to the use of pictorial and multi-media health warnings instead of warnings consisting only of text that were perceived to be less effective. This is particularly pertinent in countries with poor literacy rates such as Pakistan. In addition, cigarette pack warnings in the country are often in English, which is understood by a limited segment of the population, hence, obfuscating the necessary health promotion messages. Multi-media anti-smoking messages could therefore may improve awareness of the health consequences of smoking amongst the youth in Pakistan. Modifying label packaging to include graphic health warnings has been demonstrated as an effective means of reducing tobacco consumption and improving awareness of the health consequences of smoking in other countries within this age group\[[@B10],[@B17]-[@B19]\]. The participants did not perceive the current ban on smoking in indoor public areas to be an impediment to smoking. This suggests that they are either unaware of the relevant legislation or that they do not believe the laws will be enforced and any violations will be dealt with. They also did not perceive harming others through second hand smoke to be a major deterring factor. These findings suggest that there is a substantial lack of awareness regarding the hazards of second hand smoke amongst adolescents. In addition, the low scores for responses to questions relating to addiction and to cigarettes as a \'gateway drug\' also suggest a lack of awareness of the severity of these conditions. This is of significance in the school-going age group as addiction is cited as the commonest reason for failure of smoking cessation during adulthood\[[@B20]\]. Finally, those who identified themselves as smokers gave significantly lower responses to those of non-smokers across the question set. This suggests that the susceptibility to anti-smoking messages may decrease substantially once the habit has been initiated on a regular basis. Such early demonstration of intransigence to health promotion messages does not portend well for future smoking cessation during adulthood. This suggests that early, directed interventions aimed at students and adolescents may be beneficial as appropriate messages are delivered before the habit is initiated. The study was limited by the fact it was carried out in private schools where the medium of instruction is English and the students belonged to relatively higher socio-economic group. This could explain why the impact of smoking on disposable incomes was not cited as a major deterring factor. This could however, be of greater relevance for adolescents belonging to a lower socio-economic group. Based on these findings, a follow-up study is now being carried in public schools where Urdu is the medium of instruction. Conclusion ========== Graphic visual images and multi-media aids that vividly depict cosmetic distortions and loss of normal organ function as outcomes of the diseases associated with smoking are perceived by high school students as the most effective modalities in deterring them from smoking. These aids, in the form of health warnings, health promotion campaigns and material in school curricula, may be useful as effective tobacco control modalities in developing countries with young populations. Students that have already initiated the habit may be more resistant to tobacco control messages, hence, early intervention may prove to be beneficial. In addition, lack of awareness of other hazardous effects of smoking such as addiction and secondhand smoke exposure needs to be addressed in Pakistan. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= SMAZ participated in the study design, manuscript writing, data collection and analysis. ALB participated in data analysis and manuscript writing. AS participated in data collection and analysis. SHI participated in data collection. JAK participated in study design, coordination and provided technical supervision. All authors have read and approved the final manuscript. Pre-publication history ======================= The pre-publication history for this paper can be accessed here: <http://www.biomedcentral.com/1471-2458/11/117/prepub> Acknowledgements ================ We would like to thank the following for assistance with data collection: Dr Fatimah Zaidi (Rawalpindi), Usman Barlass (Lahore), Aarish Noor (Faisalabad).

PubMed Central

2024-06-05T04:04:17.241354

2011-2-18

PMC3051909

Background ========== The primary aims of tuberculosis (TB) control programmes are early diagnosis and prompt treatment of infectious cases to limit transmission \[[@B1]\]. To this end, the World Health Organisation (WHO) has developed specific outcome measures to evaluate TB control. Hence, treatment outcomes are recorded internationally and targets of 70% case detection and 85% cure in smear positive pulmonary TB have been set \[[@B2]\]. However, these broad outcome measures do not provide detailed insight into the pathways of clinical care or identify reasons for missing the targets. Methods of TB diagnosis have not changed significantly for many decades; resting primarily on clinical history, clinical examination, chest radiograph (CXR), and sputum smear and culture. Despite this long experience, there is overwhelming evidence from studies published over the last 50 years that TB diagnosis is prone to significant error \[[@B3]-[@B9]\]. Misdiagnosis occurs both if TB is missed and if TB is over-diagnosed. For example, a recent South African study found 21% of adults dying in hospital with a pre-mortem diagnosis of \"TB\" had no TB at autopsy \[[@B10]\], while in Italy in 1996, 36% of deceased AIDS patients with clinical diagnoses of TB had no evidence of TB at autopsy \[[@B11]\]. On the other hand, and of more concern to public health, are studies from the USA that suggest 5% of notified TB cases are diagnosed only after death \[[@B12],[@B13]\], plus several large autopsy studies showing that TB is missed in life in 18-54% of cases with pathological evidence of active TB \[[@B9],[@B14]-[@B16]\]. Avoidable clinical errors can contribute to delays or error in TB diagnosis \[[@B17]\]. This study describes a novel method for evaluating TB control at the point of care using a Process-Based Performance Review tool (TB-PBPR) to identify missed opportunities for early and accurate TB diagnosis. PBPR is a teaching strategy where clinicians retrospectively review patient records to evaluate crucial clinical actions, and has been shown to improve clinical performance \[[@B18],[@B19]\]. Following initial development and piloting in the South African mining industry \[[@B20],[@B21]\], we evaluated the tool by applying it to identify missed opportunities in deceased patients in four different hospital settings. Methods ======= The TB-PBPR tool consists of a single-page structured flow sheet (see additional file [1](#S1){ref-type="supplementary-material"}). Each element is derived from clinical evidence and, as a whole, is in accordance with the 2006 International Standards for TB Care (ISTC) \[[@B22]\]. A manual containing concise, evidence-based clinical summaries was developed for use in conjunction with the TB-PBPR tool to provide guidance on best practice \[[@B23]\]. Recorded data include demographics, clinical and autopsy diagnoses, important clinical actions, missed opportunities and response to therapy. The tool evaluates the integrated process of care for a number of essential clinical actions; first through identification of whether each clinical action was performed, and second through assessment of whether the result of that clinical action was recorded and then acted on appropriately. In total, the TB-PBPR tool identifies 14 clinical actions which, if carried out, should minimize the number of missed diagnoses: eliciting TB symptoms constitutes 1, clinical examination 6 and clinical investigations 7. \"Missed opportunities\" are identified as errors causing potential failure to make timely and accurate clinical diagnoses. For example, with regard to CXR, a missed opportunity would be identified if a CXR were omitted, if a CXR were performed but the result not obtained, or if the result were obtained but not acted upon. Where no documentation is found in the clinical notes, the action is recorded as omitted. The tool takes account of the circumstances in which different investigations are indicated because certain investigations may not be required in every patient. For example, lymph node aspiration is not applicable in the absence of lymphadenopathy. When sputum examination identifies TB, further investigations to identify TB are recorded \'not applicable\'. The TB-PBPR tool evaluates a group of \'other\' investigations, which should be considered in accordance with ISTC guideline 3 (to investigate extrapulmonary TB), particularly in HIV positive cases with suspected TB and three negative sputum smears \[[@B22]\]. We evaluated the TB-PBPR tool in four hospitals (two South African platinum mine hospitals and two tertiary-care teaching hospitals (one in South Africa and one in the UK)). Cases were selected using different criteria (outlined below) to assess the tool\'s use in a range of healthcare settings, patient groups and populations. The TB rate is close to 1000 per 100,000 in the general South African population \[[@B24]\], and estimated adult HIV prevalence is 18% \[[@B25]\]. Although TB is less common in the UK than South Africa, the UK-based hospital serves the London community where TB rates (43 per 100,000) are much higher than elsewhere in the country \[[@B26]\]. A medical doctor completed each TB-PBPR flow sheet using the accompanying manual in \~40 minutes. Hospital A (South African platinum mine hospital 1) --------------------------------------------------- In this setting, autopsies are conducted for compensation purposes in terms of the Occupational Diseases in Mines and Works Act (ODMWA). Provided next of kin give consent, autopsy is performed in all men dying in employment regardless of the clinical cause of death. Cases not submitted are generally those who die off mine premises. Deceased miners\' heart and lungs are removed at their place of employment, placed in formalin and dispatched to the South African National Institute for Occupational Health (NIOH), where histopathology is performed according to a standardized protocol \[[@B27],[@B28]\]. Pathological TB is diagnosed in the presence of necrotizing granulomatous inflammation and/or presence of acid-fast bacilli, other causes having been excluded. Results are stored in the PATHAUT computerised database \[[@B29],[@B30]\]. All patients from hospital A who died and had an autopsy of cardio-respiratory organs at the NIOH between October 2006 and December 2007 (n = 110) were considered for this study. The subset with a clinical and/or autopsy diagnosis of pulmonary TB (n = 62) were selected for review using the TB-PBPR tool. Clinical notes were available for 56 cases. Hospital B (South African platinum mine hospital 2) --------------------------------------------------- No autopsies were performed for hospital B. Therefore, all patients who died during 2007 (n = 60) were considered for this study. The subset of those with a natural cause of death were selected for review (n = 35). Clinical notes were available for 26 cases. TB diagnosis was taken from clinical records and made on clinical or microbiological grounds. A health care service, comprising primary care clinics, specialised clinics and hospital facilities, is provided free of charge to all mine employees at hospitals A and B, approximately 18,000 workers in each case. The healthcare services run their own TB control programmes. Hospital C (2700-bed public sector South African tertiary-care teaching hospital) --------------------------------------------------------------------------------- A convenience sample of 20 deceased individuals with a pre-mortem clinical diagnosis of TB and undergoing autopsy during the period December 2003 to March 2005 at Chris Hani Baragwanath Hospital (CHBH), Soweto as described by Martinson et al \[[@B10]\] was selected for review. Eligibility criteria for the original study included: \>18 years of age, survival in hospital for \>24 h and next of kin consenting to a full autopsy. Hospital D (1000-bed public sector UK tertiary-care teaching hospital) ---------------------------------------------------------------------- No autopsy data were available for hospital D. Therefore all patients who were registered with the TB programme at the Royal Free Hospital (RFH), London, and who died between January 2004 and December 2007 (n = 22) were considered for this study. Clinical notes were available for 13 cases, who did not differ significantly in age, sex or ethnicity from cases for whom notes were unavailable. Ethical approval was obtained from the University of the Witwatersrand. Work in the UK hospital was undertaken as part of a clinical audit of TB services and, therefore, no local ethical approval was required. Results ======= Patients -------- We reviewed medical records from 115 patients who died at the four hospitals using the TB-PBPR tool (Table [1](#T1){ref-type="table"}). The duration of hospital admission was \>24 h in 96% (110/115) of patients. Most patients at the South African hospitals (80-96%) were known to have HIV infection and in the mining hospitals, many had previously been treated for TB. The proportion treated for TB at final admission varied according to hospital setting (57-92%), with treatment started empirically (without microbiological evidence) in 25-53% of cases. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Characteristics of cases by hospital ::: ------------------------------------------------ ------------------------- ------------------------- ------------------------- ------------------------- **Hospital A (n = 56)** **Hospital B (n = 26)** **Hospital C (n = 20)** **Hospital D (n = 13)** **Country, hospital type** SA, mining SA, mining SA, teaching UK, teaching **% male** 100 100 48 60 **Age/y; median (range)** 48 (26-64) 43 (20-64) 37 (22-61) 46 (24-69) **Duration of admission/days; median (range)** 11 (1-110) 7 (1-67) 5 (3-32) 38 (7-85) **TB treatment completed previously; n (%)** 26 (46) 10 (39) 3 (10) 0 (0) †**HIV-infected; n (%)** 54 (96) 23 (89) 16 (80) 5 (39) **TB treated at final admission; n (%)** 32 (57) 16 (62) 14 (70) 12 (92) **Empirical TB treatment; n (%)** 17 (53) 4 (25) 6 (43) 3 (25) ------------------------------------------------ ------------------------- ------------------------- ------------------------- ------------------------- † HIV status was unknown in 2, 1, 3 and 1 cases in Hospitals A-D respectively ::: Clinico-Pathological Comparison ------------------------------- During the study period, 214 deaths were recorded at Hospital A. Autopsy was performed on 110 cases, in whom active TB was found in 40% (44/110). TB was missed in life in 52% (23/44) of cases and was wrongly attributed as the cause of death in 16% (18/110). The sensitivity of clinical diagnosis for TB was 48% (21/44) and specificity 73% (48/66) when measured against autopsy. Data on clinico-pathological comparison for Hospital C cases are published elsewhere \[[@B10]\]. Symptoms and Clinical Examination --------------------------------- Eliciting of TB symptoms is evaluated by the TB-PBPR tool on the basis of whether 3 symptoms are recorded. Importantly, the tool cannot distinguish between omissions of clinical action and omissions of clinical record. Depending on the hospital, symptoms of chest complaint (cough/haemoptysis/pain) were omitted in up to 39% of patients, weight loss between 15% and 73%, and fever/night sweats in up to 81% (Table [2](#T2){ref-type="table"}). The TB-PBPR tool evaluates clinical examination on the basis of 6 clinical actions (Table [2](#T2){ref-type="table"}). Chest auscultation was omitted in 32% and 50% of patients from mine hospital A and B respectively, but always performed at both teaching hospitals. Examination for weight loss and lymphadenopathy were performed poorly at all four hospitals, being omitted in 31% to 85% of patients. Notwithstanding clinical omissions, at least one positive clinical finding was documented for most patients: 93% (52/56) at hospital A, 88% (23/26) at hospital B and 100% at both hospital C and D. ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### Clinical actions: eliciting of clinical symptoms and examination (%) ::: -------------------------- ------------------------- ------------------------- ------------------------- ------------------------- ------------- ---------------------- ------------- ---------------------- ------------- --------- ------------ ------------- **Hospital A (n = 56)** **Hospital B (n = 26)** **Hospital C (n = 20)** **Hospital D (n = 13)** **Omitted** **Action performed** **Omitted** **Action performed** **Omitted** **Action performed** **Omitted** **Action performed** **Absent** **Present** **Absent** **Present** **Absent** **Present** **Absent** **Present** **Symptoms elicited**  **Chest complaint** **38** **7** **55** **39** **0** **62** **15** **5** **80** **0** **39** **62**  **Weight loss** **63** **5** **32** **73** **0** **27** **55** **0** **45** **15** **8** **77**  **Fever/night sweats** **46** **9** **44** **81** **0** **19** **60** **5** **35** **0** **54** **46** **Examination**  **Chest auscultation**\ **32**\ **20**\ **48**\ **50**\ **19**\ **31**\ **0**\ **15**\ **85**\ **0**\ **46**\ **54**\ **abnormal**  **Evidence of weight**\ **63**\ **0**\ **38**\ **69**\ **0**\ **31**\ **35**\ **0**\ **65**\ **85**\ **0**\ **15**\ **loss**  **Pleural effusion** **39** **52** **9** **96** **0** **4** **80** **5** **15** **39** **31** **31**  **Lymphadenopathy** **86** **5** **9** **89** **12** **0** **40** **45** **15** **31** **23** **46**  **Hepatosplenomegaly** **59** **27** **14** **84** **15** **0** **25** **35** **40** **0** **31** **69**  **Neck stiffness/**\ **71**\ **23**\ **5**\ **73**\ **12**\ **15**\ **45**\ **35**\ **20**\ **15**\ **62**\ **23**\ **confusion** -------------------------- ------------------------- ------------------------- ------------------------- ------------------------- ------------- ---------------------- ------------- ---------------------- ------------- --------- ------------ ------------- The TB-PBPR tool was used to evaluate medical records to determine whether clinical actions were omitted or performed. Where an action was performed, we recorded whether symptoms and examination findings were absent or present. For example, in hospital A, clinicians omitted eliciting symptoms of chest complaint (cough/haemoptysis/pain) in 38% of patients. Chest symptoms were elicited in the remaining patients (Action performed); these symptoms were absent in 7% and present in 55% of patients. ::: Investigations -------------- Following symptoms and clinical examination, the tool assesses whether clinical investigations were performed appropriately (Table [3](#T3){ref-type="table"}). Investigations were omitted in hospitals A to C as follows; CXR in up to 38%; sputum smear in up to 85%; sputum culture in up to 90% (Table [3](#T3){ref-type="table"}). However, in hospital D, these investigations were performed in every case. Assessment of other investigations such as lymph node aspiration, pleural tap and lumbar puncture depends upon recording of relevant clinical details. For example, in the absence of examination for lymphadenopathy it was impossible to evaluate the use of lymph node aspiration (marked \'no exam\'). Nonetheless, we did identify cases in hospitals A, B and D where lymphadenopathy was present but lymph node biopsy was omitted (Table [3](#T3){ref-type="table"}). ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### Clinical actions: use of appropriate investigations (%) ::: ---------------------- ------------------------- ------------------------- ------------------------- ------------------------- -------- ------------- ------------- ---------- -------- ------------- ------------- ---------- -------- ------------- ------------- ---------- **Hospital A (n = 56)** **Hospital B (n = 26)** **Hospital C (n = 20)** **Hospital D (n = 13)** **NA** **No exam** **Omitted** **Done** **NA** **No exam** **Omitted** **Done** **NA** **No exam** **Omitted** **Done** **NA** **No exam** **Omitted** **Done** **Chest radiograph** **0** \- **38** **63** **0** \- **35** **65** **0** \- **35** **65** **0** \- **0** **100** **Sputum Smear** **0** \- **52** **48** **4** \- **42** **54** **10** \- **85** **5** **15** \- **0** **85** **Sputum Culture** **0** \- **75** **25** **4** \- **54** **42** **10** \- **90** **0** **15** \- **0** **85** **LN aspiration** **11** **80** **9** **0** **23** **77** **0** **0** **45** **35** **15** **5** **69** **8** **15** **8** **Pleural tap** **66** **21** **2** **11** **0** **96** **0** **4** **10** **70** **0** **20** **69** **8** **8** **15** **Lumbar puncture** **54** **25** **2** **20** **19** **62** **0** **19** **30** **40** **5** **25** **46** **15** **0** **39** **Other** **25** \- **68** **7** **8** \- **89** **4** **10** \- **45** **45** **54** \- **0** **46** ---------------------- ------------------------- ------------------------- ------------------------- ------------------------- -------- ------------- ------------- ---------- -------- ------------- ------------- ---------- -------- ------------- ------------- ---------- The TB-PBPR tool was used to assess whether appropriate investigations were performed. We recorded \'NA\' where the investigation was not applicable (for example, where \'Sputum Smear\' had identified acid fast bacilli), we recorded \'no exam\' where the relevant clinical examination was not documented, we recorded \'omitted\' where an investigation was applicable but not performed, and we recorded \'done\' where the investigation was performed. For example, in hospital C, lymph node (LN) aspiration was not applicable in 45% of patients and was not documented in 35% of patients. LN aspiration was omitted in 15% and done in 5% of the patients. ::: Missed Opportunities -------------------- For each of the 14 clinical actions, the tool collapses the chain of clinical process to identify a missed opportunity where the process failed. For eliciting of TB symptoms, the clinical process was considered complete provided one or more symptoms were recorded and appropriate investigations had been performed. We found a mean of 8.8, 9.8, 7.2 and 2.4 missed opportunities per patient at hospitals A-D respectively (Figure [1](#F1){ref-type="fig"}). For both mine hospitals, we were able to review attendances to the hospital or outpatient clinics in the 3 months before final admission as a surrogate measure of opportunities for earlier intervention. In hospital A, 86% (47/56) of patients had attended at least once while the proportion in hospital B was 92% (24/26). The median number of attendances was 3 and 7 respectively. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Histograms showing the distribution of total missed opportunities per case (maximum 14) for each hospital**. :::  ::: Discussion and Conclusions ========================== We applied a TB-Process Based Performance Review tool as a novel method to evaluate accurate and timely diagnosis of TB. We evaluated the tool in deceased patients, where clinical management may have failed. We therefore expected to find omissions in clinical process, and this may not be representative of the TB programmes in their entirety. Used in conjunction with autopsy results, as for hospitals A and C, the tool deconstructs a patient\'s clinical care to capture diagnostic errors. In the absence of autopsy data, as for hospitals B and D, the tool still provides valuable insight into patient care and overall TB programme performance. Where documentation was missing, we recorded an omission because clear documentation is essential for clinical governance as well as communication reasons. We found that simple but fundamental diagnostic clinical actions such as chest auscultation, CXR and sputum smear were not recorded in many cases. The tool highlights specific areas for improvement within each setting. Similar system failures have been reported in South African urban state clinics \[[@B31]\]. In the absence of a systematic clinical history, examination, and appropriate investigation, the evidence base for logical diagnostic decision-making is lost. This is important in TB (particularly with HIV co-infection) where cases can present diagnostic challenges even where all appropriate investigations seem to have been explored \[[@B8]\]. Similarly, implementation of a 19-point checklist of simple clinical actions was associated with significant improvements in surgical outcome \[[@B32]\]. Many of these 115 patients presented with symptoms that should have prompted clinicians to consider TB (Table [2](#T2){ref-type="table"}); overall 62% presented with chest symptoms, 38% with symptoms of weight loss and 37% with fever or night sweats. Other indications of the possibility of TB existed in these patients, 34% had previously been treated for TB and 85% were HIV-infected. All admitted patients survived for at least 24 h (many survived for longer). Clinicians therefore had opportunity to initiate investigations and treatment, and in many cases to monitor the response to treatment. Furthermore, in hospitals A and B, we found most cases made contact with medical services in the three months before final admission. We would expect to find further missed opportunities in these earlier patient/clinician interactions. We highlight that sputum culture results were missing for so many of the South African patients, although this investigation was available in all hospitals. The dangers of multidrug resistance have been well described \[[@B33]\], and a high index of suspicion must be maintained, particularly where patients fail to improve on TB treatment or have recurrent TB (ISTC, standard 14 \[[@B22]\]). On the other hand, HIV testing was performed well, acknowledging the importance of ascertaining HIV status where TB is suspected. Different criteria were used for selection at each hospital, with the important distinction that (in this study) patients at Hospitals C and D were diagnosed with TB pre-mortem. However, a differential diagnosis that included TB was common to all. Although the selection criteria varied, and this limits comparison, the four hospitals do allow some useful broad observations to be made. We demonstrate that the tool identifies missed opportunities in a variety of settings, both in public and private hospitals, and in developed and developing countries. We recognise that not all missed opportunities carry equal weight but found the total number of missed opportunities to be a useful assessment of overall performance. The findings in hospital D, although the number of patients was small, suggest that it may be possible to achieve low numbers of missed opportunities for some patient groups, and this supports previous data showing that, despite low rates of error, some deaths are unavoidable \[[@B17]\]. Omissions in clinical care occur throughout the world and are not limited to TB; one study found that 45% of US adults do not receive care that is consistent with current recommendations \[[@B34]\]. If simple clinical actions are omitted in these settings, where TB prevalence is high, this raises concerns about settings where clinicians have far less experience of treating TB. The TB-PBPR tool was designed and used here for in-patients and may require adaptation before use in some low income outpatient settings where clinical records may be less detailed. However, many of the key missed opportunities such as basic history taking and sputum smear are common to nearly all settings. Further evaluation will assess whether the TB-PBPR tool can be used to improve local clinical and programme management. Successful TB control requires basic clinical and public health management to be performed efficiently and consistently. Clinical omissions and misdiagnoses have implications for both the individual and the community, delaying treatment and increasing the period of infectivity leading to increased transmission, treatment failure, medical costs, and deaths. The tool was designed with an educational objective in mind, to be used by clinicians to reflect on clinical practice and monitor missed opportunities. The TB-PBPR tool may be particularly useful to improve clinical care in patients with a range of poor outcomes, (e.g, development of drug resistance and recurrence) and its use is not limited to deceased patients. We suggest that the tool may augment broader WHO measures for TB programmes because it allows detailed evaluation to feedback into a TB programme and improve clinical care. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= JM, PS and NF designed the study. NF, JM, MW and ND completed the TB-PBPR tool flow sheets, and the data were collated by NF. All other authors participated in the design and coordination of the study. All authors contributed to the manuscript, read and approved the final manuscript. Pre-publication history ======================= The pre-publication history for this paper can be accessed here: <http://www.biomedcentral.com/1471-2458/11/127/prepub> Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **The TB-PBPR tool**. ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ The study was financially supported by the Colt Foundation. The authors are grateful to Lazarus Selope and Angelita Solamalai for their assistance in this study. We also thank the Mine Health and Safety Council South Africa for funding development of the TB-PBPR tool.

PubMed Central

2024-06-05T04:04:17.243770

2011-2-22

PMC3051910

Background ========== Tuberculosis (TB) remains a global health problem even though it has nearly been eradicated in some developed countries \[[@B1],[@B2]\]. The incidence in 2005 was 76 per 100,000 persons in Taiwan, 80 per 100,000 in the Republic of Korea, and 600 per 100000 in South Africa \[[@B3],[@B4]\]. TB remains a leading cause of mortality in many countries. The mortality rate has been reported to be 6% in those with pulmonary TB, and as high as 31% in those with disseminated TB \[[@B3],[@B4]\]. Because of variable manifestations and the difficulty in collecting clinical samples, extra-pulmonary TB is usually difficult to diagnose early \[[@B5]\]. Tuberculous pleurisy (TP) is the second most common extra-pulmonary infection \[[@B5]\], and accounts for approximately 5% of all forms of TB \[[@B6]\]. The gold standard for the diagnosis of TP is still mycobacterial culture of pleural effusion (PE), pleura tissue and respiratory specimens, which requires weeks to yield. The treatment could thus be delayed, resulting in an increased mortality rate \[[@B7]\]. For those requiring hospitalization, the mortality rate is further increasing due to increasingly severe infections and weaker host states \[[@B8],[@B9]\]. The prognostic factors for hospitalized patients with TP are unclear. Only limited information is available on whether or not pulmonary involvement has a negative prognostic impact \[[@B6],[@B10]\]. However, the mortality rate is high in tuberculosis patients if they are not promptly diagnosed and treated \[[@B11]\]. Therefore, we conducted this retrospective study to investigate the in-hospital mortality rate of culture-confirmed TP with an emphasis on the clinical impact of pulmonary involvement. Methods ======= Subjects of study ----------------- This retrospective study was conducted in a tertiary-care referral center in northern Taiwan by reviewing the medical charts as in our previous study \[[@B12]\]. The study was approved by the Institutional Review Board of the Research Ethics Committee of National Taiwan University Hospital (No.: 200809076R). The informed consent was deemed unnecessary for this retrospective study. We reviewed the mycobacterial laboratory registry database of the hospital and identified all patients with PE specimens sent for mycobacterial culture from January 2001 to December 2008. Among them, those who were hospitalized for PE before the diagnosis of TP was established by mycobacterial culture for PE were included for further investigation. Patients were classified into two groups according to the disease extent of TB: the isolated pleurisy group and pleuro-pulmonary group. The former was considered if all respiratory samples from a patient were culture-negative for *M tuberculosis*and there were no pulmonary parenchymal lesions compatible with active TB on chest radiographs, defined as new patch(es) of consolidation, collapse, lymphadenopathy, mass or nodule, cavitary lesion or infiltrate without other proven etiology \[[@B13]\]. The others were classified into the pleuro-pulmonary group. Data collection --------------- Patient data were collected by reviewing medical records and recorded in a standardized case report form by one chest physician, then verified by another physician from July 2009 to December 2009. Data included age, gender, underlying co-morbidities, initial symptoms, laboratory data and radiographic findings when the index PE sample was collected, as well as the course and outcome of anti-tuberculous treatment. Mycobacterial culture and susceptibility testing were performed according to standard procedures \[[@B3],[@B14]\]. In our hospital, acid-fast smear and mycobacterial culture for pleural effusion samples were routinely performed in cases of lymphocytic pleural exudate by Light\'s criteria \[[@B15]\]. For patients with adequate cough power, sputum samples were collected by spontaneous expectoration after explanation without supervision. For the others, sputum samples were collected by a nurse using a suction tube inserted through mouth or nasal cavity. We routinely ordered at least three sets of mycobacterial cultures for sputum samples collected from each patient. Bilateral lesions were considered if the contra-lateral lung or pleural cavity were involved. Three histological findings of pleura tissue were considered typical for TP: (1) granulomatous inflammation, (2) caseous necrosis, and (3) the presence of acid fast bacilli \[[@B16]\]. Patients received standard short-course anti-TB treatment with isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and pyrazinamide (PZA) for the initial 2 months, and INH plus RIF for the following 4 months. The standard regimen was modified if drug resistance or adverse effects were encountered \[[@B17],[@B18]\]. Patients were followed for at least 6 months after the index PE samples were collected, or until death or loss of follow-up. Residual pleural thickening (RPT) on radiographs after 6 months of treatment was defined as minor if the pleural thickness was less than 10 mm, or major if equal to or greater than 10 mm. One pulmonologist and one radiologist, both blinded to the clinical data, interpreted the chest radiographs. If their opinions differed, the films were further reviewed by another senior pulmonologist blinded to the results. Statistics ---------- The inter-group differences were compared by using the independent *t*test for numerical variables and the *chi*-square test or Fisher\'s exact test for categorical variables as appropriate. Survival curves were generated using the Kaplan-Meier method and were compared using the log-rank test. Variables having a significant difference (*p*\< 0.05) for in-hospital mortality in univariate analysis were further tested by logistic regression with the forward conditional method. Results ======= During the 8-year study period, a total of 496 samples from 412 patients out of 24,759 PE samples yielded *M. tuberculosis*. Among them, 205 patients were hospitalized when TP was culture-confirmed. The indications for hospitalization were intolerant fever or dyspnea in 99, massive and/or loculated PE in 51, prolonged symptoms (\> 14 days) in 51, and presence of lung mass in 14. Among the 205 patients, 51 were further classified into the isolated pleurisy group. The other 154, including 97 (63%) whose sputum samples were culture-positive for *M. tuberculosis*, were classified into the pleuro-pulmonary group. A total of 3,112 patients had culture-confirmed pulmonary TB. The clinical characteristics of the patients with TP are listed in Table [1](#T1){ref-type="table"}. Patients in the isolated pleurisy group were younger and less frequently had underlying co-morbid illnesses than those in the pleuro-pulmonary group. Among patients aged less than 65 years, underlying co-morbid illnesses were still less common in the isolated pleurisy group (11% *vs*. 45%, *p*= 0.003), but similar between the two groups in those aged 65 years or older (48% *vs*. 47%, *p*= 0.968). Malignancy and diabetes mellitus were the most common co-morbidities in the two groups. The serostatus of *Human Immunodeficiency Virus*(HIV) was tested in 63 (31%) patients and was positive in 6, with no inter-group difference. Of the 142 patients with unknown HIV serostatus, all were free of other acquired immunodeficiency syndrome (AIDS)-defined illness during follow-up. Male predominance was noted in both groups. The duration of symptoms was about 17 days, and 51% of the patients in the isolated TP group presented with fever. Fever was also more common in those aged less than 65 years (54% *vs*. 23%, *p*\< 0.001), without underlying co-morbidities (40% *vs*. 24%, p = 0.017), or without hypoalbuminemia (defined as a serum level of albumin less than 3.5 g/dL) (42% *vs*. 26%, *p*= 0.049). More patients in the isolated pleurisy group suffered from chest pain, but dyspnea was most common in the pleuro-pulmonary group. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Clinical characteristics of the patients with tuberculous pleurisy ::: Isolated pleurisy group (N = 51) Pleuro-pulmonary group (N = 154) *p*value ----------------------------------------- ---------------------------------- ---------------------------------- ---------- Age (years) 52.6 \[27.7\] 70.4 \[16.5\] \< 0.001 Age ≥ 65 years 23 (43%) 114 (74%) \< 0.001 Male gender 35 (69%) 114 (74%) 0.453 Underlying co-morbid condition\* 14 (27%) 72 (47%) 0.015  Diabetes mellitus 4 (8%) 27 (18%) 0.118  Malignancy 7 (14%) 22 (14%) 0.921  Renal failure 3 (6%) 16 (10%) 0.575  Cirrhosis of liver 2 (4%) 7 (5%) 1.000  Autoimmune diseases 0 7 (5%) 0.198  Acquired immunodeficiency syndrome^\#^ 1 (2%) 5 (3%) 1.000 Symptoms  Duration, days 17.8 \[31.0\] 17.3 \[27.4\] 0.923  Cough 2 (4%) 19 (12%) 0.112  Fever 26 (51%) 43 (28%) 0.002  Dyspnea 13 (25%) 51 (33%) 0.360  Chest pain 6 (12%) 3 (2%) 0.007  Others† 4 (8%) 38 (25%) 0.010 Data are no. (%) or mean \[SD\] \* Three and twelve in the isolated pleurisy group and pleuro-pulmonary group, respectively, had two underlying co-morbid conditions. † Other symptoms included gastrointestinal symptoms, consciousness change and other non-specific symptoms. ^\#^63 patients received human immunodeficiency tests. ::: The results of laboratory tests revealed that more patients in the pleuro-pulmonary group had anemia and hypoalbuminemia (Table [2](#T2){ref-type="table"}). The two findings were also significantly associated with an age of 65 years or older (*p*= 0.008 and *p*\< 0.001, respectively) and underlying comorbid condition (*p*\< 0.001 for both). Pleural biopsy was performed in 69% (n = 35) of the isolated pleurisy group and in 33% (n = 51) of the pleuro-pulmonary group, with 75.6% (n = 65) showing granulomatous inflammation with/without caseating changes. Patients with a typical pleural pathology were treated earlier after index PE culture than those who did not have a typical pleural pathology (8.0 *vs*. 14.6 days, *p*\< 0.001). The resistance patterns were similar between the isolated pleurisy group and pleuro-pulmonary group. Nineteen patients had resistance against at least one first-line drug, and four patients had multidrug-resistant TB. Radiographically, the isolated pleurisy group had fewer patients with bilateral lesions and more with loculated PE. ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### Laboratory and radiographic findings of the patients with tuberculous pleurisy ::: Isolated pleurisy group (N = 51) Pleuro-pulmonary group(N = 154) *p*value ----------------------------------- ---------------------------------- --------------------------------- ---------- Positive AFB in PE 1 (2%) 4 (8%) 1.000 Receiving pleura biopsy 35 (69%) 51 (33%) \< 0.001  Granulomatous inflammation 25 (71%) 40 (78%) 0.458 Pretreatment resistance pattern  Anyone-drug resistance 5 (10%) 14 (9%) 0.837   Isoniazid 4 (8%) 13 (8%) 0.931   Rifampicin 1 (2%) 3 (2%) 0.977   Ethambutol 2 (4%) 4 (3%) 0.605  Multidrug resistance 1 (2%) 3 (2%) 0.977 Radiographic findings  Bilateral lesions 5 (10%) 61 (40%) \< 0.001  Loculated PE 22 (43%) 23 (15%) \< 0.001 PE analysis  Leukocyte (/μL) 3016 \[5297\] 1938 \[4649\] 0.239  Lymphocyte (%) 82 \[24\] 75 \[25\] 0.092  Neutrophil (%) 11 \[18\] 17 \[21\] 0.096  Total protein (g/dL) 4.6 \[1.0\] 4.2 \[3.1\] 0.264  Lactate dehydrogenase (U/L) 965 \[593\] 1166 \[1837\] 0.292  Glucose (mg/dL) 87 \[42\] 104 \[62\] 0.202 Blood tests  Leukocyte \> 11000 or \< 4000/μL 6 (12%) 29 (19%) 0.286  Anemia 21 (41%) 98 (60%) 0.003  Albumin \< 3.5 g/dL 19 (37%) 83 (54%) 0.007  Total bilirubin \> 1.2 mg/dL 5 (10%) 20 (13%) 0.800 AFB = acid-fast bacilli, PE = pleural effusion Data are no. (%) or mean \[SD\] \* Hemoglobin \< 12 g/dL in men or \< 11 g/dL in women was considered anemia. ::: A total of 29 patients did not receive anti-tuberculous treatment (Table [3](#T3){ref-type="table"}). Of them, 19 patients in the pleuro-pulmonary group died before the diagnosis of TP was culture-confirmed. Another five in the pleuro-pulmonary group and five in the isolated pleurisy group were discharged and lost to follow-up before the results of mycobacterial culture became available. Among those who received anti-tuberculous treatment, the median interval from the sampling date of index PE specimen to anti-tuberculous treatment was 6 days in the isolated pleurisy group and 9 days in the pleuro-pulmonary group (*p*= 0.367) (Table [3](#T3){ref-type="table"}). About two-thirds of each group received anti-tuberculous treatment within 2 weeks after the index PE samples were collected. Nine patients underwent video-assisted thoracoscopy for decortication and 19 received tube thoracostomy. There was no significant between-group difference. ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### Treatment and outcomes ::: Isolated pleurisy group (N = 51) Pleuro-pulmonary group (N = 154) *p*value ------------------------------------ ---------------------------------- ---------------------------------- ---------- Anti-tuberculous treatment 46 (90%) 130 (84%) 0.305 Tube thoracostomy or decortication 4 (8%) 24 (16%) 0.163 Days-to-treatment 6 \[26.8\] 9 \[15.6\] 0.367  Within 2 weeks 35 (69%) 86 (56%) 0.264  More than 2 weeks 11 (21%) 44 (28%)  Not treated 5 (10%) 24 (16%) Residual pleura thickening\*  ≥ 10 mm 10 (29%) 24 (35%) 0.542  \< 10 mm 25 (71%) 45 (65%) In-hospital mortality rate 2 (4%) 37 (24%) 0.001 Length of hospital stay: days 22 \[20.8\] 33 \[27.9\] 0.003 Data are no. (%) or mean \[SD\] \* After six months of anti-tuberculous treatment, only 36 patients in the isolated pleurisy group and 72 in the pleuro-pulmonary group were still being followed in our hospital. ::: Outcome analysis showed that the pleuro-pulmonary group had a higher in-hospital mortality rate and longer length of hospital stay than the isolated pleurisy group (Table [3](#T3){ref-type="table"}). Among the 39 patients who died before discharge, 2 patients belonged to the isolated pleurisy group and both had underlying malignancy. The remaining 37 patients had pleuro-pulmonary TB. Among them, 24 (65%) of them had underlying diseases, including malignancy in 12, diabetes mellitus in 6, end-stage renal disease in 6, liver cirrhosis in 4, and autoimmune disease requiring immunosuppressant in 1 (5 of them had two underlying diseases). None of the 39 patients had HIV infection. The cause of death was multi-organ failure in 28, refractory respiratory failure in 10, and massive gastrointestinal bleeding in 1. Among those who died of multi-organ failure, only three were documented to have concomitant bacteremia or fungemia. The role of pleuro-pulmonary involvement continued in 2-month survival analysis (Figure [1](#F1){ref-type="fig"}, *p*= 0.003). Within the first 6 months of treatment, 67 patients died and 30 were lost to follow-up. Of the remaining 108 patients, 35 of the 36 patients in the isolated pleurisy group and 69 of the 72 in the pleuro-pulmonary group had received chest radiography after six months. The proportion of patients with RPT ≥ 10 mm was similar in the two groups (*p*= 0.542). ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Survival curves were plotted using the Kaplan-Meier method for patients with tuberculous pleurisy according to the disease extent (the isolated pleurisy group and pleuro-pulmonary group)**. Black dots represent patients who were still alive at the end of the study. :::  ::: The 65 patients with typical pleura pathology for TP were all alive at the time of discharge, whereas only 101 patients (72%) of the remaining 140 patients were alive at discharge (*p*\< 0.001 by the *chi*-square test). Thus, we concluded that \"typical pleura pathology\" was a significant predictor of in-hospital mortality, and then excluded the 65 patients from multivariate logistic regression analysis. The results showed that pulmonary involvement, underlying comorbidity and not receiving anti-TB treatment were independent risk factors of in-hospital mortality (Table [4](#T4){ref-type="table"}). ::: {#T4 .table-wrap} Table 4 ::: {.caption} ###### Factors possibly associated with in-hospital mortality ::: Characteristics Unlvariate *p*value Multivariate *p*value Multivariate OR (95% CI.) ------------------------------------ ------------------- --------------------- ----------------------- --------------------------- Age ≥ 65 years 0.025 0.865 \< 65 years Underlying co-morbid illness Yes 0.001 0.036 2.60 (1.06\~6.38) No Disease extent Pleuro-pulmonary 0.001 0.014 8.67 (1.56\~48.27) Isolated pleurisy Serum albumin level \< 3.5 g/dL \< 0.001 0.344 ≥ 3.5 g/dL Anemia Presence 0.008 0.444 Absence Drug resistance Anyone 0.370 All sensitive Radiographic finding Bilateral 0.002 0.211 Unilateral Days to anti-tuberculous treatment No treated \< 0.001 \< 0.001 12.17 (3.88\~38.14) \> 14 days 0.164 0.914 1.06 (0.38\~2.92) ≤ 14 days The 65 patients with typical pleural pathology for TP were all alive at discharge, whereas 39 of the remaining 140 patients died in hospital (*p*\< 0.001 by the *chi*-square test). Therefore, logistic regression was performed on the 140 patients who had not received a pleural biopsy or had no typical pleural pathology for TP. ::: Discussion ========== The pleural cavity is a common site of involvement in extra-pulmonary TB \[[@B5],[@B16]\]; however, the outcomes and prognostic factors are unclear in hospitalized populations. In this retrospective study, those with pleuro-pulmonary TP accounted for three-fourths of all TP patients requiring hospitalization and had a higher in-hospital mortality rate. The in-hospital mortality rate was also higher among patients who had underlying comorbidities, did not receive anti-TB treatment and had no typical pleural pathology for TP. Although the residual RPT was similar, our analysis showed that the in-hospital mortality rate was six-fold higher in patients with pulmonary involvement than those with isolated pleurisy (24% *vs*. 4%). Compatible with a previous report showing high mortality in hospitalized TB patients \[[@B8]\], our previous study revealed that patients with neutrophil-predominant TP had an in-hospital mortality rate of 36% \[[@B7]\]. There are several possible explanations for the high in-hospital mortality rate of patients with TP, especially for those with pulmonary involvement. Because patients with isolated pleurisy are more likely to have local and systemic inflammatory symptoms such as chest pain and fever rather than hypoalbuminemia, pulmonary involvement probably represents an extensive and serious infection in a compromised and malnourished host. Another possible explanation is that TB is usually at the top of the list of the differential diagnoses for lymphocyte-rich pleurisy \[[@B15]\], whereas it accounts for only 1\~2% of the etiologies for pneumonia \[[@B19]\], thus treatment is frequently delayed. Although a delay in treatment for more than 14 days was not an independent poor prognostic factor, the 19 cases of rapid mortality in our study suggest that TP could be an immediately fatal disease, and timely and effective anti-tuberculous treatment is vital, especially for those with pleuro-pulmonary involvement. However, two previous studies failed to demonstrate a difference in clinical outcomes between isolated TP and pleuro-pulmonary TB \[[@B6],[@B10]\]. Again there are several possible explanations. First, the previous studies analyzed survival after completing anti-TB treatment and relapse, rather than in-hospital mortality. These long-term outcomes were more likely to be confounded by other factors, such as age, underlying co-morbidity, and socioeconomic status. Second, those needing admission were probably more severe cases, especially in a referral medical center. Finally, the patients in the previous reports were younger, around the fifth to early sixth decade, and less than 10% of them had underlying comorbid conditions \[[@B16],[@B20]\]. Our results revealed that histologic examination of the pleural biopsy is the key step for the early diagnosis of TP, because it can effectively demonstrate a typical pathology of TP in more than three-fourths of patients within 3 days, which is higher than the yield rate of mycobacterial cultures for PE samples (11%) \[[@B21]\]. Moreover, even when using the fluorometric BACTEC technique, the results of mycobacterial culture still take one to two weeks \[[@B22]\]. Hence, a typical pleura pathology could result in the early diagnose of TP and improved outcomes. Therefore, for in-patients with lymphocyte-rich PE, the possibility of tuberculosis should be kept in mind and pleural histology should be performed at an early stage if clinically feasible. For the early diagnosis of TP, biomarkers in pleural effusion such as adenosine deaminase and interferon-gamma have been shown to be helpful, but further investigations are needed for the application of nucleic acid amplification tests and interferon-gamma release assays \[[@B23],[@B24]\]. Our study has several limitations. First, in this retrospective study, the number of patients with culture-confirmed TP could have been underestimated because mycobacterial cultures were not routinely performed for every PE sample, and most studies show the sensitivity to be less than 30% \[[@B16]\]. Therefore, the patients with culture-negative TP might have been missed. However, the selected patients were all true cases of TP and represented a homogenous population for detailed analysis. Second, the 6-month follow-up rate was less than 90%. Third, our study population was selected from a large medical referral center. Whether our findings can be extrapolated to all TP patients should be further confirmed. Conclusion ========== Our study revealed that for hospitalized patients with TP, pulmonary involvement, underlying comorbidities, no typical pleura pathology and not receiving anti-TB treatment were associated with a worse in-hospital outcome. Aggressive examination, such as pleural biopsy, for pleural effusion with unknown cause is suggested for the early diagnosis and treatment if clinically appropriate. Competing interests =================== All of the authors declare no competing interest of any nature or kind in related products, services, and/or companies. Authors\' contributions ======================= JYW, JTW, and CCS designed the study, collected all relevant data and wrote the manuscript. CJY, and LL contributed to analyzing data. All authors read and approved the final manuscript. Pre-publication history ======================= The pre-publication history for this paper can be accessed here: <http://www.biomedcentral.com/1471-2334/11/46/prepub> Acknowledgements ================ We thank Dr. Yao-Wen Kuo for collecting the clinical data and Dr. Huey-Dong Wu and the members of the Taiwan Anti-Mycobacteria Investigation (TAMI) group for data collection and analysis. We are grateful to the Medical Information Management Office of our hospital for their help in reviewing the patient charts. This study was supported by the Institute for Biotechnology and Medicine Industry, Taiwan, and academic grant of National Taiwan University Hospital (NTUH. 100-N1685).

PubMed Central

2024-06-05T04:04:17.246320

2011-2-21

PMC3051911

Background ========== Over the last years epidemiological characteristics of infective endocarditis (IE) have been changing in industrialized countries as a result of advances in medical practice: decreasing prevalence of rheumatic heart disease as a predisposing condition, increased longevity, increasing number of patients who undergo invasive procedures \[[@B1]-[@B5]\]. Therefore, the emerging population at risk for IE consists of patients with health care-associated infections (acquired during hospitalization or following invasive procedures performed in other health-care settings) \[[@B6]-[@B8]\], elderly patients with valvular sclerosis, patients with valvular prostheses, and haemodialysis patients \[[@B1],[@B5],[@B9]\]. Most studies have recently shown a trend towards increasing incidence of *Staphylococcus aureus*endocarditis \[[@B1],[@B10],[@B11]\]. Morbidity and mortality are still considerable \[[@B2],[@B5],[@B10]\]: the incidence of IE ranges within 3-10 episodes/100,000 person-year \[[@B2]\]; the in-hospital mortality rate of patients with IE varies from 9,6 to 26% \[[@B2]\]. Larger studies are usually multicentric surveys \[[@B1]\] with selected patients (e.g., only centers with cardiac surgery, with a high proportion of transferred patients) and limited follow-up (only in-hospital or short-term). On the other hand, few high quality population-based studies reviewed in 2007 \[[@B9]\] were heterogeneous as regards population size and demographic structure (male/female ratio ranging from 1.2/1 to 2.5/1, mean or median age ranging from 51 to 69 years), case and outcome definition (from inhospital mortality to 1 year mortality, with overall mortality ranging from 14% to 46% according to different definitions); crude incidence varied from 1.4 to 6.2 per 100,000. The objective of our study was to provide population-based descriptive epidemiological data of IE in the Veneto Region (North-Eastern Italy) through linkage of electronic archives of hospital discharge records (HDR) and mortality records. Methods ======= The total population of the Veneto Region was 4,885,548 on January 1, 2009. In the Region there are about 65 hospitals (including public and private institutes) with an overall number of about 16,000 hospital beds for acute care; there are approximately 900,000 discharges from Veneto hospitals each year. One primary and up to five secondary discharge diagnoses, plus one primary and up to five secondary procedures are registered in the regional archive of HDRs, which includes all discharges from Veneto hospitals and all discharges of Veneto residents hospitalized outside the region. HDRs with a primary or secondary International Classification of Diseases, 9th Revision, Clinical Modification -versions 1997 and 2002- diagnosis code of IE (421.x = acute and sub-acute endocarditis; 98.84 = gonococcal endocarditis; 112.81 = candidal endocarditis) were extracted starting from 1 January 1999. In order to identify a cohort of incident cases with adequate follow-up and to prevent double counting of the included subjects, the first hospitalization (day-case excluded) for IE in the years 2000-2008 was selected; patients already discharged in 1999 with a diagnosis of IE were removed (prevalent cases). Demographic (age, gender) and clinical information (Charlson comorbidity computed from discharge diagnoses \[[@B12]\]) were extracted from the selected HDR. For each subject, all hospitalizations in the year before the first admission for IE were traced and diagnostic and intervention codes analyzed in order to retrieve information on comorbidities and risk factors (cancer, diabetes mellitus, chronic renal failure, congestive heart failure, previous cardiac valve surgery). Furthermore, all hospitalizations in the year following the first admission for IE were selected in order to gain information on hospital transfers (zero or one day difference between discharge and subsequent admission for IE), overall in-hospital mortality, re-admissions, and cardiac valve surgeries. Finally, the cohort of hospitalized IE was linked to the regional mortality registry of the years 2000-2008 to estimate survival of patients; data were censored after a follow-up of 365 days. The microbiologic aetiology of IE is rarely reported in HDR by means of diagnostic codes 38.x or 41.x. Additionally, six regional hospitals sent microbiological data to a common database in the years 2004-2006; information on isolates from blood cultures was extracted and linked to HDR to identify the causative microorganisms and their influence on outcomes in such small subset of the cohort. The study was carried out on data routinely collected by health services and linkage was performed on anonymized records without any possibility of identification of individuals. The study was approved by the Institutional Review Board of the Vicenza Hospital. Continuous variables are presented as medians with interquantile ranges; categorical variables are presented as frequencies/percentages. The presence of time trends across the time periods was assessed by means of the Chi-square test for linear trend or a non parametric trend test derived from the Wilcoxon rank-sum test, as appropriate. The influence of predictive variables on short term mortality (dependent variable = vital status at 90 days) was evaluated by computing the Odds Ratio (OR) with 95% Confidence Intervals (CI). Variables resulting statistically significant at univariate analysis were selected by two models of stepwise logistic regression, including or excluding the Charlson index (which already takes into account diseases reported in the index admission). Statistical analyses were performed using commercially available software (Stata version 9.1; SAS version 9.1). Results ======= After excluding prevalent cases, 1,863 residents in the Veneto Region were hospitalized for IE in the period 2000-2008. The number of incident IE increased from 562 in 2000-2002 to 700 in 2006-2008 (+25%), with a corresponding crude rate rising from 4.1 to 4.9 per 100,000 person-years (+17%; p = 0.003). Table [1](#T1){ref-type="table"} shows the distribution of demographic characteristics, risk factors and comorbidities in the selected population, and significant changes through 2000-2008. The male to female ratio was 1.7:1, and 60% of subjects were aged 65 and older with a significant increase across the study period. The median age (interquantile range) was 68 years (57-77) in the whole cohort, increasing from 66 years (54-74) in 2000-2002 to 70 years (58-78) in 2006-2008 (p \< 0.001). Globally, the rate of IE in people aged 65 and older was 20.3 per 100,000 person-years in male and 10.9 per 100,000 in female subjects. About two out five subjects were hospitalized in the three months preceding the index admission; in 12% a diagnostic code for congestive heart failure was reported in the year before the onset of IE. Information retrieved both from the index and from prior hospitalizations showed that a relevant proportion of the cohort was affected by diabetes mellitus (16%), cancer (10%), and chronic renal failure (8%). ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Demographic and clinical characteristics of hospitalized subjects with infective endocarditis in 2000-2002, 2003-2005, 2006-2008, and p value of the Chi square test for linear trend across the study periods ::: 2000-2002 (n = 562) 2003-2005 (n = 601) 2006-2008 (n = 700) p for trend ----------------------------------------- --------------------- --------------------- --------------------- -------------- Age ≥ 65 years 52.31% 63.56% 63.43% **\< 0.001** Females 39.15% 41.60% 33.00% **0.017** Chronic renal failure 7.30% 7.99% 8.86% 0.309 Cancer 8.90% 11.15% 10.00% 0.563 Diabetes mellitus 16.01% 17.80% 15.29% 0.673 Previous congestive heart failure 12.99% 12.31% 11.43% 0.396 Valve procedures, previous 12 months 6.76% 5.49% 6.29% 0.767 All hospitalizations, previous 3 months 39.15% 41.60% 35.57% 0.159 Charlson index \> 0 47.51% 48.92% 47.86% 0.927 ::: Table [2](#T2){ref-type="table"} shows the sparse microbiological data retrieved from diagnostic codes of HDR in the whole cohort (available in 502 subjects), and from blood isolates in the few hospitals participating to the microbiological archive (available in 106 subjects). Although raw (ICD9-CM codes can be hardly translated into a microbiological classification), limited, and related to different subsets of the cohort, the two sources of information are consistent in indicating that about 40% of IE were due to Staphylococci (mainly *S. aureus*), followed by Streptococci, Enterococci and Gram negatives. ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### Microbiological data retrieved from secondary diagnostic codes in discharge records (n = 502), and from blood culture samples (six hospitals, 2004-2006: n = 106) ::: Hospital discharge records Isolates from blood ------------------------------------------------- --------------------- ---------------------------------- ------------ *Staphylococci* *210 (42%)* *Staphylococci* *41 (39%)* *S. aureus*(38.11, 41.11) 87 *S. aureus* 31 Coagulase-negative Staphylococci (38.19, 41.19) 30 Coagulase-negative Staphylococci 7 *Staphylococcus spp*(38.1, 38.10, 41.1, 41.10) 93 *Staphylococcus spp* 3 *Streptococci + Enterococci* *213 (42%)* *Streptococci+Enterococci* *43 (41%)* *Streptococci*, all (38.0, 41.0x not 41.04) 186 *S. bovis* 11 *S. mitis* 8 Other *Streptococci* 11 *Enterococci*, all (41.04) 27 *Enterococcus faecalis* 10 *Enterococcus spp*. 3 Gram-negative bacteria (38.4x, 41.3-41.7) 50 (10%) Gram-negative bacteria 13 (12%) Others (38.2, 38.3, 41.2, 41.8, 98.84, 112.81 29 (6%) Others 9 (8%) List of ICD-9-CM codes adopted: 38.1 Staphylococcal septicemia; 38.10 Staphylococcal septicemia, unspecified; 38.11 Staphylococcus aureus septicaemia; 38.19 Other staphylococcal septicemia Bacterial infection in conditions classified elsewhere and of unspecified site: 41.1 Staphylococcus; 41.10 Staphylococcus, unspecified; 41.11 Staphylococcus aureus; 41.19 Other Staphylococcus 38.0 Streptococcal septicemia Bacterial infection in conditions classified elsewhere and of unspecified site: 41.0 Streptococcus; 41.04 Group D \[Enterococcus\] 38.4 Septicemia due to other gram-negative organisms Bacterial infection in conditions classified elsewhere and of unspecified site: 41.3 K. pneumoniae; 41.4 E. coli; 41.5 H. influenzae; 41.6 P. mirabilis; 41.7 Pseudomonas 38.2 Pneumococcal septicaemia; 38.3 Septicemia due to anaerobes Bacterial infection in conditions classified elsewhere and of unspecified site: 41.2 Pneumococcus; 41.8 Other specified bacterial infections 98.84 gonococcal endocarditis; 112.81 candidal endocarditis ::: Table [3](#T3){ref-type="table"} shows surgical treatment and outcomes of IE. The median length of stay increased from 23 to 33 days when including hospital transfers, with a rising trend through the study period. If the analysis was restricted to survivors, the median stay was 24 and 35 days excluding or including hospital transfers, respectively. Furthermore, a substantial proportion of subjects surviving the first hospitalization were re-admitted (transfers excluded) with a diagnostic code of IE within 1 year. 23% of subjects underwent a cardiac valve procedure in the index admission or in the following year; such percentage heavily decreased with age (\< 55 yrs = 36%; 55-64 yrs = 32%, 65-74 yrs = 23%; ≥75 yrs = 10%; p for trend \<0.001). Among subjects submitted to cardiac valve procedures, 37% were treated in the index admission, 24% following an hospital transfer, and 38% in a subsequent readmission within 1 year. The inhospital mortality was 14.3% when excluding hospital transfers, with only a slight and non significant increase through study years; it rose to 18.5% when transfers were accounted for. The linkage with mortality data showed that a substantial proportion of deaths happened between 30 and 90 days from the admission for IE (Figure [1](#F1){ref-type="fig"}); an increasing time trend in overall mortality was observed at 90 and 365 days of follow-up (Table [3](#T3){ref-type="table"}). ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### Hospitalization data and follow-up of subjects with infective endocarditis (IE) in 2000-2002, 2003-2005, 2006-2008, and p value of the test for linear trend across the study periods ::: ------------------------------------------------------------------------------------------------------------------------------------------------- 2000-2002 (n = 562) 2003-2005 (n = 601) 2006-2008 (n = 700) p for trend ----------------------------------------------------------------- --------------------- --------------------- --------------------- ------------- Median length of stay, including (excluding) hospital transfers 30\ 34\ 35\ **0.024**\ (23) (23) (25) (0.072) In-hospital mortality, including (excluding) hospital transfers 16.9%\ 19.3%\ 19.1%\ 0.328\ (13.5) (15.3) (14.0) (0.853) Valve surgery in the index admission or within 1 year 23.5% 23.8% 22.0% 0.512 Repeated admissions with IE within 1 year among survivors 25.1% 25.2% 24.3% 0.645 90 days mortality 16.2% 20.8% 22.9% **0.004** 365 days mortality 24.6% 28.8% 31.5%\* **0.013** ------------------------------------------------------------------------------------------------------------------------------------------------- \*data limited to 2006-2007 ::: ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Survival curves of subjects with infective endocarditis according to age class**. :::  ::: Figure [1](#F1){ref-type="fig"} shows survival of subjects according to age: the survival curves of younger patients flatten after 60-90 days, while curves of older patients (especially those aged over 74) continue to drop until the end of follow-up probably due to several comorbidities. The raise of incident cases observed among residents in the Veneto Region and the increase in 90-day fatality produced a growing mortality rate associated to IE, from 0.7 to 1.1 per 100,000 person-years (+65%; p \< 0.001). Table [4](#T4){ref-type="table"} shows the association of demographic and clinical variables already reported in Table [1](#T1){ref-type="table"} with 90 days mortality; the risk of death increased with age and the Charlson comorbidity index, in subjects hospitalized in the previous three months (only at univariate analysis), in those with a previous diagnosis of heart failure, and in patients with a mention of cancer and chronic renal failure. In the subsets of the cohort with information on microbiology, infections due to Staphylococci (n = 210/502 according to HDR) or to *S. aureus*(n = 31/106 according to blood isolates) were significantly associated to mortality, with an estimated OR (95% CI) equal to 3.0 (1.8-5.0) and to 4.2 (1.5-11.4), respectively. ::: {#T4 .table-wrap} Table 4 ::: {.caption} ###### Variables associated to 90-days mortality: odds ratio (OR) with 95% Confidence Interval (CI), at univariate analysis, and at stepwise logistic regression including (Model 1) or excluding (Model2) the Charlson index. ::: Univariate Model 1 Model 2 ----------------------------------- ------------------ ------------------ ------------------ **OR (CI)** **OR (CI)** **OR (CI)** Age (years) 1.03 (1.02-1.04) 1.03 (1.02-1.04) 1.03 (1.02-1.04) Gender (females vs males) 0.89 (0.70-1.13) Chronic renal failure 1.83 (1.24-2.68) 1.50 (1.02-2.20) Cancer 1.76 (1.23-2.49) 1.69 (1.20-2.38) Diabetes mellitus 1.12 (0.81-1.52) Previous heart failure 2.24 (1.63-3.06) 1.85 (1.35-2.56) 1.80 (1.32-2.48) Previous valve procedures 1.11 (0.67-1.77) Previous hospitalizations (3 mth) 1.35 (1.07-1.71) Charlson index 1 vs 0 2.19 (1.66-2.87) 2.00 (1.52-2.65) Charlson index ≥2 vs 0 2.78 (2.09-3.70) 2.44 (1.82-3.26) ::: Discussion ========== Our study demonstrates an increasing trend in incidence and mortality for IE in the Veneto Region over the last decade. The main limit of the study is the lack of validation of IE tracked by ICD9-CM discharge codes: such disease misclassification could have led to the inclusion of false positive cases and the exclusion of false negatives. Discharge diagnoses were chosen based on a pilot investigation carried out in recent years in a single Veneto hospital by chart review of discharges with a broader extraction of diagnostic codes, including as well as 421.x, 98.84, 112.81, also 93.2 (syphilitic endocarditis), 391.1 (acute rheumatic endocarditis), 424.9x (endocarditis, valve unspecified), 966.61 (infection and inflammatory reaction due to cardiac device implant and graft). IE diagnoses were validated according to the modified Duke criteria \[[@B13]\], demonstrating a positive predictive value and a sensitivity for IE of the selection applied in the present study equal to 91/123 = 81% and 91/98 = 93%, respectively (Pellizzer, personnel communication). To what extent such findings are applicable to the entire region and study period remains uncertain, but disease misclassification does not probably account for such sharp time trends found in our study; moreover, the incidence rate (4.4 per 100000 person-years) is in the range reported in literature and in particular it\'s similar to incidences estimated by multicenter prospective surveys conducted in other regions of Northern Italy \[[@B14],[@B15]\]. Furthermore, since the period analyzed to exclude prevalent cases increases over time (minimum = 365 days in 2000), possibly not all prevalent cases have been deleted from early study years, leading to a small underestimation of the real increase of IE incidence; this effect was tested using a constant wash-out time of 365 days through the study period. Our investigation is a large population-based survey spanning over several years that through record-linkage allows for a complete follow-up of IE cases as regards multiple outcomes: surgical interventions, hospital re-admissions, short-term and middle-term mortality. Descriptive data on incidence, surgical treatment, case-fatality obtained by the record-linkage system are within the range reported in the international literature. It must be remarked that in our analyses day 0 is the date of admission; as a consequence, health care-associated cases would have altered figures on length of stay and survival. However survival curves (except for the oldest age group) flatten after the first 60-90 days from admission; therefore 90-day mortality seems to be a good estimate of short term mortality associated to IE. Although recent studies report similar mortality rates in patients diagnosed and treated in tertiary care hospitals and those referred to tertiary centres from other hospitals \[[@B16],[@B17]\], our data show that some usual outcome measures, such as simple in hospital mortality, could be inadequate since they miss a relevant burden of deaths occurring after discharge at home or in subsequent hospitalizations. On the other hand, constraints in clinical data (risk factors, comorbidities, diagnostic work-out and medical therapy) and the almost complete lack of microbiological data derivable from HDR limit our interpretation. Although more accurate diagnostic techniques (such as a higher use of transesophageal echocardiography) can play a role in rising incidence rates \[[@B18],[@B19]\], we cannot exclude that population at risk itself is increasing, considering the increasing share of elderly subjects among patients with IE. According to literature, we confirm a high mortality associated to IE, particularly in older ages and in subjects with comorbidities \[[@B2],[@B10],[@B20]-[@B22]\]; a novel finding is the poor prognosis in subjects with prior hospitalizations for heart failure. However, the increasing trend in mortality can only partially be explained by the growing number of affected elderly patients. It must be enlighten that some well identified predictors of poor prognosis such as some echocardiographic findings (size of vegetations, presence of periannular complications, severity of valve dysfunction at diagnosis) and the presence of foreign material \[[@B2],[@B18],[@B23]-[@B25]\] couldn\'t be deduced from HDR. Moreover, we couldn\'t get differences in treatment protocols over time and among different hospitals. In particular, our survey lacks information on indications for surgery; we found that 23% of patients underwent surgical treatment, with a probability sharply decreasing with age. Recent multicentric studies reported surgery in about half of cases \[[@B1],[@B26]\]. However, some studies included only centres with cardiac surgery units, and the percentage of surgical therapy decreased when restricting analysis to patients admitted directly to study sites \[[@B1]\]; moreover they dealt with a younger population (median age under 60). Among population-based studies, the share of patients submitted to surgery ranged from 12.8% to 40% \[[@B9],[@B14],[@B15]\], with the exception of a survey in France where 49% of subjects were surgically treated \[[@B27]\]. Although there are still some areas of debate and individualized factors must be considered, it\'s been advocated that early surgery could be worth even in patients with high operative risk \[[@B27]\]; in general, in all IE cases, early surgical consultation is recommended \[[@B2],[@B26]\]. The high proportion of patients with previous hospitalization may explain the consistent - although limited - microbiological data, being *S. aureus*the leading microorganism isolated. We also found that infections caused by Staphylococci are significantly associated to mortality, a finding consistent with literature \[[@B1],[@B3],[@B4],[@B11],[@B14],[@B28]\]. Whether an increasing number and severity of comorbidities in subjects developing IE or, as previously hypothized \[[@B1],[@B4],[@B11]\], an increasing share of IE due to Staphylococci, could have led to the observed raise in mortality remains uncertain and deserves further investigations on a clinical basis. Conclusions =========== The study demonstrates an increasing incidence and mortality for IE over the last decade. Some usual outcome measures (in hospital mortality) miss a relevant burden of deaths occurring after discharge. Analyses through electronic archives allow to draw a region-wide picture of IE, overcoming those referral biases that unavoidably affect single clinic or multicentric studies, and therefore represent a first fundamental step to detect critical issues related to infective endocarditis. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= GP and SP designed the study and revised the manuscript, ES and UF collected data and performed statistical analyses, UF and DB wrote the first draft of the manuscript. All authors read and approved the final manuscript. Pre-publication history ======================= The pre-publication history for this paper can be accessed here: <http://www.biomedcentral.com/1471-2334/11/48/prepub> Acknowledgements ================ The authors would like to thank Dr Chiara Facchin for the support in the pilot validation study of discharge codes. The study was funded by the Regional Health Policy Department, Veneto Region

PubMed Central

2024-06-05T04:04:17.249601

2011-2-23

PMC3051912

Background ========== NSCLC accounts for the majority of lung cancer cases and chemotherapy has been the mainstay of treatments of lung cancers \[[@B1]\]. Up to date, DDP still remains the most widely used first-line chemotherapeutic agent for NSCLC treatment. However, continuous infusion or multiple administration of DDP often cause severe side effects, including myelosuppression, asthenia, and gastrointestinal disorders, as well as long-term cardiac, renal, and neurological consequences \[[@B2]\]. Therefore, improving the sensitivity to drug doses strategies is still a challenge for chemotherapy efficacy. Novel therapeutic modalities combining genetic and chemotherapeutic approaches will play important roles in the fight against cancer in future. MicroRNAs (miRNAs) are small, endogenous non-coding RNAs that have been identified as post-transcriptional regulators of gene expression. MiRNAs exert their functions through imperfect base-pairing with the 3\'-untranslated region (3\'-UTR) of target mRNAs \[[@B3]\]. In human cancer, miRNAs can act as oncogenes or tumour suppressor genes during tumourigenesis. Evidence collected to date shows the involvement of microRNA and identifies this class of regulatory RNAs as diagnostic and prognostic cancer biomarkers, as well as additional therapeutic tools \[[@B4]-[@B6]\]. Meanwhile, the associations of dysregulation of miRNAs with chemoresistance of human cancers are attracting more and more attention \[[@B7]\]. Some researches have shown that dysregulation of miRNAs can contribute to the chemoresistance of cisplatin in human tumor cells \[[@B8],[@B9]\]. Recently miR-451 has been reported to be induced during zebrafish, mouse, and human erythroid maturation as an key factor involved in regulates erythrocyte differentiation \[[@B10]-[@B12]\]. It was also reported that miR-451 might function as tumor suppressor and modulate MDR1/P-glycoprotein expression in human cancer cells \[[@B13]\]. Meanwhile, miR-451 has been reported to be involved in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin \[[@B14]\]. However, to our best knowledge, there have been no reports about the association of miR-451 expression with the sensitivity of NSCLC cells to DDP. In the present study, we identify miR-451 to be downregulated in human NSCLC and report for the first time that upregulation of miR-451 can enhance DDP chemosensitivity in NSCLC cell line (A549) by inducing apoptosis enhancement, which identifies miR-451 as a valid therapeutic target in strategies employing novel multimodality therapy for patients with NSCLC. Methods ======= Patients and tissue samples --------------------------- A total of 10 pairs of matched NSCLC and noncancerous tissue samples were surgically obtained from patients in Nanjing Chest Hospital, Jisnsu Province and diagnosed by an independent pathologist. None of the patients had received chemotherapy or radiotherapy before surgery. Samples were snap-frozen in liquid nitrogen and stored at -80°C until RNA extraction. Written informed consent was obtained from all patients before surgery. Cell culture ------------ NSCLC cell line (A549) was cultured in Dulbecco\'s modified Eagle\'s medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. All cell lines were cultured under the atmosphere of 5% CO~2~with humidity at 37°C. Plasmid construction -------------------- The precursor sequence of miR-451 generated by annealing and primer extension with miR-451-precursor-F (5\'-*TGCTGAAACCGTTACCATTACTGAGTTGTTTTGGCCACTGACTGA- CAACTCAGTTGGTAACGGTTT*-3\') and miR-451-precursor-R (5\'-*CCTGAAACCGTTACCAAC-TGAGTTGTCAGTCAGTGGCCAAAACAACTCAGTAATGGTAACGGTTTC*-3\') was digested with BamHI and BglII and cloned into the BamHI-BglII fragment of the pcDNA-GW/EmGFP-miR vector (GenePharma, Shanghai, China). A construct including the non-specific miR-NC (99 bp) was used as a negative control. The constructed vectors were named pcDNA-GW/EmGFP-miR-451 and pcDNA-GW/EmGFP-miR-NC, respectively. Cell transfection ----------------- A549 cells were seeded into 6-well plates and transfected with the miR-415-expressing vector or the control vector expressing a non-specific miR-NC using Lipofectamine 2000 (Invitrogen), and were selected with spectinomycin (100 μg/ml) to generate two stable monoclonal cell lines (a miR-218 stable cell line, A549/miR-451, and a control stable cell line, A549/miR-NC). Quantitative real-time polymerase chain reaction (qRT-PCR) assay ---------------------------------------------------------------- Total RNA was extracted using TRIzol reagent (Invitrogen, CA, USA). Reverse-transcribed complementary DNA was synthesized with the Prime-Script RT reagent Kit (TaKaRa, Dalian, China). Realtime polymerase chain reaction (PCR) was performed with SYBR Premix Ex Taq (TaKaRa, Dalian, China). For miRNA detection, mature miR-451 was reverse-transcribed with specific RT primers (miR-451: 5\'-*CTCAACTGGTGTCGTGGAGTCGGCAATTCAGTTGAGAAA-CTCAG*-3\' and U6: 5\'-*TGGTGTCGTGGAGTCG*-3\') quantified with a TaqMan probe, and normalized by U6 small nuclear RNA using TaqMan miRNA assays (Applied Biosystems, CA). Stem-loop conventional RT-PCR assay ----------------------------------- Total RNA was extracted using TRIzol reagent (Invitrogen, USA). Reverse-transcribed complementary DNA was synthesized with the Prime-Script RT reagent Kit (TaKaRa, Dalian, China). Conventional PCR was used to assay miRNA expression with the specific forward primers and the universal reverse primer complementary to the anchor primer. U6 was used as internal control (Invitrogen, USA). The PCR primers for mature miR-451 or U6 were designed as follows: miR-451 sense, 5\'-*ACACTCCAGCTGGGAAACCGTTACCATTACT*-3\' and reverse, 5\'-*CTGGTGTCGTGGAGTCGGCAA*-3\'. U6 sense, 5\'- *CTCGCTTCGGCAGCACA*-3\' and reverse, 5\'-*AACGCTTCACGAATTTGCGT*-3\'. Then, the RT-PCR products were electrophoresed through a 1.5% agarose gel with ethidium bromide. Signals were quantified by densitometric analysis using the Labworks Image Acquisition (UVP, Inc., Upland, CA). Western Blot assay ------------------ Thirty micrograms of protein extract were separated in a 15% SDS-polyacrylamide gel and electrophoretically transferred onto a PDVF membrane (Millipore, Netherlands). Membranes were blocked overnight with 5% non-fat dried milk and incubated for 2 h with antibodies to phospharylated Akt (pAkt-473), total Akt, Bcl-2 and Bax (Santa Cruz Biotechnology, Santa Cruz, CA) and GAPDH (Sigma, USA). After washing with TBST (10 mM Tris, pH 8.0, 150 mMNaCl, and 0.1% Tween 20), the membranes were incubated for 1 h with horseradish peroxidase-linked goat-anti-rabbit antibody. The membranes were washed again with TBST, and the proteins were visualized using ECL chemiluminescence and exposed to x-ray film. 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay ----------------------------------------------------------------------- The mock or stably transfected A549 cells were seeded into 96-well plates (6.0 × 10^3^cells/well) and allowed to attach overnight. After cellular adhesion, freshly prepared anticancer drugs (DDP) were added with various concentrations. After 72 h, cell viability was assessed using MTT assay. The absorbance at 490 nm (A490) of each well was read on a spectrophotometer. Three independent experiments were performed in quadruplicate. Colony formation assay ---------------------- Approximately 500 mock A549 or stable transfect A549 cells (A549/miR-451 and A549/miR-NC) were placed in a fresh 6-well plate with or without DDP for another 12 h and maintained in RMPI 1640 containing 10% FBS for 2 weeks. Colonies were fixed with methanol and stained with 0.1% crystal violet in 20% methanol for 15 min. Flow cytometry analysis of apoptosis ------------------------------------ Cells were treated with or without DDP for another 12 h and harvested and fixed with 2.5% glutaraldehyde for 30 minutes. After routine embedment and section, the cells were observed under electronic microscope. The apoptosis rates were determined using Annexin V-FITC and PI staining flow cytometry. Hoechst staining assay ---------------------- Cells were cultured on 6-well tissue culture plates to confluence and treated with or without DDP for another 12 h. Then, Hoechst 33342 (Sigma, USA) was added to the culture medium of living cells; changes in nuclear morphology were detected by fluorescence microscopy using a filter for Hoechst 33342 (365 nm). The percentages of Hoechst-positive nuclei per optical field (at least 50 fields) were counted. Caspase-3 activity ------------------ The activity of Caspase-3 was measured using Caspase-3 Colorimetric Assay Kit (Nanjing Keygen Biotech. Co., Ltd) following the manufacturer\'s instruction. In brief, cells were seeded in the 6-wells and were cultured for 24 h. Then, the cells were administered with or without DDP for another 12 h and harvested, resuspended in 50 μL of lysis buffer and incubated on ice for 30 min, and cellular debris was pelleted. The lysates (50 μL) were transferred to 96-well plates. The lysates were added to 50 μL 2.0 × Reaction Buffer along with 5 μL Caspase-3 Substrate and incubated for 4 h at 37°C, 5% CO~2~incubator. The activities were quantified spectrophotometrically at a wavelength of 405 nm. Terminal Transferase dUTP Nick End Labeling (TUNEL) Assay --------------------------------------------------------- Tissues were plated on polylysine-coated slides, fixed with 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS) for 1 h at 25°C, rinsed with 0.1 M PBS, pH 7.4, and permeabilized with 1% Triton X-100 in 0.01 M citrate buffer (pH 6.0). DNA fragmentation was detected using TUNEL Apoptosis Detection Kit (Nanjing KeyGen, China), which specifically labeled 3\'-hydroxyl termini of DNA strand breaks using fluorescein isothiocyanate (FITC)-conjugated dUTP. DNA was also labeled with FITC DNA-binding dye for 5 min. FITC labels were observed with a fluorescence microscope. The percentage of apoptotic cells was calculated as the number of apoptotic cells per number of total cells × 100%. Animal experiment ----------------- All experimental procedures involving animals were in accordance with the Guide for the Care and Use of Laboratory Animals and were performed according to the institutional ethical guidelines for animal experiment. Each aliquot of mock or stably transfected A549 cells were injected into the flanks of BALB/c nude mice (Nu/Nu, female, 4-6 weeks old) which were purchased from the Experimental Animal Centre of Nanjing Medical University and maintained under pathogen-free conditions (n = 8/group). One day after tumor cell implantation, mice were treated with CDDP (3.0 mg/kg body weight; i.p., thrice/week), Tumor volume was followed up for 4 weeks and measured once weekly. The tumor volume formed was calculated by the following formula: V = 0.4 × D × d^2^(V, volume; D, longitudinal diameter; d, latitudinal diameter). All mice were killed and s.c. tumors were resected and fixed in 10% PBS. TUNEL staining assay was performed on 5 μm sections of the excised tumors. The number of apoptotic cells in five random high-power fields was counted. Statistical analysis -------------------- All experimental data were shown as the mean ± SEM. Differences between samples were analyzed using the Student\'s *t*test. Statistical significance was accepted at *P*\< 0.05. Results ======= MiR-451 is significantly downregulated in human NSCLC tissues ------------------------------------------------------------- In this study, a stem-loop qRT-PCR assay was performed to determine the expression of miR-451 in 10 pairs of matched NSCLC and noncancerous lung tissue samples. As shown in Figure [1A](#F1){ref-type="fig"}, the expression levels of miR-451in NSCLC tissues were less than approximately 36.4% of those in noncancerous lung tissues. In addition, conventional RT-PCR assay was also performed to analyze the expression of miR-451 in 2 pairs of matched NSCLC and noncancerous tissue samples. The gel electrophoresis of RT-PCR products confirmed the downregulation of miR-451 expression in NSCLC tissues (Figure [1B](#F1){ref-type="fig"}). Therefore, it was concluded that the downregulation of miR-451 might be involved in lung carcinogenesis. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Detection of miR-451 expression in tissue samples**. A. Quantitative RT-PCR analysis of miR-451 expression in 10 cases of NSCLC and corresponding noncancerous tissues. \*\**P*\< 0.01. N: noncancerous tissues; T: tumor tissues. B. Conventional stem-loop RT-PCR analysis of miR-451 expression in NSCLC and corresponding noncancerous tissues. Gel images of electrophoresis. U6 was used as an internal control. All experiments were performed in triplicate. :::  ::: The expression of miR-451 could be significantlu upregulated in A549 cells by pcDNA-GW/miR-45 --------------------------------------------------------------------------------------------- To upregulate the expression of miR-451 in NSCLC cell line (A549), pcDNA-GW/miR-451 was transfected and stable transfectants (A549/miR-451 or A549/miR-NC) were successfully established. As shown in Figure [2A](#F2){ref-type="fig"}, qRT-PCR assay showed that the relative level of miR-451 expression in A549/miR-451 could be significantly upregulated by 3.8-fold compared with that in mock A549 or A549/miR-NC cells (*P*\< 0.05). The gel electrophoresis of RT-PCR products confirmed the upregulation of miR-451 expression in A549/miR-451 cells (Figure [2B](#F2){ref-type="fig"}). ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Detection of miR-451 expression in mock or stably transfected A549 cells**. A. Quantitative RT-PCR analysis of miR-451 expression in A549, A549/miR-NC or A549/miR-451 cells. B. Conventional stem-loop RT-PCR analysis of miR-451 expression in A549, A549/miR-NC or A549/miR-451 cells. Gel images of electrophoresis. U6 was used as an internal control. All experiments were performed in triplicate. :::  ::: Upregulation of miR-451 inhibits growth and enhances apoptosis of NSCLC cell line (A549) ---------------------------------------------------------------------------------------- To analyze the effect of miR-451 expression on phenotypes of NSCLC cell line, we performed MTT, colony formation and flow cytometric assays. As shown in Figure [3A](#F3){ref-type="fig"}, A549/miR-451 cell line had a significant increase in cell viability compared with mock A549 or A549/miR-NC cell line (*P*\< 0.05). The number of colonies formed from A549/miR-451 cells was significantly lower than that formed from mock A549 or A549/miR-NC cells (*P*\< 0.05; Figure [3B](#F3){ref-type="fig"}). Moreover, flow cytometric analysis showed that the apoptotic rate of A549/miR-451 cells (11.6 ± 1.5%) was significantly higher than that of mock A549 or A549/miR-NC cells (*P*\< 0.05; Figure [3C](#F3){ref-type="fig"}). Thus, upregulation of miR-451 could induce growth inhibition and apoptosis enhancement in A549 cells. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Effect of miR-451 upregulation on growth and apoptosis of A549 cells**. A. MTT analysis of cell viability in mock A549, A549/miR-NC or A549/miR-451 cells. \*P \< 0.05. B. Detecting colony formation ability of mock A549, A549/miR-NC or A549/miR-451 cells, \*P \< 0.05. C. Flow cytomerty analysis of apoptosis in mock A549, A549/miR-NC or A549/miR-451, \**P*\< 0.05; N.S, *P*\> 0.05. All experiments were performed in triplicate. :::  ::: Upregulation of miR-451 expression inactivates the Akt signaling pathway of A549 cells -------------------------------------------------------------------------------------- It has been reported that activation of the Akt signaling pathway can regulate many biological phenomena of lung cancer cells, such as cell proliferation and survival, motility and migration. Thus, we analyzed the effects of miR-451 on the Akt signaling pathway in A549 cells (Figure [4A](#F4){ref-type="fig"}). Results showed that the upregulation of miR-451 could significantly downregulate the expression of pAkt protein but had no effects on the expression of total Akt protein. Additionally, the expression of Bcl-2 protein was downregulated and the expression of Bax protein was upregulated. The activity of caspase-3 in A549/miR-451 cells was also found to be significantly enhanced compared with that in mock A549 or A549/miR-NC cells (*P*\< 0.05; Figure [4B](#F4){ref-type="fig"}). Therefore, it was concluded that the elevation of caspase-3 activity might be induced by the elevated ratio of Bax/Bcl-2. However, the exact mechanisms of miR-451 affecting the Akt signaling pathway need to be elucidated in future. ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Effect of miR-451 upregulation on the Akt signaling pathway**. A. Western Blot analysis of pAkt (473), total Akt, Bcl-2 and Bax protein expression in mock A549, A549/miR-NC or A549/miR-451 cells. GAPDH was used as an internal control. B. Analysis of relative caspase-3 activity in mock A549, A549/miR-NC or A549/miR-451 cells. All experiments were performed in triplicate. :::  ::: Upregulation of miR-451 enhances in vitro sensitivity of A549 cells to DDP -------------------------------------------------------------------------- Dysregulation of miRNA expression has been reported to be associated with chemoresistance of human cancers. However, whether miR-451 expression affects the sensitivity of NSCLC cells is not fully understood. To determine this, the mock or stably transfected A549 cells were treated with various concentrations (0, 5, 10, 15, 20 and 25 μg/ml) of DDP for 12 h or 5 μg/ml of DDP for 0, 12, 24, 26 and 48 h. The results from MTT assay indicated that upregulation of miR-451 led to a significant decrease in cell viability of A549 cells in response to DDP in a dose- or time -dependent manner compared with those of A549/miR-NC and mock A549 cells (Figure [5A](#F5){ref-type="fig"} and [5B](#F5){ref-type="fig"}). The cells were treated 5 μg/ml DDP for 12 h and the number of colonies was determined. As shown in Figure [5C](#F5){ref-type="fig"}, the number of colonies formed from A549/miR-451 cells treated with DDP was significantly lower than that formed from A549/miR-NC and mock A549 cells (P \< 0.05). These data obviously showed that upresgulation of miR-451 might effectively enhance the sensitivity of A549 cells to DDP. ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **Effect of miR-451 upregulation on the in vitro sensitivity of A549 cells to DDP**. A. Effects of various concentrations (0, 5, 10, 15, 20 and 25 μg/ml) of DDP on cells (mock A549, A549/miR-NC or A549/miR-451) for 12 h assessed by MTT assay. B. Effects of 5 μg/ml DDP on cells (mock A549, A549/miR-NC or A549/miR-451) for varied time length (0, 12, 24, 36 and 48 h) evaluated by MTT assays. C. Effects of 5 μg/ml DDP on colony formation of cells (mock A549, A549/miR-NC or A549/miR-451). All experiments were performed in triplicate, \**P*\< 0.05. :::  ::: Upregulation of miR-451 enhances DDP-induced apoptosis of A549 cells -------------------------------------------------------------------- The precise underlying mechanisms by which upregulation of miR-451 enhances chemosensitivity of A549 cells to DDP were further investigated. Then, the apoptosis was detected by flow cytometric assay. As shown in Figure [6A](#F6){ref-type="fig"}, the apoptotic rare of A549/miR-451 treated with 5 μg/ml DDP was increased by approximately 11.7% in comparison with mock A549 cells treated with 5 μg/ml DDP (*P*\< 0.05). However, the apoptotic rate of A549/miR-NC cells treated with DDP showed no significant difference compared with that of mock A549 cells treated with DDP (*P*\> 0.05). Figure [6B](#F6){ref-type="fig"} showed the results of AnnexinV-FITC apoptosis detection assay, which confirmed the results of flow cytomeric assay. Finally, the activity of caspase-3 was also determined by colorimetric assay. As shown in Figure [6C](#F6){ref-type="fig"}, the caspase-3 activity in A549/miR-451 cells treated with DDP remarkably increased by approximately 308% compared that mock A549 or A549/miR-NC cells treated with DDP (*P*\< 0.05). Therefore, upregulation of miR-451 might increase DDP chemosensitivity of A549 cells by enhancing DDP-induced apoptosis. ::: {#F6 .fig} Figure 6 ::: {.caption} ###### **Effect of combined miR-451 upregulation with DDP (5 μg/ml) on apoptosis of A549 cells**. A. Flow cytometry analysis of apoptosis in mock A549, A549/miR-NC or A549/miR-451 cells. B. Hoechst staining analysis of apoptosis in mock A549, A549/miR-NC or A549/miR-451 cells. C. Analysis of relative caspase-3 activity in mock A549, A549/miR-NC or A549/miR-451 cells. All experiments were performed in triplicate. :::  ::: Upregulation of miR-451 increases in vivo chemosensitivity of A549 cells to DDP ------------------------------------------------------------------------------- To explore whether upregulation of miR-451 on chemosensitivity of A549 cells to DDP in vivo, s.c. tumors were developed in nude mice followed by treatment with DDP or PBS. As shown in Figure [7A](#F7){ref-type="fig"}, the tumors formed from A549/miR-451cells grew significantly slower than those from A549/miR-NC after the treatment with DDP. At 28 days after inoculation, the average tumor volume of A549/miR-451 cells (212 ± 36 mm^3^) was significantly lower than that of A549/miR-NC (323 ± 13 mm^3^) following DDP treatment (*P*\< 0.05; Figure [7B](#F7){ref-type="fig"}). TUNEL assay showed that the apoptotic rate of tumors developed from A549/miR-451 cells (15.8 ± 2.2%) was significantly higher than that of tumors developed from A549/miR-NC cells (9.6 ± 1.5%) following DDP treatment (*P*\< 0.05; Figure [7C](#F7){ref-type="fig"}). Like the results observed from in vitro experiments, upregulation of miR-451 could also increase in vivo chemosensitivity of A549 cells to DDP by inducing apoptosis enhancement. ::: {#F7 .fig} Figure 7 ::: {.caption} ###### **Effect of miR-451 upregulation on the in vivo sensitivity of A549 cells to DDP**. A. Growth of tumors in the mice injected with A549/miR-451 or A549/miR-451 with or without DDP treatement. The inoculation was performed in eight mice. B. Average tumor volume at day 28 after the inoculation of A549/miR-NC or A549/miR-451 cells with or without DDP treatment (n = 8/group). C. TUNEL staining analysis of apoptosis in tumor tissues at day 28 after the inoculation of A549/miR-NC or A549/miR-451 cells with or without DDP treatment (n = 8/group). :::  ::: Discussion ========== MiRNAs are a growing class of small, noncoding RNAs (17-27 nucleotides) that regulate gene expression by targeting mRNAs for translational repression, degradation, or both. Increasing evidence suggests that deregulation of miRNAs has been frequently observed in tumor tissues. These miRNAs have regulatory roles in the pathogenesis of cancer in humans, through the suppression of genes involved in cell proliferation, differentiation, apoptosis, metastasis and resistance \[[@B15]-[@B18]\]. Recently, many studies have shown that miRNAs play an important role in malignant transformation. It is likely, therefore, that they can also modulate sensitivity and resistance to anticancer drugs in substantial ways. The mechanisms responsible for chemotherapy resistance by miRNAs have not been clearly identified. Current published data on the association of miRNAs with chemoresistance are limited. While altered expression of miRNAs in primary human NSCLCs has been used for tumor diagnosis and prognosis \[[@B19]\], the potential involvement of miRNAs in induction of drug resistance, particularly, in cisplatin resistance has not been explored. Here, we showed that miR-451 is frequently downregulated in human NSCLC tissues compared with corresponding noncancerous lung tissues, which is consistent with the results of Gao\'et al \[[@B20]\]. It was also reported that microRNA-451 could regulate macrophage migration inhibitory factor production and proliferation of gastrointestinal cancer cells \[[@B21]\]. Nan and his colleagues revealed that miR-451 impacts glioblastoma cell proliferation, invasion and apoptosis, perhaps via regulation of the PI~3~K/AKT signaling pathway \[[@B22]\]. Thus, miR-451 was proposed as a tumor-suppressor of human cancers. In other reports, Godlewski and his colleagues showed that miRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells, which represents a fundamental mechanism that contributes to cellular adaptation in response to altered energy availability \[[@B23]\]. At the same time, they also identified a potential feedback loop between LKB1 and miR-451, which allows a sustained and robust response to glucose deprivation \[[@B24]\]. P-glycoprotein, which is the MDR1 gene product, confers cancer cell resistance to a broad range of chemotherapeutics. Zhu, et al demonstrate for the first time the roles of miRNAs in the regulation of drug resistance mediated by MDR1/P-glycoprotein, and suggest the potential for targeting miR-27a and miR-451 as a therapeutic strategy for modulating MDR in cancer cells \[[@B13]\]. Olga and his colleagues reported that the enforced increase of miR-451 levels in the MCF-7/DOX cells down-regulates expression of mdr1 and increases sensitivity of the MCF-7-resistant cancer cells to DOX \[[@B14]\]. All these data provide a strong rationale for the development of miRNA-based therapeutic strategies aiming to overcome chemoresistance of tumor cells. However, whether the expression of miR-451 can affect the sensitivity of lung cancer cells to DDP is still unclear. In the present study, we found that the upregulation of miR-451 could significantly inhibit growth and colony formation of NSCLC cell line (A549). Upregulation of miR-451 could also enhance caspase-3-dependent apoptosis of A549 cells by inactivating the Akt signalling pathway which induced the reverse of Bcl-2/Bax ratio. Furthermore, upregulation of miR-451 could significantly increase the in vitro and in vivo sensitivity of A549 cells to DDP. To the best of our knowledge, we provided the first insight into the roles and possible mechanisms of miR-451 upregulation in chemosensitivity of A549 cells to DDP. These data suggest that appropriate combination of DDP application with miR-451 regulation might be a potential approach to NSCLC therapy. For higher-dose DDP would produce potentially serious toxic effects such as nephro- and ototoxicity would be increased, combination of DDP application with miR-451 upregulation for the treatment of NSCLC would contribute to lower-dose DDP administration and result in a reduction of DDP toxic side-effects. Although inhibition of Akt signal pathway has been reported to be able to improve chemotherapeutic effect of human tumor cells, whether upregulation of miR-451 enhance DDP chemosensitivity of A549 cells by inactivating the Akt signal pathway needs to be further elucidated. Moreover, only A549 cell line has been used in this study, further researches should be conducted on other cell lines to testify our experimental data. In conclusion, upregulation of miR-451 could increase the sensitivity of A549 cells to DDP both in vitro and in vivo, suggesting that appropriate combination of DDP application with miR-451 upregulation might be a potential strategy for the treatment of human NSCLC in future. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= HBB and XP contributed to clinical data, samples collection, MTT, apoptosis and caspase-3 activity detection analyses and manuscript writing. JSY contributed to animal experiment. ZXW and WD were responsible for the study design and manuscript writing. All authors read and approved the final manuscript. Acknowledgements ================ This work was supported by grants from the National Natural Science Foundation of China (No. 30973477), the Natural Science Foundation of Jiangsu province (No. BK2010590), the Jiangsu Provincial Personnel Department \"the Great of Six Talented Man Peak\" Project (No. 09-B1-021), the Scientific Research Foundation of Jiangsu Province Health Department (No. H200710) and the Medical Science Development Subject in Science and Technology Project of Nanjing (No. ZKX08017 and YKK08091).

PubMed Central

2024-06-05T04:04:17.252625

2011-2-17

PMC3051913

Background ========== Lipid droplets are the intracellular sites for storage of neutral lipids. Long dismissed as inert inclusions, they are now recognized as dynamic organelles with a myriad of functions well beyond fat storage \[reviewed in, \[[@B1]\], \[[@B2]\]\]. In many cells, lipid droplets are highly motile, actively moving along cytoskeletal tracks \[[@B3]\]. Such motion is implicated in the delivery of nutrients \[[@B4],[@B5]\], the growth and turnover of lipid droplets \[[@B6]-[@B8]\], the exchange of lipids and proteins between various cellular compartments \[[@B9]-[@B12]\], and even the assembly of viral particles \[[@B13]\]. Despite the ubiquity and potential biological significance of droplet motion, its mechanism is not well understood \[[@B3]\]. Most characterized droplet motion occurs along microtubules, driven by motor proteins, such as the minus-end directed cytoplasmic dynein \[[@B8],[@B13]-[@B16]\] and the plus-end directed kinesin-1 \[[@B17]\]. The same motor proteins are also employed in many other transport processes and are responsible for the motion of various vesicles, mitochondria, RNP particles, chromosomes and nuclei. Motion of these cargoes is regulated distinctly from that of lipid droplets \[*e.g*., \[[@B18],[@B19]\]\]. At least in part, specificity of droplet motion is achieved via distinct motor regulators that are present exclusively on lipid droplets. For example, in both mammals and flies, members of the Perilipin family modulate droplet motion \[[@B6],[@B13],[@B20]\]; these proteins localize largely or exclusively to lipid droplets \[[@B21]\]. In *Drosophila*embryos, droplet motion is controlled by Klarsicht (Klar) \[[@B19]\], a protein highly enriched on lipid droplets at this stage of development \[[@B22]\]. Presumably, unique motor regulators present only on droplets control specifically those motors attached to this cargo. Klar\'s role is not limited to lipid droplets; in different cells, Klar controls distinct transport processes. In early embryos, it regulates the bidirectional motion of lipid droplets \[[@B19]\], which are transported by cytoplasmic dynein \[[@B14]\] and kinesin-1 \[[@B17]\]. In embryonic salivary glands, in contrast, Klar is required for efficient transport of secretory vesicles \[[@B23]\], possibly by modulating the activity of cytoplasmic dynein. In developing photoreceptors, Klar promotes apical migration of nuclei \[[@B24]\]. Motion of these nuclei is powered by cytoplasmic dynein \[[@B25]\], and also involves the activity of kinesin-1 \[[@B26]\]. The intracellular localization of Klar reflects these varying functions in different tissues: in early embryos, Klar is present on lipid droplets \[[@B22]\]; in photoreceptors, it is enriched on the nuclear envelope \[[@B24],[@B27]\]. Apparently, Klar regulates the same or a similar set of motors in all these instances, and it is the location of Klar that determines which subset of cellular motors is controlled. Thus, determining how Klar is targeted intracellularly is a key to understanding its cargo specificity. This tissue-specific targeting of Klar correlates with isoform variation \[[@B22]\]. The *klar*locus encodes at least three protein isoforms that are due to the use of multiple promoters and Poly A sites \[[@B22]\]. The alpha (α) isoform is required for nuclear migration in photoreceptors \[[@B22],[@B24]\]; the beta (β) isoform controls the motion of embryonic lipid droplets \[[@B22]\]; no function has yet been described for the gamma (γ) isoform. Because the α and β isoforms are predicted to have identical N-terminal regions of 1726 amino acids, but carry unique C-terminal regions (536 aa for Klar α, 114 aa for Klar β), these C-terminal domains may be cis-acting targeting sequences that dictate where in the cell Klar accumulates \[[@B22]\]. For Klar α, there is ample support for this model. Its C-terminal region contains a 60 aa KASH (Klarsicht/ANC-1/Syne Homology) domain. KASH domains typically localize to the outer nuclear envelope, and together with SUN domain proteins in the inner nuclear envelope establish a bridge linking cytoplasmic and nucleoplasmic proteins \[[@B28],[@B29]\]. Indeed, the KASH domain of Klar is sufficient to target unrelated proteins to the nuclear envelope, in cultured cells \[[@B22]\] as well as in photoreceptors \[[@B30]\]. In addition, mutations of Klar α that truncate the protein within or just N-terminal to the KASH domain fail to localize to the nuclear envelope \[[@B22],[@B30]\]. Thus, the KASH domain is necessary and sufficient to target Klar to the nuclear envelope. Available evidence is consistent with the notion that the unique C-terminal region of Klar β has an analogous role in targeting to lipid droplets. For example, in cultured cells, this so-called LD domain is sufficient to recruit RFP to lipid droplets \[[@B22]\]. However, whether the LD domain is necessary and sufficient for droplet targeting *in vivo*has not been clearly established. For one, the exact distribution of LD fusion proteins in cultured cells is distinct from the distribution of endogenous Klar *in vivo*: in embryos, Klar β is present in one or a few dots per lipid droplet, suggesting that it may be recruited to privileged sites \[[@B22]\]. In cultured cells, in contrast, RFP-LD fusions are evenly distributed all over the droplet surface, raising the possibility that targeting in the two systems occurs by distinct mechanisms. From mutational analysis, it is clear that *in vivo*droplet localization requires C-terminal regions of Klar β \[[@B22]\]. However, all available *klar*alleles either only disrupt Klar α or truncate both Klar α and Klar β within the shared N-terminal region. Therefore, they cannot be used to distinguish if droplet targeting is due to the Klar β-specific LD domain or due to regions shared between Klar α and Klar β. To examine the role of specifically the LD domain, we identified a new *klar*allele that deletes the last 64 aa of this domain. This allele abolishes droplet localization entirely. We also expressed a GFP-LD fusion protein and find that it targets to lipid droplets in early embryos, in the female germ line, and in somatic tissues. This analysis establishes that *in vivo*the LD domain is necessary and sufficient for targeting to lipid droplets. Results ======= Identifying a *klar*allele with a lesion in the LD domain --------------------------------------------------------- The transcripts for Klar α and β diverge after exon 15, followed either by exons 16, 17 and 18 (Klar α) or exon 15ext (Klar β) \[[@B22]\]. Exon 15ext encodes the LD domain. Klar β proteins lacking C-terminal regions fail to localize to embryonic lipid droplets \[[@B22]\]. All characterized *klar*alleles with lesions in Klar β remove not only the LD domain (114 amino acids), but also at least 128 amino acids encoded by exons 14 and 15, exons shared with Klar α. Thus, these reagents do not allow a conclusive test if targeting to embryonic lipid droplets requires the LD domain (unique to Klar β) or is mediated by regions common to both Klar α and Klar β. To address this issue, we searched for new *klar*alleles with lesions specifically in the LD domain. Since Klar β null alleles are viable \[[@B22]\], we took advantage of a collection of EMS mutagenized, homozygously viable third chromosomes \[[@B31]\]. We employed TILLING (Targeting Induced Local Lesions IN Genomes) \[[@B32]-[@B34]\] to find sequence changes in a genomic region that includes *klar*exon 15ext. We recovered two candidate lines (Z3-3772, Z3-1711) with predicted sequence changes in exon 15ext. We focused on the potential *klar*mutation in line Z3-3772 since it was predicted to result in deletion of roughly half of the LD domain. Many lines from the mutant collection are mixtures of homozygotes and heterozygotes; the latter carry not only the mutagenized chromosome but also a balancer chromosome. In particular, for strain Z3-3772, the TILLING analysis had employed DNA from heterozygotes as in the extant stock homozygotes are rare to non-existent. When we extracted the non-balancer chromosome from this stock and sequenced exon 15ext, the predicted protein sequence of the corresponding LD domain was identical to the canonical sequence of Klar (Figure [1A](#F1){ref-type="fig"}). ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Sequence of the LD domain in various strains and species**. (A) Comparison of *D. melanogaster*strains. Exon 15ext was sequenced in various strains, and the encoded protein was compared to the canonical sequence available on FlyBase. Shown are the *klar^MW^*and *klar^Z^*allele, the wild-type strain Tai255.1, as well as three mutagenized chromosomes from the Zuker collection (Z3-3772, Z3-1140, Z3-1711). Changes from the canonical sequence are indicated in red. The wild-type LD domain encompasses 114 amino acids. (B) Sequence variation in the LD domain across fly species. Candidate *klar*exons 15 and 15ext were identified in sixteen fly species based on sequence similarity to the corresponding *D. melanogaster*exons. Predicted protein sequences were aligned with Clustal2. \* = position at which residues are absolutely conserved; : = position at which residues show similar chemical properties; . = partial conservation. Color scheme highlights chemically similar amino acids. A 26 aa stretch in exon 15 and a 46 aa stretch in exon 15ext are highly conserved. The red arrow indicates at which point the protein sequence of the *klar^MW^*allele diverges from the wild-type sequence; this allele deletes the entire 46 aa conserved region (amino acids 51-96) in exon 15ext. (C) Helical wheel diagram for amino acids 57-74 of the *D. melanogaster*LD domain. Potentially charged residues are represented in light blue; for uncharged residues, hydrophobicity is indicated by a scale from red (most hydrophilic) to green (most hydrophobic). This amino-acid sequence is compatible with an amphipathic helix structure. A similar pattern of hydrophobicity is conserved across all seventeen species shown in (B). :::  ::: To reconcile this observation with the TILLING results, we hypothesized that the mutation in the parental line might exist on the balancer chromosome, TM6B. We generated flies heterozygous for the TM6B chromosome from line Z3-3772 and for *Df(3L)emc^E12^*, a large deletion that removes - among many other genes - the entire *klar*locus. Genomic sequencing revealed the absence of a contiguous 25 bp stretch in the middle of exon 15ext. This deletion is not a general feature of the TM6B balancer chromosome. Although many of the lines from the mutant collection were analyzed as heterozygotes, the deletion was recovered only once. In particular, our screen identified sequence variations for 19 other lines for which DNA from heterozygous flies had been characterized; but for none of these lines was the 25 bp deletion identified. We also extracted a TM6B chromosome from a different stock of the collection and found that the 25 bp deletion was not present. Thus, this deletion in exon 15ext did not pre-exist on the TM6B chromosome and apparently arose spontaneously since the mutagenesis scheme employed to generate the collection \[[@B31]\] did not expose the balancer chromosomes to EMS. In the following, we will refer to the TM6B chromosome carrying this deletion as TM6B^MW^and to the corresponding *klar*allele as *klar^MW^*. The TM6B chromosome without this deletion and the corresponding *klar*allele will be called TM6B^Z^and *klar^Z^*, respectively. What is the consequence of this change in the genomic sequence? The 25 bp deletion in exon 15ext shifts the open reading frame and should result in a truncated LD domain: While the initial 50 amino acids are unchanged, the C-terminal 64 residues are replaced by an unrelated five-amino-acid sequence (Figure [1A](#F1){ref-type="fig"}). To determine if *klar^MW^*carried additional lesions, we sequenced all the coding exons of *klar*in this allele. The predicted Klar protein(s) display a number of differences to the canonical Klar sequence available on FlyBase (Table [1](#T1){ref-type="table"}), but with the exception of the truncation of the LD domain, all changes are also found for allele *klar^Z^*. Furthermore, all these additional changes have been observed - individually or in combination - in presumably wild-type versions of Klar (Table [1](#T1){ref-type="table"}) and thus apparently represent naturally occurring, benign variations. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Predicted sequence variation in Klar^MW^ ::: AA \# Observed change Exon affected Notes ------------- ----------------- --------------- --------- 633 Ser to Thr 7 a, b 1013 Ser to Thr 9 a, b 1210 Ser to Ala 11 a, c 1358 Asp to Glu 11 a, b, c 1366 Ser to His 11 a, b, c 1510 Thr to Ser 13 a, b, c 1577 Ile to Asn 14 a, b, c Frame shift See Fig. 1A 15ext 1887 Thr to Ser 17 a, b 1909 Ser to Ala 17 a, b The protein coding exons of *klar^MW^*were sequenced, and the predicted protein sequence was compared to the wild-type Klar sequence available on FlyBase. The position of the sequence change is given relative to the protein sequence of the originally reported Klar α protein \[[@B24]\]. Exons numbering follows the convention established previously \[[@B22]\]. Notes indicate if a particular amino acid change is shared with other *klar*alleles. ^a^present in Klar^Z^ ^b^present in a wild-type Klar α cDNA (GenBank [AAD43129](AAD43129), as reported in \[[@B24]\]) ^c^present in various wild-type *klar*alleles (S. Jangi, Y. Guo, MAW, unpublished observations) ::: The LD domain is necessary for droplet localization *in vivo* ------------------------------------------------------------- The identification of *klar^MW^*provides an opportunity to test the functional consequences of disrupting the LD domain specifically. Although the other amino acid changes encoded by *klar^MW^*are likely benign, they could in principle be responsible for any phenotypes observed with *klar^MW^*. In the following, we therefore compare *klar^MW^*to the *klar^Z^*allele, which shares these changes, apart from the LD domain lesion. We first asked if the mutant Klar^MW^protein was expressed. We extracted proteins from early embryos of various genotypes and detected Klar by Western analysis (Figure [2A](#F2){ref-type="fig"}). The Klar β null allele *klar^YG3^*\[[@B22]\] served as specificity control. Embryos from mothers carrying TM6B^Z^over *Df(3L)emc^E12^*only have a single copy of the *klar*locus, and they express Klar β at reduced levels compared to the wild type. Klar^1^protein lacks the C-terminal 286 amino acids, and therefore migrates slightly faster than the wild-type protein \[[@B22]\]. Finally, Klar^MW^was expressed at similar levels to the single copy of wild-type Klar^Z^. Its apparent molecular weight was similar to that of Klar^Z^, but larger than that of Klar^1^; these observations are consistent with a lack of \~60 amino acids in Klar^MW^. ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Klar^MW^is expressed in embryos, but not localized to lipid droplets**. (A) Klar Western of embryos (cycle 14/Phase II) of various genotypes. Since *klar^MW^*and *klar^Z^*are present on TM6B balancer chromosomes, these alleles were analyzed in combination with *Df(3L)emc^E12^*, a deletion that encompasses the entire *klar*locus. The Klar^MW^protein is expressed and stable, as it accumulates to similar levels as the wild-type protein Klar^Z^. (B) Embryos were centrifuged to separate organelles by density, fixed and stained for Klar. The lipid-droplet layer was recognized by its distinctive appearance by bright-field microscopy. In this image, embryos are arranged with the lipid-droplet layer pointing up. Klar signal is enriched on the droplet layer in *klar^Z^*embryos, but not detectable on the droplet layer when the LD domain is truncated (*klar^MW^*) or Klar β is not expressed (*klar^YG3^*). :::  ::: To test if the mutant Klar was present on lipid droplets, we employed the assay previously used \[[@B22]\] to demonstrate that Klar is associated with embryonic lipid droplets: *in-vivo*centrifugation \[[@B11],[@B35]\]. When syncytial embryos are centrifuged, the major organelles sort out by density. In particular, lipid droplets accumulate on the side of the embryo that points up during centrifugation. In the wild type, this lipid-droplet layer is highly enriched for Klar; mutant Klar proteins that fail to target to lipid droplets are absent from this layer \[[@B22]\]. We therefore determined Klar distribution in centrifuged embryos of various genotypes (Figure [2B](#F2){ref-type="fig"}). While in *klar^Z^*Klar was highly enriched on the droplet layer, Klar signal was absent from the droplet layer in the LD truncation mutant *klar^MW^*. We conclude that truncation of the LD domain abolishes targeting of Klar to lipid droplets. Thus, the LD domain is indeed necessary for droplet localization *in vivo*. The LD domain truncation disrupts lipid-droplet transport in embryos -------------------------------------------------------------------- During early embryogenesis, lipid droplets display stereotyped shifts in their overall distribution as the relative balance of plus- and minus-end motion changes in a temporally controlled manner \[[@B19]\]. In wild-type embryos, droplets are initially found throughout the periphery (Phase I: syncytial blastoderm). During cellularization (Phase II), lipid droplets move inwards, deplete from peripheral regions, and accumulate around the central yolk. This accumulation reverses during gastrulation (Phase III): the droplet population shifts outward and disperses throughout the embryo periphery. These shifts can be revealed by staining fixed embryos with the lipid-droplet specific dye Nile Red (Figure [3A](#F3){ref-type="fig"}) or by observing living embryos under transmitted light (Figure [3B](#F3){ref-type="fig"}): Since lipid droplets scatter light, cytoplasm full of droplets is opaque, while cytoplasm depleted of droplets is transparent \[[@B19]\]. As a result, wild-type embryos have a clear periphery in Phase II (not shown) and a cloudy periphery in Phase III (Figure [3B](#F3){ref-type="fig"}). ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **The *klar^MW^*allele does not support normal lipid-droplet transport in embryos**. (A) Embryos were fixed and stained with Nile Red to reveal lipid droplets. In all genotypes shown, lipid droplets are spread throughout the periphery in Phase I and move inward in Phase II. In the wild type, lipid droplets shift back into the periphery in Phase III. In *klar^YG3^*and *klar^MW^*, the bulk of lipid droplets remains in the central yolk in Phase III. (B) Living embryos were placed in halocarbon oil and imaged by bright-field microscopy after Phase III, as described \[[@B19],[@B22]\]. Embryo transparency reveals global lipid-droplet distribution \[[@B19]\]. *Klar^YG3^*, *klar^MW^*, and GFP-LD *klar^YG3^*embryos display a transparent periphery, indicating that lipid droplets failed to spread out from their inward accumulation in Phase II. For all other genotypes shown, embryos are opaque, characteristic of normal outward droplet transport. Normal transport in the wild-type strain Tai255.1 has been observed previously \[[@B58]\]. :::  ::: Klar β is important for the correct balance between plus- and minus-end motion. In the absence of Klar β, the global droplet distribution in Phases I and II is similar to the wild type, but becomes dramatically different in Phase III: lipid droplets remain around the center, instead of shifting back to the periphery. To assess if the LD domain contributes to Klar\'s function in this transport process, we compared *klar^MW^*and *klar^Z^*embryos. In both genotypes, the periphery turned clear in Phase II (not shown), just like for all other *klar*alleles previously characterized. In Phase III, *klar^Z^*embryos were opaque, like the wild type; a single copy of *klar*is indeed sufficient to support normal net droplet transport in Phase III \[[@B19]\]. In contrast, *klar^MW^*embryos were clear, very similar to embryos lacking Klar β altogether (Figure [3B](#F3){ref-type="fig"}). This droplet mislocalization was confirmed by Nile Red staining (Figure [3A](#F3){ref-type="fig"}): In *klar^MW^*embryos, droplets accumulate around the central yolk in Phase II, and stay centrally in Phase III. Thus, *klar^MW^*behaves like a Klar β loss-of-function allele. We conclude that the LD domain is essential for Klar β function. Since it also disrupts the localization of Klar β to droplets, we conclude that proper targeting to droplets is necessary for Klar β to control droplet motion. Presumably, Klar β has to be in close proximity to the motors it regulates. Sequence variation in the LD domain ----------------------------------- The TILLING approach had uncovered a second strain (Z3-1770) with mutations in exon 15ext. We verified those changes by genomic sequencing; they are predicted to result in amino-acid changes at five positions (Figure [1A](#F1){ref-type="fig"}). In addition, in a survey of various laboratory strains, we found three amino-acid changes in Tai255.1, a stock collected from the wild in 1983. None of these changes apparently compromise Klar\'s function: In both strains, Klar localized to lipid droplets (data not shown), and lipid droplets displayed normal outward transport in Phase III (Figure [3B](#F3){ref-type="fig"}). To identify other positions in the LD domain at which variation can be tolerated, we compared the sequence of this domain across seventeen fly species (Figure [1B](#F1){ref-type="fig"}). More than half of the LD domain displays dramatic sequence variation over this evolutionary time span (\~250 Mya). But a 46 amino-acid stretch is highly conserved: 31 positions were either identical or similar among these species. This conservation suggests that this region is functionally important, likely for droplet targeting. This region is deleted in the non-targeting *klar^MW^*allele (arrow in Figure [1B](#F1){ref-type="fig"}). The LD domain truncation supports nuclear migration in photoreceptors --------------------------------------------------------------------- Besides droplet transport, the best-characterized role of Klar is in the migration of nuclei in developing photoreceptors \[[@B19],[@B24]\]. Here, Klar localizes to the nuclear envelope \[[@B24]\], and has been proposed to act as an anchor for cytoplasmic dynein \[[@B36]\]. Numerous lines of evidence suggest that this transport process requires the Klar α isoform \[[@B22],[@B24]\], but the available data do not clearly address if - in addition to Klar α - Klar β is also required to support nuclear migration. This uncertainty is in large part due to the fact that previously it was not possible to selectively abolish just Klar β function without also affecting Klar α \[[@B22],[@B27]\]. *Klar^MW^*now provides a unique opportunity to address if Klar β is required for proper positioning of photoreceptor nuclei. To reveal the position of photoreceptor nuclei in third-instar eye discs, we employed the marker Elav (Figure [4](#F4){ref-type="fig"}). We then examined apical and basal focal planes of these discs for the presence of Elav-positive nuclei. In the wild type (not shown) and in *klar^Z^*, only the apical sections had nuclei, indicating successful migration of nuclei. In *klar^YG3^*(both Klar α and Klar β disrupted), nuclei were present in both apical and basal sections, indicating disrupted nuclear migration; nuclei were also found in the optical nerve. In *klar^MW^*eye discs, nuclei were apical and not present basally nor in the optical nerve. Thus, Klar β is not essential for apical positioning of photoreceptor nuclei. ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **The *klar^MW^*allele supports nuclear migration in photoreceptors**. Eye discs from third-instar larvae were fixed, stained with anti-Elav to reveal photoreceptor nuclei and examined by confocal microscopy. In *klar^Z^*discs, the photoreceptor nuclei are present in apical positions; a few nuclei are visible in the basal section because the disc curves at the edges. Nuclei are absent from the optical nerve (ON). This is the pattern observed in wild-type discs \[[@B22],[@B24]\]. In *klar^YG3^*discs, many nuclei are found basally and in the optical nerve because apical migration of nuclei has failed. *Klar^MW^*discs display the wild-type pattern. :::  ::: A GFP-tagged LD domain localizes to embryonic lipid droplets ------------------------------------------------------------ The previous analysis established that the LD domain is necessary *in vivo*for the droplet localization of Klar as well as for Klar\'s role in regulating droplet transport. To address whether the LD domain is sufficient for these functions, we generated transgenes to allow Gal4-mediated expression of a GFP-LD fusion protein. Since the lipid droplets of the early embryo originate during oogenesis, we combined these transgenes with Gal4 drivers specifically expressed in the female germ line (matα4-Gal4-VP16), so that the fusion protein could be produced when those lipid droplets are first generated. Western analysis confirmed that GFP-LD was expressed in ovaries and embryos (Figure [5A, B](#F5){ref-type="fig"}). Molecular weight standards indicate that its apparent molecular weight is in good agreement with the predicted molecular weight of 41.4 kDa (data not shown). ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **GFP-LD distribution in early embryos**. (A, B) Western analysis of wild-type (WT) and GFP-LD expressing (GL) animals. GL samples are from females carrying both a GFP-LD transgene and the matα4-Gal4-VP16 driver or from embryos laid by these females. GFP-LD was detected with anti-GFP antibodies; corresponding WT samples demonstrate specificity of detection. (A) GFP-LD is present in both ovaries and embryos. (B) GFP-LD is expressed at similar levels in Phase I, II, and III embryos. Tubulin serves as loading control. (C, D) GFP-LD expressing embryos examined live by confocal microscopy. In otherwise wild-type embryos, GFP-LD is present in distinct puncta that accumulate around the central yolk (C). In embryos mutant for Halo, GFP-LD puncta accumulate just under the nuclei (D); these puncta are shifted outwards relative to the embryos in C. Top: whole-embryo view. Bottom: detail of the embryonic periphery. The embryos in C and D are age-matched (top: early Phase II; bottom: mid Phase II). Scale bars in D represent 60 μm (top) and 10 μm (bottom), respectively. (E) GFP-LD expressing embryos imaged live by epifluorescence microscopy. Comparison to a wild-type embryo demonstrates that most of the signal is due to GFP-LD. Global distribution of GFP-LD in Phases I, II, and III mimics the distribution of lipid droplets at these embryonic stages (Fig. 3A); in particular, GFP-LD is spread throughout the periphery in Phase III if endogenous Klar β is present, but not if it is absent. (F) Even when expressed in the absence of endogenous Klar β, GFP-LD is present in discrete puncta (scale bar = 6 μm). (G) Triglyceride levels in wild-type and GFP-LD expressing embryos (0-1.5 hrs old) are very similar. Error bars represent the standard deviation from two different experiments. :::  ::: To determine the intracellular distribution of GFP-LD, we detected GFP fluorescence in living and in fixed embryos or stained fixed embryos with anti-GFP antibodies. All three methods revealed that the fusion protein was present in discrete puncta (Figure [5C, a](#F5){ref-type="fig"}nd data not shown), reminiscent of lipid droplets in size and abundance. These GFP-LD puncta moved actively, in a back-and forth manner (see the movies provided as Additional Files [1](#S1){ref-type="supplementary-material"} and [2](#S2){ref-type="supplementary-material"}), similar to the bidirectional movement of lipid droplets \[[@B19]\]. In addition, the global distribution of GFP signal also mimicked that of lipid droplets (Figure [5E](#F5){ref-type="fig"}). The generally peripheral distribution in Phase I was followed by accumulation around the central yolk in Phase II. In Phase III, GFP-LD was again broadly peripheral. If GFP-LD indeed marks lipid droplets, its distribution should change predictably if lipid-droplet transport is altered. Inward transport of lipid droplets in Phase II requires the transport regulator Halo; in its absence, lipid droplets accumulate close to the plasma membrane, under the nuclei, rather than around the yolk in the center \[[@B18]\]. Halo has no known role in the transport of any cargo beyond lipid droplets. In embryos lacking Halo, GFP-LD puncta also accumulate under the nuclei (Figure [5D](#F5){ref-type="fig"}), instead of around the yolk (Figure [5C](#F5){ref-type="fig"}). Furthermore, outward transport of lipid droplets in Phase III requires Klar β (Figure [3A](#F3){ref-type="fig"}). In the absence of endogenous Klar β, GFP-LD remained highly enriched in the yolk sack in Phase III (Figure [5E](#F5){ref-type="fig"}), just like lipid droplets \[[@B19],[@B22]\]. Thus, in these genotypes, GFP-LD distribution reflects the distribution of lipid droplets. Finally, at higher magnification, the GFP-LD structures appeared as rings (Figure [6C, D](#F6){ref-type="fig"}), in the known size-range of embryonic lipid droplets (\~500 nm in diameter). Such ring structures are very characteristic for lipid droplets, as droplet proteins accumulate at the droplet surface and are excluded from the hydrophobic core full of neutral lipids \[[@B37]\]. Rings of GFP-LD were apparent in both fixed and living embryos. Co-staining of fixed embryos with the droplet-specific dye Nile Red revealed that GFP-LD signal was present around Nile-Red positive structures (Figure [6C, D](#F6){ref-type="fig"}). We conclude that the GFP-LD puncta are lipid droplets. ::: {#F6 .fig} Figure 6 ::: {.caption} ###### **GFP-LD puncta are lipid droplets**. (A, B) GFP-LD co-purifies with lipid droplets. (A) Pre-cellularization embryos were embedded in agar and centrifuged. In the image, the embryos are arranged such that the lipid-droplet layer points up. GFP-LD is highly enriched in the droplet layer, whether or not the embryos express endogenous Klar β. Under the same imaging conditions, autofluorescence in wild-type embryos is negligible. (B) Lipid droplets were isolated from wild-type (WT) and GFP-LD expressing (GL) embryos by floatation. Equal amounts of protein from embryo lysates (Lys) and from the droplet fraction (DF) were compared by Western analysis. The cytoplasmic protein tubulin is absent from the droplet fraction. Both the lipid-droplet protein LSD-2 and GFP-LD are highly enriched in the droplet fraction. GFP-LD was detected as in Fig. 5. (C, D) GFP-LD expressing embryos were fixed and stained with Nile Red to reveal lipid droplets. GFP-LD is present in rings around lipid droplets; intensity of GFP-LD signal varies between droplets (scale bar = 5 μm). Panel D shows a magnified view of parts of panel C. :::  ::: There are two unexpected patterns of the GFP-LD signal. First, it is present in fairly uniform rings, rather than the discrete spots observed for endogenous Klar β \[[@B22]\]. Full-length Klar β might be restricted to certain regions on the droplet surface via interactions of the N-terminal region with other proteins. Alternatively, the binding partners that keep Klar β locally restricted may be limiting, present in lower amounts than the well expressed GFP-LD. Second, only some of the Nile-Red positive structures display strong GFP-LD signal (Figure [6C, D](#F6){ref-type="fig"}), while on others GFP levels were much weaker or barely detectable. It is striking that drastic intensity variations can be observed between neighboring lipid droplets in the same cell. This observation suggests that GFP-LD displays differential affinity to different droplets or that, once droplets are generated with distinct GFP-LD levels, GFP-LD does not readily exchange between droplets. GFP-LD localizes to droplets in the absence of endogenous Klar β ---------------------------------------------------------------- The above analysis suggests that the LD domain is sufficient to target an unrelated protein to lipid droplets. This conclusion, however, might be misleading if the LD domain were a dimerization motif. In that case, GFP-LD could physically interact with full-length Klar β and would be targeted to lipid droplets secondarily, even if full length Klar were to bind to the droplets via other domains. Although the analysis of *klar^MW^*makes this possibility unlikely, we performed a rigorous test of this idea by examining GFP-LD in a Klar β null background. GFP-LD was still present in distinct cytoplasmic rings the size of lipid droplets (Figure [5F](#F5){ref-type="fig"}) that moved bidirectionally (not shown). In addition, global GFP-LD distribution followed that of lipid droplets: throughout the periphery in Phase I, and accumulated in or around the central yolk in Phases II and III (Figure [5E](#F5){ref-type="fig"}). Thus, GFP-LD localization to lipid droplets does not require endogenous Klar β. The GFP-LD fusion co-purifies with lipid droplets ------------------------------------------------- Lipid droplets are rich in neutral lipids and have a low buoyant density. This property makes it possible to biochemically separate droplets from other cellular structures. We therefore asked if GFP-LD copurifies with lipid droplets. In a first test, we employed *in-vivo*centrifugation of intact embryos \[[@B35]\]. In such centrifuged embryos, GFP-LD signal was highly enriched in the lipid-droplet layer (Figure [6A](#F6){ref-type="fig"}), just like endogenous Klar (Figure [2B](#F2){ref-type="fig"}). This enrichment is not due to the GFP portion as many other GFP fusion proteins are excluded from the droplet layer in this assay \[[@B11]\]. It also does not depend on endogenous Klar β since GFP-LD was enriched in the droplet layer in the Klar β null background (Figure [6A](#F6){ref-type="fig"}). Second, we lysed embryos and enriched for droplets using a sucrose step-gradient (Figure [6B](#F6){ref-type="fig"}). The top, lipid-droplet fraction was highly depleted for the cytoplasmic protein tubulin and greatly enriched for the *bona-fide*lipid-droplet protein LSD-2. GFP-LD was similarly enriched in this fraction. Taken together, these two approaches demonstrate that GFP-LD co-purifies with lipid droplets and provide independent evidence that the LD domain is sufficient to target an unrelated protein to lipid droplets. The LD domain mediates droplet localization in many cell types -------------------------------------------------------------- How proteins are targeted to lipid droplets is not well understood \[[@B1]\]. Droplet-localized proteins fall into two broad classes. Some proteins localize to lipid droplets in essentially all cells they are expressed in, such as the Perilipin family members PLIN1and PLIN2 (formerly called Perilipin and ADRP, respectively) \[[@B21],[@B38]\]. This constitutive localization is in contrast to the conditional recruitment of, *e.g*., hormone-sensitive lipase; this enzyme moves from a general cytoplasmic distribution to the surface of lipid droplets in response to hormonal signaling \[[@B39]\]. In addition, specific proteins from other cellular compartments localize to lipid droplets only in certain developmental stages or under specific environmental conditions \[[@B40]\]. For early embyronic droplets in *Drosophila*, certain histones are such conditional lipid-droplet proteins \[[@B11]\]; many more proteins potentially behave similarly as the proteomes of embryonic and of fat-body droplets show considerable differences \[[@B11],[@B41]\]. We therefore asked whether localization of GFP-LD occurs only in early embryos or is a general phenomenon. We first examined ovaries since lipid droplets are abundant in nurse cells and in oocytes from mid-oogenesis onwards. GFP-LD expressed with a Gal4 driver specific for the female germ-line (matα4-Gal4-VP16) accumulates during oogenesis (Figure [5A](#F5){ref-type="fig"}), and is present in ring structures in both oocytes and nurse cells (Figure [7A, B](#F7){ref-type="fig"}). These rings co-stained with Nile Red and are apparently of low buoyant density: In centrifuged ovaries, where the major constituents of nurse cells and oocytes sort out by density \[[@B11]\], GFP-LD was highly enriched in the lipid-droplet layer (Figure [7C](#F7){ref-type="fig"}). We conclude that GFP-LD is present on lipid droplets in oocytes and nurse cells. ::: {#F7 .fig} Figure 7 ::: {.caption} ###### **GFP-LD fusion protein localizes to lipid droplets in many types of cells**. The intracellular distribution of GFP-LD was examined in animals expressing GFP-LD in the female germ line (A, B, C: matα4-Gal4-VP16 driver) or in somatic cells (D, E, F: Act5C-Gal4 driver). Colocalization with Nile Red signal (A, B, D, E, F) or enrichment in the lipid-droplet layer after centrifugation (C) indicates that GFP-LD is associated with lipid droplets. (A) Stage 13 oocyte. (B) Stage 10 nurse cells. (C) Egg chamber after centrifugation. Bright-field microscopy (BF) reveals distinct layering. Prominent brown lipid-droplet layers are evident in the nurse cells (left) and the oocyte (right); the oocyte also shows a gray yolk layer. GFP-LD is enriched in the droplet layers of both nurse cells and oocyte. The merged image also shows yolk autofluoresence in blue. (D) Follicle cells. (E) Larval salivary gland. (F) Wing imaginal disc. In all cases, the intensity of GFP-LD signal varies dramatically between lipid droplets. GFP-LD signal was also present, at lower levels, elsewhere in the cell (*e.g*., E). Scale bars = 5 μm. :::  ::: Using the ubiquitously active Act5C-Gal4 driver, we also expressed GFP-LD in somatic cells. In a number of adult and larval tissues, we found discrete GFP puncta, including in follicle cells in the adult ovary, larval salivary glands, and imaginal discs. These structures are lipid droplets, as they appear as rings at higher magnification and co-label with Nile Red (Figure [7D, E, F](#F7){ref-type="fig"}). Since in the wild type lipid droplets are abundant in certain imaginal discs \[[@B42]\], in follicle cells (MAW, unpublished observations), as well as in nurse cells and oocytes \[[@B43]\], GFP-LD likely does not induce lipid storage *de-novo*in these tissues, but localizes to pre-existing droplets. In summary, targeting of the LD domain to lipid droplets is not an embryo-specific phenomenon. GFP-LD also localizes to lipid droplets in the female germ line and in a number of somatic tissues. In addition, an analogous RFP-LD fusion protein localizes to lipid droplets in cultured *Drosophila*cells \[[@B22]\]. Thus, GFP-LD is not a conditional droplet protein, and the mechanism targeting the LD domain to lipid droplets is quite general. Discussion ========== A *klar*allele specific for the Klar β isoform ---------------------------------------------- Because the *klar*locus encodes at least three proteins with different exon content, different lesions in *klar*have distinct effects on the isoforms and thus on distinct biological processes \[[@B22]\]. Lesions in exons 0 through 15 disrupt both Klar α and Klar β; these so-called class I alleles impair both nuclear migration in photoreceptors and motion of embryonic lipid droplets. Lesions in exons 16 through 18 disrupt Klar α and Klar γ; such class II alleles impair nuclear migration, but not droplet motion. The new allele *klar^MW^*disrupts Klar β but not Klar α; it alters droplet motion but not nuclear migration. It constitutes a new type of allele (class III) that selectively impairs the β isoform. *Klar^MW^*provides a unique tool to separately examine the functions of Klar α and Klar β. Klar is widely expressed \[[@B22]\] and has been implicated in a number of biological processes beyond droplet motion and nuclear migration \[[@B23],[@B44]-[@B48]\]. In most cases, it is unknown which Klar isoform is involved. The combination of class I, II and III alleles should make it possible to disentangle this functional complexity. Droplet targeting by the LD domain ---------------------------------- Our analysis of GFP-LD fusions suggests that targeting of Klar β to lipid droplets is a multi-step process. In many cells, GFP-LD strongly accumulates on lipid droplets (Figure [6](#F6){ref-type="fig"}, [7](#F7){ref-type="fig"}). In mid-stage oocytes, in follicle cells, and in the salivary gland, GFP fluorescence is also detected diffusely and in membranous structures and tubules reminiscent of the nuclear envelope or the ER (not shown). Under sensitive imaging conditions, similar additional GFP-LD distribution becomes apparent also in early embryos. These observations suggest that - in addition to strong affinity to lipid droplets - GFP-LD has a weak affinity to certain membranous compartments. We do not know yet whether this additional localization represents nascent GFP-LD in transition to lipid droplets, ectopic localization due to high levels of expression, or genuine multiple targeting. Dual localization of proteins to both the ER and lipid droplets is common, presumably because lipid droplets originate from the ER \[[@B1]\]. Nevertheless, GFP-LD clearly accumulates strongly on lipid droplets in many tissues, forming characteristic ring structures. Intriguingly, this distribution is distinct from the distribution of full-length Klar β, which is present in discrete dots on embryonic droplets \[[@B22]\], a distribution similar to that of the motor dynein \[[@B14]\]; thus, full-length Klar may be recruited to distinct spots by physical interactions with microtubule motors. GFP-LD may not be restricted to such dots because interactions with the motors might require sequences in the N-terminal region of Klar β or because GFP-LD is overexpressed relative to its interaction partners. We favor the former explanation since even those lipid droplets with comparatively low GFP-LD signal show a ring-like distribution of GFP-LD (Figure [6C, D](#F6){ref-type="fig"}). In the future, these hypotheses can be distinguished by comparing the distribution of GFP-LD and GFP-Klar β expressed at similar levels. What is the molecular mechanism by which the LD domain, a region just 114 amino acids in length, is recruited to lipid droplets? Evolutionary conservation and mutational analysis point to a 46 amino acid region as critical for targeting (Figure [1B](#F1){ref-type="fig"}). Many proteins localize to droplets via hydrophobic targeting motifs thought to insert into the phospholipid monolayer surrounding droplets and to make contacts with the hydrophobic core. Examples include the proline knot motif of plant oleosins \[[@B49]\], hydrophobic patches in caveolin \[[@B50]\] or amphipathic helices in various Perilipin family members \[[@B21]\]. Consistent with this possibility, the 46 aa conserved region of the LD domain is fairly hydrophobic (light blue residues in Figure [1B](#F1){ref-type="fig"}) and the regular interspersion of charged residues is compatible with this region forming an amphipathic helix (Figure [1C](#F1){ref-type="fig"}). Alternatively, this motif may allow the LD domain to physically interact with resident droplet proteins, *e.g*. just like hormone-sensitive lipase is recruited to droplets by binding to PLIN1 \[[@B39]\]. If so, the binding partners of the LD domain cannot be exclusive to embyronic droplets since droplet targeting occurs in many types of cells (Figure [7](#F7){ref-type="fig"}). As a first step towards uncovering the targeting mechanism, a structure-function analysis of this region should reveal which features of the sequence (*e.g*., general hydrophobicity versus specific residues) are essential for proper droplet targeting. These studies can be conducted in the more accessible cultured-cell system, since the LD domain shows the same targeting properties *in vivo*(Figure [6](#F6){ref-type="fig"}, [7](#F7){ref-type="fig"}) as in cultured cells \[[@B22]\]. Since GFP-LD localizes to the droplet surface, it might potentially interfere with lipid metabolism. For example, in cultured mammalian cells, overexpression of PLIN2 promotes lipid-droplet accumulation, presumably by shielding the droplets from access by lipases \[[@B51],[@B52]\]. We have not noticed dramatic effects on lipid storage upon GFP-LD overexpression. Total triglyceride levels in wild-type and GFP-LD expressing embryos are very similar (Figure [5G](#F5){ref-type="fig"}), and in a range of cell types, lipid droplets carrying high levels of GFP-LD are very similar in size to nearby droplets with low GFP-LD levels (Figure [6](#F6){ref-type="fig"} and [7](#F7){ref-type="fig"}). These data do not rule out that GFP-LD causes minor quantitative changes in lipid storage or only produces effects in specific cell types or under certain physiological conditions. Why is GFP-LD distribution not uniform? --------------------------------------- It is striking that not all lipid droplets accumulate GFP-LD to the same level. Lipid droplets in close proximity in the same cell can have dramatically different GFP-LD signal (Figures [6](#F6){ref-type="fig"}, [7](#F7){ref-type="fig"}). An exciting development in recent years has been the realization that not all lipid droplets within a given cell are identical; in particular, they can carry different proteins \[[@B37],[@B38],[@B41],[@B53]\]. However, the lipid droplets in early *Drosophila*embryos appear quite uniform, in size distribution and motile behavior \[[@B14],[@B18],[@B19]\]; droplet proteins previously examined displayed no obvious variation between droplets \[[@B11],[@B20]\]. To our knowledge, the uneven distribution of GFP-LD is the first hint that different embyronic droplets might have distinct properties. Currently, we cannot distinguish whether GFP-LD is preferentially recruited to certain types of droplets existing naturally or whether GFP-LD expression causes differences between droplets. For example, Gal4 drivers often show mosaic expression in nurse cells \[[@B54]\]; and we sometimes observed, in the same egg chamber, nurse cells with variable GFP-LD expression (data not shown). Droplets that originated in different nurse cells may therefore carry distinct levels of GFP-LD once they reach the oocyte. We suspect that such mosaic expression does not fully account for the differential labeling because we observe drastic variation in GFP-LD levels also between droplets in single nurse cells as well as in other cells (Figure [7](#F7){ref-type="fig"}). The role of the LD domain for droplet transport ----------------------------------------------- The LD domain is necessary not only for droplet localization of Klar β, but also for Klar β\'s function in regulating droplet transport. Our results indicate that although the LD domain is sufficient for droplet localization, by itself it does not mediate Klar\'s transport functions. When expressed in the Klar β null background, most GFP-LD signal remains in the yolk sack in Phase III (Figure [5E](#F5){ref-type="fig"}). In addition, Klar β null embryos remain clear in Phase III, whether or not they express GFP-LD (Figure [3B](#F3){ref-type="fig"}). Simply targeting GFP-LD to lipid droplets is apparently not sufficient to restore Klar β\'s function. Although it is conceivable that GFP-LD expression levels were simply not high enough for rescue of the transport defects, we disfavor this explanation since a full-length, GFP-tagged Klar β construct expressed at much lower levels is sufficient to profoundly alter droplet motion (YVY and MAW, unpublished observations). We therefore conclude that proper regulation of droplet motors requires the N-terminal region of Klar β and not just the LD domain. This model is further supported by the fact that Klar α shares those N-terminal regions and is also involved in motor regulation. Whether the LD domain simply targets Klar β to lipid droplets or has additional functions is not yet clear. For example, because in yeast the LD domain can interact with the droplet protein LSD-2, it has been suggested that it participates in transmitting developmental signals from LSD-2 via Klar to motors \[[@B20]\]. In the future, it will be interesting to investigate whether expression of GFP-LD alters subtle aspects of droplet motion, *e.g*., the exact distances traveled in a single run or the frequency of pausing \[[@B14]\]. However, our data suggest that such effects, if they exist at all, do not alter the net outcome of transport. GFP-LD expressing embryos displayed the same transparency changes as the wild type: the embryo periphery became transparent in Phase II and cloudy in Phase III (Figure [3B](#F3){ref-type="fig"}, and data not shown). Also, in the presence of GFP-LD, inward droplet transport in Phase II still depends on Halo (Figure [5D](#F5){ref-type="fig"}) and outward droplet transport in Phase III depends on endogenous Klar β (Figure [5E](#F5){ref-type="fig"}), just as for embryos not expressing the fusion protein \[[@B18]\]. These conclusions hold true whether we examine transparency changes in the embryos (to reveal the behavior of the entire droplet population) or GFP fluorescence directly (Figure [3B](#F3){ref-type="fig"}; Figure [5D, E](#F5){ref-type="fig"}). Since LD has the ability to bind to lipid droplets in a wide range of cells, Klar β may control droplet motility in many tissues. In *Drosophila*, droplet motion has so far been described only in early embryos \[[@B19]\] and in oocytes \[[@B55]\], but no systematic analysis has been conducted. New GFP fusions to mark lipid droplets *in vivo*\[[@B37],[@B56]\], including the GFP-LD constructs described here, will make it possible to address to what extent droplets move in other tissues and whether disruption of Klar β alters that movement. Conclusions =========== To test the function of the LD domain of Klar β, we generated inducible GFP-LD fusion constructs and identified a *klar*allele that specifically disrupts the LD domain. Using these tools, we demonstrate that the LD domain is both necessary and sufficient for droplet targeting *in vivo*. We conclude that Klar β is targeted to lipid droplets via an isoform-specific protein motif, just like Klar α is targeted to the nuclear envelope via the KASH domain. Thus, it is controlled inclusion of cis-acting targeting sequences that mediates the differential intracellular localization of Klar in distinct tissues. Although Klar\'s LD domain is necessary for Klar β to act in the regulation of lipid-droplet transport, by itself it does not mediate Klar\'s transport functions. Likely it is the N-terminal regions shared between Klar α and Klar β that mediate motor regulation. In this model, variable C-terminal targeting sequences control Klar\'s intracellular distribution and thus dictate which subset of intracellular motors is controlled by Klar. Methods ======= Fly stocks ---------- Oregon R was used as the wild-type stock. The stocks carrying *klar*alleles *klar^YG3^*and *klar^1^*and the deficiency *Df(3L)emc^E12^*were described previously \[[@B19],[@B22]\]. The collection of mutagenized third chromosomes was generated by the Zuker laboratory \[[@B31]\]. Line Z3-1711 might represent a different chromosome than the others from the collection: it did not display the recessive eye color markers characteristic for these stocks \[[@B31]\], and it had five simultaneous amino-acid changes in the LD domain (Figure [1A](#F1){ref-type="fig"}). However, for the purposes of the analysis described here, the exact origin of this chromosome is not important. The critical information is the presence of these mutations in the LD domain and the wild-type phenotype for droplet transport and Klar localization. Tai255.1 is a wild-type *D. melanogaster*strain isolated in 1983 at Ivory Coast \[[@B57]\]; it displays normal net droplet transport \[[@B58]\]. To generate the GFP-LD expressing flies, GFP was amplified from pEGP-C1 (Clontech) and cloned into the *Kpn*I and *Not*I sites of pUASp \[[@B54]\]. A tobacco etch virus (TEV) protease site (GAGAATTTGTATTTTCAGGGT) was generated by oligo nucleotide synthesis and cloned 3\' to the GFP gene. The LD domain was amplified from cDNA clone LD08331 \[[@B22]\] and cloned in frame 3\' to the TEV site. The resulting plasmid was injected into *Drosophila*embryos by Genetic Services, Inc. (Cambridge, MA). Transgenic flies were selected by eye color. In total, twenty lines mapping to the X, second or third chromosome were established. To express the fusion proteins, transgenic animals were crossed with lines carrying matβ4-Gal4-VP16 or Act5C-Gal4 drivers. TILLING, genomic sequencing, and sequence analysis -------------------------------------------------- TILLING analysis was performed by the Fly-TILL service as described \[[@B32]\]. In \~6000 strains from the Zuker collection \[[@B31]\], we screened a 1519 bp genomic region from the end of exon 12 through the coding region of exon 15ext. Nucleotide changes were uncovered in 23 lines; in two cases (Z3-1711 and Z3-3772), these changes mapped to exon 15ext. For these two strains, we sequenced PCR products encompassing exon 15ext as described below. The nucleotide changes observed in line Z3-3772 were due to changes on the balancer chromosome (see main text for details). DNA primers were created to bookend individual exons of *klar*piecemeal using annealing temperatures and GC content to determine the most effective oligo sequences (primer sequences available upon request). Purified DNA from adult flies was used to individually PCR amplify these genomic fragments. PCR products were depleted of free nucleotides with ExoSAP-IT and sequenced at the Life Sciences Core Laboratories Center at Cornell University. Sequencing results were compared to the canonical sequences available on FlyBase. To determine the pattern of evolutionary conservation in the LD domain, we first identified the likely *klar*exon 15 in the available genome annotations for the *Drosophila*and mosquito species accessible via the FlyBase BLAST server. We also identified related sequences from the *G. morsitans*genome project (Sanger Institute) as well as in a cDNA from the medfly *C. capitata*(GenBank \# [FG077614.1](FG077614.1)). In *Drosophila melanogaster*, exon 15ext follows immediately downstream of exon 15. In all 16 additional fly species examined, the corresponding DNA sequences downstream of exon 15 have the potential to encode proteins with significant similarity to the *D. melanogaster*LD domain (Figure [1B](#F1){ref-type="fig"}). These protein sequences were aligned with Clustal2. The helical wheel in Figure [1C](#F1){ref-type="fig"} was drawn using the helical wheel plotting script from the Zidovetzki laboratory, UC Riverside <http://rzlab.ucr.edu/scripts/wheel/wheel.cgi>. *In-vivo*centrifugation, fixation, immunostaining, and imaging -------------------------------------------------------------- Living embryos were centrifuged to separate lipid droplets from other cellular components, as described \[[@B35]\]. Embryos were either embedded in agar to keep them in a fixed orientation during centrifugation, or they were centrifuged in random orientations in microcentrifuge tubes filled with buffer, and the lipid-droplet layer was identified by its characteristic appearance by bright-field microscopy. To separate organelles by density in oocytes and nurse cells, females were centrifuged in buffer-filled microfuge tubes as described \[[@B11]\]. To stain lipid droplets, dechorionated embryos or dissected fly tissues were fixed in 4% formaldehyde in PBS for 10-15 min using standard procedures \[[@B59],[@B60]\]. For embryos, this treatment is sufficient to make the vitelline membrane permeable to Nile Red. After washing, these samples were suspended with 1% BSA in PBS and stained with Nile Red at 20 μg/ml. In some cases (Figure [7D, E, F](#F7){ref-type="fig"}), unfixed tissues were directly stained with Nile Red. For immunodetection of GFP or Klar, dechorionated embryos were heat fixed and devitellinized using standard heptane-methanol procedures \[[@B59],[@B60]\]. They were stained either with mouse monoclonal Klar-M as described \[[@B22]\] or with rabbit anti-GFP (Torrey Pines Biolabs) at 1:10,000. Before use, the anti-GFP antibody was exposed to heat-fixed wild-type embryos to remove cross-reacting antibodies. Two approaches were employed to examine GFP-LD fluorescence in living embryos. For confocal microscopy, embryos were hand-dechorionated, placed in halocarbon oil on a glass slide, and covered with a cover glass that was supported by spacers. For epifluorescence microscopy, embryos were placed into halocarbon oil on a glass slide. The halocarbon oil turns the chorion transparent (see Figure [3B](#F3){ref-type="fig"}). Micrographs were acquired on a Leica SP5 confocal microscope or a Nikon Eclipse E600 fluorescence microscope with a 4MP Spot Insight camera. Images were processed in Adobe Photoshop and assembled with Adobe Illustrator. Western analysis ---------------- For Western analysis, proteins were typically separated on a 10% SDS PAGE gel and transferred to PVDF membranes using standard Towbin or CAPS transfer. Mouse anti- alpha tubulin (Sigma-Aldrich) was used at 1:10,000, and mouse anti-GFP (Roche) at 1:1000. LSD-2 was detected with a rabbit polyclonal anti-serum \[[@B20]\] at 1:20,000. To consistently detect Klar β, this general procedure was optimized: Proteins were separated on 6% gels, and transferred in 25 mM Tris, 192 mM glycine, 10% methanol, 0.01% SDS to PVDF membranes (2 hrs at 100 V). Membranes were sequentially exposed to Klar-M (1:50, overnight at 4°C), rat anti-mouse IgG (1:1000; 1 hr at room temperature) and HRP-conjugated goat anti-rabbit IgG (1:1000; 1 hr at room temperature). Droplet purification -------------------- To generate samples enriched in lipid droplets, we adapted the protocol described previously \[[@B11]\]. For each genotype, 150 μl of embryos (0-3 hrs old) were dechorionated, resuspended in 300 μl TKM (50 mM Tris, pH 7.4, 25 mM KCl, 5 mM MgCl~2~) containing 1 M sucrose plus protease inhibitor cocktail (Sigma-Aldrich), and then mechanically disrupted on ice. The lysate was transferred to a fresh 1.5 ml tube and overlaid sequentially with 200 μl TKM containing 0.5 M sucrose, 200 μl TKM containing 0.25 M sucrose, and 400 μl TKM. After centrifugation at 1000 g for 5 min, 5000 g for 5 min and 13400 g for 10 min, the buoyant lipid droplets were collected from the top of the gradient. The amount of protein in the isolated lipid droplets was measured by Bradford protein assay (Quick Start, Bio-Rad) before solubilizing the lipid droplets in SDS-containing buffer for subsequent SDS-PAGE analysis. Fractions such prepared are similar to those described by Cermelli et al. \[[@B11]\]: the overall pattern of major Coomassie-stainable proteins is similar; the droplet protein LSD-2 and several histones are consistently enriched, and the cytoplasmic protein tubulin is absent (Figure [6B](#F6){ref-type="fig"}; Li and Welte, unpublished observations). Triglyceride measurements ------------------------- Embryos were collected for 1.5 hr, dechorionated with 50% bleach, and resuspended in triton salt solution \[[@B59],[@B60]\]. 200 embryos before cellularization stages were handselected, resuspended in 200 μl homogenizing buffer (0.01 M KH~2~PO~4~, 1 mM EDTA, pH 7.4), and mechanically disrupted. 40 μl of this lysate were mixed with 1 ml activated Triglyceride Reagent (Liquicolor Triglycerides, Stanbio), and triglyceride levels were determined according to the manufacturer\'s instructions. For each experiment, three independent samples were analyzed per genotype, and the data shown in Figure [5G](#F5){ref-type="fig"} are based on two independent experiments. Authors\' contributions ======================= YVY generated and characterized the GFP-LD transgenes, contributed to the functional analysis of *klar^MW^*, consulted on a range of technical issues, and helped to draft the manuscript. ZL performed the biochemical purification of lipid droplets and the triglyceride measurements. NPR performed Western analysis, immunostaining, and genomic sequencing. JE performed the bulk of genomic sequencing, including primer design. MAW conceived and designed the study, performed the imaging analysis, aligned sequences and drafted the manuscript. All authors read and approved the final manuscript. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **Motion of GFP-LD puncta in living embryos**. Images were acquired by confocal microscopy at 2.5 images per second. Playback at 12 frames per second. Scale bar = 7.5 μm. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 2 **Motion of GFP-LD puncta in living embryos**. Images were acquired by confocal microscopy at 1.35 images per second. Playback at 6 frames per second. Scale bar = 7.5 μm. ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ We thank the Bloomington *Drosophila*stock center for fly stocks, the *Drosophila*TILLING Project for performing the TILLING analysis, and the Zuker laboratory for generating and sharing the mutagenized third chromosome lines. We are grateful to Matthew Brockway and Joshua Geiger for help with immunostaining and sequencing, and to Gurpreet Arora for critical reading of the manuscript. This work was supported by start-up support from the University of Rochester and NIGMS grant GM64687 to MAW.

PubMed Central

2024-06-05T04:04:17.254975

2011-2-24

PMC3051914

Background ========== Primordial germ cells derived from the epiblast of pre-gastrulating embryos are the founder population of the future gametes. A unique attribute of PGC is the acquisition of totipotency, which is required for the generation of a new organism. Extensive epigenetic reprogramming of PGC underlies the capacity of these cells for acquiring totipotency \[[@B1],[@B2]\]. Genome-wide DNA demethylation in mouse PGC results in the complete erasure of methylation marks in single-copy and imprinted genes, and a moderate reduction in retrotransposons and other repetitive elements \[[@B3]-[@B5]\]. This demethylation is a unique reprogramming event, most of which is restricted to a short window of time between E10.5-13.5 in the mouse, and is critical for erasing epigenetic memory and preventing the transmission of epimutations to the next generation \[[@B3],[@B4],[@B6]\]. Just before these major DNA demethylation events, changes in histone marks contribute to the establishment of a distinctive chromatin signature in PGC \[[@B1]\]. Reduction in H3K9me2 is followed by an increase in H3K27me3 levels in migrating mouse PGC between E7.75 and E8.75, at a time when these cells undergo G2 arrest and transcriptional quiescence \[[@B3],[@B7]\]. When the PGC reach the genital ridges they undergo major conformational changes including loss of linker histone H1 and replacement of nucleosomal histones \[[@B8]\]. Together, these dynamic events define a critical period for the epigenetic reprogramming of the mouse germ line. Most of our knowledge in mammalian germ line development originates from studies in mice. A recent study demonstrated that mouse and rat embryonic germ (EG) cells share common ground state properties, suggesting that the molecular circuitry of pluripotency is conserved in rodents \[[@B9]\]. Very little is known about the sequence of events during PGC development in other species \[[@B10]\], and studying these events in non-rodents is important for establishing the conserved mechanisms of PGC development in mammals. The pig is a good model for studying mammalian development, due to the developmental and physiological similarities with most other mammals, including humans. Furthermore, the pig is also excellent for modelling human disease, and therefore great effort has been devoted to develop efficient genetic modification technologies in this species \[[@B11]\]. Pig EG cell lines derived from gonadal PGC of E28-35 embryos have been used to generate transgenic animals \[[@B12]\]. In the pig, migratory PGC can be identified in the dorsal mesentery of the hindgut in E18-20 and the colonisation of the genital ridges occurs around E23-24 \[[@B13]\]. However, the events characterizing the epigenetic reprogramming of pig PGC remain largely unexplored. A recent report showed demethylation of the differentially methylated domain of *IGF2-H19*gene cluster and centromeric repeats between E24-E28 followed by de novo methylation in male PGC by E30-E31, demonstrating that major DNA demethylation occurs in the pig germ line shortly after colonizing the gonadal ridges \[[@B14]\]. There is also evidence that the imprinted gene *PEG10*is biallelically expressed in EG cells derived from E27 embryos, indicating that demethylation has occurred \[[@B15]\]. In the present study we extended these initial observations by investigating the methylation reprogramming of imprinted genes, retrotransposons and genome-wide histone modifications in migratory and gonadal PGC. We show that imprinted gene demethylation occurs asynchronously in pig PGC, with *IGF2-H19*demethylation not beginning before E22, and *IGF2R*demethylation already starting in male PGC at this time point. We also show that SINE repeats undergo moderate progressive demethylation between E22-E31. Finally, we show that migratory pig PGC undergo reprogramming of H3K27me3 and H3K9me2 concurrent with a G2 arrest. Results & Discussion ==================== OCT4 expression identifies the early pig germ line -------------------------------------------------- In mice, *Oct4*(also known as *Oct3/4*and *Pou5f1*) plays a critical role during the specification of PGC precursors \[[@B16]\] and is required for germ cell survival in late migratory stages \[[@B17]\]. Cell type specific expression of this marker has been demonstrated in migratory PGC \[[@B18]\] and can be used to isolate these cells using fluorescence activated cell sorting (FACS) \[[@B8]\]. During pig development, OCT4 expression is detected in the pluripotent epiblast and becomes confined to migratory PGC by E17 \[[@B19]\]. To determine the suitability of OCT4 for identifying pig germ cells in late migratory and early gonadal stages we performed antibody based staining of OCT4 in combination with SSEA-1, another known germ line marker \[[@B13]\], in sections of embryos between E17 and E42 (Figure [1](#F1){ref-type="fig"}). In E17 embryos, OCT4/SSEA1 cells were identified mostly in the hindgut with a few of them approaching the position of the genital ridges, which has not yet formed (Figure [1A](#F1){ref-type="fig"}). The PGC are large spherical cells with strong specific OCT4 nuclear localisation and SSEA-1 staining of the plasma membrane (Figure [1F](#F1){ref-type="fig"}). In E22 PGC, which are positioned in the primordium of the genital ridges, we detected clear OCT4/SSEA1 staining (Figure [1B,G](#F1){ref-type="fig"}). The genital ridges begin to take the shape of early gonads at E25, a process that continues in E31 embryos (Figure [1C,D](#F1){ref-type="fig"}). PGC maintain OCT4/SSEA-1 staining in E25 PGC, however, SSEA-1 specific staining was noticeably weaker in many of the OCT4 positive cells in E31 PGC (Figure [1H,I](#F1){ref-type="fig"}). By E42 the tissue of the early gonads has begun organising. At this age, germ cell cords are present in both male and female gonads, though larger and more regular in males. Male gonads are rounded with only a slim cellular connection to the mesonephros \[[@B20]\]. The specimen shown here fulfilled the criteria of male gonad with a characteristic attenuated appearance of the mesonephric connection and well defined large cords (Figure [1E](#F1){ref-type="fig"}; Additional File [1](#S1){ref-type="supplementary-material"}). The expression of the two markers was somewhat inconsistent and several putative germ cells expressed only one of the two markers (not shown). Most cells, however, still expressed both (Figure [1J](#F1){ref-type="fig"}). Down regulation of Oct4 is seen in the mouse female germ line around E17.5 coinciding with the time of entry into meiosis. In males, Oct4 expression, however, does not decrease \[[@B18]\]. In our study we see down regulation of this marker in some individual male germ cells (data not shown). ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Identification of PGC by immunostaining**. The top panel shows transversal sections of porcine embryos in the area where the PGC are found; hind gut of E17 (Figure 1A), genital ridges or primitive gonads of E22 (Figure 1B), E25 (Figure 1C), E31 (Figure 1D) and E42 (Figure 1E). Arrows indicate the PGC containing tissue (hind gut, genital ridges or gonads). Arrowhead depicts the mesonephric connection. The bottom panel shows double fluorescence immunostaining of the OCT4 and SSEA-1 in transversal sections of porcine embryos of the ages E17 (Figure 1F), E22 (Figure 1G), E25 (Figure 1H), E31 (Figure 1I) and E42 (Figure 1J). 5-7 PGC containing sections of one embryo of each stage were stained. Scale bars = 10 µm :::  ::: These results show that OCT4 is expressed in migratory and early gonadal PGC and can be used as a reliable marker of pig PGC between E17-E31. Furthermore, it is expressed in the majority of putative germ cells at E42. We therefore used OCT4 staining followed by FACS sorting to obtain purified PGC at different developmental stages. Reprogramming of gender specific methylation imprints at CTCF3 in *IGF2-H19*gene cluster is initiated after germ cell arrival to the genital ridges --------------------------------------------------------------------------------------------------------------------------------------------------- Demethylation of imprinted genes occurs in PGC located in the genital ridges between E10.5-E13.5 in mice \[[@B4]\], and this event appears to progress synchronously for most imprinted genes \[[@B21]\] including the *Igf2-H19*gene cluster \[[@B22]\]. To determine the timing of demethylation of the paternally imprinted control region of the pig *IGF2-H19*gene cluster we examined this region after bisulfite conversion of DNA extracted from purified PGC. Our analysis focussed on one of the binding sites for the insulator protein CTCF, since this site has previously been shown to be differentially methylated in somatic tissues and reprogrammed prior to E24 during porcine germ line development \[[@B14]\]. We determined that the level of methylation in PGC at the time of arrival to the genital ridges (E22) was not below the 50% expected for a monoallelic methylated sequence, indicating that DNA demethylation has not initiated at this stage in male and female PGC (Figure [2](#F2){ref-type="fig"} and data not shown). Samples from pig brain showed a typical pattern of differential methylation for this region (56.06%), as expected for somatic cells. In contrast, DNA methylation decreased significantly in female PGC at E25 (27.27%) and was followed by further reduction at E29-31 (11.04%) and E42 (6.99%). The results indicate that demethylation of CTCF3 begins in PGC shortly after they arrive to the genital ridges and de novo methylation is not resumed in female PGC at E42. This pattern of imprint demethylation follows closely the dynamic reported in the mouse differentially methylated domain of *Igf2-H19*\[[@B23]\]. Re-establishment of imprints occurs in mouse male germ cells from E14.5 starting with the paternal allele \[[@B24]\]. De novo methylation of this region occurs by E31 in male pig PGC \[[@B14]\]. Lack of polymorphism information restricted our capacity to establish the dynamic of paternal allele methylation, as established in mice. However, the evidence that i) CTCF3 is fully methylated in pig sperm and unmethylated in oocytes \[[@B14]\], ii) biparental embryos show almost complete demethylation in female PGC between E25 and E42, and iii) de novo methylation occurs in male PGC, supports the idea that the paternal allele is subject to methylation reprogramming in the pig. ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Methylation dynamics of the *IGF2-H19*gene cluster**. Methylation of the CpG regulatory box CTCF3 region for *IGF2-H19*gene cluster was investigated by bisulfite sequencing. A DNA pool from germ cells of 6-8 embryos of each gender in the stages E22, E25, E29-31 and E42 was bisulphite converted and used for the analysis after one PCR reaction and subsequent transformation and cloning. The position of the CTCF3 is indicated on the schematic representation of the gene cluster and the sequence of the investigated fragment after bisulfite mutagenesis is showed below. Empty and filled circles indicate unmethylated and methylated CpGs, respectively. 12-18 clones were analysed from each group. Each horizontal line represents one clone. Percent methylation mean ± SEM for each group is indicated below. :::  ::: Reprogramming of gender specific imprints of the *IGF2R*gene is initiated in porcine germ cells prior to arrival in the genital ridges -------------------------------------------------------------------------------------------------------------------------------------- The *IGF2R*gene is imprinted in rodents, artiodactyls and marsupials, but is biallelically expressed in primates \[[@B25],[@B26]\]. Imprinting regulation in the mouse *Igf2r*depends on two differentially methylated regions (DMRs): DMR1 located in the promoter region and DMR2 in intron 2 (DMR2), representing the primary imprinting signal for this gene \[[@B27],[@B28]\]. Although it has been shown that *IGF2R*is imprinted in the pig \[[@B26],[@B29]\], there is no information on the imprinting control region for this gene. We performed this analysis from the recently published pig genome sequence. The putative porcine *IGF2R*gene is located on chromosome 1 between 8.50 Mb and 8.60 Mb (Additional File [2](#S2){ref-type="supplementary-material"}). The gene structure is very similar to orthologues from other species such as human, mouse and cow, but alignments showed that while the mRNA sequences are highly homologous, the intron sequences demonstrate low conservation between species (data not shown). We confirmed that the porcine promoter region contains a CpG island spanning the entire predicted exon 1 as seen in other described mammalian *IGF2R*genes \[[@B30],[@B31]\]. Furthermore, we identified the large CpG island of intron 2, also present in human, mouse, dog, sheep, and cow, but absent in chicken, lemur, tree shrew, opossum or platypus \[[@B26],[@B31]\]. Additional File [2B](#S2){ref-type="supplementary-material"} shows CpG distribution in the two predicted CpG islands. In the mouse, the CpG island in the promoter region of the *Igf2r*is methylated in the repressed paternal allele, but unmethylated in the active maternal allele. This DMR is unmethylated in both alleles in opossum and domestic dog despite the imprinted status of the gene \[[@B31],[@B32]\]. Here we examined the methylation status of the porcine DMR1 in fetal brain by direct sequencing of bisulfite converted DNA and found no CpGs methylation (data not shown). We confirmed these findings by sequencing individual clones from brain, heart and liver DNA (n = 12, 12 and 12 respectively), which show almost complete demethylation (Figure [3](#F3){ref-type="fig"}). To exclude the possibility of PCR bias favouring unmethylated DNA we methylated genomic DNA using Sss1 prior to bisulfite conversion. A PCR fragment was obtained from the methylated sample (not shown), indicating that our observations with unmethylated DNA are not due to PCR bias. These results indicate that DMR1 in the pig *IGF2R*is not differentially methylated. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Methylation dynamics of the *IGF2R*gene**. The two CpG islands of the *IGF2R*gene are known from other species as Differentially Methylated Region 1 (DMR1) and 2 (DMR2). A fragment of these regions was investigated for methylation of CpGs (See Additional file [2](#S2){ref-type="supplementary-material"}). The positions of the DMRs are indicated on the schematic representation of the gene and the sequences of the investigated fragments after bisulfite mutagenesis are showed above and below, respectively. DNA from liver and heart of an E45 embryo and a pool of DNA from ten E31 brains were analysed for DMR1. A DNA pool from germ cells of six-eight embryos of each gender in the stages E22, E25, E29-31 and E42 was used for the analysis of DMR2. Furthermore, DNA pools from a sperm sample and from ten E31 brains were included. The DNA was bisulphite converted and used for the analysis after one PCR reaction and subsequent transformation and cloning. Empty and filled circles indicate unmethylated and methylated CpGs, respectively. 11-15 clones were analysed from each group. Each horizontal line represents one clone. Percent methylation mean ± SEM for each group is indicated below. :::  ::: We next examined the methylation status of the DMR2 located in intron 2, which is maternally methylated in mice \[[@B33]\], human \[[@B34]\], cattle \[[@B35]\] and sheep \[[@B36]\]. Our analysis from bisulfite converted brain DNA showed that this region is differentially methylated (Figure [3](#F3){ref-type="fig"}), suggesting that this region plays a role in imprinting control of the pig *IGF2R*. We used this fragment to investigate the dynamic methylation reprogramming in purified PGC from porcine embryos of different developmental stages. In mice, DMR2 demethylation of *Igf2r*begins as early as E9.5 in migratory PGC \[[@B37]\], indicating that a gonadal environment is not needed to initiate DNA demethylation. We found that only male porcine PGC from E22 embryos show low levels of methylation with only 11.36% methylated CpGs. Gender specific differences were not observed in the methylation level of this gene in migratory mouse PGC \[[@B37]\]. Importantly, although at this developmental stage the gonadal primordium has the characteristics of an indifferent gonad \[[@B38]\], *SRY*and its downstream target *SOX9*are expressed in the migratory path of pig PGC between E21-E23 \[[@B39],[@B40]\], indicating that at the molecular level sexual dimorphism has already been established. Thus, demethylation of *IGF2R*in male PGC provides evidence supporting sex specific differences in the germ cells at this stage. The levels of methylation remained low in mature pig sperm (Figure [3](#F3){ref-type="fig"}), in agreement with *Igf2r*methylation reported in mice \[[@B41]\] and sheep sperm \[[@B42]\]. Interestingly, early gonadal PGC from female E22 and E25 embryos showed approximately 50% methylation, indicating that demethylation had not yet initiated. In PGC from female E29-31 embryos this DMR2 was almost completely demethylated, and by E42 the methylation level reached 63%, indicating de novo methylation by this stage (Figure [3](#F3){ref-type="fig"}). Since the same E42 samples were used to analyse the methylation status of *H19*, which is almost completely unmethylated in PGC (Figure [2](#F2){ref-type="fig"}), we think it is unlikely that the samples were contaminated with somatic cells. In mice the *Igf2r*DMR2 remains unmethylated in female germ cells until after birth, where de novo DNA methylation is acquired during oocyte growth \[[@B43],[@B44]\]. The precocious de novo methylation observed in female pig PGC suggests that acquisition of DNA methylation in the *Igf2r*is controlled differently in the two species. In line with our observations, a recent report showed that sheep oocytes derived from small preantral follicles possess a monoallelic pattern of methylation \[[@B42]\], indicating that precocious *IGF2R*methylation also occurs in sheep. Together, our results demonstrate that imprinted DMR2 of *IGF2R*in the pig undergoes methylation reprogramming, with a precocious onset of demethylation in male migratory PGC, and early de novo methylation initiated in female germ cells before birth. Short Interspersed Nuclear Elements are partially demethylated in the developing germ line ------------------------------------------------------------------------------------------ Retrotransposable elements are abundant repeat sequences in the genome subject to methylation reprogramming during early embryo development \[[@B45]\] and in mouse PGC arriving to the primitive gonad \[[@B4],[@B46]\]. In the porcine genome, they are diffusely distributed in the euchromatic chromosomal regions, i.e. away from centromeric DNA repeat blocks \[[@B47]\]. Demethylation of repeats, such as SINE, occurs during pig preimplantation development \[[@B48]\], however there is only limited information on how these repeats are reprogrammed in PGC. Analysis of centromeric DNA repeats shows that these sequences are demethylated extensively between E26-E31 in female PGC, however male PGC show only moderate demethylation by E28 and are remethylated by E31 \[[@B14]\]. We investigated the methylation dynamics of SINE repeats after bisulfite sequencing analysis of DNA obtained from PGC. Because of the high polymorphism within repeat sequences, individual clones did not have identical numbers of CpGs. Thus, the total methylation level for each examined group was calculated. The methylation level was investigated in gender separated DNA, but since we found no differences between genders, the data presented represents the collective data (Figure [4](#F4){ref-type="fig"}). SINE repeats were highly methylated in control DNA from brain of E31 embryos (74.4%). In PGC we detected lower levels of methylation in E22 (58.0%) and E25 (56.8%), reaching the lowest level E29-31 (26%). This was followed by an increase at E42 (56.1%), indicating that de novo methylation had resumed by this time. The dynamic demethylation observed in our experiments are in agreement with the overall pattern of DNA demethylation observed for LINE1, SINE and other repeats such as IAPs in mouse gonadal PGC between E11.5-E13.5 \[[@B4],[@B5],[@B46]\]. However, the interval needed for demethylation of repeats in the pig appears to be extended over a period of 8-10 days from around E22-E31. ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Methylation dynamics of short interspersed repeats**. Short Interspersed Nuclear Elements (SINE) were investigated for their methylation level in the porcine germ line. A DNA pool from germ cells of 13-16 embryos of the stages E22, E25, E29-31 and E42 was bisulphite converted and used for the analysis after one PCR reaction and subsequent transformation and cloning. 11-24 clones were analysed from each group. Due to high mutagenic rate in this type of elements, single clones are not identical regarding number and position of CpGs. The mean methylation level was calculated as suggested by Yang et al. \[[@B52]\] and results shown in the diagram. The sequence of an example of the investigated fragments after bisulfite mutagenesis is shown. Bars on the columns indicate SEM. E: embryonic stage. :::  ::: The overall reduction in methylation of SINE repeats is lower compared to the reported demethylation of centromeric repeats, which show extensive and gender specific demethylation in PGC at similar stages \[[@B14]\]. This suggests that the different genomic contexts of interspersed versus centromeric repeats can impact on the demethylation machinery in PGC. Cell cycle distribution and dynamics of histone modifications in porcine PGC ---------------------------------------------------------------------------- Epigenetic reprogramming in the mouse germline includes changes in histone modifications occurring before the cells arrive to their definitive location in the gonadal ridges \[[@B1],[@B2]\]. During mouse PGC migration through the hindgut a progressive loss of di-methylation of lysine 9 on histone 3 (H3K9me2) takes place, reaching almost complete erasure by E8.75 \[[@B7]\]. The reduction in H3K9me2 precedes the increase in the levels of the repressive tri-methylation of lysine 27 on histone 3 (H3K37me3) mark, which is established from E8.25 and maintained in PGC until E10.5 \[[@B7],[@B8]\]. The changes in histone modifications occur in PGC arrested in G2 of the cell cycle, defining a clear window of time for epigenetic reprogramming \[[@B2]\]. There is currently no information on the similarities in epigenetic reprogramming of the germ cells in other mammals. We therefore investigated whether these histone marks are reprogrammed in migratory pig PGC between E15-E21 (Figure [5A-X](#F5){ref-type="fig"}). We found that H3K27me3 was higher in PGC migrating through the hindgut of E15 embryos than their somatic neighbours (Figure [5A-D](#F5){ref-type="fig"}), and this mark remained high in E17 and E21 (Figure [5E-L](#F5){ref-type="fig"}). By contrast, H3K9me2 staining was reduced in PGC compared to their somatic neighbours in E15 (Figure [5M-P](#F5){ref-type="fig"}) and in E17 (Figure [5Q-T](#F5){ref-type="fig"}), and was completely erased from PGC in E21 (Figure [5U-X](#F5){ref-type="fig"}). We find that acquisition of H3K27me3 occurred before H3K9me2 was completely erased, suggesting that the extended window of time required for histone remodelling in the pig allows for a continuum in the sequence of events. ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **Cell cycle distribution and H3K27 trimethylation and H3K9 dimethylation in porcine PGC**. Reprogramming of histone modifications H3K27me3 and H3K9me2 was investigated by immunohistochemistry in paraffin sections of porcine E15 (n = 1, Figure 5A-D, M-P), E17 (n = 1, Figure 5E-H, Q-T) and E21 (n = 1, Figure 5I-L, U-X) embryos. Micrographs show the histone modifications in green (Figure 5A, E, I, M, Q, U). PGC are identified by OCT4 expression in red and counterstained with Hoechst for DNA stain in blue. Arrowheads mark PGC. Figure 5Y shows the cell cycle distribution after FACS analysis of PGC during development (n = 13-24 for each stage). Arrowheads denote the G1 and G2 peaks. Scale bars = 10 μm. :::  ::: Next, we examined the DNA content of FACS sorted PGC to determine their cell cycle stage. The earliest stage of PGC that we were able to isolate was from E17 embryos, which showed a great proportion of cells in G2 (44%). This distribution resembles the patterns reported for murine PGC at about E9.75, a time point just following the G2 arrest observed between E7.5-E9 in the PGC population \[[@B7]\]. In contrast, the porcine PGC from E22, E25 and E29-31 show nearly identical distribution displaying a clear G1 peak, a small broad S phase and a minor G2 peak (15-21%) (Figure [5Y](#F5){ref-type="fig"}). This cell cycle distribution resembles that of mouse somatic cells \[[@B49]\], and that of the somatic fraction of the porcine cell suspension used for sorting in this study (data not shown). These results show that the dynamic changes in H3K27me3 and H3K9me2 in pig PGC correspond overall with the pattern described for mouse migratory PGC \[[@B3]\]. It is interesting however, that we observe these dynamic changes occurring over a longer period of about 6 days, which is more than three times the interval required in mice. The protraction of this process is likely due to the slower development in the pig. Conclusions =========== The present study establishes that pig migratory and gonadal PGC undergo an overall sequence of epigenetic reprogramming remarkably similar to that described in mice. First, gonadal PGC undergo extensive demethylation in the imprinted *IGF2-H19*cluster. Secondly, the DMR2 of *IGF2R*is demethylated precociously in pre-gonadal PGC, specifically in male PGC. Thirdly, retrotransposable elements undergo progressive demethylation in PGC colonizing the primitive gonad. Finally, the changes in DNA methylation are preceded by reprogramming of H3K9me2 and H3K27me3 in migratory PGC. Although the period of time required for accomplishing these events is more than three times that required in mice (Figure [6](#F6){ref-type="fig"}), the dynamic reprogramming occurs at equivalent developmental stages as demonstrated in rodents, indicating that the difference probably stems from the fact that development is slower in the pig. Together these results support the idea that the epigenetic reprogramming of PGC is conserved in mammals. The extended time frame provides a useful window of opportunity for detailed dissection of the sequence of events leading to the reprogramming of PGC in slow developing embryos. For instance, the precocious demethylation observed for *IGF2R*in male pig PGC, highlights the advantage of having an extended window of time for studying these reprogramming events. Finally, a better understanding of the dynamic events during germ cell establishment may contribute to designing new strategies for the derivation of EG cells. ::: {#F6 .fig} Figure 6 ::: {.caption} ###### **Diagramatic representation of the dynamic events during reprogramming of the germ cells in the mouse and the pig**. Schematic overview of the events studied in the current report compared with the same events in mouse PGC. Erasure of *Igf2/H19*imprints occurs in gonadal PGC of both species. Male pig migratory PGC lose *IGF2R*imprints before reaching the gonads, in contrast to the findings in mice \[[@B37]\], where demethylation occurs at the same time in male and female PGC after entering the gonad. Remodeling of repetitive sequences follows a similar dynamic in mice and pig PGC, with partial demethylation followed by remethylation after arrival to the genital ridges. The major changes in H3K9me2 and H3K27me3 occur in migratory PGC prior to their arrival to the genital ridge and are concurrent with the G2 arrest. The timelines for embryonic age are aligned according to the time points of PGC specification and arrival in the genital ridges for both species. Coloured boxes on the left hand side show the level of each epigenetic mark in somatic cells. Coloured lines depict presence of the indicated epigenetic marks at respective time points, and the lack of colour reflects the absence of the marks. :::  ::: Methods ======= Embryos collection ------------------ All the procedures involving animals have been approved by the School of Biosciences Ethics Review Committee (University of Nottingham, UK). Embryos were collected from British Landrace sows or Yorkshire X Landrace gilts artificially inseminated or mated 15 (n = 1), 17 (n = 14), 18 (n = 13), 21 (n = 1), 22 (n = 15), 25 (n = 14), 29 (n = 4), 31 (n = 11) and 42 (n = 18) days prior to embryo collections. Embryos were recovered from the pregnant uteri within between 30 min and 2 hrs of slaughter. Immunohistochemistry -------------------- One embryo of each of the stages E15, E17, E21, E22, E25, E31 and E42 were fixed in 4% paraformaldehyde (PFA) in PBS overnight at 4°C. Tissue was hereafter dehydrated through increasing ethanol concentrations to xylene and embedded in paraffin. Transversal sections of 4-5 μm thickness containing the PGC were collected on SuperFrost Plus microscope slides (Menzel, Braunschweig, Germany). Tissue preparation for methylation analysis ------------------------------------------- Hindgut or genital ridges/early gonads were dissected from each embryo and roughly chopped before treatmentwith 0.1% collagenase/0.1% dispase for 11 minutes and subsequently 1 minute in 0.25% trypsin with EDTA at 37°C. Tissue was disintegrated by gentle pipetting after addition of Dulbecco\'s Modified Eagle Medium (DMEM) with 4-10% fetal bovine serum (FBS) and centrifuged 5 minutes at 600 × g. Cells were resuspended in FBS with 10% DMSO and stored in liquid nitrogen up to 10 weeks. Sequence homology ----------------- The putative *IGF2R*gene was identified by aligning the porcine partial coding sequence (Accession number AF339885) to the porcine genome (assembly version 8, Pre.Ensembl). The promoter region and exon 1 of the gene were deduced using the annotated *IGF2R*gene sequences of Bos Taurus (Accession number NM174352). The putative DMRs were identified by the freeware CpG Island Searcher \[[@B50]\]. DNA extraction, gender determination and bisulfite conversion ------------------------------------------------------------- Genomic DNA was extracted from porcine embryo tissue using Blood and Tissue DNA extraction kit (Qiagen, Hilden, Germany). The amount of extracted DNA was quantified on a NanoDrop spectrophotometer (Thermo Scientific, Waltham, MA, USA) and a maximum of 1 μg was used for bisulfite conversion. For gender determination we followed the protocol reported by \[[@B51]\]. Primers used are presented in Table 1. For bisulfite mutagenesis DNA was converted with EZ DNA Methylation-Gold kit (Zymo Research, Orange, CA, USA) and eluted in 10 μl nuclease free water following manufacturer\'s instructions. PCR amplification of bisulfite converted DNA -------------------------------------------- The bisulfite converted DNA was amplified by PCR. All primers, annealing temperatures and sizes of products are listed in Table 1. The PCR amplification consisted of a denaturing step of 5 min at 95°C followed by 50-52 cycles of 30 sec at 94°C, 30 sec at 57°C - 64°C and 1 min at 72°C. Finally, there was an extra elongation step of 15 min at 72°C. The amplified products were analysed by electrophoresis on 2% agarose gels. The amplified products were sequenced by direct sequencing after purification with Qiagen Gel Extraction kit (Qiagen, Hilden, Germany) or as individual clones after transformation using pGEM-T EasyVector System (Promega, Charbonniéres, France) in Escherichia coli DH5α. The obtained nucleotide sequences were analysed with the freeware Chromas Lite (Technelysium Pty Ltd). The methylation level of repeat sequences was calculated using the approach proposed by Yang et al. \[[@B52]\]. The method is based on the assumption that the mutation rate for CpG → TpG is identical on the two strands. Briefly, the number of potential CpGs in the investigated sequence was identified for all positions where one or more of the clones had a methylated CpG (See Table 1 for approximate numbers of investigated CpGs). Unmethylated CpGs were then calculated as TpGs deducted the number of TpAs (representing TpG mutations on the opposite strand) in the potential CpG positions. The efficiency of the genomic DNA conversion was evaluated by the number of non-converted non-CpG cytosines and no clones carrying more than one of these were included in the analyses. Immunohistochemistry on PFA fixed, and paraffin embedded tissue --------------------------------------------------------------- Sections were deparaffinated in xylene and rehydrated through descending concentrations of ethanol. The epitopes were demasked by 15 minutes microwave boiling of the slides in TE-buffer (0,01 M Tris, 0,001 M EDTA), pH 8.0 (AppliChem) or 0.01 M citrate buffer (pH 6.0) followed by 15 minutes cool down and 15 minutes wash in demineralised water. Tissue was permeabilised in 1% Triton X-100, blocked in 2% BSA/PBS prior to 1 hour incubation with primary antibodies; rabbit monoclonal anti-H3K27me3 (Upstate; 1:200), mouse monoclonal anti-H3K9me2 (Abcam, 1:200) and goat polyclonal anti-OCT3/4 (SantaCruz; 1:200). Negative controls were incubated in blocking buffer. After extended washes, the sections were incubated for 40 minutes with secondary antibodies; Alexa Fluor ^®^594 conjugated donkey anti-goat IgG (Invitrogen; 1:250), Alexa Fluor ^®^488 conjugated donkey anti-rabbit IgG (Invitrogen; 1:250) and Alexa Fluor ^®^488 conjugated donkey anti-mouse IgG (Invitrogen; 1:250). For chromogenic detection the ABC technique was performed using the Vectastain Elite ABC kit (Vector Laboratories, Peterborough, U.K.) with DAB (Vector Laboratories, Peterborough, U.K.) as a substrate to visualise the positive cells. The sections were counterstained with haematoxylin and mounted using DPX mounting media (VWR International Ltd., Poole, U.K.). For immunofluorescence slides were mounted in Fluorescence Mounting Medium (DakoCytomation) and pictures of areas containing PGC were captured in 40× magnification with Leica DMRB fluorescence microscope through Leica DFC350FX camera. Immunocytochemistry on ethanol fixed cell suspensions ----------------------------------------------------- Cell suspensions were thawed and added DMEM medium with 10% FBS. The cells were spun down and resuspended in medium twice to wash out DMSO before ice cold 99% ethanol was added dropwise to a final concentration of 70%. Cells were fixed at -20°C for 20 min. Before fixation, the suspension was filtered through a 30 μm nylon mesh (Miltenyi, Bergisch Gladbach, Germany) to ensure single cell suspension. Cells were washed twice in PBS with 0.1% Tween-20 and 1% BSA, permeabilised 30 min in 2% Triton X 100 with 0.1 mg/ml RNase A. The cells were resuspended in 5% BSA in PBS and incubated 1 hour 4°C to block unspecific antibody binding. Cells were incubated with goat anti-OCT3/4 antibody over night at 4°C (SantaCruz, 1:500 in blocking buffer), washed twice and incubated 1 hour RT with Phycoerythrin (PE)-conjugated donkey anti-goat IgG (AbCam, 1:100 in blocking buffer). Finally, the cells were washed three times before added 7-amino-actinomycin D (Invitrogen) to a final concentration of 4 μM. Cell suspensions were stored cold and in the dark until analysis. Negative controls were treated identically but incubated in blocking buffer instead of either the first or both antibodies. In addition, cells of the human embryonic kidney 293T cell line were used as negative cell samples while mouse embryonic stem cells were used as positive cell samples for adjustment of the flow cytometer. Fluorescence-activated cell sorting (FACS) analysis --------------------------------------------------- Cell suspensions were analysed on an Altra Flow Cytometer (Beckman Coulter, Brea, CA, USA). Signals for forward scatter, side scatter and fluorescence (PE for OCT4 and 7-AAD for DNA content) were collected for a minimum of 50000 cells in each group. Representative FACS plots are shown in additional file [3](#S3){ref-type="supplementary-material"}. Data were analyzed using WinMDI (<http://facs.scripps.edu/software.html>; authored by Dr. J. Trotter (The Scripps Research Institute, California, USA), with FSC/SSC and pulse width gating to exclude doublets. Cells were sorted on the basis of their OCT4 expression into a negative and a positive sample. The positive samples contained a minimum of 500 putative PGC. Cell cycle analysis was carried out using the freeware Cylchred (Dr. T. Hoy, Cardiff University, School of Medicine (Cardiff, UK) to give the proportion of cells in each phase of the cell cycle. Authors\' contributions ======================= SMWH conceived and designed the study, performed experiments and wrote the paper. NC performed gendertyping and bisulphite sequencing analysis. DAC contributed with sample collection and immunocytochemistry. PDT participated in the design and coordination of the study. RA conceived, designed and coordinated the study, performed cloning experiments and wrote the paper. All authors read and approved the final manuscript. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 **Germ cell cords in a male E42 pig gonad**. A section of a male gonad shows OCT4 staining (brown) in germ cells organized into testicular cords. Scale bar 20 μm. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 2 **Representation of the IGF2R gene**. **A**. The exon/intron structure of the coding region is indicated by red bars and connecting lines, respectively. The coding sequence is positioned on the reverse strand of chromosome 1. The graph below shows the CG content of the sequence. Two CpG islands are identified (asterisk) in the promoter region and intron 2, respectively (Modified figure from <http://www.ensembl.org>). These positions correspond with CpG islands known from other species, and was used for the methylation analysis in the present study. **B**. shows the two islands identified on <http://www.cpgislands.com> each, with indication of the position of the bisulfite primers used (blue arrows). The position of exon 1 also is indicated. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 3 **FACS plots of sorted PGC**. Porcine PGC were sorted on the basis of their specific OCT4 expression. Sorting was managed using the software WinMDI through manually determined gates for the different populations of cells. Representative plots from the sorting are shown for cell suspensions from embryos E22, E25 E29, E31 and E42. The square (R2) in the plot indicates the OCT4 positive gates. Plots show OCT4 staining intensity versus linear forward scatter. ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ SMWH was supported by grants from K. Hoejgaards Foundation, N. & F.S. Jacobsens Foundation, C. & O. Brorsons travel grant for younger scientists, the joint Foundation between S. Chr. Soerensens & wifes Memory Foundation, the Association of Farmers associations of Jutland, The Foundation J. Skrikes Establishment, and G. J. Soerensens & wifes Foundation. DAC was supported by scholarship from CONACYT-Mexico. Part of this study was supported by grants from The University of Nottingham and the Royal Society to RA.

PubMed Central

2024-06-05T04:04:17.260027

2011-2-25

PMC3051915

Background ========== The formation of the vascular system is essential for nutrient and waste transport in the growing embryo. In mice, the developing vasculature initially forms in intraembryonic and extraembryonic regions. In the extraembryonic yolk sac at approximately E7.0-7.5, angioblasts are formed from the differentiation of mesodermal cells. These angioblasts differentiate into endothelial cells, elaborate cell contacts, and lumenize into simple tubes; resulting in the formation of a capillary plexus network \[[@B1],[@B2]\]. The simple plexus of the yolk sac is remodeled and refined after E8.5 to form the larger diameter vessels. During this process, extensive movements of endothelial cells within the plexus occur through a process termed intussusceptive arborization \[[@B3]\], reallocating cells from the capillaries to larger vessels, to assemble a more complex vasculature network \[[@B4],[@B5]\]. This process forms the vitelline arteriole and venule, which participate in the contiguous blood flow with the embryonic vasculature, concomitant with the initiation of flow after E9.0. Although likely context dependent, vessel remodeling also occurs in the adult, during wound healing, reproductive cycling, and tumor progression \[[@B6]\]. More work needs to be done to define the shared and distinct regulatory paths that control vascular differentiation in the various sites of development and in the adult. Both vasculogenic and angiogenic processes are highly regulative, and under the control of a number of signaling pathways, including the vascular endothelial growth factor (VEGF) pathway, the Notch pathway, and the transforming growth factor-β (TGF-β) pathway, among others \[[@B7]-[@B10]\]. Notch signaling is an evolutionary conserved pathway and a determinant of cell fate \[[@B11]\]. Four Notch receptors (Notch 1-4) exist in mice and human along with five ligands (Jagged1 and -2, and Dll1, -3, and -4) \[[@B12]\]. The Notch receptors are activated upon ligand binding, which initiates the proteolysis of its intracellular domain (N-ICD). The N-ICD translocates to the nucleus where it interacts with a family of DNA-binding proteins, termed recombination signal-binding protein for immunoglobulin kappa J region (RBPJ; also known as C-promoter binding factor 1, CBF1), forming a transcriptional activator complex at the regulatory elements of target genes, thereby directing changes in gene expression transcription \[[@B12]\]. Much work has been done to define the roles of the Notch signaling pathway during vascular differentiation. *Notch1*, *Notch4*, *Dll4*, *Jagged1*, and *Jagged2*are all expressed in the arterial endothelium of vertebrates, *Notch4*being solely expressed in the endothelia of mouse embryos \[[@B13],[@B14]\]. Mutations in these genes lead to defects in the vasculature, many of which are embryonic lethal. Mutant mice lacking *Notch1*do not survive post E11.5 and harbor defects in vascular remodeling in the embryo, yolk sac, and placenta \[[@B15]\]. Deletion of *Notch4*has no visible effect and embryos are viable; however, *Notch1^-/-^Notch4^-/-^*double mutants have more severe vascular phenotypes than the *Notch1^-/-^*and are embryonic lethal at E9.5 \[[@B10],[@B16]\]. Expression of an activated form of *Notch4*or *Notch1*also leads to vascular defects similar to those seen in the *Notch1^-/-^*and *Notch1^-/-^Notch4^-/-^*mice, as well as embryonic lethality at \~E10 \[[@B17],[@B18]\]. Although Notch clearly plays important roles in the formation of the early embryonic vasculature, very little is known about the nature of the downstream targets in vivo, and how changes in Notch activity elicit the observed morphological processes. In vitro analysis has indicated novel Notch targets, including receptors of the VEGF family, VEGFR-3 (*Flt4*) and VEGFR-1 (*Flt1*) \[[@B19],[@B20]\]. Given that several signaling cascades are required for the morphological differentiation of the embryonic vasculature, it is likely that these pathways interact during vascular development. To better define the activity of Notch signaling in vascular differentiation, a detailed morphological and molecular analysis was performed using developmental models in which the Notch signaling pathway is altered. A gain-of-function Notch1 transgenic model showed that expanded Notch1 signaling in the early vasculature results in defects in embryo growth, defective differentiation during remodeling of the yolk sac vasculature, altered patterns of gene expression, and ultimately embryonic lethality. These phenotypes were compared to embryos lacking Notch signaling in the endothelia, via a tissue-specific loss of RBPJ function. Embryos lacking endothelial *Rbpj*exhibited distinct growth, vascular, and gene expression defects compared to the Notch1 gain-of-function model. Gene expression analysis in the yolk sacs of these models demonstrated altered patterns of expression of a distinct subset of Notch targets. Additionally, several secreted ligands, including the TGF-β ligand TGFβ2 and the VEGF ligands VEGFC and Placenta Growth Factor (PlGF), were altered in these models, suggesting a role for an altered VEGF signaling pathway in the observed phenotypes of these models. Our data suggest a model in which Notch signaling in the endothelia is critical for elaborating a specialized local environment of the developing arterial vasculature, by influencing the expression of secreted factors, which may be important in autocrine or paracrine signaling to direct further morphological differentiation of the vasculature during remodeling. Results ======= Conditional transgenesis to modulate Notch signaling in the early endothelia ---------------------------------------------------------------------------- To further understand the functions of Notch signaling in early vascular development, genetic models were employed to modulate Notch activity in the embryonic endothelia. These models employ endothelial-specific Cre-mediated recombination in vivo. To activate and expand Notch1 signaling in the endothelia, a transgenic line *Rosa^Notch^*\[[@B21]\] was used, which harbors a NOTCH 1 intracellular domain (N1ICD) cDNA downstream of a floxed STOP fragment targeted to the *Rosa26*locus. Removal of the STOP cassette through *loxP*-mediated recombination, via an endothelial CRE expressing transgene, results in expression of N1ICD in endothelial cells (designated as EC-N1ICD embryos; Figure [1A](#F1){ref-type="fig"}). To delete Notch signaling in the early endothelia, a mouse line was used which harbors a conditional allele of *Rbpj*(*Rbpj^f^*mice) \[[@B22]\]. Crossing these mice to endothelial-specific CRE transgenic mice results in the deletion of exons 6 and 7, which encode the DNA binding domain of *Rbpj*, abrogating the activity of RBPJ only in endothelial cells (designated as EC-Rbpj-KO embryos; Figure [1B](#F1){ref-type="fig"}). The conditional deletion would be predicted to disrupt both Notch1 and Notch4 signaling, which have known redundant functions in early embryonic vascular differentiation \[[@B10]\]. Ablation of *Rbpj*in the endothelia was used to assure a complete disruption of Notch signaling in the developing vasculature. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Conditional mouse EC-N1ICD and EC-Rbpj-KO transgene constructs**. (A) Upon crossing of mice that carry the *Rosa^Notch^*transgene to a transgenic mouse that expresses CRE in the endothelia, recombination removes the neomycin cassette and induces expression of the *Notch1*intracellular domain only in endothelial cells. (B) Upon crossing of mice that carry the *Rbpj^f^*transgene \[[@B22]\] to a transgenic mouse that expresses Cre in the endothelia, recombination will remove the neomycin cassette along with exons 6 and 7, which encode for the DNA binding domains of RBPJ, abrogating the promoter activity of RBPJ only in endothelial cells. :::  ::: *Tie2-Cre*\[[@B23]\] or *Flk1-Cre*\[[@B24]\] transgenic mice were crossed to either *Rosa^Notch^*or *Rbpj^f^*mice. Each of these transgenes expresses the *Cre*recombinase gene and direct expression principally to the vascular endothelium. Identical phenotypes were observed when the *Flk1-Cre*and *Tie2-Cre*transgenic lines were crossed to the *Rosa^Notch^*and *Rbpj^f^*models (data not shown). Previous work has demonstrated that these Cre expressing transgenes exhibit restricted endothelial expression of Cre recombinase activity to the endothelial and hematopoietic lineages \[[@B24]\]. The early embryonic expression and recombinase activity of the *Tie2-Cre*and *Flk1-Cre*transgenes was confirmed by crossing these transgenes to a conditional *LacZ*reporter \[[@B25]\]. Both transgenes showed specific expression within the early endothelial and hematopoietic lineages at E8.5 (Additional File [1](#S1){ref-type="supplementary-material"}). Regulated Notch signaling is essential for the growth and development of the early embryo ----------------------------------------------------------------------------------------- To activate Notch1 signaling throughout the embryonic endothelia, female mice heterozygous for the *Rosa^Notch^*transgene were crossed with male mice hemizygous for the *Tie2-Cre*transgene, and the resulting embryos were analyzed. At E8.5 the EC-N1ICD mice were morphologically normal and identical to the wild type siblings, with open neural folds and vascularized allantois characteristic of this time point (Additional File [2](#S2){ref-type="supplementary-material"}). Compared to stage-matched wild type embryos at E9.5, EC-N1ICD embryos exhibited an enlarged heart and a reduction in overall size (Figure [2A,B](#F2){ref-type="fig"}). Growth defects were much more pronounced at E10.5 (data not shown), and no viable embryos were observed after E10.5. ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Defects in growth and yolk sac vasculature remodeling in EC-N1ICD and EC-Rbpj-KO embryos**. (A-C) Lateral view of E9.5 wild type (A), EC-N1ICD (B), and EC-Rbpj-KO (C) embryos. EC-N1ICD and EC-Rbpj-KO embryos were smaller in size than the wild type and exhibited cardiovascular defects. (D-F) Whole mount E9.5 wild type (D), EC-N1ICD (E), and EC-Rbpj-KO (F) embryos with surrounding yolk sac. The EC-N1ICD and EC-Rbpj-KO yolk sac lacked the large, well-defined blood vessels seen in the wild type. The blood in the EC-N1ICD yolk sac collected near the attachment to the placenta. (G-I) Immunofluorescence image of E9.5 wild type (G), EC-N1ICD (H) and EC-Rpbj-KO (H) yolk sac visualized with an antibody to PECAM1. Wild type embryos showed a remodeled yolk sac vasculature, with both large and small caliber vessels. The EC-N1ICD yolk sac did not exhibit branching; all vessels were of a large caliber. The EC-Rbpj-KO yolk sac also failed to show vascular remodeling, although all vessels were of a small caliber. Scale bars are 500 μm (A-C), 1 mm (D-F) and 100 μm (G-I). Arrows (G-I), avascular inter-vessel space. Asterisk (G), capillary collapse. :::  ::: To ablate Notch signaling in the embryo, *Tie2-Cre*mice were used in a two-generation cross to generate *Tie2-Cre*; *Rbpj^f/f^*embryos (EC-Rbpj-KO), which lack RBPJ binding activity in the endothelia. The EC-Rbpj-KO embryos displayed severe growth retardation defects at E9.5 similar to those observed in the EC-N1ICD embryos (Figure [2C](#F2){ref-type="fig"}). The morphological analyses of the gain-of-function and loss-of-function embryos were consistent with other models \[[@B10],[@B17],[@B18],[@B26]\] and confirmed that the appropriate Notch signaling in the endothelia of the early embryo is critical for proper growth and development of the embryo. Vascular defects in EC-N1ICD and EC-Rbpj-KO embryos --------------------------------------------------- A detailed comparison of the vasculature was performed to define the vascular defects in the embryonic and extraembryonic vasculature of EC-N1ICD and EC-Rbpj-KO embryos. At E8.5, no overt defects were observed in the developing vasculature of either the EC-N1ICD or EC-Rbpj-KO. In particular, the vascular plexus of the EC-N1ICD yolk sac, visualized by histochemical staining of endothelial cells with an antibody to PECAM1 (CD31), appeared unaffected when compared to stage-matched wild type embryos (Additional File [2](#S2){ref-type="supplementary-material"}; data not shown). The most severe defects were seen in the yolk sac of the developing embryo beginning at approximately E9.5. Gross morphological examination of the vasculature of the yolk sac by whole mount light microscopy showed that at E9.5 the EC-N1ICD yolk sac was the same size as the stage-matched wild type control; however these embryos lacked large diameter vessels (Figure [2D,E](#F2){ref-type="fig"}), indicating a failure in appropriate blood vessel remodeling occurring at this time point \[[@B5]\]. The EC-N1ICD yolk sac vessels did contain blood cells, although the blood tended to pool near the proximal end of the yolk sac adjacent to the chorioallantoic plate (Figure [2E](#F2){ref-type="fig"}). EC-Rbpj-KO embryos also lacked vascular remodeling in the yolk sac, failing to form the large vitelline blood vessels \[[@B26]\] (Figure [2F](#F2){ref-type="fig"}). Immunofluorescence of PECAM1 stained E9.5 yolk sac revealed the failure of this remodeling in both the EC-N1ICD and EC-Rbpj-KO embryos in greater detail. In the EC-N1ICD embryos, no distinction between large caliber vessels and capillaries was observed (Figure [2H](#F2){ref-type="fig"}); instead, the vasculature consisted of vessels with an enlarged surface area with greatly decreased avascular inter-vessel space compared to wild type controls, as assessed by lack of PECAM1 expression (\'pillars\'; Figure [2G,H](#F2){ref-type="fig"}, arrows). In contrast to the EC-N1ICD vessel defects, the EC-Rbpj-KO embryos exhibited a qualitatively different vessel phenotype in the yolk sac. Although EC-Rbpj-KO embryos also exhibited a lack of vascular remodeling, the yolk sac of these embryos displayed numerous small avascular intervessel spaces (Figure [2I](#F2){ref-type="fig"}, arrow). These results indicated that the yolk sac vasculature of the EC-Rbpj-KO embryos failed to form the large vitelline blood vessels, reminiscent of the simple vascular plexus seen at E8.5. Histological sectioning of yolk sac tissue was performed to visualize the vessels in cross-section via PECAM1 immunochemistry and hematoxylin and eosin staining. In the wild type yolk sac a distribution of large and small caliber vessels were present and were filled with blood cells; in striking contrast, the EC-N1ICD yolk sac contained primarily large caliber lumenized vessels that contained blood cells (Figure [3A,B](#F3){ref-type="fig"}). Both wild type and EC-N1ICD embryos had a range of yolk sac vessel diameter. However, in wild type yolk sac a majority of the vessels measured consisted of small capillaries, while in the EC-N1ICD yolk sac a larger proportion of vessels consisted of a larger cross-sectional area. In EC-N1ICD yolk sac, approximately 36% of vessels measured had an area of 16000 μm^2^or greater, while in wild type yolk sac only 5% measured this size (Figure [3E](#F3){ref-type="fig"}). This enlarged vessel phenotype in response to Notch activation was observed in other sites of vessel differentiation in the developing embryo. The dorsal aortae (DA) of EC-N1ICD embryos were approximately twice the cross-sectional area of wild type embryos (Figure [3C,D](#F3){ref-type="fig"}, asterisks). The embryo-derived vasculature of the placenta of EC-N1ICD embryos did invade into the labyrinth layer of the placenta (Figure [3G](#F3){ref-type="fig"}, arrowheads), but exhibited greatly enlarged vessel diameter (Figure [3G](#F3){ref-type="fig"}, arrows). The EC-Rbpj-KO embryos exhibited a decrease in vessel diameter, including the DA, and arteriovenous malformations \[[@B26]\]. EC-Rbpj-KO embryonic-derived vasculature of the placenta was also reduced in size and did not invade the labyrinth layer of the placenta (Figure [3H](#F3){ref-type="fig"}, arrow). Immunostaining of E9.5 wild type and EC-N1ICD embryos using anti-SMA, indicated that the dorsal aortae of wild type are surrounded by smooth muscle cells, while the EC-N1ICD did not recruit any SMA-positive cells to the dorsal aorta \[[@B27]\] (Figure [3F,G](#F3){ref-type="fig"}). ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Defects in vessel diameter in EC-N1ICD and EC-Rbpj-KO embryos**. Histological sections (lateral) of PECAM1 and NFR-stained E9.5 yolk sac (A, B) and embryos (C, D) at the level of the heart. The wild type yolk sac contained both large and small caliber vessels (A, arrowheads). The EC-N1ICD yolk sacs contained primarily large caliber vessels (B, arrowheads), however they were lumenized. The dorsal aortae of the EC-N1ICD embryos (D, asterisk) were approximately twice the area of wild type dorsal aortae (C, asterisk). (E) Distribution of vessel area in the yolk sac of wild type and EC-N1ICD embryos. Both wild type and EC-N1ICD embryos had an array of differently sized vessels. However, wild type yolk sac had a majority of vessels with an area of 0-4000 μm^2^, while EC-N1ICD contained many vessels with an area of 30000 μm^2^or greater. (F, G) Histological sections of E9.5 dorsal aorta stained with an antibody to smooth muscle α-actin. The dorsal aortae of the wild type contain SMA-positive cells (F), while the EC-N1ICD dorsal aortae are SMA-negative. (H-J) Histological sections of the placental vasculature in wild type (H), EC-N1ICD (I), and EC-Rbpj-KO (J) embryos. Blood vessels containing nucleated erythrocytes in EC-N1ICD placenta (I, arrow) were of larger caliber than blood vessels in wild type placenta (H, arrow). In both, the fetal vasculature invaded into the maternal portion of the placenta. The vessels of the EC-Rbpj-KO placenta (J, arrow) were small in size and had not invaded into the labyrinthine layer. Asterisk (H-J), maternal blood. Scale bars are 100 μm (A-D). :::  ::: The morphological analyses of the models of altered Notch signaling were consistent with previous analysis of Notch function in the vasculature \[[@B10],[@B17],[@B18],[@B26]\]. These results point to multiple roles for Notch signaling in the formation of both the intra- and extraembryonic vasculature, including the remodeling of the yolk sac vasculature, the regulation of vessel diameter, and the invasion of the fetal vasculature into the labyrinth layer of the placenta. Identification of Notch regulated genes in EC-N1ICD yolk sac and EC-Rbpj-KO yolk sac ------------------------------------------------------------------------------------ Gene expression defects in the Notch models were examined to determine potential molecular mechanisms of how altered Notch disrupts vascular differentiation, through altered expression of putative Notch targets. RNA from yolk sacs of E9.5 wild type, EC-N1ICD and EC-Rbpj-KO embryos (resulting from a cross with *Tie2-Cre*or *Flk1-Cre*mice) was isolated for gene expression analysis via microarray and semiquantitative RT-PCR. Whole genome microarray identified a large number of gene expression defects in these Notch models, many of which were confirmed with RT-PCR (Figure [4](#F4){ref-type="fig"}). To identify putative Notch targets, genes were categorized on the altered response in the gain-of-function and loss-of-function models (Additional File [3](#S3){ref-type="supplementary-material"}). Only a relatively small set of genes displayed upregulation in the EC-N1ICD model and downregulation in the EC-Rbpj-KO model, which would be suggestive of genes that are positively regulated by the Notch1-Rbpj axis. Interestingly, no genes were identified as being downregulated in the EC-N1ICD model and upregulated in EC-Rbpj-KO (Additional File [3](#S3){ref-type="supplementary-material"}). ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Gene expression in transgenic EC-N1ICD and EC-Rbpj-KO embryo yolk sacs**. Semiquantitative RT-PCR analysis was used to confirm gene expression differences seen in whole genome microarrays. (A) RT-PCR analysis of *Hey1*and *Heyl*in wild type, EC-N1ICD, and EC-Rbpj-KO E9.5 yolk sacs. Quantitated relative mRNA levels are shown in the lower graph. (B) RT-PCR analysis of genes critical for the formation of the early embryonic vasculature. Quantitated relative mRNA levels of select genes are shown in the graphs to the right. \* p \< .05, \*\* p \< .01, \*\*\* p \< .001 compared to wild type. :::  ::: The members of the Hairy/Enhancer of split-related (HES/HEY) family are well described Notch targets, many of which are directly regulated by Notch1 signaling via its binding to RBPJ \[[@B28]\] to regulatory regions of these loci. The microarray datasets revealed that in yolk sacs of EC-N1ICD embryos, both *Hey1*and *Heyl*were highly induced, and expression of these genes was reduced in the EC-Rbpj-KO; these results were confirmed by semi-quantitative RT-PCR (Figure [4A](#F4){ref-type="fig"}). Expression of *Hey1*and *Heyl*was increased 4.4-fold and 20.5-fold in the EC-N1ICD model respectively, and decreased to 35% and 46% of wild type levels in the EC-Rbpj-KO yolk sac tissue, respectively. Interestingly, the expression of other HES family members, such as *Hes1*and *Hes6*was not affected in these Notch models (data not shown), consistent with a context-dependent regulation of Notch targets \[[@B29],[@B30]\]; i.e. Notch signaling invokes distinct downstream targets depending on both the cell type and the local environment. The expression of the endogenous Notch ligands and receptors was also examined in detail. Previous work has suggested a potential autoregulatory loop for Notch signaling in the control of ligands and receptors \[[@B31],[@B32]\]. Although expression of the Notch family receptors was not altered in either the EC-N1ICD or EC-Rbpj-KO yolk sacs, the Notch ligands Delta-like 4 (*Dll4*) and Jagged 1 (*Jag1*) showed higher expression in EC-N1ICD (2.5-fold and 2.0-fold, respectively) with little or no change in expression in EC-Rbpj-KO yolk sac. These findings point to specific Notch pathway targets in the extraembryonic yolk sac vasculature. Notch-Rbpj signaling regulates vascular expression of key signaling molecules ----------------------------------------------------------------------------- Given the defects in vessel diameter and remodeling in response to altered Notch activity, we wished to focus gene expression analysis on secreted factors. Genes encoding several known and putative secreted factors were differentially expressed in the Notch models (Additional File [4](#S4){ref-type="supplementary-material"}). Expression defects of a subset of these genes were confirmed via RT-PCR, with a focus on genes with putative roles in vascular differentiation and that display coordinate defects in expression in the EC-N1ICD and EC-Rbpj-KO models. Although the expression of some VEGF family members was not significantly different in yolk sac, the microarray datasets indicated that expression of the VEGF family members *Vegfc*, encoding VEGF-C, and *Pgf*, encoding Placenta Growth Factor (PlGF), were both increased in EC-N1ICD and *Vegfc*was decreased in EC-Rbpj-KO (Additional File [4](#S4){ref-type="supplementary-material"}). RT-PCR confirmed that *Vegfc*was upregulated 2.6-fold in the EC-N1ICD and decreased to 8% in the EC-Rbpj-KO compared to control yolk sac tissue; *Pgf*was upregulated 1.9-fold in the EC-N1ICD and decreased to 74% in the EC-Rbpj-KO compared to control yolk sac tissue. The secreted cytokine *Tgfb2*also exhibited increased expression in the yolk sacs of EC-N1ICD yolk sac tissue (4.7-fold) and decreased expression in EC-Rbpj-KO (49% of wild type levels) (Figure [4B](#F4){ref-type="fig"}). Given that the N1ICD was activated specifically in the endothelia in this transgenic model, we wished to confirm that the gene expression defects in this model are confined to the endothelial lineage, to determine if the gene expression defects are intrinsic to the endothelium, or are associated with another cell type within the yolk sac. To these ends, gene expression of Notch regulated genes was examined in endothelial cells purified via flow cytometry. Via fluorescent activated cell sorting (Additional File [5](#S5){ref-type="supplementary-material"}), PECAM1 + cells were isolated from dissociated yolk sacs of E9.5 wild type or EC-N1ICD embryos (from a cross with *Flk1-Cre*mice) and RNA was isolated from the purified cells for gene expression analysis via real time PCR. To confirm the enrichment of sorted endothelial cells within the PECAM1+ population, expression of lineage markers were compared between RNA from purified PECAM1+ cells and from whole unsorted wild type yolk sac tissue. Endothelial specific genes such as *Cdh5*(*VE-cadherin*) and *Pecam1*exhibited significant enrichment in PECAM1+ cells (5.7-fold and 6.7-fold respectively). In contrast, the levels of the primitive visceral endodermal marker *Rhox5 (Pem)*\[[@B33]\] were reduced to 10% in the sorted cells compared to whole wild type yolk sac tissue (Figure [5A](#F5){ref-type="fig"}), demonstrating a substantial reduction of visceral endoderm cells in the purified endothelial cells. These findings demonstrate a specific enrichment of yolk sac endothelial cells via flow sorting. ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **Gene expression in transgenic EC-N1ICD PECAM1+ sorted yolk sac tissues**. Real time-PCR analysis was used to analyze gene expression differences seen in PECAM1+ sorted yolk sac cells. (A) Real time-PCR analysis of *Cdh5, Pecam1*and *Rhox5*in wild type E9.5 whole yolk sac tissues and sorted yolk sac endothelial cells. (B) Real time-PCR analysis of select Notch responsive genes. \* p \< .05, \*\* p \< .01, \*\*\* p \< .001 compared to wild type. :::  ::: The Notch-responsive genes identified in the previous analysis of whole yolk sac tissues were then examined in the sorted yolk sac endothelial cells. The endothelial marker, *Pecam1*exhibited statistically equivalent expression between the EC-N1CD and wild type sorted cells, similar to that seen in whole yolk sac tissues (data not shown). However, expression of *Hey1*and *Heyl*was increased 4.4-fold and 16.7-fold in the EC-N1ICD sorted endothelial cells respectively. Similarly, the VEGF family members *Vegfc*and *Pgf*were upregulated 2.1-fold and 1.9-fold, respectively in sorted EC-N1ICD endothelial cells compared to wild type, while *Tgfb2*was increased 6.9-fold (Figure [5B](#F5){ref-type="fig"}). These results demonstrate that the expression of these genes is upregulated specifically in the endothelial lineages in EC-N1ICD yolk sac. Taken together, the gene expression defects demonstrate that Notch-Rbpj signaling acts to regulate many key genes specifically in the endothelia of the developing yolk sac. The misexpression of some of these factors may contribute to the vascular differentiation defects seen in the transgenic models. Putative Notch regulated genes contain potential RBPJ binding sites in the upstream regulatory region ----------------------------------------------------------------------------------------------------- The in vivo studies have identified a number of putative Notch regulated genes in the developing vasculature. Many of these genes are known Notch targets, including *Hey1*and *Heyl*, with known RBPJ binding sites within regulatory elements \[[@B28]\]. These studies however also identified altered expression of several genes, including *Vegfc*, *Tgfb2*, and *Pgf*, for which their regulation by Notch signaling has not previously been described. Bioinformatic tools were used to determine if these genes are potentially direct targets of Notch signaling through RBPJ. Several RBPJ binding sites, with a core consensus binding sequence GTGGGAA \[[@B34]\], have been previously identified in known Notch targets such as the HES family members \[[@B28],[@B35]\]. The bioinformatic tool, ECR browser \[[@B36]\], was used to determine if canonical RBPJ binding sites were observed in the promoter proximal regions of loci encoding the secreted factors, *Vegfc*, *Pgf*, and *Tgfb2*. The mouse, human, and rat genomic sequences of each of the target genes were aligned and examined for the RBPJ conserved transcription factor binding sites (TFBS) within the evolutionary conserved regions (ECRs) upstream and downstream of the start site. In each of the genes a GTGGGAA consensus sequence was found, indicating a potential RBPJ site (Additional File [6](#S6){ref-type="supplementary-material"}). In the *Vegfc*locus, an RBPJ binding site is apparent approximately 7.8kb upstream of the start site, while the *Pgf*locus harbors an RBPJ binding site 4.1kb upstream and one 3.8kb downstream of the transcriptional start site. RBPJ sites were observed at approximately 2.5kb and 5.8kb upstream of the start site of the *Tgfb2*locus. The putative Notch binding sites in each gene suggests that these genes may be direct targets of Notch signaling. Discussion ========== Numerous studies have indicated critical roles for Notch signaling in the proper formation and maintenance of the early vascular system in the mouse. However, the mechanisms by which Notch signaling regulates such diverse aspects of endothelial differentiation in its various contexts are active areas of research. Our analysis details the morphological and molecular defects associated with altered Notch signaling in vivo, with a focus on the extraembryonic vasculature of the yolk sac. This work has characterized distinct morphological defects in the early embryonic and extraembryonic vasculature associated with loss or gain of Notch activity. Substantial gene expression differences in these models point to putative Notch target genes, and suggest potential mechanisms by which Notch signaling directs endothelial cell differentiation. Morphological analysis of both EC-N1ICD and EC-Rbpj-KO models confirmed that the regulation of Notch signaling is critical in the formation of the intra- and extraembryonic vasculature of the developing embryo. Detailed examination of the yolk sac vasculature, dorsal aortae, and fetal vasculature of the placenta revealed an enlarged vessel phenotype in the EC-N1ICD, remarkably apparent within the yolk sac, in which the plexus is converted to a mass of large diameter vessels (Figure [6A](#F6){ref-type="fig"}). In contrast, small caliber non-remodeled vessels are present in the EC-Rbpj-KO yolk sac model (Figure [6A](#F6){ref-type="fig"}). Other Notch models have demonstrated malformations in vessel diameter resulting from altered Notch activity, including other models of activated Notch in vivo \[[@B18],[@B27]\]. *Notch1*deficient mice \[[@B15]\], mice lacking *Rbpj*in the endothelia, and *Dll4^+/-^*embryos \[[@B26]\] each exhibit collapsed dorsal aortae and a lack of vascular remodeling. In contrast, embryos overexpressing either *Dll4*\[[@B37]\] or *Notch4*\[[@B17]\] have enlarged dorsal aortae. Data indicated that the enlargement of the dorsal aortae in mice overexpressing *Dll4*was due not to a proliferation of endothelial cells, but to the improper migration of these cells \[[@B26]\]. These data point to an important role for Notch signaling to regulate vessel diameter. ::: {#F6 .fig} Figure 6 ::: {.caption} ###### **Notch regulates the expression of key genes and the remodeling of the yolk sac vasculature**. (A) Proposed model depicts the Notch pathway as a key component in the regulation of the remodeling of the vasculature. In wild type yolk sac Notch acts in concert with VEGF and other signaling families to direct the integration of the endothelial cells into both large and small caliber vessels. When Notch is activated this integration is increased leading to very large caliber vessels with limited intra-vascular space. When Notch activity is abrogated the integration is limited and the vascular retains the simple unremodeled appearance of the early vascular plexus. (B) Proposed model of signaling in the endodermal and endothelial cells of the early yolk sac. Signaling from the endoderm and regulation from blood flow activates Notch signaling in select endothelial cells. Notch activates the expression of select secreted genes that act in both a paracrine and juxtacrine manner to direct endothelial cell migration and integration within the developing vasculature. :::  ::: Given that Notch signaling is associated with arterial identity \[[@B13],[@B14]\], this function of Notch signaling to control vessel size may represent an aspect of Notch function in the definition of the arteriole. The mechanisms of how Notch and other signaling pathways control vessel size in the various regions of the developing embryo are not well defined, and are likely context dependent. Some models suggest that directional cell division is important to dictate whether endothelial cell proliferation within a patent vessel results in an increase in luminal diameter \[[@B38]\]. Other models suggest the recruitment of endothelial or angioblast cells into existing vessels as an important mechanism to increase vessel diameter \[[@B39]\]. The remodeling process of the yolk sac makes extensive use of reallocation of cells during remodeling (discussed below), suggesting complex roles for Notch signaling in controlling endothelial cell behavior during remodeling. The yolk sac vasculature represents a genetically tractable model to study endothelial differentiation, and the work presented here has made extensive analysis of this tissue. Endothelial differentiation within the yolk sac is initiated as groups of cells from the proximally situated extraembryonic mesoderm condense into blood islands by approximately embryonic day 7.0, which subsequently migrate toward the distal region of the yolk sac. The peripheral cells will differentiate to the endothelial cells lining the vasculature, whereas the inner cells become blood cells. The endothelial cells expand and fuse to form the vascular plexus, which is contiguous with the embryonic vasculature at the onset of blood flow \[[@B40]\]. The capillaries are then remodeled into the hierarchical vascular network of vitelline artery, capillaries, and vitelline vein. Observations of vessel remodeling in the yolk sac, particularly in the chick embryo, suggest that the formation of large diameter vessels is from pre-existing capillary-derived endothelial cells. This process involves the collapse of some capillary microvessels, and the endothelial cells from the capillary are then recruited into the nascent vessels to result in a larger diameter vessel (Figure [2G](#F2){ref-type="fig"}, asterisk). This mode of remodeling resembles the process of intussusceptive arborization, which has been suggested to be an efficient and rapid mode of angiogenesis in a variety of sites \[[@B3]\]. Although Notch signaling does play a significant role in sprouting angiogenesis \[[@B41]\] in many other contexts, the remodeling of the yolk sac in the early embryo may not utilize a sprouting angiogenesis method. Instead, this early vascular remodeling is a rather distinct vascular mechanism that is not entirely clear and remains to be studied in detail. Based on this model of endothelial remodeling within the yolk sac plexus, the defects in vessel diameter and the remodeling failure in the Notch models used in this study indicate a possible defect in the reallocation of endothelial cells from capillaries into arterioles, suggesting that Notch plays a significant role in this migration. The phenotype observed in the EC-N1ICD yolk sac vasculature is possibly due to increased mobilization and disorganized recruitment of capillary-derived endothelial cells, resulting in a field of enlarged vessels. Conversely the failure of the yolk sac remodeling in the EC-Rbpj-KO model is due to the abrogation of endothelial cell migration to form the larger caliber vessels. Live imaging of the behavior of endothelial yolk sac cells in the Notch models used in this study will be required to elaborate this model. A detailed understanding of the downstream effectors of Notch signaling during vascular differentiation in vivo, particularly within the extraembryonic tissues, has been lacking. The molecular analysis of the Notch models presented here identified a variety of gene expression defects associated with altered Notch activity. Both the gain- and loss-of-function in vivo models suggest misregulation of a number of genes. Data indicated that two of the Notch family ligands, *Dll4*and *Jag1*were upregulated in EC-N1ICD yolk sac, indicating a possible positive feedback loop for Notch signaling to direct expression of its ligands. There is some precedence for a positive regulatory loop in which Notch regulates the expression of ligands, including *Jag1*in NIH 3T3 cells \[[@B31]\] and *Dll1*in glioma cells \[[@B32]\]. Importantly, the gene expression analysis also identified a number of secreted factors whose expression within the endothelia is altered in the Notch models. These data suggest that the Notch signaling pathway regulates a number of secreted factors important in endothelial differentiation such as, *Pgf*, *Vegfc*, and *Tgfb2*, either directly or indirectly. Targeted deletions of select TGF-β signaling components in mice result in the improper formation of the yolk sac vasculature, indicating the importance for TGF-β signaling in the formation of the early vascular system \[[@B42]\]. Vegf signaling has critical early roles in the formation of the blood vessels in the early embryo \[[@B43],[@B44]\]. VEGF has also been shown to act as an upstream component of Notch in the signaling cascade directing the differentiation of the zebrafish vasculature \[[@B45]\]. PlGF has known roles in pathological angiogenesis \[[@B46],[@B47]\], and may act as a VEGF agonist by countering the effects of the VEGFA antagonist Flt1. In addition to the essential functions of VEGFC in the developmental origin of the lymphatic system \[[@B48],[@B49]\], there is conflicting data to suggest it plays a broader role in angiogenesis. Although this factor has known angiogenic activities in certain assays \[[@B50]\], no vascular defects have been reported in mice lacking *Vegfc*\[[@B48]\]. The expression of VEGFC within the yolk sac however suggests a potential non-lymphatic function for this factor in this tissue. A putative role for VEGFC in angiogenesis may involve the modulation of its receptors, Kdr (VEGFR2) and Flt4 (VEGFR3), both of which play a critical role in early angiogenesis. Notch signaling is essential for vessel remodeling, as our data shows that Notch regulates the expression of a variety of secreted factors. Notch signaling may play potential nonautonomous roles in the remodeling of the yolk sac capillary plexus (Figure [6B](#F6){ref-type="fig"}). Notch signaling is important for the regulation of select signaling molecules, including members of the VEGF family and TGF-β family, which would emanate from the developing arteriole where activity of Notch signaling is highest. These molecules then act in a paracrine and autocrine manner to elaborate the local arterial microenvironment about Notch expressing cells, which may potentially influence adjacent capillary endothelial cells, smooth muscle or mural cells, and hematopoietic cells. Indeed, nonautonomous functions for Notch signaling in the endothelium have been suggested, including attenuating proliferation of smooth muscle cells \[[@B27]\]. Testing of the nonautonomous functions of Notch signaling in the vasculature will require determining the roles of Notch-regulated secreted factors in vivo. These experiments may include the use of conditional transgenics and knockouts of these factors in the endothelia, and determining remodeling and endothelial differentiation defects in these models. Yolk sac vessel remodeling occurs after the initiation of blood flow, which initiates at approximately E8.5 in the mouse \[[@B40]\], and this flow is essential for the remodeling process. It is formally possible that the enlarged luminal diameter of the dorsal aorta in the Notch gain-of-function model could give rise to a secondary failure of yolk sac remodeling solely due to reduced flow and associated shear stress. However, the vessel architecture reported in mouse models with remodelling defects solely due to altered blood flow \[[@B40]\] display very different phenotypes from those observed in the N1ICD model. This comparison suggests that the remodeling defects and some of the associated gene expression defects in the yolk sac in this Notch1 gain-of-function model are not secondary to embryonic vessel defects or defects in blood flow. The cellular and subsequent molecular response to the shear stress associated with blood flow is not completely understood, but may involve a complex cell surface signalling molecules including KDR, PECAM1, and VE-cadherin \[[@B51]\]. Shear stress thus initiates a molecular cascade in endothelial cells to direct further morphological changes to direct remodeling. An important question is what is the link between blood flow and Notch signaling, both of which are essential for vessel remodeling. During remodeling, an arteriole rudiment is first observed at the site of yolk sac vasculature contact with the omphalomesentric artery. Early *Dll4*expression is observed at this arteriole rudiment within the yolk sac \[[@B52]\], indicating it is likely the Notch ligand that initiates Notch activity within this restricted region of the yolk sac vasculature. It remains to be seen the extent to which fluid dynamics control the expression of Notch signalling components and the subsequent remodeling process. Conclusions =========== The transcriptional network controlled by Notch signaling during extraembryonic endothelial differentiation is largely unknown. The present data demonstrate a role for Notch signaling in the regulation of a number of key genes in the embryonic vasculature of the yolk sac, including a variety of secreted factors important for endothelial differentiation. These downstream targets suggest a mechanism for Notch regulation of vessel diameter size during the remodeling process in the yolk sac vasculature. Further work on the in vivo models will help to further define the relationship between the transcriptional networks regulated by Notch to direct endothelial differentiation, and the role of these Notch downstream targets in endothelial migration and vascular remodeling. The understanding of these interactions and processes will aid in the development of treatments affecting vascular differentiation, including heart disease and tumor progression. Methods ======= Mice and embryos ---------------- The generation of *Rosa^Notch^*mice, *loxP*-flanked *Rbpj*, *Tie2-Cre*and *Flk1-Cre*mice have been described previously \[[@B21]-[@B24]\]. *Tie2-Cre*mice and *loxP*-flanked *Rbpj*mice were mated to obtain *Tie2-Cre; Rbpj^f/+^*males. Breeding pairs of *Tie2-Cre*or *Flk1-Cre*mice and *Rosa^Notch^*mice or *Tie2-Cre; Rbpj^f/+^*males and *Rbpj^f/+^*females were intercrossed and the presence of a vaginal plug was identified as E0.5. Embryos were dissected from the decidual tissue at E8.5, E9.5, or E10.5 and treated according to the intended protocol. Placenta were separated from the embryo along with the mesometrial portion of the decidua and prepared for histology. All experimental procedures were performed with prior approval of the University Institutional Animal Care and Use Committee in accordance with guidelines established by the American Veterinary Medical Association. Genotyping of Progeny --------------------- The genotypes of all offspring were analyzed by PCR on genomic DNA isolated from ear punches, yolk sac samples, or embryonic tissue depending on the intended protocol. Genomic DNA was isolated using the DNeasy Blood & Tissue Kit (Qiagen). The *Tie2-Cre*and *Flk1-Cre*transgene presence was tested with the primers Cre-R3, 5\'-AAT GCT TCT GTC CGT TTG-3\' and Cre-F3, 5\'-GGA TTA ACA TTC TCC CAC C-3\', giving a 458-bp band \[[@B53]\]. PCR genotyping for *Rosa^Notch^*mice was performed as described \[[@B25]\]. The wild type, floxed, and deleted *Rbpj*alleles were genotyped as described \[[@B54]\]. Immunochemistry --------------- Embryos with or without the surrounding yolk sac were fixed in 4% paraformaldehyde/PBS overnight at 4°C. The following day they were rinsed in PBS, dehydrated in methanol, and bleached in 1mL of 1.5% H~2~O~2~in methanol for 4-5 hours at room temperature. Embryos were then rehydrated through methanol into PBS, blocked in PBSMT (PBS, 3% nonfat dry milk, 0.1% Triton X-100) for 2 hours at room temperature and incubated with 1:50 anti-PECAM1 antibody (BD Pharmingen) overnight at 4°C. Embryos were washed 5 times for 1 hour each with PBSMT and incubated with 1:100 HRP-coupled anti-rat IgG (\#14-16-12, kpl.com) overnight at 4°C. Embryos were again washed 5 times in PBSMT with a final wash in PBT (PBS, 0.2% BSA, 0.1% Triton X-100). Then embryos were incubated in developing solution (0.3 mg/mL DAB, 0.5% NiCl~2~in PBT) for 20 minutes at room temperature followed by the addition of H~2~O~2~at a 0.03% final concentration. Once the color developed (approximately 10min.), the embryos were rinsed in PBT and then PBS and fixed overnight in 2% paraformaldehyde/0.1% gluteraldehyde/PBS at 4°C. Embryos were then rinsed in PBS and either equilibrated into 70% glycerol for imaging or dehydrated in ethanol for paraffin embedding. X-gal staining -------------- Untreated whole-mount E8.0 and E8.5 embryos with surrounding yolk sac were fixed on ice for 10 min in a fixation solution. The samples were then washed 3 times in 1X PBS pH 7.4 and stained overnight at 37°C per established procedures \[[@B55]\]. The next day, the samples were rinsed in PBS and fixed overnight in a 3.7% paraformaldehyde/PBS solution. The following day, the samples were again rinsed, imaged and stored in 70% EtOH for paraffin embedding. Histology --------- Untreated whole-mount embryos, whole-mount PECAM1 stained embryos and placenta were fixed in 3% paraformaldehyde overnight, dehydrated into 70% ethanol and embedded in paraffin wax. Embryos were then sectioned on the transverse generally in 8 μm sections. For histological observation, Hematoxylin and Eosin or Nuclear Fast Red staining was conducted on the paraffin sections and sections were observed. Preparation of single yolk sac cell suspension ---------------------------------------------- E9.5 embryos were obtained from timed matings between *Flk1-Cre*females and *Rosa^Notch^*males. Yolk sacs were incubated in 0.1% collagenase (StemCell Technologies Inc)/phosphate-buffered saline (PBS)/20% fetal bovine serum at 37°C for 30 minutes. The digested yolk sacs were aspirated through 27-gauge needles to fully separate the cells. Genotyping was performed on DNA isolated from corresponding embryo tissues. Cell sorting with PECAM1 and analysis of PECAM1+ cells ------------------------------------------------------ Single-cell suspensions from yolk sacs were incubated for 30 minutes at 4°C with anti-PECAM1 antibody conjugated to phycoerythrin cyanine 7 (eBioscience Inc). The PECAM1+ cells were isolated by cell sorting with the use of a BD FACSAria cell sorter (BD Biosciences). Total RNA was isolated from the sorted cells using an RNeasy mini kit (Qiagen) and RNA was used for real time PCR analysis. RT-PCR analysis --------------- Embryos were dissected at E9.5. The uterus and decidua were carefully removed and discarded. The yolk sac was separated from the embryo and the embryo was used for genotyping. Total RNA was isolated from the yolk sac using an RNeasy mini kit (Qiagen). cDNA was generated using SuperScript III reverse transcriptase (Invitrogen). Semiquantitative RT-PCR was performed using a number of primers from IDT (idtdna.com) (Additional File [7](#S7){ref-type="supplementary-material"}), with ribosomal protein L7 (5\'-GAA GCT CAT CTA TGA GAA GGC-3\' and 5\'-AAG ACG AAG GAG CTG CAG AAC-3\') as a control. The annealing temperature and number of PCR cycles was optimized for each reaction. Real Time PCR ------------- RNA was isolated from sorted endothelial cells using an RNeasy mini kit (Qiagen). cDNA from endothelial cells was generated using Superscrpit III reverse transcriptase (Invitrogen) and quantitative real-time PCR analysis was performed using Taqman primer sets with the 7500 Real Time PCR system (Applied Biosystems). Gene expression was normalized to GAPDH. Specific ABI Taqman primer/probe assay IDs are available upon request. Microarray Analysis ------------------- RNA was isolated from yolk sac tissues using an RNeasy mini kit (Qiagen). RNA was initially analyzed with the Mouse Genome 430 A Array from Affymetrix. Microarray data was deposited to the Gene Expression Omnibus (GSE22418). Yolk sac immunofluorescence --------------------------- Embryos were dissected at E9.5 in PBS. The uterus and decidua were carefully removed and discarded. The yolk sac was separated from the embryo by severing the vitelline arteries and the embryo was used for genotyping. The yolk sacs were collected in separate wells of a 24 well plate and then fixed in 1mL of 3% paraformaldehyde/PBS for 15 minutes on ice. Then the yolk sacs were permeabilized in 1mL of PBS containing 0.02% Triton X-100 for 30 minutes. Yolk sacs were transferred to separate 1.5mL Epindorf tubes containing 500uL of blocking solution (PBS, 3% BSA, 5% donkey serum (Jackson ImmunoResearch)) for 2 hours at room temperature. Blocking solution was changed once at 1 hour. Yolk sacs were then incubated with 1:33 anti-PECAM1 antibody (\#557355, BD Pharmingen) overnight at 4°C. Embryos were washed 5 times for 1 hour each with blocking solution and incubated with 1:75 FITC-conjugated AffiniPure Anti-Rat IgG (\#712-095-153, Jackson ImmunoResearch) overnight at 4°C. Embryos were again washed 5 times in blocking solution with a final 20-minute wash in PBS. The yolk sacs were transferred via Pasteur pipette to a drop of *SlowFade*Gold antifade reagent (Molecular Probes) on a glass slide and covered with a cover slip. Histology Immunofluorescence ---------------------------- Embryos were prepared following the above protocol for histology. Tissues were deparrafinized through xylene and EtOH into cold tap water. Antigen retrieval was performed by immersing the slides in 10 mM calcium citrate for 20 minutes in a steam chamber. Sections were washed first with water and then 2 times with PBS. Sections were then incubated in PBT (PBS, 0.2% BSA, 0.1% Triton X-100) for 2 hours at room temperature. Sections were stained with a-smooth muscle actin (1:250 dilution; catalog no. A2547; Sigma-Aldrich, Inc) for 1 hour at 4°C. Sections were washed 3 times with PBT and then stained with Alexa Fluor 546 goat anti-mouse IgG (1:250 dilution; catalog no. A11003; Invitrogen) for 30 minutes at room temperature in the dark. Sections were again washed 3 times with blocking solution. A small amount of ProLong Gold antifade reagent with DAPI (Invitrogen) was applied and the samples were covered with a cover slip, allowed to set, and imaged. Slides were stored at -20°C. Identification of TFBSs ----------------------- The ECR browser \[[@B36]\] was used to determine the location of potential RBPJ binding sites. The evolutionary conserved regions of the mouse, human, and rat were examined upstream and flanking the transcription start site of each gene for the presence of the RBPJ binding sequence (GTGGGAA) \[[@B34]\]. Microscopy and image acquisition -------------------------------- Images were acquired with a Nikon SMZ800 dissecting microscope for whole embryos and a Nikon ECLIPSE 55i for embryonic sections using a Leica DFC480 camera and Leica FireCam 3.0 software. Images for yolk sac immunofluorescence were acquired with an Olympus 1X71 microscope and Olympus DP71 camera using Olympus DP71 controller software. Adobe Photoshop CS2 was used for photograph editing. Statistical Analysis -------------------- Data bars represent the means +/- standard error of the mean. RNA analyses of yolk sac tissues were performed with an n of 5. The statistical significance of the data was determined using a t-test with a p-value of \< 0.05 considered statistically significant. Authors\' contributions ======================= JLV conceived the project, obtained funding, participated in the design of the experiments, and co-wrote the manuscript; JNC participated in the design of the experiments, performed experiments, analyzed data and co-wrote the manuscript. YF and PEF designed and assisted in the yolk sac cell suspension experiment. NKN carried out the *Flk1-Cre*lacZ experiments. All authors read and approved the final manuscript. Supplementary Material ====================== ::: {.caption} ###### Additional file 1 ***Tie2-Cre*and *Flk1-Cre*are expressed in the endothelia of the early embryo**. (A-E) X-Gal staining of embryos from R26R cross with *Tie2-Cre*transgene. (A-C) Whole mount E8.5 embryos. (D, E) Histological sections of E8.5 embryos. (F-I) X-Gal staining of embryos from R26R cross with *Flk1-Cre*transgene. (F) Whole mount E8.0 embryo with surrounding yolk sac. (G) Whole mount E8.5 embryo. (H) Yolk sac from a E8.5 embryo. (I) Histological section of E8.5 embryo. Note expression in the endothelia of dorsal aorta (DA), heart (He), anterior cardinal vein (ACV), yolk sac (YS), allantois (Al), lateral plate (LP), and vitelline artery (VA). ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 2 **Embryonic growth and vascular remodeling is normal in early EC-N1ICD embryos**. (A, B) Whole mount E8.5 wild type (A) and EC-N1ICD littermate (B) embryos with surrounding yolk sac stained with an antibody to PECAM1. EC-N1ICD yolk sac vasculature appeared normal. (C, D) Lateral view of E8.5 wild type embryo (C) and EC-N1ICD littermate (D) stained with an antibody to PECAM1. EC-N1ICD embryos appeared normal. Scale bars are 500 μm (A, B) and 250 μm (C, D). ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 3 **Gene expression in EC-N1ICD and EC-Rbpj-KO yolk sac tissues**. A graphical representation of possible outcomes of expression data and the corresponding genes that display this type of expression. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 4 Expression of genes encoding secreted factors in EC-N1ICD and EC-Rbpj-KO yolk sac tissues ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 5 **Histograms obtained from PECAM1-PE Cy7 fluorescent activated cell sorting**. Representative histograms showing the distribution of dissociated yolk sac cells for the (A) isotype control and PECAM1 stained (B) wild type yolk sac and (C) EC-N1ICD yolk sac. The gating used to purify PECAM1+ cells is indicated. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 6 **rVista visualization of conserved RBPJ binding sites**. Using the ECR browser, the genomic sequence of each of the three secreted genes, *Vegfc*, *Pgf*, and *Tgfb2*was examined for the RBPJ binding site. The red bars identify the resulting binding sites. ::: ::: {.caption} ###### Click here for file ::: ::: {.caption} ###### Additional file 7 Primer pairs used for RT-PCR ::: ::: {.caption} ###### Click here for file ::: Acknowledgements ================ We thank Stanton Fernald of the KU Medical Center Imaging Core for aid in image acquisition, Lucy Xiu for technical assistance, Katie Burgess for assistance with statistical analysis, the KUMC-Microarray Facility for generating array data sets, and the KUMC Flow Cytometry Core. This work was supported by an American Heart Association grant 0665481Z and National Institutes of Health COBRE grant P20RR024214 (to JLV) and an American Heart Association Heartland Affiliate predoctoral fellowship 0715516Z (to JNC).

PubMed Central

2024-06-05T04:04:17.263790

2011-2-25

PMC3051916

Background ========== Recently, theoretical and experimental studies have shown the potential of entomopathogenic fungi as next generation agents for the control of malaria mosquitoes \[[@B1]-[@B5]\] However, most of this work has focused on targeting adult mosquitoes. Larval control has a convincing history of malaria eradication and recent studies have also shown this approach to be highly effective \[[@B6]-[@B11]\]. It is, therefore, worthwhile to investigate the ability of entomopathogenic fungi to control mosquito larvae and the feasibility of their operational use. Our previous work showed the efficacy of *Metarhizium anisopliae*(ICIPE-30) and *Beauveria bassiana*(IMI- 391510) spores in infecting and killing larvae of *Anopheles stephensi*and *An. gambiae*under laboratory conditions \[[@B12]\]. Other isolates of *M. anisopliae*and *B. bassiana*have also been shown to affect culicine and anopheline larvae \[[@B13]-[@B17]\]. The main infection sites were the feeding and respiratory apparatus \[[@B16]\]. Most of these studies had been carried out in the laboratory and proved the application of dry fungal spores to be more effective than the application of formulated spores \[[@B13],[@B14],[@B18]\]. Applying dry spores in the field, however, has certain limitations. Fungal spores are hydrophobic by nature so when applied in an aquatic environment, they clump together, reducing the area that is effectively covered. As a result, massive amounts of fungal spores are required. Contact with water also disrupts the infection process. Attachment of spores to the host is an important step of the infection process. The outer layer of spores has highly organised surface proteins known as rodlets, which are mainly responsible for attachment to the host \[[@B19]\]. For successful infection, germination should follow spore attachment to the host. When dry fungal spores are applied to an aquatic habitat, typical for mosquito larvae, the nutrients in the water are usually sufficient to stimulate germination in the spores following water intake \[[@B20],[@B21]\]. Once a spore germinates, the outer layer is ruptured reducing the chance of attachment to the host. Water contact, thus, reduces the pathogenicity of the floating spores. In addition, dry unformulated fungal spores are more exposed to UV radiation and high temperatures, which are known to negatively affect spore persistence and germination rate \[[@B22],[@B23]\]. In addition to strain selection and genetic modification, formulation can have a considerable impact on improving the efficacy of biopesticides. An ideal formulation aids the handling and application of the biopesticides, as well as increases its efficacy by improving contact with the host and protecting the active agent from environmental factors \[[@B24]\]. Considering the surface feeding behaviour of anopheline larvae, any formulation intended to infect them should spread the fungal spores over the water surface \[[@B25],[@B26]\]. The larvae are then most likely to come in contact with spores. The spores should spread uniformly, providing equal coverage, over the entire treated area. In addition, spores should be prevented from germinating before host attachment, and at least to some extent be protected from environmental factors. In this context we developed and tested dry (organic and inorganic), oil (mineral and synthetic) and water-based formulations of *M. anisopliae*and *B. bassiana*for their efficacy against anopheline larvae. The objectives of this study were to (a) develop formulations suitable for the positioning (water surface or bottom) and uniform spread of *M. anisopliae*and *B. bassiana*spores, (b) assess the efficacy of selected spore formulations in killing anopheline larvae, (c) assess the selected formulations for their potential to increase spore persistence, and (d) assess the potential of formulations to suppress populations of mosquito larvae in a field situation. Methods ======= Mosquitoes ---------- *Anopheles gambiae s.s.*(Suakoko strain, courtesy of Prof. M. Coluzzi, reared in laboratory for 23 years) and *An. stephensi*(Strain STE 2, MR4 no. 128, origin India, reared in laboratory for 2 years after obtaining the eggs from MR4) were reared separately, but under similar conditions, in climate-controlled rooms at Wageningen University, The Netherlands. The temperature was maintained at 27 ± 1°C. Relative humidity was set at 70 ± 5% and the rooms had a 12L:12D photoperiod. Larvae were kept in plastic trays filled with tap water. First instar larvae were fed on Liquifry No. 1 (Interpet Ltd., Surrey, UK) while older instar stages were fed on Tetramin^®^(Tetra, Melle, Germany). The resulting pupae were transferred to holding cages (30 × 30 × 30 cm) in small cups, where they emerged as adults with *ad libitum*access to 6% glucose water. The female mosquitoes were blood-fed with the Hemotek membrane feeding system. Human blood (Sanquin^®^, Nijmegen, The Netherlands) was used for this purpose and mosquitoes could feed on it through a Parafilm M^®^membrane. Eggs were laid on moist filter paper, and were subsequently transferred to the larval trays. For the field bioassays *An. gambiae*s.s. eggs (Kisumu, strain, reared in laboratory for 8 years) were obtained from the Kenya Medical Research Institute (KEMRI) and reared at the Ahero Multipurpose Development Training Institute (AMDTI), Kenya. Rearing was carried out under local climate conditions (described below) and larvae were fed on Tetramin^®^. Fungal spores ------------- *Metarhizium anisopliae*(ICIPE-30) and *Beauveria bassiana*(IMI- 391510) spores were obtained from the Department of Bioprocess Engineering, Wageningen University, and stored as dry spores in Falcon™ tubes at 4°C. *Metarhizium anisopliae*spores are olivaceous green, cylindrical and 2.5-3.5 μm long while *B. bassiana*spores are hyaline, spherical or sub-spherical and have a diameter of 2-3 μm \[[@B27]\]. Carrier materials ----------------- Wheat flour, white pepper, WaterSavr (WaterSavr™, Sodium bicarbonate version, Flexible Solutions International Ltd., Victoria BC, Canada), 0.1% Tween 80 aqueous solution, Ondina oil 917 (Shell Ondina^®^Oil 917, Shell, The Netherlands) and ShellSol T (Shellsol T^®^, Shell, The Netherlands) were tested for their potential as carrier of fungal spores. Wheat flour and white pepper served as organic dry carriers. These were tested because anopheline larvae are known to aggregate around and feed on powdered organic materials (wheat flour, alfalfa flour, blood meal and liver powder) even when a choice of inorganic materials (chalk, charcoal and kaolin) is also available \[[@B28]\]. One inorganic dry powder, known as WaterSavr, was also tested. WaterSavr consists of fine bicarbonate granules that self-spread over the water surface forming a thin layer which has been shown to reduce evaporation \[[@B29]\]. Its biodegradability, safety and surface-spreading features made it a suitable candidate for inclusion in our tests. Surfactants, such as Tween 80, can be used to overcome the hydrophobic nature of fungal spores and form a homogeneous aqueous solution. Fungal spores formulated in Tween 80 have been used in bioassays to test the efficacy of fungal spores against mosquito larvae \[[@B13],[@B16],[@B30]-[@B34]\]. ShellSol T is a synthetic isoparaffinic hydrocarbon solvent. Ondina oil 917, slightly denser than ShellSol T, is a highly refined mineral oil. Both ShellSol T and Ondina oil 917 have been successfully used as carrier for fungal spores to target the adult stage of mosquitoes \[[@B1],[@B35]\]. Formulations ------------ The first selection of carriers suitable for formulating entomopathogenic fungal spores consisted of a test in which the carrier material was evaluated for its ability to spread over the water surface. For this purpose, plastic trays (25 × 25 × 8 cm) were filled with 1 L of tap water and the carriers applied on the water surface (441 cm^2^). The least amount of each carrier required to cover the entire surface was recorded. Once that amount was determined, *M. anisopliae*spores (10 mg, \~ 4.7 × 10^8^spores) were added to the carriers. The quantity of the carriers was increased to make a consistent suspension or mixture of fungal spores and carriers. The resulting formulations were applied to select the carriers that spread the spores evenly over the water surface evenly. *Metarhizium anisopliae*spores were used because of their colour (olivaceous green) which made it easy to visualize them whilst spreading. Efficacy of formulations against *Anopheles gambiae*larvae ---------------------------------------------------------- The next step consisted of testing selected formulations against *An. gambiae*larvae in laboratory bioassays. Bioassays were performed under climatic conditions similar to the mosquito rearing. Plastic trays (25 × 25 × 8 cm) were filled with 1 L of tap water and allowed to acclimatise overnight. Fifty second-instar larvae were added to each tray. Unformulated or formulated spores were applied to the water surface of each tray. The number of larvae that died or pupated was recorded daily for the next eight days. For each treatment, the carrier alone (in the same quantity as in the formulation) served as the control. In the case of unformulated spores, the control was untreated tap water. The larvae were provided with Tetramin^®^as food at the rate of 0.2 - 0.3 mg/larva per day. The experiments were replicated three times. Pathogenicity of floating unformulated spores over time ------------------------------------------------------- A third experiment was performed to evaluate how the pathogenicity of fungal spores is affected by being in contact with water over a time period of seven days. At the start, 15 plastic trays (same size as above) were each filled with one liter of water. These trays were kept overnight in a climate-controlled room to acclimitise. *Metarhizium anisopliae*spores were applied to the water surface in five trays (10 mg per tray). Similarly, 10 mg of *B. bassiana*spores (\~ 2 × 10^9^spores) were applied on the water surface in five other trays. The remaining five trays served as the control. After one day, 50 second-instar *An. stephensi*larvae were added to one of the trays treated with *M. anisopliae*spores, *B. bassiana*spores and one untreated control tray. Similarly larvae were added to remaining trays after either 2, 3, 5 or 7 days after fungal treatment. The mortality and/or pupation was followed for 9 days. The larvae were fed at the same rate as mentioned before. This experiment was replicated three times. Effect of formulation on persistence of pathogenicity ----------------------------------------------------- Based on the results of the formulation experiments, the carriers WaterSavr and ShellSol T were selected and tested further for their ability to increase the persistence of pathogenicity in fungal spores in contact with water. Unformulated and formulated (either with WaterSavr or ShellSol T) *M. anisopliae*and *B. bassiana*spores were applied to plastic trays containing 1 L of acclimatized water. One replicate consisted of 18 trays. A pair of trays was applied with one of the following nine treatments: (1) 10 mg of dry *M. anisopliae*spores, (2) 10 mg of dry *B. bassiana*spores, (3) *M. anisopliae*spores mixed with WaterSavr (10 mg/130 mg), (4) *B. bassiana*spores mixed with WaterSavr (10 mg/130 mg), (5) *M. anisopliae*spores mixed with ShellSol T (10 mg/200 μl), (6) *B. bassiana*spores mixed with ShellSol T (10 mg/200 μl), (7) WaterSavr (130 mg) only, (8) ShellSol (200 μl) only or (9) no treatment. Trays treated with WaterSavr or ShellSol T without fungal spores and the untreated trays served as control for their respective treatments. Fifty second-instar *An. stephensi*larvae were added to one tray of each pair on the same day the fungal spores were applied. The same number of larvae was added to the other tray of the pair on the seventh day (based on the results of the previous experiment). The larvae were checked for mortality or pupation for the following 10 days after being added to the trays. The experiment was replicated three times. The trays were topped up with acclimatised tap water, every other day, to compensate for evaporation. Field bioassays --------------- To evaluate the efficacy of unformulated and formulated fungal spores in the field, experiments were carried out in Kenya in May and June, 2010. The experiments were conducted in a restricted part of the Ahero Multipurpose Development and Training Institute (AMDTI) compound. This institute is located 24 km southeast of Kisumu, in western Kenya (0°10\'S, 34°55\'E). Malaria is highly endemic in this region and transmission occurs throughout the year. A mean annual *Plasmodium falciparum*sporozoite inoculation rates (EIR) of 0.4-17 infective bites per year has been shown by recent studies for this region \[[@B36]\]. The region has an annual mean temperature range of 17°C to 32°C, average annual rainfall of 1,000 - 1,800 mm and average relative humidity of 65% \[[@B37]\]. Bioassays were conducted outdoors in 33 plastic containers (0.30 m diameter). The plastic containers had two nylon-screened holes (3 cm^2^), close to the brim, allowing excess rain water to flow out while retaining the larvae. Dry soil from a rice paddy at the Ahero irrigation scheme (4 km from AMDTI) was softened up by adding water. The softened soil was placed at the bottom of each plastic container to form a 2 cm thick layer. One L of tap water was then added to each plastic container. The water level was 3 cm above soil level and exposed a surface area of 450 cm^2^. Each plastic container was placed in a larger tub that also had a bottom layer of soil but was filled with water to the top. The larger tubs were employed to prevent ants from accessing the plastic container inside. Forty second-instar *An. gambiae s.s.*larvae, were added to each container. The large tubs, with the containers inside, were arranged in three rows 0.5 m apart from each other (Figure [1a](#F1){ref-type="fig"}). ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Field bioassays**. **(a)**Forty *An. gambiae*larvae were placed in plastic containers (with nylon screened holes, indicated by an arrow) with a soil layer (2 cm) at the bottom and a 3 cm layer of water. The screened holes were a precautionary measure to retain larvae in the tubs in case of overflow due to heavy rain. The plastic containers were placed in larger tubs, also filled with soil and water, to prevent ants from access to the bioassays. **(b)**Unformulated (dry) *Metarhizium anisopliae*(10 mg) spores applied on the water surface. Note the two large clumps just outside the centre of the containers. **(c)**Shellsol T-formulated *Metarhizium anisopliae*(10 mg) spores applied on the water surface. Note that spores are spread more evenly over the surface by ShellSol T than dry spores (Figure b). :::  ::: Dry and ShellSol T formulated spores of both fungal species were tested. ShellSol T was the only formulation that successfully met the criteria investigated in the laboratory studies. Two different concentrations (10 mg spores/200 μl ShellSol T and 20 mg spores/230 μl ShellSol T) of both *M. anisopliae*and *B. bassiana*spores were tested. For the larger amount of spores, 230 μl ShellSol T was required to make a consistent suspension. Each treatment was randomly applied to three plastic containers. The 11 treatments consisted of dry *M. anisopliae*spores (10 mg and 20 mg), dry *B. bassiana*spores (10 mg and 20 mg), ShellSol T formulated *M. anisopliae*spores (10 mg/200 μl and 20 mg/230 μl), ShellSol T formulated *B. bassiana*spores (10 mg/200 μl and 20 mg/230 μl) and only ShellSol T (200 μl and 230 μl) while the one remaining tub was untreated. The ShellSol T (200 μl and 230 μl) and the untreated container served as control for their respective treatments. The number of larvae that died in the containers could not be recorded because it was difficult to recover them in the turbid water and/or bottom soil. Therefore, larval survival was assessed as the number of pupae produced. No food was provided to the larvae after being placed in the container. The plastic containers were checked twice daily (for the following 15 days) and pupae were removed with a dipper. To prevent oviposition or emergence of local mosquitoes in the water of larger tubs in which treated plastic containers were placed, Aquatain (a silicone-based oil) was applied to the water surface \[[@B38]\]. Water (0.5 L, kept outdoors in Jerry cans) was added to every plastic container when the water level had been reduced by evaporation to less than 1 cm. Meteorological data was obtained from the National Irrigation Board (NIB) research station located approximately 4 km from the experimental site. Water surface (5 mm top layer) temperature was measured daily at the same time, in each container, with a digital thermometer (GTH 175/Pt, Greisinger electronics, Germany). Statistical analysis -------------------- Differences in larval survival were analysed using Cox regression \[[@B39]\]. The survival of larvae treated with formulated or unformulated fungal spores were compared with their respective control larvae and the resulting Hazard Ratio (HR) values were used to evaluate differences in mortality rates. The proportional hazard assumption of Cox regression was tested by plotting the cumulative hazard rates against time for the treated and control groups to confirm that the resulting curves did not cross \[[@B40]\]. To test the pathogenicity of fungal spores over time, HR\'s were computed for larvae exposed to spores floating on water for different time periods. In addition, the arcsine-square root transformed proportions of dead larvae were compared directly, after being corrected for their respective controls using the Abbott\'s formula, by a one-way ANOVA and LSD post-hoc test of the arcsine transformed mortality proportion \[[@B41]\]. Similarly, the persistence of pathogenicity in formulated and unformulated spores was also compared. The arcsine-square root transformed proportions of larvae that pupated in the field trial were compared by one-way ANOVA and LSD post-hoc tests. All the analyses were performed using SPSS version 15 software (SPSS Inc. Chicago, IL, USA). Results ======= Formulations ------------ In the case of both ShellSol T and Ondina oil 917, 100 μl of the oil was required to cover a water surface of 441 cm^2^. The amounts could not be determined for 0.1% Tween 80 and wheat flour. Tween 80 solution could not be visualised as it is colourless. The wheat flour formed clumps rather than spreading. White pepper spread across the water surface evenly and 30 mg of it was sufficient to cover the entire surface area. Similarly 130 mg of Watersavr spread and covered the water surface of 441 cm^2^(Table [1](#T1){ref-type="table"}). After determining these amounts, 10 mg of *Metarhizium anisopliae*spores was added to each of the carriers. The quantity of ShellSol T and Ondina oil 917 had to be doubled (200 μl) to form a homogenous suspension. In case of the 0.1% Tween 80 solution, 4 ml was required to form a consistent suspension. Wheat flour was not tested further because of clumping. The quantity of white pepper and WaterSavr (30 mg and 130 mg respectively) required for covering the water surface (441 cm^2^) was also enough to form a consistent mixture with 10 mg of fungal spores (Table [1](#T1){ref-type="table"}). Formulations, apart from the 0.1% Tween 80 solution which caused the spores to sink, resulted in a fairly uniform spread of fungal spores on the water surface (Table [1](#T1){ref-type="table"}). Therefore 0.1% Tween 80 solution was not tested further. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Carriers tested for their ability to spread spores and the composition of formulations tested ::: Amount required to ---------------- -------------------- -------- ----------------------- -------------- Wheat flour \-- \-- \-- \-- 0.1% Tween 80 \-- 4 ml causes spores to sink \-- White pepper 30 mg 30 mg on the water surface 10 mg/30 mg WaterSavr 130 mg 130 mg on the water surface 10 mg/130 mg Ondina oil 917 100 μl 200 μl on the water surface 10 mg/200 μl ShellSol T 100 μl 200 μl on the water surface 10 mg/200 μl The amount of each carrier required to cover a water surface area of 441 cm^2^, the amount required to form a consistent mixture with 10 mg of *Metarhizium anisopliae*spores, the ability of the carriers to spread the spores over the water surface and the composition of formulations with suitable carriers \-- Not Tested or could not be determined ::: Efficacy of formulations against *Anopheles gambiae*larvae ---------------------------------------------------------- Bioassays were conducted with unformulated *M. anisopliae*spores (10 mg) and *M. anisopliae*spores formulated in pepper (10 mg/30 mg), WaterSavr (10 mg/130 mg), ShellSol T (10 mg/200 μl )) or Ondina oil 917 (10 mg/200 μl) against *An. gambiae*larvae. Only 2.7 ± 1.8% of the larvae treated with unformulated *M. anisopliae*spores pupated while 47.6 ± 3.9% pupated in the relevant control. The treated larvae had a nearly two times higher daily risk of mortality as compared to the untreated control larvae (HR (95%CI) = 1.8 (1.4-2.4), Table [2](#T2){ref-type="table"}, Figure [2a](#F2){ref-type="fig"}). WaterSavr formulation reduced the pupation of the larvae from 67.2 ± 10.6% to 1.3 ± 0.6%, exposing the formulation-treated larvae to nearly three times higher daily risk of mortality as compared to the control (Table [2](#T2){ref-type="table"}, Figure [2c](#F2){ref-type="fig"}). With the ShellSol T formulation 1.3 ± 0.6% of the treated larvae pupated while the larvae treated with ShellSol T (without fungal spores) showed 85.4 ± 14.5% pupation. Larvae exposed to ShellSol T formulated spores of *M. anisopliae*had a mortality risk four times higher compared to larvae treated with ShellSol T only (HR (95%CI) = 3.7 (2.5-5.4), Table [2](#T2){ref-type="table"}, Figure [2e](#F2){ref-type="fig"}). However, with white pepper and Ondina oil there was no significant difference in the mortality of larvae treated with the formulation or the carrier alone, or the formulations and fungal spores together. Both pepper and Ondina oil 917 killed 100% larvae even without fungal spores (Table [2](#T2){ref-type="table"}, Figure [2b](#F2){ref-type="fig"} and [2d](#F2){ref-type="fig"}). These two carriers were not tested further as the objective was to develop a formulation that enhances the spreading and efficacy of the fungal spores to infect and kill larvae. ::: {#T2 .table-wrap} Table 2 ::: {.caption} ###### Percentage pupation and Hazard ratios of larvae exposed to tested formulations ::: **Average % Pupation ± S.E**. ---------------- ------------------------------- ----------- --------------- --------- Unformulated 47.6 ± 3.9 2.7 ± 1.8 1.8 (1.4-2.4) \<0.001 White pepper 0 0 0.9 (0.7-1.2) 0.959 WaterSavr 67.2 ± 10.6 1.3 ± 0.6 2.7 (1.9-3.8) \<0.001 Ondina oil 917 0 0 1.0 (0.8-1.2) 0.806 ShellSol T 85.4 ± 14.5 1.3 ± 0.6 3.7 (2.5-5.4) \<0.001 Average percentage pupation (±S.E.) of *An. gambiae*larvae exposed to unformulated spores and formulated *Metarhizium anisopliae*spores (n = 3). The carrier in each formulation (White pepper, WaterSavr, Ondina oil 917 or ShellSol T) served as the control. In case of unformulated spores the control was completely untreated. Carrier and *Metarhizium anisopliae*spores together formed the treatment. Hazard ratio\'s (HR) indicate the mortality risk in the treatments as compared to their respective controls ::: ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Laboratory bioassays to test the efficacy of unformulated and formulated *Metarhizium anisopliae*spores**. The average percentage cumulative survival (±S.E.) of *An. gambiae*larvae (n = 3) exposed to **(a)**Unformulated *Metarhizium anisopliae*spores (control (C) and unformulated spores (Ma spores) **(b)**Pepper (control (P)) and Pepper formulated spores (Ma spores + P) **(c)**WaterSavr (control (WS)) and WaterSavr formulated spores (Ma spores + WS) **(d)**Ondina Oil (control (OO)) and Ondina oil formulated spores (Ma spores + OO) **(e)**ShellSol T (control (SS)) and ShellSol T formulated spores (Ma spores + SS) over 8 days post-treatment. Larvae that pupated are included as surviving. :::  ::: Pathogenicity of floating unformulated spores over time ------------------------------------------------------- The pathogenicity of dry *M. anisopliae*and *B. bassiana*spores was substantially reduced over a period of five days (Figure [3](#F3){ref-type="fig"}). *Anopheles stephensi*larvae exposed to *M. anisopliae*spores, applied to water seven days earlier, showed a similar pupation proportion as their control (Table [3](#T3){ref-type="table"}). *Beauveria bassiana*spores lost their effectiveness after being in contact with water for three days. *Metarhizium anisopliae*spores lost their effectiveness after five days (Table [3](#T3){ref-type="table"}). After seven days the control mortality was significantly higher than the mortality of larvae exposed to *M. anisopliae*treatment. ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Laboratory bioassays to test the persistence of floating unformulated fungal spores**. The average percentage corrected mortality (±S.E.) of *An. stephensi*larvae (n = 3) exposed to spores of *Metarhizium anisopliae*and *Beauveria bassiana*that had been floating on the water surface for 1, 2, 3, 5 or 7 days. Bars with letter in common show no significant difference (LSD post hoc test, α = 0.05). :::  ::: ::: {#T3 .table-wrap} Table 3 ::: {.caption} ###### Percentage pupation and Hazard ratio\'s of larvae exposed to unformulated floating fungal spores ::: Average % Pupation (S.E.) HR(95% CI) p value ------- --------------------------- -------------------- ------------ --------------- ------------ -------------- --------- Day 1 82.2 ± 13.5 36.1 ± 22.2 54.5 ± 8.4 5.2(3.4-8.0) \<0.001 3.2(2.0-5.0) \<0.001 Day 2 74.6 ± 10.8 46.7 ± 4.9 64.5 ± 5.3 2.5(1.7-3.6) \<0.001 2.0(1.3-3.0) 0.001 Day 3 96.0 ± 2.3 80.7 ± 8.5 92.8 ± 3.4 6.6(2.5-17.2) \<0.001 2.1(0.7-6.0) 0.169 Day 5 96.7 ± 1.7 87.4 ± 2.7 94.0 ± 3.0 4.4(1.6-11.8) 0.003 1.7(0.5-5.0) 0.347 Day 7 84.6 ± 2.6 84.7 ± 3.3 72.7 ± 2.9 0.3(0.2-0.6) \<0.001^a^ 1.1(0.7-1.9) 0.625 Average percentage pupation (±S.E.) in the control and treated *An. stephensi*larvae exposed to *Metarhizium anisopliae*and *Beauveria bassiana*spores floating on the water surface for 1, 2, 3, 5 and 7 days (n = 3). The controls consisted of untreated trays filled with water at the same time as the treated trays. Hazard ratio\'s (HR) indicate the mortality risk of larvae as compared to the controls for both *Metarhizium anisopliae*and *Beauveria bassiana*spores a\. HR lower than 1 represents higher mortality in the control group. ::: Effect of formulation on persistence of pathogenicity ----------------------------------------------------- Fungal spores formulated with ShellSol T were more persistent compared to the unformulated spores or spores formulated in WaterSavr. Seven days after application only ShellSol T formulated fungal spores (both *M. anisopliae*and *B. bassiana*) still caused significant mortality in the *An. stephensi*larvae (Table [4](#T4){ref-type="table"}). Formulation in WaterSavr seemed to reduce the efficacy of fungal spores. When the *An. stephensi*larvae were exposed to WaterSavr-formulated *M. anisopliae*and *B. bassiana*spores, on the same day the fungal spores were applied, the corrected proportion larval-mortality was significantly lower as compared to larvae exposed to unformulated *M. anisopliae*and *B. bassiana*spores. Larvae exposed to *M. anisopliae*spores formulated with WaterSavr, applied that same day, had a lower mortality risk (HR (95% CI), 8.9 (4.4-18.1)) than those exposed to the unformulated spores (HR (95% CI), 44.6 (10.9-181.7)). There was no significant difference in the corrected proportion mortality of larvae exposed to unformulated and WaterSavr-formulated *M. anisopliae*spores, seven days after their application on water (Figure [4](#F4){ref-type="fig"}). Similar results were observed for *B. bassiana*spores. There was no significant difference between the corrected larval-mortality proportion due to unformulated and WaterSavr formulated *B. bassiana*spores, applied on water seven days before exposing the larvae. Also, the proportion larval mortality caused by WaterSavr-formulated *B. bassiana*spores was significantly lower than with ShellSol T-formulated *B. bassiana*spores (Figure [4](#F4){ref-type="fig"}). ::: {#T4 .table-wrap} Table 4 ::: {.caption} ###### Hazard ratios of larvae exposed to (un)formulated fungal spores, 0 and 7 days post-application ::: Fungus Day Formulation HR (95%CI) p value -------------------------- ----- -------------- --------------------- --------- *Metarhizium anisopliae* 0 Unformulated 44.6 (10.9-181.7) \<0.001 WaterSavr 8.9 (4.4-18.1) \<0.001 ShellSol T 140.1 (18.4-1067.2) \<0.001 7 Unformulated 1.0 (0.5-2.0) 0.816 WaterSavr 1.1 (0.7-1.8) 0.477 ShellSol T 1.5 (1.0-2.2) 0.030 *Beauveria bassiana* 0 Unformulated 36.1 (8.9-146.8) \<0.001 WaterSavr 10.5 (4.7-23.5) \<0.001 ShellSol T 137.9 (18.0-1053.4) \<0.001 7 Unformulated 0.9 (0.4-1.7) 0.716 WaterSavr 1.5 (0.1-2.3) 0.091 ShellSol T 1.9 (1.3-2.9) 0.001 Hazard ratio\'s (HR) indicate the mortality risk of *An. stephensi*larvae exposed to unformulated, WaterSavr-formulated and ShellSol T-formulated *Metarhizium anisopliae*and *Beauveria bassiana*spores, 0 and 7 days after application (n = 3) ::: ::: {#F4 .fig} Figure 4 ::: {.caption} ###### **Laboratory bioassays to test the persistence of formulated fungal spores**. The average percentage corrected mortality (±S.E.) of *An. stephensi*larvae (n = 3) exposed to unformulated, WaterSavr-formulated and ShellSol T-formulated *Metarhizium anisopliae*(Ma) and *Beauveria bassiana*(Bb) spores, immediately (Day 0) or seven days (Day 7) after application. Letters in common (upper case for Ma and lower case for Bb) show no significant difference (LSD post hoc test, α = 0.05). :::  ::: Field bioassays --------------- During the experimental period (15 days), the mean minimum and maximum temperatures were 15.7°C and 30.9°C, respectively, with a mean relative humidity of 54% and total rainfall of 19.4 mm. Water surface temperature ranged from 21°C to 38.8°C. Similar to the laboratory observations, unformulated spores clumped together on the water surface (Figure [1b](#F1){ref-type="fig"}) while ShellSol T-formulated fungal spores were uniformly spread (Figure [1c](#F1){ref-type="fig"}). The efficacy of unformulated fungal spores was found to be low under field conditions as compared to laboratory conditions. At dose rates of both 10 mg and 20 mg, the same (p \> 0.05) level of pupation was observed in the *An. gambiae*larvae treated with unformulated *M. anisopliae*and *B. bassiana*spores as in the untreated *An. gambiae*larvae (Figure [5](#F5){ref-type="fig"}). As observed in the laboratory bioassays, ShellSol T on its own had no harmful effect on larval development and pupation. A similar proportion (p \> 0.05) of larvae pupated in the containers treated with ShellSol T (200 μl and 230 μl) and the untreated containers (Figure [5](#F5){ref-type="fig"}). ::: {#F5 .fig} Figure 5 ::: {.caption} ###### **Field bioassays testing the efficacy of fungal spores formulated in ShellSol T**. The average percentage pupation of *An. gambiae*larvae (n = 3) exposed to unformulated and ShellSol T formulated *Metarhizium anisopliae*(Ma) or *Beauveria bassiana*(Bb) spores at two doses, 10 mg/200 μl and 20 mg/230 μl. Controls included no treatment at all or treatment with only ShellSol T (200 μl or 230 μl). Letters in common show no significant difference (LSD post hoc test, α = 0.05). :::  ::: The percentage pupation observed in *An. gambiae*larvae treated with ShellSol T-formulated *M. anisopliae*spores was 43% (low dose, 10 mg) and 49% (high dose, 20 mg) lower than that of the corresponding unformulated treatments. However for the lower dose (10 mg) the proportion of larvae that pupated was not significantly different (p = 0.08, Figure [5](#F5){ref-type="fig"}). The percentage pupation observed in *An. gambiae*larvae treated with ShellSol T-formulated *B. bassiana*spores was 39% (low dose, 10 mg) and 50% (high dose, 20 mg) lower than that in the corresponding unformulated treatments. At both lower and higher dose the proportion of larvae that pupated was significantly different (p \< 0.05, Figure [5](#F5){ref-type="fig"}). Discussion ========== The results of this study show how certain formulations can improve the ability of entomopathogenic fungus spores to spread over a water surface as well as increase their persistence. The results also show that better spreading and persistence leads to an enhanced efficacy of fungal spores. The study also demonstrates that both *M. anisopliae*and *B. bassiana*caused a high impact on the survival of *An. gambiae*s.s. larvae under field conditions, when formulated in Shellsol T. *Anopheles stephensi*and *An. gambiae*larvae were found to be equally susceptible to unformulated *M. anisopliae*and *B. bassiana*spores \[[@B12]\]. This suggests that these fungi are likely to also affect other anopheline vector species. Formulating fungal spores with Tween 80 and wheat flour was found to be unsuitable. Spores formulated with Tween 80 did not spread over the water surface, the primary feeding site of anopheline larvae, but sunk to the bottom \[[@B25],[@B28]\]. Surfactants are known to impair attachment of the spore to the host so even if the spores were spread on the water surface they would not have been effective against anopheline larvae \[[@B20],[@B42]\]. Wheat flour, although due to its organic nature could have served as a bait, did not spread the fungal spores over the water surface \[[@B28]\]. The wheat flour clumped together and sunk. Powdered pepper and Ondina oil caused 100% mortality in anopheline larvae even without the fungal spores. Extracts of fruits of the *Piperaceae*family have been shown to be toxic for *Aedes aegypti*L. larvae \[[@B43]\], but the exact toxicity mechanism remains unclear. Although fungal spores were effectively spread with white pepper, pepper was considered an unsuitable carrier due to its own toxic effect on the anopheline larvae. Ondina oil, in the amount tested (200 μl), formed an oily layer over the water surface causing the larvae to suffocate. As compared to ShellSol T, Ondina oil is denser and evaporates less. This may explain the difference in the mortality observed with Ondina oil and ShellSol T controls. The amount of Ondina oil tested could not be reduced as, in that case, it was not possible to make a homogeneous suspension with the fungal spores. Dry unformulated *M. anisopliae*and *B. bassiana*spores lost their pathogenicity five days after being applied to the water surface as the survival of larvae exposed to the fungal spores five days after application was similar to that of the controls. Similar results were shown in a study by Alves et al. (2002), where *M. anisopliae*caused no mortality in *Cx. quinquefasciatus*Say larvae introduced four days after the spores were applied \[[@B13]\]. This is in contrast to Pereira et al. (2009), who found *M. anisopliae*spores to cause 50% mortality in *Ae. aegypti*larvae exposed to fungal spores that were applied ten days previously \[[@B34]\]. The studies mentioned here were carried out in controlled climate conditions (25-27°C) in the laboratory. In field conditions the spores are more likely to lose their pathogenicity in less time due to exposure to hight temperatures and UV-radiations. This may explain why unformulated fungal spores did not cause any significant reduction in pupation in the field bioassays, where the water surface temperatures were measured to be as high as 38.8°C. The measured (water surface) temperatures agree with those reported by Paaijmans et al. (2008) for similar sized water-bodies and are known to exhibit high daily fluctuations \[[@B44]\]. When the larvae were exposed to fungal spores on the same day as the spores were applied, unformulated spores and spores formulated in WaterSavr or Shellsol T caused larval mortality over the next few days. However, only fungal spores formulated in ShellSol T caused significantly higher mortality in larvae introduced seven days after the fungal spores had been applied. Fungal spores formulated in ShellSol T remained pathogenic possibly because ShellSol T prevented spores from absorbing the amount of moisture required to stimulate germination \[[@B21],[@B31]\]. ShellSol T was also considered a good carrier of fungal spores in other studies \[[@B31],[@B45]\]. WaterSavr, on the other hand, did not protect fungal spores. ShellSol T was the only formulation that we tested in the field as the laboratory results showed high persistence of pathogenicity in the fungal spores formulated only with this product. Unformulated *M. anisopliae*and *B. bassiana*did not suppress the larval population effectively in the field. In contrast to the situation in the laboratory, the spores were exposed to sunlight, rain and fluctuating temperatures in the field which might have reduced spore survival. By contrast, only 10-20% of the larvae treated with spores formulated in ShellSol T, developed into pupae. Both *M. anisopliae*and *B. bassiana*spores were found to be equally effective when formulated in ShellSol T. Oil formulations are known to improve spore survival, improve fungal efficacy against insects and reduce spore sensitivity to UV radiation \[[@B31],[@B45]\]. In the field residual effect of formulated spores could not be tested after a certain number of days because the plastic containers began to harbour *Culex*larvae and thus had to be drained. The presence of *Culex*larvae is an indication that ovipositing female *Culex*mosquitoes were not repelled by the fungus treatment. It is disadvantageous for a larval control agent to have an oviposition-repellent effect because in that case ovipositing mosquito females are forced to seek and deposit their eggs at alternative untreated sites. This means that the control agent only targets the existing larval population and needs to be reapplied after the site has been inhabited again. Studies specifically designed to establish the response of ovipositing anopheline female mosquitoes to fungal spores and the residual effect of fungal spore treatment are required for a better understanding. Oil-formulated *M. anisopliae*spores have been shown to have an increased ovicidal activity in case of *Ae. aegypti*eggs \[[@B46]\]. This might be an added advantage if anopheline eggs are also affected by *M. anisopliae*spores similar to the *Ae. aegypti*eggs. Pathogenicity of control agents in the field is generally lower than that in the laboratory settings \[[@B47]\]. In the field bioassays, therefore, a higher dose (20 mg/450 cm^2^) of fungal spores was also tested together with the dose tested in the laboratory (10 mg/441 cm^2^). The laboratory dose, however, showed similar efficacy in the field by reducing pupation similar to the higher dose. Therefore doses lower than used in the current study should be evaluated to establish the lowest effective amount of fungal spores required to treat a certain area. ShellSol T was a candidate carrier that not only facilitated the application of spores but also improved their efficacy by providing maximum chance for contact (spreading the spores on the water surface) with the larvae and increasing spore persistence. The fungal spores readily suspend in ShellSol T with a slight agitation. This is advantageous as the spores can be conveniently mixed in ShellSol T, on the spot, which means that during transport and storage only the bio-active agent would have to be kept at low temperatures rather than the whole mixture. This can reduce the cooling space requirement as ShellSol T itself is a stable product and has no particular storage demands. It has been shown that the percentage germination of dry spores is generally higher than that of oil-formulated spores when stored at the same temperature for the same number of days \[\[[@B23]\]; unpublished data\]. The fungal spores *Metarhizium flavoviride*had a germination rate of 80% when stored at 30°C for 90 days as compared to 90% when stored dry under similar environmental conditions \[[@B23]\]. In this context, it seems more efficient to store fungal spores separately and only mix them with the oil-component shortly before application. The results of this study show the necessity of a good formulation for fungal spores when these are to be utilised in the field. The efficacy of unformulated (dry) spores was so low in the field situation that their application, as such, is not justified. While ShellSol T-formulated spores were highly effective in killing anopheline larvae in the field an important point to consider is the potential increased risk to the non-target organisms due to their improved persistence and/or undesirable properties of the solvent \[[@B33],[@B48]-[@B50]\]. ShellSol T has a low toxicity effect on fish, aquatic invertebrates and microorganisms at concentration higher than 1 g/liter \[[@B51]\]. Considering the volume of ShellSol T that we tested (200-230 μl on 1 L of water), the concentration of ShellSol T was 0.15 g/L which is nearly seven times lower than the lowest lethal concentration. ShellSol T evaporates and therefore is less likely to remain in the aquatic habitats. Detailed safety studies, however, are necessary to have a better understanding of any adverse effect ShellSol T might have on the environment and non-target organisms, at the required doses. Besides formulation, it is very important to identify the best delivery method (where, when and how) to fully utilize the entomopathogenic potential of *M. anisopliae*and *B. bassiana*spores. Frequency of re-application has to be determined based on the residual effect of formulated spores in the field. The feasibility of applying formulated spores at artificial breeding sites, baited to attract ovipositing females, is also worth testing \[[@B52]\]. A good delivery system will reduce the chances of non-target organisms coming into contact with fungal spores. Conclusions =========== From a number of candidate products tested for the formulation of entomopathogenic fungi, ShellSol T emerged as a promising carrier of fungal spores when targeting anopheline larvae. Spores of *B. bassiana*and *M. anisopliae*formulated in ShellSol T had an increased efficacy against larvae of *An. gambiae s.s*. as compared to unformulated spores and were also more persistent under field conditions in Kenya. Other oils with physical properties similar to ShellSol T may also serve as good carriers. Together with a sound delivery system, these formulated fungi can be utilised in the field, providing additional tools for biological control of malaria vectors. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= TB designed the study, carried out the experimental work, performed the statistical analysis and drafted the manuscript. CJMK helped with the study design, statistical analyses, and drafting the manuscript. WT provided scientific guidance in interpretation of the findings and drafting the manuscript. All authors read and approved the final manuscript. Acknowledgements ================ We thank MR4 for providing *An. stephensi*eggs and Léon Westerd, André Gidding and Frans van Aggelen for rearing the *An. gambiae*mosquitoes. Frank van Breukelen and Mgeni Jumbe are acknowledged for providing *Metarhizium*and *Beauveria*spores. We are grateful to Vince Pascarelli for shipping free samples of WaterSavr. In Kenya, we are thankful to Dr Andrew Githeko for supplying *An. gambiae*eggs, Joel K. Tanui (Research officer, NIB) for access to the meteorological data and Fred Kisanya (Principal, AMDTI) for allowing us to conduct experiments in the institute premises. We appreciate Daniel Ogwang\'s assistance during the field tests. Tullu Bukhari is funded by HEC, Pakistan, through NUFFIC (The Netherlands). Financial support for the field study was received from the UBS Optimus Foundation, Switzerland and the Adessium Foundation, The Netherlands.

PubMed Central

2024-06-05T04:04:17.268159

2011-2-22

PMC3051917

Background ========== *Beauveria bassiana*is a soil-borne cosmopolitan fungus that infects mostly soil-dwelling insects \[[@B1]\]. For forty two years it has been known that mosquito adults of *Culex*, *Anopheles albimanus*, and the dengue vector *Aedes aegypti*are susceptible to infections by this pathogen \[[@B2]\]. Recently, this fungus and *Metarhizium anisopliae*as well have received considerable attention by medical entomologists as potential microbial control agents against the malaria \[[@B3]-[@B5]\]) and dengue vectors \[[@B6],[@B7]\]. The mortality of adult mosquitoes has been evaluated in many studies after various methods of fungal infection involving both dry and oil-formulated conidia as appears in a recent review \[[@B8]\]). Nonetheless, these fungi could be also disseminated by virgin males toward females in the case of the dengue vector *A. aegypti*due to the male tendency to mate multiple times with different females \[[@B9]\]. An early report stated that a virgin male of *A. aegypti*is capable of mating with and inseminating up to seven females after the first thirty minutes of confinement in a cage \[[@B10]\]. Besides, preliminary observations on the sexual activity of *A. aegypti*virgin males in our laboratory showed that a 6-8 day old male confined with 20 females of the same age inseminated an average of 14, 13 and 5 females after the first 0.5, 1 and 24 hours of captivity in cages (one for each time) (unpublished data). Fungal transmission by sexual activity in insects is a type of horizontal transmission known as autodissemination because occurs between individuals of the same species and generation \[[@B11]\]. To our knowledge, the first report of this type of transmission in vectors of human diseases was for *M. anisopliae*in the tsetse fly *Glossina morsitans morsitans*in 1990 \[[@B12]\]. Following this, previous work in our laboratory has shown that *M. anisopliae*was transmitted by real mating (females infected and inseminated) or copulation attempts (females infected but non-inseminated) from virgin *A. aegypti*males inoculated with conidia to *A. aegypti*females (unpublished data); we demonstrated that a highly virulent strain of *M. anisopliae*caused 90% mortality plus an effect of sterilization when fecundity was recorded in infected females. Therefore, in the present study we evaluated: 1) the virulence of eight Mexican strains of *B. bassiana*, after passage through mosquito adults, against females of *A. aegypti*by exposure of insects to filter papers impregnated with conidia, 2) the transmission rate by mating behavior (true mating and mating attempts) from virgin males to females for two isolates, and 3) the impact of both strains transmitted by sexual activity upon female fecundity. Methods ======= Mosquitoes ---------- A colony of *Aedes aegypti*was established with larvae collected from dengue endemic neighborhoods located at Monterrey, NL, Mexico. Male and female mosquitoes emerging within a 24 h period were kept together for mating and were provided with cotton pads soaked in 5% sucrose solution *ad libitum*. Adults were maintained at 27 (± 2)°C, 85 (± 10%) RH in a 12:12 h L:D photoperiod. Insects were blood fed on the forearm of one of the authors (AMGM) to stimulate egg production. Following the blood meal, oviposition occurred in beakers half filled with water and lined with filter paper. Egg eclosion was stimulated by total immersion of the filter paper in water at 37°C but previously boiled to reduce oxygen tension, in which 0.04 grams of \"Tetramin^®^\" was added for neonates. Larvae were maintained at a density of 200/liter in plastic trays and fed with 3 grams of the same food during the 2^nd^and 5^th^day. Pupae were switched into water-filled beakers and transferred to cages for adult emergence. Recently hatched males and females (3-day old) were separated for bioassays. Fungal strains and preparation of conidia suspension ---------------------------------------------------- Eight strains of *B. bassiana*described in Table [1](#T1){ref-type="table"} were collected from different localities (States) in Mexico. All were cultured first on potato-dextrose-agar (PDA) and incubated at 25°C for 20 days for conidiation. Following incubation, conidia harvest was prepared in 0.5% Tween 20 in 0.85% sodium chloride in distilled water (5 ml of Tween 20 in 1 liter of saline solution) from plates using a micro spatula to carefully separate the spore layer from the agar. Later, a small number of *A. aegypti*females were infected with *B. bassiana*and the pathogen re-isolated from the sporulating cadavers by removing a sample of conidia from the exterior of the cadaver and inoculating again on PDA in Petri dishes. These isolation plates were incubated at 25°C for 20 days. Then, conidia from uncontaminated plates were used to prepare a concentration of 6 × 10^8^conidia ml^-1^per isolate, determined using a Fisher hemocytometer. ::: {#T1 .table-wrap} Table 1 ::: {.caption} ###### Median Lethal Time (LT~50~)^1^± Standard Error (SE) in days computed for samples of forty 6-8 day old females of *A. aegypti*after exposure for 48 hours to a filter paper impregnated with 6 × 10^8^conidia ml ^-1^of each one of eight isolates of *B. bassiana*collected from various localities in Mexico ::: Isolate^1^ LT~50~± SE Host/Source Locality and State ------------ --------------- ---------------------------- --------------------- Bb-CBG1 5.03 ± 0.69 Soil Texcoco, México. Bb-CBG2 2.70 ± 0.29\* Coleoptera (*Aphodius*sp.) Zuazua, Nuevo León Bb-CBG3 3.20 ± 0.42 Soil Marín, Nuevo León Bb-CBG4 5.33 ± 0.53\* Soil Metztitlan, Hidalgo Bb-CBG5 4.06 ± 0.46 Soil Marín, Nuevo León Bb-CBG6 3.30 ± 0.47 Soil Cuernavaca, Morelos Bb-CBG7 3.46 ± 0.47 Soil La Ceiba, Puebla Bb-CBG8 3.60 ± 0.51 Soil Chapingo, México. Control 14.26 ± 0.43 ^1^Significance within the same column, χ^2^= 194.85, df = 8, p \< 0.0001. \*Isolates with the highest and lowest virulence. ::: Infection of mosquitoes ----------------------- Two bioassays were conducted to study the effect of: 1) conidia of eight strains of *B. bassiana*on survival of adult female *A. aegypti*. In this bioassay 1, exposure of females to conidia was for 48 hours to estimate the virulence as the median lethal time (LT~50~) for each strain. 2) limited exposure (48 hours) of females to virgin males previously inoculated for 48 hours with conidia of two fungal strains (those found to be the most and least virulent in the results of bioassay 1 to evaluate the impact of conidia transmitted by mating behavior on female survival, infection (inseminated and not), mortality and fecundity. In bioassay 1, nine treatments were set up: the eight strains of *B. bassiana*plus a control (filter paper only with solutions without fungus). Each treatment was twice replicated, and twenty females were tested per replicate. To prepare one treatment, seven ml with a concentration of 6 × 10^8^conidia ml^-1^was poured on a sterile filter paper in a Petri dish and allowed to dry at 25°C, 60% RH, in laboratory for 24 hours before being placed into an exposure chamber (Figure [1](#F1){ref-type="fig"}) constructed by two half dishes positioned upside down, and both halves taped. A 1 cm hole covered with net in the top half allowed the introduction of twenty 6-8 day old female mosquitoes with a mouth aspirator. Following a 48-h period, two groups of twenty females each were separated; each group was removed from the chamber and switched to 1-liter plastic pot with a cotton mesh-netting top. Pots were maintained at laboratory conditions described above for filter drying. Insects were fed on 5% sucrose offered on cotton pads placed on the netting surface of each pot. Dead insects were removed daily and rinsed in 1% sodium hypochlorite for 20 seconds and then washed twice in distilled water for 20 seconds. All dead mosquitoes were placed in Petri dishes lined with damp filter paper and maintained at 25°C to stimulate conidiogenesis. ::: {#F1 .fig} Figure 1 ::: {.caption} ###### **Chamber for exposure of *A. aegypti*to 6 × 10^8^conidia ml^-1^of *B. bassiana***. A cotton ball soaked with 5% sucrose was placed over the net of the hole at top half. :::  ::: For bioassay 2, three treatments were prepared. Two isolates: the most (Bb-CBG2) and the least virulent (Bb-CBG4) that resulted from the bioassay 1, plus the control; each one was twice replicated, twenty females per replicate. Ten 6-8 day old virgin males were exposed for 48 hours to the same dose for each strain. Thereby, four contaminated males (two of each strain) were transferred individually to 1-liter plastic pots with a cotton mesh-netting top, and confined with twenty 6-8 day old females. Clean males were introduced with twenty females each in two plastic pots as a control. Insects of each replicate were confined for just 48 hours with a male, and blood fed on the forearm of the same volunteer (AMGM) in the first six hours of confinement. Afterwards, engorged females were transferred individually to beakers half filled with water and lined with filter paper for oviposition. All females were dissected immediately after death to check for the presence of sperm in the spermathecae and retention of fully developed eggs in ovaries. Fecundity was considered as the sum of laid and retained eggs from the first gonotrophic cycle. After dissection the cadavers were immersed in 1% sodium hypochlorite for 20 seconds and then washed twice in distilled water for 20 seconds. All carcasses were placed in a humid Petri dish chamber for sporulation to confirm death by the fungus. Mortality and infection rate by successful (insemination) and failed (no insemination) pairings were evaluated on a daily basis until death of the last female in both treated groups and control. Statistical analyses -------------------- The median lethal time (LT~50~) was obtained from the survival analysis computed with the Kaplan-Meier model for the forty females per treatment in both bioassays. Each curve was computed by pooling the two replicates per treatment, after previously performing a test for variation between both replicates by analysis of variance (ANOVA). The mortality and infection rates for true mating (females inseminated and then sporulated), mating attempt (females non-inseminated and then sporulated), and mean fecundity among treatments were analyzed by ANOVA for unbalanced experiments, and Ryan tests for multiple mean comparisons were also computed with proc glm in SAS \[[@B13]\]. Results ======= Susceptibility of *A. aegypti*females to eight strains of *B. bassiana* ----------------------------------------------------------------------- The results shown in Table [1](#T1){ref-type="table"} demonstrated that all fungal strains caused significantly increased mortality (χ^2^= 194.85, df = 8, p \< 0.0001). The 50% mortality (LT~50~) was reached in all strains within the first five days after of the initial exposure to the fungi, whereas in the control the LT~50~was 14 days after of fungal exposure, therefore the maximum life of treated mosquitoes was around 11 days, while those in the control lived almost 25 days. In this screening assay the mortality was evaluated by exposure to filter papers impregnated with 6 × 10^8^conidia ml ^-1^and allowed the identification of the most (Bb-CBG2) and the least virulent (Bb-CBG4) isolates, which had an LT~50~of 2.70 (± 0.29) and 5.33 (± 0.53) days respectively. Susceptibility of *A. aegypti females*to two *B. bassiana*strains transmitted by sexual behavior ------------------------------------------------------------------------------------------------ Results of bioassay 2 that comprised these two strains and the control demonstrated the fungal transmission by mating behavior from contaminated males to healthy females. Figure [2](#F2){ref-type="fig"} shows the survival curves for females confined with a male previously inoculated with either one of the isolates identified in bioassay 1 and the control. Each curve describes the daily death probability for all individuals per treatment, calculated by the Kaplan-Meier model. From these analyses the resulting LT~50~were 7.92 (± 0.46), 8.82 (± 0.48), and 13.92 (± 0.58) days for the Bb-CBG2, Bb-CBG4, and the control, respectively (χ^2^= 56.29, df = 2, p \< 0.0001). Overall, among the forty mosquitoes placed together with the male contaminated with the Bb-CBG2, there were 36 sporulating females (9 with eggs and 27 with no eggs) while in the non-sporulating ones, two laid eggs and other two did not lay eggs. For females confined with the male inoculated with the Bb-CBG4, 31 were mycosed (15 with eggs and 16 with no eggs) and 9 non-mycosed, of which three laid eggs and six did not lay eggs. The females whose carcasses showed conidiogenesis but laid eggs before death represent the females killed by the fungal infection acquired by successful mating where insemination occurred. While those that sporulated without laying eggs comprised the sector of females killed by the pathogen but where infections were transmitted through copulation attempts or other physical contacts carried out by the contaminated male. Figure [3](#F3){ref-type="fig"} shows the results of bioassay 2 where both Bb-CBG2 and Bb-CBG4 caused the same total 78-90% (31, 36/40) mortality (mosquitoes with conidiation) in females exposed to a male contaminated with either isolate, however, this mortality was registered at the end of 15 days, an interval shorter than 22 days that the healthy mosquitoes lived in the control (F = 157.39, df = 2, p \< 0.0001). According to data, 23 and 38% of mosquitoes killed by the fungi actually were infected through copulations with successful inseminations (true matings). The rates of mortality for females infected but not inseminated were 67 (27/40) and 40% (16/40) representing likely the mortality of failed copulations (no insemination). The insemination rate in the control was 78%. ::: {#F2 .fig} Figure 2 ::: {.caption} ###### **Mean cumulative proportional survival (±Standard Error) calculated by the Kaplan-Meier model for forty females of *A. aegypti*confined with a virgin male previously exposed to 6 × 10^8^conidia ml^-1^of two isolates of *B. bassiana*plus Control (healthy male)**. Mortality by fungus was demonstrated by sporulation in cadavers (see text). :::  ::: ::: {#F3 .fig} Figure 3 ::: {.caption} ###### **Proportion of four categories of females of *A. aegypti*confined with a fungus-contaminated male, for two strains of *B. bassiana*plus control (clean male)**. Symbols: A = Sporulated-inseminated, B = Sporulated-not inseminated, C = Not sporulated-inseminated, D = Not sporulated-not inseminated females. :::  ::: Lastly, both strains of *B. bassiana*transmitted by mating behavior exerted a negative impact on egg production. Fecundity of females exposed to the male with the virulent strain Bb-CBG2 had a mean of 2.05 (± 1.02) eggs per female; this mean was 95% lower than the one observed for healthy females in the control which was 42.56 (± 6.90). Likewise, the less virulent Bb-CBG4 diminished the fecundity in 67% in comparison with the control (F = 165.30, df = 3, p \< 0.0001). The secondary pathogenic effect also was observed in the number of ovipositing females (with sporulation) per treatment because these were 9 and 15 for the Bb-CBG2 and Bb-CBG4, and 31 in the control. Besides, in both isolates there were non-infected females that laid eggs. In general, 4 and 9 out of 40 females were not infected (without conidiogenesis), and of these, 2 and 3 laid eggs before death. Discussion ========== This is the first study that demonstrates the transmission of *B. bassiana*by mating behavior from virgin males contaminated with conidia to healthy females in *A. aegypti*. Concerning the bioassay 1, the range 2.70 (± 0.29) - 5.33 (± 0.53) days of the LT~50~observed in Table [1](#T1){ref-type="table"} for the eight isolates of *B. bassiana*we tested against *A. aegypti*, is similar to the 4.1 (± 0.3) days observed for an African strain of *Metarhizium anisopliae*\[[@B6]\]. However, our strains were more pathogenic than the ones investigated in Brazil \[[@B7]\] where assessed three isolates of *B. bassiana*against *A. aegypti*females by indirect contact to a fungal suspension of 1 × 10^9^conidia ml^-1^; they reported a mean total mortality of 26, 30 and 70% for the three strains, while the LT~50~was estimated in 4 days only for the most virulent isolate. Nevertheless, they did not pass the strains through mosquito adults and then re-isolated the fungi on PDA to be used in their bioassays. Other relevant point in bioassay 1 is that the most virulent strain Bb-CBG2 was the only one isolated originally from a dead insect with sporulation, while the rest were isolated from soil (Table [1](#T1){ref-type="table"}). Of particular relevance for our study is the number of females that were infected by mating behavior but not inseminated, because they could represent an indirect measure of the transmission of *B. bassiana*by copulation attempts; moreover, also is the chance of acquiring conidia from plastic pots and this possibility is the same for both inseminated and not inseminated females, and we did not evaluate the transmission rate through this path. Unfortunately there is not a study reporting accurate measures of successful and failed matings in virgin males of *A. aegytpi*to discuss this point. There is just a recent paper \[[@B14]\] where the insemination rate was determined in females confined with virgin males, but in healthy insects, and the rate varied from 69 to 89%, a range similar to the one (80-90%) of our study. It is important to mention that the males inoculated with the virulent Bb-CBG2 died within the 4-6 days after fungus exposure while those with the Bb-CBG4 died in 5-8 days. Whether the males are capable of detecting a severe pathogenic process and then switching to a more aggressive sexual behavior, still remains unknown; however a male infected with a virulent strain is invaded more rapidly by the fungus, and paralysis produced by dextrusins is one of the pathogenic effects \[[@B15]\]. Perhaps the males infected with the Bb-CBG2 were incapable of inseminating the majority of females they approached due to their weakness and slow movements or flight, although the females could also refuse to mate with sick males. Further investigations are necessary to determine the impact of virulence on the role of copulation attempts in this type of horizontal transmission of fungi in *A. aegypti*. There are only two reports that address the transmission of fungi among mosquitoes during mating, but their results are not comparable with our study because of the different methodologies. In one study \[[@B3]\] found only 34.0% mortality in males after pairing inoculated females of the mosquito *Anopheles gambiae*(s. s.) during a confinement of 1 hour, where clean females were previously exposed for 24 hours to 1.6 × 10^10^conidia m^-2^of an isolate of *M. anisopliae*, a study quite different to ours; we inoculated males instead of females, and we exposed them for 48 hours to *B. bassiana*. The second report was our first study (unpublished data) in this research line but with two Mexican isolates of *M. anisopliae*; we found 90% mortality in females exposed to a male contaminated with the strain CBG-Ma-2 applied with the same method we used here. In addition, a paper stated for the tsetse fly, *Glossina morsitans morsitans*\[[@B12]\] reporting a 55.0% mortality of clean females paired for two weeks with males that were sprayed with a fungal suspension either of *M. anisopliae*or *B. bassiana*. Reduction in fecundity is a secondary effect of fungal infections in insects; moreover there is little data for mosquitos. To our knowledge, the first report was in 1985 \[[@B16]\] where observed a reduction in egg viability of *A. aegypti*mosquitoes infected with the entomopathogenic fungus, *Aspergillus parasiticus*Speare. In the other case \[[@B17]\] infected *A. gambiae*adults with *M. anisopliae*but not by mating transmission; anyway they observed that the decrease in egg-laying capacity was most likely to be a direct effect of the reduced amount of blood ingested per blood meal. Finally is our early report (unpublished data) about *M. anisopliae*transmitted by mating behavior, where we observed a severe decrease in the mean fecundity to almost zero (sterilization) in infected females of *A. aegypti*, compared with fecundity in control. Results of studies about the impact of entomopathogenic fungi on human health are controversial. Although they causing opportunistic infections in man \[[@B18]\], they also offer a given extent of safety in human habitats \[[@B19]\]. Whether the intention of our research line is to releasing virgin, fungus-contaminated males of *A. aegypti*at outdoor and indoor conditions to establish a dengue biocontrol, the males will spread conidia not only on females by mating but everywhere each time they make contact with any surface, including skin or head hair of humans. The amount of conidia a male is capable of carrying is unknown; this issue and others are part of ongoing investigations in semi-field and field conditions to explore in more detail this delivery procedure of *B. bassiana*from males to females of *A. aegypti*in Mexico. Conclusions =========== Eight Mexican strains of *B. bassiana*(after a mosquito-passage) were highly pathogenic against *A. aegypti*females with a maximum LT~50~of five days, by exposure of insects to filter papers impregnated with 6 × 10^8^conidia ml ^-1^. This is the first report of transmission of *B. bassiana*by mating behavior from virgin, fungus-contaminated males to females in *A. aegypti*, causing 90% mortality in 15 days. The strains Bb-CBG2 and Bb-CBG4 transmitted sexually from contaminated males decreased the fecundity in 95 and 67% in exposed females. Competing interests =================== The authors declare that they have no competing interests. Authors\' contributions ======================= AMGM collected the fungi in field and isolated them in laboratory, he also performed the bioassays. JAGH collected the *A. aegypti*in field and established the colony used in this study. He is also responsible for maintenance of experimental strains of *B. bassiana*in our laboratory. EART was responsible for the maintenance of mosquito colonies. MARP helped to conceive the original objective of the study, and participated in draft the MS. FRV is responsible for the original idea for this study, conceived the experimental design, performed the statistical analyses and prepared the early draft. Acknowledgements ================ This study was financially supported by Secretaría de Investigación y Posgrado-Instituto Politécnico Nacional (IPN)- Megaproyecto II Red Biotecnología. Filiberto Reyes-Villanueva holds a posdoctoral scholarship from Consejo Nacional de Ciencia y Tecnología-México. Mario A. Rodríguez-Pérez holds a scholarship from Comisión de Operación y Fomento de Actividades Académicas (COFAA)/IPN. We thank COFAA-IPN to cover the publication fees of the present research article. Authors appreciate the kind assistance of Dr. Annabel F.V. Howard in reviewing the concepts and editing the MS. The strain Bb-CBG2 of this study was deposited at the United States Department of Agriculture (USDA) as CBG-Bb-1 and code NRRL 50367.

PubMed Central

2024-06-05T04:04:17.272475

2011-2-26

PMC3051918

Related literature {#sec1} ================== For properties of cinnamic acid derivatives, see: Shi *et al.* (2005[@bb6]); Point *et al.* (1998[@bb4]). For synthetic procedures, see: Wu *et al.* (2008[@bb7]). For a related structure, see: Mouillé *et al.* (1975[@bb3]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~28~H~29~FN~2~O~3~*M* *~r~* = 460.53Monoclinic,*a* = 10.235 (2) Å*b* = 7.8420 (16) Å*c* = 30.385 (6) Åβ = 96.65 (3)°*V* = 2422.4 (8) Å^3^*Z* = 4Mo *K*α radiationμ = 0.09 mm^−1^*T* = 293 K0.20 × 0.10 × 0.10 mm ### Data collection {#sec2.1.2} Enraf--Nonius CAD-4 diffractometerAbsorption correction: ψ scan (North *et al.*, 1968)[@bb8] *T* ~min~ = 0.983, *T* ~max~ = 0.9914730 measured reflections4463 independent reflections2366 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.0313 standard reflections every 200 reflections intensity decay: 1% ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.061*wR*(*F* ^2^) = 0.170*S* = 1.014463 reflections307 parametersH-atom parameters constrainedΔρ~max~ = 0.13 e Å^−3^Δρ~min~ = −0.18 e Å^−3^ {#d5e430} Data collection: *CAD-4 EXPRESS* (Enraf--Nonius, 1994[@bb1]); cell refinement: *CAD-4 EXPRESS*; data reduction: *XCAD4* (Harms & Wocadlo, 1995[@bb2]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb5]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb5]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811006210/pv2381sup1.cif](http://dx.doi.org/10.1107/S1600536811006210/pv2381sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006210/pv2381Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006210/pv2381Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?pv2381&file=pv2381sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?pv2381sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?pv2381&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [PV2381](http://scripts.iucr.org/cgi-bin/sendsup?pv2381)). This study was supported financially by grant No. BK2010538 from the Natural Science Foundation of Jiangsu Province. The authors extend special thanks to Professor Hua-Qin Wang of the Analysis Centre, Nanjing University, for the data collection. Comment ======= Cinnamic acid derivatives have been reported to possess many useful properties, including alpha-glucosidase inhibition, acyl-CoA inhibition, LDL-oxidation inhibition, tyrosinase inhibition, antioxidant, antimicrobial, neuroprotective activities (Shi *et al.*, 2005; Point *et al.*, 1998). We report here the synthesis and crystal structure of a novel cinnamic acid derivative. In the title molecule (Fig. 1), the conformation about the ethene bond C7═C8 is E. The piperazine ring adopts a chair conformation. There are intramolecular and intermolecular C---H···O hydrogen bonds in the title compound (Fig. 2) which consilidate the crystal structure. The bond lenths and angles in the title compound agree well with the corresponding bond lengths and angles in a closely related compound, *trans*-cinnamyl-1-diphenylmethyl-4-piperazine (Mouillé *et al.*, 1975). Experimental {#experimental} ============ The synthesis follows the method of Wu *et al.* (2008). A mixture of (*E*)-3-(4-fluoro phenyl)acrylic acid (1.66 g; 10 mmol), dimethyl sulfoxide (4 ml) and dichloromethane (60 ml) was stirred for 6 h at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in acetone (60 ml) and reacted with 1-(bis(4-methoxyphenyl)methyl) piperazine (4.69 g; 15 mmol) in the presence of triethylamine (12 ml) for 5 h at room temperature. The resultant mixture was cooled. The solid thus obtained was filtered and recrystallized from ethanol to afford the title compound. Pale-yellow single crystals of the title compound suitable for *X*-ray diffraction studies were grown from a mixture of CHCl~3~ and hexane (1:1) by slow evaporation at room temperature. Refinement {#refinement} ========== All H atoms were placed geometrically at distances C---H = 0.93, 0.96, 0.97 and 0.98 Å for aryl, methyl, methylene and methyne type H-atoms, respectively, and included in the refinement in riding motion approximation with *U*~iso~(H) = 1.2 or 1.5*U*~eq~ of the carrier atom. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Molecular structure of the title compound, showing the atom labeling scheme and 70% probability displacement ellipsoids. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Packing diagram of the title compound showing hydrogen bonds as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e134 .table-wrap} ------------------------- ------------------------------------- C~28~H~29~FN~2~O~3~ *F*(000) = 976 *M~r~* = 460.53 *D*~x~ = 1.263 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 25 reflections *a* = 10.235 (2) Å θ = 10--13° *b* = 7.8420 (16) Å µ = 0.09 mm^−1^ *c* = 30.385 (6) Å *T* = 293 K β = 96.65 (3)° Block, pale-yellow *V* = 2422.4 (8) Å^3^ 0.20 × 0.10 × 0.10 mm *Z* = 4 ------------------------- ------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e264 .table-wrap} ------------------------------------------ ---------------------------------------------- Enraf--Nonius CAD-4 diffractometer 2366 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.031 graphite θ~max~ = 25.4°, θ~min~ = 1.4° ω and 2θ scans *h* = 0→12 Absorption correction: multi-scan ψ scan *k* = 0→9 *T*~min~ = 0.983, *T*~max~ = 0.991 *l* = −36→36 4730 measured reflections 3 standard reflections every 200 reflections 4463 independent reflections intensity decay: 1% ------------------------------------------ ---------------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e379 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.061 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.170 H-atom parameters constrained *S* = 1.01 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.080*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4463 reflections (Δ/σ)~max~ \< 0.001 307 parameters Δρ~max~ = 0.13 e Å^−3^ 0 restraints Δρ~min~ = −0.18 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------ ::: Special details {#specialdetails} =============== ::: {#d1e533 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. (North *et al.*, 1968) Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e641 .table-wrap} ------ -------------- ------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ F 1.1036 (2) −0.8047 (3) 0.03071 (8) 0.1138 (8) N1 0.5564 (2) 0.0310 (3) 0.08123 (8) 0.0606 (7) O1 0.4552 (2) −0.1690 (3) 0.03651 (7) 0.0783 (7) C1 0.9101 (3) −0.4669 (4) 0.06924 (11) 0.0723 (10) H1A 0.9196 −0.3770 0.0893 0.087\* O2 0.06003 (19) 0.8563 (3) 0.14269 (7) 0.0658 (6) N2 0.5216 (2) 0.3082 (3) 0.13971 (8) 0.0540 (6) C2 1.0149 (4) −0.5726 (5) 0.06570 (13) 0.0838 (11) H2A 1.0948 −0.5563 0.0831 0.101\* O3 0.93784 (18) 0.7764 (3) 0.25379 (7) 0.0653 (6) C3 0.9982 (4) −0.7018 (5) 0.03591 (13) 0.0779 (10) C4 0.8809 (4) −0.7385 (5) 0.01176 (12) 0.0841 (11) H4A 0.8712 −0.8333 −0.0067 0.101\* C5 0.7775 (4) −0.6302 (5) 0.01579 (11) 0.0755 (10) H5A 0.6967 −0.6512 −0.0007 0.091\* C6 0.7909 (3) −0.4905 (4) 0.04381 (10) 0.0592 (8) C7 0.6790 (3) −0.3740 (4) 0.04508 (10) 0.0636 (9) H7A 0.5982 −0.4155 0.0324 0.076\* C8 0.6773 (3) −0.2193 (4) 0.06162 (10) 0.0619 (9) H8A 0.7551 −0.1731 0.0755 0.074\* C9 0.5553 (3) −0.1162 (4) 0.05889 (10) 0.0574 (8) C10 0.4434 (3) 0.1440 (4) 0.07401 (10) 0.0677 (9) H10A 0.3688 0.0814 0.0595 0.081\* H10B 0.4629 0.2365 0.0546 0.081\* C11 0.4086 (3) 0.2162 (4) 0.11695 (10) 0.0633 (9) H11A 0.3345 0.2932 0.1112 0.076\* H11B 0.3834 0.1246 0.1357 0.076\* C12 0.6265 (3) 0.1835 (4) 0.15010 (11) 0.0662 (9) H12A 0.5962 0.0944 0.1686 0.079\* H12B 0.7016 0.2387 0.1666 0.079\* C13 0.6676 (3) 0.1057 (4) 0.10871 (11) 0.0658 (9) H13A 0.7075 0.1927 0.0919 0.079\* H13B 0.7331 0.0182 0.1167 0.079\* C14 0.4907 (3) 0.4005 (4) 0.17929 (9) 0.0539 (8) H14A 0.4654 0.3170 0.2008 0.065\* C15 0.3763 (3) 0.5219 (4) 0.16789 (10) 0.0496 (7) C16 0.2791 (3) 0.5383 (4) 0.19576 (10) 0.0562 (8) H16A 0.2837 0.4723 0.2213 0.067\* C17 0.1757 (3) 0.6503 (4) 0.18645 (10) 0.0588 (8) H17A 0.1113 0.6587 0.2056 0.071\* C18 0.1677 (3) 0.7490 (4) 0.14916 (10) 0.0517 (7) C19 0.2627 (3) 0.7373 (4) 0.12093 (10) 0.0564 (8) H19A 0.2579 0.8045 0.0956 0.068\* C20 0.3658 (3) 0.6239 (4) 0.13073 (10) 0.0576 (8) H20A 0.4302 0.6165 0.1116 0.069\* C21 0.0545 (3) 0.9718 (4) 0.10672 (11) 0.0739 (10) H21A −0.0246 1.0382 0.1056 0.111\* H21B 0.0548 0.9093 0.0796 0.111\* H21C 0.1295 1.0461 0.1106 0.111\* C22 0.6118 (3) 0.4964 (4) 0.20031 (9) 0.0487 (7) C23 0.6794 (3) 0.6068 (4) 0.17551 (10) 0.0654 (9) H23A 0.6512 0.6209 0.1455 0.078\* C24 0.7869 (3) 0.6956 (4) 0.19426 (10) 0.0640 (9) H24A 0.8311 0.7679 0.1768 0.077\* C25 0.8303 (3) 0.6793 (4) 0.23854 (10) 0.0516 (7) C26 0.7663 (3) 0.5699 (4) 0.26369 (10) 0.0594 (8) H26A 0.7956 0.5555 0.2936 0.071\* C27 0.6569 (3) 0.4799 (4) 0.24439 (10) 0.0583 (8) H27A 0.6134 0.4066 0.2619 0.070\* C28 0.9994 (3) 0.7437 (5) 0.29707 (11) 0.0853 (11) H28A 1.0722 0.8203 0.3037 0.128\* H28B 1.0305 0.6282 0.2989 0.128\* H28C 0.9372 0.7606 0.3180 0.128\* ------ -------------- ------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1478 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ F 0.1173 (18) 0.1002 (17) 0.1298 (19) 0.0444 (15) 0.0391 (15) 0.0195 (15) N1 0.0469 (15) 0.0636 (17) 0.0693 (17) 0.0060 (14) −0.0021 (13) −0.0110 (15) O1 0.0608 (14) 0.0883 (17) 0.0834 (16) −0.0077 (13) −0.0015 (12) −0.0212 (13) C1 0.075 (2) 0.053 (2) 0.084 (2) 0.0013 (19) −0.0119 (19) −0.0117 (18) O2 0.0542 (12) 0.0670 (14) 0.0768 (15) 0.0124 (12) 0.0106 (10) 0.0043 (12) N2 0.0361 (13) 0.0562 (15) 0.0682 (16) 0.0014 (12) −0.0003 (11) −0.0075 (13) C2 0.075 (2) 0.059 (2) 0.113 (3) 0.006 (2) −0.010 (2) −0.003 (2) O3 0.0502 (12) 0.0750 (15) 0.0689 (14) −0.0098 (12) −0.0008 (10) −0.0058 (12) C3 0.087 (3) 0.067 (3) 0.083 (3) 0.019 (2) 0.026 (2) 0.017 (2) C4 0.109 (3) 0.079 (3) 0.066 (2) 0.015 (3) 0.017 (2) −0.018 (2) C5 0.081 (2) 0.080 (3) 0.065 (2) −0.004 (2) 0.0024 (18) −0.019 (2) C6 0.067 (2) 0.0534 (19) 0.0571 (18) −0.0045 (17) 0.0063 (16) −0.0043 (16) C7 0.059 (2) 0.069 (2) 0.062 (2) −0.0046 (18) 0.0049 (16) −0.0068 (18) C8 0.0550 (19) 0.060 (2) 0.070 (2) −0.0064 (17) 0.0063 (15) −0.0123 (18) C9 0.0530 (19) 0.063 (2) 0.0568 (19) −0.0047 (17) 0.0098 (15) −0.0026 (17) C10 0.0502 (18) 0.075 (2) 0.074 (2) 0.0085 (18) −0.0097 (16) −0.0102 (18) C11 0.0391 (16) 0.067 (2) 0.081 (2) 0.0023 (16) −0.0036 (15) −0.0091 (18) C12 0.0475 (18) 0.063 (2) 0.085 (2) 0.0043 (16) −0.0082 (16) −0.0163 (18) C13 0.0429 (17) 0.064 (2) 0.089 (2) 0.0022 (16) 0.0026 (16) −0.0136 (19) C14 0.0489 (17) 0.0533 (18) 0.0598 (19) −0.0024 (15) 0.0077 (14) 0.0045 (16) C15 0.0384 (15) 0.0494 (17) 0.0606 (18) −0.0038 (14) 0.0045 (13) −0.0015 (15) C16 0.0540 (18) 0.0579 (19) 0.0587 (18) −0.0039 (16) 0.0150 (15) 0.0081 (16) C17 0.0470 (17) 0.065 (2) 0.066 (2) 0.0046 (16) 0.0166 (15) 0.0020 (17) C18 0.0414 (16) 0.0525 (18) 0.0610 (19) −0.0016 (15) 0.0059 (14) −0.0063 (16) C19 0.0553 (18) 0.0559 (19) 0.0588 (19) 0.0031 (16) 0.0096 (15) 0.0058 (16) C20 0.0430 (16) 0.067 (2) 0.066 (2) 0.0037 (16) 0.0170 (14) 0.0057 (17) C21 0.059 (2) 0.074 (2) 0.088 (3) 0.0111 (18) 0.0009 (18) 0.006 (2) C22 0.0414 (15) 0.0493 (17) 0.0557 (18) 0.0038 (14) 0.0063 (13) −0.0022 (15) C23 0.062 (2) 0.085 (2) 0.0485 (18) −0.0180 (19) 0.0023 (15) 0.0081 (17) C24 0.0528 (18) 0.079 (2) 0.061 (2) −0.0176 (18) 0.0077 (15) 0.0101 (18) C25 0.0406 (16) 0.0512 (18) 0.063 (2) 0.0044 (15) 0.0061 (15) −0.0050 (16) C26 0.0550 (18) 0.073 (2) 0.0476 (17) 0.0007 (18) −0.0041 (15) 0.0037 (16) C27 0.0533 (18) 0.062 (2) 0.0598 (19) −0.0049 (17) 0.0067 (15) 0.0113 (17) C28 0.063 (2) 0.100 (3) 0.086 (3) −0.003 (2) −0.0217 (19) 0.003 (2) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2128 .table-wrap} ---------------------- ------------ ----------------------- ------------ F---C3 1.370 (4) C12---H12A 0.9700 N1---C9 1.338 (4) C12---H12B 0.9700 N1---C10 1.453 (4) C13---H13A 0.9700 N1---C13 1.455 (4) C13---H13B 0.9700 O1---C9 1.235 (3) C14---C15 1.517 (4) C1---C2 1.370 (4) C14---C22 1.525 (4) C1---C6 1.379 (4) C14---H14A 0.9800 C1---H1A 0.9300 C15---C20 1.378 (4) O2---C18 1.382 (3) C15---C16 1.385 (4) O2---C21 1.416 (3) C16---C17 1.380 (4) N2---C12 1.459 (3) C16---H16A 0.9300 N2---C11 1.466 (3) C17---C18 1.367 (4) N2---C14 1.469 (3) C17---H17A 0.9300 C2---C3 1.357 (5) C18---C19 1.372 (4) C2---H2A 0.9300 C19---C20 1.386 (4) O3---C25 1.374 (3) C19---H19A 0.9300 O3---C28 1.414 (3) C20---H20A 0.9300 C3---C4 1.364 (5) C21---H21A 0.9600 C4---C5 1.373 (5) C21---H21B 0.9600 C4---H4A 0.9300 C21---H21C 0.9600 C5---C6 1.385 (4) C22---C27 1.372 (4) C5---H5A 0.9300 C22---C23 1.384 (4) C6---C7 1.469 (4) C23---C24 1.370 (4) C7---C8 1.314 (4) C23---H23A 0.9300 C7---H7A 0.9300 C24---C25 1.373 (4) C8---C9 1.482 (4) C24---H24A 0.9300 C8---H8A 0.9300 C25---C26 1.365 (4) C10---C11 1.503 (4) C26---C27 1.394 (4) C10---H10A 0.9700 C26---H26A 0.9300 C10---H10B 0.9700 C27---H27A 0.9300 C11---H11A 0.9700 C28---H28A 0.9600 C11---H11B 0.9700 C28---H28B 0.9600 C12---C13 1.501 (4) C28---H28C 0.9600 C9---N1---C10 119.3 (2) C12---C13---H13B 109.3 C9---N1---C13 126.8 (3) H13A---C13---H13B 108.0 C10---N1---C13 113.4 (2) N2---C14---C15 110.8 (2) C2---C1---C6 121.7 (3) N2---C14---C22 110.1 (2) C2---C1---H1A 119.2 C15---C14---C22 110.8 (2) C6---C1---H1A 119.2 N2---C14---H14A 108.3 C18---O2---C21 117.3 (2) C15---C14---H14A 108.3 C12---N2---C11 107.0 (2) C22---C14---H14A 108.3 C12---N2---C14 112.1 (2) C20---C15---C16 117.0 (3) C11---N2---C14 113.3 (2) C20---C15---C14 122.4 (3) C3---C2---C1 117.7 (3) C16---C15---C14 120.6 (3) C3---C2---H2A 121.1 C17---C16---C15 121.5 (3) C1---C2---H2A 121.1 C17---C16---H16A 119.3 C25---O3---C28 117.8 (3) C15---C16---H16A 119.3 C2---C3---C4 123.5 (4) C18---C17---C16 120.1 (3) C2---C3---F 118.5 (4) C18---C17---H17A 120.0 C4---C3---F 118.0 (4) C16---C17---H17A 120.0 C3---C4---C5 117.5 (3) C17---C18---C19 120.1 (3) C3---C4---H4A 121.3 C17---C18---O2 115.6 (3) C5---C4---H4A 121.3 C19---C18---O2 124.3 (3) C4---C5---C6 121.5 (3) C18---C19---C20 119.1 (3) C4---C5---H5A 119.3 C18---C19---H19A 120.5 C6---C5---H5A 119.3 C20---C19---H19A 120.5 C1---C6---C5 118.0 (3) C15---C20---C19 122.3 (3) C1---C6---C7 122.9 (3) C15---C20---H20A 118.9 C5---C6---C7 119.1 (3) C19---C20---H20A 118.9 C8---C7---C6 129.0 (3) O2---C21---H21A 109.5 C8---C7---H7A 115.5 O2---C21---H21B 109.5 C6---C7---H7A 115.5 H21A---C21---H21B 109.5 C7---C8---C9 122.1 (3) O2---C21---H21C 109.5 C7---C8---H8A 119.0 H21A---C21---H21C 109.5 C9---C8---H8A 119.0 H21B---C21---H21C 109.5 O1---C9---N1 121.8 (3) C27---C22---C23 117.2 (3) O1---C9---C8 119.2 (3) C27---C22---C14 121.9 (3) N1---C9---C8 119.0 (3) C23---C22---C14 120.9 (3) N1---C10---C11 111.3 (2) C24---C23---C22 121.3 (3) N1---C10---H10A 109.4 C24---C23---H23A 119.3 C11---C10---H10A 109.4 C22---C23---H23A 119.3 N1---C10---H10B 109.4 C23---C24---C25 120.9 (3) C11---C10---H10B 109.4 C23---C24---H24A 119.6 H10A---C10---H10B 108.0 C25---C24---H24A 119.6 N2---C11---C10 110.0 (2) C26---C25---C24 119.0 (3) N2---C11---H11A 109.7 C26---C25---O3 125.2 (3) C10---C11---H11A 109.7 C24---C25---O3 115.8 (3) N2---C11---H11B 109.7 C25---C26---C27 119.8 (3) C10---C11---H11B 109.7 C25---C26---H26A 120.1 H11A---C11---H11B 108.2 C27---C26---H26A 120.1 N2---C12---C13 111.2 (3) C22---C27---C26 121.8 (3) N2---C12---H12A 109.4 C22---C27---H27A 119.1 C13---C12---H12A 109.4 C26---C27---H27A 119.1 N2---C12---H12B 109.4 O3---C28---H28A 109.5 C13---C12---H12B 109.4 O3---C28---H28B 109.5 H12A---C12---H12B 108.0 H28A---C28---H28B 109.5 N1---C13---C12 111.6 (2) O3---C28---H28C 109.5 N1---C13---H13A 109.3 H28A---C28---H28C 109.5 C12---C13---H13A 109.3 H28B---C28---H28C 109.5 N1---C13---H13B 109.3 C6---C1---C2---C3 0.4 (5) N2---C14---C15---C20 −43.6 (4) C1---C2---C3---C4 −4.6 (6) C22---C14---C15---C20 79.0 (3) C1---C2---C3---F 177.5 (3) N2---C14---C15---C16 138.6 (3) C2---C3---C4---C5 4.9 (6) C22---C14---C15---C16 −98.9 (3) F---C3---C4---C5 −177.2 (3) C20---C15---C16---C17 0.7 (4) C3---C4---C5---C6 −1.0 (5) C14---C15---C16---C17 178.7 (3) C2---C1---C6---C5 3.1 (5) C15---C16---C17---C18 −0.4 (4) C2---C1---C6---C7 −176.5 (3) C16---C17---C18---C19 −0.1 (4) C4---C5---C6---C1 −2.8 (5) C16---C17---C18---O2 179.6 (2) C4---C5---C6---C7 176.9 (3) C21---O2---C18---C17 174.3 (3) C1---C6---C7---C8 15.0 (5) C21---O2---C18---C19 −5.9 (4) C5---C6---C7---C8 −164.7 (3) C17---C18---C19---C20 0.2 (4) C6---C7---C8---C9 178.1 (3) O2---C18---C19---C20 −179.5 (3) C10---N1---C9---O1 −9.2 (4) C16---C15---C20---C19 −0.6 (4) C13---N1---C9---O1 179.7 (3) C14---C15---C20---C19 −178.6 (3) C10---N1---C9---C8 171.6 (3) C18---C19---C20---C15 0.2 (4) C13---N1---C9---C8 0.6 (5) N2---C14---C22---C27 −128.0 (3) C7---C8---C9---O1 −7.7 (5) C15---C14---C22---C27 109.0 (3) C7---C8---C9---N1 171.5 (3) N2---C14---C22---C23 53.2 (4) C9---N1---C10---C11 137.5 (3) C15---C14---C22---C23 −69.8 (3) C13---N1---C10---C11 −50.3 (4) C27---C22---C23---C24 0.0 (5) C12---N2---C11---C10 −63.1 (3) C14---C22---C23---C24 178.9 (3) C14---N2---C11---C10 172.9 (2) C22---C23---C24---C25 −0.7 (5) N1---C10---C11---N2 57.9 (3) C23---C24---C25---C26 1.4 (5) C11---N2---C12---C13 62.0 (3) C23---C24---C25---O3 −179.1 (3) C14---N2---C12---C13 −173.2 (2) C28---O3---C25---C26 9.6 (4) C9---N1---C13---C12 −139.8 (3) C28---O3---C25---C24 −169.8 (3) C10---N1---C13---C12 48.7 (4) C24---C25---C26---C27 −1.4 (4) N2---C12---C13---N1 −55.2 (4) O3---C25---C26---C27 179.2 (3) C12---N2---C14---C15 −176.8 (2) C23---C22---C27---C26 0.0 (4) C11---N2---C14---C15 −55.6 (3) C14---C22---C27---C26 −178.9 (3) C12---N2---C14---C22 60.3 (3) C25---C26---C27---C22 0.7 (5) C11---N2---C14---C22 −178.5 (2) ---------------------- ------------ ----------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3330 .table-wrap} --------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C5---H5A···O1^i^ 0.93 2.28 3.131 (4) 152 C17---H17A···O3^ii^ 0.93 2.60 3.499 (4) 163 C10---H10A···O1 0.97 2.30 2.715 (4) 105 C7---H7A···O1 0.93 2.43 2.786 (4) 102 --------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*−1, −*z*; (ii) *x*−1, *y*, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ----------- ------------- C5---H5*A*⋯O1^i^ 0.93 2.28 3.131 (4) 152 C17---H17*A*⋯O3^ii^ 0.93 2.60 3.499 (4) 163 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.274968

2011-2-23

PMC3051919

Related literature {#sec1} ================== For the synthesis, see: Lai *et al.* (1993[@bb5]). For a related structure, see: Bringmann & Messer (2001[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~8~H~8~Br~2~O*M* *~r~* = 279.96Monoclinic,*a* = 7.3604 (5) Å*b* = 4.4310 (6) Å*c* = 14.0245 (10) Åβ = 92.482 (1)°*V* = 456.96 (8) Å^3^*Z* = 2Mo *K*α radiationμ = 8.81 mm^−1^*T* = 298 K0.16 × 0.12 × 0.10 mm ### Data collection {#sec2.1.2} Bruker SMART CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb6]) *T* ~min~ = 0.333, *T* ~max~ = 0.4735557 measured reflections2250 independent reflections1882 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.042 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.037*wR*(*F* ^2^) = 0.090*S* = 0.992250 reflections102 parametersH-atom parameters constrainedΔρ~max~ = 0.57 e Å^−3^Δρ~min~ = −0.29 e Å^−3^Absolute structure: Flack (1983[@bb4]), 1275 Friedel pairsFlack parameter: 0.02 (2) {#d5e411} Data collection: *SMART* (Bruker, 1997[@bb2]); cell refinement: *SAINT* (Bruker, 1999[@bb3]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb7]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811003151/ng5106sup1.cif](http://dx.doi.org/10.1107/S1600536811003151/ng5106sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003151/ng5106Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003151/ng5106Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?ng5106&file=ng5106sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?ng5106sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?ng5106&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [NG5106](http://scripts.iucr.org/cgi-bin/sendsup?ng5106)). This research was supported by the Top-class Foundation of Pingdingshan University (No. 2006045). Comment ======= In the title compound,*C*\~8\~H\~8\~Br\~2Õ, the adjacent molecules are molecules are joined togethe by the O1---H1···O1 (-*x*, *y* - 1/2, 2 - *z*) hydrogen bond, forming a one-dimensional chain running parallel to the \[010\] direction(Table 1 and Figure 2). Also Br···Br interaction was observed in (I) with a distance of 3.362 (1) Å between them All the bond lengths and angles are similar to the reported compound (Bringmann *et al.*, 2001). Experimental {#experimental} ============ The title compound, synthesized by 2,3-dimethyl phenylamine through three steps such as bromination, diazotization-bromination-hydrolysis reaction.The operating process was based on the literarure (Lai *et al.*, 1993) and made some improvement. Firstly, 1-amino-4-bromo-2,3-dimethylbenzene was prepared from 2,3-dimethyl phenylamine as described in the literarure(Lai *et al.*, 1993). Then treatment as follows: Sodiumnitrite (1.75 g, 25 mmol) in water (10 ml) was added dropwise into the rapidly stirring mixture of 40% hydrogen bromide (15 ml) containing l-amino-2,3-dimethylbenzene (5.00 g, 25 mmol). The mixture was kept in an ice-bath stiring for 2 h, while the temperature was kept below 5°C by the addition of pieces of ice. Then added 1.97 g (14 mmol) cuprous bromide which was pretreatmented by refluxing with 10 ml 40% hydrogen bromide solution for 1 h. After the addition the mixture was heated refluxing for an additional 1 h, and then cooled to room temperature, extract by methylenechloride. The organic layer was washed by water, dried by anhydrous natriumsulfate, evaporated under reduced pressure and chromatographed on silica gel with hexane as the eluent. The title compound was obtained as needle crystal solid 1.82 grams. Yield was 26%. Colorless needle-like single crystals suitable for X-ray diffraction studies were obtained by slow evaporation of a solution of the title compound in chloroform: methanol (3: 1) at room temperature. Refinement {#refinement} ========== In (I), all carbon H atoms were positioned geometrically and refined as riding atoms, with C---H = 0.93 Å and *U*\\ĩso\\\~(H) = 1.2*U*\\\~eq\\\~(C) for aromatic H atoms, and C---H = 0.96 Å and *U*\\ĩso\\\~(H) =1.5*U*\\\~eq\\\~(C) for methyl H atoms. H1 atom was found first from the difference map and placed at its ideal position with the O---H=0.82Å and U\\ĩso\\\~(H)=1.5U\\\~eq\\\~(O). The Friedel pairs is 1275. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The structure of the title compound, showing 30% probability displacement ellipsoids and the atom-numbering scheme. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Part of the crystal packing, showing the formation of the one-dimensional chain in (I) by the O1---H1···O1(-x, y - 1/2, 2 - z) hydrogen bond. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e139 .table-wrap} ----------------------- --------------------------------------- C~8~H~8~Br~2~O *F*(000) = 268 *M~r~* = 279.96 *D*~x~ = 2.035 Mg m^−3^ Monoclinic, *P*2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2yb Cell parameters from 2355 reflections *a* = 7.3604 (5) Å θ = 2.8--24.5° *b* = 4.4310 (6) Å µ = 8.81 mm^−1^ *c* = 14.0245 (10) Å *T* = 298 K β = 92.482 (1)° Needle, colorless *V* = 456.96 (8) Å^3^ 0.16 × 0.12 × 0.10 mm *Z* = 2 ----------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e264 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker SMART CCD area-detector diffractometer 2250 independent reflections Radiation source: fine-focus sealed tube 1882 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.042 phi and ω scans θ~max~ = 28.3°, θ~min~ = 2.8° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −9→9 *T*~min~ = 0.333, *T*~max~ = 0.473 *k* = −5→5 5557 measured reflections *l* = −18→18 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e379 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.037 H-atom parameters constrained *wR*(*F*^2^) = 0.090 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0403*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 0.99 (Δ/σ)~max~ = 0.001 2250 reflections Δρ~max~ = 0.57 e Å^−3^ 102 parameters Δρ~min~ = −0.29 e Å^−3^ 0 restraints Absolute structure: Flack (1983), 1275 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: 0.02 (2) ---------------------------------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e538 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e637 .table-wrap} ----- ------------- --------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Br1 0.87217 (5) −0.34219 (12) 0.92038 (3) 0.05521 (15) Br2 0.86105 (8) 0.29262 (15) 0.57447 (4) 0.0790 (2) C1 0.5729 (5) 0.0139 (10) 0.8491 (3) 0.0436 (9) C2 0.4789 (5) 0.2000 (10) 0.7846 (3) 0.0458 (10) C3 0.5600 (6) 0.2866 (12) 0.6995 (3) 0.0496 (9) C4 0.7350 (6) 0.1753 (13) 0.6843 (3) 0.0516 (9) C5 0.8255 (5) −0.0114 (11) 0.7471 (3) 0.0498 (10) H5 0.9405 −0.0835 0.7342 0.060\* C6 0.7440 (5) −0.0922 (9) 0.8300 (3) 0.0429 (9) C7 0.2920 (6) 0.3103 (13) 0.8071 (4) 0.0621 (12) H7A 0.2479 0.1971 0.8597 0.093\* H7B 0.2110 0.2837 0.7522 0.093\* H7C 0.2978 0.5204 0.8237 0.093\* C8 0.4589 (8) 0.4836 (14) 0.6281 (4) 0.0684 (14) H8A 0.5442 0.5917 0.5911 0.103\* H8B 0.3849 0.6245 0.6610 0.103\* H8C 0.3828 0.3605 0.5866 0.103\* O1 0.4886 (4) −0.0551 (8) 0.9326 (2) 0.0533 (8) H1 0.5505 −0.1777 0.9634 0.080\* ----- ------------- --------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e914 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Br1 0.0508 (2) 0.0528 (2) 0.0620 (3) 0.0041 (2) 0.00077 (17) −0.0045 (2) Br2 0.0927 (4) 0.0918 (4) 0.0547 (3) −0.0172 (3) 0.0285 (3) −0.0037 (3) C1 0.043 (2) 0.0419 (19) 0.046 (2) −0.0093 (17) 0.0072 (16) −0.0128 (19) C2 0.047 (2) 0.042 (3) 0.049 (2) −0.0074 (17) 0.0016 (16) −0.0067 (17) C3 0.061 (2) 0.044 (2) 0.043 (2) −0.012 (2) −0.0015 (18) −0.007 (2) C4 0.059 (2) 0.054 (2) 0.043 (2) −0.015 (2) 0.0118 (16) −0.004 (2) C5 0.045 (2) 0.049 (2) 0.056 (3) −0.006 (2) 0.0103 (18) −0.014 (2) C6 0.043 (2) 0.042 (2) 0.043 (2) −0.0011 (17) −0.0010 (16) −0.0099 (18) C7 0.046 (2) 0.066 (3) 0.074 (3) 0.004 (2) 0.007 (2) 0.001 (3) C8 0.089 (4) 0.063 (3) 0.052 (3) −0.001 (3) −0.006 (3) 0.002 (3) O1 0.0545 (17) 0.0582 (19) 0.0482 (18) 0.0023 (15) 0.0143 (13) 0.0007 (15) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1163 .table-wrap} ------------------- ------------ -------------------- ------------ Br1---C6 1.903 (4) C5---C6 1.379 (6) Br2---C4 1.905 (4) C5---H5 0.9300 C1---C6 1.381 (5) C7---H7A 0.9600 C1---O1 1.383 (5) C7---H7B 0.9600 C1---C2 1.387 (6) C7---H7C 0.9600 C2---C3 1.411 (6) C8---H8A 0.9600 C2---C7 1.507 (6) C8---H8B 0.9600 C3---C4 1.404 (7) C8---H8C 0.9600 C3---C8 1.501 (7) O1---H1 0.8200 C4---C5 1.361 (7) C6---C1---O1 122.4 (4) C5---C6---Br1 119.5 (3) C6---C1---C2 120.6 (4) C1---C6---Br1 119.9 (3) O1---C1---C2 117.1 (3) C2---C7---H7A 109.5 C1---C2---C3 119.8 (4) C2---C7---H7B 109.5 C1---C2---C7 119.4 (4) H7A---C7---H7B 109.5 C3---C2---C7 120.9 (4) C2---C7---H7C 109.5 C4---C3---C2 117.2 (4) H7A---C7---H7C 109.5 C4---C3---C8 122.4 (4) H7B---C7---H7C 109.5 C2---C3---C8 120.4 (4) C3---C8---H8A 109.5 C5---C4---C3 122.8 (4) C3---C8---H8B 109.5 C5---C4---Br2 116.6 (3) H8A---C8---H8B 109.5 C3---C4---Br2 120.6 (4) C3---C8---H8C 109.5 C4---C5---C6 119.0 (4) H8A---C8---H8C 109.5 C4---C5---H5 120.5 H8B---C8---H8C 109.5 C6---C5---H5 120.5 C1---O1---H1 109.5 C5---C6---C1 120.6 (4) C6---C1---C2---C3 −1.2 (6) C2---C3---C4---Br2 −177.2 (3) O1---C1---C2---C3 178.0 (4) C8---C3---C4---Br2 4.2 (7) C6---C1---C2---C7 179.6 (4) C3---C4---C5---C6 −1.1 (7) O1---C1---C2---C7 −1.3 (6) Br2---C4---C5---C6 177.0 (3) C1---C2---C3---C4 0.3 (6) C4---C5---C6---C1 0.2 (6) C7---C2---C3---C4 179.6 (4) C4---C5---C6---Br1 −177.9 (3) C1---C2---C3---C8 178.9 (4) O1---C1---C6---C5 −178.2 (4) C7---C2---C3---C8 −1.8 (7) C2---C1---C6---C5 0.9 (6) C2---C3---C4---C5 0.8 (7) O1---C1---C6---Br1 −0.1 (5) C8---C3---C4---C5 −177.8 (5) C2---C1---C6---Br1 179.0 (3) ------------------- ------------ -------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1530 .table-wrap} ----------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O1---H1···O1^i^ 0.82 2.25 2.913 (4) 139. O1---H1···Br1 0.82 2.57 3.108 (3) 124. C8---H8A···Br2 0.96 2.70 3.200 (6) 113. ----------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, *y*−1/2, −*z*+2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------- --------- ------- ----------- ------------- O1---H1⋯O1^i^ 0.82 2.25 2.913 (4) 139 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.280775

2011-2-26

PMC3051920

Related literature {#sec1} ================== For applications of Schiff base compounds, see: Ando *et al.* (2004[@bb1]); Guo *et al.* (2010[@bb4]). For the preparation of the Schiff base, see: Pouralimardan *et al.* (2007[@bb6]); Sacconi (1954[@bb7]). For related structures, see: Monfared *et al.* (2009[@bb5]); Sun *et al.* (2008[@bb9]); Yu, Zhao *et al.* (2010[@bb12]); Yu, Li *et al.* (2010[@bb11]); Zhang *et al.* (2004[@bb13]); Zou *et al.* (2010[@bb14]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Co(C~15~H~12~N~2~O~3~)(C~5~H~5~N)~3~\]ClO~4~*M* *~r~* = 663.95Monoclinic,*a* = 10.7591 (5) Å*b* = 13.2318 (6) Å*c* = 21.0558 (10) Åβ = 94.610 (1)°*V* = 2987.9 (2) Å^3^*Z* = 4Mo *K*α radiationμ = 0.72 mm^−1^*T* = 185 K0.20 × 0.18 × 0.12 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2004[@bb3]) *T* ~min~ = 0.869, *T* ~max~ = 0.9197543 measured reflections4991 independent reflections4431 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.027 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.036*wR*(*F* ^2^) = 0.072*S* = 1.004991 reflections398 parameters2 restraintsH-atom parameters constrainedΔρ~max~ = 0.35 e Å^−3^Δρ~min~ = −0.29 e Å^−3^Absolute structure: Flack (1983[@bb15]), 2332 Friedel pairsFlack parameter: 0.011 (12) {#d5e526} Data collection: *APEX2* (Bruker, 2004[@bb3]); cell refinement: *SAINT* (Bruker, 2004[@bb3]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb8]); molecular graphics: *DIAMOND* (Brandenburg, 1999[@bb2]); software used to prepare material for publication: *SHELXL97* and *publCIF* (Westrip, 2010[@bb10]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004715/mw2001sup1.cif](http://dx.doi.org/10.1107/S1600536811004715/mw2001sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004715/mw2001Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004715/mw2001Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?mw2001&file=mw2001sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?mw2001sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?mw2001&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [MW2001](http://scripts.iucr.org/cgi-bin/sendsup?mw2001)). We thank the project supported by the Department of Education of Jilin Province, China (200837) and Changchun University of Science and Technology for their financial support. Comment ======= The development of routes and strategies for the design and construction of Schiff base compounds are of great interest not only because of their intriguing structural motifs but also because of their important applications in antitumor activities (Ando *et al.,* 2004), magnetochemistry (Guo *et al.*, 2010), and so on. Acylhydrazone ligands are widely used to assemble coordination polymers, which have received a considerable interest over the last decade. From the structural point of view, selection of the Schiff base ligand 3-methoxysalicylaldehyde benzoylhydrazide(H~2~*L*) is a good choice for construction of coordination polymers with defined geometry and special properties, due to its containing a combination of nitrogen and oxygen donor atoms (Yu, Zhao *et al.*, 2010). Some geometrically intriguing supramolecular structures derived from this ligand have been reported including structurally characterized species with Mn~2~ (Yu, Li *et al.*, 2010), Cu~4~ (Monfared *et al.*, 2009), Fe~1~ (Zou *et al.*, 2010) units among others. As a continuation of our efforts on this system, we report the synthesis and characterization of the title cobalt(III) compound. The molecular structure of \[Co^III^(C~15~H~12~N~2~O~3~)(C~5~H~5~N)~3~\]ClO~4~, together with the atom-numbering scheme, is illustrated in Fig. 1. Selected bond lengths are given in Table 1. The asymmetric unit of the title compound consists of a mononuclear cation \[Co^III^(C~15~H~12~N~2~O~3~)(C~5~H~5~N)~3~\]^+^, accompanied by one perchlorate anion. Several mononuclear compounds with similar structures have been reported previously (Sun *et al.*, 2008; Zhang *et al.*, 2004). The cobalt(III) atom has a distorted octahedral geometry, which consists of two oxygen atoms (O1 and O2) and one nitrogen atom (N2) of *L*^2-^ and three nitrogen atoms (N3, N4 and N5) from three pyridine molecules. In the ligand, the angles for the equatorial donor atoms \[82.99 (11)° for O1---Co1---N2 and 93.38 (11)° for O2---Co1---N2\] correspond, respectively, with the more constrained five-membered chelate ring O1---C7---N1---N2---Co1 and the less constrained six-membered ring N2---C8---C9---C10---O2---Co1. The N~2~O~2~ equatorial plane, defined by O1 O2, N3 and N5, shows a small but significant tetrahedral distortion. The maximum displacements from the least-squares plane through atoms O1, O2, N3 and N5 are 0.027 (3)and 0.025 (3) Å for atoms O1 and O2, respectively; Co1 is 0.0396 (4) Å below this plane. Experimental {#experimental} ============ The 3-methoxysalicylaldehyde benzoylhydrazide ligand (H~2~*L*) was prepared in a manner similar to the reported procedures (Pouralimardan *et al.*, 2007; Sacconi, 1954). The title compound was synthesized by adding Co(ClO~4~)~2~.6H~2~O (0.2 mmol) to a solution of H~2~*L* (0.20 mmol) in methanol 20 ml. The resulting mixture was stirred at room temperature to afford a dark brown solution. After 10 min pyridine (1 ml) was added and the solution was stirred for 3 h. Slow evaporation of the resulting dark brown solution over three weeks afforded brown crystals of the product. Refinement {#refinement} ========== All H atoms were placed in calculated positions and refined using a riding model \[C--H (aromatic) = 0.95 Å; C--H (CH~3~) = 0.98 Å; and *U*ĩso(H) = 1.5*U*eq(C)\]. The displacement ellipsoids for O6 and O7 are significantly larger than those of their neighbors suggesting some degree of disorder in this side of the anion however attempts to model this disorder with a split-atom model proved unsatisfactory. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the title compound. Displacement ellipsoids are drawn at the 40% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e230 .table-wrap} ------------------------------------------------ --------------------------------------- \[Co(C~15~H~12~N~2~O~3~)(C~5~H~5~N)~3~\]ClO~4~ *F*(000) = 1368 *M~r~* = 663.95 *D*~x~ = 1.476 Mg m^−3^ Monoclinic, *Cc* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: C -2yc Cell parameters from 4029 reflections *a* = 10.7591 (5) Å θ = 4.9--50.1° *b* = 13.2318 (6) Å µ = 0.72 mm^−1^ *c* = 21.0558 (10) Å *T* = 185 K β = 94.610 (1)° Block, brown *V* = 2987.9 (2) Å^3^ 0.20 × 0.18 × 0.12 mm *Z* = 4 ------------------------------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e369 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker APEXII CCD area-detector diffractometer 4991 independent reflections Radiation source: fine-focus sealed tube 4431 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.027 φ and ω scans θ~max~ = 25.1°, θ~min~ = 1.9° Absorption correction: multi-scan (*SADABS*; Bruker, 2004) *h* = −12→12 *T*~min~ = 0.869, *T*~max~ = 0.919 *k* = −15→10 7543 measured reflections *l* = −24→25 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e486 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.036 H-atom parameters constrained *wR*(*F*^2^) = 0.072 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0182*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.00 (Δ/σ)~max~ = 0.001 4991 reflections Δρ~max~ = 0.35 e Å^−3^ 398 parameters Δρ~min~ = −0.29 e Å^−3^ 2 restraints Absolute structure: Flack (1983), 2332 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: 0.011 (12) ---------------------------------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e645 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e744 .table-wrap} ------ ------------- -------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl1 0.16794 (8) 0.46289 (8) 0.39641 (4) 0.0359 (2) Co1 0.43297 (3) 0.52399 (3) 0.15848 (2) 0.02070 (11) C1 −0.0228 (3) 0.4207 (3) 0.15340 (18) 0.0328 (9) H1A 0.0004 0.3967 0.1952 0.039\* C2 −0.1460 (3) 0.4165 (3) 0.12945 (19) 0.0374 (10) H2 −0.2070 0.3888 0.1546 0.045\* C3 −0.1808 (3) 0.4523 (3) 0.06960 (19) 0.0366 (9) H3 −0.2658 0.4495 0.0535 0.044\* C4 −0.0923 (3) 0.4925 (3) 0.03236 (16) 0.0299 (8) H4 −0.1162 0.5174 −0.0091 0.036\* C5 0.0310 (3) 0.4960 (2) 0.05629 (16) 0.0243 (8) H5 0.0917 0.5238 0.0309 0.029\* C6 0.0675 (3) 0.4598 (2) 0.11655 (15) 0.0203 (7) C7 0.1985 (3) 0.4645 (2) 0.14193 (15) 0.0211 (7) C8 0.4045 (3) 0.3970 (3) 0.26468 (16) 0.0257 (8) H8 0.3563 0.3500 0.2863 0.031\* C9 0.5224 (3) 0.4264 (3) 0.29441 (16) 0.0272 (8) C10 0.6075 (3) 0.4826 (2) 0.26093 (16) 0.0244 (7) C11 0.7181 (3) 0.5184 (3) 0.29505 (18) 0.0309 (8) C12 0.7422 (4) 0.4979 (3) 0.35821 (19) 0.0405 (10) H12 0.8168 0.5219 0.3804 0.049\* C13 0.6570 (4) 0.4416 (3) 0.3905 (2) 0.0439 (11) H13 0.6743 0.4275 0.4346 0.053\* C14 0.5498 (3) 0.4068 (3) 0.35949 (17) 0.0360 (9) H14 0.4928 0.3688 0.3821 0.043\* C15 0.9083 (4) 0.6080 (4) 0.2875 (2) 0.0614 (14) H15A 0.8939 0.6510 0.3241 0.074\* H15B 0.9524 0.6467 0.2566 0.074\* H15C 0.9587 0.5494 0.3020 0.074\* C16 0.5344 (3) 0.3336 (3) 0.11885 (17) 0.0279 (8) H16 0.5618 0.3288 0.1628 0.033\* C17 0.5655 (3) 0.2574 (3) 0.07847 (18) 0.0323 (9) H17 0.6123 0.2008 0.0946 0.039\* C18 0.5280 (4) 0.2640 (3) 0.01462 (19) 0.0400 (10) H18 0.5497 0.2130 −0.0142 0.048\* C19 0.4576 (3) 0.3469 (3) −0.00668 (17) 0.0356 (9) H19 0.4300 0.3539 −0.0505 0.043\* C20 0.4281 (3) 0.4198 (3) 0.03744 (16) 0.0290 (9) H20 0.3780 0.4757 0.0231 0.035\* C21 0.4288 (3) 0.6714 (3) 0.05572 (16) 0.0272 (8) H21 0.3416 0.6592 0.0539 0.033\* C22 0.4729 (4) 0.7378 (3) 0.01264 (17) 0.0346 (9) H22 0.4175 0.7704 −0.0182 0.042\* C23 0.6008 (4) 0.7560 (3) 0.01530 (18) 0.0342 (9) H23 0.6348 0.8008 −0.0140 0.041\* C24 0.6760 (4) 0.7082 (3) 0.06089 (18) 0.0346 (9) H24 0.7633 0.7204 0.0640 0.041\* C25 0.6260 (3) 0.6423 (3) 0.10249 (17) 0.0280 (8) H25 0.6799 0.6091 0.1338 0.034\* C26 0.2924 (3) 0.6392 (3) 0.24550 (17) 0.0311 (9) H26 0.2249 0.5971 0.2303 0.037\* C27 0.2755 (4) 0.7074 (3) 0.29368 (19) 0.0407 (10) H27 0.1967 0.7133 0.3106 0.049\* C28 0.3734 (4) 0.7665 (3) 0.31680 (18) 0.0434 (11) H28 0.3639 0.8119 0.3510 0.052\* C29 0.4846 (4) 0.7596 (3) 0.29042 (17) 0.0379 (9) H29 0.5528 0.8012 0.3053 0.045\* C30 0.4966 (3) 0.6918 (2) 0.24201 (16) 0.0293 (8) H30 0.5742 0.6876 0.2236 0.035\* N1 0.2366 (2) 0.4037 (2) 0.18851 (12) 0.0218 (6) N2 0.3587 (2) 0.4305 (2) 0.20981 (13) 0.0221 (7) N3 0.4673 (2) 0.4141 (2) 0.09866 (13) 0.0236 (7) N4 0.5022 (2) 0.6234 (2) 0.09999 (13) 0.0226 (7) N5 0.4026 (2) 0.6309 (2) 0.21957 (12) 0.0231 (7) O1 0.2693 (2) 0.53324 (17) 0.11795 (11) 0.0231 (6) O2 0.5914 (2) 0.50462 (18) 0.19950 (11) 0.0249 (6) O3 0.7924 (2) 0.5744 (2) 0.25842 (12) 0.0397 (7) O4 0.0449 (2) 0.4311 (2) 0.40770 (12) 0.0444 (7) O5 0.1830 (3) 0.4614 (2) 0.33036 (12) 0.0529 (8) O6 0.1873 (4) 0.5628 (3) 0.41864 (19) 0.1058 (16) O7 0.2518 (3) 0.3989 (4) 0.4303 (2) 0.1226 (19) ------ ------------- -------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1664 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.0324 (5) 0.0473 (6) 0.0278 (5) −0.0055 (5) 0.0017 (4) −0.0020 (4) Co1 0.0196 (2) 0.0223 (2) 0.0201 (2) 0.0008 (2) 0.00069 (16) 0.0003 (2) C1 0.031 (2) 0.039 (2) 0.029 (2) 0.0017 (17) 0.0005 (17) 0.0075 (18) C2 0.0226 (19) 0.048 (2) 0.042 (2) −0.0104 (19) 0.0074 (18) 0.001 (2) C3 0.0205 (18) 0.036 (2) 0.053 (3) −0.0018 (17) −0.0017 (18) −0.0009 (19) C4 0.0265 (19) 0.035 (2) 0.027 (2) 0.0033 (17) −0.0041 (16) 0.0033 (16) C5 0.0213 (18) 0.0247 (19) 0.0279 (19) −0.0019 (15) 0.0080 (15) 0.0005 (15) C6 0.0212 (16) 0.0208 (18) 0.0190 (17) 0.0007 (14) 0.0019 (13) −0.0030 (14) C7 0.0209 (17) 0.0215 (18) 0.0212 (18) −0.0024 (14) 0.0044 (14) −0.0049 (15) C8 0.0300 (19) 0.025 (2) 0.023 (2) 0.0059 (16) 0.0062 (16) 0.0068 (16) C9 0.0233 (18) 0.030 (2) 0.028 (2) 0.0036 (16) −0.0002 (15) 0.0020 (16) C10 0.0230 (18) 0.0251 (18) 0.0240 (19) 0.0065 (16) −0.0047 (14) 0.0001 (16) C11 0.0258 (19) 0.030 (2) 0.036 (2) 0.0004 (16) −0.0044 (16) 0.0023 (17) C12 0.036 (2) 0.049 (3) 0.034 (2) 0.0016 (19) −0.0123 (17) 0.0012 (19) C13 0.040 (2) 0.062 (3) 0.028 (2) −0.001 (2) −0.0042 (18) 0.003 (2) C14 0.033 (2) 0.044 (2) 0.030 (2) 0.0042 (18) −0.0036 (17) 0.0096 (18) C15 0.042 (3) 0.070 (3) 0.068 (3) −0.025 (2) −0.017 (2) 0.019 (3) C16 0.0209 (17) 0.029 (2) 0.034 (2) 0.0002 (16) 0.0039 (15) 0.0010 (16) C17 0.028 (2) 0.024 (2) 0.045 (2) 0.0037 (16) 0.0055 (18) −0.0034 (17) C18 0.041 (2) 0.032 (2) 0.048 (3) 0.0020 (19) 0.015 (2) −0.0157 (19) C19 0.043 (2) 0.039 (2) 0.025 (2) −0.0064 (19) 0.0038 (17) −0.0085 (17) C20 0.034 (2) 0.0222 (19) 0.030 (2) −0.0026 (17) 0.0018 (17) −0.0033 (16) C21 0.0302 (19) 0.024 (2) 0.027 (2) −0.0002 (16) 0.0018 (16) 0.0007 (16) C22 0.044 (2) 0.035 (2) 0.024 (2) 0.0009 (19) −0.0030 (18) 0.0046 (17) C23 0.046 (2) 0.027 (2) 0.031 (2) −0.006 (2) 0.0118 (19) 0.0030 (18) C24 0.032 (2) 0.033 (2) 0.039 (2) −0.0063 (18) 0.0079 (17) −0.0001 (18) C25 0.0244 (19) 0.030 (2) 0.030 (2) −0.0004 (16) 0.0044 (16) 0.0021 (16) C26 0.035 (2) 0.030 (2) 0.029 (2) 0.0049 (17) 0.0048 (17) −0.0030 (16) C27 0.051 (3) 0.032 (2) 0.041 (2) 0.005 (2) 0.021 (2) −0.0032 (19) C28 0.071 (3) 0.033 (3) 0.027 (2) 0.000 (2) 0.009 (2) −0.0062 (18) C29 0.049 (2) 0.030 (2) 0.033 (2) −0.0051 (19) −0.0034 (19) −0.0027 (17) C30 0.034 (2) 0.0231 (19) 0.030 (2) −0.0036 (17) 0.0001 (16) −0.0008 (16) N1 0.0174 (14) 0.0254 (16) 0.0220 (15) −0.0027 (12) −0.0023 (11) 0.0008 (12) N2 0.0221 (15) 0.0241 (17) 0.0204 (16) 0.0015 (13) 0.0032 (12) −0.0018 (13) N3 0.0206 (15) 0.0267 (17) 0.0237 (17) 0.0005 (13) 0.0039 (13) 0.0009 (13) N4 0.0235 (15) 0.0204 (16) 0.0240 (16) −0.0005 (13) 0.0023 (13) −0.0032 (12) N5 0.0279 (16) 0.0214 (16) 0.0201 (16) 0.0015 (14) 0.0022 (13) 0.0005 (13) O1 0.0204 (13) 0.0250 (14) 0.0240 (14) −0.0020 (10) 0.0016 (11) 0.0028 (11) O2 0.0183 (12) 0.0336 (15) 0.0223 (14) −0.0002 (10) −0.0011 (11) 0.0032 (11) O3 0.0259 (13) 0.0492 (18) 0.0421 (16) −0.0111 (13) −0.0093 (12) 0.0085 (14) O4 0.0353 (15) 0.0655 (19) 0.0331 (15) −0.0087 (14) 0.0075 (12) −0.0004 (13) O5 0.0571 (18) 0.073 (2) 0.0310 (16) −0.0146 (16) 0.0199 (14) −0.0125 (14) O6 0.170 (4) 0.074 (3) 0.082 (3) −0.071 (3) 0.058 (3) −0.050 (2) O7 0.052 (2) 0.178 (5) 0.137 (4) 0.029 (3) 0.003 (2) 0.094 (4) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2485 .table-wrap} ----------------- ------------- ------------------- ----------- Cl1---O7 1.392 (4) C15---O3 1.416 (4) Cl1---O5 1.413 (3) C15---H15A 0.9800 Cl1---O6 1.412 (4) C15---H15B 0.9800 Cl1---O4 1.427 (2) C15---H15C 0.9800 Co1---O2 1.866 (2) C16---N3 1.338 (4) Co1---N2 1.864 (3) C16---C17 1.377 (5) Co1---O1 1.898 (2) C16---H16 0.9500 Co1---N5 1.957 (3) C17---C18 1.375 (5) Co1---N3 1.977 (3) C17---H17 0.9500 Co1---N4 1.987 (3) C18---C19 1.387 (5) C1---C2 1.381 (5) C18---H18 0.9500 C1---C6 1.391 (4) C19---C20 1.393 (5) C1---H1A 0.9500 C19---H19 0.9500 C2---C3 1.370 (5) C20---N3 1.326 (4) C2---H2 0.9500 C20---H20 0.9500 C3---C4 1.388 (5) C21---N4 1.334 (4) C3---H3 0.9500 C21---C22 1.374 (5) C4---C5 1.381 (5) C21---H21 0.9500 C4---H4 0.9500 C22---C23 1.394 (5) C5---C6 1.384 (5) C22---H22 0.9500 C5---H5 0.9500 C23---C24 1.361 (5) C6---C7 1.468 (4) C23---H23 0.9500 C7---O1 1.314 (4) C24---C25 1.376 (5) C7---N1 1.309 (4) C24---H24 0.9500 C8---N2 1.297 (4) C25---N4 1.352 (4) C8---C9 1.423 (5) C25---H25 0.9500 C8---H8 0.9500 C26---N5 1.349 (4) C9---C14 1.402 (5) C26---C27 1.381 (5) C9---C10 1.411 (4) C26---H26 0.9500 C10---O2 1.324 (4) C27---C28 1.369 (5) C10---C11 1.422 (4) C27---H27 0.9500 C11---O3 1.372 (4) C28---C29 1.362 (5) C11---C12 1.361 (5) C28---H28 0.9500 C12---C13 1.400 (5) C29---C30 1.372 (5) C12---H12 0.9500 C29---H29 0.9500 C13---C14 1.360 (5) C30---N5 1.349 (4) C13---H13 0.9500 C30---H30 0.9500 C14---H14 0.9500 N1---N2 1.399 (3) O7---Cl1---O5 112.1 (2) H15A---C15---H15B 109.5 O7---Cl1---O6 109.1 (3) O3---C15---H15C 109.5 O5---Cl1---O6 108.3 (2) H15A---C15---H15C 109.5 O7---Cl1---O4 107.9 (2) H15B---C15---H15C 109.5 O5---Cl1---O4 109.92 (16) N3---C16---C17 122.6 (3) O6---Cl1---O4 109.6 (2) N3---C16---H16 118.7 O2---Co1---N2 93.38 (11) C17---C16---H16 118.7 O2---Co1---O1 175.67 (11) C18---C17---C16 119.4 (4) N2---Co1---O1 82.99 (11) C18---C17---H17 120.3 O2---Co1---N5 89.42 (11) C16---C17---H17 120.3 N2---Co1---N5 89.80 (12) C17---C18---C19 118.4 (3) O1---Co1---N5 92.92 (11) C17---C18---H18 120.8 O2---Co1---N3 89.06 (11) C19---C18---H18 120.8 N2---Co1---N3 89.56 (11) C18---C19---C20 118.7 (3) O1---Co1---N3 88.55 (10) C18---C19---H19 120.7 N5---Co1---N3 178.31 (13) C20---C19---H19 120.7 O2---Co1---N4 90.21 (11) N3---C20---C19 122.5 (3) N2---Co1---N4 176.30 (13) N3---C20---H20 118.7 O1---Co1---N4 93.39 (11) C19---C20---H20 118.7 N5---Co1---N4 91.12 (10) N4---C21---C22 123.3 (3) N3---Co1---N4 89.61 (12) N4---C21---H21 118.3 C2---C1---C6 120.3 (3) C22---C21---H21 118.3 C2---C1---H1A 119.9 C21---C22---C23 118.5 (4) C6---C1---H1A 119.9 C21---C22---H22 120.8 C3---C2---C1 120.4 (3) C23---C22---H22 120.8 C3---C2---H2 119.8 C24---C23---C22 118.5 (4) C1---C2---H2 119.8 C24---C23---H23 120.8 C2---C3---C4 120.2 (3) C22---C23---H23 120.8 C2---C3---H3 119.9 C23---C24---C25 120.2 (3) C4---C3---H3 119.9 C23---C24---H24 119.9 C5---C4---C3 119.3 (3) C25---C24---H24 119.9 C5---C4---H4 120.3 N4---C25---C24 121.8 (3) C3---C4---H4 120.3 N4---C25---H25 119.1 C4---C5---C6 121.1 (3) C24---C25---H25 119.1 C4---C5---H5 119.4 N5---C26---C27 121.4 (4) C6---C5---H5 119.4 N5---C26---H26 119.3 C5---C6---C1 118.7 (3) C27---C26---H26 119.3 C5---C6---C7 120.9 (3) C28---C27---C26 119.5 (4) C1---C6---C7 120.4 (3) C28---C27---H27 120.3 O1---C7---N1 123.9 (3) C26---C27---H27 120.3 O1---C7---C6 117.3 (3) C29---C28---C27 119.5 (4) N1---C7---C6 118.7 (3) C29---C28---H28 120.2 N2---C8---C9 124.0 (3) C27---C28---H28 120.2 N2---C8---H8 118.0 C28---C29---C30 119.0 (4) C9---C8---H8 118.0 C28---C29---H29 120.5 C14---C9---C10 119.5 (3) C30---C29---H29 120.5 C14---C9---C8 119.3 (3) N5---C30---C29 122.6 (3) C10---C9---C8 121.0 (3) N5---C30---H30 118.7 O2---C10---C9 124.4 (3) C29---C30---H30 118.7 O2---C10---C11 117.3 (3) C7---N1---N2 108.2 (3) C9---C10---C11 118.3 (3) C8---N2---N1 118.6 (3) O3---C11---C12 125.7 (3) C8---N2---Co1 126.4 (3) O3---C11---C10 113.5 (3) N1---N2---Co1 114.7 (2) C12---C11---C10 120.9 (3) C20---N3---C16 118.4 (3) C11---C12---C13 120.0 (4) C20---N3---Co1 121.1 (2) C11---C12---H12 120.0 C16---N3---Co1 120.5 (2) C13---C12---H12 120.0 C21---N4---C25 117.7 (3) C14---C13---C12 120.7 (4) C21---N4---Co1 121.2 (2) C14---C13---H13 119.7 C25---N4---Co1 121.0 (2) C12---C13---H13 119.7 C30---N5---C26 118.0 (3) C13---C14---C9 120.7 (4) C30---N5---Co1 120.1 (2) C13---C14---H14 119.7 C26---N5---Co1 121.5 (2) C9---C14---H14 119.7 C7---O1---Co1 109.2 (2) O3---C15---H15A 109.5 C10---O2---Co1 121.7 (2) O3---C15---H15B 109.5 C11---O3---C15 117.3 (3) ----------------- ------------- ------------------- ----------- ::: ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Selected bond lengths (Å) ::: ---------- ----------- Co1---O2 1.866 (2) Co1---N2 1.864 (3) Co1---O1 1.898 (2) Co1---N5 1.957 (3) Co1---N3 1.977 (3) Co1---N4 1.987 (3) ---------- ----------- :::

PubMed Central

2024-06-05T04:04:17.284213

2011-2-12

PMC3051921

Related literature {#sec1} ================== For the structures of nickel(II) complexes with 4-(2-amino­eth­yl)morpholine (*L*), see: Chattopadhyay *et al.* (2005[@bb3]); Laskar *et al.* (2001[@bb4]). For the structures of other metal complexes with the ligand (*L*), see: Shi *et al.* (2006[@bb7]) and literature cited therein. Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[CdCl~2~(C~6~H~14~N~2~O)~2~\]*M* *~r~* = 443.68Orthorhombic,*a* = 19.6443 (2) Å*b* = 10.6159 (1) Å*c* = 8.3553 (1) Å*V* = 1742.43 (3) Å^3^*Z* = 4Mo *K*α radiationμ = 1.57 mm^−1^*T* = 100 K0.18 × 0.16 × 0.03 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb5]) *T* ~min~ = 0.765, *T* ~max~ = 0.95420511 measured reflections2009 independent reflections1619 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.026 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.039*wR*(*F* ^2^) = 0.078*S* = 1.282009 reflections103 parameters2 restraintsH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 1.00 e Å^−3^Δρ~min~ = −1.06 e Å^−3^ {#d5e534} Data collection: *APEX2* (Bruker, 2007[@bb2]); cell refinement: *SAINT* (Bruker, 2007[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb6]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb6]); molecular graphics: *X-SEED* (Barbour, 2001[@bb1]); software used to prepare material for publication: *SHELXL97* and *publCIF* (Westrip, 2010[@bb8]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811003709/si2331sup1.cif](http://dx.doi.org/10.1107/S1600536811003709/si2331sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003709/si2331Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003709/si2331Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?si2331&file=si2331sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?si2331sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?si2331&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [SI2331](http://scripts.iucr.org/cgi-bin/sendsup?si2331)). The authors thank the University of Malaya for funding this study (FRGS grant No. FP004/2010B). Comment ======= The title compound was obtained upon complexation of 4-(2-aminoethyl)morpholine with CdCl~2~. Similar to what was observed in the other metal complexes of 4-(2-aminoethyl)morpholine (Chattopadhyay *et al.*, 2005; Laskar *et al.*, 2001), the morpholine ring adopts a chair conformation and the amine acts as an *N,N\'*-bidentate ligand to form a five-membered chelate ring with the metal center. Within the formed chelate ring, the Cd---N distances are considerably different from one another (Table 1). By contrast, the Pt---N bond lenghts in the square-planar complex of PtCl~2~ with the amine ligand (Shi *et al.*, 2006) are only slightly different \[2.018 (6) and 2.075 (5) Å\]. The Cd^II^ ion, placed on a 2-fold rotation axis, is six-coordinated by two of the amine ligands and two Cl atoms in a distorted octahedral geometry. The crystal structure is consolidated by intermolecular N---H···Cl and C---H···O and also intramolecular C---H···Cl hydrogen bonding interactions (Table 2). Experimental {#experimental} ============ A solution of cadmium(II) chloride (0.92 g, 5.0 mmol) in minimum amount of water was added to an ethanolic solution (50 ml) of 4-(2-aminoethyl)morpholine (1.30 g, 10 mmol). The resulting solution was refluxed for 30 min, then left at room temperature. The crystals of the title complex were obtained in a few days. Refinement {#refinement} ========== The C-bound hydrogen atoms were placed at calculated positions (C---H 0.99 Å) and were treated as riding on their parent atoms. The amine hydrogen atoms were located in a difference Fourier map and refined with a restrained N---H distance of 0.91 (3) Å. For all hydrogen atoms *U*iso(H) were set to 1.2 times *U*eq(carrier atom). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Thermal ellipsoid plot of the title compound at the 50% probability level. Unlabelled non-H atoms in the complex are related to labelled atoms by \[1 - x, y, 1/2 - z\]. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e125 .table-wrap} -------------------------------- --------------------------------------- \[CdCl~2~(C~6~H~14~N~2~O)~2~\] *F*(000) = 904 *M~r~* = 443.68 *D*~x~ = 1.691 Mg m^−3^ Orthorhombic, *Pcca* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2a 2ac Cell parameters from 6671 reflections *a* = 19.6443 (2) Å θ = 3.3--30.4° *b* = 10.6159 (1) Å µ = 1.57 mm^−1^ *c* = 8.3553 (1) Å *T* = 100 K *V* = 1742.43 (3) Å^3^ Plate, colorless *Z* = 4 0.18 × 0.16 × 0.03 mm -------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e253 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker APEXII CCD diffractometer 2009 independent reflections Radiation source: fine-focus sealed tube 1619 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.026 φ and ω scans θ~max~ = 27.5°, θ~min~ = 1.9° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −25→24 *T*~min~ = 0.765, *T*~max~ = 0.954 *k* = −13→13 20511 measured reflections *l* = −10→10 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e370 .table-wrap} ------------------------------------- --------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.039 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.078 H atoms treated by a mixture of independent and constrained refinement *S* = 1.28 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.*P*)^2^ + 9.8151*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2009 reflections (Δ/σ)~max~ \< 0.001 103 parameters Δρ~max~ = 1.00 e Å^−3^ 2 restraints Δρ~min~ = −1.06 e Å^−3^ ------------------------------------- --------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e527 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e626 .table-wrap} ----- -------------- -------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cd1 0.5000 0.74719 (3) 0.2500 0.01253 (10) Cl1 0.5000 0.49837 (12) 0.2500 0.0181 (3) Cl2 0.5000 0.99440 (12) 0.2500 0.0173 (3) O1 0.31029 (15) 0.7816 (3) −0.0516 (3) 0.0249 (7) N1 0.37113 (16) 0.7319 (3) 0.2563 (4) 0.0182 (6) N2 0.47563 (16) 0.7529 (3) 0.5179 (3) 0.0112 (6) H2C 0.497 (2) 0.815 (3) 0.566 (5) 0.013\* H2D 0.491 (2) 0.682 (3) 0.565 (5) 0.013\* C1 0.3397 (2) 0.6315 (4) 0.1558 (5) 0.0213 (9) H1A 0.2916 0.6197 0.1878 0.026\* H1B 0.3640 0.5509 0.1736 0.026\* C2 0.3431 (2) 0.6660 (4) −0.0196 (5) 0.0256 (9) H2A 0.3913 0.6719 −0.0529 0.031\* H2B 0.3213 0.5986 −0.0836 0.031\* C3 0.3403 (2) 0.8793 (4) 0.0428 (5) 0.0212 (9) H3A 0.3166 0.9597 0.0206 0.025\* H3B 0.3886 0.8895 0.0114 0.025\* C4 0.3365 (2) 0.8516 (4) 0.2191 (5) 0.0213 (9) H4A 0.3583 0.9210 0.2796 0.026\* H4B 0.2882 0.8465 0.2524 0.026\* C5 0.3615 (2) 0.6927 (4) 0.4264 (5) 0.0217 (9) H5A 0.3753 0.6035 0.4383 0.026\* H5B 0.3126 0.6990 0.4542 0.026\* C6 0.4020 (2) 0.7721 (4) 0.5403 (5) 0.0210 (9) H6A 0.3909 0.8620 0.5230 0.025\* H6B 0.3894 0.7501 0.6516 0.025\* ----- -------------- -------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e984 .table-wrap} ----- -------------- -------------- -------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cd1 0.01464 (18) 0.01259 (17) 0.01036 (17) 0.000 0.00092 (15) 0.000 Cl1 0.0252 (7) 0.0131 (5) 0.0161 (6) 0.000 −0.0003 (6) 0.000 Cl2 0.0234 (6) 0.0130 (5) 0.0155 (6) 0.000 −0.0011 (5) 0.000 O1 0.0217 (15) 0.0351 (17) 0.0178 (14) 0.0025 (13) −0.0058 (12) 0.0038 (13) N1 0.0172 (14) 0.0242 (17) 0.0133 (14) −0.0006 (13) 0.0010 (13) 0.0038 (16) N2 0.0181 (14) 0.0074 (13) 0.0082 (13) 0.0010 (12) −0.0001 (11) −0.0005 (12) C1 0.0172 (19) 0.0103 (17) 0.036 (3) −0.0043 (15) −0.0047 (18) 0.0025 (18) C2 0.023 (2) 0.028 (2) 0.026 (2) −0.0008 (18) −0.0047 (18) −0.0127 (19) C3 0.018 (2) 0.019 (2) 0.026 (2) −0.0005 (16) −0.0020 (17) 0.0088 (17) C4 0.0158 (18) 0.0178 (19) 0.030 (2) 0.0017 (15) −0.0001 (17) −0.0073 (17) C5 0.023 (2) 0.024 (2) 0.017 (2) −0.0008 (17) 0.0024 (16) 0.0048 (17) C6 0.019 (2) 0.032 (2) 0.0114 (17) 0.0013 (17) 0.0030 (15) 0.0007 (17) ----- -------------- -------------- -------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1242 .table-wrap} --------------------- ------------- ---------------- ----------- Cd1---N2 2.290 (3) C1---H1A 0.9900 Cd1---N2^i^ 2.290 (3) C1---H1B 0.9900 Cd1---N1 2.537 (3) C2---H2A 0.9900 Cd1---N1^i^ 2.537 (3) C2---H2B 0.9900 Cd1---Cl2 2.6244 (13) C3---C4 1.503 (6) Cd1---Cl1 2.6414 (14) C3---H3A 0.9900 O1---C2 1.411 (5) C3---H3B 0.9900 O1---C3 1.430 (5) C4---H4A 0.9900 N1---C4 1.475 (5) C4---H4B 0.9900 N1---C1 1.490 (5) C5---C6 1.500 (6) N1---C5 1.493 (5) C5---H5A 0.9900 N2---C6 1.472 (5) C5---H5B 0.9900 N2---H2C 0.88 (3) C6---H6A 0.9900 N2---H2D 0.90 (3) C6---H6B 0.9900 C1---C2 1.513 (6) N2---Cd1---N2^i^ 176.95 (15) C2---C1---H1B 109.5 N2---Cd1---N1 76.88 (11) H1A---C1---H1B 108.1 N2^i^---Cd1---N1 103.32 (11) O1---C2---C1 112.0 (3) N2---Cd1---N1^i^ 103.32 (11) O1---C2---H2A 109.2 N2^i^---Cd1---N1^i^ 76.88 (11) C1---C2---H2A 109.2 N1---Cd1---N1^i^ 172.65 (15) O1---C2---H2B 109.2 N2---Cd1---Cl2 88.47 (8) C1---C2---H2B 109.2 N2^i^---Cd1---Cl2 88.47 (8) H2A---C2---H2B 107.9 N1---Cd1---Cl2 93.68 (8) O1---C3---C4 112.2 (3) N1^i^---Cd1---Cl2 93.68 (8) O1---C3---H3A 109.2 N2---Cd1---Cl1 91.53 (8) C4---C3---H3A 109.2 N2^i^---Cd1---Cl1 91.53 (8) O1---C3---H3B 109.2 N1---Cd1---Cl1 86.32 (8) C4---C3---H3B 109.2 N1^i^---Cd1---Cl1 86.32 (8) H3A---C3---H3B 107.9 Cl2---Cd1---Cl1 180.0 N1---C4---C3 110.6 (3) C2---O1---C3 109.8 (3) N1---C4---H4A 109.5 C4---N1---C1 107.9 (3) C3---C4---H4A 109.5 C4---N1---C5 112.5 (3) N1---C4---H4B 109.5 C1---N1---C5 106.5 (3) C3---C4---H4B 109.5 C4---N1---Cd1 113.6 (2) H4A---C4---H4B 108.1 C1---N1---Cd1 116.6 (2) N1---C5---C6 112.4 (3) C5---N1---Cd1 99.4 (2) N1---C5---H5A 109.1 C6---N2---Cd1 109.5 (2) C6---C5---H5A 109.1 C6---N2---H2C 108 (3) N1---C5---H5B 109.1 Cd1---N2---H2C 111 (3) C6---C5---H5B 109.1 C6---N2---H2D 113 (3) H5A---C5---H5B 107.9 Cd1---N2---H2D 110 (3) N2---C6---C5 111.3 (3) H2C---N2---H2D 106 (4) N2---C6---H6A 109.4 N1---C1---C2 110.7 (3) C5---C6---H6A 109.4 N1---C1---H1A 109.5 N2---C6---H6B 109.4 C2---C1---H1A 109.5 C5---C6---H6B 109.4 N1---C1---H1B 109.5 H6A---C6---H6B 108.0 --------------------- ------------- ---------------- ----------- ::: Symmetry codes: (i) −*x*+1, *y*, −*z*+1/2. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1731 .table-wrap} --------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N2---H2C···Cl2^ii^ 0.88 (3) 2.54 (3) 3.344 (3) 152 (4) N2---H2D···Cl1^iii^ 0.90 (3) 2.46 (3) 3.333 (3) 161 (4) C1---H1B···Cl1 0.99 2.80 3.540 (4) 132 C5---H5B···O1^iv^ 0.99 2.57 3.509 (5) 158 --------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (ii) −*x*+1, −*y*+2, −*z*+1; (iii) −*x*+1, −*y*+1, −*z*+1; (iv) −*x*+1/2, *y*, *z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Selected bond lengths (Å) ::: ----------- ------------- Cd1---N2 2.290 (3) Cd1---N1 2.537 (3) Cd1---Cl2 2.6244 (13) Cd1---Cl1 2.6414 (14) ----------- ------------- ::: ::: {#table2 .table-wrap} Table 2 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- ---------- ---------- ----------- ------------- N2---H2*C*⋯Cl2^i^ 0.88 (3) 2.54 (3) 3.344 (3) 152 (4) N2---H2*D*⋯Cl1^ii^ 0.90 (3) 2.46 (3) 3.333 (3) 161 (4) C1---H1*B*⋯Cl1 0.99 2.80 3.540 (4) 132 C5---H5*B*⋯O1^iii^ 0.99 2.57 3.509 (5) 158 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.291910

2011-2-02

PMC3051922

Related literature {#sec1} ================== For the synthesis and biological activity of 3-aza­bicyclo­\[3.3.1\] nonan-9-ones, see: Jeyaraman & Avila (1981[@bb6]); Barker *et al.* (2005[@bb1]); Parthiban *et al.* (2009*a* [@bb9], 2010*b* [@bb13],*c* [@bb14]); Cox *et al.* (1985[@bb3]). For related structures, see: Parthiban *et al.* (2009*b* [@bb10],*c* [@bb12], 2010*a* [@bb11]); Smith-Verdier *et al.* (1983[@bb16]); Padegimas & Kovacic (1972[@bb8]). For ring puckering parameters, see: Cremer & Pople (1975[@bb4]); Nardelli (1983[@bb7]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~28~H~37~NO~3~*M* *~r~* = 435.59Orthorhombic,*a* = 7.7780 (5) Å*b* = 31.457 (2) Å*c* = 9.9560 (6) Å*V* = 2436.0 (3) Å^3^*Z* = 4Mo *K*α radiationμ = 0.08 mm^−1^*T* = 298 K0.35 × 0.28 × 0.25 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2004[@bb2]) *T* ~min~ = 0.974, *T* ~max~ = 0.98110360 measured reflections2991 independent reflections1900 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.025 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.056*wR*(*F* ^2^) = 0.163*S* = 1.022991 reflections155 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.32 e Å^−3^Δρ~min~ = −0.18 e Å^−3^ {#d5e366} Data collection: *APEX2* (Bruker, 2004[@bb2]); cell refinement: *APEX2* and *SAINT-Plus* (Bruker, 2004[@bb2]); data reduction: *SAINT-Plus* and *XPREP* (Bruker, 2004[@bb2]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb15]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb15]); molecular graphics: *ORTEP-3* (Farrugia, 1997[@bb5]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811005058/bq2279sup1.cif](http://dx.doi.org/10.1107/S1600536811005058/bq2279sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005058/bq2279Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005058/bq2279Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?bq2279&file=bq2279sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?bq2279sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?bq2279&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BQ2279](http://scripts.iucr.org/cgi-bin/sendsup?bq2279)). This research was supported by the Industrial Technology Development program, which was conducted by the Ministry of Knowledge Economy of the Korean Government. The authors acknowledge the Department of Chemistry, IIT Madras, for the X-ray data collection. Comment ======= Naturally abundant diterpenoid/norditerpenoid alkaloids contain the 3-azabicyclononane nucleus, which is an important class of pharmacophore due to its broad spectrum of biological activities such as antibacterial, antimycobacterial, antifungal, anticancer, antitussive, anti-inflammatory, sedative, antipyretic and calcium antagonistic activity (Jeyaraman & Avila, 1981; Barker *et al.*, 2005; Parthiban *et al.*, 2009*a*, 2010*b*, 2010*c*). Its biological significant prompted the medicinal chemists to synthesize some structural analogs. Since the stereochemistry plays an important role in biological actions, it is important to establish the stereochemistry of the synthesized bio-potent molecules. For the synthesized title compound, several stereomers are possible with conformations such as chair-chair (Parthiban *et al.*, 2009*b*, 2009*c*, 2010*a*; Cox *et al.*, 1985), chair-boat (Smith-Verdier *et al.*, 1983) and boat-boat (Padegimas & Kovacic, 1972). Hence, the title crystal was undertaken for this study to explore its stereochemistry, unambiguously. The analysis of torsion angles, asymmetry parameters and puckering parameters calculated for the title compound shows that the piperidine ring adopts a near ideal chair conformation. According to Cremer & Pople, the total puckering amplitude, Q~T~ is -0.613 (2) Å and the phase angle θ is 178.67 (19)° (Cremer & Pople, 1975). The smallest displacement asymmetry parameters q~2~ and q~3~ are 0.005 (2) and -0.612 (2)°, respectively (Nardelli, 1983). However, the cyclohexane ring deviates from the ideal chair conformation according to Cremer and Pople by Q~T~ = 0.573 (2) and θ = 16.1 (2)° (Cremer & Pople, 1975) as well as Nardelli by q~2~ = 0.158 (2) and q~3~ = 0.550 (2)° (Nardelli, 1983). Hence, the title compound C~28~H~37~NO~3~, exists in a twin-chair conformation with equatorial orientation of the 4-butoxyphenyl groups on both sides of the secondary amino group on the heterocycle. The aryl groups are orientated at an angle of 38.54 (3)° to each other. The torsion angle of C3---C2---C1---C6 and its mirror image is 176.03 (4)°. The crystal packing is stabilized by weak van der Waals interactions. Experimental {#experimental} ============ The title compound was synthesized by a modified and an optimized Mannich condensation in one-pot, using 4-butoxybenzaldehyde (0.1 mol, 17.82 g/17.29 ml), cyclohexanone (0.05 mol, 4.90 g/5.18 ml) and ammonium acetate (0.075 mol, 5.78 g) in a 50 ml of absolute ethanol. The mixture was gently warmed on a hot plate at 303--308 K (30--35° C) with moderate stirring till the complete consumption of the starting materials, which was monitored by TLC. At the end, the crude azabicyclic ketone was separated by filtration and gently washed with 1:5 cold ethanol-ether mixture. X-ray diffraction quality crystals of the title compound were obtained by slow evaporation from ethanol. Refinement {#refinement} ========== The nitrogen H atom was located in a difference Fourier map and refined isotropically. Other hydrogen atoms were fixed geometrically and allowed to ride on the parent carbon atoms with aromatic C---H = 0.93 Å, aliphatic C---H = 0.98Å and methylene C---H = 0.97 Å. The displacement parameters were set for phenyl, methylene and aliphatic H atoms at *U*~iso~(H) = 1.2*U*~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Anisotropic displacement representation of the molecule with 30% probability ellipsoids. Symmetry code: (i) x, -y+1/2, z. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e168 .table-wrap} ------------------------ --------------------------------------- C~28~H~37~NO~3~ *F*(000) = 944 *M~r~* = 435.59 *D*~x~ = 1.188 Mg m^−3^ Orthorhombic, *Pnma* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ac 2n Cell parameters from 4431 reflections *a* = 7.7780 (5) Å θ = 3.3--26.9° *b* = 31.457 (2) Å µ = 0.08 mm^−1^ *c* = 9.9560 (6) Å *T* = 298 K *V* = 2436.0 (3) Å^3^ Block, colorless *Z* = 4 0.35 × 0.28 × 0.25 mm ------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e289 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker APEXII CCD area-detector diffractometer 2991 independent reflections Radiation source: fine-focus sealed tube 1900 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.025 phi and ω scans θ~max~ = 28.3°, θ~min~ = 2.2° Absorption correction: multi-scan (*SADABS*; Bruker, 2004) *h* = −10→9 *T*~min~ = 0.974, *T*~max~ = 0.981 *k* = −21→41 10360 measured reflections *l* = −11→13 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e404 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.056 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.163 H atoms treated by a mixture of independent and constrained refinement *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0606*P*)^2^ + 1.2024*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2991 reflections (Δ/σ)~max~ \< 0.001 155 parameters Δρ~max~ = 0.32 e Å^−3^ 0 restraints Δρ~min~ = −0.18 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e561 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e660 .table-wrap} ------ ------------ ------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 1.1848 (3) 0.71161 (6) 0.10972 (19) 0.0455 (5) H1 1.2239 0.7136 0.2031 0.055\* C2 1.3471 (3) 0.71050 (6) 0.0188 (2) 0.0487 (5) H2 1.4165 0.6857 0.0432 0.058\* C3 1.4496 (4) 0.7500 0.0466 (3) 0.0494 (7) C4 1.3130 (3) 0.70937 (6) −0.1338 (2) 0.0523 (5) H4A 1.4208 0.7044 −0.1801 0.063\* H4B 1.2372 0.6857 −0.1536 0.063\* C5 1.2325 (4) 0.7500 −0.1884 (3) 0.0547 (7) H5A 1.1109 0.7500 −0.1667 0.066\* H5B 1.2429 0.7500 −0.2855 0.066\* C6 1.0781 (3) 0.67181 (6) 0.09708 (18) 0.0440 (4) C7 0.9491 (3) 0.66660 (6) 0.0020 (2) 0.0542 (5) H7 0.9213 0.6891 −0.0544 0.065\* C8 0.8618 (3) 0.62882 (7) −0.0105 (2) 0.0560 (5) H8 0.7765 0.6260 −0.0753 0.067\* C9 0.9001 (3) 0.59496 (6) 0.0730 (2) 0.0495 (5) C10 1.0237 (3) 0.59983 (6) 0.1706 (2) 0.0530 (5) H10 1.0487 0.5775 0.2288 0.064\* C11 1.1108 (3) 0.63806 (6) 0.1821 (2) 0.0500 (5) H11 1.1936 0.6411 0.2489 0.060\* C12 0.8378 (3) 0.52285 (6) 0.1337 (2) 0.0601 (6) H12A 0.8154 0.5296 0.2271 0.072\* H12B 0.9567 0.5139 0.1253 0.072\* C13 0.7190 (3) 0.48792 (7) 0.0868 (3) 0.0663 (6) H13A 0.6013 0.4978 0.0945 0.080\* H13B 0.7413 0.4825 −0.0075 0.080\* C14 0.7355 (4) 0.44743 (7) 0.1615 (3) 0.0752 (7) H14A 0.7082 0.4523 0.2553 0.090\* H14B 0.8538 0.4377 0.1566 0.090\* C15 0.6187 (4) 0.41318 (8) 0.1070 (3) 0.0882 (9) H15A 0.5020 0.4231 0.1080 0.132\* H15B 0.6283 0.3882 0.1618 0.132\* H15C 0.6517 0.4065 0.0165 0.132\* N1 1.0856 (3) 0.7500 0.0803 (2) 0.0456 (5) O1 1.5979 (3) 0.7500 0.0826 (2) 0.0692 (6) O2 0.8061 (2) 0.55880 (5) 0.05158 (16) 0.0662 (5) H1N 0.991 (4) 0.7500 0.127 (3) 0.052 (9)\* ------ ------------ ------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1175 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0549 (11) 0.0463 (10) 0.0354 (10) 0.0017 (9) −0.0014 (8) 0.0015 (8) C2 0.0523 (11) 0.0457 (10) 0.0480 (11) 0.0066 (9) −0.0010 (9) 0.0022 (8) C3 0.0480 (16) 0.0612 (17) 0.0392 (15) 0.000 −0.0013 (13) 0.000 C4 0.0609 (12) 0.0500 (11) 0.0459 (11) −0.0011 (9) 0.0079 (10) −0.0064 (9) C5 0.0652 (19) 0.0616 (18) 0.0374 (15) 0.000 −0.0012 (14) 0.000 C6 0.0516 (10) 0.0444 (10) 0.0360 (10) 0.0038 (8) 0.0046 (8) 0.0018 (8) C7 0.0670 (13) 0.0523 (12) 0.0434 (11) 0.0004 (10) −0.0066 (10) 0.0120 (9) C8 0.0617 (12) 0.0598 (13) 0.0465 (12) −0.0056 (10) −0.0106 (10) 0.0068 (9) C9 0.0540 (11) 0.0458 (10) 0.0487 (12) 0.0017 (9) 0.0047 (9) 0.0021 (9) C10 0.0566 (12) 0.0458 (11) 0.0565 (13) 0.0079 (9) −0.0016 (10) 0.0125 (9) C11 0.0534 (11) 0.0511 (11) 0.0456 (11) 0.0063 (9) −0.0059 (9) 0.0055 (9) C12 0.0604 (13) 0.0494 (12) 0.0704 (15) 0.0043 (10) 0.0027 (12) 0.0078 (10) C13 0.0629 (13) 0.0600 (14) 0.0761 (17) −0.0033 (11) 0.0005 (12) 0.0103 (12) C14 0.0776 (16) 0.0589 (14) 0.0893 (19) 0.0063 (12) 0.0013 (15) 0.0050 (13) C15 0.104 (2) 0.0565 (14) 0.104 (2) −0.0075 (14) 0.0128 (18) −0.0072 (14) N1 0.0490 (13) 0.0441 (12) 0.0439 (13) 0.000 0.0054 (11) 0.000 O1 0.0563 (13) 0.0787 (15) 0.0725 (16) 0.000 −0.0153 (12) 0.000 O2 0.0762 (10) 0.0504 (8) 0.0721 (11) −0.0099 (8) −0.0117 (9) 0.0099 (7) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1525 .table-wrap} ---------------------- -------------- ----------------------- -------------- C1---N1 1.463 (2) C9---O2 1.369 (2) C1---C6 1.507 (3) C9---C10 1.376 (3) C1---C2 1.554 (3) C10---C11 1.385 (3) C1---H1 0.9800 C10---H10 0.9300 C2---C3 1.502 (2) C11---H11 0.9300 C2---C4 1.543 (3) C12---O2 1.417 (2) C2---H2 0.9800 C12---C13 1.510 (3) C3---O1 1.208 (3) C12---H12A 0.9700 C3---C2^i^ 1.502 (2) C12---H12B 0.9700 C4---C5 1.523 (3) C13---C14 1.481 (3) C4---H4A 0.9700 C13---H13A 0.9700 C4---H4B 0.9700 C13---H13B 0.9700 C5---C4^i^ 1.523 (3) C14---C15 1.510 (4) C5---H5A 0.9700 C14---H14A 0.9700 C5---H5B 0.9700 C14---H14B 0.9700 C6---C11 1.382 (3) C15---H15A 0.9600 C6---C7 1.390 (3) C15---H15B 0.9600 C7---C8 1.374 (3) C15---H15C 0.9600 C7---H7 0.9300 N1---C1^i^ 1.463 (2) C8---C9 1.384 (3) N1---H1N 0.87 (3) C8---H8 0.9300 N1---C1---C6 112.25 (17) O2---C9---C8 115.55 (18) N1---C1---C2 109.31 (16) C10---C9---C8 119.29 (19) C6---C1---C2 112.33 (15) C9---C10---C11 119.77 (18) N1---C1---H1 107.6 C9---C10---H10 120.1 C6---C1---H1 107.6 C11---C10---H10 120.1 C2---C1---H1 107.6 C6---C11---C10 121.80 (19) C3---C2---C4 106.96 (18) C6---C11---H11 119.1 C3---C2---C1 107.76 (17) C10---C11---H11 119.1 C4---C2---C1 115.76 (17) O2---C12---C13 107.21 (19) C3---C2---H2 108.7 O2---C12---H12A 110.3 C4---C2---H2 108.7 C13---C12---H12A 110.3 C1---C2---H2 108.7 O2---C12---H12B 110.3 O1---C3---C2 124.15 (12) C13---C12---H12B 110.3 O1---C3---C2^i^ 124.15 (12) H12A---C12---H12B 108.5 C2---C3---C2^i^ 111.7 (2) C14---C13---C12 114.7 (2) C5---C4---C2 113.74 (17) C14---C13---H13A 108.6 C5---C4---H4A 108.8 C12---C13---H13A 108.6 C2---C4---H4A 108.8 C14---C13---H13B 108.6 C5---C4---H4B 108.8 C12---C13---H13B 108.6 C2---C4---H4B 108.8 H13A---C13---H13B 107.6 H4A---C4---H4B 107.7 C13---C14---C15 112.4 (2) C4---C5---C4^i^ 114.1 (2) C13---C14---H14A 109.1 C4---C5---H5A 108.7 C15---C14---H14A 109.1 C4^i^---C5---H5A 108.7 C13---C14---H14B 109.1 C4---C5---H5B 108.7 C15---C14---H14B 109.1 C4^i^---C5---H5B 108.7 H14A---C14---H14B 107.9 H5A---C5---H5B 107.6 C14---C15---H15A 109.5 C11---C6---C7 117.37 (18) C14---C15---H15B 109.5 C11---C6---C1 119.07 (18) H15A---C15---H15B 109.5 C7---C6---C1 123.54 (17) C14---C15---H15C 109.5 C8---C7---C6 121.36 (18) H15A---C15---H15C 109.5 C8---C7---H7 119.3 H15B---C15---H15C 109.5 C6---C7---H7 119.3 C1---N1---C1^i^ 111.3 (2) C7---C8---C9 120.3 (2) C1---N1---H1N 109.8 (9) C7---C8---H8 119.8 C1^i^---N1---H1N 109.8 (9) C9---C8---H8 119.8 C9---O2---C12 118.72 (17) O2---C9---C10 125.15 (18) N1---C1---C2---C3 58.7 (2) C1---C6---C7---C8 176.3 (2) C6---C1---C2---C3 −176.04 (17) C6---C7---C8---C9 0.5 (3) N1---C1---C2---C4 −61.0 (2) C7---C8---C9---O2 −179.7 (2) C6---C1---C2---C4 64.3 (2) C7---C8---C9---C10 1.5 (3) C4---C2---C3---O1 −111.7 (3) O2---C9---C10---C11 179.82 (19) C1---C2---C3---O1 123.2 (3) C8---C9---C10---C11 −1.6 (3) C4---C2---C3---C2^i^ 66.0 (3) C7---C6---C11---C10 2.4 (3) C1---C2---C3---C2^i^ −59.1 (3) C1---C6---C11---C10 −176.39 (18) C3---C2---C4---C5 −52.9 (2) C9---C10---C11---C6 −0.4 (3) C1---C2---C4---C5 67.2 (2) O2---C12---C13---C14 179.6 (2) C2---C4---C5---C4^i^ 43.6 (3) C12---C13---C14---C15 −177.8 (2) N1---C1---C6---C11 −145.94 (19) C6---C1---N1---C1^i^ 172.73 (12) C2---C1---C6---C11 90.4 (2) C2---C1---N1---C1^i^ −61.9 (2) N1---C1---C6---C7 35.4 (3) C10---C9---O2---C12 −1.0 (3) C2---C1---C6---C7 −88.3 (2) C8---C9---O2---C12 −179.72 (19) C11---C6---C7---C8 −2.4 (3) C13---C12---O2---C9 −179.18 (19) ---------------------- -------------- ----------------------- -------------- ::: Symmetry codes: (i) *x*, −*y*+3/2, *z*.

PubMed Central

2024-06-05T04:04:17.295741

2011-2-16

PMC3051923

Related literature {#sec1} ================== For background to the synthesis of lactam and thiol­actam derivatives of oleanolic acid, see: Bednarczyk-Cwynar (2007[@bb1]). For ring conformation analysis, see Cremer & Pople (1975[@bb2]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~32~H~49~ClO~4~*M* *~r~* = 533.16Monoclinic,*a* = 14.1022 (2) Å*b* = 6.6481 (1) Å*c* = 15.2632 (2) Åβ = 90.621 (1)°*V* = 1430.88 (4) Å^3^*Z* = 2Cu *K*α radiationμ = 1.45 mm^−1^*T* = 130 K0.35 × 0.10 × 0.05 mm ### Data collection {#sec2.1.2} Oxford Diffraction SuperNova Single source at offset Atlas diffractometerAbsorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2007[@bb6]) *T* ~min~ = 0.452, *T* ~max~ = 1.00010416 measured reflections5530 independent reflections5337 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.032 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.043*wR*(*F* ^2^) = 0.119*S* = 1.045530 reflections342 parameters1 restraintH-atom parameters constrainedΔρ~max~ = 0.41 e Å^−3^Δρ~min~ = −0.35 e Å^−3^Absolute structure: Flack (1983[@bb5]), 2413 Friedel pairsFlack parameter: 0.024 (14) {#d5e481} Data collection: *CrysAlis PRO* (Oxford Diffraction, 2007[@bb6]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb3]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb4]) and *PLATON* (Spek, 2009[@bb8]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S160053681100585X/bt5473sup1.cif](http://dx.doi.org/10.1107/S160053681100585X/bt5473sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S160053681100585X/bt5473Isup2.hkl](http://dx.doi.org/10.1107/S160053681100585X/bt5473Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?bt5473&file=bt5473sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?bt5473sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?bt5473&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BT5473](http://scripts.iucr.org/cgi-bin/sendsup?bt5473)). Comment ======= In a POCl~3~-catalysed Beckmann rearrangement of 3β-acetoxy-12-hydroxyiminoolean-28-olic acid methyl ester, an unexpected compound with a chlorine instead of nitrogen atom was obtained along with the typical nitrile and lactam products. The X-ray analysis allowed to identify the compound as 3β-acetoxy-12α-chloro-D-friedooleanan-28,14β-olide (3β-acetoxy-12α-chloro-14β-isooleanan-28,14β-olide) (I). The mechanism of the reaction that led to compound (I) requires further investigations. The X-ray analysis has revealed that the title compound contains a δ-lactone ring with the C28═O4 group adjacent to C17. Formation of the lactone bridge is possible because of the change in the configuration of the chiral centers C13 and C14. As a result, the ether oxygen atom O3 at C14 and the methyl group at C13 are axial with respect to rings *C* and *D*. The former substituent reveals β-configuration, while the latter one has α-configuration. This observation shows that methyl group C27 has undergone 1,2-shift from C14 to C13 retaining its original orientation. The chlorine atom at C12, belonging to ring *C*, is oriented equatorially and assumes α-configuration. Rings *A*, *B* and *E* of the triterpenoid skeleton adopt chair conformations, each with different degree of distortion. Ring *C* has a twisted-boat conformation. Puckering parameters (Cremer & Pople, 1975) are *Q* = 0.747 (2) Å, θ = 95.61 (15)°, φ = 36.80 (17)°, while ring *D* reveals a conformation halfway between boat and twisted-boat \[Cremer & Pople puckering parameters: *Q* = 0.839 (2) Å, θ = 88.13 (14)°, φ = 48.76 (15)°\]. The values of the dihedral angles in the title compound confirm the *trans* configuration of rings *A*/*B*, *B*/*C* and *C*/D \[13.96 (8), 17.63 (4) and 13.26 (4)°\] and the *cis* configuration of rings *D*/*E* \[46.54 (6)°\]. The acetoxy group at C3 is planar and adopts β-orientation. The carbonyl group C31═O2 of the above acetoxy group is synperiplanar with respect to the O1---C3 bond \[torsion angle C3---O1---C31---O2: -5.0 (3)°\] and adopts a conformation similar to synperiplanar with respect to the C2---C3 bond \[torsion angle C2---C3---C31---O2: 72.9 (2)°\]. In the crystal lattice, the molecules are connected with three-centered weak hydrogen bonds C32---H32A···O4^i^···H16B^ii^---C16^ii^ \[(i) *x*, -1+*y*, 1+*z*; (ii) *x*, *y*, 1+*z*\] into layers extending parallel to the *bc* plane. The layer thickness is about a half of the *a* parameter length. Experimental {#experimental} ============ The title compound was obtained as a by-product in POCl~3~-catalysed Beckmann rearrangement reaction and recrystallized from ethanol solution at room temperature. Refinement {#refinement} ========== All H-atoms were placed in geometrically calculated positions and were refined with a riding model with C---H = 0.96--0.98 Å and with *U*~iso~ = 1.2 *U*~eq~(C) or 1.5 *U*~eq~(C) for methyl groups. The methyl H atoms were refined as rigid groups, which were allowed to rotate. The absolute configuration of the title compound was established by refinement of the Flack (1983) parameter. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of (I), showing the atomic labelling scheme. Non-H atoms are drawn as 30% probability displacement ellipsoids and H atoms are drawn as spheres of an arbitrary size. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The hydrogen bonding (dotted lines) in the title structure. H atoms not involved in hydrogen bonds have been omitted for clarity. \[Symmetry codes: (i) x, -1 + y, 1 + z; (ii) x, y, 1 + z\] :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e299 .table-wrap} ------------------------ --------------------------------------- C~32~H~49~ClO~4~ *F*(000) = 580 *M~r~* = 533.16 *D*~x~ = 1.237 Mg m^−3^ Monoclinic, *P*2~1~ Cu *K*α radiation, λ = 1.54184 Å Hall symbol: P 2yb Cell parameters from 7077 reflections *a* = 14.1022 (2) Å θ = 2.9--73.7° *b* = 6.6481 (1) Å µ = 1.45 mm^−1^ *c* = 15.2632 (2) Å *T* = 130 K β = 90.621 (1)° Needle, colourless *V* = 1430.88 (4) Å^3^ 0.35 × 0.10 × 0.05 mm *Z* = 2 ------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e423 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction SuperNova Single source at offset Atlas diffractometer 5530 independent reflections Radiation source: SuperNova (Cu) X-ray Source 5337 reflections with *I* \> 2σ(*I*) mirror *R*~int~ = 0.032 Detector resolution: 10.5357 pixels mm^-1^ θ~max~ = 73.8°, θ~min~ = 2.9° ω scans *h* = −17→17 Absorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2007) *k* = −8→8 *T*~min~ = 0.452, *T*~max~ = 1.000 *l* = −18→18 10416 measured reflections ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e543 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.043 H-atom parameters constrained *wR*(*F*^2^) = 0.119 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0742*P*)^2^ + 0.2024*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.04 (Δ/σ)~max~ \< 0.001 5530 reflections Δρ~max~ = 0.41 e Å^−3^ 342 parameters Δρ~min~ = −0.35 e Å^−3^ 1 restraint Absolute structure: Flack (1983), 2413 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: 0.024 (14) ---------------------------------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e705 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. CrysAlisPro (Oxford Diffraction, 2007) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e810 .table-wrap} ------ --------------- ------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl1 −0.01593 (3) 0.72974 (8) −0.07850 (3) 0.03101 (13) O1 0.34716 (12) 0.4238 (3) 0.40093 (10) 0.0353 (4) O2 0.26503 (15) 0.1327 (3) 0.40399 (12) 0.0463 (4) O3 0.27784 (11) 0.9153 (2) −0.15431 (10) 0.0298 (3) O4 0.26583 (13) 1.0712 (2) −0.28151 (11) 0.0372 (4) C1 0.19066 (14) 0.5857 (4) 0.21099 (14) 0.0296 (4) H1A 0.1293 0.6516 0.2094 0.036\* H1B 0.1835 0.4547 0.1837 0.036\* C2 0.22185 (15) 0.5574 (4) 0.30664 (14) 0.0322 (5) H2A 0.2251 0.6871 0.3357 0.039\* H2B 0.1760 0.4749 0.3370 0.039\* C3 0.31775 (16) 0.4575 (3) 0.30991 (14) 0.0302 (4) H3 0.3122 0.3263 0.2810 0.036\* C4 0.39682 (15) 0.5760 (4) 0.26497 (15) 0.0330 (5) C5 0.36160 (14) 0.6135 (3) 0.16899 (14) 0.0284 (4) H5 0.3543 0.4785 0.1440 0.034\* C6 0.43350 (14) 0.7172 (5) 0.10948 (16) 0.0399 (5) H6A 0.4371 0.8589 0.1243 0.048\* H6B 0.4957 0.6585 0.1191 0.048\* C7 0.40540 (14) 0.6949 (4) 0.01315 (16) 0.0382 (6) H7A 0.4075 0.5535 −0.0024 0.046\* H7B 0.4517 0.7645 −0.0223 0.046\* C8 0.30584 (14) 0.7777 (3) −0.00945 (15) 0.0290 (4) C9 0.23589 (13) 0.6866 (3) 0.05772 (13) 0.0224 (4) H9 0.2401 0.5413 0.0478 0.027\* C10 0.26190 (13) 0.7119 (3) 0.15757 (13) 0.0256 (4) C11 0.13101 (13) 0.7367 (4) 0.03798 (13) 0.0270 (4) H11A 0.0917 0.6278 0.0592 0.032\* H11B 0.1139 0.8575 0.0697 0.032\* C12 0.11030 (13) 0.7687 (3) −0.05947 (13) 0.0241 (4) H12 0.1244 0.9096 −0.0730 0.029\* C13 0.17042 (14) 0.6377 (3) −0.11985 (14) 0.0261 (4) C14 0.27356 (13) 0.7205 (3) −0.10760 (13) 0.0277 (4) C15 0.34176 (15) 0.5844 (3) −0.15818 (15) 0.0304 (4) H15A 0.3441 0.4524 −0.1311 0.037\* H15B 0.4051 0.6412 −0.1564 0.037\* C16 0.30721 (16) 0.5649 (3) −0.25483 (16) 0.0323 (5) H16A 0.3600 0.5894 −0.2936 0.039\* H16B 0.2848 0.4289 −0.2652 0.039\* C17 0.22661 (14) 0.7154 (3) −0.27601 (14) 0.0281 (4) C18 0.13854 (14) 0.6671 (3) −0.21902 (13) 0.0237 (4) H18 0.0968 0.7849 −0.2214 0.028\* C19 0.08285 (15) 0.4893 (3) −0.25754 (14) 0.0285 (4) H19A 0.0270 0.4666 −0.2224 0.034\* H19B 0.1219 0.3694 −0.2540 0.034\* C20 0.05171 (17) 0.5218 (4) −0.35383 (15) 0.0364 (5) C21 0.14176 (17) 0.5539 (4) −0.40761 (14) 0.0339 (5) H21A 0.1240 0.5786 −0.4682 0.041\* H21B 0.1796 0.4322 −0.4057 0.041\* C22 0.20191 (16) 0.7308 (4) −0.37383 (14) 0.0344 (4) H22A 0.2602 0.7367 −0.4069 0.041\* H22B 0.1676 0.8551 −0.3842 0.041\* C23 0.48479 (19) 0.4402 (5) 0.26288 (18) 0.0484 (7) H23A 0.4724 0.3265 0.2257 0.073\* H23B 0.4994 0.3943 0.3211 0.073\* H23C 0.5376 0.5148 0.2405 0.073\* C24 0.42270 (18) 0.7675 (4) 0.31517 (18) 0.0431 (6) H24A 0.4655 0.8468 0.2810 0.065\* H24B 0.4526 0.7323 0.3698 0.065\* H24C 0.3662 0.8436 0.3262 0.065\* C25 0.25426 (19) 0.9299 (4) 0.19146 (16) 0.0384 (5) H25A 0.3139 0.9971 0.1841 0.058\* H25B 0.2383 0.9285 0.2524 0.058\* H25C 0.2058 0.9998 0.1589 0.058\* C26 0.3105 (2) 1.0101 (4) 0.00024 (18) 0.0398 (5) H26A 0.2478 1.0653 −0.0060 0.060\* H26B 0.3505 1.0648 −0.0443 0.060\* H26C 0.3359 1.0439 0.0570 0.060\* C27 0.16265 (15) 0.4122 (3) −0.09463 (13) 0.0279 (4) H27A 0.1900 0.3917 −0.0375 0.042\* H27B 0.1960 0.3321 −0.1366 0.042\* H27C 0.0971 0.3731 −0.0942 0.042\* C28 0.25886 (16) 0.9156 (3) −0.24151 (15) 0.0302 (4) C29 0.0028 (2) 0.3326 (5) −0.38573 (18) 0.0538 (8) H29A 0.0450 0.2201 −0.3790 0.081\* H29B −0.0144 0.3476 −0.4464 0.081\* H29C −0.0533 0.3098 −0.3520 0.081\* C30 −0.01811 (19) 0.6979 (5) −0.36211 (16) 0.0477 (7) H30A −0.0713 0.6747 −0.3247 0.072\* H30B −0.0398 0.7088 −0.4218 0.072\* H30C 0.0131 0.8204 −0.3450 0.072\* C31 0.31790 (16) 0.2516 (4) 0.43831 (14) 0.0357 (5) C32 0.36249 (19) 0.2262 (6) 0.52764 (16) 0.0495 (6) H32A 0.3218 0.1459 0.5636 0.074\* H32B 0.3713 0.3558 0.5542 0.074\* H32C 0.4228 0.1606 0.5221 0.074\* ------ --------------- ------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1985 .table-wrap} ----- ------------- ------------- ------------- -------------- --------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.0209 (2) 0.0390 (3) 0.0330 (2) 0.0011 (2) −0.00120 (16) −0.0023 (2) O1 0.0357 (8) 0.0442 (9) 0.0259 (7) 0.0047 (7) −0.0085 (6) −0.0020 (7) O2 0.0516 (10) 0.0507 (11) 0.0365 (9) −0.0055 (9) −0.0073 (8) 0.0023 (8) O3 0.0297 (8) 0.0218 (7) 0.0381 (8) −0.0039 (6) 0.0031 (6) 0.0019 (6) O4 0.0483 (10) 0.0235 (7) 0.0398 (8) −0.0068 (7) 0.0048 (7) 0.0053 (6) C1 0.0181 (9) 0.0431 (11) 0.0275 (10) 0.0026 (8) −0.0025 (7) −0.0031 (9) C2 0.0220 (9) 0.0473 (13) 0.0271 (10) 0.0022 (9) −0.0037 (8) −0.0037 (9) C3 0.0300 (10) 0.0364 (11) 0.0241 (9) 0.0037 (9) −0.0059 (8) −0.0034 (8) C4 0.0203 (9) 0.0431 (12) 0.0355 (11) 0.0055 (9) −0.0052 (8) −0.0014 (10) C5 0.0191 (9) 0.0333 (11) 0.0328 (10) 0.0023 (8) −0.0021 (7) 0.0002 (8) C6 0.0167 (8) 0.0579 (15) 0.0451 (12) −0.0006 (11) −0.0044 (8) 0.0114 (12) C7 0.0174 (9) 0.0555 (15) 0.0418 (12) −0.0025 (10) 0.0030 (8) 0.0086 (10) C8 0.0193 (9) 0.0303 (11) 0.0373 (11) −0.0012 (7) −0.0015 (8) 0.0074 (8) C9 0.0170 (8) 0.0216 (9) 0.0286 (9) 0.0007 (6) −0.0007 (7) −0.0021 (7) C10 0.0192 (8) 0.0270 (10) 0.0305 (9) 0.0025 (8) −0.0050 (7) −0.0052 (8) C11 0.0203 (8) 0.0306 (9) 0.0300 (9) 0.0040 (9) −0.0023 (7) −0.0041 (9) C12 0.0180 (8) 0.0238 (10) 0.0305 (9) 0.0021 (7) −0.0011 (7) −0.0001 (7) C13 0.0209 (9) 0.0279 (9) 0.0294 (10) −0.0014 (8) 0.0019 (7) −0.0018 (8) C14 0.0211 (8) 0.0288 (10) 0.0333 (10) −0.0001 (9) 0.0022 (7) 0.0047 (9) C15 0.0212 (9) 0.0272 (9) 0.0429 (11) 0.0009 (8) 0.0047 (8) −0.0003 (9) C16 0.0275 (11) 0.0285 (10) 0.0412 (11) −0.0015 (8) 0.0091 (9) −0.0047 (9) C17 0.0276 (9) 0.0221 (9) 0.0348 (10) −0.0039 (8) 0.0087 (8) 0.0009 (8) C18 0.0221 (9) 0.0212 (8) 0.0278 (9) −0.0014 (7) 0.0037 (7) 0.0015 (7) C19 0.0276 (10) 0.0305 (10) 0.0274 (10) −0.0075 (8) 0.0022 (8) −0.0007 (8) C20 0.0303 (11) 0.0519 (14) 0.0270 (10) −0.0083 (10) 0.0001 (9) −0.0029 (9) C21 0.0364 (12) 0.0390 (12) 0.0263 (10) 0.0000 (10) 0.0033 (8) 0.0013 (9) C22 0.0408 (11) 0.0295 (10) 0.0330 (10) −0.0025 (10) 0.0101 (8) 0.0009 (9) C23 0.0321 (12) 0.0718 (19) 0.0413 (13) 0.0215 (13) −0.0058 (10) 0.0050 (13) C24 0.0338 (11) 0.0483 (15) 0.0469 (13) −0.0085 (11) −0.0169 (10) −0.0006 (11) C25 0.0430 (13) 0.0325 (11) 0.0394 (12) 0.0080 (10) −0.0144 (10) −0.0102 (10) C26 0.0450 (13) 0.0319 (11) 0.0422 (13) −0.0106 (10) −0.0083 (11) 0.0030 (10) C27 0.0281 (10) 0.0255 (9) 0.0302 (10) −0.0036 (8) 0.0023 (8) −0.0004 (8) C28 0.0280 (10) 0.0254 (9) 0.0372 (11) −0.0033 (8) 0.0089 (8) 0.0014 (9) C29 0.0549 (18) 0.0704 (19) 0.0361 (13) −0.0270 (15) 0.0009 (12) −0.0084 (13) C30 0.0374 (12) 0.072 (2) 0.0342 (11) 0.0081 (13) −0.0040 (9) 0.0052 (12) C31 0.0312 (10) 0.0468 (13) 0.0290 (10) 0.0090 (11) −0.0011 (8) −0.0004 (10) C32 0.0479 (13) 0.0700 (18) 0.0304 (11) 0.0069 (16) −0.0079 (10) 0.0091 (14) ----- ------------- ------------- ------------- -------------- --------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2708 .table-wrap} ----------------------- -------------- ----------------------- -------------- Cl1---C12 1.8191 (19) C15---H15B 0.9700 O1---C31 1.346 (3) C16---C17 1.546 (3) O1---C3 1.463 (3) C16---H16A 0.9700 O2---C31 1.203 (3) C16---H16B 0.9700 O3---C28 1.355 (3) C17---C28 1.500 (3) O3---C14 1.480 (3) C17---C22 1.533 (3) O4---C28 1.206 (3) C17---C18 1.557 (2) C1---C2 1.532 (3) C18---C19 1.533 (3) C1---C10 1.548 (3) C18---H18 0.9800 C1---H1A 0.9700 C19---C20 1.545 (3) C1---H1B 0.9700 C19---H19A 0.9700 C2---C3 1.507 (3) C19---H19B 0.9700 C2---H2A 0.9700 C20---C29 1.513 (4) C2---H2B 0.9700 C20---C30 1.534 (4) C3---C4 1.533 (3) C20---C21 1.534 (3) C3---H3 0.9800 C21---C22 1.536 (3) C4---C24 1.528 (4) C21---H21A 0.9700 C4---C23 1.535 (3) C21---H21B 0.9700 C4---C5 1.562 (3) C22---H22A 0.9700 C5---C6 1.532 (3) C22---H22B 0.9700 C5---C10 1.559 (3) C23---H23A 0.9600 C5---H5 0.9800 C23---H23B 0.9600 C6---C7 1.526 (3) C23---H23C 0.9600 C6---H6A 0.9700 C24---H24A 0.9600 C6---H6B 0.9700 C24---H24B 0.9600 C7---C8 1.544 (3) C24---H24C 0.9600 C7---H7A 0.9700 C25---H25A 0.9600 C7---H7B 0.9700 C25---H25B 0.9600 C8---C9 1.553 (3) C25---H25C 0.9600 C8---C26 1.554 (3) C26---H26A 0.9600 C8---C14 1.607 (3) C26---H26B 0.9600 C9---C11 1.542 (2) C26---H26C 0.9600 C9---C10 1.573 (3) C27---H27A 0.9600 C9---H9 0.9800 C27---H27B 0.9600 C10---C25 1.543 (3) C27---H27C 0.9600 C11---C12 1.528 (3) C29---H29A 0.9600 C11---H11A 0.9700 C29---H29B 0.9600 C11---H11B 0.9700 C29---H29C 0.9600 C12---C13 1.531 (3) C30---H30A 0.9600 C12---H12 0.9800 C30---H30B 0.9600 C13---C27 1.552 (3) C30---H30C 0.9600 C13---C14 1.564 (3) C31---C32 1.505 (3) C13---C18 1.587 (3) C32---H32A 0.9600 C14---C15 1.535 (3) C32---H32B 0.9600 C15---C16 1.554 (3) C32---H32C 0.9600 C15---H15A 0.9700 C31---O1---C3 116.63 (18) C15---C16---H16A 109.3 C28---O3---C14 117.76 (16) C17---C16---H16B 109.3 C2---C1---C10 112.78 (17) C15---C16---H16B 109.3 C2---C1---H1A 109.0 H16A---C16---H16B 108.0 C10---C1---H1A 109.0 C28---C17---C22 110.32 (19) C2---C1---H1B 109.0 C28---C17---C16 106.33 (18) C10---C1---H1B 109.0 C22---C17---C16 113.95 (18) H1A---C1---H1B 107.8 C28---C17---C18 103.14 (16) C3---C2---C1 109.51 (17) C22---C17---C18 112.56 (16) C3---C2---H2A 109.8 C16---C17---C18 109.82 (17) C1---C2---H2A 109.8 C19---C18---C17 110.67 (17) C3---C2---H2B 109.8 C19---C18---C13 114.17 (16) C1---C2---H2B 109.8 C17---C18---C13 109.81 (16) H2A---C2---H2B 108.2 C19---C18---H18 107.3 O1---C3---C2 110.13 (17) C17---C18---H18 107.3 O1---C3---C4 107.68 (17) C13---C18---H18 107.3 C2---C3---C4 114.56 (19) C18---C19---C20 113.35 (18) O1---C3---H3 108.1 C18---C19---H19A 108.9 C2---C3---H3 108.1 C20---C19---H19A 108.9 C4---C3---H3 108.1 C18---C19---H19B 108.9 C24---C4---C3 112.0 (2) C20---C19---H19B 108.9 C24---C4---C23 108.2 (2) H19A---C19---H19B 107.7 C3---C4---C23 107.4 (2) C29---C20---C30 108.6 (2) C24---C4---C5 114.1 (2) C29---C20---C21 108.7 (2) C3---C4---C5 106.04 (17) C30---C20---C21 112.6 (2) C23---C4---C5 108.86 (19) C29---C20---C19 108.3 (2) C6---C5---C10 110.29 (18) C30---C20---C19 111.1 (2) C6---C5---C4 114.97 (17) C21---C20---C19 107.46 (18) C10---C5---C4 116.68 (17) C20---C21---C22 112.59 (19) C6---C5---H5 104.4 C20---C21---H21A 109.1 C10---C5---H5 104.4 C22---C21---H21A 109.1 C4---C5---H5 104.4 C20---C21---H21B 109.1 C7---C6---C5 111.14 (19) C22---C21---H21B 109.1 C7---C6---H6A 109.4 H21A---C21---H21B 107.8 C5---C6---H6A 109.4 C17---C22---C21 113.23 (19) C7---C6---H6B 109.4 C17---C22---H22A 108.9 C5---C6---H6B 109.4 C21---C22---H22A 108.9 H6A---C6---H6B 108.0 C17---C22---H22B 108.9 C6---C7---C8 114.00 (19) C21---C22---H22B 108.9 C6---C7---H7A 108.8 H22A---C22---H22B 107.7 C8---C7---H7A 108.8 C4---C23---H23A 109.5 C6---C7---H7B 108.8 C4---C23---H23B 109.5 C8---C7---H7B 108.8 H23A---C23---H23B 109.5 H7A---C7---H7B 107.6 C4---C23---H23C 109.5 C7---C8---C9 107.22 (17) H23A---C23---H23C 109.5 C7---C8---C26 107.2 (2) H23B---C23---H23C 109.5 C9---C8---C26 110.55 (19) C4---C24---H24A 109.5 C7---C8---C14 111.84 (18) C4---C24---H24B 109.5 C9---C8---C14 110.34 (16) H24A---C24---H24B 109.5 C26---C8---C14 109.59 (18) C4---C24---H24C 109.5 C11---C9---C8 113.67 (17) H24A---C24---H24C 109.5 C11---C9---C10 112.29 (15) H24B---C24---H24C 109.5 C8---C9---C10 117.06 (16) C10---C25---H25A 109.5 C11---C9---H9 104.0 C10---C25---H25B 109.5 C8---C9---H9 104.0 H25A---C25---H25B 109.5 C10---C9---H9 104.0 C10---C25---H25C 109.5 C25---C10---C1 106.53 (18) H25A---C25---H25C 109.5 C25---C10---C5 115.01 (17) H25B---C25---H25C 109.5 C1---C10---C5 107.68 (17) C8---C26---H26A 109.5 C25---C10---C9 114.12 (17) C8---C26---H26B 109.5 C1---C10---C9 107.86 (15) H26A---C26---H26B 109.5 C5---C10---C9 105.32 (15) C8---C26---H26C 109.5 C12---C11---C9 113.15 (15) H26A---C26---H26C 109.5 C12---C11---H11A 108.9 H26B---C26---H26C 109.5 C9---C11---H11A 108.9 C13---C27---H27A 109.5 C12---C11---H11B 108.9 C13---C27---H27B 109.5 C9---C11---H11B 108.9 H27A---C27---H27B 109.5 H11A---C11---H11B 107.8 C13---C27---H27C 109.5 C11---C12---C13 113.91 (16) H27A---C27---H27C 109.5 C11---C12---Cl1 108.18 (13) H27B---C27---H27C 109.5 C13---C12---Cl1 111.72 (14) O4---C28---O3 118.8 (2) C11---C12---H12 107.6 O4---C28---C17 127.6 (2) C13---C12---H12 107.6 O3---C28---C17 113.55 (18) Cl1---C12---H12 107.6 C20---C29---H29A 109.5 C12---C13---C27 111.07 (17) C20---C29---H29B 109.5 C12---C13---C14 104.35 (16) H29A---C29---H29B 109.5 C27---C13---C14 112.24 (17) C20---C29---H29C 109.5 C12---C13---C18 110.54 (16) H29A---C29---H29C 109.5 C27---C13---C18 109.62 (16) H29B---C29---H29C 109.5 C14---C13---C18 108.90 (15) C20---C30---H30A 109.5 O3---C14---C15 104.16 (15) C20---C30---H30B 109.5 O3---C14---C13 107.05 (16) H30A---C30---H30B 109.5 C15---C14---C13 108.61 (18) C20---C30---H30C 109.5 O3---C14---C8 103.27 (17) H30A---C30---H30C 109.5 C15---C14---C8 115.83 (17) H30B---C30---H30C 109.5 C13---C14---C8 116.64 (15) O2---C31---O1 124.5 (2) C14---C15---C16 109.57 (17) O2---C31---C32 124.9 (3) C14---C15---H15A 109.8 O1---C31---C32 110.7 (2) C16---C15---H15A 109.8 C31---C32---H32A 109.5 C14---C15---H15B 109.8 C31---C32---H32B 109.5 C16---C15---H15B 109.8 H32A---C32---H32B 109.5 H15A---C15---H15B 108.2 C31---C32---H32C 109.5 C17---C16---C15 111.53 (17) H32A---C32---H32C 109.5 C17---C16---H16A 109.3 H32B---C32---H32C 109.5 C10---C1---C2---C3 −58.0 (3) C27---C13---C14---O3 165.62 (16) C31---O1---C3---C2 87.0 (2) C18---C13---C14---O3 44.0 (2) C31---O1---C3---C4 −147.49 (19) C12---C13---C14---C15 174.07 (17) C1---C2---C3---O1 −178.22 (19) C27---C13---C14---C15 53.7 (2) C1---C2---C3---C4 60.2 (2) C18---C13---C14---C15 −67.9 (2) O1---C3---C4---C24 −53.5 (2) C12---C13---C14---C8 41.0 (2) C2---C3---C4---C24 69.4 (2) C27---C13---C14---C8 −79.4 (2) O1---C3---C4---C23 65.1 (2) C18---C13---C14---C8 159.04 (17) C2---C3---C4---C23 −172.0 (2) C7---C8---C14---O3 −108.90 (18) O1---C3---C4---C5 −178.59 (17) C9---C8---C14---O3 131.84 (15) C2---C3---C4---C5 −55.7 (2) C26---C8---C14---O3 9.9 (2) C24---C4---C5---C6 60.6 (3) C7---C8---C14---C15 4.3 (3) C3---C4---C5---C6 −175.7 (2) C9---C8---C14---C15 −115.00 (19) C23---C4---C5---C6 −60.4 (3) C26---C8---C14---C15 123.0 (2) C24---C4---C5---C10 −70.9 (3) C7---C8---C14---C13 134.01 (19) C3---C4---C5---C10 52.9 (2) C9---C8---C14---C13 14.8 (2) C23---C4---C5---C10 168.2 (2) C26---C8---C14---C13 −107.2 (2) C10---C5---C6---C7 −61.6 (3) O3---C14---C15---C16 −60.3 (2) C4---C5---C6---C7 164.0 (2) C13---C14---C15---C16 53.5 (2) C5---C6---C7---C8 57.3 (3) C8---C14---C15---C16 −172.97 (17) C6---C7---C8---C9 −50.2 (3) C14---C15---C16---C17 10.2 (2) C6---C7---C8---C26 68.5 (3) C15---C16---C17---C28 47.7 (2) C6---C7---C8---C14 −171.3 (2) C15---C16---C17---C22 169.42 (18) C7---C8---C9---C11 −173.74 (19) C15---C16---C17---C18 −63.3 (2) C26---C8---C9---C11 69.7 (2) C28---C17---C18---C19 167.84 (17) C14---C8---C9---C11 −51.7 (2) C22---C17---C18---C19 49.0 (2) C7---C8---C9---C10 52.7 (2) C16---C17---C18---C19 −79.1 (2) C26---C8---C9---C10 −63.9 (2) C28---C17---C18---C13 −65.2 (2) C14---C8---C9---C10 174.74 (16) C22---C17---C18---C13 175.90 (18) C2---C1---C10---C25 −70.6 (2) C16---C17---C18---C13 47.8 (2) C2---C1---C10---C5 53.3 (2) C12---C13---C18---C19 −106.4 (2) C2---C1---C10---C9 166.51 (17) C27---C13---C18---C19 16.4 (2) C6---C5---C10---C25 −67.8 (3) C14---C13---C18---C19 139.51 (18) C4---C5---C10---C25 65.8 (3) C12---C13---C18---C17 128.64 (17) C6---C5---C10---C1 173.67 (18) C27---C13---C18---C17 −108.59 (18) C4---C5---C10---C1 −52.7 (2) C14---C13---C18---C17 14.6 (2) C6---C5---C10---C9 58.8 (2) C17---C18---C19---C20 −56.0 (2) C4---C5---C10---C9 −167.64 (18) C13---C18---C19---C20 179.47 (17) C11---C9---C10---C25 −64.6 (2) C18---C19---C20---C29 176.8 (2) C8---C9---C10---C25 69.6 (2) C18---C19---C20---C30 −64.1 (3) C11---C9---C10---C1 53.6 (2) C18---C19---C20---C21 59.5 (3) C8---C9---C10---C1 −172.27 (17) C29---C20---C21---C22 −174.1 (2) C11---C9---C10---C5 168.34 (17) C30---C20---C21---C22 65.6 (3) C8---C9---C10---C5 −57.5 (2) C19---C20---C21---C22 −57.1 (3) C8---C9---C11---C12 28.7 (3) C28---C17---C22---C21 −163.09 (19) C10---C9---C11---C12 164.46 (17) C16---C17---C22---C21 77.4 (2) C9---C11---C12---C13 33.5 (3) C18---C17---C22---C21 −48.5 (3) C9---C11---C12---Cl1 158.41 (15) C20---C21---C22---C17 53.8 (3) C11---C12---C13---C27 53.4 (2) C14---O3---C28---O4 −176.93 (19) Cl1---C12---C13---C27 −69.55 (19) C14---O3---C28---C17 5.6 (3) C11---C12---C13---C14 −67.8 (2) C22---C17---C28---O4 0.0 (3) Cl1---C12---C13---C14 169.29 (13) C16---C17---C28---O4 124.0 (2) C11---C12---C13---C18 175.31 (16) C18---C17---C28---O4 −120.4 (2) Cl1---C12---C13---C18 52.36 (19) C22---C17---C28---O3 177.17 (17) C28---O3---C14---C15 55.2 (2) C16---C17---C28---O3 −58.8 (2) C28---O3---C14---C13 −59.7 (2) C18---C17---C28---O3 56.7 (2) C28---O3---C14---C8 176.65 (16) C3---O1---C31---O2 −5.0 (3) C12---C13---C14---O3 −74.01 (19) C3---O1---C31---C32 173.44 (19) ----------------------- -------------- ----------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e4630 .table-wrap} --------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C16---H16B···O4^i^ 0.97 2.41 3.358 (2) 167 C32---H32A···O4^ii^ 0.96 2.55 3.390 (3) 146 --------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) *x*, *y*−1, *z*; (ii) *x*, *y*−1, *z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ----------- ------------- C16---H16*B*⋯O4^i^ 0.97 2.41 3.358 (2) 167 C32---H32*A*⋯O4^ii^ 0.96 2.55 3.390 (3) 146 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.300403

2011-2-23

PMC3051924

Related literature {#sec1} ================== For background of this work see: Boeckmann & Näther (2010[@bb1]); Wriedt *et al.* (2009*a* [@bb7],*b* [@bb6]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Ni(NCS)~2~(C~2~H~3~N)~2~\]*M* *~r~* = 256.98Orthorhombic,*a* = 9.0666 (4) Å*b* = 9.1215 (3) Å*c* = 12.0696 (6) Å*V* = 998.17 (7) Å^3^*Z* = 4Mo *K*α radiationμ = 2.32 mm^−1^*T* = 293 K0.11 × 0.09 × 0.06 mm ### Data collection {#sec2.1.2} Stoe IPDS-2 diffractometerAbsorption correction: numerical (*X-SHAPE* and *X-RED32*; Stoe & Cie, 2008)[@bb5] *T* ~min~ = 0.683, *T* ~max~ = 0.77211157 measured reflections2694 independent reflections2479 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.023 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.027*wR*(*F* ^2^) = 0.051*S* = 1.292694 reflections120 parametersH-atom parameters constrainedΔρ~max~ = 0.29 e Å^−3^Δρ~min~ = −0.28 e Å^−3^Absolute structure: Flack (1983[@bb3]), 1141 Friedel pairsFlack parameter: −0.003 (13) {#d5e387} Data collection: *X-AREA* (Stoe & Cie, 2008)[@bb5]; cell refinement: *X-AREA* [@bb5]; data reduction: *X-AREA*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb4]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008)[@bb4]; molecular graphics: *XP* in *SHELXTL* (Sheldrick, 2008[@bb4]) and *DIAMOND* (Brandenburg, 1999[@bb2]); software used to prepare material for publication: *XCIF* in *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004132/im2264sup1.cif](http://dx.doi.org/10.1107/S1600536811004132/im2264sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004132/im2264Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004132/im2264Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?im2264&file=im2264sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?im2264sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?im2264&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [IM2264](http://scripts.iucr.org/cgi-bin/sendsup?im2264)). We gratefully acknowledge financial support by the DFG (project No. NA 720/3-1) and the State of Schleswig-Holstein. We thank Professor Dr Wolfgang Bensch for access to his experimental facilities. Comment ======= In recent work, we have shown that thermal decomposition reactions are an elegant route for discovering and synthesising new ligand-deficient coordination polymers with attractive magnetic properties (Boeckmann & Näther, 2010; Wriedt *et al.*, 2009*a*, 2009*b*). In our investigation on the syntheses, structures and properties of such compounds based on paramagnetic transition metals, pseudo-halides and N-donor ligands, we have reacted nickel(II) thiocyanate and *trans*-1,2-bis(4-pyridyl)-ethylene in acteonitrile. In this reaction single crystals of the title compound were obtained accidentally in a mixture with an unknown phase. To identify the reaction product the compound was investigated by single crystal X-ray diffraction. In the crystal structure of the title compound, each nickel(II) cation is coordinated by four bridging thiocyanato anions and by two acetonitrile molecules (Fig. 1). The NiN~4~S~2~ octahedron is slightly distorted with two long Ni---SCN distances of 2.5305 (6) Å and 2.5341 (6) Å as well as two short Ni---NCS distances of 2.021 (2) Å and 2.023 (2) Å. The angles around the metal atom range from 87.88 (6) ° to 93.23 (6) ° and 178° (Tab. 1). The nickel cations are linked by the thiocyanato anions into chains, that are further connected into a three-dimensional network (Fig. 2). The shortest intramolecular Ni···Ni distance amounts to 5.7052 (4) Å and the shortest intermolecular Ni···Ni distance amounts to 9.0666 (4) Å. Experimental {#experimental} ============ Ni(NCS)~2~ was obtained from Alfa Aesar and *trans*-1,2-bis(4-pyridyl)-ethylene (bpe) was obtained from Sigma Aldrich. All chemicals were used without further purification. 0.6 mmol (104.7 mg) Ni(NCS)~2~ and 0.15 mmol (28.2 mg) bpe were reacted with 1 ml acetonitrile in a closed test-tube at 120°C for three days. On cooling blue block-shaped single crystals of the title compound were obtained in a mixture with a unknown phase. It must be noted, that the reaction without bpe does not lead to the formation of the title compound. Refinement {#refinement} ========== H atoms were positioned with idealized geometry, allowed to rotate but not to tip and were refined isotropically with *U*~iso~(H) = 1.5*U*~eq~(C) and C---H distances of 0.96 Å using a riding model. The absolute structure was determined on the basis of 1127 Friedel pairs. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Crystal structure of the title compound with labelling and displacement ellipsoids drawn at the 30 % probability level. Symmetry codes: i = x-1/2, -y+3/2, -z+1; ii = -x, y-1/2, -z+3/2. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Crystal structure of the title compound approximately viewed along the crystallographic b-axis. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e139 .table-wrap} ------------------------------- ---------------------------------------- \[Ni(NCS)~2~(C~2~H~3~N)~2~\] *F*(000) = 520 *M~r~* = 256.98 *D*~x~ = 1.710 Mg m^−3^ Orthorhombic, *P*2~1~2~1~2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2ac 2ab Cell parameters from 11157 reflections *a* = 9.0666 (4) Å θ = 2.8--29.2° *b* = 9.1215 (3) Å µ = 2.32 mm^−1^ *c* = 12.0696 (6) Å *T* = 293 K *V* = 998.17 (7) Å^3^ Block, blue *Z* = 4 0.11 × 0.09 × 0.06 mm ------------------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e267 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Stoe IPDS-2 diffractometer 2694 independent reflections Radiation source: fine-focus sealed tube 2479 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.023 ω scans θ~max~ = 29.2°, θ~min~ = 2.8° Absorption correction: numerical (*X-SHAPE* and *X-RED32*; Stoe & Cie, 2008) *h* = −12→10 *T*~min~ = 0.683, *T*~max~ = 0.772 *k* = −12→12 11157 measured reflections *l* = −16→16 ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e384 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.027 H-atom parameters constrained *wR*(*F*^2^) = 0.051 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0221*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.29 (Δ/σ)~max~ = 0.001 2694 reflections Δρ~max~ = 0.29 e Å^−3^ 120 parameters Δρ~min~ = −0.28 e Å^−3^ 0 restraints Absolute structure: Flack (1983), 1127 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: −0.003 (13) ---------------------------------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e548 .table-wrap} ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ \> 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e593 .table-wrap} ----- -------------- ------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Ni1 −0.10172 (3) 0.83322 (3) 0.62898 (2) 0.02615 (6) N1 −0.0070 (2) 1.0335 (2) 0.63730 (18) 0.0388 (4) C1 0.0391 (2) 1.1504 (3) 0.64845 (15) 0.0307 (4) S1 0.10459 (8) 1.31745 (6) 0.66142 (4) 0.03781 (12) N2 0.0983 (2) 0.7362 (2) 0.61691 (15) 0.0356 (4) C2 0.2172 (2) 0.6972 (2) 0.60194 (15) 0.0283 (4) S2 0.38867 (6) 0.64753 (7) 0.58006 (4) 0.03776 (13) N3 −0.2036 (2) 0.6293 (2) 0.62176 (17) 0.0341 (4) C3 −0.2491 (2) 0.5139 (3) 0.6242 (2) 0.0335 (4) C4 −0.3109 (3) 0.3669 (3) 0.6278 (3) 0.0468 (6) H4A −0.4134 0.3723 0.6472 0.070\* H4B −0.2593 0.3098 0.6823 0.070\* H4C −0.3007 0.3215 0.5565 0.070\* N4 −0.3065 (2) 0.9326 (2) 0.63801 (17) 0.0365 (4) C5 −0.4170 (2) 0.9893 (2) 0.63197 (19) 0.0344 (4) C6 −0.5579 (3) 1.0633 (3) 0.6230 (3) 0.0452 (5) H6A −0.5743 1.1215 0.6881 0.068\* H6B −0.6351 0.9920 0.6161 0.068\* H6C −0.5575 1.1256 0.5589 0.068\* ----- -------------- ------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e886 .table-wrap} ----- -------------- -------------- -------------- --------------- --------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Ni1 0.02348 (10) 0.02426 (11) 0.03072 (11) −0.00044 (11) −0.00046 (11) −0.00142 (9) N1 0.0458 (11) 0.0336 (10) 0.0371 (9) −0.0091 (8) −0.0039 (10) −0.0018 (9) C1 0.0340 (9) 0.0322 (11) 0.0258 (9) −0.0008 (9) −0.0008 (7) 0.0003 (8) S1 0.0523 (3) 0.0278 (3) 0.0333 (2) −0.0104 (3) −0.0001 (2) 0.00087 (19) N2 0.0288 (7) 0.0434 (9) 0.0346 (9) 0.0041 (9) 0.0021 (10) −0.0025 (7) C2 0.0318 (9) 0.0280 (10) 0.0252 (8) −0.0010 (8) −0.0010 (7) −0.0013 (7) S2 0.0262 (2) 0.0527 (3) 0.0343 (2) 0.0089 (3) 0.0010 (2) 0.0033 (2) N3 0.0339 (8) 0.0314 (10) 0.0369 (9) −0.0033 (7) 0.0016 (9) −0.0011 (9) C3 0.0351 (9) 0.0332 (11) 0.0322 (9) −0.0013 (8) −0.0007 (9) 0.0025 (9) C4 0.0585 (15) 0.0327 (12) 0.0492 (13) −0.0105 (11) −0.0028 (14) −0.0001 (12) N4 0.0334 (9) 0.0379 (10) 0.0382 (9) 0.0053 (8) −0.0016 (9) −0.0003 (9) C5 0.0333 (10) 0.0368 (10) 0.0332 (9) −0.0002 (9) 0.0007 (10) −0.0034 (9) C6 0.0326 (10) 0.0485 (13) 0.0547 (14) 0.0061 (10) 0.0018 (12) −0.0008 (13) ----- -------------- -------------- -------------- --------------- --------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1179 .table-wrap} ---------------------- ------------- ------------------- ------------ Ni1---N1 2.0210 (19) S2---Ni1^iv^ 2.5305 (6) Ni1---N2 2.0231 (18) N3---C3 1.131 (3) Ni1---N4 2.0685 (19) C3---C4 1.454 (3) Ni1---N3 2.0782 (18) C4---H4A 0.9600 Ni1---S2^i^ 2.5305 (6) C4---H4B 0.9600 Ni1---S1^ii^ 2.5341 (6) C4---H4C 0.9600 N1---C1 1.154 (3) N4---C5 1.130 (3) C1---S1 1.643 (2) C5---C6 1.449 (3) S1---Ni1^iii^ 2.5341 (6) C6---H6A 0.9600 N2---C2 1.149 (3) C6---H6B 0.9600 C2---S2 1.641 (2) C6---H6C 0.9600 N1---Ni1---N2 91.02 (8) N2---C2---S2 178.0 (2) N1---Ni1---N4 89.02 (8) C2---S2---Ni1^iv^ 100.02 (7) N2---Ni1---N4 178.89 (9) C3---N3---Ni1 173.7 (2) N1---Ni1---N3 178.69 (9) N3---C3---C4 178.7 (3) N2---Ni1---N3 90.23 (8) C3---C4---H4A 109.5 N4---Ni1---N3 89.73 (8) C3---C4---H4B 109.5 N1---Ni1---S2^i^ 90.09 (6) H4A---C4---H4B 109.5 N2---Ni1---S2^i^ 89.40 (5) C3---C4---H4C 109.5 N4---Ni1---S2^i^ 89.50 (6) H4A---C4---H4C 109.5 N3---Ni1---S2^i^ 90.29 (6) H4B---C4---H4C 109.5 N1---Ni1---S1^ii^ 90.35 (6) C5---N4---Ni1 173.2 (2) N2---Ni1---S1^ii^ 93.23 (6) N4---C5---C6 179.2 (3) N4---Ni1---S1^ii^ 87.88 (6) C5---C6---H6A 109.5 N3---Ni1---S1^ii^ 89.22 (6) C5---C6---H6B 109.5 S2^i^---Ni1---S1^ii^ 177.34 (2) H6A---C6---H6B 109.5 C1---N1---Ni1 174.6 (2) C5---C6---H6C 109.5 N1---C1---S1 178.77 (19) H6A---C6---H6C 109.5 C1---S1---Ni1^iii^ 98.29 (7) H6B---C6---H6C 109.5 C2---N2---Ni1 170.90 (18) ---------------------- ------------- ------------------- ------------ ::: Symmetry codes: (i) *x*−1/2, −*y*+3/2, −*z*+1; (ii) −*x*, *y*−1/2, −*z*+3/2; (iii) −*x*, *y*+1/2, −*z*+3/2; (iv) *x*+1/2, −*y*+3/2, −*z*+1.

PubMed Central

2024-06-05T04:04:17.311728

2011-2-05

PMC3051925

Related literature {#sec1} ================== For the structure of a CuCl~2~ complex of the same Schiff base, see: Saleh Salga *et al.* (2010[@bb5]). For the structure of a similar Cd^II^ complex, see: Bian *et al.* (2003[@bb3]). For a description of the geometry of complexes with five-coordinate metal atoms, see: Addison *et al.* (1984[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[CdCl~2~(C~11~H~17~N~3~)\]*M* *~r~* = 374.58Triclinic,*a* = 8.0276 (2) Å*b* = 9.6048 (2) Å*c* = 10.0851 (2) Åα = 102.534 (1)°β = 103.365 (1)°γ = 97.850 (1)°*V* = 724.09 (3) Å^3^*Z* = 2Mo *K*α radiationμ = 1.86 mm^−1^*T* = 100 K0.23 × 0.11 × 0.04 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb6]) *T* ~min~ = 0.674, *T* ~max~ = 0.9295023 measured reflections2652 independent reflections2547 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.014 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.016*wR*(*F* ^2^) = 0.038*S* = 1.082652 reflections157 parametersH-atom parameters constrainedΔρ~max~ = 0.29 e Å^−3^Δρ~min~ = −0.39 e Å^−3^ {#d5e442} Data collection: *APEX2* (Bruker, 2007[@bb4]); cell refinement: *SAINT* (Bruker, 2007[@bb4]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *X-SEED* (Barbour, 2001[@bb2]); software used to prepare material for publication: *SHELXL97* and *publCIF* (Westrip, 2010[@bb8]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005538/pv2387sup1.cif](http://dx.doi.org/10.1107/S1600536811005538/pv2387sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005538/pv2387Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005538/pv2387Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?pv2387&file=pv2387sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?pv2387sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?pv2387&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [PV2387](http://scripts.iucr.org/cgi-bin/sendsup?pv2387)). The authors thank University of Malaya for funding this study (FRGS grant No. FP004/2010B). Comment ======= The title compound was obtained *via* the complexation of CdCl~2~ by *N,N*-dimethyl-*N\'*-\[methyl(2-pyridyl)methylene\]ethane-1,2-diamine. Similar to the structure of the analogous copper(II) complex (Saleh Salga *et al.*, 2010), the cadmium(II) ion is penta-coordinated by the *N,N\',N\"*-tridentate Schiff base ligand and two Cl atoms in a distorted square-pyramidal geometry, the τ value (Addison *et al.*, 1984) being 0.17. This arrangement is similar to what was observed in the structure of \[CdCl~2~(C~10~H~15~N~3~)\], the closest analogous cadmium complex (Bian *et al.*, 2003). In the crystal, pairs of the molecules, related by symmetry -*x*, -*y*, -*z* + 1, are bonded into centrosymmetric dimers *via* C7---H7B···Cl2 interaction. Experimental {#experimental} ============ A mixture of 2-acetylpyridine (0.61 g, 5 mmol) and *N*,*N*-dimethylethyldiamine (0.44 g, 5 mmol) in ethanol (50 ml) was refluxed for 2 hr followed by addition of a solution of cadmium(II) chloride (0.92 g, 5 mmol) in a minimum amount of water. The resulting solution was refluxed for 30 min, then set aside at room temperature. The colorless crystals of the title compound were obtained after a few days. Refinement {#refinement} ========== Hydrogen atoms were placed at calculated positions at distances C---H = 0.95, 0.98 and 0.99 ° for aryl, methyl and methylene type H-atoms, respectively, and were treated as riding on their parent atoms, with *U*~iso~(H) = 1.2--1.5 times *U*~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Thermal ellipsoid plot of the title compound at the 50% probability level. Hydrogen atoms are drawn as spheres of arbitrary radius. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e157 .table-wrap} ----------------------------- --------------------------------------- \[CdCl~2~(C~11~H~17~N~3~)\] *Z* = 2 *M~r~* = 374.58 *F*(000) = 372 Triclinic, *P*1 *D*~x~ = 1.718 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 8.0276 (2) Å Cell parameters from 5105 reflections *b* = 9.6048 (2) Å θ = 2.2--29.7° *c* = 10.0851 (2) Å µ = 1.86 mm^−1^ α = 102.534 (1)° *T* = 100 K β = 103.365 (1)° Plate, colorless γ = 97.850 (1)° 0.23 × 0.11 × 0.04 mm *V* = 724.09 (3) Å^3^ ----------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e294 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker APEXII CCD diffractometer 2652 independent reflections Radiation source: fine-focus sealed tube 2547 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.014 φ and ω scans θ~max~ = 25.5°, θ~min~ = 2.2° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −9→9 *T*~min~ = 0.674, *T*~max~ = 0.929 *k* = −11→11 5023 measured reflections *l* = −12→12 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e411 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.016 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.038 H-atom parameters constrained *S* = 1.08 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0151*P*)^2^ + 0.4207*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2652 reflections (Δ/σ)~max~ = 0.001 157 parameters Δρ~max~ = 0.29 e Å^−3^ 0 restraints Δρ~min~ = −0.39 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e568 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e667 .table-wrap} ------ ---------------- --------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cd1 −0.076971 (16) 0.190459 (13) 0.205336 (13) 0.01438 (5) Cl1 −0.19397 (6) 0.14396 (5) −0.04976 (5) 0.02368 (11) Cl2 −0.21885 (7) 0.34705 (5) 0.35214 (5) 0.02337 (11) N1 −0.1880 (2) −0.04027 (16) 0.23109 (16) 0.0155 (3) N2 0.1417 (2) 0.10346 (17) 0.33828 (16) 0.0171 (3) N3 0.1925 (2) 0.34724 (17) 0.22918 (16) 0.0187 (3) C1 −0.3543 (3) −0.1088 (2) 0.1769 (2) 0.0193 (4) H1 −0.4351 −0.0611 0.1283 0.023\* C2 −0.4143 (3) −0.2472 (2) 0.1886 (2) 0.0214 (4) H2 −0.5330 −0.2941 0.1471 0.026\* C3 −0.2973 (3) −0.3147 (2) 0.2619 (2) 0.0233 (4) H3 −0.3346 −0.4091 0.2719 0.028\* C4 −0.1247 (3) −0.2432 (2) 0.3208 (2) 0.0202 (4) H4 −0.0429 −0.2874 0.3732 0.024\* C5 −0.0729 (2) −0.1063 (2) 0.30211 (19) 0.0166 (4) C6 0.1124 (2) −0.0244 (2) 0.35613 (19) 0.0173 (4) C7 0.2517 (3) −0.0968 (2) 0.4217 (2) 0.0244 (4) H7A 0.2968 −0.1510 0.3482 0.037\* H7B 0.2025 −0.1639 0.4697 0.037\* H7C 0.3470 −0.0229 0.4902 0.037\* C8 0.3182 (2) 0.1896 (2) 0.3762 (2) 0.0212 (4) H8A 0.3840 0.1458 0.3117 0.025\* H8B 0.3803 0.1910 0.4737 0.025\* C9 0.3074 (3) 0.3439 (2) 0.3656 (2) 0.0211 (4) H9A 0.2626 0.3932 0.4431 0.025\* H9B 0.4260 0.3985 0.3773 0.025\* C10 0.2668 (3) 0.2957 (2) 0.1115 (2) 0.0246 (4) H10A 0.3822 0.3559 0.1282 0.037\* H10B 0.1898 0.3027 0.0233 0.037\* H10C 0.2779 0.1942 0.1045 0.037\* C11 0.1656 (3) 0.4971 (2) 0.2359 (2) 0.0286 (5) H11A 0.2779 0.5613 0.2511 0.043\* H11B 0.1150 0.5301 0.3140 0.043\* H11C 0.0860 0.4995 0.1470 0.043\* ------ ---------------- --------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1172 .table-wrap} ----- ------------- ------------- ------------- ------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cd1 0.01536 (8) 0.01317 (8) 0.01511 (8) 0.00330 (5) 0.00430 (5) 0.00417 (5) Cl1 0.0233 (2) 0.0301 (3) 0.0159 (2) 0.0048 (2) 0.00258 (18) 0.00570 (19) Cl2 0.0298 (3) 0.0205 (2) 0.0265 (2) 0.0112 (2) 0.0154 (2) 0.00792 (19) N1 0.0182 (8) 0.0151 (7) 0.0148 (7) 0.0045 (6) 0.0055 (6) 0.0048 (6) N2 0.0165 (8) 0.0180 (8) 0.0158 (8) 0.0040 (6) 0.0032 (6) 0.0031 (6) N3 0.0202 (8) 0.0168 (8) 0.0194 (8) 0.0030 (6) 0.0076 (7) 0.0029 (6) C1 0.0193 (10) 0.0203 (10) 0.0203 (9) 0.0059 (8) 0.0072 (8) 0.0063 (8) C2 0.0200 (10) 0.0221 (10) 0.0230 (10) 0.0011 (8) 0.0091 (8) 0.0063 (8) C3 0.0294 (11) 0.0165 (9) 0.0289 (11) 0.0041 (8) 0.0149 (9) 0.0084 (8) C4 0.0264 (10) 0.0196 (10) 0.0211 (10) 0.0107 (8) 0.0114 (8) 0.0095 (8) C5 0.0220 (10) 0.0162 (9) 0.0141 (9) 0.0075 (8) 0.0081 (7) 0.0033 (7) C6 0.0205 (10) 0.0200 (9) 0.0129 (9) 0.0080 (8) 0.0056 (7) 0.0036 (7) C7 0.0222 (10) 0.0253 (10) 0.0275 (11) 0.0083 (8) 0.0044 (9) 0.0107 (9) C8 0.0169 (10) 0.0226 (10) 0.0218 (10) 0.0035 (8) 0.0028 (8) 0.0038 (8) C9 0.0206 (10) 0.0194 (10) 0.0198 (10) −0.0004 (8) 0.0057 (8) −0.0001 (8) C10 0.0239 (11) 0.0297 (11) 0.0202 (10) 0.0027 (9) 0.0100 (8) 0.0032 (8) C11 0.0326 (12) 0.0171 (10) 0.0388 (12) 0.0030 (9) 0.0150 (10) 0.0083 (9) ----- ------------- ------------- ------------- ------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1477 .table-wrap} ----------------- -------------- ------------------- ------------- Cd1---N2 2.3188 (15) C4---C5 1.390 (3) Cd1---N1 2.3644 (15) C4---H4 0.9500 Cd1---N3 2.3909 (16) C5---C6 1.499 (3) Cd1---Cl1 2.4434 (5) C6---C7 1.497 (3) Cd1---Cl2 2.4561 (5) C7---H7A 0.9800 N1---C1 1.335 (2) C7---H7B 0.9800 N1---C5 1.350 (2) C7---H7C 0.9800 N2---C6 1.277 (2) C8---C9 1.522 (3) N2---C8 1.459 (2) C8---H8A 0.9900 N3---C10 1.471 (2) C8---H8B 0.9900 N3---C11 1.474 (2) C9---H9A 0.9900 N3---C9 1.478 (2) C9---H9B 0.9900 C1---C2 1.389 (3) C10---H10A 0.9800 C1---H1 0.9500 C10---H10B 0.9800 C2---C3 1.379 (3) C10---H10C 0.9800 C2---H2 0.9500 C11---H11A 0.9800 C3---C4 1.388 (3) C11---H11B 0.9800 C3---H3 0.9500 C11---H11C 0.9800 N2---Cd1---N1 69.42 (5) N1---C5---C6 115.96 (16) N2---Cd1---N3 73.39 (5) C4---C5---C6 122.77 (17) N1---Cd1---N3 141.34 (5) N2---C6---C7 123.96 (18) N2---Cd1---Cl1 131.13 (4) N2---C6---C5 116.71 (16) N1---Cd1---Cl1 98.62 (4) C7---C6---C5 119.29 (16) N3---Cd1---Cl1 97.82 (4) C6---C7---H7A 109.5 N2---Cd1---Cl2 112.49 (4) C6---C7---H7B 109.5 N1---Cd1---Cl2 100.86 (4) H7A---C7---H7B 109.5 N3---Cd1---Cl2 102.71 (4) C6---C7---H7C 109.5 Cl1---Cd1---Cl2 116.315 (17) H7A---C7---H7C 109.5 C1---N1---C5 119.09 (16) H7B---C7---H7C 109.5 C1---N1---Cd1 124.01 (12) N2---C8---C9 109.01 (16) C5---N1---Cd1 116.87 (12) N2---C8---H8A 109.9 C6---N2---C8 121.86 (16) C9---C8---H8A 109.9 C6---N2---Cd1 120.70 (13) N2---C8---H8B 109.9 C8---N2---Cd1 116.44 (11) C9---C8---H8B 109.9 C10---N3---C11 110.06 (16) H8A---C8---H8B 108.3 C10---N3---C9 111.56 (15) N3---C9---C8 112.34 (15) C11---N3---C9 108.99 (15) N3---C9---H9A 109.1 C10---N3---Cd1 110.95 (11) C8---C9---H9A 109.1 C11---N3---Cd1 110.21 (12) N3---C9---H9B 109.1 C9---N3---Cd1 104.94 (11) C8---C9---H9B 109.1 N1---C1---C2 122.72 (18) H9A---C9---H9B 107.9 N1---C1---H1 118.6 N3---C10---H10A 109.5 C2---C1---H1 118.6 N3---C10---H10B 109.5 C3---C2---C1 118.40 (18) H10A---C10---H10B 109.5 C3---C2---H2 120.8 N3---C10---H10C 109.5 C1---C2---H2 120.8 H10A---C10---H10C 109.5 C2---C3---C4 119.34 (18) H10B---C10---H10C 109.5 C2---C3---H3 120.3 N3---C11---H11A 109.5 C4---C3---H3 120.3 N3---C11---H11B 109.5 C3---C4---C5 119.17 (18) H11A---C11---H11B 109.5 C3---C4---H4 120.4 N3---C11---H11C 109.5 C5---C4---H4 120.4 H11A---C11---H11C 109.5 N1---C5---C4 121.26 (17) H11B---C11---H11C 109.5 ----------------- -------------- ------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1979 .table-wrap} ------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C7---H7B···Cl2^i^ 0.98 2.77 3.679 (2) 155 ------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*, −*y*, −*z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------- --------- ------- ----------- ------------- C7---H7*B*⋯Cl2^i^ 0.98 2.77 3.679 (2) 155 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.315331

2011-2-19

PMC3051926

Related literature {#sec1} ================== For examples of the use of Tp\*, see: Lobbia *et al.* (1991[@bb2]); Mashima *et al.* (1997[@bb3]); Nihei *et al.* (2010[@bb4]). For details of Cr(III) bonding, see: Wright-Garcia *et al.* (2003)[@bb6]. Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Cr(C~15~H~22~BN~6~)Cl~2~(C~5~H~8~N~2~)\]·C~4~H~8~O*M* *~r~* = 588.33Monoclinic,*a* = 10.9417 (13) Å*b* = 11.1563 (13) Å*c* = 24.036 (3) Åβ = 96.381 (2)°*V* = 2915.9 (6) Å^3^*Z* = 4Mo *K*α radiationμ = 0.61 mm^−1^*T* = 298 K0.2 × 0.2 × 0.2 mm ### Data collection {#sec2.1.2} Bruker SMART CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2000[@bb1]) *T* ~min~ = 0.886, *T* ~max~ = 0.88624008 measured reflections5422 independent reflections4930 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.108 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.088*wR*(*F* ^2^) = 0.189*S* = 1.335422 reflections351 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.64 e Å^−3^Δρ~min~ = −0.36 e Å^−3^ {#d5e480} Data collection: *SMART* (Bruker, 2000[@bb1]); cell refinement: *SAINT* (Bruker, 2000[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb5]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb5]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005344/br2160sup1.cif](http://dx.doi.org/10.1107/S1600536811005344/br2160sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005344/br2160Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005344/br2160Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?br2160&file=br2160sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?br2160sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?br2160&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BR2160](http://scripts.iucr.org/cgi-bin/sendsup?br2160)). This work was supported by Hefei Normal University (No. 2008jyy006). Comment ======= Since hydrotris(3,5-dimethylpyrazolyl)borate(Tp\*) serves as tridentate, anionic, six-electron donor ligands, investigations of organometallic and inorganic chemistry using this type of ligand has developed rapidly (Mashima, *et al.*, 1997; Nihei, *et al.*, 2010; Wright-Garcia, *et al.*, 2003 and Lobbia, *et al.*, 1991). The molecular structure of title compound is shown in Fig.1. The Cr atom has an octahedral geometry and is coordinated by three N atoms from the tridentate Tp\* ligand, one N atom from Dmpy ligand, and two Cl atoms. N3, N5 and Cl1, Cl2 lie in the equatorial plane. There are full non-classic hydrogen bonds in this complex. Intermolecules connect *via* hydrogen bond with C20 (Dmpy) and O1 (THF). A pair of THF uncoordination molecules around a center of symmetry exist in the stacking of copound. The other coordinated bond angles are shown in Table 1. The molecular packing diagram of the title compound is shown in Fig.2. Experimental {#experimental} ============ Tp\*SnCl~3~ was prepared according to the literature procedure (Mashima, *et al*.,1997). Treatment of Tp\*SnCl~3~ (261 mg, 0.5 mmol) with CrCl~3~.3THF (187 mg 0.5 mmol) in 50 ml THF for 4 h at room temperature afforded a green solution that was evacuated to 20 ml, and the solution was carefully layered with 40 ml pentane. After 3 days at 253 K, green block crystals were obtained and were isolated *via* filtration. Refinement {#refinement} ========== The H atoms on some of the C atoms and on the B atom were located in a difference Fourier map and refined with the restraints C--H = 0.96--0.97) Å and B---H = 1.09 (5) Å,and N---H = 0.77 (4) Å, *U*~iso~(H) = 1.5Ueq(carrier). H atoms on pyrazolyl ring C atoms were placed in geometrically idealized positions and refined in riding mode, with C--H = 0.93 Å and *U*~iso~(H) = 1.2Ueq(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title complex, showing ellipsoids at the 30% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The molecular packing diagram of the title complex, with the hydrogen atoms ommitted. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e137 .table-wrap} ------------------------------------------------------ ---------------------------------- \[Cr(C~15~H~22~BN~6~)Cl~2~(C~5~H~8~N~2~)\]·C~4~H~8~O *Z* = 4 *M~r~* = 588.33 *F*(000) = 1236 Monoclinic, *P*2~1~/*c* *D*~x~ = 1.340 Mg m^−3^ Hall symbol: -P 2ybc Mo *K*α radiation, λ = 0.71073 Å *a* = 10.9417 (13) Å θ = 1.0--25.5° *b* = 11.1563 (13) Å µ = 0.61 mm^−1^ *c* = 24.036 (3) Å *T* = 298 K β = 96.381 (2)° Block, green *V* = 2915.9 (6) Å^3^ 0.2 × 0.2 × 0.2 mm ------------------------------------------------------ ---------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e280 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART CCD area-detector diffractometer 5422 independent reflections Radiation source: fine-focus sealed tube 4930 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.108 φ and ω scans θ~max~ = 25.5°, θ~min~ = 1.7° Absorption correction: multi-scan (*SADABS*; Bruker, 2000) *h* = −11→13 *T*~min~ = 0.886, *T*~max~ = 0.886 *k* = −13→13 24008 measured reflections *l* = −29→29 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e397 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.088 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.189 H atoms treated by a mixture of independent and constrained refinement *S* = 1.33 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0478*P*)^2^ + 5.8124*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 5422 reflections (Δ/σ)~max~ = 0.061 351 parameters Δρ~max~ = 0.64 e Å^−3^ 0 restraints Δρ~min~ = −0.36 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e554 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e653 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ H20 −0.049 (4) 0.229 (4) 0.8535 (17) 0.000 (14)\* Cr1 0.21415 (6) 0.13372 (6) 0.86917 (3) 0.0257 (2) Cl1 0.21345 (12) 0.33718 (10) 0.84889 (5) 0.0403 (3) Cl2 0.12131 (12) 0.17258 (13) 0.94879 (5) 0.0443 (3) O1 0.8845 (5) 0.3794 (4) 0.8944 (2) 0.0768 (14) B1 0.4295 (5) −0.0476 (5) 0.8590 (3) 0.0390 (13) N1 0.3892 (4) 0.1397 (4) 0.91225 (17) 0.0366 (9) N2 0.4684 (3) 0.0481 (4) 0.90276 (16) 0.0354 (9) N3 0.2138 (3) −0.0490 (3) 0.88608 (16) 0.0324 (9) N4 0.3152 (4) −0.1143 (3) 0.87563 (16) 0.0340 (9) N5 0.2998 (3) 0.0980 (3) 0.79742 (15) 0.0292 (8) N6 0.3927 (3) 0.0142 (3) 0.80210 (16) 0.0324 (9) N7 0.0439 (3) 0.1082 (3) 0.82229 (15) 0.0281 (8) N8 −0.0520 (4) 0.1813 (4) 0.83032 (19) 0.0327 (9) C1 0.3947 (6) 0.3210 (6) 0.9731 (3) 0.0663 (18) H1A 0.3673 0.3722 0.9421 0.099\* H1B 0.4560 0.3618 0.9978 0.099\* H1C 0.3263 0.3007 0.9930 0.099\* C2 0.4486 (5) 0.2090 (5) 0.9518 (2) 0.0435 (13) C3 0.5638 (5) 0.1617 (6) 0.9677 (2) 0.0519 (15) H3 0.6229 0.1929 0.9946 0.062\* C4 0.5747 (5) 0.0616 (6) 0.9367 (2) 0.0459 (14) C5 0.6814 (5) −0.0219 (7) 0.9356 (3) 0.070 (2) H5A 0.6545 −0.1028 0.9404 0.105\* H5B 0.7439 −0.0017 0.9654 0.105\* H5C 0.7142 −0.0148 0.9004 0.105\* C6 0.0046 (5) −0.0972 (6) 0.9141 (3) 0.0526 (15) H6A 0.0070 −0.0197 0.9316 0.079\* H6B −0.0225 −0.1558 0.9393 0.079\* H6C −0.0513 −0.0953 0.8804 0.079\* C7 0.1302 (5) −0.1293 (5) 0.9003 (2) 0.0397 (12) C8 0.1793 (5) −0.2434 (5) 0.8988 (2) 0.0451 (13) H8 0.1409 −0.3145 0.9071 0.054\* C9 0.2944 (5) −0.2318 (5) 0.8830 (2) 0.0410 (12) C10 0.3865 (6) −0.3265 (5) 0.8738 (3) 0.0609 (17) H10A 0.4042 −0.3241 0.8356 0.091\* H10B 0.3538 −0.4037 0.8817 0.091\* H10C 0.4607 −0.3125 0.8982 0.091\* C11 0.1907 (5) 0.2217 (5) 0.7202 (2) 0.0413 (12) H11A 0.1118 0.1834 0.7141 0.062\* H11B 0.2128 0.2520 0.6853 0.062\* H11C 0.1871 0.2867 0.7461 0.062\* C12 0.2851 (4) 0.1326 (4) 0.7437 (2) 0.0333 (10) C13 0.3698 (5) 0.0739 (5) 0.7147 (2) 0.0396 (12) H13 0.3799 0.0830 0.6770 0.047\* C14 0.4356 (4) −0.0002 (4) 0.7523 (2) 0.0365 (11) C15 0.5383 (5) −0.0845 (6) 0.7431 (3) 0.0543 (15) H15A 0.6119 −0.0601 0.7657 0.081\* H15B 0.5520 −0.0831 0.7043 0.081\* H15C 0.5167 −0.1643 0.7533 0.081\* C16 0.0693 (5) −0.0696 (5) 0.7607 (2) 0.0422 (12) H16A 0.1463 −0.0397 0.7508 0.063\* H16B 0.0232 −0.1038 0.7283 0.063\* H16C 0.0844 −0.1298 0.7892 0.063\* C17 −0.0019 (4) 0.0306 (4) 0.78224 (19) 0.0315 (10) C18 −0.1248 (5) 0.0575 (5) 0.7659 (2) 0.0418 (12) H18 −0.1770 0.0179 0.7388 0.050\* C19 −0.1540 (4) 0.1526 (4) 0.7972 (2) 0.0399 (12) C20 −0.2733 (5) 0.2176 (6) 0.7987 (3) 0.0641 (18) H20A −0.3247 0.1736 0.8213 0.096\* H20B −0.3139 0.2251 0.7614 0.096\* H20C −0.2576 0.2960 0.8145 0.096\* C21 0.8285 (10) 0.3483 (8) 0.9424 (5) 0.117 (4) H21A 0.8886 0.3138 0.9707 0.141\* H21B 0.7636 0.2901 0.9331 0.141\* C22 0.7779 (10) 0.4587 (9) 0.9632 (4) 0.114 (3) H22A 0.7904 0.4616 1.0038 0.137\* H22B 0.6906 0.4648 0.9511 0.137\* C23 0.8465 (10) 0.5566 (7) 0.9387 (4) 0.102 (3) H23A 0.8925 0.6037 0.9678 0.122\* H23B 0.7910 0.6091 0.9158 0.122\* C24 0.9310 (9) 0.4931 (7) 0.9039 (3) 0.088 (2) H24A 0.9346 0.5348 0.8687 0.105\* H24B 1.0134 0.4894 0.9235 0.105\* H1 0.504 (5) −0.109 (4) 0.857 (2) 0.037 (13)\* ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1677 .table-wrap} ----- ------------ ------------- ------------- -------------- ------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cr1 0.0216 (4) 0.0282 (4) 0.0277 (4) 0.0017 (3) 0.0047 (3) 0.0002 (3) Cl1 0.0453 (7) 0.0290 (6) 0.0468 (7) −0.0007 (5) 0.0061 (5) 0.0009 (5) Cl2 0.0448 (7) 0.0573 (8) 0.0325 (6) 0.0046 (6) 0.0124 (5) −0.0039 (6) O1 0.080 (3) 0.053 (3) 0.103 (4) −0.007 (2) 0.038 (3) −0.026 (3) B1 0.024 (3) 0.039 (3) 0.055 (4) 0.008 (2) 0.009 (2) 0.009 (3) N1 0.028 (2) 0.042 (2) 0.039 (2) 0.0012 (18) 0.0032 (17) −0.0029 (19) N2 0.025 (2) 0.043 (2) 0.037 (2) 0.0004 (18) 0.0010 (16) 0.0071 (18) N3 0.031 (2) 0.031 (2) 0.036 (2) 0.0056 (17) 0.0095 (17) 0.0056 (17) N4 0.032 (2) 0.032 (2) 0.039 (2) 0.0058 (17) 0.0053 (17) 0.0065 (17) N5 0.025 (2) 0.030 (2) 0.034 (2) 0.0016 (16) 0.0105 (16) 0.0019 (16) N6 0.025 (2) 0.035 (2) 0.039 (2) 0.0022 (16) 0.0113 (16) 0.0010 (17) N7 0.025 (2) 0.0279 (19) 0.0328 (19) 0.0055 (15) 0.0074 (15) −0.0001 (16) N8 0.033 (2) 0.026 (2) 0.040 (2) 0.0021 (17) 0.0058 (18) −0.0068 (19) C1 0.056 (4) 0.074 (4) 0.066 (4) −0.007 (3) −0.009 (3) −0.029 (3) C2 0.038 (3) 0.051 (3) 0.040 (3) −0.009 (2) −0.002 (2) −0.002 (2) C3 0.036 (3) 0.077 (4) 0.039 (3) −0.012 (3) −0.010 (2) 0.002 (3) C4 0.028 (3) 0.067 (4) 0.042 (3) −0.003 (3) −0.001 (2) 0.013 (3) C5 0.032 (3) 0.086 (5) 0.088 (5) 0.011 (3) −0.012 (3) 0.017 (4) C6 0.045 (3) 0.056 (4) 0.062 (4) −0.008 (3) 0.027 (3) 0.006 (3) C7 0.039 (3) 0.041 (3) 0.040 (3) −0.004 (2) 0.009 (2) 0.007 (2) C8 0.052 (3) 0.034 (3) 0.051 (3) −0.008 (2) 0.011 (3) 0.014 (2) C9 0.051 (3) 0.035 (3) 0.037 (3) 0.003 (2) 0.004 (2) 0.006 (2) C10 0.074 (4) 0.037 (3) 0.073 (4) 0.017 (3) 0.010 (3) 0.005 (3) C11 0.046 (3) 0.042 (3) 0.036 (3) 0.003 (2) 0.003 (2) 0.009 (2) C12 0.030 (2) 0.033 (2) 0.038 (3) −0.008 (2) 0.008 (2) −0.001 (2) C13 0.038 (3) 0.048 (3) 0.035 (3) −0.004 (2) 0.017 (2) 0.002 (2) C14 0.028 (2) 0.037 (3) 0.048 (3) −0.005 (2) 0.016 (2) −0.003 (2) C15 0.041 (3) 0.058 (4) 0.068 (4) 0.008 (3) 0.024 (3) −0.003 (3) C16 0.038 (3) 0.039 (3) 0.051 (3) −0.009 (2) 0.009 (2) −0.015 (2) C17 0.030 (2) 0.027 (2) 0.037 (2) −0.0058 (19) 0.007 (2) 0.000 (2) C18 0.035 (3) 0.041 (3) 0.047 (3) −0.009 (2) −0.005 (2) −0.002 (2) C19 0.028 (3) 0.037 (3) 0.053 (3) 0.001 (2) 0.000 (2) 0.003 (2) C20 0.034 (3) 0.058 (4) 0.098 (5) 0.008 (3) −0.001 (3) −0.006 (4) C21 0.121 (8) 0.070 (5) 0.180 (11) 0.000 (5) 0.100 (8) 0.005 (6) C22 0.141 (9) 0.096 (7) 0.116 (7) 0.021 (6) 0.068 (7) −0.018 (6) C23 0.166 (9) 0.060 (5) 0.080 (5) 0.010 (6) 0.015 (6) −0.018 (4) C24 0.126 (7) 0.065 (5) 0.075 (5) −0.014 (5) 0.026 (5) −0.010 (4) ----- ------------ ------------- ------------- -------------- ------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2358 .table-wrap} ----------------- ------------- ------------------- ------------ Cr1---N1 2.075 (4) C7---C8 1.384 (7) Cr1---N3 2.078 (4) C8---C9 1.362 (7) Cr1---N7 2.086 (4) C8---H8 0.9300 Cr1---N5 2.090 (4) C9---C10 1.493 (7) Cr1---Cl2 2.3054 (14) C10---H10A 0.9600 Cr1---Cl1 2.3214 (14) C10---H10B 0.9600 O1---C24 1.376 (9) C10---H10C 0.9600 O1---C21 1.410 (10) C11---C12 1.498 (7) B1---N2 1.527 (8) C11---H11A 0.9600 B1---N6 1.544 (7) C11---H11B 0.9600 B1---N4 1.545 (7) C11---H11C 0.9600 B1---H1 1.07 (5) C12---C13 1.385 (7) N1---C2 1.336 (6) C13---C14 1.370 (7) N1---N2 1.375 (6) C13---H13 0.9300 N2---C4 1.353 (6) C14---C15 1.501 (7) N3---C7 1.351 (6) C15---H15A 0.9600 N3---N4 1.374 (5) C15---H15B 0.9600 N4---C9 1.346 (6) C15---H15C 0.9600 N5---C12 1.340 (6) C16---C17 1.488 (7) N5---N6 1.376 (5) C16---H16A 0.9600 N6---C14 1.343 (6) C16---H16B 0.9600 N7---C17 1.349 (6) C16---H16C 0.9600 N7---N8 1.360 (5) C17---C18 1.390 (7) N8---C19 1.337 (6) C18---C19 1.359 (7) N8---H20 0.77 (4) C18---H18 0.9300 C1---C2 1.496 (8) C19---C20 1.497 (7) C1---H1A 0.9600 C20---H20A 0.9600 C1---H1B 0.9600 C20---H20B 0.9600 C1---H1C 0.9600 C20---H20C 0.9600 C2---C3 1.381 (8) C21---C22 1.462 (11) C3---C4 1.355 (9) C21---H21A 0.9700 C3---H3 0.9300 C21---H21B 0.9700 C4---C5 1.496 (8) C22---C23 1.484 (13) C5---H5A 0.9600 C22---H22A 0.9700 C5---H5B 0.9600 C22---H22B 0.9700 C5---H5C 0.9600 C23---C24 1.493 (11) C6---C7 1.493 (7) C23---H23A 0.9700 C6---H6A 0.9600 C23---H23B 0.9700 C6---H6B 0.9600 C24---H24A 0.9700 C6---H6C 0.9600 C24---H24B 0.9700 N1---Cr1---N3 87.45 (16) C9---C8---H8 126.5 N1---Cr1---N7 173.26 (15) C7---C8---H8 126.5 N3---Cr1---N7 87.18 (15) N4---C9---C8 107.7 (5) N1---Cr1---N5 86.80 (15) N4---C9---C10 122.9 (5) N3---Cr1---N5 89.14 (15) C8---C9---C10 129.4 (5) N7---Cr1---N5 89.05 (14) C9---C10---H10A 109.5 N1---Cr1---Cl2 92.71 (12) C9---C10---H10B 109.5 N3---Cr1---Cl2 90.66 (11) H10A---C10---H10B 109.5 N7---Cr1---Cl2 91.42 (11) C9---C10---H10C 109.5 N5---Cr1---Cl2 179.48 (11) H10A---C10---H10C 109.5 N1---Cr1---Cl1 93.14 (12) H10B---C10---H10C 109.5 N3---Cr1---Cl1 179.14 (12) C12---C11---H11A 109.5 N7---Cr1---Cl1 92.19 (11) C12---C11---H11B 109.5 N5---Cr1---Cl1 90.26 (11) H11A---C11---H11B 109.5 Cl2---Cr1---Cl1 89.94 (5) C12---C11---H11C 109.5 C24---O1---C21 106.1 (6) H11A---C11---H11C 109.5 N2---B1---N6 108.9 (4) H11B---C11---H11C 109.5 N2---B1---N4 109.2 (4) N5---C12---C13 109.5 (4) N6---B1---N4 107.8 (4) N5---C12---C11 123.9 (4) N2---B1---H1 109 (3) C13---C12---C11 126.6 (4) N6---B1---H1 112 (3) C14---C13---C12 106.5 (4) N4---B1---H1 110 (3) C14---C13---H13 126.7 C2---N1---N2 106.4 (4) C12---C13---H13 126.7 C2---N1---Cr1 136.2 (4) N6---C14---C13 107.8 (4) N2---N1---Cr1 117.2 (3) N6---C14---C15 123.3 (5) C4---N2---N1 109.4 (4) C13---C14---C15 128.9 (5) C4---N2---B1 130.5 (5) C14---C15---H15A 109.5 N1---N2---B1 120.1 (4) C14---C15---H15B 109.5 C7---N3---N4 106.1 (4) H15A---C15---H15B 109.5 C7---N3---Cr1 135.7 (3) C14---C15---H15C 109.5 N4---N3---Cr1 117.7 (3) H15A---C15---H15C 109.5 C9---N4---N3 109.9 (4) H15B---C15---H15C 109.5 C9---N4---B1 131.0 (4) C17---C16---H16A 109.5 N3---N4---B1 119.0 (4) C17---C16---H16B 109.5 C12---N5---N6 106.4 (4) H16A---C16---H16B 109.5 C12---N5---Cr1 136.3 (3) C17---C16---H16C 109.5 N6---N5---Cr1 117.2 (3) H16A---C16---H16C 109.5 C14---N6---N5 109.7 (4) H16B---C16---H16C 109.5 C14---N6---B1 130.7 (4) N7---C17---C18 109.5 (4) N5---N6---B1 119.6 (4) N7---C17---C16 124.2 (4) C17---N7---N8 104.7 (4) C18---C17---C16 126.3 (4) C17---N7---Cr1 135.4 (3) C19---C18---C17 107.0 (4) N8---N7---Cr1 119.9 (3) C19---C18---H18 126.5 C19---N8---N7 112.2 (4) C17---C18---H18 126.5 C19---N8---H20 124 (3) N8---C19---C18 106.5 (4) N7---N8---H20 123 (3) N8---C19---C20 122.8 (5) C2---C1---H1A 109.5 C18---C19---C20 130.7 (5) C2---C1---H1B 109.5 C19---C20---H20A 109.5 H1A---C1---H1B 109.5 C19---C20---H20B 109.5 C2---C1---H1C 109.5 H20A---C20---H20B 109.5 H1A---C1---H1C 109.5 C19---C20---H20C 109.5 H1B---C1---H1C 109.5 H20A---C20---H20C 109.5 N1---C2---C3 109.4 (5) H20B---C20---H20C 109.5 N1---C2---C1 123.2 (5) O1---C21---C22 106.7 (7) C3---C2---C1 127.4 (5) O1---C21---H21A 110.4 C4---C3---C2 107.3 (5) C22---C21---H21A 110.4 C4---C3---H3 126.4 O1---C21---H21B 110.4 C2---C3---H3 126.4 C22---C21---H21B 110.4 N2---C4---C3 107.5 (5) H21A---C21---H21B 108.6 N2---C4---C5 122.7 (6) C21---C22---C23 104.9 (7) C3---C4---C5 129.8 (5) C21---C22---H22A 110.8 C4---C5---H5A 109.5 C23---C22---H22A 110.8 C4---C5---H5B 109.5 C21---C22---H22B 110.8 H5A---C5---H5B 109.5 C23---C22---H22B 110.8 C4---C5---H5C 109.5 H22A---C22---H22B 108.8 H5A---C5---H5C 109.5 C22---C23---C24 104.2 (7) H5B---C5---H5C 109.5 C22---C23---H23A 110.9 C7---C6---H6A 109.5 C24---C23---H23A 110.9 C7---C6---H6B 109.5 C22---C23---H23B 110.9 H6A---C6---H6B 109.5 C24---C23---H23B 110.9 C7---C6---H6C 109.5 H23A---C23---H23B 108.9 H6A---C6---H6C 109.5 O1---C24---C23 106.8 (7) H6B---C6---H6C 109.5 O1---C24---H24A 110.4 N3---C7---C8 109.1 (5) C23---C24---H24A 110.4 N3---C7---C6 124.3 (5) O1---C24---H24B 110.4 C8---C7---C6 126.6 (5) C23---C24---H24B 110.4 C9---C8---C7 107.1 (5) H24A---C24---H24B 108.6 ----------------- ------------- ------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3442 .table-wrap} -------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C20---H20C···O1^i^ 0.96 2.51 3.265 (8) 135 N8---H20···O1^i^ 0.77 (4) 2.11 (4) 2.820 (6) 153.8 -------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) *x*−1, *y*, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- ---------- ---------- ----------- ------------- C20---H20*C*⋯O1^i^ 0.96 2.51 3.265 (8) 135 N8---H20⋯O1^i^ 0.77 (4) 2.11 (4) 2.820 (6) 153.8 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.320370

2011-2-19

PMC3051927

Related literature {#sec1} ================== For the distribution of the fungus *Lacta­rius piperatus* in China, see: Xie *et al.* (1996[@bb12]). For the anti-tumor activity of this species see: Mo *et al.* (1995[@bb6]). A series of sesquiterpenes has been isolated from the genus *Lacta­rius*, see: De Bernardi *et al.* (1993[@bb2]); Sterner *et al.* (1990[@bb9]). For the isolation of amino acids and sesquiterpenes from *L. piperatus* growing in Europe and Japan and their biological activity, see: Fushiya *et al.* (1988[@bb4]); Sterner *et al.* (1985*a* [@bb10],*b* [@bb11]); Yaoita *et al.* (1999[@bb13]). For standard bond lengths, see: Allen *et al.* (1987[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~15~H~18~O~3~*M* *~r~* = 247.30Orthorhombic,*a* = 9.5150 (19) Å*b* = 10.885 (2) Å*c* = 12.594 (3) Å*V* = 1304.4 (5) Å^3^*Z* = 4Mo *K*α radiationμ = 0.09 mm^−1^*T* = 298 K0.30 × 0.20 × 0.20 mm ### Data collection {#sec2.1.2} Enraf--Nonius CAD-4 diffractometerAbsorption correction: ψ scan (North *et al.*, 1968[@bb7]) *T* ~min~ = 0.975, *T* ~max~ = 0.9832616 measured reflections1367 independent reflections1209 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.0213 standard reflections every 200 reflections intensity decay: 1% ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.035*wR*(*F* ^2^) = 0.091*S* = 1.061367 reflections164 parametersH-atom parameters constrainedΔρ~max~ = 0.15 e Å^−3^Δρ~min~ = −0.12 e Å^−3^ {#d5e490} Data collection: *CAD-4 Software* (Enraf--Nonius, 1989[@bb3]); cell refinement: *CAD-4 Software*; data reduction: *XCAD4* (Harms & Wocadlo, 1995[@bb5]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb8]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb8]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811006519/sj5106sup1.cif](http://dx.doi.org/10.1107/S1600536811006519/sj5106sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006519/sj5106Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006519/sj5106Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?sj5106&file=sj5106sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?sj5106sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?sj5106&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [SJ5106](http://scripts.iucr.org/cgi-bin/sendsup?sj5106)). This work was supported by the Natural Science Foundation of Zhejiang Province (Project Y2101290), the Zhejiang Traditional Chinese Medicine Administration Fund (Project 2009 C A003) and Zhejiang Traditional Chinese Medicine University (Project 2009ZY06). Comment ======= The fungus *Lactarius piperatus* (Fr.) S. F. Gary (family Russulaceae, Basidiomycotina) is widely distributed in China (Xie *et al.*, 1996). The ethanolic extract has been reported to inhibit the growth of several tumor cell lines (Mo *et al.*, 1995). *L. Piperatus*, growing in Europe and Japan, has been investigated, and a new amino acid and a few sesquiterpenes were isolated (Fushiya *et al.*, 1988; Sterner *et al.*, 1985*a*; Yaoita *et al.*, 1999), but *L. piperatus* growing in China has not been previously investigated chemically. A series of sesquiterpenes, belonging to the marasmane, lactarane, isolactarane, and secolactarane types, has been isolated from the genus of Lactarius (De Bernardi *et al.*, 1993, Sterner *et al.*, 1990). These sesquiterpenes provide a chemical defense system against parasites and predators (Sterner *et al.*, 1985*b*). The molecular structure of the title compound is shown in Fig. 1. All bond lengths are within normal ranges (Allen *et al.*, 1987). The central cyclohexyl ring C5-C6-C7-C10-C11-C12 adopts a chair conformation. The dihedral angle between the C7-C8-C9-O1-C10 ring and the plane defined by C12-C1-C2-C3-C4 is 75.3 (3)°. Atom C5 deviates 0.692 (2) Å from the plane defined by C12-C1-C2-C3-C4. In the crystal, molecules are linked via intermolecular O---H···O hydrogen bonds (Table 1) to form chains along the *a* axis (Fig. 2). Experimental {#experimental} ============ Plant material: *Lactarius piperatus* (Fr.) S. F. Gary was collected from the Kunming area in Yunnan province of China and authenticated by Prof. Mu Zang, Kunming Institute of Botany, where a voucher specimen labeled as HKAS 30213, was deposited. Extraction and Isolation: The fresh mushroom (5 kg) was extracted with 95% EtOH and yielded 91 g of crude extract, which was then suspended in 2 L water. The suspension was partitioned with EtOAc (4× 200 ml) to give an EtOAc-soluble portion, and a water-soluble fraction. After removal of the EtOAc under reduced pressure, 49 g of dark residue was obtained, and this was subjected to silica-gel chromatography, eluted with a stepwise gradient solvent system of petroleum/acetone 10 : 0 to 5 : 5, followed by MeOH, to afford four major fractions (monitored by TLC). Fr. 1 consisted mainly of fatty acids. Fr. 4 was much smaller and complex. The separation and purification were focused on Fr. 2 and 3, in which the sesquiterpenes were concentrated. A portion of sub-fraction Fr. 2 was re-chromatographed on silica gel using a petroleum ether-acetone (8:2) system and the isolated product was recrystallized from chloroform-methanol (7:3) to yield the active component as light colorless crystals. Refinement {#refinement} ========== H atoms were positioned geometrically and refined using the riding-model approximation, with C---H = 0.93--0.97 Å, O---H = 0.82 Å, and *U*~iso~(H) = 1.2*U*~eq~(C) or *U*~iso~(H) = 1.5*U*~eq~(O). In the absence of significant anomalous dispersion effects, Freidel pairs were merged. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compounds with atom labels and the 30% probability displacement ellipsoids for non-hydrogen atoms. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Molecular packing of the title compound, viewed along the a axis. Hydrogen bonds are drawn as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e171 .table-wrap} ------------------------------- ------------------------------------- C~15~H~18~O~3~ *F*(000) = 532 *M~r~* = 247.30 *D*~x~ = 1.259 Mg m^−3^ Orthorhombic, *P*2~1~2~1~2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2ac 2ab Cell parameters from 25 reflections *a* = 9.5150 (19) Å θ = 10--13° *b* = 10.885 (2) Å µ = 0.09 mm^−1^ *c* = 12.594 (3) Å *T* = 298 K *V* = 1304.4 (5) Å^3^ Block, colourless *Z* = 4 0.30 × 0.20 × 0.20 mm ------------------------------- ------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e295 .table-wrap} ------------------------------------------------------ ---------------------------------------------- Enraf--Nonius CAD-4 diffractometer 1209 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.021 graphite θ~max~ = 25.3°, θ~min~ = 2.5° ω/2θ scans *h* = 0→11 Absorption correction: ψ scan (North *et al.*, 1968) *k* = 0→12 *T*~min~ = 0.975, *T*~max~ = 0.983 *l* = −15→15 2616 measured reflections 3 standard reflections every 200 reflections 1367 independent reflections intensity decay: 1% ------------------------------------------------------ ---------------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e414 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.035 H-atom parameters constrained *wR*(*F*^2^) = 0.091 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0474*P*)^2^ + 0.1815*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.06 (Δ/σ)~max~ = 0.001 1367 reflections Δρ~max~ = 0.15 e Å^−3^ 164 parameters Δρ~min~ = −0.12 e Å^−3^ 0 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.036 (3) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e595 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e694 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O1 0.40511 (17) 0.69401 (16) 0.36817 (13) 0.0514 (5) C1 −0.0968 (3) 0.6294 (2) 0.4001 (2) 0.0512 (6) H1A −0.0918 0.6506 0.4715 0.061\* O2 0.51038 (18) 0.85545 (16) 0.29192 (14) 0.0627 (5) C2 −0.2158 (3) 0.6509 (3) 0.3493 (2) 0.0609 (8) H2A −0.2893 0.6871 0.3866 0.073\* O3 0.34477 (19) 0.48626 (15) 0.36469 (14) 0.0576 (5) H3A 0.3854 0.4559 0.3136 0.086\* C3 −0.2383 (3) 0.6201 (3) 0.2348 (2) 0.0607 (8) H3B −0.2599 0.6949 0.1962 0.073\* H3C −0.3188 0.5658 0.2288 0.073\* C4 −0.1128 (3) 0.5590 (2) 0.18373 (19) 0.0478 (6) C5 0.0243 (2) 0.60217 (19) 0.22901 (16) 0.0387 (5) H5A 0.0223 0.6920 0.2238 0.046\* C6 0.1574 (3) 0.5615 (2) 0.16947 (18) 0.0440 (6) H6A 0.1696 0.4732 0.1748 0.053\* H6B 0.1513 0.5837 0.0950 0.053\* C7 0.2764 (2) 0.6267 (2) 0.22127 (18) 0.0405 (5) C8 0.3544 (2) 0.7232 (2) 0.19078 (17) 0.0424 (5) C9 0.4327 (2) 0.7661 (2) 0.2838 (2) 0.0460 (6) C10 0.2974 (3) 0.6033 (2) 0.33811 (19) 0.0425 (6) C11 0.1634 (2) 0.6320 (2) 0.39810 (17) 0.0423 (5) H11A 0.1507 0.7204 0.3999 0.051\* H11B 0.1735 0.6039 0.4708 0.051\* C12 0.0308 (2) 0.5729 (2) 0.34989 (18) 0.0395 (5) C13 0.0256 (3) 0.4326 (2) 0.3715 (2) 0.0569 (7) H13B 0.0301 0.4181 0.4466 0.085\* H13C 0.1040 0.3934 0.3374 0.085\* H13D −0.0604 0.3994 0.3439 0.085\* C14 −0.1255 (3) 0.4774 (3) 0.1063 (2) 0.0644 (8) H14A −0.0457 0.4425 0.0761 0.077\* H14B −0.2142 0.4549 0.0821 0.077\* C15 0.3624 (3) 0.7890 (3) 0.0874 (2) 0.0607 (7) H15A 0.3043 0.7478 0.0363 0.091\* H15B 0.4580 0.7895 0.0629 0.091\* H15C 0.3303 0.8719 0.0964 0.091\* ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1189 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.0459 (9) 0.0572 (10) 0.0510 (9) −0.0036 (9) −0.0053 (8) −0.0002 (9) C1 0.0518 (14) 0.0515 (14) 0.0503 (13) −0.0019 (13) 0.0146 (12) −0.0027 (12) O2 0.0517 (10) 0.0567 (11) 0.0797 (12) −0.0136 (10) 0.0040 (11) −0.0053 (10) C2 0.0462 (15) 0.0611 (17) 0.0754 (19) 0.0031 (14) 0.0136 (14) −0.0024 (16) O3 0.0614 (11) 0.0476 (9) 0.0636 (11) 0.0159 (9) 0.0033 (10) 0.0107 (9) C3 0.0448 (14) 0.0588 (16) 0.0784 (19) −0.0034 (13) −0.0039 (13) 0.0088 (16) C4 0.0525 (15) 0.0402 (12) 0.0507 (13) −0.0079 (12) −0.0067 (12) 0.0077 (11) C5 0.0455 (13) 0.0272 (10) 0.0433 (13) −0.0020 (10) 0.0012 (11) 0.0012 (9) C6 0.0532 (14) 0.0388 (12) 0.0402 (11) −0.0012 (12) 0.0036 (11) −0.0045 (10) C7 0.0425 (12) 0.0366 (12) 0.0425 (11) 0.0061 (10) 0.0074 (10) −0.0040 (11) C8 0.0407 (12) 0.0394 (11) 0.0471 (12) 0.0056 (11) 0.0090 (10) −0.0018 (10) C9 0.0358 (11) 0.0439 (13) 0.0582 (14) 0.0033 (11) 0.0074 (11) −0.0032 (12) C10 0.0436 (12) 0.0370 (12) 0.0470 (12) 0.0028 (11) −0.0037 (11) 0.0014 (10) C11 0.0512 (13) 0.0365 (11) 0.0391 (11) 0.0019 (11) 0.0017 (11) −0.0005 (10) C12 0.0454 (13) 0.0328 (11) 0.0403 (11) −0.0010 (10) 0.0039 (10) 0.0016 (10) C13 0.0671 (17) 0.0367 (12) 0.0668 (16) −0.0045 (13) 0.0016 (15) 0.0124 (12) C14 0.0676 (18) 0.0618 (16) 0.0638 (16) −0.0190 (15) −0.0125 (15) −0.0062 (14) C15 0.0710 (18) 0.0546 (15) 0.0566 (14) −0.0034 (15) 0.0161 (14) 0.0059 (13) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1557 .table-wrap} --------------------- ------------- ----------------------- -------------- O1---C9 1.347 (3) C6---H6A 0.9700 O1---C10 1.473 (3) C6---H6B 0.9700 C1---C2 1.321 (4) C7---C8 1.342 (3) C1---C12 1.501 (3) C7---C10 1.507 (3) C1---H1A 0.9300 C8---C9 1.465 (3) O2---C9 1.225 (3) C8---C15 1.487 (3) C2---C3 1.496 (4) C10---C11 1.515 (3) C2---H2A 0.9300 C11---C12 1.541 (3) O3---C10 1.392 (3) C11---H11A 0.9700 O3---H3A 0.8200 C11---H11B 0.9700 C3---C4 1.510 (4) C12---C13 1.552 (3) C3---H3B 0.9700 C13---H13B 0.9600 C3---H3C 0.9700 C13---H13C 0.9600 C4---C14 1.325 (4) C13---H13D 0.9600 C4---C5 1.499 (3) C14---H14A 0.9300 C5---C6 1.537 (3) C14---H14B 0.9300 C5---C12 1.557 (3) C15---H15A 0.9600 C5---H5A 0.9800 C15---H15B 0.9600 C6---C7 1.488 (3) C15---H15C 0.9600 C9---O1---C10 108.89 (17) O2---C9---C8 128.8 (2) C2---C1---C12 124.2 (2) O1---C9---C8 110.22 (19) C2---C1---H1A 117.9 O3---C10---O1 109.03 (18) C12---C1---H1A 117.9 O3---C10---C7 115.6 (2) C1---C2---C3 123.3 (3) O1---C10---C7 103.28 (19) C1---C2---H2A 118.3 O3---C10---C11 110.0 (2) C3---C2---H2A 118.3 O1---C10---C11 108.62 (18) C10---O3---H3A 109.5 C7---C10---C11 109.95 (19) C2---C3---C4 113.4 (2) C10---C11---C12 113.98 (17) C2---C3---H3B 108.9 C10---C11---H11A 108.8 C4---C3---H3B 108.9 C12---C11---H11A 108.8 C2---C3---H3C 108.9 C10---C11---H11B 108.8 C4---C3---H3C 108.9 C12---C11---H11B 108.8 H3B---C3---H3C 107.7 H11A---C11---H11B 107.7 C14---C4---C5 124.7 (2) C1---C12---C11 108.96 (18) C14---C4---C3 122.4 (2) C1---C12---C13 107.7 (2) C5---C4---C3 112.8 (2) C11---C12---C13 111.6 (2) C4---C5---C6 116.17 (18) C1---C12---C5 107.21 (19) C4---C5---C12 110.03 (18) C11---C12---C5 109.40 (18) C6---C5---C12 112.67 (19) C13---C12---C5 111.8 (2) C4---C5---H5A 105.7 C12---C13---H13B 109.5 C6---C5---H5A 105.7 C12---C13---H13C 109.5 C12---C5---H5A 105.7 H13B---C13---H13C 109.5 C7---C6---C5 106.03 (17) C12---C13---H13D 109.5 C7---C6---H6A 110.5 H13B---C13---H13D 109.5 C5---C6---H6A 110.5 H13C---C13---H13D 109.5 C7---C6---H6B 110.5 C4---C14---H14A 120.0 C5---C6---H6B 110.5 C4---C14---H14B 120.0 H6A---C6---H6B 108.7 H14A---C14---H14B 120.0 C8---C7---C6 132.0 (2) C8---C15---H15A 109.5 C8---C7---C10 109.8 (2) C8---C15---H15B 109.5 C6---C7---C10 116.6 (2) H15A---C15---H15B 109.5 C7---C8---C9 107.6 (2) C8---C15---H15C 109.5 C7---C8---C15 131.0 (2) H15A---C15---H15C 109.5 C9---C8---C15 121.3 (2) H15B---C15---H15C 109.5 O2---C9---O1 120.9 (2) C12---C1---C2---C3 0.7 (5) C9---O1---C10---C7 4.8 (2) C1---C2---C3---C4 1.4 (4) C9---O1---C10---C11 −111.9 (2) C2---C3---C4---C14 148.5 (3) C8---C7---C10---O3 −122.8 (2) C2---C3---C4---C5 −32.3 (3) C6---C7---C10---O3 69.8 (3) C14---C4---C5---C6 9.1 (3) C8---C7---C10---O1 −3.8 (2) C3---C4---C5---C6 −170.1 (2) C6---C7---C10---O1 −171.18 (18) C14---C4---C5---C12 −120.4 (3) C8---C7---C10---C11 111.9 (2) C3---C4---C5---C12 60.4 (3) C6---C7---C10---C11 −55.4 (3) C4---C5---C6---C7 173.61 (19) O3---C10---C11---C12 −79.2 (2) C12---C5---C6---C7 −58.2 (2) O1---C10---C11---C12 161.56 (18) C5---C6---C7---C8 −105.0 (3) C7---C10---C11---C12 49.2 (3) C5---C6---C7---C10 59.0 (2) C2---C1---C12---C11 144.3 (3) C6---C7---C8---C9 166.2 (2) C2---C1---C12---C13 −94.5 (3) C10---C7---C8---C9 1.5 (2) C2---C1---C12---C5 26.0 (3) C6---C7---C8---C15 −9.7 (4) C10---C11---C12---C1 −167.5 (2) C10---C7---C8---C15 −174.5 (2) C10---C11---C12---C13 73.7 (3) C10---O1---C9---O2 173.7 (2) C10---C11---C12---C5 −50.6 (2) C10---O1---C9---C8 −4.2 (2) C4---C5---C12---C1 −54.9 (2) C7---C8---C9---O2 −176.0 (2) C6---C5---C12---C1 173.76 (18) C15---C8---C9---O2 0.4 (4) C4---C5---C12---C11 −172.89 (18) C7---C8---C9---O1 1.7 (3) C6---C5---C12---C11 55.7 (2) C15---C8---C9---O1 178.1 (2) C4---C5---C12---C13 63.0 (3) C9---O1---C10---O3 128.3 (2) C6---C5---C12---C13 −68.4 (3) --------------------- ------------- ----------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2332 .table-wrap} ------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O3---H3A···O2^i^ 0.82 1.99 2.796 (2) 169 C1---H1A···O1^ii^ 0.93 2.63 3.495 (2) 118 ------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, *y*−1/2, −*z*+1/2; (ii) . ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------ --------- ------- ----------- ------------- O3---H3*A*⋯O2^i^ 0.82 1.99 2.796 (2) 169 C1---H1*A*⋯O1 0.93 2.63 3.495 (2) 118 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.327353

2011-2-26

PMC3051928

Related literature {#sec1} ================== For related structures, see: Barbour *et al.* (1996[@bb1]); Brito *et al.* (2004[@bb2]); Yin *et al.* (2006[@bb6]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~4~H~10~NO^+^·C~8~H~10~NO~4~S^−^*M* *~r~* = 304.37Monoclinic,*a* = 9.2141 (5) Å*b* = 14.8227 (9) Å*c* = 10.4740 (7) Åβ = 91.120 (2)°*V* = 1430.24 (15) Å^3^*Z* = 4Mo *K*α radiationμ = 0.25 mm^−1^*T* = 293 K0.34 × 0.25 × 0.24 mm ### Data collection {#sec2.1.2} Bruker SMART APEX CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2001[@bb3]) *T* ~min~ = 0.910, *T* ~max~ = 0.93113039 measured reflections3105 independent reflections2962 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.034 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.044*wR*(*F* ^2^) = 0.117*S* = 1.123105 reflections191 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.27 e Å^−3^Δρ~min~ = −0.52 e Å^−3^ {#d5e492} Data collection: *SMART* (Bruker, 2007[@bb4]); cell refinement: *SAINT* (Bruker, 2007[@bb4]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb5]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb5]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811003722/is2665sup1.cif](http://dx.doi.org/10.1107/S1600536811003722/is2665sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003722/is2665Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003722/is2665Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?is2665&file=is2665sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?is2665sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?is2665&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [IS2665](http://scripts.iucr.org/cgi-bin/sendsup?is2665)). Comment ======= Several supramolecular structures of morpholinium sulfonate have been reported previously (Barbour *et al.*, 1996; Yin *et al.*, 2006; Brito *et al.*, 2004). As an extension of research, we report here the structure of the title compound, (I). As shown in Figs. 1 and 2, the 4-amino-5-methoxy-2-methylbenzensulfonate anion is linked to the morpholinium cation by N1---H1B···O3, N1---H1B···O2 and N1---H1A···O2^i^ hydrogen bonds (Table 1). Bond lengths of morpholine ring are very similar to those observed previously (Barbour *et al.*, 1996; Yin *et al.*, 2006; Brito *et al.*, 2004). N2---H2A···O1^ii^ and N2---H2B···O5^iii^ hydrogen bonds (Table 1) also play important roles in stabilizing the crystal. Experimental {#experimental} ============ 4-Amino-5-methoxy-2-methylbenzensulfonic acid (2.2 g) and morpholine (0.9 g), in a molar ratio of 1:1, were mixed and dissolved in sufficient ethanol by heating to 373 K, at which point a clear solution resulted. The system was then cooled slowly to room temperature. Crystals (2.5 g) were formed, collected and washed with ethanol. Refinement {#refinement} ========== H atoms attached to atom N2 were located in a difference Fourier map, and were refined freely. H atoms attached to atom N1 were treated as riding (N---H = 0.90 Å), with *U*~iso~(H) = 1.2*U*~eq~(N). Other H atoms were placed in calculated positions (C---H = 0.93--0.97 Å), with *U*~iso~(H) = 1.2 or 1.5*U*~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound, showing the atom-numbering scheme and 50% probability displacement ellipsoids for non-H atoms. Hydrogen bond is illustrated as dashed lines. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The crystal packing of the title compound, viewed down the a axis. Hydrogen bonds are drawn as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e149 .table-wrap} ----------------------------------- --------------------------------------- C~4~H~10~NO^+^·C~8~H~10~NO~4~S^−^ *F*(000) = 648.0 *M~r~* = 304.37 *D*~x~ = 1.413 Mg m^−3^ Monoclinic, *P*2~1~/*c* Melting point: 467 K Hall symbol: -P 2ybc Mo *K*α radiation, λ = 0.71073 Å *a* = 9.2141 (5) Å Cell parameters from 3615 reflections *b* = 14.8227 (9) Å θ = 2.3--25.3° *c* = 10.4740 (7) Å µ = 0.25 mm^−1^ β = 91.120 (2)° *T* = 293 K *V* = 1430.24 (15) Å^3^ Block, colorless *Z* = 4 0.34 × 0.25 × 0.24 mm ----------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e291 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEX CCD diffractometer 3105 independent reflections Radiation source: fine-focus sealed tube 2962 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.034 φ and ω scans θ~max~ = 27.0°, θ~min~ = 3.2° Absorption correction: multi-scan (*SADABS*; Bruker, 2001) *h* = −11→11 *T*~min~ = 0.910, *T*~max~ = 0.931 *k* = −18→18 13039 measured reflections *l* = −13→13 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e408 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.044 H atoms treated by a mixture of independent and constrained refinement *wR*(*F*^2^) = 0.117 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0661*P*)^2^ + 0.3546*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.12 (Δ/σ)~max~ \< 0.001 3105 reflections Δρ~max~ = 0.27 e Å^−3^ 191 parameters Δρ~min~ = −0.52 e Å^−3^ 0 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.083 (5) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e589 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e688 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ H2A 0.152 (2) 0.1046 (13) 0.8007 (19) 0.044 (5)\* H2B 0.219 (2) 0.1123 (13) 0.925 (2) 0.052 (6)\* C1 0.48589 (15) 0.11584 (9) 0.87597 (13) 0.0312 (3) C2 0.62334 (14) 0.11986 (9) 0.82610 (13) 0.0316 (3) H2 0.7039 0.1236 0.8808 0.038\* C3 0.64240 (14) 0.11834 (8) 0.69411 (13) 0.0290 (3) C4 0.52301 (15) 0.11504 (9) 0.61017 (13) 0.0316 (3) C5 0.38583 (15) 0.10920 (10) 0.66357 (14) 0.0343 (3) H5 0.3052 0.1060 0.6090 0.041\* C6 0.36395 (14) 0.10799 (9) 0.79442 (14) 0.0307 (3) C7 0.53473 (19) 0.11758 (12) 0.46690 (14) 0.0450 (4) H7A 0.4465 0.0951 0.4284 0.067\* H7B 0.6147 0.0806 0.4414 0.067\* H7C 0.5505 0.1786 0.4397 0.067\* C8 0.57504 (19) 0.12216 (13) 1.09045 (15) 0.0467 (4) H8C 0.5405 0.1230 1.1763 0.070\* H8D 0.6294 0.1761 1.0748 0.070\* H8E 0.6363 0.0705 1.0790 0.070\* C9 0.91130 (17) 0.12103 (11) 0.23520 (16) 0.0427 (4) H9A 0.8646 0.1790 0.2222 0.051\* H9B 0.8363 0.0758 0.2453 0.051\* C10 1.12875 (18) 0.18648 (12) 0.33325 (16) 0.0462 (4) H10A 1.1928 0.1849 0.4078 0.055\* H10B 1.0931 0.2477 0.3228 0.055\* C11 1.21090 (17) 0.15881 (13) 0.21691 (16) 0.0471 (4) H11A 1.2914 0.1999 0.2047 0.056\* H11B 1.2502 0.0987 0.2293 0.056\* C12 1.0018 (2) 0.09834 (14) 0.12131 (16) 0.0526 (4) H12A 1.0400 0.0377 0.1310 0.063\* H12B 0.9408 0.0996 0.0448 0.063\* O1 0.91647 (12) 0.12197 (9) 0.75110 (12) 0.0501 (3) O2 0.83977 (12) 0.02929 (7) 0.57210 (11) 0.0449 (3) O3 0.83980 (11) 0.19031 (7) 0.55105 (10) 0.0416 (3) O5 1.11893 (13) 0.15976 (10) 0.10715 (11) 0.0533 (3) O4 0.45499 (12) 0.11751 (9) 1.00344 (10) 0.0447 (3) N1 1.00509 (15) 0.12414 (9) 0.35140 (12) 0.0383 (3) H1A 1.0389 0.0685 0.3690 0.046\* H1B 0.9527 0.1427 0.4181 0.046\* N2 0.22873 (14) 0.09542 (10) 0.84692 (15) 0.0416 (3) S1 0.82261 (3) 0.11518 (2) 0.63924 (3) 0.03170 (15) ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1207 .table-wrap} ----- ------------- ------------- ------------ -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0266 (7) 0.0409 (7) 0.0263 (6) 0.0017 (5) 0.0007 (5) −0.0003 (5) C2 0.0234 (6) 0.0425 (7) 0.0287 (6) 0.0004 (5) −0.0023 (5) 0.0000 (5) C3 0.0247 (6) 0.0331 (6) 0.0292 (6) 0.0013 (4) 0.0016 (5) −0.0007 (5) C4 0.0310 (7) 0.0359 (7) 0.0278 (6) 0.0026 (5) −0.0022 (5) −0.0020 (5) C5 0.0261 (6) 0.0428 (8) 0.0337 (7) 0.0015 (5) −0.0068 (5) −0.0025 (5) C6 0.0240 (6) 0.0330 (6) 0.0351 (7) 0.0022 (5) −0.0005 (5) −0.0005 (5) C7 0.0442 (9) 0.0628 (10) 0.0279 (7) 0.0011 (7) −0.0031 (6) −0.0029 (6) C8 0.0391 (8) 0.0722 (11) 0.0285 (7) 0.0002 (7) −0.0041 (6) 0.0019 (7) C9 0.0326 (8) 0.0515 (9) 0.0441 (9) 0.0013 (6) 0.0020 (6) 0.0035 (6) C10 0.0465 (9) 0.0476 (9) 0.0444 (8) −0.0033 (7) −0.0013 (7) −0.0057 (7) C11 0.0357 (7) 0.0563 (10) 0.0495 (9) −0.0041 (7) 0.0074 (7) 0.0044 (7) C12 0.0480 (10) 0.0733 (12) 0.0366 (8) −0.0010 (8) 0.0003 (7) −0.0092 (8) O1 0.0255 (5) 0.0828 (9) 0.0420 (6) −0.0007 (5) −0.0006 (5) 0.0016 (5) O2 0.0445 (6) 0.0391 (6) 0.0515 (6) 0.0111 (4) 0.0101 (5) −0.0029 (5) O3 0.0421 (6) 0.0389 (6) 0.0442 (6) −0.0001 (4) 0.0136 (5) 0.0033 (4) O5 0.0477 (7) 0.0754 (9) 0.0371 (6) 0.0013 (6) 0.0099 (5) 0.0109 (6) O4 0.0280 (5) 0.0799 (9) 0.0263 (5) 0.0004 (5) 0.0018 (4) 0.0003 (5) N1 0.0404 (7) 0.0415 (7) 0.0336 (6) 0.0080 (5) 0.0096 (5) 0.0055 (5) N2 0.0233 (6) 0.0583 (8) 0.0431 (7) 0.0010 (5) 0.0007 (5) −0.0006 (6) S1 0.0252 (2) 0.0379 (2) 0.0322 (2) 0.00271 (11) 0.00416 (14) 0.00068 (12) ----- ------------- ------------- ------------ -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1599 .table-wrap} ---------------- ------------- ------------------- ------------- C1---O4 1.3707 (17) C9---C12 1.507 (2) C1---C2 1.3806 (19) C9---H9A 0.9700 C1---C6 1.4029 (19) C9---H9B 0.9700 C2---C3 1.3972 (19) C10---N1 1.482 (2) C2---H2 0.9300 C10---C11 1.504 (2) C3---C4 1.3955 (19) C10---H10A 0.9700 C3---S1 1.7683 (13) C10---H10B 0.9700 C4---C5 1.395 (2) C11---O5 1.415 (2) C4---C7 1.507 (2) C11---H11A 0.9700 C5---C6 1.389 (2) C11---H11B 0.9700 C5---H5 0.9300 C12---O5 1.422 (2) C6---N2 1.3842 (18) C12---H12A 0.9700 C7---H7A 0.9600 C12---H12B 0.9700 C7---H7B 0.9600 O1---S1 1.4461 (12) C7---H7C 0.9600 O2---S1 1.4645 (11) C8---O4 1.4211 (18) O3---S1 1.4575 (11) C8---H8C 0.9600 N1---H1A 0.9000 C8---H8D 0.9600 N1---H1B 0.9000 C8---H8E 0.9600 N2---H2A 0.86 (2) C9---N1 1.480 (2) N2---H2B 0.86 (2) O4---C1---C2 125.26 (12) N1---C10---C11 109.53 (13) O4---C1---C6 114.54 (12) N1---C10---H10A 109.8 C2---C1---C6 120.19 (12) C11---C10---H10A 109.8 C1---C2---C3 120.51 (12) N1---C10---H10B 109.8 C1---C2---H2 119.7 C11---C10---H10B 109.8 C3---C2---H2 119.7 H10A---C10---H10B 108.2 C4---C3---C2 120.74 (12) O5---C11---C10 110.65 (13) C4---C3---S1 121.87 (11) O5---C11---H11A 109.5 C2---C3---S1 117.32 (10) C10---C11---H11A 109.5 C5---C4---C3 117.32 (12) O5---C11---H11B 109.5 C5---C4---C7 118.94 (13) C10---C11---H11B 109.5 C3---C4---C7 123.74 (13) H11A---C11---H11B 108.1 C6---C5---C4 123.13 (12) O5---C12---C9 111.88 (15) C6---C5---H5 118.4 O5---C12---H12A 109.2 C4---C5---H5 118.4 C9---C12---H12A 109.2 N2---C6---C5 122.87 (13) O5---C12---H12B 109.2 N2---C6---C1 119.06 (13) C9---C12---H12B 109.2 C5---C6---C1 118.01 (13) H12A---C12---H12B 107.9 C4---C7---H7A 109.5 C11---O5---C12 110.65 (12) C4---C7---H7B 109.5 C1---O4---C8 116.84 (12) H7A---C7---H7B 109.5 C9---N1---C10 110.61 (12) C4---C7---H7C 109.5 C9---N1---H1A 109.5 H7A---C7---H7C 109.5 C10---N1---H1A 109.5 H7B---C7---H7C 109.5 C9---N1---H1B 109.5 O4---C8---H8C 109.5 C10---N1---H1B 109.5 O4---C8---H8D 109.5 H1A---N1---H1B 108.1 H8C---C8---H8D 109.5 C6---N2---H2A 119.5 (13) O4---C8---H8E 109.5 C6---N2---H2B 116.8 (15) H8C---C8---H8E 109.5 H2A---N2---H2B 112.7 (19) H8D---C8---H8E 109.5 O1---S1---O3 112.93 (7) N1---C9---C12 109.57 (13) O1---S1---O2 112.40 (7) N1---C9---H9A 109.8 O3---S1---O2 110.23 (7) C12---C9---H9A 109.8 O1---S1---C3 106.58 (7) N1---C9---H9B 109.8 O3---S1---C3 107.47 (6) C12---C9---H9B 109.8 O2---S1---C3 106.86 (6) H9A---C9---H9B 108.2 ---------------- ------------- ------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2127 .table-wrap} -------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1A···O2^i^ 0.90 1.92 2.795 (3) 162 N1---H1B···O2 0.90 2.56 3.126 (2) 121 N1---H1B···O3 0.90 1.89 2.790 (3) 175 N2---H2A···O1^ii^ 0.86 (2) 2.23 (2) 3.054 (3) 159.1 (2) N2---H2B···O5^iii^ 0.85 (2) 2.25 (2) 3.077 (4) 161.5 (2) -------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) −*x*+2, −*y*, −*z*+1; (ii) *x*−1, *y*, *z*; (iii) *x*−1, *y*, *z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- ---------- ---------- ----------- ------------- N1---H1*A*⋯O2^i^ 0.90 1.92 2.795 (3) 162 N1---H1*B*⋯O2 0.90 2.56 3.126 (2) 121 N1---H1*B*⋯O3 0.90 1.89 2.790 (3) 175 N2---H2*A*⋯O1^ii^ 0.86 (2) 2.23 (2) 3.054 (3) 159.1 (2) N2---H2*B*⋯O5^iii^ 0.85 (2) 2.25 (2) 3.077 (4) 161.5 (2) Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.333051

2011-2-12

PMC3051929

Related literature {#sec1} ================== For background to the coordination chemistry of 1,10-phenanthroline and its derivatives, see: Wang *et al.* (2010[@bb5]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Cd~2~(C~8~H~10~O~4~)~2~(C~23~H~14~N~4~O)~2~(H~2~O)~2~\]·H~2~O*M* *~r~* = 1342.92Triclinic,*a* = 9.870 (3) Å*b* = 11.871 (4) Å*c* = 12.459 (4) Åα = 66.788 (4)°β = 86.066 (4)°γ = 87.462 (4)°*V* = 1338.2 (7) Å^3^*Z* = 1Mo *K*α radiationμ = 0.87 mm^−1^*T* = 293 K0.21 × 0.18 × 0.16 mm ### Data collection {#sec2.1.2} Bruker APEX diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb3]) *T* ~min~ = 0.41, *T* ~max~ = 0.646918 measured reflections4657 independent reflections4195 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.012 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.026*wR*(*F* ^2^) = 0.066*S* = 1.044657 reflections400 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.40 e Å^−3^Δρ~min~ = −0.36 e Å^−3^ {#d5e586} Data collection: *SMART* (Bruker, 1997[@bb1]); cell refinement: *SAINT* (Bruker, 1999[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb4]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb4]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb4]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811004727/sj5103sup1.cif](http://dx.doi.org/10.1107/S1600536811004727/sj5103sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004727/sj5103Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004727/sj5103Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?sj5103&file=sj5103sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?sj5103sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?sj5103&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [SJ5103](http://scripts.iucr.org/cgi-bin/sendsup?sj5103)). The authors thank the Key Laboratory of Preparation and Applications of Environmentally Friendly Materials and the Institute Foundation of Siping City (No. 2009011) for supporting this work. Comment ======= The coordination chemistry of 1,10-phenanthroline-like ligands has generated considerable recent interest (Wang *et al.*, 2010). 1-(1H-imidazo\[4,5-f\]\[1,10\]phenanthrolin-2-yl)naphthalen-2-ol (L), is a good candidate as a N-donor ligand, as it has excellent coordinating ability. In this work, we selected 1,4-H~2~chdc^2-^ ligand (1,4-H~2~chdc = cyclohexane-1,4-dicarboxylic acid) as an organic linker and L as an N-donor chelating ligand, to generate a new Cd^II^ complex, \[Cd~2~(L)~2~(1,4-chdc)~2~(H~2~O)~2~\]^.^H~2~O. The asymmetric unit of the title compound, (I), consists of one half of the dimeric complex, which lies about an inversion centre, and a half occupancy solvent water molecule which occupies a general position. Each Cd^II^ cation is six-coordinated by the N1 & N2 atoms from one L ligand (L = 1-(1H-imidazo\[4,5-f\]\[1,10\]phenanthrolin-2-yl)naphthalen-2-ol), the O1, O3 and O4 atoms from two different 1,4-chdc^2-^ ligands (1,4-H~2~chdc = cyclohexane-1,4-dicarboxylic acid), O3 and O4 coordinating in a bidentate fashion with O1 monodentate. The distorted octahedral coordination sphere is completed by the O1W atom of a coordinated water molecule. In the crystal structure O-H···O and N-H···O H-bonding interactions, Table 1, stabilize the packing. Experimental {#experimental} ============ A mixture of CdCl~2~^.^2.5H~2~O (0.5 mmol), 1,4-H~2~chdc (0.5 mmol) and L (0.5 mmol) in 10 mL distilled water was heated at 460 K in a Teflon-lined stainless steel autoclave for seven days. The reaction system was then slowly cooled to room temperature. Pale yellow crystals of (I) suitable for single crystal X-ray diffraction analysis were collected from the final reaction system by filtration, washed several times with distilled water and dried in air at ambient temperature. Yield: 29% based on Cd(II). Refinement {#refinement} ========== All H atoms on C and N atoms were positioned geometrically (N-H = 0.86 Å and C-H = 0.93 Å) and refined as riding, with U~iso~(H)=1.2U~eq~(carrier). The water H-atoms of O1W were located in difference Fourier maps, and were refined freely. However, the hydrogen atoms of the half occupancy water molecule were not located in difference Fourier maps. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The structure of (I), showing the atomic numbering scheme with displacement ellipsoids drawn at the 30% probability level. Hydrogen atoms have been omitted for clarity. \[Symmetry codes: (i) 2-x, -y, 1-z\] :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e160 .table-wrap} ----------------------------------------------------------------- --------------------------------------- \[Cd~2~(C~8~H~10~O~4~)~2~(C~23~H~14~N~4~O)~2~(H~2~O)~2~\]·H~2~O *Z* = 1 *M~r~* = 1342.92 *F*(000) = 681 Triclinic, *P*1 *D*~x~ = 1.666 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 9.870 (3) Å Cell parameters from 4657 reflections *b* = 11.871 (4) Å θ = 1.9--25.2° *c* = 12.459 (4) Å µ = 0.87 mm^−1^ α = 66.788 (4)° *T* = 293 K β = 86.066 (4)° Block, pale yellow γ = 87.462 (4)° 0.21 × 0.18 × 0.16 mm *V* = 1338.2 (7) Å^3^ ----------------------------------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e323 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker APEX diffractometer 4657 independent reflections Radiation source: fine-focus sealed tube 4195 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.012 φ and ω scans θ~max~ = 25.2°, θ~min~ = 1.9° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −11→11 *T*~min~ = 0.41, *T*~max~ = 0.64 *k* = −13→14 6918 measured reflections *l* = −7→14 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e440 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.026 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.066 H atoms treated by a mixture of independent and constrained refinement *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0338*P*)^2^ + 0.5714*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4657 reflections (Δ/σ)~max~ = 0.001 400 parameters Δρ~max~ = 0.40 e Å^−3^ 0 restraints Δρ~min~ = −0.36 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e597 .table-wrap} ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ \> 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e642 .table-wrap} ------ --------------- --------------- --------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) Cd1 0.616015 (18) 0.060066 (16) 0.681838 (16) 0.03702 (8) C14 0.3661 (2) 0.4379 (2) 1.1701 (2) 0.0327 (5) N1 0.6509 (2) 0.05928 (18) 0.86655 (18) 0.0359 (5) C11 0.4036 (2) 0.3089 (2) 0.9525 (2) 0.0320 (5) C19 0.2604 (2) 0.5310 (2) 1.1481 (2) 0.0351 (6) N3 0.3363 (2) 0.38774 (18) 0.99551 (19) 0.0351 (5) C12 0.5066 (2) 0.2464 (2) 1.0227 (2) 0.0325 (5) O3 1.36041 (17) −0.21386 (17) 0.50727 (16) 0.0434 (4) O1W 0.4350 (2) −0.0379 (2) 0.6417 (2) 0.0485 (5) O5 0.5359 (2) 0.3191 (2) 1.2950 (2) 0.0529 (5) N4 0.5031 (2) 0.28855 (18) 1.11010 (18) 0.0354 (5) H4 0.5566 0.2661 1.1668 0.043\* O4 1.18245 (19) −0.18121 (18) 0.40333 (16) 0.0482 (5) C29 1.2364 (2) −0.2339 (2) 0.4977 (2) 0.0341 (5) O1 0.7412 (2) −0.10599 (18) 0.72164 (19) 0.0572 (5) C4 0.5946 (2) 0.1583 (2) 1.0002 (2) 0.0335 (5) N2 0.4511 (2) 0.1855 (2) 0.72357 (19) 0.0388 (5) C28 1.1619 (3) −0.3238 (2) 0.6062 (2) 0.0417 (6) H28 1.2225 −0.3952 0.6395 0.050\* C13 0.3986 (2) 0.3733 (2) 1.0911 (2) 0.0330 (5) C5 0.5733 (2) 0.1395 (2) 0.8980 (2) 0.0321 (5) C6 0.4653 (2) 0.2070 (2) 0.8212 (2) 0.0330 (5) C25 0.8894 (2) −0.2291 (2) 0.6558 (2) 0.0378 (6) H25 0.8691 −0.2996 0.7290 0.045\* C10 0.3794 (2) 0.2901 (2) 0.8494 (2) 0.0334 (5) C15 0.4384 (2) 0.4081 (2) 1.2701 (2) 0.0375 (6) C3 0.6987 (3) 0.0894 (2) 1.0710 (2) 0.0414 (6) H3 0.7152 0.0989 1.1395 0.050\* C18 0.2375 (3) 0.5914 (2) 1.2272 (2) 0.0382 (6) C30 1.0302 (3) −0.3707 (3) 0.5831 (3) 0.0528 (8) H30A 1.0046 −0.4443 0.6502 0.063\* H30B 1.0463 −0.3930 0.5162 0.063\* C16 0.4145 (3) 0.4692 (3) 1.3466 (3) 0.0440 (6) H16 0.4655 0.4481 1.4120 0.053\* O2 0.7087 (3) −0.1025 (3) 0.5475 (2) 0.0881 (9) C17 0.3173 (3) 0.5587 (2) 1.3248 (3) 0.0457 (7) H17 0.3031 0.5991 1.3752 0.055\* C24 0.7707 (3) −0.1388 (2) 0.6379 (3) 0.0436 (6) C1 0.7484 (3) −0.0044 (2) 0.9354 (2) 0.0431 (6) H1 0.8009 −0.0599 0.9139 0.052\* C26 1.0203 (3) −0.1744 (3) 0.6697 (3) 0.0443 (6) H26A 1.0060 −0.1441 0.7315 0.053\* H26B 1.0448 −0.1056 0.5976 0.053\* C7 0.3521 (3) 0.2430 (3) 0.6540 (3) 0.0479 (7) H7 0.3423 0.2277 0.5873 0.058\* C21 0.1335 (3) 0.6827 (2) 1.2073 (3) 0.0475 (7) H21 0.1201 0.7227 1.2582 0.057\* C8 0.2622 (3) 0.3256 (3) 0.6773 (3) 0.0519 (7) H8 0.1937 0.3641 0.6269 0.062\* C31 0.9114 (3) −0.2774 (3) 0.5593 (3) 0.0486 (7) H31A 0.9299 −0.2094 0.4851 0.058\* H31B 0.8291 −0.3160 0.5535 0.058\* C20 0.1736 (3) 0.5655 (3) 1.0538 (3) 0.0465 (7) H20 0.1855 0.5279 1.0008 0.056\* C2 0.7751 (3) 0.0085 (2) 1.0378 (2) 0.0450 (6) H2 0.8444 −0.0375 1.0835 0.054\* C9 0.2756 (3) 0.3495 (2) 0.7742 (2) 0.0421 (6) H9 0.2164 0.4046 0.7906 0.051\* C27 1.1360 (3) −0.2690 (3) 0.6991 (2) 0.0517 (7) H27A 1.1145 −0.3344 0.7744 0.062\* H27B 1.2182 −0.2307 0.7055 0.062\* C22 0.0534 (3) 0.7124 (3) 1.1158 (3) 0.0546 (8) H22 −0.0144 0.7724 1.1042 0.066\* C23 0.0727 (3) 0.6528 (3) 1.0385 (3) 0.0560 (8) H23 0.0167 0.6726 0.9764 0.067\* O2W 0.9490 (10) −0.0713 (7) 0.2643 (8) 0.152 (3) 0.50 H5 0.561 (3) 0.295 (3) 1.356 (3) 0.048 (10)\* HW12 0.386 (4) −0.001 (3) 0.592 (3) 0.060 (12)\* HW11 0.472 (5) −0.090 (4) 0.625 (4) 0.111 (18)\* ------ --------------- --------------- --------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1574 .table-wrap} ----- -------------- -------------- -------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cd1 0.03780 (12) 0.03642 (12) 0.03781 (12) 0.00468 (8) 0.00499 (8) −0.01731 (9) C14 0.0305 (12) 0.0311 (13) 0.0377 (14) −0.0019 (10) 0.0047 (10) −0.0156 (11) N1 0.0367 (11) 0.0300 (11) 0.0392 (12) 0.0052 (9) 0.0063 (9) −0.0137 (9) C11 0.0327 (12) 0.0284 (12) 0.0371 (13) 0.0014 (10) 0.0042 (10) −0.0163 (11) C19 0.0345 (13) 0.0305 (13) 0.0402 (14) −0.0041 (10) 0.0086 (11) −0.0151 (11) N3 0.0340 (11) 0.0325 (11) 0.0422 (12) 0.0049 (9) 0.0002 (9) −0.0191 (10) C12 0.0344 (12) 0.0315 (13) 0.0332 (13) −0.0001 (10) 0.0040 (10) −0.0152 (11) O3 0.0332 (9) 0.0511 (11) 0.0413 (10) −0.0014 (8) 0.0006 (8) −0.0136 (9) O1W 0.0520 (13) 0.0472 (12) 0.0519 (13) 0.0006 (10) −0.0018 (11) −0.0257 (11) O5 0.0503 (12) 0.0695 (14) 0.0514 (13) 0.0228 (10) −0.0181 (11) −0.0371 (12) N4 0.0334 (11) 0.0390 (12) 0.0374 (12) 0.0074 (9) −0.0029 (9) −0.0195 (10) O4 0.0448 (11) 0.0589 (12) 0.0374 (11) −0.0027 (9) −0.0047 (9) −0.0146 (10) C29 0.0367 (13) 0.0322 (13) 0.0378 (14) 0.0042 (10) 0.0031 (11) −0.0198 (11) O1 0.0623 (13) 0.0473 (12) 0.0633 (14) 0.0190 (10) 0.0024 (11) −0.0264 (11) C4 0.0302 (12) 0.0316 (13) 0.0366 (14) 0.0013 (10) 0.0047 (10) −0.0125 (11) N2 0.0399 (12) 0.0424 (12) 0.0389 (12) 0.0057 (10) 0.0004 (10) −0.0223 (10) C28 0.0345 (13) 0.0335 (14) 0.0488 (16) 0.0088 (11) 0.0044 (12) −0.0093 (12) C13 0.0315 (12) 0.0315 (13) 0.0370 (14) −0.0014 (10) 0.0051 (10) −0.0155 (11) C5 0.0322 (12) 0.0266 (12) 0.0351 (13) −0.0009 (10) 0.0078 (10) −0.0110 (10) C6 0.0337 (12) 0.0284 (12) 0.0353 (13) −0.0006 (10) 0.0059 (10) −0.0121 (11) C25 0.0328 (13) 0.0340 (13) 0.0436 (15) 0.0014 (10) 0.0032 (11) −0.0131 (12) C10 0.0340 (13) 0.0299 (12) 0.0356 (13) 0.0001 (10) 0.0040 (10) −0.0131 (11) C15 0.0322 (13) 0.0405 (14) 0.0441 (15) −0.0007 (11) 0.0032 (11) −0.0221 (12) C3 0.0430 (14) 0.0421 (15) 0.0370 (14) 0.0051 (12) 0.0000 (12) −0.0145 (12) C18 0.0402 (14) 0.0311 (13) 0.0444 (15) −0.0056 (11) 0.0111 (12) −0.0178 (12) C30 0.0441 (15) 0.0369 (15) 0.081 (2) −0.0043 (12) 0.0143 (15) −0.0295 (15) C16 0.0442 (15) 0.0504 (16) 0.0449 (16) −0.0055 (13) −0.0003 (12) −0.0267 (14) O2 0.0831 (18) 0.111 (2) 0.0816 (18) 0.0567 (16) −0.0378 (15) −0.0501 (17) C17 0.0539 (16) 0.0430 (15) 0.0509 (17) −0.0057 (13) 0.0092 (14) −0.0312 (14) C24 0.0358 (14) 0.0378 (14) 0.0567 (18) 0.0027 (11) 0.0033 (13) −0.0193 (14) C1 0.0428 (15) 0.0357 (14) 0.0491 (16) 0.0106 (12) 0.0044 (13) −0.0170 (13) C26 0.0382 (14) 0.0574 (17) 0.0456 (16) 0.0024 (12) 0.0019 (12) −0.0301 (14) C7 0.0503 (16) 0.0559 (18) 0.0447 (16) 0.0137 (14) −0.0087 (13) −0.0279 (14) C21 0.0514 (16) 0.0386 (15) 0.0561 (18) 0.0003 (12) 0.0147 (14) −0.0253 (14) C8 0.0519 (17) 0.0604 (19) 0.0505 (18) 0.0216 (14) −0.0163 (14) −0.0296 (15) C31 0.0335 (13) 0.0531 (17) 0.072 (2) 0.0000 (12) −0.0013 (13) −0.0381 (16) C20 0.0512 (16) 0.0433 (16) 0.0483 (16) 0.0128 (13) −0.0021 (13) −0.0231 (13) C2 0.0436 (15) 0.0411 (15) 0.0462 (16) 0.0141 (12) −0.0050 (12) −0.0138 (13) C9 0.0399 (14) 0.0422 (15) 0.0475 (16) 0.0117 (12) −0.0043 (12) −0.0222 (13) C27 0.0359 (14) 0.080 (2) 0.0354 (15) 0.0092 (14) −0.0004 (12) −0.0205 (15) C22 0.0536 (18) 0.0425 (16) 0.066 (2) 0.0158 (14) 0.0079 (16) −0.0229 (15) C23 0.0563 (18) 0.0518 (18) 0.0589 (19) 0.0204 (14) −0.0070 (15) −0.0224 (15) O2W 0.196 (8) 0.118 (6) 0.146 (7) 0.012 (6) −0.077 (7) −0.048 (5) ----- -------------- -------------- -------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2409 .table-wrap} ---------------------- ------------- ------------------- ----------- Cd1---O1 2.1806 (19) C6---C10 1.405 (3) Cd1---N2 2.328 (2) C25---C24 1.519 (4) Cd1---N1 2.346 (2) C25---C31 1.522 (4) Cd1---O3^i^ 2.3474 (19) C25---C26 1.522 (4) Cd1---O1W 2.358 (2) C25---H25 0.9800 Cd1---O4^i^ 2.431 (2) C10---C9 1.404 (4) Cd1---C29^i^ 2.750 (3) C15---C16 1.410 (4) C14---C15 1.392 (4) C3---C2 1.367 (4) C14---C19 1.444 (3) C3---H3 0.9300 C14---C13 1.480 (3) C18---C17 1.408 (4) N1---C1 1.331 (3) C18---C21 1.419 (4) N1---C5 1.355 (3) C30---C31 1.538 (4) C11---C12 1.375 (3) C30---H30A 0.9700 C11---N3 1.376 (3) C30---H30B 0.9700 C11---C10 1.425 (3) C16---C17 1.358 (4) C19---C20 1.418 (4) C16---H16 0.9300 C19---C18 1.431 (3) O2---C24 1.232 (4) N3---C13 1.325 (3) C17---H17 0.9300 C12---N4 1.364 (3) C1---C2 1.388 (4) C12---C4 1.430 (3) C1---H1 0.9300 O3---C29 1.280 (3) C26---C27 1.523 (4) O3---Cd1^i^ 2.3474 (19) C26---H26A 0.9700 O1W---HW12 0.79 (4) C26---H26B 0.9700 O1W---HW11 0.79 (5) C7---C8 1.394 (4) O5---C15 1.353 (3) C7---H7 0.9300 O5---H5 0.75 (3) C21---C22 1.354 (4) N4---C13 1.374 (3) C21---H21 0.9300 N4---H4 0.8600 C8---C9 1.361 (4) O4---C29 1.238 (3) C8---H8 0.9300 O4---Cd1^i^ 2.431 (2) C31---H31A 0.9700 C29---C28 1.518 (4) C31---H31B 0.9700 C29---Cd1^i^ 2.750 (3) C20---C23 1.372 (4) O1---C24 1.263 (3) C20---H20 0.9300 C4---C5 1.407 (4) C2---H2 0.9300 C4---C3 1.408 (4) C9---H9 0.9300 N2---C7 1.328 (3) C27---H27A 0.9700 N2---C6 1.355 (3) C27---H27B 0.9700 C28---C30 1.524 (4) C22---C23 1.401 (4) C28---C27 1.538 (4) C22---H22 0.9300 C28---H28 0.9800 C23---H23 0.9300 C5---C6 1.468 (3) O1---Cd1---N2 154.70 (8) C31---C25---C26 109.6 (2) O1---Cd1---N1 90.33 (8) C24---C25---H25 107.3 N2---Cd1---N1 71.31 (7) C31---C25---H25 107.3 O1---Cd1---O3^i^ 118.02 (7) C26---C25---H25 107.3 N2---Cd1---O3^i^ 87.26 (7) C9---C10---C6 118.0 (2) N1---Cd1---O3^i^ 132.00 (7) C9---C10---C11 124.2 (2) O1---Cd1---O1W 90.15 (9) C6---C10---C11 117.8 (2) N2---Cd1---O1W 86.39 (8) O5---C15---C14 119.8 (2) N1---Cd1---O1W 124.30 (7) O5---C15---C16 118.3 (2) O3^i^---Cd1---O1W 95.35 (8) C14---C15---C16 121.9 (2) O1---Cd1---O4^i^ 89.09 (8) C2---C3---C4 119.2 (3) N2---Cd1---O4^i^ 108.12 (8) C2---C3---H3 120.4 N1---Cd1---O4^i^ 91.54 (7) C4---C3---H3 120.4 O3^i^---Cd1---O4^i^ 54.35 (6) C17---C18---C21 120.6 (2) O1W---Cd1---O4^i^ 144.16 (7) C17---C18---C19 119.7 (2) O1---Cd1---C29^i^ 103.41 (8) C21---C18---C19 119.7 (3) N2---Cd1---C29^i^ 99.92 (8) C28---C30---C31 113.8 (2) N1---Cd1---C29^i^ 113.53 (7) C28---C30---H30A 108.8 O3^i^---Cd1---C29^i^ 27.66 (7) C31---C30---H30A 108.8 O1W---Cd1---C29^i^ 120.39 (8) C28---C30---H30B 108.8 O4^i^---Cd1---C29^i^ 26.75 (7) C31---C30---H30B 108.8 C15---C14---C19 118.2 (2) H30A---C30---H30B 107.7 C15---C14---C13 119.5 (2) C17---C16---C15 120.1 (3) C19---C14---C13 122.3 (2) C17---C16---H16 120.0 C1---N1---C5 118.8 (2) C15---C16---H16 120.0 C1---N1---Cd1 124.85 (16) C16---C17---C18 121.2 (2) C5---N1---Cd1 116.05 (16) C16---C17---H17 119.4 C12---C11---N3 110.9 (2) C18---C17---H17 119.4 C12---C11---C10 120.9 (2) O2---C24---O1 123.6 (3) N3---C11---C10 128.2 (2) O2---C24---C25 121.1 (3) C20---C19---C18 116.8 (2) O1---C24---C25 115.3 (3) C20---C19---C14 124.2 (2) N1---C1---C2 122.9 (2) C18---C19---C14 118.9 (2) N1---C1---H1 118.6 C13---N3---C11 105.0 (2) C2---C1---H1 118.6 N4---C12---C11 105.4 (2) C25---C26---C27 111.3 (2) N4---C12---C4 130.9 (2) C25---C26---H26A 109.4 C11---C12---C4 123.7 (2) C27---C26---H26A 109.4 C29---O3---Cd1^i^ 93.97 (15) C25---C26---H26B 109.4 Cd1---O1W---HW12 121 (3) C27---C26---H26B 109.4 Cd1---O1W---HW11 103 (3) H26A---C26---H26B 108.0 HW12---O1W---HW11 108 (4) N2---C7---C8 122.4 (3) C15---O5---H5 116 (2) N2---C7---H7 118.8 C12---N4---C13 107.5 (2) C8---C7---H7 118.8 C12---N4---H4 126.2 C22---C21---C18 121.2 (3) C13---N4---H4 126.2 C22---C21---H21 119.4 C29---O4---Cd1^i^ 91.14 (15) C18---C21---H21 119.4 O4---C29---O3 120.3 (2) C9---C8---C7 119.5 (3) O4---C29---C28 123.0 (2) C9---C8---H8 120.3 O3---C29---C28 116.7 (2) C7---C8---H8 120.3 O4---C29---Cd1^i^ 62.11 (14) C25---C31---C30 111.5 (2) O3---C29---Cd1^i^ 58.37 (13) C25---C31---H31A 109.3 C28---C29---Cd1^i^ 173.23 (18) C30---C31---H31A 109.3 C24---O1---Cd1 116.31 (19) C25---C31---H31B 109.3 C5---C4---C3 118.0 (2) C30---C31---H31B 109.3 C5---C4---C12 116.2 (2) H31A---C31---H31B 108.0 C3---C4---C12 125.9 (2) C23---C20---C19 121.8 (3) C7---N2---C6 119.1 (2) C23---C20---H20 119.1 C7---N2---Cd1 124.19 (17) C19---C20---H20 119.1 C6---N2---Cd1 116.56 (16) C3---C2---C1 119.4 (3) C29---C28---C30 114.4 (2) C3---C2---H2 120.3 C29---C28---C27 110.7 (2) C1---C2---H2 120.3 C30---C28---C27 110.5 (2) C8---C9---C10 119.4 (2) C29---C28---H28 106.9 C8---C9---H9 120.3 C30---C28---H28 106.9 C10---C9---H9 120.3 C27---C28---H28 106.9 C26---C27---C28 112.2 (2) N3---C13---N4 111.2 (2) C26---C27---H27A 109.2 N3---C13---C14 126.9 (2) C28---C27---H27A 109.2 N4---C13---C14 121.9 (2) C26---C27---H27B 109.2 N1---C5---C4 121.8 (2) C28---C27---H27B 109.2 N1---C5---C6 117.5 (2) H27A---C27---H27B 107.9 C4---C5---C6 120.8 (2) C21---C22---C23 119.9 (3) N2---C6---C10 121.6 (2) C21---C22---H22 120.0 N2---C6---C5 117.8 (2) C23---C22---H22 120.0 C10---C6---C5 120.6 (2) C20---C23---C22 120.6 (3) C24---C25---C31 113.5 (2) C20---C23---H23 119.7 C24---C25---C26 111.5 (2) C22---C23---H23 119.7 ---------------------- ------------- ------------------- ----------- ::: Symmetry codes: (i) −*x*+2, −*y*, −*z*+1. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3566 .table-wrap} ---------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N4---H4···O5 0.86 1.93 2.513 (3) 124 O5---H5···O3^ii^ 0.75 (3) 1.81 (3) 2.546 (3) 167 (3) O1W---HW12···O2^iii^ 0.79 (4) 1.96 (4) 2.738 (4) 171 (4) O1W---HW11···O2 0.79 (5) 2.49 (5) 3.059 (4) 130 (4) O1W---HW11···O5^iv^ 0.79 (5) 2.51 (5) 3.118 (3) 135 (4) ---------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (ii) −*x*+2, −*y*, −*z*+2; (iii) −*x*+1, −*y*, −*z*+1; (iv) −*x*+1, −*y*, −*z*+2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------------ ---------- ---------- ----------- ------------- N4---H4⋯O5 0.86 1.93 2.513 (3) 124 O5---H5⋯O3^i^ 0.75 (3) 1.81 (3) 2.546 (3) 167 (3) O1*W*---H*W*12⋯O2^ii^ 0.79 (4) 1.96 (4) 2.738 (4) 171 (4) O1*W*---H*W*11⋯O2 0.79 (5) 2.49 (5) 3.059 (4) 130 (4) O1*W*---H*W*11⋯O5^iii^ 0.79 (5) 2.51 (5) 3.118 (3) 135 (4) Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.337844

2011-2-12

PMC3051930

Related literature {#sec1} ================== For a general overview on monocarba-*closo*-dodeca­borates, see: Körbe *et al.* (2006[@bb8]). For the synthesis and properties of 2-amino- and 2-azaniumyl­carba-*closo*-dodeca­boron clusters, see: Finze (2009[@bb4]). For structures and properties of related {*closo*-1-CB~11~} clusters with NH~2~ and NH~3~ groups, see: Jelínek *et al.* (1986[@bb7]); Finze (2007[@bb3]); Finze *et al.* (2007[@bb5]); Finze & Sprenger (2010[@bb6]). For hydrogen-bond motifs, see: Etter (1990[@bb2]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} CH~14~B~11~N·C~2~H~6~O*M* *~r~* = 205.11Monoclinic,*a* = 9.5753 (2) Å*b* = 9.2549 (2) Å*c* = 13.9095 (5) Åβ = 97.519 (3)°*V* = 1222.04 (6) Å^3^*Z* = 4Mo *K*α radiationμ = 0.06 mm^−1^*T* = 120 K0.28 × 0.26 × 0.20 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcalibur Eos diffractometerAbsorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009[@bb9]) *T* ~min~ = 0.729, *T* ~max~ = 1.00061096 measured reflections3561 independent reflections3199 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.0303 standard reflections every 60 min intensity decay: none ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.029*wR*(*F* ^2^) = 0.069*S* = 1.023561 reflections208 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.31 e Å^−3^Δρ~min~ = −0.22 e Å^−3^ {#d5e529} Data collection: *CrysAlis PRO* (Oxford Diffraction, 2009[@bb9]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb10]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb10]); molecular graphics: *DIAMOND* (Brandenburg, 2011)[@bb1]; software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811006222/br2161sup1.cif](http://dx.doi.org/10.1107/S1600536811006222/br2161sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006222/br2161Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006222/br2161Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?br2161&file=br2161sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?br2161sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?br2161&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BR2161](http://scripts.iucr.org/cgi-bin/sendsup?br2161)). This work was supported by the Deutsche Forschungsgemeinschaft (DFG) and by the Fonds der Chemischen Industrie (FCI). Comment ======= Icosahedral monocarba-*closo*-dodecaborates with functional groups, for example amino or ammonio that are bonded to the cluster atoms are building blocks for a broad range of applications (Körbe *et al.*, 2006). The properties and the reactivity of the amino groups depend on (i) the further substituents of the {*closo*-1-CB~11~} cluster and (ii) the type of the cluster atom, either carbon or boron that it is bonded to. The influence of the substituents is evident from a comparison of the properties of \[1-H~2~N-*closo*-1-CB~11~*X*~11~\]^-^ with X equal to either H or F. The non-fluorinated anion is indefinitely stable in concentrated aqueous bases and acids whereas the fluorinated anion decomposes in acidic aqueous solutions and undergoes substituent exchange reactions in basic aqueous solutions (Finze *et al.*, 2007). Furthermore, \[1-H~2~N-*closo*-1-CB~11~F~11~\]^-^ reacts with strong non-nucleophilic bases under aprotic conditions to result in a cluster rearrangement that so far was observed for highly fluorinated aminocarba-*closo*-dodecaborates only (Finze, 2007). The difference in the properties of amino groups that are either bonded to the cluster carbon atom or to one of the boron atoms is demonstrated by a comparison of the p*K*~a~value of 1-H~3~N-*closo*-CB~11~H~11~ 6.0 (Jelínek *et al.*, 1986) and of 2-H~3~N-*closo*-CB~11~H~11~ \>10.5 (Finze, 2009). The inner salt 2-H~3~N-*closo*-1-CB~11~H~11~ crystallizes as ethanol solvate in the monoclinic space group *P*2~1~/*c* with one complete molecule and one ethanol molecule in the asymmetric unit. The cluster carbon atom is unambiguously assigned as evident from comparative refinements (Figure 1). Furthermore, the experimental inner cluster carbon-boron and boron-boron bond lengths are in excellent agreement to values derived from DFT calculations at the B3LYP/6--311++G(d,p) and at the MP2/6--311++G(d,p) level of theory, which were reported earlier (Finze, 2009). In this earlier contribution it was concluded on the basis of experimental inner-cluster *d*(C---B) and *d*(B---B) of the related {*closo*-1-CB~11~} species \[1-Ph-2-H~2~N-*closo*-1-CB~11~H~10~\]^-^ and 1-Ph-2-Me~3~N-*closo*-1-CB~11~H~10~ in conjunction with theoretical bond lengths of \[2-H~2~N-*closo*-1-CB~11~H~11~\]^-^ and 2-H~3~N-*closo*-1-CB~11~H~11~ that there is a small amount of B---N π-interaction for the amino derivatives whereas for the ammonio derivatives this π-interaction was not observed. The *d*(B2---N1) of 1.5396 (10) Å in the structure of the title compound supports these previous results. As a consequence of this weakened B2---N1 bond the inner-cluster C1---B2 bond is strengthened as documented by *d*(C1---B2) of 1.6872 (11) Å. The title compound 2-H~3~N-*closo*-1-CB~11~H~11~.CH~3~CH~2~OH forms dimers in the solid state (Table 1, Figure 2). The hydrogen-bonded ring consists of two ammonio derivatives and two ethanol molecules and has to be described as *R*^2^~4~(8) (Etter, 1990). A very similar hydrogen-bonded system was previously found for the related ammonio substituted carborane 1-H~3~N-2-F-*closo*-1-CB~11~H~10~ in the structure of its acetone solvate (Finze & Sprenger, 2010). Experimental {#experimental} ============ 2-H~3~N-*closo*-1-CB~11~H~11~ was synthesized according to a published procedure that also includes the spectroscopic data (Finze, 2009). The title compound was dissolved in a minimum amount of diethyl ether, ethanol, and chloroform (20:1:1). The clear colorless solution was stored at 3 °C in a refrigerator resulting in colorless crystals within two days. A single crystal suitable for structure determination was harvested under a dry nitrogen atmosphere and was directly transferred into the cooling stream of an Oxford-Xcalibur diffractometer equipped with an EOS-CCD detector. Refinement {#refinement} ========== All hydrogen atoms were located from difference Fourier synthesis. The H atoms of the 2-aminocarba-*closo*-dodecaborane and the H atom of the hydroxy group of the ethanol molecule were refined without any restraints. For the H atoms of the CH~2~ and CH~3~ group a riding model was employed and for each group a common *U*~iso~ value was refined. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### In the carborane 2-H3N-closo-1-CB11H11 the hydrogen atoms are drawn with an arbitrary radius and the displacement ellipsoids are shown at the 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Hydrogen-bonded motif formed by 2-H3N-closo-1-CB11H11.CH3CH2OH (Symmetry code: \' = -x + 2, -y + 2, -z + 2; hydrogen atoms are drawn with an arbitrary radius and the displacement ellipsoids are shown at the 50% probability level). :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e395 .table-wrap} ------------------------- ---------------------------------------- CH~14~B~11~N·C~2~H~6~O *F*(000) = 432 *M~r~* = 205.11 *D*~x~ = 1.115 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 48838 reflections *a* = 9.5753 (2) Å θ = 3.0--35.4° *b* = 9.2549 (2) Å µ = 0.06 mm^−1^ *c* = 13.9095 (5) Å *T* = 120 K β = 97.519 (3)° Block, colourless *V* = 1222.04 (6) Å^3^ 0.28 × 0.26 × 0.20 mm *Z* = 4 ------------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e526 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction Xcalibur Eos diffractometer 3199 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.030 graphite θ~max~ = 30.0°, θ~min~ = 4.3° ω scans *h* = −13→13 Absorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009) *k* = −13→13 *T*~min~ = 0.729, *T*~max~ = 1.000 *l* = −19→19 61096 measured reflections 3 standard reflections every 60 min 3561 independent reflections intensity decay: none ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e645 .table-wrap} ------------------------------------- ----------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.029 Hydrogen site location: difference Fourier map *wR*(*F*^2^) = 0.069 H atoms treated by a mixture of independent and constrained refinement *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + 0.6*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 3561 reflections (Δ/σ)~max~ \< 0.001 208 parameters Δρ~max~ = 0.31 e Å^−3^ 0 restraints Δρ~min~ = −0.22 e Å^−3^ ------------------------------------- ----------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e795 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. *CrysAlis PRO*, Oxford Diffraction Ltd., Version 1.171.33.52 (release 06--11-2009). Numerical absorption correction based on Gaussian integration over a multifaceted crystal model.. Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e903 .table-wrap} ----- -------------- -------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 0.64079 (8) 0.84830 (8) 0.78113 (5) 0.01344 (14) H1 0.5827 (11) 0.9122 (12) 0.8122 (7) 0.018 (3)\* B2 0.80596 (8) 0.81753 (9) 0.83584 (6) 0.01164 (14) N1 0.85434 (7) 0.89268 (8) 0.93327 (5) 0.01414 (13) H1A 0.9385 (13) 0.8604 (13) 0.9609 (8) 0.027 (3)\* H1B 0.8607 (12) 0.9893 (14) 0.9280 (8) 0.026 (3)\* H1C 0.7976 (12) 0.8764 (13) 0.9748 (8) 0.024 (3)\* B3 0.67585 (9) 0.68137 (9) 0.83322 (6) 0.01329 (15) H3 0.6339 (11) 0.6570 (11) 0.8994 (7) 0.018 (3)\* B4 0.56348 (9) 0.70103 (10) 0.72203 (6) 0.01463 (16) H4 0.4514 (11) 0.6832 (12) 0.7204 (8) 0.022 (3)\* B5 0.62540 (9) 0.85015 (9) 0.65759 (6) 0.01452 (16) H5 0.5509 (11) 0.9214 (12) 0.6171 (7) 0.019 (3)\* B6 0.77708 (9) 0.92320 (9) 0.72901 (6) 0.01289 (15) H6 0.7950 (11) 1.0393 (11) 0.7353 (7) 0.019 (3)\* B7 0.84826 (8) 0.63822 (9) 0.80794 (6) 0.01176 (14) H7 0.9196 (11) 0.5751 (12) 0.8583 (7) 0.019 (3)\* B8 0.69640 (9) 0.56516 (9) 0.73553 (6) 0.01280 (15) H8 0.6694 (11) 0.4511 (12) 0.7382 (7) 0.020 (3)\* B9 0.66519 (9) 0.66986 (9) 0.62665 (6) 0.01348 (15) H9 0.6180 (11) 0.6216 (12) 0.5578 (7) 0.019 (3)\* B10 0.79711 (9) 0.80728 (9) 0.63111 (6) 0.01288 (15) H10 0.8360 (11) 0.8478 (11) 0.5659 (7) 0.018 (3)\* B11 0.91068 (8) 0.78779 (9) 0.74285 (6) 0.01167 (15) H11 1.0217 (11) 0.8179 (11) 0.7508 (8) 0.019 (3)\* B12 0.84085 (8) 0.63102 (9) 0.67959 (6) 0.01164 (14) H12 0.9092 (11) 0.5566 (11) 0.6440 (7) 0.017 (2)\* O1 0.88753 (6) 1.20322 (7) 0.94495 (5) 0.01863 (12) H1O 0.9206 (15) 1.2323 (16) 0.9014 (10) 0.045 (4)\* C2 0.78862 (9) 1.30879 (9) 0.97377 (6) 0.02120 (17) H2A 0.7249 1.3401 0.9176 0.035 (2)\* H2B 0.8390 1.3926 1.0021 0.035 (2)\* C3 0.70730 (10) 1.23985 (10) 1.04632 (7) 0.02545 (19) H3A 0.7713 1.2070 1.1008 0.043 (2)\* H3B 0.6550 1.1592 1.0170 0.043 (2)\* H3C 0.6435 1.3092 1.0677 0.043 (2)\* ----- -------------- -------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1374 .table-wrap} ----- ------------ ------------ ------------ ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0119 (3) 0.0125 (3) 0.0161 (3) 0.0009 (3) 0.0025 (3) −0.0011 (3) B2 0.0120 (3) 0.0121 (3) 0.0109 (3) −0.0006 (3) 0.0020 (3) −0.0010 (3) N1 0.0162 (3) 0.0148 (3) 0.0116 (3) −0.0014 (2) 0.0026 (2) −0.0018 (2) B3 0.0134 (3) 0.0129 (4) 0.0140 (3) −0.0008 (3) 0.0036 (3) −0.0005 (3) B4 0.0116 (3) 0.0141 (4) 0.0181 (4) −0.0007 (3) 0.0016 (3) −0.0019 (3) B5 0.0141 (4) 0.0135 (4) 0.0153 (4) 0.0017 (3) −0.0007 (3) −0.0001 (3) B6 0.0140 (3) 0.0113 (3) 0.0134 (3) −0.0001 (3) 0.0021 (3) 0.0003 (3) B7 0.0123 (3) 0.0114 (3) 0.0118 (3) 0.0001 (3) 0.0022 (3) 0.0007 (3) B8 0.0130 (3) 0.0117 (3) 0.0139 (3) −0.0011 (3) 0.0026 (3) −0.0005 (3) B9 0.0139 (3) 0.0128 (4) 0.0133 (3) 0.0002 (3) 0.0002 (3) −0.0010 (3) B10 0.0151 (4) 0.0119 (3) 0.0116 (3) 0.0003 (3) 0.0016 (3) 0.0005 (3) B11 0.0118 (3) 0.0117 (3) 0.0117 (3) −0.0005 (3) 0.0024 (3) 0.0000 (3) B12 0.0124 (3) 0.0111 (3) 0.0115 (3) 0.0004 (3) 0.0022 (3) 0.0000 (3) O1 0.0193 (3) 0.0187 (3) 0.0190 (3) 0.0011 (2) 0.0069 (2) 0.0008 (2) C2 0.0232 (4) 0.0159 (4) 0.0251 (4) 0.0040 (3) 0.0055 (3) 0.0024 (3) C3 0.0242 (4) 0.0254 (4) 0.0286 (4) 0.0045 (3) 0.0108 (3) 0.0023 (4) ----- ------------ ------------ ------------ ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1692 .table-wrap} ---------------- ------------- ----------------- ------------- C1---B2 1.6872 (11) B5---B6 1.7821 (12) C1---B3 1.7207 (12) B5---H5 1.075 (10) C1---B4 1.7094 (12) B6---B10 1.7636 (12) C1---B5 1.7055 (12) B6---B11 1.7832 (12) C1---B6 1.7196 (11) B6---H6 1.090 (11) C1---H1 0.953 (10) B7---B12 1.7787 (11) B2---N1 1.5396 (10) B7---B8 1.7896 (12) B2---B11 1.7589 (11) B7---B11 1.7985 (12) B2---B7 1.7634 (12) B7---H7 1.083 (10) B2---B3 1.7691 (12) B8---B12 1.7809 (12) B2---B6 1.7702 (12) B8---B9 1.7898 (12) N1---H1A 0.898 (12) B8---H8 1.088 (11) N1---H1B 0.900 (12) B9---B12 1.7822 (12) N1---H1C 0.857 (12) B9---B10 1.7878 (12) B3---B8 1.7641 (12) B9---H9 1.099 (10) B3---B4 1.7742 (12) B10---B11 1.7856 (12) B3---B7 1.7777 (12) B10---B12 1.7937 (12) B3---H3 1.075 (10) B10---H10 1.091 (10) B4---B9 1.7692 (12) B11---B12 1.7811 (12) B4---B8 1.7816 (12) B11---H11 1.091 (10) B4---B5 1.7885 (13) B12---H12 1.110 (10) B4---H4 1.083 (11) O1---C2 1.4532 (10) B5---B10 1.7761 (12) O1---H1O 0.768 (15) B5---B9 1.7770 (12) C2---C3 1.4958 (12) B2---C1---B5 114.11 (6) B11---B6---H6 125.5 (6) B2---C1---B4 113.81 (6) B5---B6---H6 121.8 (5) B5---C1---B4 63.16 (5) B2---B7---B3 59.94 (5) B2---C1---B6 62.60 (5) B2---B7---B12 106.02 (6) B5---C1---B6 62.71 (5) B3---B7---B12 106.91 (6) B4---C1---B6 115.05 (6) B2---B7---B8 106.64 (6) B2---C1---B3 62.53 (5) B3---B7---B8 59.27 (5) B5---C1---B3 114.82 (6) B12---B7---B8 59.88 (5) B4---C1---B3 62.29 (5) B2---B7---B11 59.17 (4) B6---C1---B3 114.99 (6) B3---B7---B11 107.76 (6) B2---C1---H1 117.9 (6) B12---B7---B11 59.72 (5) B5---C1---H1 118.2 (6) B8---B7---B11 107.85 (6) B4---C1---H1 118.1 (6) B2---B7---H7 120.6 (6) B6---C1---H1 117.5 (6) B3---B7---H7 121.1 (5) B3---C1---H1 117.3 (6) B12---B7---H7 124.6 (5) N1---B2---C1 118.49 (6) B8---B7---H7 123.9 (6) N1---B2---B11 125.67 (6) B11---B7---H7 121.2 (6) C1---B2---B11 106.60 (6) B3---B8---B12 107.41 (6) N1---B2---B7 124.58 (6) B3---B8---B4 60.05 (5) C1---B2---B7 106.76 (6) B12---B8---B4 107.30 (6) B11---B2---B7 61.41 (5) B3---B8---B9 107.38 (6) N1---B2---B3 118.02 (6) B12---B8---B9 59.88 (5) C1---B2---B3 59.66 (5) B4---B8---B9 59.39 (5) B11---B2---B3 109.94 (6) B3---B8---B7 60.03 (5) B7---B2---B3 60.43 (5) B12---B8---B7 59.76 (5) N1---B2---B6 119.03 (6) B4---B8---B7 108.02 (6) C1---B2---B6 59.59 (5) B9---B8---B7 107.76 (6) B11---B2---B6 60.70 (5) B3---B8---H8 120.9 (5) B7---B2---B6 110.51 (6) B12---B8---H8 123.2 (5) B3---B2---B6 110.12 (6) B4---B8---H8 121.2 (6) B2---N1---H1A 112.1 (7) B9---B8---H8 122.7 (6) B2---N1---H1B 113.1 (7) B7---B8---H8 121.8 (6) H1A---N1---H1B 107.4 (10) B4---B9---B5 60.58 (5) B2---N1---H1C 111.7 (8) B4---B9---B12 107.78 (6) H1A---N1---H1C 105.5 (10) B5---B9---B12 108.06 (6) H1B---N1---H1C 106.6 (10) B4---B9---B10 108.28 (6) C1---B3---B8 104.97 (6) B5---B9---B10 59.77 (5) C1---B3---B2 57.81 (5) B12---B9---B10 60.32 (5) B8---B3---B2 107.51 (6) B4---B9---B8 60.07 (5) C1---B3---B4 58.54 (5) B5---B9---B8 108.71 (6) B8---B3---B4 60.47 (5) B12---B9---B8 59.81 (5) B2---B3---B4 106.86 (6) B10---B9---B8 108.47 (6) C1---B3---B7 104.68 (6) B4---B9---H9 121.0 (5) B8---B3---B7 60.70 (5) B5---B9---H9 121.0 (6) B2---B3---B7 59.63 (5) B12---B9---H9 122.5 (5) B4---B3---B7 108.88 (6) B10---B9---H9 121.8 (5) C1---B3---H3 118.3 (6) B8---B9---H9 121.4 (6) B8---B3---H3 128.6 (6) B6---B10---B5 60.46 (5) B2---B3---H3 118.2 (6) B6---B10---B11 60.32 (5) B4---B3---H3 121.0 (5) B5---B10---B11 108.48 (6) B7---B3---H3 125.7 (5) B6---B10---B9 108.17 (6) C1---B4---B9 104.15 (6) B5---B10---B9 59.81 (5) C1---B4---B3 59.17 (5) B11---B10---B9 107.78 (6) B9---B4---B3 107.84 (6) B6---B10---B12 107.86 (6) C1---B4---B8 104.69 (6) B5---B10---B12 107.59 (6) B9---B4---B8 60.54 (5) B11---B10---B12 59.68 (5) B3---B4---B8 59.49 (5) B9---B10---B12 59.69 (5) C1---B4---B5 58.31 (5) B6---B10---H10 121.1 (6) B9---B4---B5 59.93 (5) B5---B10---H10 121.5 (5) B3---B4---B5 108.24 (6) B11---B10---H10 121.5 (5) B8---B4---B5 108.57 (6) B9---B10---H10 122.2 (6) C1---B4---H4 119.8 (6) B12---B10---H10 122.4 (6) B9---B4---H4 126.9 (6) B2---B11---B12 106.11 (6) B3---B4---H4 119.3 (6) B2---B11---B6 59.96 (5) B8---B4---H4 125.9 (6) B12---B11---B6 107.55 (6) B5---B4---H4 120.0 (6) B2---B11---B10 106.46 (6) C1---B5---B10 104.26 (6) B12---B11---B10 60.38 (5) C1---B5---B9 103.98 (6) B6---B11---B10 59.23 (5) B10---B5---B9 60.42 (5) B2---B11---B7 59.42 (5) C1---B5---B6 59.03 (5) B12---B11---B7 59.59 (4) B10---B5---B6 59.42 (5) B6---B11---B7 108.32 (6) B9---B5---B6 107.84 (6) B10---B11---B7 108.14 (6) C1---B5---B4 58.52 (5) B2---B11---H11 121.8 (6) B10---B5---B4 107.94 (6) B12---B11---H11 123.8 (6) B9---B5---B4 59.50 (5) B6---B11---H11 120.5 (6) B6---B5---B4 108.23 (6) B10---B11---H11 122.5 (6) C1---B5---H5 119.9 (6) B7---B11---H11 122.0 (6) B10---B5---H5 126.7 (6) B7---B12---B8 60.37 (5) B9---B5---H5 126.7 (6) B7---B12---B11 60.69 (5) B6---B5---H5 119.7 (6) B8---B12---B11 109.01 (6) B4---B5---H5 119.7 (6) B7---B12---B9 108.58 (6) C1---B6---B10 104.21 (6) B8---B12---B9 60.31 (5) C1---B6---B2 57.80 (4) B11---B12---B9 108.23 (6) B10---B6---B2 106.93 (6) B7---B12---B10 108.66 (6) C1---B6---B11 104.15 (6) B8---B12---B10 108.60 (6) B10---B6---B11 60.45 (5) B11---B12---B10 59.93 (5) B2---B6---B11 59.34 (5) B9---B12---B10 59.99 (5) C1---B6---B5 58.26 (5) B7---B12---H12 121.5 (5) B10---B6---B5 60.12 (5) B8---B12---H12 121.3 (5) B2---B6---B5 106.55 (6) B11---B12---H12 121.4 (5) B11---B6---B5 108.32 (6) B9---B12---H12 121.4 (5) C1---B6---H6 118.9 (5) B10---B12---H12 121.3 (5) B10---B6---H6 129.1 (5) C2---O1---H1O 109.4 (11) B2---B6---H6 118.1 (5) O1---C2---C3 108.36 (7) ---------------- ------------- ----------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2785 .table-wrap} ------------------ ------------ ------------ ------------ --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1B···O1 0.900 (12) 2.006 (12) 2.8937 (9) 168.5 (10) N1---H1A···O1^i^ 0.898 (12) 2.065 (12) 2.9446 (9) 166.1 (10) ------------------ ------------ ------------ ------------ --------------- ::: Symmetry codes: (i) −*x*+2, −*y*+2, −*z*+2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------ ------------ ------------ ------------ ------------- N1---H1*B*⋯O1 0.900 (12) 2.006 (12) 2.8937 (9) 168.5 (10) N1---H1*A*⋯O1^i^ 0.898 (12) 2.065 (12) 2.9446 (9) 166.1 (10) Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.345228

2011-2-26

PMC3051931

Related literature {#sec1} ================== For related structures, see: Aatiq & Bakri, (2007[@bb1]); Boilot *et al.* (1987[@bb3]); Chakir *et al.* (2006)[@bb15]; Hong (1976[@bb7]); Masquelier *et al.* (2000[@bb9]); Trubach *et al.* (2004[@bb12]); Rodrigo *et al.* (1989[@bb10]); Zatovskii *et al.* (2006[@bb13]); Zhao *et al.* (2009[@bb14]). For compounds with the same structure type, see: Benmokhtar *et al.* (2007[@bb2]); Leclaire *et al.* (1989[@bb8]). For related structures, see: Brochu *et al.* (1997[@bb5]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} Al~0.5~Nb~1.5~(PO~4~)~3~*M* *~r~* = 437.76Trigonal,*a* = 8.5679 (6) Å*c* = 21.898 (2) Å*V* = 1392.14 (19) Å^3^*Z* = 6Mo *K*α radiationμ = 2.51 mm^−1^*T* = 293 K0.15 × 0.05 × 0.05 mm ### Data collection {#sec2.1.2} Bruker SMART 1K CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 1997[@bb6]) *T* ~min~ = 0.704, *T* ~max~ = 0.8852295 measured reflections302 independent reflections298 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.029 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.027*wR*(*F* ^2^) = 0.064*S* = 1.39302 reflections27 parametersΔρ~max~ = 0.45 e Å^−3^Δρ~min~ = −0.39 e Å^−3^ {#d5e525} Data collection: *SMART* (Bruker, 1997[@bb6]); cell refinement: *SAINT* (Bruker, 1997[@bb6]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb11]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb11]); molecular graphics: *DIAMOND* (Brandenburg, 2004[@bb4]); software used to prepare material for publication: *SHELXTL* (Sheldrick, 2008[@bb11]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811003886/fj2384sup1.cif](http://dx.doi.org/10.1107/S1600536811003886/fj2384sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003886/fj2384Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003886/fj2384Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?fj2384&file=fj2384sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?fj2384sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?fj2384&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [FJ2384](http://scripts.iucr.org/cgi-bin/sendsup?fj2384)). The authors acknowledge the Doctoral Foundation of Henan Polytechnic University (B2010--92, 648483). Comment ======= The mixed phosphates *AM*~2~(PO~4~)~3~ family (*A* = alkali metals; *M* = Ti, Zr, Ge, Sn) which usually belong to the NASICON (Na~3~Zr~2~Si~2~PO~12~: Boilot, *et al.*, 1987) or the NZP (NaZr~2~(PO~4~)~3~: Hong, 1976) structure-type have been extensively investigated for the low thermal expansion behavior of some members. The crystal structure that features a flexible three-dimensional framework of PO~4~ tetrahedra sharing comers with MO~6~ octahedra, is amenable to a wide variety of chemical substitutions at the various crystallographic positions, thus yielding a large number of closely related compounds, such as Na~3~MgZr(PO~4~)~3~ (Chakir, *et al.*, 2006), Na~3~Fe~2~(PO~4~)~3~ (Masquelier, *et al.*, 2000), NaFeNb(PO~4~)~3~ (Zatovskii, *et al.*, 2006), NaTi~2~(PO~4~)~3~ (Rodrigo, *et al.*, 1989) and NaGe~2~P~3~O12 (Zhao *et al.*, 2009). The three-dimensional network consisting of PO~4~ and MO~6~ octahedra delimit two different types of channels in which the *A* atoms are usually located to compensate the negative charges. It is reported that the *A* atoms can completely empty in some areas, such as Fe~0.5~Nb~1.5~(PO~4~)~3~ (Trubach, *et al.*, 2004) and Fe~0.5~Sb~1.5~(PO~4~)~3~ (Aatiq & Bakri, 2007), Nb~2~(PO~4~)~3~(Leclaire, *et al.*,1989) and Fe~0.5~Ti~2~(PO~4~)~3~(Benmokhtar, *et al.*, 2007), *etc*. In order to inrich this type of compounds, we synthesis the compound Al~0.5~Nb~1.5~(PO~4~)~3~ by a high-temperature reaction and determine the crystal structure from single-crystal X-ray diffraction analysis. As shown in Fig. 1, the asymmetric unit of Al~0.5~Nb~1.5~(PO~4~)~3~ contains a single P and Al/Nb atoms. The P atom is four coordinated by four oxygen atoms, forming isolated PO~4~ tetrahedron. Al and Nb atoms are in mixed occupancy disorder locating at the 3 axes with the moral ratio of 1: 3, being coordinated by six oxygen atoms to form Al/NbO~6~ octahedra. Al/NbO~6~ octahedra and PO~4~ tetrahedra are further interconnected *via* corner-sharing O atoms to form the three-dimensional framework of Al~0.5~Nb~1.5~(PO~4~)~3~, as shown in Fig. 2. The Al/Nb---O bonds have two groups of different distances, that is, 1.913 (3) and 1.949 (3) Å. The PO~4~ tetrahedra are regular with two groups of P--O bond distances of 1.521 (3) and 1.529 (3) Å, and O--P--O bond angles weak dispersion from 107.91 (16) to 111.3 (2)*^o^*, which is about the ideal value of 109.48°. On the other hand, this structure can be viewed as a NZP structure, in which the Na atom sites empty and the Zr atoms site are replaced by Al and Nb atoms in disordered manner on the principle of aliovalent pair combination Zr^4+^→ 0.25 A l^3+^ + 0.73 N b^5+^. Experimental {#experimental} ============ The finely ground reagents K~2~CO~3~, Al~2~O~3~, Nb~2~O~5~ and NH~4~H~2~PO~4~ were mixed in the molar ratio K: Al: Nb: P = 1: 3: 10: 20, were placed in a Pt crucible, and heated at 573 K for 4 h. The mixture was then re-ground and heated at 1473 K for 20 h, then cooled to 973 K at a rate of 3 K h^-1^, and finally quenched to room temperature. A few colorless crystals of the title compound with prismatic shape were obtained. Refinement {#refinement} ========== The structure contains substitutional disorder in which Al1 and Nb1 occupy the same position. The atomic positional and anisotropic displacement parameters of Al1 and Nb1 atoms were constrained to be identical by using EADP and EXYZ constraint instructions (*SHELXL97*; Sheldrick, 2008). The ratio of Al1 and Nb1 was fixed to 1: 3 to achieve charge balance. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The expanded asymmetric unit of Al0.5Nb1.5(PO4)3 showing the coordination environments of the P and Al/Nb atoms. The displacement ellipsoids are drawn at the 50% probability level.\[Symmetry codes: (i) x, y, z; (ii) -x + y, -x, z; (iii) -y, x-y, z; (iv) 0.66667 - x, 0.33333 - x + y, 0.83333 - z; (v) 0.66667 - y, 0.33333 - x, -0.16667 + z; (vi) -1/3 + x, 1/3 + x-y, -0.16667 + z; (vii) -0.33333 - x + y, -2/3 + y, -0.16667 + z.\] :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### View of the crystal structure of Al0.5Nb1.5(PO4)3 along \[010\]. PO4 and Al/NbO6 units are given in the polyhedral representation. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e503 .table-wrap} -------------------------- -------------------------------------- Al~0.5~Nb~1.5~(PO~4~)~3~ *D*~x~ = 3.133 Mg m^−3^ *M~r~* = 437.76 Mo *K*α radiation, λ = 0.71073 Å Trigonal, *R*3*c* Cell parameters from 247 reflections Hall symbol: -R 3 2\"c θ = 2.6--25.0° *a* = 8.5679 (6) Å µ = 2.51 mm^−1^ *c* = 21.898 (2) Å *T* = 293 K *V* = 1392.14 (19) Å^3^ Prism, colourless *Z* = 6 0.15 × 0.05 × 0.05 mm *F*(000) = 1254 -------------------------- -------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e622 .table-wrap} ------------------------------------------------------------ ------------------------------------- Bruker SMART 1K CCD area-detector diffractometer 302 independent reflections Radiation source: fine-focus sealed tube 298 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.029 ω scans θ~max~ = 25.7°, θ~min~ = 3.3° Absorption correction: multi-scan (*SADABS*; Bruker, 1997) *h* = −7→10 *T*~min~ = 0.704, *T*~max~ = 0.885 *k* = −10→8 2295 measured reflections *l* = −26→21 ------------------------------------------------------------ ------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e736 .table-wrap} ------------------------------------- -------------------------------------------------------------------------------------------------- Refinement on *F*^2^ 0 restraints Least-squares matrix: full Primary atom site location: structure-invariant direct methods *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.027 Secondary atom site location: difference Fourier map *wR*(*F*^2^) = 0.064 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0163*P*)^2^ + 17.3988*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.39 (Δ/σ)~max~ \< 0.001 302 reflections Δρ~max~ = 0.45 e Å^−3^ 27 parameters Δρ~min~ = −0.39 e Å^−3^ ------------------------------------- -------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e888 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e987 .table-wrap} ----- ------------ -------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) Nb1 0.0000 0.0000 0.35896 (3) 0.0091 (2) 0.75 Al1 0.0000 0.0000 0.35896 (3) 0.0091 (2) 0.25 P1 0.3333 0.38482 (17) 0.4167 0.0143 (4) O1 0.1675 (4) 0.1984 (4) 0.40796 (12) 0.0173 (6) O2 0.3025 (4) 0.4696 (4) 0.47305 (12) 0.0194 (7) ----- ------------ -------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1086 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Nb1 0.0092 (3) 0.0092 (3) 0.0090 (4) 0.00460 (14) 0.000 0.000 Al1 0.0092 (3) 0.0092 (3) 0.0090 (4) 0.00460 (14) 0.000 0.000 P1 0.0179 (8) 0.0126 (5) 0.0141 (7) 0.0089 (4) −0.0043 (6) −0.0022 (3) O1 0.0172 (15) 0.0132 (14) 0.0183 (14) 0.0053 (13) −0.0039 (12) −0.0051 (11) O2 0.0253 (16) 0.0164 (15) 0.0162 (14) 0.0102 (14) −0.0008 (12) −0.0052 (11) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1218 .table-wrap} ------------------------ ------------- ----------------------- ------------- Nb1---O1 1.913 (3) P1---O2 1.521 (3) Nb1---O1^i^ 1.913 (3) P1---O2^vi^ 1.521 (3) Nb1---O1^ii^ 1.913 (3) P1---O1^vi^ 1.529 (3) Nb1---O2^iii^ 1.949 (3) P1---O1 1.529 (3) Nb1---O2^iv^ 1.949 (3) O2---Al1^vii^ 1.949 (3) Nb1---O2^v^ 1.949 (3) O2---Nb1^vii^ 1.949 (3) O1---Nb1---O1^i^ 91.63 (12) O1^ii^---Nb1---O2^v^ 89.81 (12) O1---Nb1---O1^ii^ 91.63 (12) O2^iii^---Nb1---O2^v^ 88.66 (12) O1^i^---Nb1---O1^ii^ 91.63 (12) O2^iv^---Nb1---O2^v^ 88.66 (12) O1---Nb1---O2^iii^ 89.81 (12) O2---P1---O2^vi^ 111.3 (2) O1^i^---Nb1---O2^iii^ 89.86 (12) O2---P1---O1^vi^ 110.32 (15) O1^ii^---Nb1---O2^iii^ 177.90 (12) O2^vi^---P1---O1^vi^ 107.91 (16) O1---Nb1---O2^iv^ 177.90 (12) O2---P1---O1 107.91 (16) O1^i^---Nb1---O2^iv^ 89.81 (12) O2^vi^---P1---O1 110.32 (15) O1^ii^---Nb1---O2^iv^ 89.86 (12) O1^vi^---P1---O1 109.1 (2) O2^iii^---Nb1---O2^iv^ 88.66 (12) P1---O1---Nb1 152.96 (18) O1---Nb1---O2^v^ 89.86 (12) P1---O2---Al1^vii^ 155.8 (2) O1^i^---Nb1---O2^v^ 177.90 (12) P1---O2---Nb1^vii^ 155.8 (2) ------------------------ ------------- ----------------------- ------------- ::: Symmetry codes: (i) −*x*+*y*, −*x*, *z*; (ii) −*y*, *x*−*y*, *z*; (iii) −*y*+2/3, −*x*+1/3, *z*−1/6; (iv) −*x*+*y*−1/3, *y*−2/3, *z*−1/6; (v) *x*−1/3, *x*−*y*+1/3, *z*−1/6; (vi) −*x*+2/3, −*x*+*y*+1/3, −*z*+5/6; (vii) −*x*+*y*+1/3, *y*+2/3, *z*+1/6.

PubMed Central

2024-06-05T04:04:17.351840

2011-2-12

PMC3051932

Related literature {#sec1} ================== The neutral compound 2,6-bis­(2-meth­oxy­phen­yl)pyridine has been previously reported (Silva *et al.*, 1997[@bb6]) and copper(II) complexes of the related ligand 2,6-bis­(2′-hy­droxy­phen­yl)pyridine have also been characterized (Steinhauser *et al.*, 2004[@bb8]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} (C~19~H~18~NO~2~)~2~\[Cu~2~Br~6~\]*M* *~r~* = 1191.23Orthorhombic,*a* = 11.5329 (1) Å*b* = 17.0104 (4) Å*c* = 21.0021 (5) Å*V* = 4120.18 (14) Å^3^*Z* = 4Mo *K*α radiationμ = 6.89 mm^−1^*T* = 298 K0.25 × 0.20 × 0.18 mm ### Data collection {#sec2.1.2} Nonius KappaCCD diffractometerAbsorption correction: multi-scan (*DENZO-SMN*; Otwinowski & Minor, 1997[@bb4]) *T* ~min~ = 0.207, *T* ~max~ = 0.30128095 measured reflections4177 independent reflections3240 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.075 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.042*wR*(*F* ^2^) = 0.104*S* = 1.054177 reflections235 parametersH-atom parameters constrainedΔρ~max~ = 0.36 e Å^−3^Δρ~min~ = −0.55 e Å^−3^ {#d5e449} Data collection: *KappaCCD Server Software* (Nonius, 1997[@bb3]); cell refinement: *DENZO-SMN* (Otwinowski & Minor, 1997[@bb4]); data reduction: *DENZO-SMN*; program(s) used to solve structure: *SIR92* (Altomare *et al.*, 1994[@bb1]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *PLATON* (Spek, 2009[@bb7]); software used to prepare material for publication: *SHELXL97* and *maXus* (Mackay *et al.*, 1999[@bb2]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811003588/vn2002sup1.cif](http://dx.doi.org/10.1107/S1600536811003588/vn2002sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003588/vn2002Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003588/vn2002Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?vn2002&file=vn2002sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?vn2002sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?vn2002&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [VN2002](http://scripts.iucr.org/cgi-bin/sendsup?vn2002)). The authors acknowledge financial support from the Young Scientist and Technologist Programme (YSTP), the Center of Excellence for Innovation in Chemistry (PERCH-CIC) and the Office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative. Comment ======= An attempt to synthesize copper(II) complex of 2,6-bis(2-methoxyphenyl)- pyridine in CH~2~Cl~2~ unexpectedly yielded the ionic complex (C~9~H~18~NO~2~).0.5(Cu~2~Br~6~). The single crystals of the title compound crystallizes in the orthorhombic unit cell in space group P~bca~. Each asymmetric unit cell contains one molecule of 2,6-bis(2-methoxy- phenyl)pyridinium cation and half a molecule of hexabromodicuprate(II). Crystallographic data of the title compound reveals intramolecular N---H···O hydrogen bonds forcing both methoxy groups to be in close proximity to the nitrogen atom of the pyridinium ring (N···O distances of 2.625 (4) and 2.630 (4) Å). The pyridinium and two methoxyphenyl rings are almost co-planar, having the dihedral angles between them of 7.5 (5)° and 15.0 (5)°. In addition, weak intermolecular π-π stacking interactions between pyridine and phenyl moieties of the neighboring molecules with centroid-centroid distances of 3.649 (2) and 3.850 (2) Å are present. Note that the centroid of the complete dianion coincides with the inversion center. Moreover, the hexabromodicuprate(II) dianion displays a distorted tetrahedral geometry at both copper(II) ions with Cu---Br bond distances of 2.3385 (7) and 2.3304 (7) Å for terminal bromides, and 2.4451 (6) Å for bridging bromides, respectively. The neutral compound 2,6-bis(2-methoxyphenyl)pyridine has been previously reported (Silva *et al.*, 1997) and their crystals were obtained from an ethyl acetate solution. The published crystal structure reveals that both methoxy groups are on opposite sides of the pyridine nitrogen to avoid the N···O lone pair repulsion. In addition, copper(II) complexes of the related ligand 2,6-bis(2\'- hydroxyphenyl)pyridine have previously been synthesized and characterized (Steinhauser *et al.*, 2004). Experimental {#experimental} ============ The title compound, (C~9~H~18~NO~2~).0.5(Cu~2~Br~6~) (1), was prepared from a reaction of CuBr~2~ (0.5 mmol) with one equivalent of 2,6-bis(2-methoxyphenyl)pyridine (0.5 mmol) in dichloromethane (30 ml) at room temperature for 3 h. The reaction solution was filtered to remove any unreacted CuBr~2~. X-ray quality single crystals were obtained from slow evaporation of a dichloromethane solution of 1 at room temperature. Refinement {#refinement} ========== Structure refinement was performed using least-squares analysis. All non-H atoms were refined anisotropically whereas all H atoms were placed in calculated positions and treated as riding with C,*N*---H = 0.96 with *U*~iso~(H) = 1.2 *U*~eq~(C,*N*), including the methoxy H atoms. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### ORTEP diagram of the title compound (1). Displacement ellipsoids are drawn at the 30% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e179 .table-wrap} ------------------------------------ ---------------------------------------- (C~19~H~18~NO~2~)~2~\[Cu~2~Br~6~\] *F*(000) = 2312 *M~r~* = 1191.23 *D*~x~ = 1.920 Mg m^−3^ Orthorhombic, *Pbca* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ac 2ab Cell parameters from 32254 reflections *a* = 11.5329 (1) Å θ = 1.0--26.4° *b* = 17.0104 (4) Å µ = 6.89 mm^−1^ *c* = 21.0021 (5) Å *T* = 298 K *V* = 4120.18 (14) Å^3^ Cube, dark green *Z* = 4 0.25 × 0.20 × 0.18 mm ------------------------------------ ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e311 .table-wrap} --------------------------------------------------------------------------- -------------------------------------- Nonius KappaCCD diffractometer 3240 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.075 ω scans θ~max~ = 26.4°, θ~min~ = 2.9° Absorption correction: multi-scan (*DENZO-SMN*; Otwinowski & Minor, 1997) *h* = −14→14 *T*~min~ = 0.207, *T*~max~ = 0.301 *k* = −21→21 28095 measured reflections *l* = −22→26 4177 independent reflections --------------------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e424 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.042 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.104 H-atom parameters constrained *S* = 1.05 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0575*P*)^2^ + 1.1145*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4177 reflections (Δ/σ)~max~ \< 0.001 235 parameters Δρ~max~ = 0.36 e Å^−3^ 0 restraints Δρ~min~ = −0.55 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e581 .table-wrap} ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. multi-scan from symmetry-related measurements *SORTAV* (Blessing 1995) Geometry. All standard uncertainties (except dihedral angles between l.s. planes) are estimated using the full covariance matrix. The standard uncertainties in cell dimensions are are used in calculating the standard uncertainties of bond distances, angles and torsion angles. Angles between l.s. planes have standard uncertainties calculated from atomic positional standard uncertainties; the errors in cell dimensions are not used in this case. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e610 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Br1 −0.03538 (4) 0.45904 (3) 0.07154 (2) 0.07414 (19) Br2 0.14159 (4) 0.30603 (3) 0.00330 (2) 0.05795 (15) Br3 0.31781 (4) 0.47771 (3) −0.02118 (2) 0.06266 (16) Cu1 0.12512 (4) 0.44281 (3) −0.00337 (2) 0.05014 (16) N1 0.3781 (2) 0.23294 (16) 0.25843 (14) 0.0384 (7) H20 0.3754 0.2367 0.2128 0.046\* O1 0.3184 (2) 0.16507 (18) 0.15107 (14) 0.0609 (8) O2 0.4577 (2) 0.30722 (17) 0.15766 (13) 0.0571 (7) C1 0.2958 (3) 0.1857 (2) 0.28504 (18) 0.0438 (9) C2 0.2983 (4) 0.1787 (3) 0.3505 (2) 0.0613 (11) H2 0.2431 0.1451 0.3713 0.074\* C3 0.3783 (4) 0.2192 (3) 0.3857 (2) 0.0678 (12) H3 0.3768 0.2142 0.4312 0.081\* C4 0.4595 (3) 0.2663 (2) 0.35705 (19) 0.0535 (10) H4 0.5156 0.2941 0.3822 0.064\* C5 0.4602 (3) 0.2733 (2) 0.29171 (17) 0.0388 (8) C6 0.2118 (3) 0.1434 (2) 0.2446 (2) 0.0461 (9) C7 0.2227 (3) 0.1327 (2) 0.1792 (2) 0.0500 (10) C8 0.1406 (4) 0.0902 (3) 0.1446 (3) 0.0658 (12) H8 0.1496 0.0835 0.0995 0.079\* C9 0.0476 (4) 0.0583 (3) 0.1753 (3) 0.0768 (16) H9 −0.0088 0.0294 0.1512 0.092\* C10 0.0341 (4) 0.0672 (3) 0.2395 (3) 0.0751 (15) H10 −0.0311 0.0436 0.2606 0.090\* C11 0.1135 (3) 0.1099 (3) 0.2742 (2) 0.0614 (12) H11 0.1027 0.1172 0.3191 0.074\* C12 0.3434 (4) 0.1461 (3) 0.0865 (2) 0.0712 (13) H12A 0.4127 0.1730 0.0734 0.085\* H12B 0.2798 0.1624 0.0600 0.085\* H12C 0.3544 0.0904 0.0824 0.085\* C13 0.5483 (3) 0.3218 (2) 0.25782 (18) 0.0421 (8) C14 0.5472 (3) 0.3374 (2) 0.19176 (19) 0.0445 (9) C15 0.6341 (4) 0.3824 (2) 0.1641 (2) 0.0569 (11) H15 0.6337 0.3919 0.1191 0.068\* C16 0.7214 (4) 0.4135 (3) 0.2013 (3) 0.0671 (13) H16 0.7812 0.4448 0.1821 0.081\* C17 0.7238 (3) 0.4001 (3) 0.2657 (3) 0.0669 (13) H17 0.7844 0.4222 0.2914 0.080\* C18 0.6385 (3) 0.3547 (2) 0.2938 (2) 0.0550 (10) H18 0.6421 0.3458 0.3389 0.066\* C19 0.4346 (4) 0.3398 (3) 0.0959 (2) 0.0667 (12) H19A 0.3696 0.3133 0.0772 0.080\* H19B 0.5016 0.3331 0.0693 0.080\* H19C 0.4174 0.3948 0.1000 0.080\* ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1188 .table-wrap} ----- ------------- ------------- ------------- --------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Br1 0.0777 (3) 0.0785 (4) 0.0662 (3) 0.0310 (2) 0.0336 (2) 0.0342 (3) Br2 0.0599 (3) 0.0497 (3) 0.0643 (3) 0.00570 (18) 0.01288 (19) 0.0059 (2) Br3 0.0578 (3) 0.0655 (3) 0.0646 (3) −0.00476 (19) 0.0102 (2) 0.0042 (2) Cu1 0.0534 (3) 0.0490 (3) 0.0480 (3) 0.0075 (2) 0.0124 (2) 0.0064 (2) N1 0.0394 (16) 0.0413 (16) 0.0344 (16) 0.0002 (12) 0.0000 (12) 0.0008 (13) O1 0.0662 (18) 0.0702 (19) 0.0464 (18) −0.0161 (15) 0.0017 (13) −0.0131 (16) O2 0.0643 (17) 0.0674 (19) 0.0395 (16) −0.0155 (14) −0.0049 (12) 0.0100 (14) C1 0.0392 (19) 0.044 (2) 0.048 (2) 0.0010 (15) 0.0072 (16) 0.0039 (18) C2 0.062 (3) 0.072 (3) 0.050 (3) −0.013 (2) 0.011 (2) 0.007 (2) C3 0.079 (3) 0.086 (3) 0.039 (2) −0.009 (3) 0.003 (2) 0.004 (2) C4 0.060 (2) 0.058 (3) 0.043 (2) −0.0058 (19) −0.0026 (18) −0.005 (2) C5 0.0388 (19) 0.0363 (19) 0.041 (2) 0.0044 (14) −0.0021 (14) −0.0026 (16) C6 0.041 (2) 0.036 (2) 0.061 (3) 0.0040 (14) 0.0015 (17) 0.0058 (18) C7 0.047 (2) 0.042 (2) 0.061 (3) 0.0006 (16) −0.0013 (18) −0.0037 (19) C8 0.061 (3) 0.055 (3) 0.082 (4) −0.004 (2) −0.014 (2) −0.014 (3) C9 0.054 (3) 0.052 (3) 0.124 (5) −0.006 (2) −0.020 (3) −0.012 (3) C10 0.046 (3) 0.054 (3) 0.126 (5) −0.0071 (19) 0.003 (3) 0.011 (3) C11 0.045 (2) 0.054 (3) 0.085 (3) 0.0010 (19) 0.009 (2) 0.009 (2) C12 0.089 (3) 0.071 (3) 0.054 (3) 0.001 (2) 0.002 (2) −0.020 (2) C13 0.0374 (18) 0.039 (2) 0.050 (2) 0.0028 (14) −0.0009 (15) −0.0031 (17) C14 0.046 (2) 0.040 (2) 0.048 (2) 0.0004 (16) 0.0024 (16) 0.0020 (17) C15 0.060 (3) 0.052 (3) 0.059 (3) −0.001 (2) 0.014 (2) 0.010 (2) C16 0.050 (3) 0.052 (3) 0.099 (4) −0.008 (2) 0.012 (2) 0.008 (3) C17 0.043 (2) 0.062 (3) 0.096 (4) −0.006 (2) −0.005 (2) −0.007 (3) C18 0.049 (2) 0.054 (2) 0.062 (3) −0.0034 (18) −0.0075 (19) −0.003 (2) C19 0.081 (3) 0.077 (3) 0.042 (3) −0.005 (2) −0.006 (2) 0.011 (2) ----- ------------- ------------- ------------- --------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1693 .table-wrap} ------------------- ------------ ------------------- ----------- Br2---Cu1 2.3385 (7) C2---H2 0.9600 Br3---Cu1 2.3304 (7) C19---H19A 0.9600 Br1---Cu1 2.4451 (6) C19---H19B 0.9600 C5---N1 1.362 (4) C19---H19C 0.9600 C5---C4 1.377 (5) C3---H3 0.9600 C5---C13 1.490 (5) C7---C6 1.392 (6) O2---C14 1.356 (4) C7---C8 1.396 (6) O2---C19 1.435 (5) C11---C6 1.413 (5) O1---C7 1.367 (5) C11---H11 0.9600 O1---C12 1.423 (5) C12---H12A 0.9600 C14---C15 1.389 (5) C12---H12B 0.9600 C14---C13 1.413 (5) C12---H12C 0.9600 N1---C1 1.363 (4) C13---C18 1.402 (5) N1---H20 0.9600 C8---C9 1.364 (7) C10---C9 1.365 (8) C8---H8 0.9600 C10---C11 1.377 (7) C18---C17 1.382 (6) C10---H10 0.9601 C18---H18 0.9600 C4---C3 1.372 (6) C16---C17 1.372 (7) C4---H4 0.9600 C16---H16 0.9600 C15---C16 1.380 (6) C17---H17 0.9600 C15---H15 0.9598 C9---H9 0.9600 C2---C3 1.368 (6) C1---C6 1.476 (5) C2---C1 1.380 (6) Br3---Cu1---Br2 100.69 (2) O1---C7---C8 122.1 (4) Br3---Cu1---Br1 142.79 (3) C6---C7---C8 121.3 (4) Br2---Cu1---Br1 97.77 (2) C10---C11---C6 121.0 (5) N1---C5---C4 117.6 (3) C10---C11---H11 120.1 N1---C5---C13 120.5 (3) C6---C11---H11 118.9 C4---C5---C13 121.8 (3) O1---C12---H12A 109.4 C14---O2---C19 118.1 (3) O1---C12---H12B 109.4 C7---O1---C12 118.9 (3) H12A---C12---H12B 109.5 O2---C14---C15 122.5 (4) O1---C12---H12C 109.6 O2---C14---C13 117.0 (3) H12A---C12---H12C 109.5 C15---C14---C13 120.5 (4) H12B---C12---H12C 109.5 C5---N1---C1 124.8 (3) C18---C13---C14 117.4 (4) C5---N1---H20 120.1 C18---C13---C5 118.0 (3) C1---N1---H20 115.2 C14---C13---C5 124.5 (3) C9---C10---C11 120.3 (5) C9---C8---C7 119.6 (5) C9---C10---H10 119.9 C9---C8---H8 120.4 C11---C10---H10 119.8 C7---C8---H8 120.1 C3---C4---C5 119.4 (4) C17---C18---C13 121.4 (4) C3---C4---H4 120.5 C17---C18---H18 118.5 C5---C4---H4 120.1 C13---C18---H18 120.0 C16---C15---C14 120.1 (4) C17---C16---C15 120.6 (4) C16---C15---H15 119.8 C17---C16---H16 119.5 C14---C15---H15 120.1 C15---C16---H16 119.9 C3---C2---C1 120.6 (4) C16---C17---C18 120.0 (4) C3---C2---H2 120.0 C16---C17---H17 120.2 C1---C2---H2 119.4 C18---C17---H17 119.9 O2---C19---H19A 109.5 C8---C9---C10 120.9 (5) O2---C19---H19B 109.4 C8---C9---H9 119.1 H19A---C19---H19B 109.5 C10---C9---H9 120.0 O2---C19---H19C 109.5 N1---C1---C2 116.4 (3) H19A---C19---H19C 109.5 N1---C1---C6 120.6 (3) H19B---C19---H19C 109.5 C2---C1---C6 123.0 (3) C2---C3---C4 121.2 (4) C7---C6---C11 117.0 (4) C2---C3---H3 118.9 C7---C6---C1 124.9 (3) C4---C3---H3 120.0 C11---C6---C1 118.1 (4) O1---C7---C6 116.5 (3) ------------------- ------------ ------------------- ----------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2246 .table-wrap} --------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H20···O1 0.96 1.90 2.625 (4) 131 N1---H20···O2 0.96 1.92 2.630 (4) 129 --------------- --------- --------- ----------- --------------- ::: ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------- --------- ------- ----------- ------------- N1---H20⋯O1 0.96 1.90 2.625 (4) 131 N1---H20⋯O2 0.96 1.92 2.630 (4) 129 :::

PubMed Central

2024-06-05T04:04:17.353784

2011-2-05

PMC3051933

Related literature {#sec1} ================== For a similar compound, see: Ali *et al.* (2011[@bb2]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~47~H~54~N~6~O~2~*M* *~r~* = 734.96Triclinic,*a* = 11.4805 (4) Å*b* = 13.8247 (4) Å*c* = 14.6180 (6) Åα = 104.808 (3)°β = 103.706 (3)°γ = 100.642 (3)°*V* = 2103.58 (14) Å^3^*Z* = 2Mo *K*α radiationμ = 0.07 mm^−1^*T* = 100 K0.30 × 0.25 × 0.20 mm ### Data collection {#sec2.1.2} Agilent SuperNova Dual diffractometer with an Atlas detectorAbsorption correction: multi-scan (*CrysAlis PRO*; Agilent, 2010[@bb1]) *T* ~min~ = 0.822, *T* ~max~ = 1.00017578 measured reflections9290 independent reflections6994 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.031 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.051*wR*(*F* ^2^) = 0.127*S* = 1.019290 reflections514 parameters2 restraintsH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.47 e Å^−3^Δρ~min~ = −0.30 e Å^−3^ {#d5e425} Data collection: *CrysAlis PRO* (Agilent, 2010[@bb1]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb4]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb4]); molecular graphics: *X-SEED* (Barbour, 2001[@bb3]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb5]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811006374/zs2092sup1.cif](http://dx.doi.org/10.1107/S1600536811006374/zs2092sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006374/zs2092Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006374/zs2092Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?zs2092&file=zs2092sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?zs2092sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?zs2092&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [ZS2092](http://scripts.iucr.org/cgi-bin/sendsup?zs2092)). We thank the Higher Education Commission of Pakistan and the University of Malaya for supporting this study. Comment ======= Some background on di(aryl)methane compounds having oxyacetate substituents was presented in an earlier report (Ali *et al.*, 2011). The title compound also has an *N*-heterocyclic substituent in the rings (Scheme I). Experimental {#experimental} ============ 6,6\'-Methylenebis(2-(2*H*-benzo\[*d*\]\[1,2,3\]triazol-2-yl)-4-(2,4,4-\\ trimethylpentan-2-yl)phenol) (0.01 g) and potassium carbonate (0.05 g) were dissolved in acetone (20 ml) at 323 K. Propargyl bromide (0.04 ml) was added and the reaction was stirred for 20 h. The progress of the reaction was monitored by thin layer chromatography (hexane: dichloromethane 60:40). The reaction was quenched by adding 1 M hydrochloric acid (10 ml). The aqueous phase was extracted with dichloromethane, the solvent evaporated and the crude product was recrystallized from dichloromethane (yield 80%). Refinement {#refinement} ========== Carbon-bound H-atoms were placed in calculated positions \[C---H = 0.95 to 0.99 Å and *U*~iso~(H) = 1.2 to 1.5*U*~eq~(C)\] and were included in the refinement in the riding model approximation. The acetylenic H-atoms were located in a difference Fourier map and were refined with a distance restraint of C---H = 0.95±0.01 Å and their isotropic displacement parameters also refining. The structure contains solvent accessible voids of 66 Å^3^. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Thermal ellipsoid plot (Barbour, 2001) of C47H54N6O2 at the 70% probability level with hydrogen atoms drawn as spheres of arbitrary radius. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e125 .table-wrap} ------------------------- --------------------------------------- C~47~H~54~N~6~O~2~ *Z* = 2 *M~r~* = 734.96 *F*(000) = 788 Triclinic, *P*1 *D*~x~ = 1.160 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 11.4805 (4) Å Cell parameters from 6715 reflections *b* = 13.8247 (4) Å θ = 2.5--29.3° *c* = 14.6180 (6) Å µ = 0.07 mm^−1^ α = 104.808 (3)° *T* = 100 K β = 103.706 (3)° Block, beige γ = 100.642 (3)° 0.30 × 0.25 × 0.20 mm *V* = 2103.58 (14) Å^3^ ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e261 .table-wrap} ------------------------------------------------------------------- -------------------------------------- Agilent SuperNova Dual diffractometer with an Atlas detector 9290 independent reflections Radiation source: SuperNova (Mo) X-ray Source 6994 reflections with *I* \> 2σ(*I*) Mirror *R*~int~ = 0.031 Detector resolution: 10.4041 pixels mm^-1^ θ~max~ = 27.5°, θ~min~ = 2.5° ω scans *h* = −11→14 Absorption correction: multi-scan (*CrysAlis PRO*; Agilent, 2010) *k* = −17→17 *T*~min~ = 0.822, *T*~max~ = 1.000 *l* = −18→18 17578 measured reflections ------------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e381 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.051 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.127 H atoms treated by a mixture of independent and constrained refinement *S* = 1.01 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0421*P*)^2^ + 1.0461*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 9290 reflections (Δ/σ)~max~ = 0.001 514 parameters Δρ~max~ = 0.47 e Å^−3^ 2 restraints Δρ~min~ = −0.30 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e540 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O1 0.62069 (10) 0.57849 (8) 0.68366 (8) 0.0181 (2) O2 0.46427 (10) 0.92915 (9) 0.74295 (8) 0.0180 (2) N1 0.75682 (14) 0.48200 (11) 0.55515 (11) 0.0253 (3) N2 0.79630 (13) 0.58497 (10) 0.58114 (10) 0.0175 (3) N3 0.91866 (13) 0.62735 (11) 0.61580 (10) 0.0210 (3) N4 0.63903 (13) 1.12608 (10) 1.02490 (10) 0.0191 (3) N5 0.62242 (12) 1.07152 (10) 0.93082 (9) 0.0170 (3) N6 0.62881 (13) 1.12402 (11) 0.86637 (10) 0.0208 (3) C1 0.86471 (17) 0.45397 (14) 0.57584 (13) 0.0243 (4) C2 0.8856 (2) 0.35465 (16) 0.56490 (17) 0.0382 (5) H2 0.8190 0.2935 0.5382 0.046\* C3 1.0059 (2) 0.35097 (17) 0.59449 (17) 0.0418 (6) H3 1.0231 0.2854 0.5892 0.050\* C4 1.1068 (2) 0.44130 (18) 0.63295 (14) 0.0368 (5) H4 1.1891 0.4345 0.6529 0.044\* C5 1.08845 (18) 0.53777 (16) 0.64196 (13) 0.0313 (4) H5 1.1561 0.5981 0.6666 0.038\* C6 0.96427 (16) 0.54370 (14) 0.61302 (12) 0.0218 (4) C7 0.71225 (15) 0.64916 (12) 0.57571 (11) 0.0164 (3) C8 0.62335 (15) 0.64286 (12) 0.62555 (11) 0.0160 (3) C9 0.54520 (14) 0.70952 (12) 0.62302 (11) 0.0159 (3) C10 0.55881 (15) 0.77843 (12) 0.56992 (11) 0.0169 (3) H10 0.5046 0.8226 0.5672 0.020\* C11 0.64859 (15) 0.78633 (12) 0.52001 (11) 0.0165 (3) C12 0.72566 (15) 0.71951 (12) 0.52388 (11) 0.0175 (3) H12 0.7876 0.7222 0.4909 0.021\* C13 0.52191 (16) 0.48396 (12) 0.63901 (12) 0.0214 (4) H13A 0.5508 0.4290 0.5995 0.026\* H13B 0.4500 0.4956 0.5944 0.026\* C14 0.48590 (16) 0.45259 (13) 0.71871 (13) 0.0227 (4) C15 0.45817 (19) 0.42907 (15) 0.78391 (15) 0.0319 (4) C16 0.66093 (15) 0.86743 (13) 0.46638 (12) 0.0187 (3) C17 0.53433 (16) 0.84807 (14) 0.38963 (12) 0.0229 (4) H17A 0.5128 0.7787 0.3416 0.034\* H17B 0.5391 0.9001 0.3550 0.034\* H17C 0.4705 0.8531 0.4235 0.034\* C18 0.75675 (17) 0.85806 (14) 0.40902 (13) 0.0237 (4) H18A 0.7281 0.7915 0.3558 0.036\* H18B 0.8367 0.8619 0.4543 0.036\* H18C 0.7665 0.9147 0.3803 0.036\* C19 0.68883 (15) 0.97889 (12) 0.53917 (12) 0.0193 (3) H19A 0.6861 1.0258 0.4981 0.023\* H19B 0.6176 0.9802 0.5661 0.023\* C20 0.80758 (16) 1.03051 (13) 0.62902 (13) 0.0227 (4) C21 0.8235 (2) 0.97002 (15) 0.70266 (14) 0.0368 (5) H21A 0.8414 0.9048 0.6723 0.055\* H21B 0.7469 0.9552 0.7210 0.055\* H21C 0.8924 1.0112 0.7621 0.055\* C22 0.79155 (19) 1.13578 (14) 0.68323 (14) 0.0295 (4) H22A 0.8666 1.1738 0.7387 0.044\* H22B 0.7200 1.1248 0.7084 0.044\* H22C 0.7779 1.1759 0.6371 0.044\* C23 0.92515 (19) 1.05220 (19) 0.59749 (16) 0.0462 (6) H23A 0.9497 0.9877 0.5772 0.069\* H23B 0.9923 1.1028 0.6533 0.069\* H23C 0.9088 1.0800 0.5418 0.069\* C24 0.45816 (15) 0.71523 (12) 0.68700 (11) 0.0173 (3) H24A 0.3871 0.7399 0.6573 0.021\* H24B 0.4254 0.6457 0.6914 0.021\* C25 0.53039 (14) 0.78978 (12) 0.78966 (11) 0.0163 (3) C26 0.59913 (15) 0.75508 (12) 0.86006 (12) 0.0172 (3) H26 0.5928 0.6829 0.8451 0.021\* C27 0.67730 (15) 0.82160 (12) 0.95195 (12) 0.0171 (3) C28 0.68230 (15) 0.92638 (12) 0.97296 (12) 0.0171 (3) H28 0.7345 0.9739 1.0348 0.020\* C29 0.61161 (15) 0.96223 (12) 0.90424 (12) 0.0165 (3) C30 0.53422 (14) 0.89489 (12) 0.81258 (11) 0.0160 (3) C31 0.75537 (15) 0.77823 (13) 1.02367 (12) 0.0191 (3) C32 0.66482 (18) 0.70338 (15) 1.05332 (14) 0.0299 (4) H32A 0.6130 0.7411 1.0849 0.045\* H32B 0.7122 0.6746 1.0999 0.045\* H32C 0.6118 0.6469 0.9940 0.045\* C33 0.83766 (17) 0.86281 (14) 1.11939 (13) 0.0266 (4) H33A 0.7852 0.8932 1.1563 0.040\* H33B 0.8890 0.9169 1.1030 0.040\* H33C 0.8914 0.8325 1.1602 0.040\* C34 0.83234 (16) 0.71225 (13) 0.97307 (13) 0.0229 (4) H34A 0.8710 0.6800 1.0214 0.027\* H34B 0.7716 0.6550 0.9169 0.027\* C35 0.93593 (17) 0.75639 (15) 0.93242 (13) 0.0274 (4) C36 0.89336 (18) 0.81043 (16) 0.85695 (15) 0.0335 (5) H36A 0.9604 0.8295 0.8289 0.050\* H36B 0.8719 0.8731 0.8896 0.050\* H36C 0.8203 0.7636 0.8038 0.050\* C37 0.9750 (2) 0.66217 (19) 0.87945 (17) 0.0488 (6) H37A 1.0385 0.6850 0.8495 0.073\* H37B 0.9026 0.6127 0.8276 0.073\* H37C 1.0088 0.6288 0.9275 0.073\* C38 1.05044 (19) 0.8306 (2) 1.01414 (16) 0.0518 (7) H38A 1.1175 0.8475 0.9854 0.078\* H38B 1.0775 0.7976 1.0644 0.078\* H38C 1.0297 0.8943 1.0449 0.078\* C39 0.36827 (15) 0.97167 (13) 0.77280 (12) 0.0194 (3) H39A 0.3669 1.0357 0.7545 0.023\* H39B 0.3869 0.9901 0.8457 0.023\* C40 0.24673 (17) 0.89734 (14) 0.72536 (13) 0.0255 (4) C41 0.14749 (19) 0.83803 (16) 0.68885 (17) 0.0388 (5) C42 0.65798 (15) 1.22441 (13) 1.02168 (12) 0.0190 (3) C43 0.68485 (16) 1.31885 (13) 1.09851 (13) 0.0252 (4) H43 0.6879 1.3205 1.1644 0.030\* C44 0.70612 (17) 1.40743 (14) 1.07339 (14) 0.0297 (4) H44 0.7256 1.4723 1.1235 0.036\* C45 0.70014 (18) 1.40630 (14) 0.97485 (15) 0.0314 (4) H45 0.7158 1.4702 0.9612 0.038\* C46 0.67257 (18) 1.31596 (14) 0.89937 (14) 0.0287 (4) H46 0.6677 1.3155 0.8335 0.034\* C47 0.65172 (15) 1.22327 (13) 0.92390 (12) 0.0206 (4) H15 0.438 (2) 0.4082 (16) 0.8366 (12) 0.047 (6)\* H41 0.0684 (14) 0.7883 (15) 0.6599 (17) 0.060 (8)\* ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1893 .table-wrap} ----- ------------- ------------- ------------- -------------- ------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.0199 (6) 0.0156 (5) 0.0173 (6) 0.0022 (5) 0.0042 (5) 0.0055 (4) O2 0.0175 (6) 0.0234 (6) 0.0157 (5) 0.0079 (5) 0.0059 (4) 0.0077 (5) N1 0.0278 (8) 0.0169 (7) 0.0367 (9) 0.0076 (6) 0.0168 (7) 0.0098 (6) N2 0.0173 (7) 0.0162 (7) 0.0190 (7) 0.0043 (6) 0.0067 (5) 0.0045 (5) N3 0.0170 (7) 0.0241 (7) 0.0194 (7) 0.0066 (6) 0.0041 (6) 0.0032 (6) N4 0.0181 (7) 0.0212 (7) 0.0163 (7) 0.0043 (6) 0.0068 (6) 0.0020 (6) N5 0.0179 (7) 0.0175 (7) 0.0151 (7) 0.0041 (6) 0.0052 (5) 0.0045 (5) N6 0.0226 (8) 0.0192 (7) 0.0204 (7) 0.0046 (6) 0.0052 (6) 0.0076 (6) C1 0.0298 (10) 0.0250 (9) 0.0294 (9) 0.0139 (8) 0.0182 (8) 0.0143 (8) C2 0.0448 (13) 0.0301 (10) 0.0611 (14) 0.0200 (10) 0.0348 (11) 0.0254 (10) C3 0.0586 (15) 0.0444 (13) 0.0558 (14) 0.0372 (12) 0.0393 (12) 0.0345 (11) C4 0.0404 (12) 0.0596 (14) 0.0274 (10) 0.0361 (11) 0.0160 (9) 0.0205 (10) C5 0.0271 (10) 0.0448 (12) 0.0214 (9) 0.0187 (9) 0.0047 (8) 0.0053 (8) C6 0.0249 (9) 0.0289 (9) 0.0161 (8) 0.0137 (8) 0.0079 (7) 0.0082 (7) C7 0.0148 (8) 0.0148 (7) 0.0169 (8) 0.0038 (6) 0.0029 (6) 0.0021 (6) C8 0.0162 (8) 0.0162 (8) 0.0123 (7) 0.0017 (6) 0.0019 (6) 0.0032 (6) C9 0.0125 (8) 0.0162 (8) 0.0143 (7) 0.0010 (6) 0.0017 (6) 0.0010 (6) C10 0.0146 (8) 0.0178 (8) 0.0165 (8) 0.0045 (6) 0.0030 (6) 0.0034 (6) C11 0.0156 (8) 0.0170 (8) 0.0144 (7) 0.0029 (6) 0.0027 (6) 0.0033 (6) C12 0.0167 (8) 0.0186 (8) 0.0159 (8) 0.0037 (7) 0.0060 (6) 0.0029 (6) C13 0.0230 (9) 0.0166 (8) 0.0213 (8) 0.0000 (7) 0.0069 (7) 0.0037 (7) C14 0.0218 (9) 0.0188 (8) 0.0277 (9) 0.0055 (7) 0.0079 (7) 0.0069 (7) C15 0.0341 (11) 0.0338 (11) 0.0361 (11) 0.0095 (9) 0.0170 (9) 0.0187 (9) C16 0.0185 (8) 0.0212 (8) 0.0185 (8) 0.0066 (7) 0.0062 (6) 0.0081 (7) C17 0.0230 (9) 0.0247 (9) 0.0211 (8) 0.0074 (7) 0.0043 (7) 0.0087 (7) C18 0.0275 (10) 0.0266 (9) 0.0222 (9) 0.0096 (8) 0.0119 (7) 0.0106 (7) C19 0.0201 (9) 0.0193 (8) 0.0217 (8) 0.0061 (7) 0.0082 (7) 0.0090 (7) C20 0.0196 (9) 0.0252 (9) 0.0216 (9) 0.0035 (7) 0.0076 (7) 0.0047 (7) C21 0.0439 (13) 0.0253 (10) 0.0276 (10) 0.0054 (9) −0.0077 (9) 0.0050 (8) C22 0.0342 (11) 0.0227 (9) 0.0264 (9) 0.0031 (8) 0.0053 (8) 0.0055 (8) C23 0.0221 (11) 0.0617 (15) 0.0357 (11) −0.0067 (10) 0.0102 (9) −0.0058 (11) C24 0.0142 (8) 0.0182 (8) 0.0183 (8) 0.0024 (6) 0.0051 (6) 0.0051 (6) C25 0.0139 (8) 0.0190 (8) 0.0173 (8) 0.0033 (6) 0.0077 (6) 0.0056 (6) C26 0.0167 (8) 0.0170 (8) 0.0193 (8) 0.0047 (7) 0.0079 (6) 0.0056 (6) C27 0.0156 (8) 0.0212 (8) 0.0173 (8) 0.0054 (7) 0.0078 (6) 0.0077 (7) C28 0.0158 (8) 0.0199 (8) 0.0153 (8) 0.0036 (7) 0.0062 (6) 0.0046 (6) C29 0.0152 (8) 0.0160 (8) 0.0188 (8) 0.0036 (6) 0.0073 (6) 0.0045 (6) C30 0.0136 (8) 0.0218 (8) 0.0158 (8) 0.0069 (7) 0.0065 (6) 0.0079 (6) C31 0.0177 (8) 0.0218 (8) 0.0197 (8) 0.0066 (7) 0.0068 (7) 0.0078 (7) C32 0.0269 (10) 0.0400 (11) 0.0321 (10) 0.0116 (9) 0.0109 (8) 0.0233 (9) C33 0.0268 (10) 0.0315 (10) 0.0213 (9) 0.0142 (8) 0.0040 (7) 0.0061 (8) C34 0.0238 (9) 0.0244 (9) 0.0207 (8) 0.0099 (7) 0.0044 (7) 0.0069 (7) C35 0.0212 (9) 0.0398 (11) 0.0226 (9) 0.0124 (8) 0.0077 (7) 0.0077 (8) C36 0.0260 (10) 0.0461 (12) 0.0358 (11) 0.0118 (9) 0.0164 (8) 0.0168 (9) C37 0.0559 (15) 0.0667 (16) 0.0456 (13) 0.0417 (13) 0.0297 (12) 0.0225 (12) C38 0.0215 (11) 0.0903 (19) 0.0316 (11) 0.0005 (12) 0.0081 (9) 0.0089 (12) C39 0.0173 (8) 0.0222 (8) 0.0218 (8) 0.0093 (7) 0.0073 (7) 0.0075 (7) C40 0.0214 (10) 0.0267 (9) 0.0279 (9) 0.0080 (8) 0.0074 (7) 0.0067 (8) C41 0.0235 (11) 0.0349 (11) 0.0492 (13) 0.0047 (9) 0.0092 (9) 0.0021 (10) C42 0.0139 (8) 0.0204 (8) 0.0214 (8) 0.0045 (7) 0.0055 (6) 0.0044 (7) C43 0.0209 (9) 0.0248 (9) 0.0265 (9) 0.0055 (7) 0.0093 (7) 0.0005 (7) C44 0.0264 (10) 0.0205 (9) 0.0355 (10) 0.0057 (8) 0.0079 (8) −0.0010 (8) C45 0.0337 (11) 0.0189 (9) 0.0400 (11) 0.0068 (8) 0.0069 (9) 0.0101 (8) C46 0.0335 (11) 0.0245 (9) 0.0286 (10) 0.0076 (8) 0.0057 (8) 0.0123 (8) C47 0.0174 (8) 0.0199 (8) 0.0232 (8) 0.0058 (7) 0.0036 (7) 0.0061 (7) ----- ------------- ------------- ------------- -------------- ------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2775 .table-wrap} ----------------------- -------------- ----------------------- -------------- O1---C8 1.3795 (19) C22---H22A 0.9800 O1---C13 1.4442 (19) C22---H22B 0.9800 O2---C30 1.3801 (19) C22---H22C 0.9800 O2---C39 1.4446 (19) C23---H23A 0.9800 N1---N2 1.3342 (19) C23---H23B 0.9800 N1---C1 1.355 (2) C23---H23C 0.9800 N2---N3 1.3343 (19) C24---C25 1.519 (2) N2---C7 1.429 (2) C24---H24A 0.9900 N3---C6 1.350 (2) C24---H24B 0.9900 N4---N5 1.3375 (18) C25---C26 1.385 (2) N4---C42 1.351 (2) C25---C30 1.395 (2) N5---N6 1.3350 (19) C26---C27 1.396 (2) N5---C29 1.434 (2) C26---H26 0.9500 N6---C47 1.353 (2) C27---C28 1.389 (2) C1---C6 1.406 (3) C27---C31 1.529 (2) C1---C2 1.413 (3) C28---C29 1.389 (2) C2---C3 1.361 (3) C28---H28 0.9500 C2---H2 0.9500 C29---C30 1.394 (2) C3---C4 1.420 (3) C31---C33 1.532 (2) C3---H3 0.9500 C31---C32 1.544 (2) C4---C5 1.367 (3) C31---C34 1.556 (2) C4---H4 0.9500 C32---H32A 0.9800 C5---C6 1.412 (2) C32---H32B 0.9800 C5---H5 0.9500 C32---H32C 0.9800 C7---C12 1.386 (2) C33---H33A 0.9800 C7---C8 1.390 (2) C33---H33B 0.9800 C8---C9 1.401 (2) C33---H33C 0.9800 C9---C10 1.384 (2) C34---C35 1.547 (3) C9---C24 1.521 (2) C34---H34A 0.9900 C10---C11 1.401 (2) C34---H34B 0.9900 C10---H10 0.9500 C35---C36 1.521 (3) C11---C12 1.394 (2) C35---C38 1.530 (3) C11---C16 1.528 (2) C35---C37 1.537 (3) C12---H12 0.9500 C36---H36A 0.9800 C13---C14 1.462 (2) C36---H36B 0.9800 C13---H13A 0.9900 C36---H36C 0.9800 C13---H13B 0.9900 C37---H37A 0.9800 C14---C15 1.175 (3) C37---H37B 0.9800 C15---H15 0.951 (19) C37---H37C 0.9800 C16---C18 1.538 (2) C38---H38A 0.9800 C16---C17 1.540 (2) C38---H38B 0.9800 C16---C19 1.558 (2) C38---H38C 0.9800 C17---H17A 0.9800 C39---C40 1.460 (2) C17---H17B 0.9800 C39---H39A 0.9900 C17---H17C 0.9800 C39---H39B 0.9900 C18---H18A 0.9800 C40---C41 1.183 (3) C18---H18B 0.9800 C41---H41 0.956 (10) C18---H18C 0.9800 C42---C47 1.410 (2) C19---C20 1.551 (2) C42---C43 1.414 (2) C19---H19A 0.9900 C43---C44 1.362 (3) C19---H19B 0.9900 C43---H43 0.9500 C20---C21 1.521 (3) C44---C45 1.422 (3) C20---C23 1.530 (3) C44---H44 0.9500 C20---C22 1.536 (2) C45---C46 1.364 (3) C21---H21A 0.9800 C45---H45 0.9500 C21---H21B 0.9800 C46---C47 1.411 (2) C21---H21C 0.9800 C46---H46 0.9500 C8---O1---C13 113.93 (12) C20---C23---H23C 109.5 C30---O2---C39 114.29 (12) H23A---C23---H23C 109.5 N2---N1---C1 102.29 (14) H23B---C23---H23C 109.5 N3---N2---N1 117.53 (14) C25---C24---C9 108.40 (13) N3---N2---C7 120.33 (13) C25---C24---H24A 110.0 N1---N2---C7 122.11 (13) C9---C24---H24A 110.0 N2---N3---C6 102.41 (13) C25---C24---H24B 110.0 N5---N4---C42 102.34 (13) C9---C24---H24B 110.0 N6---N5---N4 117.52 (13) H24A---C24---H24B 108.4 N6---N5---C29 122.02 (12) C26---C25---C30 119.10 (14) N4---N5---C29 120.13 (13) C26---C25---C24 120.18 (14) N5---N6---C47 102.38 (13) C30---C25---C24 120.62 (15) N1---C1---C6 108.80 (15) C25---C26---C27 122.80 (15) N1---C1---C2 130.06 (18) C25---C26---H26 118.6 C6---C1---C2 121.14 (18) C27---C26---H26 118.6 C3---C2---C1 116.6 (2) C28---C27---C26 117.44 (15) C3---C2---H2 121.7 C28---C27---C31 122.76 (14) C1---C2---H2 121.7 C26---C27---C31 119.78 (14) C2---C3---C4 122.51 (19) C29---C28---C27 120.53 (15) C2---C3---H3 118.7 C29---C28---H28 119.7 C4---C3---H3 118.7 C27---C28---H28 119.7 C5---C4---C3 121.61 (19) C28---C29---C30 121.39 (15) C5---C4---H4 119.2 C28---C29---N5 117.37 (14) C3---C4---H4 119.2 C30---C29---N5 121.24 (15) C4---C5---C6 116.91 (19) O2---C30---C29 122.25 (14) C4---C5---H5 121.5 O2---C30---C25 119.07 (14) C6---C5---H5 121.5 C29---C30---C25 118.66 (15) N3---C6---C1 108.96 (15) C27---C31---C33 112.41 (14) N3---C6---C5 129.86 (17) C27---C31---C32 107.48 (14) C1---C6---C5 121.17 (17) C33---C31---C32 107.02 (14) C12---C7---C8 121.83 (15) C27---C31---C34 111.73 (13) C12---C7---N2 118.48 (14) C33---C31---C34 111.62 (14) C8---C7---N2 119.63 (14) C32---C31---C34 106.16 (14) O1---C8---C7 119.86 (14) C31---C32---H32A 109.5 O1---C8---C9 120.97 (14) C31---C32---H32B 109.5 C7---C8---C9 118.90 (15) H32A---C32---H32B 109.5 C10---C9---C8 118.53 (14) C31---C32---H32C 109.5 C10---C9---C24 120.36 (14) H32A---C32---H32C 109.5 C8---C9---C24 120.71 (14) H32B---C32---H32C 109.5 C9---C10---C11 123.25 (15) C31---C33---H33A 109.5 C9---C10---H10 118.4 C31---C33---H33B 109.5 C11---C10---H10 118.4 H33A---C33---H33B 109.5 C12---C11---C10 117.22 (15) C31---C33---H33C 109.5 C12---C11---C16 122.74 (14) H33A---C33---H33C 109.5 C10---C11---C16 120.02 (14) H33B---C33---H33C 109.5 C7---C12---C11 120.26 (15) C35---C34---C31 123.94 (15) C7---C12---H12 119.9 C35---C34---H34A 106.3 C11---C12---H12 119.9 C31---C34---H34A 106.3 O1---C13---C14 107.94 (13) C35---C34---H34B 106.3 O1---C13---H13A 110.1 C31---C34---H34B 106.3 C14---C13---H13A 110.1 H34A---C34---H34B 106.4 O1---C13---H13B 110.1 C36---C35---C38 108.52 (18) C14---C13---H13B 110.1 C36---C35---C37 107.67 (16) H13A---C13---H13B 108.4 C38---C35---C37 107.99 (18) C15---C14---C13 178.8 (2) C36---C35---C34 113.78 (15) C14---C15---H15 177.3 (14) C38---C35---C34 113.00 (15) C11---C16---C18 112.27 (14) C37---C35---C34 105.57 (17) C11---C16---C17 107.74 (13) C35---C36---H36A 109.5 C18---C16---C17 107.06 (14) C35---C36---H36B 109.5 C11---C16---C19 111.17 (13) H36A---C36---H36B 109.5 C18---C16---C19 111.89 (13) C35---C36---H36C 109.5 C17---C16---C19 106.36 (13) H36A---C36---H36C 109.5 C16---C17---H17A 109.5 H36B---C36---H36C 109.5 C16---C17---H17B 109.5 C35---C37---H37A 109.5 H17A---C17---H17B 109.5 C35---C37---H37B 109.5 C16---C17---H17C 109.5 H37A---C37---H37B 109.5 H17A---C17---H17C 109.5 C35---C37---H37C 109.5 H17B---C17---H17C 109.5 H37A---C37---H37C 109.5 C16---C18---H18A 109.5 H37B---C37---H37C 109.5 C16---C18---H18B 109.5 C35---C38---H38A 109.5 H18A---C18---H18B 109.5 C35---C38---H38B 109.5 C16---C18---H18C 109.5 H38A---C38---H38B 109.5 H18A---C18---H18C 109.5 C35---C38---H38C 109.5 H18B---C18---H18C 109.5 H38A---C38---H38C 109.5 C20---C19---C16 123.93 (14) H38B---C38---H38C 109.5 C20---C19---H19A 106.3 O2---C39---C40 110.99 (13) C16---C19---H19A 106.3 O2---C39---H39A 109.4 C20---C19---H19B 106.3 C40---C39---H39A 109.4 C16---C19---H19B 106.3 O2---C39---H39B 109.4 H19A---C19---H19B 106.4 C40---C39---H39B 109.4 C21---C20---C23 110.31 (18) H39A---C39---H39B 108.0 C21---C20---C22 107.26 (15) C41---C40---C39 178.5 (2) C23---C20---C22 107.14 (16) C40---C41---H41 178.0 (16) C21---C20---C19 113.27 (15) N4---C42---C47 108.93 (14) C23---C20---C19 112.49 (15) N4---C42---C43 130.09 (16) C22---C20---C19 105.95 (15) C47---C42---C43 120.94 (16) C20---C21---H21A 109.5 C44---C43---C42 116.72 (17) C20---C21---H21B 109.5 C44---C43---H43 121.6 H21A---C21---H21B 109.5 C42---C43---H43 121.6 C20---C21---H21C 109.5 C43---C44---C45 122.34 (16) H21A---C21---H21C 109.5 C43---C44---H44 118.8 H21B---C21---H21C 109.5 C45---C44---H44 118.8 C20---C22---H22A 109.5 C46---C45---C44 121.85 (18) C20---C22---H22B 109.5 C46---C45---H45 119.1 H22A---C22---H22B 109.5 C44---C45---H45 119.1 C20---C22---H22C 109.5 C45---C46---C47 116.80 (18) H22A---C22---H22C 109.5 C45---C46---H46 121.6 H22B---C22---H22C 109.5 C47---C46---H46 121.6 C20---C23---H23A 109.5 N6---C47---C42 108.82 (15) C20---C23---H23B 109.5 N6---C47---C46 129.79 (16) H23A---C23---H23B 109.5 C42---C47---C46 121.34 (15) C1---N1---N2---N3 0.61 (18) C16---C19---C20---C23 67.1 (2) C1---N1---N2---C7 −177.38 (14) C16---C19---C20---C22 −176.18 (15) N1---N2---N3---C6 −0.50 (18) C10---C9---C24---C25 −88.59 (17) C7---N2---N3---C6 177.52 (14) C8---C9---C24---C25 84.04 (17) C42---N4---N5---N6 0.14 (18) C9---C24---C25---C26 −85.49 (18) C42---N4---N5---C29 173.68 (14) C9---C24---C25---C30 90.85 (17) N4---N5---N6---C47 −0.13 (18) C30---C25---C26---C27 −3.1 (2) C29---N5---N6---C47 −173.53 (14) C24---C25---C26---C27 173.28 (14) N2---N1---C1---C6 −0.44 (18) C25---C26---C27---C28 1.7 (2) N2---N1---C1---C2 179.75 (19) C25---C26---C27---C31 −176.83 (14) N1---C1---C2---C3 −178.54 (19) C26---C27---C28---C29 0.0 (2) C6---C1---C2---C3 1.7 (3) C31---C27---C28---C29 178.46 (14) C1---C2---C3---C4 −1.1 (3) C27---C28---C29---C30 −0.2 (2) C2---C3---C4---C5 −0.4 (3) C27---C28---C29---N5 −179.48 (14) C3---C4---C5---C6 1.2 (3) N6---N5---C29---C28 138.04 (15) N2---N3---C6---C1 0.17 (17) N4---N5---C29---C28 −35.2 (2) N2---N3---C6---C5 −178.86 (17) N6---N5---C29---C30 −41.3 (2) N1---C1---C6---N3 0.2 (2) N4---N5---C29---C30 145.51 (15) C2---C1---C6---N3 −179.99 (16) C39---O2---C30---C29 −65.62 (19) N1---C1---C6---C5 179.31 (15) C39---O2---C30---C25 116.27 (15) C2---C1---C6---C5 −0.9 (3) C28---C29---C30---O2 −179.32 (14) C4---C5---C6---N3 178.34 (17) N5---C29---C30---O2 0.0 (2) C4---C5---C6---C1 −0.6 (3) C28---C29---C30---C25 −1.2 (2) N3---N2---C7---C12 55.3 (2) N5---C29---C30---C25 178.07 (14) N1---N2---C7---C12 −126.81 (16) C26---C25---C30---O2 −179.05 (13) N3---N2---C7---C8 −122.00 (16) C24---C25---C30---O2 4.6 (2) N1---N2---C7---C8 55.9 (2) C26---C25---C30---C29 2.8 (2) C13---O1---C8---C7 −104.28 (16) C24---C25---C30---C29 −173.61 (14) C13---O1---C8---C9 81.71 (17) C28---C27---C31---C33 0.1 (2) C12---C7---C8---O1 −174.05 (13) C26---C27---C31---C33 178.55 (15) N2---C7---C8---O1 3.1 (2) C28---C27---C31---C32 117.60 (17) C12---C7---C8---C9 0.1 (2) C26---C27---C31---C32 −63.94 (19) N2---C7---C8---C9 177.24 (13) C28---C27---C31---C34 −126.31 (16) O1---C8---C9---C10 174.77 (13) C26---C27---C31---C34 52.1 (2) C7---C8---C9---C10 0.7 (2) C27---C31---C34---C35 63.8 (2) O1---C8---C9---C24 2.0 (2) C33---C31---C34---C35 −63.1 (2) C7---C8---C9---C24 −172.06 (14) C32---C31---C34---C35 −179.34 (16) C8---C9---C10---C11 −1.3 (2) C31---C34---C35---C36 −56.0 (2) C24---C9---C10---C11 171.51 (14) C31---C34---C35---C38 68.3 (2) C9---C10---C11---C12 1.0 (2) C31---C34---C35---C37 −173.84 (17) C9---C10---C11---C16 −177.59 (14) C30---O2---C39---C40 −102.14 (16) C8---C7---C12---C11 −0.4 (2) N5---N4---C42---C47 −0.09 (17) N2---C7---C12---C11 −177.54 (14) N5---N4---C42---C43 −177.86 (17) C10---C11---C12---C7 −0.2 (2) N4---C42---C43---C44 176.48 (17) C16---C11---C12---C7 178.39 (14) C47---C42---C43---C44 −1.1 (2) C8---O1---C13---C14 −149.87 (14) C42---C43---C44---C45 0.9 (3) C12---C11---C16---C18 6.2 (2) C43---C44---C45---C46 0.0 (3) C10---C11---C16---C18 −175.24 (14) C44---C45---C46---C47 −0.8 (3) C12---C11---C16---C17 123.87 (16) N5---N6---C47---C42 0.06 (17) C10---C11---C16---C17 −57.60 (18) N5---N6---C47---C46 177.52 (18) C12---C11---C16---C19 −119.96 (16) N4---C42---C47---N6 0.02 (19) C10---C11---C16---C19 58.56 (19) C43---C42---C47---N6 178.03 (15) C11---C16---C19---C20 62.8 (2) N4---C42---C47---C46 −177.70 (16) C18---C16---C19---C20 −63.7 (2) C43---C42---C47---C46 0.3 (3) C17---C16---C19---C20 179.77 (15) C45---C46---C47---N6 −176.57 (18) C16---C19---C20---C21 −58.9 (2) C45---C46---C47---C42 0.6 (3) ----------------------- -------------- ----------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e4857 .table-wrap} ------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C41---H41···N3^i^ 0.96 (1) 2.38 (1) 3.283 (3) 158 (2) ------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) *x*−1, *y*, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ----------------- ---------- ---------- ----------- ------------- C41---H41⋯N3^i^ 0.96 (1) 2.38 (1) 3.283 (3) 158 (2) Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.358760

2011-2-26

PMC3051934

Related literature {#sec1} ================== For hydrogen-bonding inter­actions in proton-transfer compounds, see: Aghabozorg *et al.* (2008[@bb2], 2010*a* [@bb1],*b* [@bb3]); Sheshmani *et al.* (2005[@bb7]); Soleimannejad *et al.* (2007[@bb8]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} (C~10~H~10~N~2~)\[Ce~2~(C~7~H~3~NO~4~)~4~(H~2~O)~4~\]·5H~2~O*M* *~r~* = 1261Triclinic,*a* = 13.010 (3) Å*b* = 13.453 (3) Å*c* = 13.586 (3) Åα = 99.95 (3)°β = 99.87 (3)°γ = 104.58 (3)°*V* = 2208.3 (10) Å^3^*Z* = 2Mo *K*α radiationμ = 2.14 mm^−1^*T* = 150 K0.40 × 0.40 × 0.10 mm ### Data collection {#sec2.1.2} Stoe IPDS II diffractometerAbsorption correction: numerical (*X-SHAPE* and *X-RED32*; Stoe & Cie, 2005[@bb9]) *T* ~min~ = 0.440, *T* ~max~ = 0.80525469 measured reflections11857 independent reflections10379 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.078 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.045*wR*(*F* ^2^) = 0.120*S* = 1.0511857 reflections716 parameters12 restraintsH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 1.96 e Å^−3^Δρ~min~ = −2.01 e Å^−3^ {#d5e1037} Data collection: *X-AREA* (Stoe & Cie, 2005[@bb9]); cell refinement: *X-AREA*; data reduction: *X-AREA*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb6]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb6]); molecular graphics: *ORTEP-3* (Farrugia, 1997[@bb4]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb5]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004995/hy2405sup1.cif](http://dx.doi.org/10.1107/S1600536811004995/hy2405sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004995/hy2405Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004995/hy2405Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?hy2405&file=hy2405sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?hy2405sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?hy2405&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [HY2405](http://scripts.iucr.org/cgi-bin/sendsup?hy2405)). We are grateful to the Islamic Azad University, North Tehran Branch, for financial support. Comment ======= Through crystal engineering of some classes of crystalline compounds, one can conclude that inter- and/or intramolecular interctions such as hydrogen bonding, π--π stacking, ion pairing, and donor-acceptor interactions are famous for making aggregates of molecules. One or more of these interactions may result in the formation of specific and spontaneous self-associated compounds. Previous researches have shown that hydrogen bonding plays a key role in the preparation of self-assembled compounds. There is a very close relationship between hydrogen bonding and the formation of proton transfer compounds (Aghabozorg *et al.*, 2008, 2010*a*,b; Sheshmani *et al.*, 2005; Soleimannejad *et al.*, 2007). Herein, we report the synthesis and crystal structure of the title compound. The compound is composed of a one-dimensional anionic complex, \[Ce~2~(pydc)~4~(H~2~O)~4~\]^2-^ (pydc = pyridine-2,6-dicarboxylate), a protonated 4,4\'-bipyridine, (bipyH~2~)^2+^, as a counterion, and five uncoordinated water molecules (Fig. 1). The Ce1 atom is nine-coordinated by three pydc ligands, which act as tridentate ligands through two O atoms and one N atom. The Ce2 atom is nine-coordinated by one tridentate pydc ligand, four O atoms of coordinated water molecules and two O atoms from the carboxylate groups of the Ce1 coordination environment. By considering the angles between the atoms of coordination environment, the geometry around Ce atoms can be described as highly distorted tricapped trigonal-prismatic. The title compound shows a one-dimensional polymeric structure (Fig. 2). An important feature of the compound is the presence of extensive intermolecular O---H···O, N---H···O and C---H···O hydrogen bonds (Table 1, Fig. 2), which seem to be effective in the stabilization of the crystal structure. There is also π--π interaction, with centroid--centroid distance of 3.514 (3) Å between the pyridine ring of pydc and bipyridine (Fig. 3). This non-covalent interaction results in the formation of an interesting supramolecular structure. Experimental {#experimental} ============ A solution of Ce(NO~3~)~3~ (109 mg, 0.25 mmol) in water (10 ml) was added to an aqueous solution of pyridine-2,6-dicarboxylic acid (85 mg, 0.50 mmol) and 4,4\'-bipyridine (78 mg, 0.50 mmol) in water (35 ml) in a 1:2:2 molar ratio and refluxed for an hour. Plate yellow crystals of the title compound were obtained by allowing the mixture to stand at room temperature (yield: 40.5%; m. p.: 270°C). Refinement {#refinement} ========== H atoms of the protonated nitrogen of bipyridine and water molecules were found in a diference Fourier map and refined isotropically, except H24A, H24B, H25A and H25B which were refined with *U*~iso~(H) = 1.5*U*~eq~(O). The H atoms of the protonated nitrogen and water molecules, H5A, H6A, H18A, H18B, H19A, H21A, H22B, H23B, H25A and H25B were refined with distance restraints of N---H/O---H = 0.82 (3), 0.88 (4), 0.88 (4), 0.90 (4), 0.82 (4), 0.89 (4), 0.84 (4), 0.71 (9), 0.92 (11), 0.91 (10) Å, respectively. Also H···H distance restraints of 1.3 (4) and 1.6 (4) Å for H23A···H23B and H25A···H25B, respectively, were used. H atoms on C atoms were positioned geometrically and refined as riding atoms, with C---H = 0.93 Å and *U*~iso~(H) = 1.2*U*~eq~(C). The highest residual electron density was found at 1.24 Å from Ce2 atom and the deepest hole at 0.55 Å from Ce2 atom. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of the title compound, with displacement ellipsoids drawn at the 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The packing diagram of the title compound, showing polymeric structure. The intermolecular C---H···O, N---H···O and O---H···O hydrogen bonds are shown as dashed lines. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### The packing diagram of the title compound, showing intermolecular π--π interactions (dashed lines) between pyridine rings of pydc ligands and bipy groups. Uncoordinated water molecules have been omitted for clarity. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e184 .table-wrap} -------------------------------------------------------------- ---------------------------------------- (C~10~H~10~N~2~)\[Ce~2~(C~7~H~3~NO~4~)~4~(H~2~O)~4~\]·5H~2~O *Z* = 2 *M~r~* = 1261 *F*(000) = 1252 Triclinic, *P*1 *D*~x~ = 1.896 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 13.010 (3) Å Cell parameters from 11857 reflections *b* = 13.453 (3) Å θ = 2.5--29.1° *c* = 13.586 (3) Å µ = 2.14 mm^−1^ α = 99.95 (3)° *T* = 150 K β = 99.87 (3)° Plate, yellow γ = 104.58 (3)° 0.40 × 0.40 × 0.10 mm *V* = 2208.3 (10) Å^3^ -------------------------------------------------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e343 .table-wrap} ------------------------------------------------------------------------------ --------------------------------------- Stoe IPDS II diffractometer 11857 independent reflections Radiation source: fine-focus sealed tube 10379 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.078 ω scans θ~max~ = 29.1°, θ~min~ = 2.5° Absorption correction: numerical (*X-SHAPE* and *X-RED32*; Stoe & Cie, 2005) *h* = −15→17 *T*~min~ = 0.440, *T*~max~ = 0.805 *k* = −18→18 25469 measured reflections *l* = −18→18 ------------------------------------------------------------------------------ --------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e460 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.045 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.120 H atoms treated by a mixture of independent and constrained refinement *S* = 1.05 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.064*P*)^2^ + 5.1288*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 11857 reflections (Δ/σ)~max~ = 0.001 716 parameters Δρ~max~ = 1.96 e Å^−3^ 12 restraints Δρ~min~ = −2.01 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e619 .table-wrap} ------ --------------- --------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O23 0.6037 (3) 0.5090 (3) 0.9068 (4) 0.0387 (9) Ce1 0.003047 (16) 0.783224 (16) 0.218322 (15) 0.01548 (7) Ce2 0.503761 (15) 0.888641 (16) 0.188431 (15) 0.01464 (7) O1 0.2143 (3) 1.0504 (3) 0.1004 (3) 0.0322 (8) O2 0.1494 (2) 0.9110 (2) 0.1619 (2) 0.0218 (6) O3 −0.3036 (2) 0.8972 (3) 0.2097 (2) 0.0224 (6) O4 −0.1754 (2) 0.8143 (2) 0.2351 (2) 0.0209 (6) O5 −0.1869 (3) 0.5884 (3) −0.1116 (2) 0.0318 (7) O6 −0.1349 (2) 0.6945 (3) 0.0453 (2) 0.0231 (6) O7 0.3383 (2) 0.7579 (2) 0.2004 (2) 0.0219 (6) O8 0.1860 (2) 0.7463 (2) 0.2582 (2) 0.0206 (6) O9 −0.1245 (4) 0.4852 (3) 0.3346 (3) 0.0468 (11) O10 −0.0903 (3) 0.6100 (2) 0.2430 (2) 0.0258 (6) O11 0.1350 (3) 1.0213 (2) 0.5401 (2) 0.0252 (6) O12 0.0911 (2) 0.9458 (2) 0.3715 (2) 0.0220 (6) O13 0.6021 (3) 0.9301 (3) 0.5394 (2) 0.0246 (6) O14 0.5409 (2) 0.8720 (2) 0.3707 (2) 0.0214 (6) O15 0.6315 (3) 1.2353 (2) 0.1697 (2) 0.0267 (7) O16 0.5796 (2) 1.0588 (2) 0.1370 (2) 0.0188 (5) O17 0.3761 (3) 0.9864 (3) 0.2614 (2) 0.0236 (6) O18 0.3581 (2) 0.9170 (3) 0.0496 (2) 0.0231 (6) O19 0.5152 (3) 0.8104 (3) 0.0138 (2) 0.0307 (8) O20 0.5305 (3) 0.7001 (3) 0.1861 (3) 0.0252 (6) O21 0.6923 (3) 0.7702 (3) 0.9590 (3) 0.0336 (8) O22 0.6705 (3) 0.5749 (3) 0.1273 (4) 0.0424 (9) O24 0.5617 (4) 0.4218 (3) 0.2152 (3) 0.0414 (9) O25 0.4130 (5) 0.2170 (5) 0.2555 (4) 0.0704 (15) N1 −0.0380 (3) 0.9504 (3) 0.1641 (2) 0.0166 (6) N2 0.0640 (3) 0.6775 (3) 0.0686 (3) 0.0176 (6) N3 0.0062 (3) 0.7581 (3) 0.4076 (3) 0.0168 (6) N4 0.6135 (3) 1.0587 (3) 0.3339 (2) 0.0175 (6) N5 0.4495 (3) 0.6883 (3) 0.4101 (3) 0.0284 (8) N6 0.2235 (3) 0.1985 (3) 0.5090 (3) 0.0248 (7) C1 0.1421 (3) 0.9929 (3) 0.1318 (3) 0.0187 (7) C2 0.0364 (3) 1.0209 (3) 0.1351 (3) 0.0175 (7) C3 0.0183 (3) 1.1118 (4) 0.1106 (3) 0.0241 (8) H3 0.0721 1.1607 0.0926 0.029\* C4 −0.0831 (4) 1.1277 (4) 0.1137 (4) 0.0257 (9) H4 −0.0986 1.1868 0.0957 0.031\* C5 −0.1604 (3) 1.0556 (3) 0.1437 (3) 0.0224 (8) H5 −0.2280 1.0655 0.1471 0.027\* C6 −0.1341 (3) 0.9675 (3) 0.1689 (3) 0.0159 (7) C7 −0.2116 (3) 0.8863 (3) 0.2073 (3) 0.0171 (7) C8 −0.1185 (3) 0.6374 (3) −0.0315 (3) 0.0202 (8) C9 −0.0023 (3) 0.6335 (3) −0.0242 (3) 0.0183 (7) C10 0.0355 (3) 0.5935 (4) −0.1072 (3) 0.0232 (8) H10 −0.0128 0.5599 −0.1698 0.028\* C11 0.1463 (4) 0.6042 (4) −0.0960 (4) 0.0258 (9) H11 0.1739 0.5810 −0.1517 0.031\* C12 0.2147 (3) 0.6503 (3) 0.0002 (3) 0.0222 (8) H12 0.2892 0.6583 0.0105 0.027\* C13 0.1700 (3) 0.6841 (3) 0.0808 (3) 0.0184 (7) C14 0.2363 (3) 0.7337 (3) 0.1887 (3) 0.0186 (7) C15 −0.0873 (4) 0.5764 (3) 0.3261 (3) 0.0269 (9) C16 −0.0324 (3) 0.6614 (3) 0.4231 (3) 0.0201 (8) C17 −0.0270 (4) 0.6413 (3) 0.5207 (3) 0.0235 (8) H17 −0.0523 0.5730 0.5293 0.028\* C18 0.0169 (4) 0.7257 (4) 0.6047 (3) 0.0265 (9) H18 0.0215 0.7147 0.6709 0.032\* C19 0.0540 (4) 0.8269 (4) 0.5891 (3) 0.0239 (8) H19 0.0817 0.8850 0.6442 0.029\* C20 0.0486 (3) 0.8388 (3) 0.4890 (3) 0.0187 (7) C21 0.0944 (3) 0.9433 (3) 0.4635 (3) 0.0182 (7) C22 0.5907 (3) 0.9444 (3) 0.4513 (3) 0.0170 (7) C23 0.6353 (3) 1.0531 (3) 0.4325 (3) 0.0167 (7) C24 0.6926 (3) 1.1406 (3) 0.5114 (3) 0.0210 (8) H24 0.7049 1.1351 0.5795 0.025\* C25 0.7310 (3) 1.2366 (4) 0.4853 (3) 0.0231 (8) H25 0.7712 1.2961 0.5360 0.028\* C26 0.7091 (3) 1.2435 (3) 0.3829 (3) 0.0218 (8) H26 0.7342 1.3069 0.3641 0.026\* C27 0.6485 (3) 1.1525 (3) 0.3101 (3) 0.0178 (7) C28 0.6175 (3) 1.1501 (3) 0.1968 (3) 0.0193 (7) C29 0.3327 (4) 0.5148 (4) 0.3526 (4) 0.0292 (9) H29 0.2852 0.4613 0.2995 0.035\* C30 0.3824 (4) 0.6105 (4) 0.3339 (4) 0.0301 (10) H30 0.3691 0.6211 0.2676 0.036\* C31 0.4700 (3) 0.6775 (4) 0.5069 (4) 0.0251 (9) H31 0.5158 0.7336 0.5586 0.030\* C32 0.4232 (4) 0.5828 (3) 0.5297 (3) 0.0245 (8) H32 0.4375 0.5750 0.5969 0.029\* C33 0.3541 (3) 0.4985 (3) 0.4518 (3) 0.0214 (8) C34 0.3074 (3) 0.3929 (3) 0.4717 (3) 0.0223 (8) C35 0.3043 (3) 0.3822 (3) 0.5715 (3) 0.0237 (8) H35 0.3303 0.4405 0.6264 0.028\* C36 0.2614 (3) 0.2823 (4) 0.5865 (4) 0.0254 (9) H36 0.2592 0.2738 0.6527 0.030\* C37 0.2270 (4) 0.2074 (4) 0.4136 (4) 0.0285 (9) H37 0.2010 0.1472 0.3606 0.034\* C38 0.2682 (4) 0.3035 (4) 0.3914 (3) 0.0272 (9) H38 0.2699 0.3087 0.3243 0.033\* H5A 0.476 (4) 0.743 (3) 0.394 (4) 0.031 (15)\* H6A 0.193 (6) 0.137 (4) 0.522 (6) 0.07 (3)\* H17A 0.311 (6) 0.965 (5) 0.236 (5) 0.040 (17)\* H18A 0.333 (6) 0.971 (4) 0.070 (5) 0.06 (2)\* H19A 0.468 (6) 0.804 (8) −0.037 (5) 0.10 (3)\* H20A 0.592 (6) 0.694 (6) 0.176 (5) 0.05 (2)\* H21A 0.731 (5) 0.826 (4) 0.941 (5) 0.039 (17)\* H22A 0.741 (7) 0.583 (6) 0.130 (6) 0.07 (2)\* H23A 0.660 (8) 0.526 (9) 0.895 (9) 0.11 (4)\* H24A 0.577 (12) 0.362 (12) 0.206 (11) 0.167\* H25A 0.414 (11) 0.255 (9) 0.205 (8) 0.167\* H17B 0.378 (6) 0.998 (6) 0.324 (6) 0.06 (2)\* H18B 0.385 (5) 0.928 (5) −0.005 (4) 0.048 (19)\* H19B 0.575 (7) 0.795 (7) 0.002 (6) 0.08 (3)\* H20B 0.483 (8) 0.654 (8) 0.163 (7) 0.09 (3)\* H21B 0.743 (8) 0.739 (7) 0.985 (7) 0.08 (3)\* H22B 0.633 (9) 0.566 (10) 0.068 (5) 0.14 (5)\* H23B 0.560 (9) 0.532 (11) 0.898 (12) 0.17 (7)\* H24B 0.609 (17) 0.464 (17) 0.184 (16) 0.260\* H25B 0.365 (13) 0.152 (7) 0.243 (12) 0.260\* ------ --------------- --------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e2055 .table-wrap} ----- -------------- -------------- -------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O23 0.0246 (18) 0.034 (2) 0.052 (2) 0.0025 (15) 0.0044 (17) 0.0073 (17) Ce1 0.01187 (10) 0.01963 (12) 0.01492 (11) 0.00337 (8) 0.00220 (8) 0.00646 (8) Ce2 0.01032 (10) 0.02055 (12) 0.01249 (11) 0.00290 (8) 0.00114 (7) 0.00601 (8) O1 0.0192 (14) 0.0407 (19) 0.047 (2) 0.0100 (13) 0.0144 (14) 0.0297 (17) O2 0.0170 (13) 0.0260 (15) 0.0261 (15) 0.0073 (11) 0.0058 (11) 0.0130 (12) O3 0.0129 (12) 0.0311 (16) 0.0252 (15) 0.0066 (11) 0.0073 (11) 0.0083 (12) O4 0.0181 (13) 0.0255 (15) 0.0209 (14) 0.0047 (11) 0.0049 (11) 0.0119 (12) O5 0.0185 (14) 0.046 (2) 0.0232 (16) 0.0043 (14) −0.0029 (12) 0.0013 (14) O6 0.0156 (13) 0.0306 (16) 0.0209 (14) 0.0061 (12) −0.0002 (11) 0.0049 (12) O7 0.0120 (12) 0.0260 (15) 0.0249 (15) 0.0030 (11) −0.0011 (11) 0.0073 (12) O8 0.0163 (13) 0.0297 (15) 0.0173 (13) 0.0083 (11) 0.0021 (10) 0.0084 (12) O9 0.084 (3) 0.0209 (17) 0.0240 (17) −0.0050 (18) 0.0098 (19) 0.0058 (14) O10 0.0345 (17) 0.0192 (14) 0.0189 (14) −0.0006 (12) 0.0046 (12) 0.0062 (11) O11 0.0270 (15) 0.0212 (15) 0.0214 (14) −0.0003 (12) 0.0004 (12) 0.0047 (12) O12 0.0200 (14) 0.0241 (15) 0.0207 (14) 0.0036 (11) 0.0037 (11) 0.0066 (12) O13 0.0293 (16) 0.0316 (16) 0.0143 (13) 0.0089 (13) 0.0050 (12) 0.0086 (12) O14 0.0200 (13) 0.0250 (15) 0.0157 (13) 0.0000 (11) 0.0014 (11) 0.0075 (11) O15 0.0314 (16) 0.0233 (15) 0.0231 (15) 0.0064 (13) −0.0011 (13) 0.0088 (12) O16 0.0183 (13) 0.0191 (13) 0.0159 (13) 0.0022 (11) 0.0007 (10) 0.0039 (11) O17 0.0168 (14) 0.0355 (17) 0.0163 (14) 0.0072 (12) 0.0016 (11) 0.0025 (13) O18 0.0190 (13) 0.0343 (17) 0.0188 (14) 0.0093 (12) 0.0038 (11) 0.0112 (13) O19 0.0286 (17) 0.055 (2) 0.0164 (14) 0.0262 (16) 0.0035 (13) 0.0091 (14) O20 0.0196 (15) 0.0231 (16) 0.0325 (17) 0.0052 (13) 0.0051 (13) 0.0078 (13) O21 0.0273 (17) 0.0367 (19) 0.046 (2) 0.0141 (15) 0.0141 (15) 0.0209 (17) O22 0.0213 (17) 0.044 (2) 0.054 (3) 0.0012 (16) 0.0097 (17) 0.0030 (19) O24 0.047 (2) 0.038 (2) 0.038 (2) 0.0150 (18) 0.0022 (17) 0.0082 (17) O25 0.068 (4) 0.074 (4) 0.064 (3) 0.008 (3) 0.015 (3) 0.021 (3) N1 0.0115 (14) 0.0223 (16) 0.0149 (14) 0.0036 (12) 0.0017 (11) 0.0048 (12) N2 0.0146 (14) 0.0213 (16) 0.0161 (15) 0.0028 (12) 0.0020 (12) 0.0073 (13) N3 0.0135 (14) 0.0186 (15) 0.0182 (15) 0.0038 (12) 0.0030 (12) 0.0059 (12) N4 0.0130 (14) 0.0234 (17) 0.0157 (15) 0.0057 (12) 0.0015 (12) 0.0044 (13) N5 0.0245 (18) 0.028 (2) 0.040 (2) 0.0082 (15) 0.0157 (16) 0.0189 (18) N6 0.0173 (16) 0.0251 (18) 0.031 (2) 0.0022 (14) 0.0051 (14) 0.0114 (16) C1 0.0146 (16) 0.0237 (19) 0.0186 (18) 0.0049 (14) 0.0038 (14) 0.0075 (15) C2 0.0130 (16) 0.0236 (19) 0.0162 (17) 0.0011 (14) 0.0038 (13) 0.0107 (15) C3 0.0203 (19) 0.028 (2) 0.030 (2) 0.0085 (16) 0.0095 (16) 0.0165 (18) C4 0.025 (2) 0.027 (2) 0.030 (2) 0.0119 (17) 0.0060 (17) 0.0139 (18) C5 0.0176 (18) 0.026 (2) 0.026 (2) 0.0073 (16) 0.0050 (15) 0.0108 (17) C6 0.0136 (16) 0.0203 (18) 0.0143 (16) 0.0051 (13) 0.0017 (13) 0.0065 (14) C7 0.0126 (16) 0.0205 (18) 0.0138 (16) 0.0013 (13) −0.0017 (13) 0.0018 (14) C8 0.0182 (18) 0.026 (2) 0.0151 (17) 0.0044 (15) 0.0018 (14) 0.0047 (15) C9 0.0141 (16) 0.0205 (18) 0.0177 (17) 0.0026 (14) 0.0005 (14) 0.0040 (14) C10 0.0203 (19) 0.027 (2) 0.0175 (18) 0.0029 (16) 0.0000 (15) 0.0024 (16) C11 0.021 (2) 0.027 (2) 0.026 (2) 0.0049 (16) 0.0077 (16) −0.0011 (17) C12 0.0159 (17) 0.024 (2) 0.025 (2) 0.0042 (15) 0.0030 (15) 0.0034 (16) C13 0.0140 (16) 0.0209 (18) 0.0193 (18) 0.0046 (14) 0.0012 (14) 0.0053 (15) C14 0.0154 (17) 0.0209 (18) 0.0181 (18) 0.0030 (14) −0.0006 (14) 0.0088 (15) C15 0.033 (2) 0.021 (2) 0.023 (2) 0.0001 (17) 0.0067 (17) 0.0047 (16) C16 0.0177 (17) 0.0240 (19) 0.0195 (18) 0.0051 (15) 0.0046 (14) 0.0086 (15) C17 0.026 (2) 0.025 (2) 0.023 (2) 0.0084 (16) 0.0052 (16) 0.0125 (17) C18 0.028 (2) 0.030 (2) 0.0191 (19) 0.0042 (17) 0.0019 (16) 0.0084 (17) C19 0.026 (2) 0.027 (2) 0.0160 (18) 0.0033 (16) 0.0027 (15) 0.0049 (16) C20 0.0138 (16) 0.0258 (19) 0.0175 (17) 0.0054 (14) 0.0032 (14) 0.0087 (15) C21 0.0125 (16) 0.0238 (19) 0.0181 (17) 0.0034 (14) 0.0037 (13) 0.0071 (15) C22 0.0124 (15) 0.0259 (19) 0.0128 (16) 0.0062 (14) 0.0017 (13) 0.0051 (14) C23 0.0121 (15) 0.0251 (19) 0.0135 (16) 0.0083 (14) 0.0011 (13) 0.0031 (14) C24 0.0179 (17) 0.028 (2) 0.0163 (17) 0.0064 (15) 0.0015 (14) 0.0044 (16) C25 0.0149 (17) 0.030 (2) 0.0202 (19) 0.0046 (15) −0.0013 (14) 0.0014 (16) C26 0.0171 (17) 0.0203 (19) 0.0226 (19) 0.0001 (15) −0.0019 (15) 0.0051 (16) C27 0.0150 (16) 0.0197 (18) 0.0176 (17) 0.0049 (14) 0.0021 (13) 0.0031 (14) C28 0.0126 (16) 0.027 (2) 0.0182 (18) 0.0039 (14) 0.0017 (14) 0.0080 (15) C29 0.026 (2) 0.032 (2) 0.030 (2) 0.0034 (18) 0.0062 (18) 0.0158 (19) C30 0.031 (2) 0.036 (3) 0.031 (2) 0.012 (2) 0.0109 (19) 0.017 (2) C31 0.0186 (18) 0.025 (2) 0.034 (2) 0.0056 (16) 0.0092 (17) 0.0117 (18) C32 0.023 (2) 0.026 (2) 0.027 (2) 0.0081 (17) 0.0070 (16) 0.0098 (17) C33 0.0157 (17) 0.026 (2) 0.027 (2) 0.0058 (15) 0.0070 (15) 0.0140 (17) C34 0.0181 (18) 0.0221 (19) 0.025 (2) 0.0014 (15) 0.0043 (15) 0.0097 (16) C35 0.0215 (19) 0.024 (2) 0.025 (2) 0.0023 (16) 0.0054 (16) 0.0097 (16) C36 0.023 (2) 0.026 (2) 0.030 (2) 0.0047 (16) 0.0060 (17) 0.0153 (18) C37 0.026 (2) 0.025 (2) 0.031 (2) 0.0041 (17) 0.0027 (18) 0.0075 (18) C38 0.028 (2) 0.029 (2) 0.023 (2) 0.0033 (17) 0.0037 (17) 0.0086 (17) ----- -------------- -------------- -------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e3194 .table-wrap} -------------------------- ------------- ------------------------ ------------ O23---H23A 0.76 (10) N4---C27 1.345 (5) O23---H23B 0.71 (9) N5---C30 1.336 (7) Ce1---O10 2.450 (3) N5---C31 1.337 (6) Ce1---O4 2.500 (3) N5---H5A 0.82 (3) Ce1---O8 2.540 (3) N6---C36 1.325 (6) Ce1---O2 2.545 (3) N6---C37 1.330 (6) Ce1---O6 2.584 (3) N6---H6A 0.88 (4) Ce1---O12 2.603 (3) C1---C2 1.520 (5) Ce1---N2 2.629 (4) C2---C3 1.385 (6) Ce1---N1 2.631 (3) C3---C4 1.396 (6) Ce1---N3 2.646 (3) C3---H3 0.9300 Ce2---O3^i^ 2.444 (3) C4---C5 1.380 (6) Ce2---O7 2.464 (3) C4---H4 0.9300 Ce2---O19 2.469 (3) C5---C6 1.393 (5) Ce2---O14 2.501 (3) C5---H5 0.9300 Ce2---O16 2.520 (3) C6---C7 1.519 (5) Ce2---O18 2.585 (3) C8---C9 1.512 (5) Ce2---O17 2.585 (3) C9---C10 1.384 (6) Ce2---O20 2.641 (3) C10---C11 1.391 (6) Ce2---N4 2.646 (4) C10---H10 0.9300 O1---C1 1.244 (5) C11---C12 1.390 (6) O2---C1 1.259 (5) C11---H11 0.9300 O3---C7 1.247 (5) C12---C13 1.387 (6) O3---Ce2^ii^ 2.444 (3) C12---H12 0.9300 O4---C7 1.265 (5) C13---C14 1.509 (5) O5---C8 1.239 (5) C15---C16 1.517 (6) O6---C8 1.267 (5) C16---C17 1.392 (6) O7---C14 1.258 (5) C17---C18 1.385 (6) O8---C14 1.250 (5) C17---H17 0.9300 O9---C15 1.233 (5) C18---C19 1.392 (6) O10---C15 1.285 (5) C18---H18 0.9300 O11---C21 1.273 (5) C19---C20 1.389 (5) O12---C21 1.250 (5) C19---H19 0.9300 O13---C22 1.236 (5) C20---C21 1.507 (5) O14---C22 1.279 (5) C22---C23 1.514 (6) O15---C28 1.243 (5) C23---C24 1.393 (6) O16---C28 1.275 (5) C24---C25 1.392 (6) O17---H17A 0.82 (7) C24---H24 0.9300 O17---H17B 0.83 (8) C25---C26 1.395 (6) O18---H18B 0.90 (4) C25---H25 0.9300 O18---H18A 0.88 (4) C26---C27 1.388 (6) O18---H18B 0.90 (4) C26---H26 0.9300 O19---H19A 0.82 (4) C27---C28 1.515 (5) O19---H19B 0.88 (9) C29---C30 1.374 (6) O20---H20A 0.85 (8) C29---C33 1.395 (6) O20---H20B 0.73 (10) C29---H29 0.9300 O21---H21A 0.89 (4) C30---H30 0.9300 O21---H21B 0.93 (9) C31---C32 1.378 (6) O22---H22A 0.89 (8) C31---H31 0.9300 O22---H22B 0.84 (4) C32---C33 1.401 (6) O24---H24A 0.87 (15) C32---H32 0.9300 O24---H24B 0.9 (2) C33---C34 1.488 (6) O25---H25A 0.92 (11) C34---C38 1.394 (6) O25---H25B 0.91 (10) C34---C35 1.394 (6) N1---C6 1.338 (5) C35---C36 1.384 (6) N1---C2 1.338 (5) C35---H35 0.9300 N2---C13 1.339 (5) C36---H36 0.9300 N2---C9 1.339 (5) C37---C38 1.375 (6) N3---C20 1.334 (5) C37---H37 0.9300 N3---C16 1.338 (5) C38---H38 0.9300 N4---C23 1.340 (5) H23A---O23---H23B 129 (10) C36---N6---H6A 118 (5) O10---Ce1---O4 81.20 (11) C37---N6---H6A 121 (5) O10---Ce1---O8 90.78 (11) O1---C1---O2 124.6 (4) O4---Ce1---O8 162.20 (9) O1---C1---C2 119.4 (4) O10---Ce1---O2 154.12 (11) O2---C1---C2 116.1 (3) O4---Ce1---O2 123.00 (9) N1---C2---C3 122.6 (4) O8---Ce1---O2 68.38 (9) N1---C2---C1 114.3 (3) O10---Ce1---O6 76.37 (10) C3---C2---C1 123.1 (3) O4---Ce1---O6 72.21 (10) C2---C3---C4 118.0 (4) O8---Ce1---O6 121.45 (10) C2---C3---H3 121.0 O2---Ce1---O6 100.91 (10) C4---C3---H3 121.0 O10---Ce1---O12 121.94 (10) C5---C4---C3 119.9 (4) O4---Ce1---O12 86.20 (10) C5---C4---H4 120.1 O8---Ce1---O12 84.62 (10) C3---C4---H4 120.1 O2---Ce1---O12 72.93 (10) C4---C5---C6 118.1 (4) O6---Ce1---O12 149.70 (10) C4---C5---H5 121.0 O10---Ce1---N2 85.60 (11) C6---C5---H5 121.0 O4---Ce1---N2 132.60 (10) N1---C6---C5 122.5 (4) O8---Ce1---N2 61.78 (10) N1---C6---C7 115.5 (3) O2---Ce1---N2 71.26 (10) C5---C6---C7 122.0 (3) O6---Ce1---N2 60.45 (10) O3---C7---O4 126.2 (4) O12---Ce1---N2 137.74 (10) O3---C7---C6 117.6 (3) O10---Ce1---N1 141.05 (11) O4---C7---C6 116.1 (3) O4---Ce1---N1 62.18 (10) O5---C8---O6 126.4 (4) O8---Ce1---N1 128.08 (10) O5---C8---C9 118.1 (4) O2---Ce1---N1 60.93 (10) O6---C8---C9 115.5 (3) O6---Ce1---N1 79.99 (10) N2---C9---C10 121.9 (4) O12---Ce1---N1 71.06 (10) N2---C9---C8 114.6 (4) N2---Ce1---N1 108.86 (10) C10---C9---C8 123.4 (4) O10---Ce1---N3 61.35 (11) C9---C10---C11 119.4 (4) O4---Ce1---N3 81.32 (10) C9---C10---H10 120.3 O8---Ce1---N3 80.89 (10) C11---C10---H10 120.3 O2---Ce1---N3 126.17 (10) C12---C11---C10 118.4 (4) O6---Ce1---N3 132.92 (10) C12---C11---H11 120.8 O12---Ce1---N3 60.77 (10) C10---C11---H11 120.8 N2---Ce1---N3 129.88 (10) C13---C12---C11 118.8 (4) N1---Ce1---N3 120.63 (10) C13---C12---H12 120.6 O3^i^---Ce2---O7 134.99 (10) C11---C12---H12 120.6 O3^i^---Ce2---O19 77.20 (11) N2---C13---C12 122.5 (4) O7---Ce2---O19 98.81 (12) N2---C13---C14 114.3 (4) O3^i^---Ce2---O14 81.51 (10) C12---C13---C14 123.2 (3) O7---Ce2---O14 75.82 (10) O8---C14---O7 125.8 (4) O19---Ce2---O14 143.15 (11) O8---C14---C13 117.7 (3) O3^i^---Ce2---O16 78.67 (10) O7---C14---C13 116.4 (4) O7---Ce2---O16 146.02 (9) O9---C15---O10 127.5 (4) O19---Ce2---O16 82.61 (12) O9---C15---C16 118.2 (4) O14---Ce2---O16 122.17 (10) O10---C15---C16 114.3 (4) O3^i^---Ce2---O18 135.63 (10) N3---C16---C17 122.6 (4) O7---Ce2---O18 78.75 (10) N3---C16---C15 114.7 (3) O19---Ce2---O18 68.25 (11) C17---C16---C15 122.7 (4) O14---Ce2---O18 142.09 (10) C18---C17---C16 118.4 (4) O16---Ce2---O18 70.25 (10) C18---C17---H17 120.8 O3^i^---Ce2---O17 141.35 (11) C16---C17---H17 120.8 O7---Ce2---O17 70.97 (11) C17---C18---C19 119.3 (4) O19---Ce2---O17 134.26 (10) C17---C18---H18 120.3 O14---Ce2---O17 79.25 (10) C19---C18---H18 120.3 O16---Ce2---O17 83.74 (10) C20---C19---C18 118.2 (4) O18---Ce2---O17 66.04 (10) C20---C19---H19 120.9 O3^i^---Ce2---O20 69.27 (11) C18---C19---H19 120.9 O7---Ce2---O20 67.13 (11) N3---C20---C19 122.9 (4) O19---Ce2---O20 71.40 (12) N3---C20---C21 114.4 (3) O14---Ce2---O20 73.06 (11) C19---C20---C21 122.7 (4) O16---Ce2---O20 142.18 (10) O12---C21---O11 126.3 (4) O18---Ce2---O20 121.16 (11) O12---C21---C20 118.4 (4) O17---Ce2---O20 134.03 (11) O11---C21---C20 115.3 (3) O3^i^---Ce2---N4 73.33 (11) O13---C22---O14 124.2 (4) O7---Ce2---N4 124.35 (11) O13---C22---C23 120.6 (4) O19---Ce2---N4 136.81 (12) O14---C22---C23 115.2 (3) O14---Ce2---N4 61.05 (10) N4---C23---C24 122.7 (4) O16---Ce2---N4 61.28 (10) N4---C23---C22 114.5 (3) O18---Ce2---N4 114.97 (11) C24---C23---C22 122.8 (3) O17---Ce2---N4 68.03 (10) C25---C24---C23 117.9 (4) O20---Ce2---N4 123.80 (11) C25---C24---H24 121.0 C1---O2---Ce1 127.0 (2) C23---C24---H24 121.0 C7---O3---Ce2^ii^ 169.2 (3) C24---C25---C26 120.0 (4) C7---O4---Ce1 126.6 (2) C24---C25---H25 120.0 C8---O6---Ce1 126.4 (2) C26---C25---H25 120.0 C14---O7---Ce2 146.2 (3) C27---C26---C25 117.8 (4) C14---O8---Ce1 119.8 (2) C27---C26---H26 121.1 C15---O10---Ce1 129.0 (3) C25---C26---H26 121.1 C21---O12---Ce1 124.5 (3) N4---C27---C26 122.9 (4) C22---O14---Ce2 128.3 (2) N4---C27---C28 114.2 (3) C28---O16---Ce2 126.0 (2) C26---C27---C28 122.9 (4) Ce2---O17---H17A 119 (5) O15---C28---O16 125.6 (4) Ce2---O17---H17B 120 (5) O15---C28---C27 118.5 (4) H17A---O17---H17B 102 (7) O16---C28---C27 115.9 (3) H18B---O18---Ce2 110 (4) C30---C29---C33 119.6 (5) H18B---O18---H18A 107 (6) C30---C29---H29 120.2 Ce2---O18---H18A 115 (5) C33---C29---H29 120.2 Ce2---O18---H18B 110 (4) N5---C30---C29 120.6 (4) H18A---O18---H18B 107 (6) N5---C30---H30 119.7 Ce2---O19---H19A 122 (7) C29---C30---H30 119.7 Ce2---O19---H19B 121 (5) N5---C31---C32 119.7 (4) H19A---O19---H19B 116 (8) N5---C31---H31 120.1 Ce2---O20---H20A 116 (5) C32---C31---H31 120.1 Ce2---O20---H20B 119 (8) C31---C32---C33 120.1 (4) H20A---O20---H20B 115 (9) C31---C32---H32 120.0 H21A---O21---H21B 105 (7) C33---C32---H32 120.0 H22A---O22---H22B 114 (10) C29---C33---C32 117.9 (4) H24A---O24---H24B 104 (10) C29---C33---C34 120.1 (4) H25A---O25---H25B 120 (7) C32---C33---C34 121.9 (4) C6---N1---C2 118.9 (3) C38---C34---C35 119.3 (4) C6---N1---Ce1 119.4 (2) C38---C34---C33 120.6 (4) C2---N1---Ce1 121.7 (2) C35---C34---C33 120.2 (4) C13---N2---C9 118.9 (4) C36---C35---C34 118.2 (4) C13---N2---Ce1 117.7 (3) C36---C35---H35 120.9 C9---N2---Ce1 122.4 (3) C34---C35---H35 120.9 C20---N3---C16 118.6 (3) N6---C36---C35 121.6 (4) C20---N3---Ce1 121.9 (3) N6---C36---H36 119.2 C16---N3---Ce1 119.5 (3) C35---C36---H36 119.2 C23---N4---C27 118.7 (4) N6---C37---C38 121.5 (5) C23---N4---Ce2 120.8 (3) N6---C37---H37 119.3 C27---N4---Ce2 120.5 (2) C38---C37---H37 119.3 C30---N5---C31 122.0 (4) C37---C38---C34 118.6 (4) C30---N5---H5A 116 (4) C37---C38---H38 120.7 C31---N5---H5A 122 (4) C34---C38---H38 120.7 C36---N6---C37 120.9 (4) O10---Ce1---O2---C1 151.7 (3) O3^i^---Ce2---N4---C27 90.7 (3) O4---Ce1---O2---C1 −5.3 (4) O7---Ce2---N4---C27 −135.7 (3) O8---Ce1---O2---C1 −169.9 (4) O19---Ce2---N4---C27 41.8 (3) O6---Ce1---O2---C1 70.4 (3) O14---Ce2---N4---C27 −179.9 (3) O12---Ce1---O2---C1 −78.9 (3) O16---Ce2---N4---C27 4.7 (3) N2---Ce1---O2---C1 123.9 (3) O18---Ce2---N4---C27 −42.4 (3) N1---Ce1---O2---C1 −1.5 (3) O17---Ce2---N4---C27 −90.3 (3) N3---Ce1---O2---C1 −109.9 (3) O20---Ce2---N4---C27 140.6 (3) O10---Ce1---O4---C7 −161.8 (3) Ce1---O2---C1---O1 −176.5 (3) O8---Ce1---O4---C7 134.1 (3) Ce1---O2---C1---C2 3.4 (5) O2---Ce1---O4---C7 8.2 (3) C6---N1---C2---C3 0.6 (6) O6---Ce1---O4---C7 −83.4 (3) Ce1---N1---C2---C3 −177.1 (3) O12---Ce1---O4---C7 75.0 (3) C6---N1---C2---C1 −179.7 (3) N2---Ce1---O4---C7 −86.2 (3) Ce1---N1---C2---C1 2.7 (4) N1---Ce1---O4---C7 4.5 (3) O1---C1---C2---N1 176.1 (4) N3---Ce1---O4---C7 136.0 (3) O2---C1---C2---N1 −3.8 (5) O10---Ce1---O6---C8 −89.2 (3) O1---C1---C2---C3 −4.2 (6) O4---Ce1---O6---C8 −174.1 (3) O2---C1---C2---C3 176.0 (4) O8---Ce1---O6---C8 −6.7 (4) N1---C2---C3---C4 −1.9 (7) O2---Ce1---O6---C8 64.5 (3) C1---C2---C3---C4 178.3 (4) O12---Ce1---O6---C8 139.2 (3) C2---C3---C4---C5 2.0 (7) N2---Ce1---O6---C8 3.5 (3) C3---C4---C5---C6 −0.8 (7) N1---Ce1---O6---C8 122.0 (3) C2---N1---C6---C5 0.7 (6) N3---Ce1---O6---C8 −115.1 (3) Ce1---N1---C6---C5 178.4 (3) O3^i^---Ce2---O7---C14 −174.6 (5) C2---N1---C6---C7 −177.2 (3) O19---Ce2---O7---C14 −94.0 (5) Ce1---N1---C6---C7 0.5 (4) O14---Ce2---O7---C14 123.3 (5) C4---C5---C6---N1 −0.6 (6) O16---Ce2---O7---C14 −4.1 (6) C4---C5---C6---C7 177.2 (4) O18---Ce2---O7---C14 −28.4 (5) Ce2^ii^---O3---C7---O4 −69.7 (16) O17---Ce2---O7---C14 40.0 (5) Ce2^ii^---O3---C7---C6 111.2 (14) O20---Ce2---O7---C14 −159.4 (5) Ce1---O4---C7---O3 175.0 (3) N4---Ce2---O7---C14 84.3 (5) Ce1---O4---C7---C6 −5.9 (5) O10---Ce1---O8---C14 111.4 (3) N1---C6---C7---O3 −177.6 (3) O4---Ce1---O8---C14 174.1 (3) C5---C6---C7---O3 4.4 (6) O2---Ce1---O8---C14 −52.9 (3) N1---C6---C7---O4 3.2 (5) O6---Ce1---O8---C14 36.9 (3) C5---C6---C7---O4 −174.8 (4) O12---Ce1---O8---C14 −126.6 (3) Ce1---O6---C8---O5 174.2 (3) N2---Ce1---O8---C14 26.8 (3) Ce1---O6---C8---C9 −8.4 (5) N1---Ce1---O8---C14 −65.8 (3) C13---N2---C9---C10 0.8 (6) N3---Ce1---O8---C14 172.2 (3) Ce1---N2---C9---C10 169.0 (3) O4---Ce1---O10---C15 −95.0 (4) C13---N2---C9---C8 −175.7 (3) O8---Ce1---O10---C15 69.0 (4) Ce1---N2---C9---C8 −7.5 (5) O2---Ce1---O10---C15 104.3 (4) O5---C8---C9---N2 −172.4 (4) O6---Ce1---O10---C15 −168.7 (4) O6---C8---C9---N2 10.0 (5) O12---Ce1---O10---C15 −15.1 (4) O5---C8---C9---C10 11.2 (6) N2---Ce1---O10---C15 130.6 (4) O6---C8---C9---C10 −166.5 (4) N1---Ce1---O10---C15 −114.5 (4) N2---C9---C10---C11 −3.6 (6) N3---Ce1---O10---C15 −10.2 (4) C8---C9---C10---C11 172.6 (4) O10---Ce1---O12---C21 3.1 (3) C9---C10---C11---C12 3.2 (7) O4---Ce1---O12---C21 80.2 (3) C10---C11---C12---C13 −0.3 (7) O8---Ce1---O12---C21 −84.5 (3) C9---N2---C13---C12 2.2 (6) O2---Ce1---O12---C21 −153.5 (3) Ce1---N2---C13---C12 −166.5 (3) O6---Ce1---O12---C21 124.1 (3) C9---N2---C13---C14 −179.2 (3) N2---Ce1---O12---C21 −120.4 (3) Ce1---N2---C13---C14 12.1 (4) N1---Ce1---O12---C21 142.1 (3) C11---C12---C13---N2 −2.5 (6) N3---Ce1---O12---C21 −1.9 (3) C11---C12---C13---C14 179.1 (4) O3^i^---Ce2---O14---C22 76.6 (3) Ce1---O8---C14---O7 148.6 (3) O7---Ce2---O14---C22 −142.6 (3) Ce1---O8---C14---C13 −32.1 (5) O19---Ce2---O14---C22 131.7 (3) Ce2---O7---C14---O8 −99.1 (5) O16---Ce2---O14---C22 5.8 (4) Ce2---O7---C14---C13 81.6 (6) O18---Ce2---O14---C22 −93.3 (3) N2---C13---C14---O8 12.3 (5) O17---Ce2---O14---C22 −69.7 (3) C12---C13---C14---O8 −169.2 (4) O20---Ce2---O14---C22 147.4 (3) N2---C13---C14---O7 −168.4 (3) N4---Ce2---O14---C22 1.0 (3) C12---C13---C14---O7 10.2 (6) O3^i^---Ce2---O16---C28 −89.7 (3) Ce1---O10---C15---O9 −170.5 (4) O7---Ce2---O16---C28 97.1 (3) Ce1---O10---C15---C16 10.4 (6) O19---Ce2---O16---C28 −168.1 (3) C20---N3---C16---C17 −1.9 (6) O14---Ce2---O16---C28 −17.4 (3) Ce1---N3---C16---C17 175.8 (3) O18---Ce2---O16---C28 122.5 (3) C20---N3---C16---C15 175.2 (4) O17---Ce2---O16---C28 55.7 (3) Ce1---N3---C16---C15 −7.1 (5) O20---Ce2---O16---C28 −121.8 (3) O9---C15---C16---N3 179.8 (5) N4---Ce2---O16---C28 −12.6 (3) O10---C15---C16---N3 −1.0 (6) O3^i^---Ce2---O18---H18B 5(5) O9---C15---C16---C17 −3.1 (7) O7---Ce2---O18---H18B −141 (5) O10---C15---C16---C17 176.1 (4) O19---Ce2---O18---H18B −36 (5) N3---C16---C17---C18 2.1 (6) O14---Ce2---O18---H18B 171 (5) C15---C16---C17---C18 −174.8 (4) O16---Ce2---O18---H18B 53 (5) C16---C17---C18---C19 0.0 (7) O17---Ce2---O18---H18B 145 (5) C17---C18---C19---C20 −2.0 (7) O20---Ce2---O18---H18B −86 (5) C16---N3---C20---C19 −0.3 (6) N4---Ce2---O18---H18B 96 (5) Ce1---N3---C20---C19 −178.0 (3) O10---Ce1---N1---C6 19.7 (4) C16---N3---C20---C21 177.2 (3) O4---Ce1---N1---C6 −2.2 (3) Ce1---N3---C20---C21 −0.5 (4) O8---Ce1---N1---C6 −164.8 (3) C18---C19---C20---N3 2.3 (6) O2---Ce1---N1---C6 −178.5 (3) C18---C19---C20---C21 −175.1 (4) O6---Ce1---N1---C6 72.9 (3) Ce1---O12---C21---O11 −178.7 (3) O12---Ce1---N1---C6 −98.0 (3) Ce1---O12---C21---C20 2.5 (5) N2---Ce1---N1---C6 126.8 (3) N3---C20---C21---O12 −1.3 (5) N3---Ce1---N1---C6 −61.4 (3) C19---C20---C21---O12 176.3 (4) O10---Ce1---N1---C2 −162.7 (3) N3---C20---C21---O11 179.8 (3) O4---Ce1---N1---C2 175.5 (3) C19---C20---C21---O11 −2.6 (6) O8---Ce1---N1---C2 12.9 (3) Ce2---O14---C22---O13 177.2 (3) O2---Ce1---N1---C2 −0.9 (3) Ce2---O14---C22---C23 −1.9 (5) O6---Ce1---N1---C2 −109.5 (3) C27---N4---C23---C24 0.2 (6) O12---Ce1---N1---C2 79.6 (3) Ce2---N4---C23---C24 −179.9 (3) N2---Ce1---N1---C2 −55.6 (3) C27---N4---C23---C22 179.0 (3) N3---Ce1---N1---C2 116.2 (3) Ce2---N4---C23---C22 −1.1 (4) O10---Ce1---N2---C13 −112.1 (3) O13---C22---C23---N4 −177.4 (4) O4---Ce1---N2---C13 174.1 (2) O14---C22---C23---N4 1.8 (5) O8---Ce1---N2---C13 −18.8 (3) O13---C22---C23---C24 1.5 (6) O2---Ce1---N2---C13 56.1 (3) O14---C22---C23---C24 −179.3 (4) O6---Ce1---N2---C13 171.1 (3) N4---C23---C24---C25 −1.9 (6) O12---Ce1---N2---C13 22.7 (3) C22---C23---C24---C25 179.3 (4) N1---Ce1---N2---C13 105.0 (3) C23---C24---C25---C26 1.7 (6) N3---Ce1---N2---C13 −65.8 (3) C24---C25---C26---C27 0.2 (6) O10---Ce1---N2---C9 79.6 (3) C23---N4---C27---C26 1.9 (6) O4---Ce1---N2---C9 5.8 (4) Ce2---N4---C27---C26 −178.1 (3) O8---Ce1---N2---C9 172.9 (3) C23---N4---C27---C28 −178.9 (3) O2---Ce1---N2---C9 −112.2 (3) Ce2---N4---C27---C28 1.1 (4) O6---Ce1---N2---C9 2.8 (3) C25---C26---C27---N4 −2.0 (6) O12---Ce1---N2---C9 −145.6 (3) C25---C26---C27---C28 178.8 (4) N1---Ce1---N2---C9 −63.3 (3) Ce2---O16---C28---O15 −162.5 (3) N3---Ce1---N2---C9 125.9 (3) Ce2---O16---C28---C27 18.1 (5) O10---Ce1---N3---C20 −174.1 (3) N4---C27---C28---O15 169.0 (4) O4---Ce1---N3---C20 −89.4 (3) C26---C27---C28---O15 −11.8 (6) O8---Ce1---N3---C20 90.0 (3) N4---C27---C28---O16 −11.6 (5) O2---Ce1---N3---C20 35.4 (3) C26---C27---C28---O16 167.7 (4) O6---Ce1---N3---C20 −145.1 (3) C31---N5---C30---C29 −1.0 (7) O12---Ce1---N3---C20 1.1 (3) C33---C29---C30---N5 −1.0 (7) N2---Ce1---N3---C20 130.7 (3) C30---N5---C31---C32 1.6 (7) N1---Ce1---N3---C20 −39.1 (3) N5---C31---C32---C33 −0.2 (6) O10---Ce1---N3---C16 8.3 (3) C30---C29---C33---C32 2.3 (7) O4---Ce1---N3---C16 92.9 (3) C30---C29---C33---C34 −175.5 (4) O8---Ce1---N3---C16 −87.7 (3) C31---C32---C33---C29 −1.7 (6) O2---Ce1---N3---C16 −142.2 (3) C31---C32---C33---C34 176.0 (4) O6---Ce1---N3---C16 37.3 (3) C29---C33---C34---C38 17.7 (6) O12---Ce1---N3---C16 −176.6 (3) C32---C33---C34---C38 −160.0 (4) N2---Ce1---N3---C16 −47.0 (3) C29---C33---C34---C35 −163.5 (4) N1---Ce1---N3---C16 143.2 (3) C32---C33---C34---C35 18.8 (6) O3^i^---Ce2---N4---C23 −89.2 (3) C38---C34---C35---C36 −0.4 (6) O7---Ce2---N4---C23 44.4 (3) C33---C34---C35---C36 −179.2 (4) O19---Ce2---N4---C23 −138.1 (3) C37---N6---C36---C35 1.1 (7) O14---Ce2---N4---C23 0.2 (3) C34---C35---C36---N6 −0.4 (6) O16---Ce2---N4---C23 −175.2 (3) C36---N6---C37---C38 −1.1 (7) O18---Ce2---N4---C23 137.7 (3) N6---C37---C38---C34 0.3 (7) O17---Ce2---N4---C23 89.8 (3) C35---C34---C38---C37 0.4 (7) O20---Ce2---N4---C23 −39.4 (3) C33---C34---C38---C37 179.2 (4) -------------------------- ------------- ------------------------ ------------ ::: Symmetry codes: (i) *x*+1, *y*, *z*; (ii) *x*−1, *y*, *z*. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e6418 .table-wrap} ----------------------- ----------- ----------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N5---H5A···O14 0.82 (3) 1.83 (4) 2.647 (5) 175 (6) N6---H6A···O11^iii^ 0.88 (4) 1.63 (4) 2.514 (5) 177 (8) O17---H17A···O2 0.82 (7) 2.05 (7) 2.866 (4) 175 (6) O17---H17B···O13^iv^ 0.83 (8) 1.88 (8) 2.681 (4) 161 (7) O18---H18A···O1 0.88 (4) 2.15 (5) 2.983 (5) 157 (7) O18---H18B···O16^v^ 0.90 (4) 1.95 (4) 2.837 (4) 171 (6) O19---H19A···O15^v^ 0.82 (4) 1.93 (4) 2.736 (4) 167 (10) O19---H19B···O21^vi^ 0.88 (9) 1.81 (9) 2.689 (5) 171 (8) O20---H20A···O22 0.85 (8) 2.17 (8) 2.894 (6) 142 (7) O20---H20B···O23^vii^ 0.73 (10) 2.15 (10) 2.847 (5) 158 (10) O21---H21A···O1^iv^ 0.89 (4) 1.86 (4) 2.736 (5) 169 (6) O21---H21B···O6^viii^ 0.93 (9) 1.93 (9) 2.851 (5) 171 (8) O22---H22A···O6^i^ 0.89 (8) 2.49 (8) 3.127 (5) 128 (6) O22---H22A···O10^i^ 0.89 (8) 2.35 (8) 3.116 (5) 143 (7) O22---H22B···O23^vi^ 0.84 (4) 2.12 (7) 2.884 (7) 150 (6) O23---H23A···O5^viii^ 0.76 (10) 1.99 (10) 2.736 (6) 170 (12) O23---H23B···O24^vii^ 0.71 (9) 2.30 (11) 2.926 (6) 149 (16) O24---H24A···O15^iii^ 0.87 (15) 2.02 (15) 2.882 (5) 170 (15) O24---H24B···O22 0.9 (2) 1.9 (2) 2.764 (6) 161 O25---H25A···O24 0.92 (11) 2.52 (11) 3.137 (7) 124 (10) O25---H25B···O1^iii^ 0.91 (10) 2.43 (12) 3.120 (7) 133 (12) O25---H25B···O17^iii^ 0.91 (10) 2.32 (13) 3.034 (7) 136 (15) C5---H5···O16^ii^ 0.93 2.46 3.380 (5) 170 C11---H11···O9^ix^ 0.93 2.40 3.193 (6) 143 C24---H24···O8^iv^ 0.93 2.45 3.172 (5) 135 C29---H29···O5^ix^ 0.93 2.54 3.350 (6) 146 C30---H30···O7 0.93 2.28 3.001 (5) 134 C31---H31···O25^vii^ 0.93 2.45 3.225 (8) 141 C36---H36···O4^x^ 0.93 2.34 3.178 (5) 150 ----------------------- ----------- ----------- ----------- --------------- ::: Symmetry codes: (iii) *x*, *y*−1, *z*; (iv) −*x*+1, −*y*+2, −*z*+1; (v) −*x*+1, −*y*+2, −*z*; (vi) *x*, *y*, *z*−1; (vii) −*x*+1, −*y*+1, −*z*+1; (viii) *x*+1, *y*, *z*+1; (i) *x*+1, *y*, *z*; (ii) *x*−1, *y*, *z*; (ix) −*x*, −*y*+1, −*z*; (x) −*x*, −*y*+1, −*z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ----------------------- ----------- ----------- ----------- ------------- N5---H5*A*⋯O14 0.82 (3) 1.83 (4) 2.647 (5) 175 (6) N6---H6*A*⋯O11^i^ 0.88 (4) 1.63 (4) 2.514 (5) 177 (8) O17---H17*A*⋯O2 0.82 (7) 2.05 (7) 2.866 (4) 175 (6) O17---H17*B*⋯O13^ii^ 0.83 (8) 1.88 (8) 2.681 (4) 161 (7) O18---H18*A*⋯O1 0.88 (4) 2.15 (5) 2.983 (5) 157 (7) O18---H18*B*⋯O16^iii^ 0.90 (4) 1.95 (4) 2.837 (4) 171 (6) O19---H19*A*⋯O15^iii^ 0.82 (4) 1.93 (4) 2.736 (4) 167 (10) O19---H19*B*⋯O21^iv^ 0.88 (9) 1.81 (9) 2.689 (5) 171 (8) O20---H20*A*⋯O22 0.85 (8) 2.17 (8) 2.894 (6) 142 (7) O20---H20*B*⋯O23^v^ 0.73 (10) 2.15 (10) 2.847 (5) 158 (10) O21---H21*A*⋯O1^ii^ 0.89 (4) 1.86 (4) 2.736 (5) 169 (6) O21---H21*B*⋯O6^vi^ 0.93 (9) 1.93 (9) 2.851 (5) 171 (8) O22---H22*A*⋯O6^vii^ 0.89 (8) 2.49 (8) 3.127 (5) 128 (6) O22---H22*A*⋯O10^vii^ 0.89 (8) 2.35 (8) 3.116 (5) 143 (7) O22---H22*B*⋯O23^iv^ 0.84 (4) 2.12 (7) 2.884 (7) 150 (6) O23---H23*A*⋯O5^vi^ 0.76 (10) 1.99 (10) 2.736 (6) 170 (12) O23---H23*B*⋯O24^v^ 0.71 (9) 2.30 (11) 2.926 (6) 149 (16) O24---H24*A*⋯O15^i^ 0.87 (15) 2.02 (15) 2.882 (5) 170 (15) O24---H24*B*⋯O22 0.9 (2) 1.9 (2) 2.764 (6) 161 O25---H25*A*⋯O24 0.92 (11) 2.52 (11) 3.137 (7) 124 (10) O25---H25*B*⋯O1^i^ 0.91 (10) 2.43 (12) 3.120 (7) 133 (12) O25---H25*B*⋯O17^i^ 0.91 (10) 2.32 (13) 3.034 (7) 136 (15) C5---H5⋯O16^viii^ 0.93 2.46 3.380 (5) 170 C11---H11⋯O9^ix^ 0.93 2.40 3.193 (6) 143 C24---H24⋯O8^ii^ 0.93 2.45 3.172 (5) 135 C29---H29⋯O5^ix^ 0.93 2.54 3.350 (6) 146 C30---H30⋯O7 0.93 2.28 3.001 (5) 134 C31---H31⋯O25^v^ 0.93 2.45 3.225 (8) 141 C36---H36⋯O4^x^ 0.93 2.34 3.178 (5) 150 Symmetry codes: (i) ; (ii) ; (iii) ; (iv) ; (v) ; (vi) ; (vii) ; (viii) ; (ix) ; (x) . :::

PubMed Central

2024-06-05T04:04:17.370640

2011-2-12

PMC3051935

Related literature {#sec1} ================== For a related structure, see: Zheng & Chi (2011[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Cd(NO~2~)(C~22~H~20~N~6~)(CH~4~O)\]ClO~4~*M* *~r~* = 658.34Triclinic,*a* = 8.0241 (17) Å*b* = 11.580 (2) Å*c* = 15.842 (3) Åα = 68.595 (2)°β = 75.578 (2)°γ = 73.616 (3)°*V* = 1297.1 (5) Å^3^*Z* = 2Mo *K*α radiationμ = 1.00 mm^−1^*T* = 298 K0.32 × 0.08 × 0.04 mm ### Data collection {#sec2.1.2} Bruker SMART APEX CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb2]) *T* ~min~ = 0.740, *T* ~max~ = 0.9616780 measured reflections4712 independent reflections3966 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.025 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.044*wR*(*F* ^2^) = 0.111*S* = 1.024712 reflections357 parameters1 restraintH-atom parameters constrainedΔρ~max~ = 0.88 e Å^−3^Δρ~min~ = −0.51 e Å^−3^ {#d5e473} Data collection: *SMART* (Bruker, 1997[@bb1]); cell refinement: *SAINT* (Bruker, 1997[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb3]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL*; software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811003813/lh5203sup1.cif](http://dx.doi.org/10.1107/S1600536811003813/lh5203sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003813/lh5203Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003813/lh5203Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?lh5203&file=lh5203sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?lh5203sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?lh5203&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [LH5203](http://scripts.iucr.org/cgi-bin/sendsup?lh5203)). The authors thank the Natural Science Foundation of Shandong Province of China (No. ZR2009BM026). Comment ======= Derivatives of 1,10-phenanthroline play an important role in modern coordination chemistry and many complexes have been reported with these types of compounds as ligands \[see e.g. Zheng & Chi (2011) for a closely related Cd complex\]. To the best of our knowledge, the above cited structure is the only other complex reported to date containing a 2,9-bis(3,5-Dimethyl-1H-pyrazol-1-yl)-1,10-phenanthroline ligand. Herein we report the crystal of the title compound (I). The molecular structure of the title compound is shown in Fig. 1. The Cd^II^ ion is in a distorted pentagonal bipyramidal coordination geometry, which may be attributed to the chelation modes of the 2,9-bis(3,5-Dimethyl-1H-pyrazol-1-yl)-1,10-phenanthroline ligand and nitrite anion ligand. The dihedral angles between the planes that consist of the non-hydrogen atoms of the 1,10-phenanthroline ring system and the pyrazole rings are 4.37 (19)° (involving the pyrazole ring containing atoms N1 and N2) and 5.84 (21)° (involving the pyrazole ring containing atoms N5 and N6), respectively. In the crystal, the anion and cation are connected by an intermolecular O---H···O hydrogen bond, while pairs of weak intermolecular C---H···O hydrogen bonds connect cations into centrosymmetric dimers. In addition, there is a π--π stacking interaction involving symmetry-related complexes, the relevant distance being Cg1···Cg1^i^ 3.437 (3) Å and Cg1···Cg1^i^~perp~ = 3.378 Å (symmetry code: (i) 2-x, 1-y, 2-z; Cg1 is the centroid of the C9-C14 benzene ring; Cg1···Cg1^i^~perp~ is the perpendicular distance from Cg1 ring to Cg1^i^ ring). Experimental {#experimental} ============ A 5 ml H~2~O solution of NaNO~2~ (0.0310 g, 0.449 mmol) was added into 8 ml methanol solution of Cd(ClO~4~).6H~2~O (0.0939 g,0.224 mmol) and the solution was mixed with a 10 ml dichloromethane solution of 2,9-bis(3,5-Dimethyl-1*H*-pyrazol-1-yl)-1,10-phenanthroline (0.0353 g, 0.112 mmol), and stirred for a few minutes. Colorless single crystals were obtained after the filtrate had been allowed to stand at room temperature for about two week. Refinement {#refinement} ========== The position of the H atom of the hydroxyl group was located in a difference Fourier map and other H atoms were placed in calculated positions. All H atoms were refined as riding with O---H = 0.87 Å, *U*~iso~ = 1.5*U*~eq~(O) for hydroxyl H, C---H = 0.96 Å, *U*~iso~ = 1.5*U*~eq~(C) for methyl H, and C---H = 0.93 Å, *U*~iso~ = 1.2*U*~eq~(C) for other H atoms. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of the title compound with displacement ellipsoids shown at the 30% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e162 .table-wrap} --------------------------------------------- --------------------------------------- \[Cd(NO~2~)(C~22~H~20~N~6~)(CH~4~O)\]ClO~4~ *Z* = 2 *M~r~* = 658.34 *F*(000) = 664 Triclinic, *P*1 *D*~x~ = 1.686 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 8.0241 (17) Å Cell parameters from 2645 reflections *b* = 11.580 (2) Å θ = 2.7--26.3° *c* = 15.842 (3) Å µ = 1.00 mm^−1^ α = 68.595 (2)° *T* = 298 K β = 75.578 (2)° Prism, colorless γ = 73.616 (3)° 0.32 × 0.08 × 0.04 mm *V* = 1297.1 (5) Å^3^ --------------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e305 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker SMART APEX CCD diffractometer 4712 independent reflections Radiation source: fine-focus sealed tube 3966 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.025 φ and ω scans θ~max~ = 25.5°, θ~min~ = 1.4° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −9→9 *T*~min~ = 0.740, *T*~max~ = 0.961 *k* = −14→12 6780 measured reflections *l* = −17→19 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e422 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.044 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.111 H-atom parameters constrained *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0606*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4712 reflections (Δ/σ)~max~ = 0.006 357 parameters Δρ~max~ = 0.88 e Å^−3^ 1 restraint Δρ~min~ = −0.51 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e576 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e675 .table-wrap} ------ -------------- -------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 0.4749 (8) 1.0095 (5) 0.6046 (3) 0.0670 (16) H1A 0.3887 1.0840 0.5807 0.101\* H1B 0.4778 0.9457 0.5787 0.101\* H1C 0.5887 1.0305 0.5887 0.101\* C2 0.4278 (6) 0.9603 (4) 0.7065 (3) 0.0425 (11) C3 0.2868 (6) 1.0116 (4) 0.7631 (3) 0.0397 (10) H3 0.1989 1.0830 0.7445 0.048\* C4 0.3026 (5) 0.9373 (4) 0.8502 (3) 0.0346 (9) C5 0.1895 (7) 0.9562 (4) 0.9363 (3) 0.0490 (12) H5A 0.2561 0.9772 0.9692 0.073\* H5B 0.1501 0.8795 0.9740 0.073\* H5C 0.0894 1.0240 0.9212 0.073\* C6 0.5272 (5) 0.7363 (4) 0.9123 (3) 0.0314 (9) C7 0.4706 (6) 0.7157 (4) 1.0073 (3) 0.0388 (10) H7 0.3818 0.7749 1.0286 0.047\* C8 0.5485 (6) 0.6075 (4) 1.0668 (3) 0.0386 (10) H8 0.5104 0.5910 1.1297 0.046\* C9 0.7363 (5) 0.5504 (4) 0.9394 (3) 0.0322 (9) C10 0.6865 (6) 0.5200 (4) 1.0343 (3) 0.0358 (10) C11 0.8843 (6) 0.4699 (4) 0.9010 (3) 0.0353 (9) C12 0.7791 (6) 0.4061 (4) 1.0927 (3) 0.0432 (11) H12 0.7435 0.3841 1.1560 0.052\* C13 0.9732 (6) 0.3602 (4) 0.9608 (3) 0.0386 (10) C14 0.9175 (6) 0.3300 (4) 1.0570 (3) 0.0457 (12) H14 0.9770 0.2570 1.0962 0.055\* C15 1.1213 (6) 0.2898 (4) 0.9176 (4) 0.0488 (12) H15 1.1866 0.2163 0.9535 0.059\* C16 1.1701 (6) 0.3275 (4) 0.8248 (4) 0.0497 (12) H16 1.2676 0.2804 0.7970 0.060\* C17 1.0714 (6) 0.4380 (4) 0.7719 (3) 0.0410 (11) C18 1.3989 (8) 0.3383 (5) 0.6335 (4) 0.0791 (19) H18A 1.4800 0.3356 0.5780 0.119\* H18B 1.3571 0.2607 0.6610 0.119\* H18C 1.4572 0.3484 0.6756 0.119\* C19 1.2475 (7) 0.4470 (5) 0.6118 (4) 0.0532 (13) C20 1.2191 (7) 0.5289 (5) 0.5292 (4) 0.0585 (15) H20 1.2891 0.5264 0.4732 0.070\* C21 1.0657 (7) 0.6189 (5) 0.5418 (3) 0.0518 (13) C22 0.9811 (8) 0.7316 (6) 0.4720 (4) 0.0719 (17) H22A 0.8555 0.7452 0.4900 0.108\* H22B 1.0127 0.7175 0.4135 0.108\* H22C 1.0204 0.8050 0.4675 0.108\* C23 1.0818 (8) 0.8475 (7) 0.6558 (5) 0.092 (2) H23A 1.1478 0.7659 0.6518 0.138\* H23B 1.1211 0.8676 0.7003 0.138\* H23C 1.0994 0.9108 0.5969 0.138\* Cd1 0.74780 (4) 0.68545 (3) 0.72015 (2) 0.03683 (13) Cl1 0.73701 (17) 0.08191 (12) 0.81116 (9) 0.0547 (3) N1 0.5259 (5) 0.8567 (3) 0.7550 (2) 0.0380 (8) N2 0.4505 (4) 0.8424 (3) 0.8447 (2) 0.0319 (8) N3 0.6559 (4) 0.6565 (3) 0.8799 (2) 0.0314 (7) N4 0.9316 (5) 0.5065 (3) 0.8091 (2) 0.0370 (8) N5 1.1118 (5) 0.4859 (3) 0.6750 (3) 0.0431 (9) N6 0.9995 (5) 0.5936 (4) 0.6303 (3) 0.0482 (10) N7 0.5172 (6) 0.6276 (5) 0.6397 (3) 0.0642 (13) O1 0.8368 (6) 0.1605 (4) 0.8171 (4) 0.0963 (15) O2 0.7550 (7) 0.0832 (5) 0.7196 (3) 0.1006 (16) O3 0.5589 (6) 0.1235 (5) 0.8444 (4) 0.1071 (17) O4 0.7972 (8) −0.0435 (4) 0.8643 (4) 0.1132 (18) O5 0.5944 (5) 0.7160 (4) 0.6005 (2) 0.0651 (10) O6 0.5487 (6) 0.5674 (4) 0.7184 (3) 0.0741 (12) O7 0.9035 (5) 0.8448 (4) 0.6826 (3) 0.0770 (13) H9 0.8513 0.9132 0.6977 0.115\* ------ -------------- -------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1474 .table-wrap} ----- ------------- ------------- -------------- --------------- --------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.089 (5) 0.059 (3) 0.036 (3) 0.006 (3) −0.008 (3) −0.013 (3) C2 0.050 (3) 0.039 (2) 0.034 (2) −0.005 (2) −0.006 (2) −0.011 (2) C3 0.033 (2) 0.036 (2) 0.047 (3) 0.0013 (19) −0.0084 (19) −0.014 (2) C4 0.028 (2) 0.033 (2) 0.045 (2) −0.0069 (18) −0.0017 (18) −0.017 (2) C5 0.049 (3) 0.039 (3) 0.047 (3) −0.003 (2) 0.007 (2) −0.015 (2) C6 0.032 (2) 0.034 (2) 0.033 (2) −0.0123 (18) −0.0036 (17) −0.0124 (18) C7 0.036 (3) 0.046 (3) 0.035 (2) −0.008 (2) −0.0034 (18) −0.017 (2) C8 0.042 (3) 0.050 (3) 0.027 (2) −0.018 (2) −0.0015 (18) −0.013 (2) C9 0.031 (2) 0.033 (2) 0.037 (2) −0.0123 (18) −0.0056 (17) −0.0115 (19) C10 0.038 (3) 0.038 (2) 0.036 (2) −0.019 (2) −0.0091 (18) −0.0070 (19) C11 0.032 (2) 0.034 (2) 0.045 (2) −0.0085 (18) −0.0090 (19) −0.015 (2) C12 0.050 (3) 0.041 (3) 0.039 (2) −0.020 (2) −0.014 (2) −0.002 (2) C13 0.036 (3) 0.027 (2) 0.057 (3) −0.0088 (18) −0.017 (2) −0.011 (2) C14 0.052 (3) 0.035 (2) 0.052 (3) −0.013 (2) −0.025 (2) −0.002 (2) C15 0.044 (3) 0.032 (2) 0.073 (4) −0.001 (2) −0.025 (2) −0.015 (2) C16 0.039 (3) 0.040 (3) 0.074 (4) 0.001 (2) −0.010 (2) −0.028 (3) C17 0.035 (3) 0.034 (2) 0.060 (3) −0.0072 (19) −0.007 (2) −0.022 (2) C18 0.061 (4) 0.062 (4) 0.096 (5) −0.009 (3) 0.030 (3) −0.036 (3) C19 0.043 (3) 0.051 (3) 0.072 (4) −0.020 (2) 0.016 (2) −0.037 (3) C20 0.058 (4) 0.064 (3) 0.060 (3) −0.028 (3) 0.022 (3) −0.037 (3) C21 0.053 (3) 0.057 (3) 0.047 (3) −0.021 (3) 0.007 (2) −0.021 (3) C22 0.081 (5) 0.076 (4) 0.049 (3) −0.023 (3) 0.006 (3) −0.015 (3) C23 0.057 (4) 0.104 (5) 0.134 (6) −0.033 (4) 0.002 (4) −0.058 (5) Cd1 0.0373 (2) 0.0375 (2) 0.03387 (19) −0.00520 (13) −0.00153 (13) −0.01417 (14) Cl1 0.0500 (8) 0.0585 (8) 0.0617 (8) 0.0005 (6) −0.0168 (6) −0.0302 (7) N1 0.039 (2) 0.040 (2) 0.0287 (18) −0.0008 (16) −0.0027 (15) −0.0106 (16) N2 0.033 (2) 0.0301 (18) 0.0301 (18) −0.0057 (15) −0.0016 (14) −0.0102 (15) N3 0.0303 (19) 0.0292 (18) 0.0362 (18) −0.0068 (15) −0.0036 (14) −0.0128 (15) N4 0.034 (2) 0.0342 (19) 0.044 (2) −0.0069 (16) −0.0034 (16) −0.0162 (17) N5 0.039 (2) 0.040 (2) 0.052 (2) −0.0075 (17) 0.0034 (18) −0.0238 (19) N6 0.049 (3) 0.049 (2) 0.044 (2) −0.007 (2) 0.0004 (18) −0.020 (2) N7 0.066 (3) 0.085 (4) 0.055 (3) −0.027 (3) −0.008 (2) −0.032 (3) O1 0.082 (3) 0.093 (3) 0.142 (4) −0.022 (3) −0.035 (3) −0.056 (3) O2 0.142 (5) 0.103 (4) 0.068 (3) −0.031 (3) −0.011 (3) −0.040 (3) O3 0.048 (3) 0.138 (4) 0.155 (5) 0.006 (3) −0.012 (3) −0.091 (4) O4 0.141 (5) 0.061 (3) 0.127 (4) 0.006 (3) −0.062 (4) −0.012 (3) O5 0.078 (3) 0.068 (2) 0.047 (2) −0.016 (2) −0.0138 (19) −0.0128 (19) O6 0.094 (3) 0.086 (3) 0.053 (2) −0.049 (3) −0.010 (2) −0.013 (2) O7 0.056 (3) 0.068 (3) 0.121 (3) −0.027 (2) 0.023 (2) −0.060 (3) ----- ------------- ------------- -------------- --------------- --------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2309 .table-wrap} ------------------- ----------- ------------------- ------------- C1---C2 1.490 (6) C17---N4 1.320 (5) C1---H1A 0.9600 C17---N5 1.415 (6) C1---H1B 0.9600 C18---C19 1.486 (8) C1---H1C 0.9600 C18---H18A 0.9600 C2---N1 1.320 (6) C18---H18B 0.9600 C2---C3 1.393 (6) C18---H18C 0.9600 C3---C4 1.348 (6) C19---C20 1.336 (8) C3---H3 0.9300 C19---N5 1.379 (6) C4---N2 1.381 (5) C20---C21 1.395 (7) C4---C5 1.491 (6) C20---H20 0.9300 C5---H5A 0.9600 C21---N6 1.323 (6) C5---H5B 0.9600 C21---C22 1.485 (8) C5---H5C 0.9600 C22---H22A 0.9600 C6---N3 1.315 (5) C22---H22B 0.9600 C6---N2 1.406 (5) C22---H22C 0.9600 C6---C7 1.409 (6) C23---O7 1.393 (7) C7---C8 1.356 (6) C23---H23A 0.9600 C7---H7 0.9300 C23---H23B 0.9600 C8---C10 1.408 (6) C23---H23C 0.9600 C8---H8 0.9300 Cd1---O7 2.334 (3) C9---N3 1.350 (5) Cd1---N4 2.374 (4) C9---C10 1.393 (6) Cd1---N3 2.377 (3) C9---C11 1.442 (6) Cd1---O5 2.379 (4) C10---C12 1.430 (6) Cd1---N6 2.387 (4) C11---N4 1.345 (5) Cd1---O6 2.389 (4) C11---C13 1.402 (6) Cd1---N1 2.393 (3) C12---C14 1.352 (7) Cl1---O4 1.402 (4) C12---H12 0.9300 Cl1---O3 1.405 (5) C13---C15 1.415 (7) Cl1---O1 1.410 (4) C13---C14 1.416 (6) Cl1---O2 1.416 (4) C14---H14 0.9300 N1---N2 1.368 (4) C15---C16 1.360 (7) N5---N6 1.382 (5) C15---H15 0.9300 N7---O5 1.233 (5) C16---C17 1.394 (6) N7---O6 1.236 (5) C16---H16 0.9300 O7---H9 0.8724 C2---C1---H1A 109.5 C21---C20---H20 126.0 C2---C1---H1B 109.5 N6---C21---C20 110.0 (5) H1A---C1---H1B 109.5 N6---C21---C22 121.1 (5) C2---C1---H1C 109.5 C20---C21---C22 128.9 (5) H1A---C1---H1C 109.5 C21---C22---H22A 109.5 H1B---C1---H1C 109.5 C21---C22---H22B 109.5 N1---C2---C3 111.3 (4) H22A---C22---H22B 109.5 N1---C2---C1 120.7 (4) C21---C22---H22C 109.5 C3---C2---C1 128.1 (4) H22A---C22---H22C 109.5 C4---C3---C2 106.5 (4) H22B---C22---H22C 109.5 C4---C3---H3 126.7 O7---C23---H23A 109.5 C2---C3---H3 126.7 O7---C23---H23B 109.5 C3---C4---N2 106.5 (4) H23A---C23---H23B 109.5 C3---C4---C5 127.3 (4) O7---C23---H23C 109.5 N2---C4---C5 126.1 (4) H23A---C23---H23C 109.5 C4---C5---H5A 109.5 H23B---C23---H23C 109.5 C4---C5---H5B 109.5 O7---Cd1---N4 102.12 (14) H5A---C5---H5B 109.5 O7---Cd1---N3 99.06 (13) C4---C5---H5C 109.5 N4---Cd1---N3 68.71 (11) H5A---C5---H5C 109.5 O7---Cd1---O5 111.48 (15) H5B---C5---H5C 109.5 N4---Cd1---O5 133.19 (12) N3---C6---N2 114.6 (3) N3---Cd1---O5 132.70 (13) N3---C6---C7 122.3 (4) O7---Cd1---N6 83.66 (13) N2---C6---C7 123.1 (4) N4---Cd1---N6 66.38 (13) C8---C7---C6 118.4 (4) N3---Cd1---N6 134.51 (13) C8---C7---H7 120.8 O5---Cd1---N6 85.54 (14) C6---C7---H7 120.8 O7---Cd1---O6 162.24 (16) C7---C8---C10 120.7 (4) N4---Cd1---O6 94.55 (14) C7---C8---H8 119.7 N3---Cd1---O6 92.62 (12) C10---C8---H8 119.7 O5---Cd1---O6 51.28 (13) N3---C9---C10 122.8 (4) N6---Cd1---O6 97.66 (14) N3---C9---C11 117.2 (4) O7---Cd1---N1 77.01 (13) C10---C9---C11 119.9 (4) N4---Cd1---N1 133.55 (11) C9---C10---C8 116.6 (4) N3---Cd1---N1 65.71 (11) C9---C10---C12 119.4 (4) O5---Cd1---N1 86.45 (13) C8---C10---C12 124.0 (4) N6---Cd1---N1 154.67 (13) N4---C11---C13 123.7 (4) O6---Cd1---N1 95.94 (14) N4---C11---C9 117.5 (4) O4---Cl1---O3 109.7 (4) C13---C11---C9 118.8 (4) O4---Cl1---O1 109.2 (3) C14---C12---C10 120.9 (4) O3---Cl1---O1 109.2 (3) C14---C12---H12 119.6 O4---Cl1---O2 107.7 (3) C10---C12---H12 119.6 O3---Cl1---O2 109.6 (3) C11---C13---C15 115.0 (4) O1---Cl1---O2 111.5 (3) C11---C13---C14 120.1 (4) C2---N1---N2 105.3 (3) C15---C13---C14 124.8 (4) C2---N1---Cd1 135.0 (3) C12---C14---C13 120.8 (4) N2---N1---Cd1 118.4 (2) C12---C14---H14 119.6 N1---N2---C4 110.4 (3) C13---C14---H14 119.6 N1---N2---C6 117.5 (3) C16---C15---C13 121.3 (4) C4---N2---C6 132.0 (3) C16---C15---H15 119.4 C6---N3---C9 119.1 (3) C13---C15---H15 119.4 C6---N3---Cd1 123.0 (3) C15---C16---C17 118.8 (5) C9---N3---Cd1 117.8 (3) C15---C16---H16 120.6 C17---N4---C11 119.1 (4) C17---C16---H16 120.6 C17---N4---Cd1 122.8 (3) N4---C17---C16 122.2 (4) C11---N4---Cd1 118.0 (3) N4---C17---N5 114.7 (4) C19---N5---N6 109.7 (4) C16---C17---N5 123.2 (4) C19---N5---C17 132.7 (4) C19---C18---H18A 109.5 N6---N5---C17 117.6 (3) C19---C18---H18B 109.5 C21---N6---N5 105.9 (4) H18A---C18---H18B 109.5 C21---N6---Cd1 135.8 (4) C19---C18---H18C 109.5 N5---N6---Cd1 118.4 (3) H18A---C18---H18C 109.5 O5---N7---O6 113.4 (4) H18B---C18---H18C 109.5 N7---O5---Cd1 97.9 (3) C20---C19---N5 106.6 (5) N7---O6---Cd1 97.4 (3) C20---C19---C18 127.6 (5) C23---O7---Cd1 133.0 (4) N5---C19---C18 125.7 (5) C23---O7---H9 106.8 C19---C20---C21 107.9 (4) Cd1---O7---H9 118.9 C19---C20---H20 126.0 ------------------- ----------- ------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3264 .table-wrap} ------------------ --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O7---H9···O2^i^ 0.87 2.02 2.892 (7) 172 C8---H8···O6^ii^ 0.93 2.47 3.291 (6) 148 ------------------ --------- --------- ----------- --------------- ::: Symmetry codes: (i) *x*, *y*+1, *z*; (ii) −*x*+1, −*y*+1, −*z*+2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ---------------- --------- ------- ----------- ------------- O7---H9⋯O2^i^ 0.87 2.02 2.892 (7) 172 C8---H8⋯O6^ii^ 0.93 2.47 3.291 (6) 148 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.386775

2011-2-12

PMC3051936

Related literature {#sec1} ================== For the properties and applications of amide salt compounds, see: Fu *et al.* (2007[@bb3], 2008[@bb5], 2009[@bb2]); Fu & Xiong (2008[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} (C~6~H~14~N~2~)\[Mg(H~2~O)~6~\](SO~4~)~2~*M* *~r~* = 438.74Monoclinic,*a* = 14.968 (3) Å*b* = 9.1860 (18) Å*c* = 14.334 (3) Åβ = 117.12 (3)°*V* = 1754.2 (8) Å^3^*Z* = 4Mo *K*α radiationμ = 0.41 mm^−1^*T* = 298 K0.40 × 0.30 × 0.20 mm ### Data collection {#sec2.1.2} Rigaku SCXmini CCD diffractometerAbsorption correction: multi-scan (*CrystalClear*; Rigaku, 2005[@bb6]) *T* ~min~ = 0.89, *T* ~max~ = 0.958747 measured reflections2014 independent reflections1839 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.022 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.065*wR*(*F* ^2^) = 0.169*S* = 1.262014 reflections116 parametersH-atom parameters constrainedΔρ~max~ = 1.30 e Å^−3^Δρ~min~ = −1.08 e Å^−3^ {#d5e532} Data collection: *CrystalClear* (Rigaku, 2005[@bb6]); cell refinement: *CrystalClear*; data reduction: *CrystalClear*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb7]) and *DIAMOND* (Brandenburg, 1999[@bb1]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005368/hy2403sup1.cif](http://dx.doi.org/10.1107/S1600536811005368/hy2403sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005368/hy2403Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005368/hy2403Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?hy2403&file=hy2403sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?hy2403sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?hy2403&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [HY2403](http://scripts.iucr.org/cgi-bin/sendsup?hy2403)). This work was supported by a start-up grant from Southeast University, China. Comment ======= Salts of amide have attracted more attention as phase transition dielectric materials for their applications in micro-electronics and memory storage (Fu *et al.*, 2007, 2008, 2009; Fu & Xiong, 2008). With the purpose of obtaining phase transition crystals, the interactions of 1,4-diazabicyclo\[2.2.2\]octane with various metal ions have been studied and we have elaborated a serie of new materials with this organic molecule. In this paper, we describe the crystal structure of the title compound. The asymmetric unit is composed of an SO~4~^2-^ anion, half 1,4-diazoniabicyclo\[2.2.2\]octane cation and half \[Mg(H~2~O)~6~\]^2+^ cation. (Fig. 1). The Mg^II^ ion, lying on an inversion center, is in a slightly distorted octahedral geometry formed by six O atoms from the water molecules. The \[Mg(H~2~O)~6~\]^2+^ cation possesses typical Mg---O bond lengths \[2.035 (2)--2.086 (2) Å\], while the O---Mg---O bond angles \[88.90 (8)--91.86 (9)°\] indicating some distortion from a regular octahedron. In the crystal, the interionic hydrogen bonds are formed by all H atoms of the water molecules and the amine groups with all O atoms of the SO~4~^2-^ anion and its symmetric equivalents (Table 1). The complex cations \[Mg(H~2~O)~6~\]^2+^ and SO~4~^2-^ anions are linked through O---H···O hydrogen bonds into a three-dimensional network, indicating that SO~4~^2-^ anion is a good hydrogen-bonding acceptor. In addition, the amino cations are hydrogen bonded to the SO~4~^2-^ anions through N---H···O hydrogen bonds, which play an important role in stabilizing the crystal structure (Fig. 2). Experimental {#experimental} ============ Commercial 1,4-diazabicyclo\[2.2.2\]octane (3 mmol), H~2~SO~4~ (3 mmol) and MgSO~4~ (3 mmol) were dissolved in water. The solvent was slowly evaporated in air, affording colorless block-shaped crystals of the title compound suitable for X-ray analysis. The permittivity measurement shows that there is no phase transition within the temperature range from 100 to 400 K, while the permittivity is 10.2 at 1 MHz at room temperature. Refinement {#refinement} ========== H atoms attached to C and N atoms were positioned geometrically and treated as riding, with C---H = 0.97 and N---H = 0.91 Å and with *U*~iso~(H) = 1.2*U*~eq~(C, N). H atoms of water molecules were located in difference Fourier maps and refined as riding atoms, with O---H = 0.85 Å and *U*~iso~(H) = 1.5*U*~eq~(O). The highest residual electron density was found at 1.18 Å from H1B atom and the deepest hole at 1.42 Å from C2 atom. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of the title compound. Displacement ellipsoids are drawn at the 30% probability level. \[Symmetry codes: (A) -x, y, 0.5-z; (B) 0.5-x, 0.5-y, -z.\] :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The crystal packing of the title compound, showing the three-dimensional hydrogen-bonded network. H atoms not involved in hydrogen bonds (dashed lines) have been omitted for clarity. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e191 .table-wrap} ------------------------------------------- --------------------------------------- (C~6~H~14~N~2~)\[Mg(H~2~O)~6~\](SO~4~)~2~ *F*(000) = 928 *M~r~* = 438.74 *D*~x~ = 1.661 Mg m^−3^ Monoclinic, *C*2/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -C 2yc Cell parameters from 2014 reflections *a* = 14.968 (3) Å θ = 3.1--27.5° *b* = 9.1860 (18) Å µ = 0.41 mm^−1^ *c* = 14.334 (3) Å *T* = 298 K β = 117.12 (3)° Block, colorless *V* = 1754.2 (8) Å^3^ 0.40 × 0.30 × 0.20 mm *Z* = 4 ------------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e328 .table-wrap} ------------------------------------------------------------------ -------------------------------------- Rigaku SCXmini CCD diffractometer 2014 independent reflections Radiation source: fine-focus sealed tube 1839 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.022 Detector resolution: 13.6612 pixels mm^-1^ θ~max~ = 27.5°, θ~min~ = 3.1° ω scans *h* = −19→19 Absorption correction: multi-scan (*CrystalClear*; Rigaku, 2005) *k* = −11→11 *T*~min~ = 0.89, *T*~max~ = 0.95 *l* = −18→18 8747 measured reflections ------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e448 .table-wrap} ---------------------------------------------------------------- --------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.065 H-atom parameters constrained *wR*(*F*^2^) = 0.169 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0899*P*)^2^ + 2.4679*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.26 (Δ/σ)~max~ \< 0.001 2014 reflections Δρ~max~ = 1.30 e Å^−3^ 116 parameters Δρ~min~ = −1.08 e Å^−3^ 0 restraints Extinction correction: *SHELXTL* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.045 (4) ---------------------------------------------------------------- --------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e631 .table-wrap} ------ --------------- ------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ S1 0.61852 (4) 0.24340 (6) 0.11814 (4) 0.0233 (3) O1W 0.17086 (15) 0.3991 (2) 0.04379 (17) 0.0371 (5) H1WA 0.1091 0.3776 0.0197 0.056\* H1WB 0.1876 0.4636 0.0913 0.056\* Mg1 0.2500 0.2500 0.0000 0.0216 (3) O2W 0.37984 (14) 0.3255 (2) 0.11889 (15) 0.0352 (5) H2WA 0.4372 0.3244 0.1203 0.053\* H2WB 0.3855 0.3321 0.1805 0.053\* O1 0.68789 (16) 0.1296 (2) 0.18242 (15) 0.0383 (5) O3W 0.23727 (17) 0.1023 (2) 0.10262 (15) 0.0397 (5) H3WA 0.2082 0.0203 0.0839 0.059\* H3WB 0.2606 0.1142 0.1684 0.059\* O2 0.58702 (19) 0.3346 (3) 0.18142 (17) 0.0490 (7) N1 −0.02189 (19) 0.2779 (3) 0.15657 (17) 0.0352 (6) H1 −0.0387 0.2783 0.0870 0.042\* O3 0.52895 (16) 0.1720 (3) 0.03471 (16) 0.0450 (6) O4 0.66399 (19) 0.3290 (2) 0.06522 (19) 0.0472 (6) C1 0.0764 (3) 0.2074 (5) 0.2138 (3) 0.0538 (9) H1B 0.1276 0.2641 0.2066 0.065\* H1C 0.0748 0.1110 0.1855 0.065\* C2 −0.1004 (3) 0.1967 (5) 0.1718 (3) 0.0569 (10) H2A −0.1012 0.0955 0.1522 0.068\* H2B −0.1660 0.2382 0.1283 0.068\* C3 −0.0189 (4) 0.4288 (4) 0.1915 (3) 0.0575 (10) H3A −0.0855 0.4713 0.1572 0.069\* H3B 0.0254 0.4863 0.1734 0.069\* ------ --------------- ------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e995 .table-wrap} ----- ------------- ------------- ------------- -------------- ------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.0256 (4) 0.0261 (4) 0.0189 (4) −0.0006 (2) 0.0108 (3) −0.00084 (19) O1W 0.0286 (10) 0.0394 (11) 0.0437 (11) −0.0001 (8) 0.0166 (9) −0.0157 (9) Mg1 0.0226 (6) 0.0232 (6) 0.0179 (6) 0.0001 (4) 0.0085 (5) −0.0008 (4) O2W 0.0254 (9) 0.0532 (13) 0.0245 (9) −0.0056 (8) 0.0091 (8) −0.0064 (8) O1 0.0425 (11) 0.0411 (11) 0.0247 (9) 0.0132 (9) 0.0095 (8) 0.0013 (8) O3W 0.0609 (14) 0.0335 (11) 0.0253 (10) −0.0144 (9) 0.0203 (10) −0.0001 (8) O2 0.0632 (15) 0.0555 (15) 0.0317 (11) 0.0207 (12) 0.0247 (11) −0.0024 (10) N1 0.0370 (13) 0.0521 (15) 0.0166 (10) 0.0083 (11) 0.0122 (10) 0.0022 (9) O3 0.0314 (11) 0.0643 (16) 0.0304 (11) −0.0149 (10) 0.0064 (9) −0.0022 (10) O4 0.0637 (15) 0.0410 (13) 0.0503 (13) −0.0170 (11) 0.0378 (13) −0.0022 (10) C1 0.052 (2) 0.073 (2) 0.0464 (19) 0.0296 (18) 0.0312 (17) 0.0097 (18) C2 0.0463 (19) 0.078 (3) 0.0433 (19) −0.0272 (19) 0.0174 (15) −0.0236 (18) C3 0.080 (3) 0.0389 (18) 0.064 (2) 0.0159 (17) 0.042 (2) 0.0226 (16) ----- ------------- ------------- ------------- -------------- ------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1267 .table-wrap} ----------------------- ------------- ----------------------- ------------- S1---O4 1.458 (2) O3W---H3WB 0.8502 S1---O2 1.462 (2) N1---C3 1.467 (5) S1---O1 1.466 (2) N1---C1 1.469 (4) S1---O3 1.482 (2) N1---C2 1.490 (5) O1W---Mg1 2.0856 (19) N1---H1 0.9100 O1W---H1WA 0.8502 C1---C2^ii^ 1.513 (5) O1W---H1WB 0.8500 C1---H1B 0.9700 Mg1---O2W 2.035 (2) C1---H1C 0.9700 Mg1---O2W^i^ 2.035 (2) C2---C1^ii^ 1.513 (5) Mg1---O3W^i^ 2.0728 (19) C2---H2A 0.9700 Mg1---O3W 2.0728 (19) C2---H2B 0.9700 Mg1---O1W^i^ 2.0856 (19) C3---C3^ii^ 1.506 (8) O2W---H2WA 0.8499 C3---H3A 0.9700 O2W---H2WB 0.8502 C3---H3B 0.9700 O3W---H3WA 0.8499 O4---S1---O2 111.89 (16) Mg1---O3W---H3WA 123.8 O4---S1---O1 110.28 (14) Mg1---O3W---H3WB 125.4 O2---S1---O1 110.80 (12) H3WA---O3W---H3WB 110.9 O4---S1---O3 106.49 (14) C3---N1---C1 111.0 (3) O2---S1---O3 109.00 (14) C3---N1---C2 109.1 (3) O1---S1---O3 108.21 (14) C1---N1---C2 110.7 (3) Mg1---O1W---H1WA 112.8 C3---N1---H1 108.7 Mg1---O1W---H1WB 134.3 C1---N1---H1 108.7 H1WA---O1W---H1WB 110.8 C2---N1---H1 108.7 O2W---Mg1---O2W^i^ 180.00 (17) N1---C1---C2^ii^ 108.5 (3) O2W---Mg1---O3W^i^ 90.55 (9) N1---C1---H1B 110.0 O2W^i^---Mg1---O3W^i^ 89.45 (9) C2^ii^---C1---H1B 110.0 O2W---Mg1---O3W 89.45 (9) N1---C1---H1C 110.0 O2W^i^---Mg1---O3W 90.55 (9) C2^ii^---C1---H1C 110.0 O3W^i^---Mg1---O3W 180.00 (13) H1B---C1---H1C 108.4 O2W---Mg1---O1W^i^ 91.10 (8) N1---C2---C1^ii^ 108.2 (3) O2W^i^---Mg1---O1W^i^ 88.90 (8) N1---C2---H2A 110.1 O3W^i^---Mg1---O1W^i^ 88.14 (9) C1^ii^---C2---H2A 110.1 O3W---Mg1---O1W^i^ 91.86 (9) N1---C2---H2B 110.1 O2W---Mg1---O1W 88.90 (8) C1^ii^---C2---H2B 110.1 O2W^i^---Mg1---O1W 91.10 (8) H2A---C2---H2B 108.4 O3W^i^---Mg1---O1W 91.86 (9) N1---C3---C3^ii^ 108.51 (18) O3W---Mg1---O1W 88.14 (9) N1---C3---H3A 110.0 O1W^i^---Mg1---O1W 180.00 (10) C3^ii^---C3---H3A 110.0 Mg1---O2W---H2WA 125.8 N1---C3---H3B 110.0 Mg1---O2W---H2WB 119.9 C3^ii^---C3---H3B 110.0 H2WA---O2W---H2WB 110.8 H3A---C3---H3B 108.4 C3---N1---C1---C2^ii^ 64.8 (4) C1---N1---C2---C1^ii^ 65.4 (4) C2---N1---C1---C2^ii^ −56.5 (4) C1---N1---C3---C3^ii^ −55.0 (5) C3---N1---C2---C1^ii^ −57.0 (5) C2---N1---C3---C3^ii^ 67.3 (5) ----------------------- ------------- ----------------------- ------------- ::: Symmetry codes: (i) −*x*+1/2, −*y*+1/2, −*z*; (ii) −*x*, *y*, −*z*+1/2. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1816 .table-wrap} ---------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1···O3^i^ 0.91 1.87 2.734 (3) 157 O1W---H1WA···O3^i^ 0.85 1.90 2.751 (3) 179 O1W---H1WB···O1^iii^ 0.85 2.01 2.835 (3) 165 O2W---H2WA···O2 0.85 2.00 2.809 (3) 158 O2W---H2WB···O2^iv^ 0.85 1.83 2.674 (3) 173 O3W---H3WA···O4^v^ 0.85 1.85 2.694 (3) 170 O3W---H3WB···O1^iv^ 0.85 1.92 2.769 (3) 177 ---------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1/2, −*y*+1/2, −*z*; (iii) *x*−1/2, *y*+1/2, *z*; (iv) −*x*+1, *y*, −*z*+1/2; (v) *x*−1/2, *y*−1/2, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------------ --------- ------- ----------- ------------- N1---H1⋯O3^i^ 0.91 1.87 2.734 (3) 157 O1*W*---H1*WA*⋯O3^i^ 0.85 1.90 2.751 (3) 179 O1*W*---H1*WB*⋯O1^ii^ 0.85 2.01 2.835 (3) 165 O2*W*---H2*WA*⋯O2 0.85 2.00 2.809 (3) 158 O2*W*---H2*WB*⋯O2^iii^ 0.85 1.83 2.674 (3) 173 O3*W*---H3*WA*⋯O4^iv^ 0.85 1.85 2.694 (3) 170 O3*W*---H3*WB*⋯O1^iii^ 0.85 1.92 2.769 (3) 177 Symmetry codes: (i) ; (ii) ; (iii) ; (iv) . :::

PubMed Central

2024-06-05T04:04:17.394448

2011-2-19

PMC3051937

Related literature {#sec1} ================== For the biological activity of thio­urea derivatives, see: Zeng *et al.* (2003[@bb9]); Saeed *et al.* (2010[@bb6]). For the synthesis of thio­urea derivatives, see: Nosova *et al.* (2007[@bb3]). For related structures, see: Saeed *et al.* (2008[@bb5], 2009[@bb7]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~15~H~9~F~4~N~3~O~2~S*M* *~r~* = 371.31Monoclinic,*a* = 7.4246 (3) Å*b* = 20.3368 (7) Å*c* = 9.8954 (4) Åβ = 95.554 (3)°*V* = 1487.12 (9) Å^3^*Z* = 4Mo *K*α radiationμ = 0.28 mm^−1^*T* = 294 K0.38 × 0.30 × 0.26 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcalibur E CCD diffractometerAbsorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2006[@bb4]) *T* ~min~ = 0.860, *T* ~max~ = 1.06598 measured reflections3031 independent reflections2263 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.014 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.036*wR*(*F* ^2^) = 0.103*S* = 1.133031 reflections226 parametersH-atom parameters constrainedΔρ~max~ = 0.31 e Å^−3^Δρ~min~ = −0.34 e Å^−3^ {#d5e502} Data collection: *CrysAlis PRO* (Oxford Diffraction, 2006[@bb4]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb8]); molecular graphics: *OLEX2* (Dolomanov *et al.*, 2009[@bb1]) and *Mercury* (Macrae *et al.*, 2006[@bb2]); software used to prepare material for publication: *OLEX2*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005915/gk2335sup1.cif](http://dx.doi.org/10.1107/S1600536811005915/gk2335sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005915/gk2335Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005915/gk2335Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?gk2335&file=gk2335sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?gk2335sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?gk2335&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [GK2335](http://scripts.iucr.org/cgi-bin/sendsup?gk2335)). We thank the Analytical and Testing Center of Sichuan University for the X-ray measurements. Comment ======= *N*-(4-Carbamoylphenylcarbamothioyl)-2,3,4,5-tetrafluorobenzamide derivatives are of great importance owing to their interesting biological properties (Zeng *et al.*, 2003; Saeed *et al.*, 2010). The title compound is one of the key intermediates in our synthetic route to antiviral drugs. We report here its crystal structure. In the title compound, C~15~H~9~F~4~N~3~O~2~S, (Fig.1), the *cis,trans* geometry of the thiourea moiety is stabilized by intramolecular N2---H2···O2 and N3---H3···F1 hydrogen bonds. The central thiourea group makes dihedral angles of 47.79 (7) and 35.54 (8)° with the benzamide unit and the fluorobenzene ring, respectively. A combination of intermolecular π--π stacking interactions, N---H···O, N---H···F and N---H···S hydrogen bonds helps to stabilize the crystal structure (Table 1 and Fig.2). Experimental {#experimental} ============ A solution of 0.23 g (3 mmol) of ammonium thiocyanate in 7 ml of acetonitrile was added to a solution of 0.64 g (3 mmol) of 2,3,4,5-tetrafluorobenzoyl chloride in 2.5 ml of toluene. The mixture was heated for 5 min at 40°C and filtered from ammonium chloride, the filtrate was added to a solution of 0.32 g (3 mmol) of 4-aminobenzamide in 5 ml of acetonitrile, the mixture was stirred for 2 h at room temperature and evaporated, and the residue was washed with ethanol and recrystallized from ethanol. Yield 0.91 g (82%). Crystals suitable for X-ray analysis were obtained by slow evaporation from ethyl acetate solution. Refinement {#refinement} ========== All H atoms were positioned geometrically (C---H = 0.93 Å, N---H = 0.86 Å) and refined using a riding model approximation with *U*~iso~(H) = 1.2*U*~eq~(C,*N*). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound, with displacement ellipsoids drawn at the 30% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### A packing diagram of the title compound, showing classical hydrogen bonds of N1---H1A···O1, N2---H2···O2 and N3---H3···O1 as green dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e143 .table-wrap} ------------------------- --------------------------------------- C~15~H~9~F~4~N~3~O~2~S *F*(000) = 752 *M~r~* = 371.31 *D*~x~ = 1.658 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.7107 Å Hall symbol: -P 2ybc Cell parameters from 3669 reflections *a* = 7.4246 (3) Å θ = 3.3--29.2° *b* = 20.3368 (7) Å µ = 0.28 mm^−1^ *c* = 9.8954 (4) Å *T* = 294 K β = 95.554 (3)° Block, colourless *V* = 1487.12 (9) Å^3^ 0.38 × 0.30 × 0.26 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e277 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction Xcalibur E CCD diffractometer 3031 independent reflections Radiation source: fine-focus sealed tube 2263 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.014 Detector resolution: 16.0874 pixels mm^-1^ θ~max~ = 26.4°, θ~min~ = 3.4° ω scans *h* = −9→9 Absorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2006) *k* = −25→21 *T*~min~ = 0.860, *T*~max~ = 1.0 *l* = −11→12 6598 measured reflections ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e397 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.036 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.103 H-atom parameters constrained *S* = 1.13 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.056*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 3031 reflections (Δ/σ)~max~ \< 0.001 226 parameters Δρ~max~ = 0.31 e Å^−3^ 0 restraints Δρ~min~ = −0.34 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------ ::: Special details {#specialdetails} =============== ::: {#d1e551 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e650 .table-wrap} ----- -------------- ------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ S1 0.41600 (7) 0.40876 (2) 0.28889 (6) 0.05125 (18) F 0.98701 (18) 0.10215 (6) −0.07009 (12) 0.0623 (4) F1 0.66951 (14) 0.21050 (5) 0.34645 (9) 0.0445 (3) F2 0.72451 (16) 0.08149 (5) 0.33952 (12) 0.0543 (3) F3 0.87569 (17) 0.02540 (5) 0.12899 (13) 0.0635 (4) O1 0.66762 (17) 0.73716 (6) 0.33958 (11) 0.0386 (3) O2 0.91223 (18) 0.33325 (6) 0.09914 (14) 0.0471 (3) N1 0.7405 (2) 0.75363 (7) 0.12865 (14) 0.0434 (4) H1B 0.7340 0.7956 0.1382 0.052\* H1A 0.7683 0.7373 0.0532 0.052\* N2 0.7175 (2) 0.43553 (7) 0.17165 (14) 0.0390 (4) H2 0.8046 0.4200 0.1300 0.047\* N3 0.64026 (19) 0.32604 (7) 0.18763 (14) 0.0356 (3) H3 0.5580 0.2981 0.2036 0.043\* C1 0.7076 (2) 0.71401 (8) 0.23066 (16) 0.0304 (4) C2 0.7164 (2) 0.64135 (8) 0.21097 (16) 0.0286 (4) C3 0.7548 (3) 0.61151 (9) 0.09123 (18) 0.0392 (4) H3A 0.7823 0.6372 0.0182 0.047\* C4 0.7524 (3) 0.54374 (9) 0.07970 (18) 0.0425 (5) H4 0.7771 0.5241 −0.0013 0.051\* C5 0.7133 (2) 0.50499 (8) 0.18833 (17) 0.0343 (4) C6 0.6795 (2) 0.53412 (8) 0.30877 (17) 0.0367 (4) H6 0.6566 0.5083 0.3828 0.044\* C7 0.6796 (2) 0.60191 (8) 0.31958 (16) 0.0329 (4) H7 0.6546 0.6214 0.4007 0.039\* C8 0.6006 (2) 0.39170 (8) 0.21371 (17) 0.0345 (4) C9 0.7920 (2) 0.30012 (9) 0.14025 (17) 0.0338 (4) C10 0.8043 (2) 0.22623 (8) 0.14010 (16) 0.0315 (4) C11 0.8887 (2) 0.19686 (9) 0.03581 (18) 0.0369 (4) H11 0.9315 0.2228 −0.0316 0.044\* C12 0.9089 (2) 0.13022 (9) 0.03208 (19) 0.0410 (4) C13 0.8521 (3) 0.09051 (8) 0.1325 (2) 0.0414 (5) C14 0.7735 (2) 0.11852 (8) 0.23825 (18) 0.0369 (4) C15 0.7476 (2) 0.18583 (8) 0.24020 (16) 0.0326 (4) ----- -------------- ------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1103 .table-wrap} ----- ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.0543 (3) 0.0289 (3) 0.0750 (4) 0.0028 (2) 0.0295 (3) −0.0031 (2) F 0.0717 (9) 0.0532 (7) 0.0638 (8) 0.0202 (6) 0.0162 (6) −0.0171 (6) F1 0.0550 (7) 0.0402 (6) 0.0394 (6) 0.0026 (5) 0.0093 (5) 0.0001 (5) F2 0.0617 (8) 0.0366 (6) 0.0643 (7) −0.0022 (5) 0.0052 (6) 0.0184 (5) F3 0.0688 (8) 0.0237 (6) 0.0975 (10) 0.0083 (5) 0.0051 (7) −0.0067 (6) O1 0.0568 (8) 0.0293 (7) 0.0305 (6) 0.0036 (6) 0.0085 (6) −0.0027 (5) O2 0.0453 (8) 0.0312 (7) 0.0677 (9) −0.0037 (6) 0.0199 (7) 0.0007 (6) N1 0.0702 (11) 0.0250 (8) 0.0374 (8) −0.0013 (7) 0.0174 (8) 0.0019 (7) N2 0.0480 (9) 0.0228 (7) 0.0488 (9) −0.0001 (7) 0.0181 (7) −0.0001 (7) N3 0.0392 (8) 0.0215 (7) 0.0481 (9) 0.0008 (6) 0.0145 (7) 0.0009 (6) C1 0.0333 (9) 0.0274 (9) 0.0303 (9) 0.0002 (7) 0.0031 (7) 0.0003 (7) C2 0.0310 (9) 0.0245 (9) 0.0303 (8) 0.0002 (7) 0.0028 (7) 0.0005 (7) C3 0.0559 (12) 0.0280 (9) 0.0359 (10) −0.0041 (8) 0.0166 (9) 0.0013 (8) C4 0.0614 (12) 0.0293 (10) 0.0398 (10) −0.0009 (9) 0.0206 (9) −0.0057 (8) C5 0.0409 (10) 0.0213 (9) 0.0416 (10) −0.0004 (7) 0.0075 (8) 0.0002 (7) C6 0.0509 (11) 0.0273 (9) 0.0319 (9) −0.0022 (8) 0.0037 (8) 0.0056 (7) C7 0.0432 (10) 0.0288 (9) 0.0269 (8) −0.0004 (7) 0.0042 (7) −0.0007 (7) C8 0.0434 (10) 0.0233 (9) 0.0371 (9) 0.0023 (7) 0.0060 (8) 0.0010 (7) C9 0.0368 (10) 0.0271 (9) 0.0377 (9) 0.0016 (7) 0.0045 (7) 0.0004 (7) C10 0.0310 (9) 0.0252 (9) 0.0380 (9) 0.0018 (7) 0.0015 (7) −0.0003 (7) C11 0.0342 (9) 0.0341 (10) 0.0426 (10) 0.0040 (8) 0.0043 (8) 0.0013 (8) C12 0.0387 (10) 0.0364 (10) 0.0475 (11) 0.0104 (8) 0.0022 (8) −0.0113 (9) C13 0.0389 (10) 0.0221 (9) 0.0612 (12) 0.0040 (8) −0.0061 (9) −0.0046 (9) C14 0.0350 (10) 0.0275 (9) 0.0469 (10) −0.0027 (7) −0.0032 (8) 0.0060 (8) C15 0.0296 (9) 0.0313 (9) 0.0366 (9) 0.0018 (7) 0.0022 (7) −0.0011 (8) ----- ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1571 .table-wrap} ---------------------- -------------- ----------------------- -------------- S1---C8 1.6583 (18) C2---C7 1.389 (2) F---C12 1.341 (2) C3---H3A 0.9300 F1---C15 1.3458 (18) C3---C4 1.383 (2) F2---C14 1.332 (2) C4---H4 0.9300 F3---C13 1.3365 (18) C4---C5 1.386 (2) O1---C1 1.2383 (18) C5---C6 1.376 (2) O2---C9 1.219 (2) C6---H6 0.9300 N1---H1B 0.8600 C6---C7 1.383 (2) N1---H1A 0.8600 C7---H7 0.9300 N1---C1 1.333 (2) C9---C10 1.505 (2) N2---H2 0.8600 C10---C11 1.393 (2) N2---C5 1.423 (2) C10---C15 1.384 (2) N2---C8 1.338 (2) C11---H11 0.9300 N3---H3 0.8600 C11---C12 1.364 (2) N3---C8 1.397 (2) C12---C13 1.378 (3) N3---C9 1.367 (2) C13---C14 1.370 (3) C1---C2 1.493 (2) C14---C15 1.383 (2) C2---C3 1.385 (2) F---C12---C11 119.99 (18) C4---C3---H3A 119.8 F---C12---C13 118.62 (16) C4---C5---N2 117.77 (15) F1---C15---C10 121.45 (14) C5---N2---H2 116.5 F1---C15---C14 116.81 (15) C5---C4---H4 119.8 F2---C14---C13 120.47 (15) C5---C6---H6 120.1 F2---C14---C15 120.04 (16) C5---C6---C7 119.84 (15) F3---C13---C12 120.80 (18) C6---C5---N2 122.40 (15) F3---C13---C14 119.87 (18) C6---C5---C4 119.77 (15) O1---C1---N1 120.43 (15) C6---C7---C2 120.96 (15) O1---C1---C2 120.47 (14) C6---C7---H7 119.5 O2---C9---N3 123.76 (16) C7---C2---C1 117.15 (14) O2---C9---C10 120.32 (15) C7---C6---H6 120.1 N1---C1---C2 119.09 (14) C8---N2---H2 116.5 H1B---N1---H1A 120.0 C8---N2---C5 127.09 (15) N2---C8---S1 126.10 (13) C8---N3---H3 115.6 N2---C8---N3 115.14 (15) C9---N3---H3 115.6 N3---C8---S1 118.75 (12) C9---N3---C8 128.85 (14) N3---C9---C10 115.92 (14) C10---C11---H11 119.9 C1---N1---H1B 120.0 C11---C10---C9 117.41 (15) C1---N1---H1A 120.0 C11---C12---C13 121.38 (17) C2---C3---H3A 119.8 C12---C11---C10 120.29 (17) C2---C7---H7 119.5 C12---C11---H11 119.9 C3---C2---C1 124.10 (15) C13---C14---C15 119.49 (16) C3---C2---C7 118.74 (15) C14---C13---C12 119.32 (15) C3---C4---H4 119.8 C14---C15---C10 121.71 (15) C3---C4---C5 120.31 (16) C15---C10---C9 124.72 (15) C4---C3---C2 120.34 (16) C15---C10---C11 117.75 (15) F---C12---C13---F3 0.6 (3) C5---N2---C8---N3 −178.02 (15) F---C12---C13---C14 179.40 (16) C5---C6---C7---C2 −1.1 (3) F2---C14---C15---F1 −1.0 (2) C7---C2---C3---C4 1.4 (3) F2---C14---C15---C10 177.00 (15) C8---N2---C5---C4 −138.63 (19) F3---C13---C14---F2 1.7 (3) C8---N2---C5---C6 44.1 (3) F3---C13---C14---C15 −179.20 (15) C8---N3---C9---O2 −8.1 (3) O1---C1---C2---C3 178.02 (16) C8---N3---C9---C10 172.27 (16) O1---C1---C2---C7 −0.5 (2) C9---N3---C8---S1 −172.62 (14) O2---C9---C10---C11 −33.5 (2) C9---N3---C8---N2 8.7 (3) O2---C9---C10---C15 142.48 (18) C9---C10---C11---C12 178.10 (15) N1---C1---C2---C3 −0.9 (3) C9---C10---C15---F1 2.2 (2) N1---C1---C2---C7 −179.44 (15) C9---C10---C15---C14 −175.74 (15) N2---C5---C6---C7 179.11 (16) C10---C11---C12---F 178.65 (16) N3---C9---C10---C11 146.16 (16) C10---C11---C12---C13 −2.0 (3) N3---C9---C10---C15 −37.9 (2) C11---C10---C15---F1 178.11 (14) C1---C2---C3---C4 −177.14 (16) C11---C10---C15---C14 0.2 (2) C1---C2---C7---C6 178.11 (16) C11---C12---C13---F3 −178.74 (16) C2---C3---C4---C5 −0.6 (3) C11---C12---C13---C14 0.1 (3) C3---C2---C7---C6 −0.5 (3) C12---C13---C14---F2 −177.14 (15) C3---C4---C5---N2 −178.38 (17) C12---C13---C14---C15 2.0 (3) C3---C4---C5---C6 −1.0 (3) C13---C14---C15---F1 179.87 (15) C4---C5---C6---C7 1.9 (3) C13---C14---C15---C10 −2.1 (3) C5---N2---C8---S1 3.4 (3) C15---C10---C11---C12 1.9 (2) ---------------------- -------------- ----------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2257 .table-wrap} ------------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1B···S1^i^ 0.86 2.69 3.4861 (16) 155 N1---H1A···O1^ii^ 0.86 2.23 2.8654 (17) 130 N2---H2···O2 0.86 1.97 2.6708 (18) 138 N3---H3···F1 0.86 2.37 2.8234 (17) 113 N3---H3···O1^iii^ 0.86 2.09 2.9062 (18) 157 ------------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) −*x*+1, *y*+1/2, −*z*+1/2; (ii) *x*, −*y*+3/2, *z*−1/2; (iii) −*x*+1, *y*−1/2, −*z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------- --------- ------- ------------- ------------- N1---H1*B*⋯S1^i^ 0.86 2.69 3.4861 (16) 155 N1---H1*A*⋯O1^ii^ 0.86 2.23 2.8654 (17) 130 N2---H2⋯O2 0.86 1.97 2.6708 (18) 138 N3---H3⋯O1^iii^ 0.86 2.09 2.9062 (18) 157 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.398485

2011-2-23

PMC3051938

Related literature {#sec1} ================== For our study on the effect of substituents on the structures of this class of compounds, see: Gowda *et al.* (2007[@bb3], 2009[@bb2], 2010[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~32~H~30~Cl~4~N~4~*M* *~r~* = 612.40Monoclinic,*a* = 22.349 (3) Å*b* = 13.223 (2) Å*c* = 22.644 (3) Åβ = 108.79 (1)°*V* = 6335.1 (15) Å^3^*Z* = 8Cu *K*α radiationμ = 3.61 mm^−1^*T* = 299 K0.35 × 0.28 × 0.25 mm ### Data collection {#sec2.1.2} Enraf--Nonius CAD-4 diffractometerAbsorption correction: ψ scan (North *et al.*, 1968[@bb5]) *T* ~min~ = 0.365, *T* ~max~ = 0.46611300 measured reflections5657 independent reflections3976 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.0573 standard reflections every 120 min intensity decay: 1.0% ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.080*wR*(*F* ^2^) = 0.251*S* = 1.135657 reflections381 parameters41 restraintsH-atom parameters constrainedΔρ~max~ = 1.08 e Å^−3^Δρ~min~ = −0.80 e Å^−3^ {#d5e443} Data collection: *CAD-4-PC* (Enraf--Nonius, 1996[@bb1]); cell refinement: *CAD-4-PC*; data reduction: *REDU4* (Stoe & Cie, 1987[@bb8]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb6]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb6]); molecular graphics: *PLATON* (Spek, 2009[@bb7]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004612/bq2276sup1.cif](http://dx.doi.org/10.1107/S1600536811004612/bq2276sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004612/bq2276Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004612/bq2276Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?bq2276&file=bq2276sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?bq2276sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?bq2276&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BQ2276](http://scripts.iucr.org/cgi-bin/sendsup?bq2276)). VZR thanks the University Grants Commission, Government of India, New Delhi, for award of a research fellowship. Comment ======= The amidine moiety is an important constituent of many biologically significant compounds. As a part of studying the effect of substitutions on the structures of this class of compounds (Gowda *et al.*, 2007; 2009; 2010), the crystal structure of *N^1^*,*N^1^*-Bis(3-chlorophenyl)- *N^2^*,*N^2^*-bis(3-χhlorophenyl)-suberamidine has been determined (I) (Fig. 1). The conformations of N---H bond is *syn* to the *meta*-chloro substituent in the adjacent benzene ring. The torsion angles of C1---N1---C7---N2, C1---N1---C7---C14, C8---N2---C7---N1 C8---N2---C7---C14, N1---C7---C14---C15 and N2---C7---C14---C15 are 172.6 (3)°, -12.9 (6)°, -8.8 (6)°, 176.2 (4)°, -86.5 (5)° and 88.4 (4)°, while those of C17---N3---C23---N4, C17---N3---C23---C30, C24---N4---C23---N3, C24---N4---C23---C30, N3---C23---C30---C31 and N4---C23---C30---C31 are 172.7 (3)°, -11.1 (5)°, -14.3 (5)°, 169.0 (3)°, 128.2 (4)° and -55.5 (4)°. The conformations of the amine groups with respect to the attached phenyl rings are given by the torsion angles of C2---C1---N1---C7 = -80.6 (4), C6---C1---N1---C7 = 106.1 (4), C13---C8---N2---C7 = 153.8 (4), C9---C8---N2---C7 = -27.9 (5), C18---C17---N3---C23 = 103.0 (5), C22---C17---N3---C23 = -80.3 (5), C29---C24---N4---C23 = -41.3 (6), C25---C24---N4---C23 = 143.0 (4) In the structure, two sets of phenyl rings make inter planar angles of 74.3 (2)° (C1/C6 and C8/C13 rings) and 63.0 (2)° (C17/C22 and C24/C29 rings). Further, C1/C6 phenyl ring makes a dihedral angle of 88.5 (2)° with the plane of the aliphatic group N1---C7---C14---C15---C16 and C8/C13 ring makes the angle of 20.7 (5)° with the plane of the group N2---C7---C14---C15---C16, while C17/C22 phenyl ring makes a dihedral angle of 78.9 (4)° with the plane of the group, N3---C23---C30---C31---C32 and C24/C29 ring makes the angle of 75.1 (2)° with the plane of the group, N4---C23---C30---C31---C32. Atoms Cl2 and Cl4 in (I) are disordered and were refined using a split model. The site-occupation factors were refined so that their sum was unity \[0.79 (2) and 0.22 (2) for Cl2, 0.68 (1) and 0.32 (1) for Cl4, respectively\]. The corresponding bond distances in the disordered groups were restrained to be equal. The intermolecular N--H···N hydrogen bonds (Table 1) link the molecules into infinite chains (Fig. 2). Experimental {#experimental} ============ Suberic acid (0.2 mol) was heated with Phosphorus oxychloride (1.2 mol) at 70°C for 2 h. The acid chloride obtained was treated with 3-chloroaniline (0.8 mol). The product obtained was added to crushed ice to obtain the precipitate. It was thoroughly washed with water and then with saturated sodium bicarbonate solution and washed again with water. It was then given a wash with 2 N HCl. It was again washed with water, filtered, dried and recrystallized from ethanol. Prism like colorless single crystals of the title compound used in x-ray diffraction studies were obtained by a slow evaporation of its solution at room temperature. Refinement {#refinement} ========== The H atoms of the NH groups were located in a difference map and later restrained to the distance N---H = 0.86 (2) Å. The other H atoms were positioned with idealized geometry using a riding model with C---H = 0.93--0.97 Å. All H atoms were refined with isotropic displacement parameters (set to 1.2 times of the *U*~eq~ of the parent atom). Atoms Cl2 and Cl4 are disordered and were refined using a split model. The corresponding site-occupation factors were refined so that their sum was unity \[0.79 (2) and 0.21 (2) for Cl2, 0.68 (1) and 0.32 (1) for Cl4, respectively\] and their corresponding bond distances in the disordered groups were restrained to be equal. The U^ij^ components of Cl2, Cl4, C16 and C27 were restrained to approximate isotropic behavior. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Molecular structure of (I), showing the atom labeling and displacement ellipsoids drawn at the 50% probability level. Both disorder components are shown. The minor disorder components are shown with dashed bonds. Symmetry codes for the unlabeled atoms: -x+1, y, -z+1/2 and -x+3/2, -y+1/2, -z+1. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Molecular packing of (I) with hydrogen bonding shown as dashed lines. For more clarity the minor disorder components were omitted. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e150 .table-wrap} ------------------------ ------------------------------------- C~32~H~30~Cl~4~N~4~ *F*(000) = 2544 *M~r~* = 612.40 *D*~x~ = 1.284 Mg m^−3^ Monoclinic, *C*2/*c* Cu *K*α radiation, λ = 1.54180 Å Hall symbol: -C 2yc Cell parameters from 25 reflections *a* = 22.349 (3) Å θ = 4.1--18.3° *b* = 13.223 (2) Å µ = 3.61 mm^−1^ *c* = 22.644 (3) Å *T* = 299 K β = 108.79 (1)° Prism, colourless *V* = 6335.1 (15) Å^3^ 0.35 × 0.28 × 0.25 mm *Z* = 8 ------------------------ ------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e277 .table-wrap} ------------------------------------------------------ -------------------------------------- Enraf--Nonius CAD-4 diffractometer 3976 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.057 graphite θ~max~ = 67.0°, θ~min~ = 3.9° ω/2θ scans *h* = −26→26 Absorption correction: ψ scan (North *et al.*, 1968) *k* = −15→0 *T*~min~ = 0.365, *T*~max~ = 0.466 *l* = −27→27 11300 measured reflections 3 standard reflections every 120 min 5657 independent reflections intensity decay: 1.0% ------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e402 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.080 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.251 H-atom parameters constrained *S* = 1.13 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.1192*P*)^2^ + 8.1108*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 5657 reflections (Δ/σ)~max~ = 0.012 381 parameters Δρ~max~ = 1.08 e Å^−3^ 41 restraints Δρ~min~ = −0.80 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e559 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e658 .table-wrap} ------ -------------- -------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) C1 0.63535 (16) 0.8110 (3) 0.10493 (18) 0.0540 (9) C2 0.61041 (18) 0.7419 (4) 0.0579 (2) 0.0638 (11) H2 0.6206 0.6737 0.0650 0.077\* C3 0.57069 (19) 0.7723 (5) 0.0006 (2) 0.0774 (14) C4 0.5548 (2) 0.8728 (5) −0.0114 (3) 0.0926 (18) H4 0.5283 0.8933 −0.0504 0.111\* C5 0.5787 (2) 0.9407 (5) 0.0347 (3) 0.0955 (19) H5 0.5678 1.0085 0.0272 0.115\* C6 0.6187 (2) 0.9125 (4) 0.0929 (3) 0.0751 (13) H6 0.6344 0.9609 0.1238 0.090\* C7 0.66481 (15) 0.7380 (3) 0.20450 (18) 0.0492 (8) C8 0.77434 (16) 0.6888 (3) 0.26857 (18) 0.0478 (8) C9 0.80067 (18) 0.6761 (3) 0.2217 (2) 0.0620 (10) H9 0.7756 0.6764 0.1799 0.074\* C10 0.8655 (2) 0.6627 (4) 0.2385 (3) 0.0802 (14) C11 0.9041 (2) 0.6637 (5) 0.2994 (3) 0.0901 (17) H11 0.9477 0.6566 0.3095 0.108\* C12 0.8765 (2) 0.6757 (4) 0.3453 (3) 0.0830 (15) H12 0.9015 0.6754 0.3870 0.100\* C13 0.8120 (2) 0.6880 (3) 0.3298 (2) 0.0657 (11) H13 0.7939 0.6958 0.3611 0.079\* C14 0.59767 (18) 0.7315 (4) 0.2054 (2) 0.0710 (13) H14A 0.5928 0.6712 0.2278 0.085\* H14B 0.5690 0.7264 0.1631 0.085\* C15 0.5809 (3) 0.8240 (6) 0.2367 (3) 0.117 (2) H15A 0.5921 0.8852 0.2190 0.140\* H15B 0.6038 0.8231 0.2810 0.140\* C16 0.5112 (4) 0.8207 (10) 0.2255 (3) 0.199 (4) H16A 0.4926 0.8784 0.1996 0.238\* H16B 0.4949 0.7606 0.2011 0.238\* C17 0.63312 (17) 0.6138 (3) 0.38310 (17) 0.0518 (9) C18 0.6569 (2) 0.7033 (4) 0.4113 (2) 0.0776 (14) H18 0.6913 0.7335 0.4038 0.093\* C19 0.6292 (3) 0.7482 (4) 0.4511 (3) 0.0897 (16) C20 0.5771 (2) 0.7112 (5) 0.4608 (2) 0.0844 (15) H20 0.5567 0.7467 0.4842 0.101\* C21 0.5554 (3) 0.6213 (5) 0.4355 (3) 0.0998 (19) H21 0.5220 0.5910 0.4449 0.120\* C22 0.5819 (3) 0.5725 (4) 0.3954 (3) 0.0885 (17) H22 0.5649 0.5117 0.3769 0.106\* C23 0.69546 (16) 0.4917 (3) 0.35604 (16) 0.0447 (8) C24 0.68501 (19) 0.4508 (3) 0.24635 (17) 0.0528 (9) C25 0.7241 (2) 0.4475 (3) 0.21015 (19) 0.0644 (11) H25 0.7677 0.4434 0.2285 0.077\* C26 0.6968 (4) 0.4506 (4) 0.1452 (2) 0.0906 (18) C27 0.6336 (4) 0.4577 (5) 0.1182 (3) 0.104 (2) H27 0.6162 0.4606 0.0750 0.125\* C28 0.5958 (3) 0.4607 (5) 0.1543 (3) 0.110 (2) H28 0.5522 0.4660 0.1356 0.132\* C29 0.6208 (2) 0.4560 (4) 0.2186 (2) 0.0784 (13) H29 0.5942 0.4564 0.2429 0.094\* C30 0.72564 (18) 0.4535 (3) 0.42161 (16) 0.0509 (8) H30A 0.7085 0.4913 0.4492 0.061\* H30B 0.7706 0.4673 0.4342 0.061\* C31 0.71619 (18) 0.3416 (3) 0.43018 (17) 0.0526 (9) H31A 0.7307 0.3034 0.4008 0.063\* H31B 0.6715 0.3281 0.4211 0.063\* C32 0.75182 (19) 0.3065 (3) 0.49619 (17) 0.0524 (9) H32A 0.7958 0.3263 0.5067 0.063\* H32B 0.7344 0.3400 0.5251 0.063\* Cl1 0.53949 (8) 0.68487 (18) −0.05730 (8) 0.1244 (7) Cl2A 0.8972 (3) 0.6372 (10) 0.1775 (3) 0.125 (2) 0.79 (2) Cl2B 0.9069 (5) 0.695 (2) 0.1895 (8) 0.092 (6) 0.21 (2) Cl3 0.74629 (14) 0.44327 (16) 0.10060 (9) 0.1560 (10) Cl4A 0.6688 (3) 0.8514 (4) 0.4962 (3) 0.123 (2) 0.677 (14) Cl4B 0.6346 (7) 0.8849 (7) 0.4577 (9) 0.154 (4) 0.323 (14) N1 0.68110 (12) 0.7822 (2) 0.16139 (14) 0.0510 (7) N2 0.70837 (13) 0.6998 (2) 0.25587 (14) 0.0508 (7) H2A 0.6941 0.6794 0.2848 0.061\* N3 0.65826 (15) 0.5678 (2) 0.33991 (14) 0.0522 (7) N4 0.71358 (15) 0.4416 (2) 0.31194 (13) 0.0519 (7) H4A 0.7451 0.4009 0.3250 0.062\* ------ -------------- -------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1575 .table-wrap} ------ ------------- ------------- ------------- -------------- ------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0362 (16) 0.065 (2) 0.063 (2) −0.0013 (16) 0.0191 (16) 0.0114 (19) C2 0.049 (2) 0.075 (3) 0.072 (3) −0.0037 (19) 0.026 (2) 0.006 (2) C3 0.044 (2) 0.118 (4) 0.071 (3) −0.013 (2) 0.020 (2) 0.001 (3) C4 0.058 (3) 0.120 (5) 0.089 (4) 0.004 (3) 0.008 (3) 0.038 (4) C5 0.062 (3) 0.090 (4) 0.120 (5) 0.011 (3) 0.009 (3) 0.040 (4) C6 0.054 (2) 0.064 (3) 0.098 (3) 0.0056 (19) 0.013 (2) 0.016 (3) C7 0.0392 (17) 0.050 (2) 0.064 (2) 0.0006 (14) 0.0234 (16) 0.0047 (17) C8 0.0425 (17) 0.0381 (17) 0.063 (2) 0.0004 (14) 0.0169 (16) 0.0077 (16) C9 0.050 (2) 0.072 (3) 0.069 (3) 0.0139 (18) 0.0263 (19) 0.016 (2) C10 0.053 (2) 0.097 (4) 0.100 (4) 0.020 (2) 0.037 (2) 0.030 (3) C11 0.047 (2) 0.103 (4) 0.115 (4) 0.011 (2) 0.018 (3) 0.027 (3) C12 0.057 (2) 0.091 (4) 0.085 (3) 0.001 (2) 0.000 (2) 0.009 (3) C13 0.061 (2) 0.067 (3) 0.065 (3) 0.003 (2) 0.016 (2) 0.003 (2) C14 0.0414 (19) 0.096 (3) 0.082 (3) −0.001 (2) 0.0286 (19) 0.024 (3) C15 0.077 (3) 0.177 (7) 0.113 (5) 0.050 (4) 0.055 (3) 0.009 (5) C16 0.107 (5) 0.317 (10) 0.190 (8) 0.058 (6) 0.072 (5) −0.038 (7) C17 0.054 (2) 0.055 (2) 0.0505 (19) 0.0127 (16) 0.0225 (16) 0.0046 (17) C18 0.080 (3) 0.076 (3) 0.094 (3) −0.015 (2) 0.053 (3) −0.026 (3) C19 0.109 (4) 0.082 (3) 0.101 (4) −0.013 (3) 0.065 (3) −0.032 (3) C20 0.077 (3) 0.104 (4) 0.085 (3) 0.007 (3) 0.044 (3) −0.025 (3) C21 0.083 (3) 0.127 (5) 0.113 (4) −0.023 (3) 0.064 (3) −0.032 (4) C22 0.093 (3) 0.089 (4) 0.107 (4) −0.028 (3) 0.064 (3) −0.032 (3) C23 0.0500 (18) 0.0448 (18) 0.0433 (17) 0.0003 (15) 0.0206 (15) 0.0021 (15) C24 0.072 (2) 0.0434 (19) 0.0433 (18) 0.0061 (17) 0.0195 (17) −0.0022 (16) C25 0.100 (3) 0.047 (2) 0.054 (2) 0.008 (2) 0.036 (2) 0.0037 (18) C26 0.172 (6) 0.054 (3) 0.060 (3) 0.016 (3) 0.056 (3) 0.003 (2) C27 0.152 (5) 0.081 (4) 0.058 (3) 0.024 (4) 0.003 (3) −0.004 (3) C28 0.112 (5) 0.107 (5) 0.079 (4) 0.022 (4) −0.014 (4) −0.022 (4) C29 0.075 (3) 0.083 (3) 0.067 (3) 0.004 (2) 0.008 (2) −0.010 (2) C30 0.059 (2) 0.051 (2) 0.0449 (19) 0.0078 (16) 0.0199 (16) 0.0033 (16) C31 0.056 (2) 0.054 (2) 0.049 (2) 0.0063 (16) 0.0190 (16) 0.0091 (16) C32 0.062 (2) 0.054 (2) 0.0449 (18) 0.0097 (17) 0.0221 (16) 0.0059 (16) Cl1 0.0920 (10) 0.187 (2) 0.0875 (10) −0.0210 (11) 0.0193 (8) −0.0408 (11) Cl2A 0.0884 (18) 0.174 (6) 0.139 (2) 0.049 (3) 0.0729 (17) 0.027 (3) Cl2B 0.056 (4) 0.138 (11) 0.096 (6) 0.032 (5) 0.043 (4) 0.032 (6) Cl3 0.283 (3) 0.1340 (16) 0.1014 (12) 0.0364 (16) 0.1314 (17) 0.0228 (11) Cl4A 0.159 (4) 0.116 (3) 0.124 (3) −0.053 (2) 0.088 (3) −0.066 (2) Cl4B 0.195 (8) 0.116 (5) 0.171 (9) 0.002 (5) 0.088 (7) −0.069 (5) N1 0.0355 (14) 0.0593 (18) 0.0599 (18) −0.0003 (12) 0.0177 (13) 0.0126 (15) N2 0.0437 (15) 0.0574 (18) 0.0564 (17) 0.0006 (13) 0.0232 (13) 0.0100 (14) N3 0.0661 (19) 0.0493 (17) 0.0488 (16) 0.0118 (14) 0.0293 (14) 0.0063 (14) N4 0.0592 (17) 0.0569 (18) 0.0432 (15) 0.0162 (14) 0.0216 (13) 0.0029 (13) ------ ------------- ------------- ------------- -------------- ------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2303 .table-wrap} -------------------------- ------------- --------------------------- ------------ C1---C2 1.378 (6) C17---C22 1.375 (6) C1---C6 1.395 (6) C17---N3 1.413 (5) C1---N1 1.409 (5) C18---C19 1.383 (6) C2---C3 1.375 (6) C18---H18 0.9300 C2---H2 0.9300 C19---C20 1.344 (7) C3---C4 1.380 (8) C19---Cl4A 1.763 (6) C3---Cl1 1.718 (6) C19---Cl4B 1.815 (10) C4---C5 1.351 (9) C20---C21 1.340 (8) C4---H4 0.9300 C20---H20 0.9300 C5---C6 1.384 (7) C21---C22 1.391 (7) C5---H5 0.9300 C21---H21 0.9300 C6---H6 0.9300 C22---H22 0.9300 C7---N1 1.287 (5) C23---N3 1.281 (5) C7---N2 1.351 (5) C23---N4 1.364 (4) C7---C14 1.510 (5) C23---C30 1.506 (5) C8---C13 1.370 (6) C24---C29 1.371 (6) C8---C9 1.381 (6) C24---C25 1.377 (6) C8---N2 1.416 (4) C24---N4 1.420 (5) C9---C10 1.386 (6) C25---C26 1.399 (7) C9---H9 0.9300 C25---H25 0.9300 C10---C11 1.371 (8) C26---C27 1.348 (9) C10---Cl2B 1.712 (10) C26---Cl3 1.725 (6) C10---Cl2A 1.777 (7) C27---C28 1.353 (10) C11---C12 1.378 (8) C27---H27 0.9300 C11---H11 0.9300 C28---C29 1.383 (8) C12---C13 1.379 (6) C28---H28 0.9300 C12---H12 0.9300 C29---H29 0.9300 C13---H13 0.9300 C30---C31 1.516 (5) C14---C15 1.518 (8) C30---H30A 0.9700 C14---H14A 0.9700 C30---H30B 0.9700 C14---H14B 0.9700 C31---C32 1.522 (5) C15---C16 1.498 (10) C31---H31A 0.9700 C15---H15A 0.9700 C31---H31B 0.9700 C15---H15B 0.9700 C32---C32^ii^ 1.509 (8) C16---C16^i^ 1.355 (9) C32---H32A 0.9700 C16---H16A 0.9700 C32---H32B 0.9700 C16---H16B 0.9700 N2---H2A 0.8600 C17---C18 1.368 (6) N4---H4A 0.8600 C2---C1---C6 118.1 (4) C17---C18---H18 120.4 C2---C1---N1 121.1 (4) C19---C18---H18 120.4 C6---C1---N1 120.5 (4) C20---C19---C18 122.9 (5) C3---C2---C1 120.8 (5) C20---C19---Cl4A 119.2 (4) C3---C2---H2 119.6 C18---C19---Cl4A 117.6 (4) C1---C2---H2 119.6 C20---C19---Cl4B 112.8 (5) C2---C3---C4 121.0 (5) C18---C19---Cl4B 116.7 (5) C2---C3---Cl1 120.2 (5) C21---C20---C19 117.8 (5) C4---C3---Cl1 118.8 (4) C21---C20---H20 121.1 C5---C4---C3 118.3 (5) C19---C20---H20 121.1 C5---C4---H4 120.8 C20---C21---C22 121.3 (5) C3---C4---H4 120.8 C20---C21---H21 119.4 C4---C5---C6 122.0 (5) C22---C21---H21 119.4 C4---C5---H5 119.0 C17---C22---C21 120.3 (5) C6---C5---H5 119.0 C17---C22---H22 119.8 C5---C6---C1 119.7 (5) C21---C22---H22 119.8 C5---C6---H6 120.1 N3---C23---N4 119.4 (3) C1---C6---H6 120.1 N3---C23---C30 126.0 (3) N1---C7---N2 121.4 (3) N4---C23---C30 114.5 (3) N1---C7---C14 124.2 (3) C29---C24---C25 120.0 (4) N2---C7---C14 114.2 (3) C29---C24---N4 122.3 (4) C13---C8---C9 120.1 (3) C25---C24---N4 117.5 (4) C13---C8---N2 117.8 (3) C24---C25---C26 118.6 (5) C9---C8---N2 122.0 (3) C24---C25---H25 120.7 C8---C9---C10 118.1 (4) C26---C25---H25 120.7 C8---C9---H9 121.0 C27---C26---C25 121.1 (5) C10---C9---H9 121.0 C27---C26---Cl3 120.9 (5) C11---C10---C9 122.7 (5) C25---C26---Cl3 117.9 (5) C11---C10---Cl2B 110.7 (7) C26---C27---C28 119.7 (5) C9---C10---Cl2B 121.7 (5) C26---C27---H27 120.2 C11---C10---Cl2A 120.3 (4) C28---C27---H27 120.2 C9---C10---Cl2A 116.9 (5) C27---C28---C29 121.0 (6) C10---C11---C12 118.0 (4) C27---C28---H28 119.5 C10---C11---H11 121.0 C29---C28---H28 119.5 C12---C11---H11 121.0 C24---C29---C28 119.5 (6) C13---C12---C11 120.5 (5) C24---C29---H29 120.2 C13---C12---H12 119.8 C28---C29---H29 120.2 C11---C12---H12 119.8 C23---C30---C31 114.6 (3) C8---C13---C12 120.7 (4) C23---C30---H30A 108.6 C8---C13---H13 119.7 C31---C30---H30A 108.6 C12---C13---H13 119.7 C23---C30---H30B 108.6 C7---C14---C15 110.9 (4) C31---C30---H30B 108.6 C7---C14---H14A 109.5 H30A---C30---H30B 107.6 C15---C14---H14A 109.5 C30---C31---C32 111.9 (3) C7---C14---H14B 109.5 C30---C31---H31A 109.2 C15---C14---H14B 109.5 C32---C31---H31A 109.2 H14A---C14---H14B 108.1 C30---C31---H31B 109.2 C14---C15---C16 107.3 (7) C32---C31---H31B 109.2 C14---C15---H15A 110.3 H31A---C31---H31B 107.9 C16---C15---H15A 110.3 C32^ii^---C32---C31 112.6 (4) C14---C15---H15B 110.3 C32^ii^---C32---H32A 109.1 C16---C15---H15B 110.3 C31---C32---H32A 109.1 H15A---C15---H15B 108.5 C32^ii^---C32---H32B 109.1 C16^i^---C16---C15 120.0 (11) C31---C32---H32B 109.1 C16^i^---C16---H16A 107.3 H32A---C32---H32B 107.8 C15---C16---H16A 107.3 C7---N1---C1 120.8 (3) C16^i^---C16---H16B 107.3 C7---N2---C8 128.9 (3) C15---C16---H16B 107.3 C7---N2---H2A 115.6 H16A---C16---H16B 106.9 C8---N2---H2A 115.6 C18---C17---C22 118.2 (4) C23---N3---C17 120.5 (3) C18---C17---N3 120.9 (4) C23---N4---C24 125.8 (3) C22---C17---N3 120.8 (4) C23---N4---H4A 117.1 C17---C18---C19 119.2 (4) C24---N4---H4A 117.1 C6---C1---C2---C3 0.6 (6) C19---C20---C21---C22 −6.4 (10) N1---C1---C2---C3 −173.3 (3) C18---C17---C22---C21 0.1 (8) C1---C2---C3---C4 0.1 (6) N3---C17---C22---C21 −176.5 (5) C1---C2---C3---Cl1 −179.4 (3) C20---C21---C22---C17 3.0 (10) C2---C3---C4---C5 −0.8 (7) C29---C24---C25---C26 0.6 (6) Cl1---C3---C4---C5 178.8 (4) N4---C24---C25---C26 176.4 (4) C3---C4---C5---C6 0.7 (8) C24---C25---C26---C27 0.7 (7) C4---C5---C6---C1 0.0 (8) C24---C25---C26---Cl3 −178.5 (3) C2---C1---C6---C5 −0.6 (6) C25---C26---C27---C28 −0.9 (9) N1---C1---C6---C5 173.3 (4) Cl3---C26---C27---C28 178.3 (5) C13---C8---C9---C10 −0.1 (6) C26---C27---C28---C29 −0.3 (10) N2---C8---C9---C10 −178.0 (4) C25---C24---C29---C28 −1.7 (8) C8---C9---C10---C11 −1.3 (8) N4---C24---C29---C28 −177.3 (5) C8---C9---C10---Cl2B −154.1 (14) C27---C28---C29---C24 1.6 (10) C8---C9---C10---Cl2A 175.5 (6) N3---C23---C30---C31 128.1 (4) C9---C10---C11---C12 1.9 (9) N4---C23---C30---C31 −55.7 (4) Cl2B---C10---C11---C12 157.4 (13) C23---C30---C31---C32 175.8 (3) Cl2A---C10---C11---C12 −174.8 (7) C30---C31---C32---C32^ii^ −174.4 (4) C10---C11---C12---C13 −1.1 (9) N2---C7---N1---C1 172.6 (4) C9---C8---C13---C12 0.7 (7) C14---C7---N1---C1 −12.8 (6) N2---C8---C13---C12 178.8 (4) C2---C1---N1---C7 −80.4 (5) C11---C12---C13---C8 −0.1 (8) C6---C1---N1---C7 105.8 (5) N1---C7---C14---C15 −87.0 (6) N1---C7---N2---C8 −8.7 (6) N2---C7---C14---C15 88.0 (5) C14---C7---N2---C8 176.2 (4) C7---C14---C15---C16 170.0 (5) C13---C8---N2---C7 153.9 (4) C14---C15---C16---C16^i^ 122.4 (4) C9---C8---N2---C7 −28.1 (6) C22---C17---C18---C19 0.4 (8) N4---C23---N3---C17 172.8 (3) N3---C17---C18---C19 177.1 (5) C30---C23---N3---C17 −11.2 (6) C17---C18---C19---C20 −4.2 (9) C18---C17---N3---C23 103.0 (5) C17---C18---C19---Cl4A 169.8 (5) C22---C17---N3---C23 −80.4 (6) C17---C18---C19---Cl4B −151.6 (8) N3---C23---N4---C24 −14.6 (6) C18---C19---C20---C21 7.1 (10) C30---C23---N4---C24 169.0 (3) Cl4A---C19---C20---C21 −166.8 (6) C29---C24---N4---C23 −41.1 (6) Cl4B---C19---C20---C21 155.6 (9) C25---C24---N4---C23 143.1 (4) -------------------------- ------------- --------------------------- ------------ ::: Symmetry codes: (i) −*x*+1, *y*, −*z*+1/2; (ii) −*x*+3/2, −*y*+1/2, −*z*+1. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3669 .table-wrap} -------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N2---H2A···N3 0.86 2.24 3.049 (4) 157 N4---H4A···N1^iii^ 0.86 2.23 3.072 (4) 168 -------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (iii) −*x*+3/2, *y*−1/2, −*z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------ --------- ------- ----------- ------------- N2---H2*A*⋯N3 0.86 2.24 3.049 (4) 157 N4---H4*A*⋯N1^i^ 0.86 2.23 3.072 (4) 168 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.403656

2011-2-12

PMC3051939

Related literature {#sec1} ================== For the toxicity and insecticidal properties of the title compound, see: Dureja (1989[@bb4]); Chakravarthi *et al.* (2007[@bb3]). For related structures, see: Osman & El-Samahy (2007[@bb5]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~7~H~14~NO~5~P*M* *~r~* = 223.16Monoclinic,*a* = 10.0498 (2) Å*b* = 11.3501 (2) Å*c* = 10.4587 (2) Åβ = 115.377 (1)°*V* = 1077.87 (4) Å^3^*Z* = 4Mo *K*α radiationμ = 0.25 mm^−1^*T* = 173 K0.35 × 0.35 × 0.25 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb6]) *T* ~min~ = 0.917, *T* ~max~ = 0.94017626 measured reflections2673 independent reflections2411 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.032 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.040*wR*(*F* ^2^) = 0.119*S* = 1.082673 reflections155 parametersH-atom parameters constrainedΔρ~max~ = 0.37 e Å^−3^Δρ~min~ = −0.38 e Å^−3^ {#d5e510} Data collection: *APEX2* (Bruker, 2006[@bb2]); cell refinement: *SAINT* (Bruker, 2006[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL* and *DIAMOND* (Brandenburg, 1998[@bb1]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811003898/jh2262sup1.cif](http://dx.doi.org/10.1107/S1600536811003898/jh2262sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003898/jh2262Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003898/jh2262Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?jh2262&file=jh2262sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?jh2262sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?jh2262&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [JH2262](http://scripts.iucr.org/cgi-bin/sendsup?jh2262)). This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2010--0009089). Comment ======= Monocrotophos (systematic name: dimethyl (*E*)-1-methyl-2- (methylcarbamoyl)vinyl phosphate), is a kind of insecticide with a wide range of insects and mites (Dureja, 1989; Chakravarthi *et al.*, 2007). However it\'s crystal structure has not been reported yet. In the title compound (Scheme 1, Fig.1), the phosphate group displays rotational disorder with occupancies of 0.832 (6):0.167 (6). The dihedral angle between the acrylamide group and PO~2~ planes (P1/O1/O2) of the phosphate group is 75.69 (7)°. All bond lengths and bond angles are normal and comparable to those observed in similar structures (Osman & El-Samahy, 2007). In the crystal structure, as shown in Fig. 2, weak intermolecular N---H···O and C---H···O hydrogen bonds are observed (Table 1). These intermolecular interactions may be contribute to the stabilization of the packing. Experimental {#experimental} ============ The title compound was purchased from the Dr. Ehrenstorfer GmbH Company. Slow evaporation of a solution in CH~2~Cl~2~ gave single crystals suitable for X-ray analysis. Refinement {#refinement} ========== During refinement, atoms O1, O2 and O3 of the phosphate group are disordered and were refined using a split model. The corresponding site-occupation factors were refined so that their sum was unity \[0.832 (6) and 0.167 (6)\]. All H-atoms were positioned geometrically and refined using a riding model with d(N---H) = 0.88 Å, *U*~iso~ = 1.2*U*~eq~(N) for NH, d(C---H) = 0.98 Å, *U*~iso~ = 1.2*U*~eq~(C) for CH and d(C---H) = 0.98 Å, *U*~iso~ = 1.5*U*~eq~(C) for CH~3~ groups. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound with the atom numbering scheme: the major part is drawn with solid lines, the minor one with open lines. Displacement ellipsoids are drawn at the 50% probability level. H atoms are presented as a small spheres of arbitrary radii. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Crystal packing of the title compound with intermolecular N---H···O and C---H···O interactions shown as dashed lines. H atoms not involved in intermolecular interactions have been omitted for clarity. \[Symmetry codes: (i) x + 1/2, -y + 1/2, z + 1/2; (ii) x - 1/2, -y + 1/2, z - 1/2; (iii) x + 1, y, z + 1; (iv) -x + 1.5, y + 1/2, -z + 1/2; (v) -x + 1, -y + 1, -z; (vi) -x + 2, -y + 1, -z + 1; (vii) -x + 2.5, y + 1/2, -z + 1.5.) :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e214 .table-wrap} ------------------------- --------------------------------------- C~7~H~14~NO~5~P *F*(000) = 472 *M~r~* = 223.16 *D*~x~ = 1.375 Mg m^−3^ Monoclinic, *P*2~1~/*n* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2yn Cell parameters from 9925 reflections *a* = 10.0498 (2) Å θ = 2.4--28.3° *b* = 11.3501 (2) Å µ = 0.25 mm^−1^ *c* = 10.4587 (2) Å *T* = 173 K β = 115.377 (1)° Block, colourless *V* = 1077.87 (4) Å^3^ 0.35 × 0.35 × 0.25 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e342 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker APEXII CCD diffractometer 2673 independent reflections Radiation source: fine-focus sealed tube 2411 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.032 φ and ω scans θ~max~ = 28.3°, θ~min~ = 2.4° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −13→13 *T*~min~ = 0.917, *T*~max~ = 0.940 *k* = −15→15 17626 measured reflections *l* = −13→13 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e459 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.040 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.119 H-atom parameters constrained *S* = 1.08 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0647*P*)^2^ + 0.3928*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2673 reflections (Δ/σ)~max~ \< 0.001 155 parameters Δρ~max~ = 0.37 e Å^−3^ 0 restraints Δρ~min~ = −0.38 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e616 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e715 .table-wrap} ------ -------------- --------------- --------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) P1 0.72597 (4) 0.12670 (3) 0.30753 (4) 0.02990 (14) O1 0.87089 (17) 0.17794 (17) 0.35222 (16) 0.0442 (4) 0.833 (2) O2 0.60357 (16) 0.22189 (12) 0.25429 (17) 0.0421 (4) 0.833 (2) O3 0.69477 (16) 0.05711 (13) 0.41970 (14) 0.0404 (4) 0.833 (2) O1\' 0.8042 (9) 0.2366 (7) 0.2975 (8) 0.0385 (17) 0.167 (2) O2\' 0.5877 (7) 0.1471 (7) 0.3323 (7) 0.0414 (18) 0.167 (2) O3\' 0.8319 (8) 0.0599 (7) 0.4465 (7) 0.0446 (19) 0.167 (2) O4 0.68546 (12) 0.03323 (9) 0.18490 (11) 0.0319 (2) O5 0.75176 (15) 0.08602 (13) −0.19560 (13) 0.0486 (3) N1 0.55391 (16) 0.20368 (14) −0.26018 (15) 0.0423 (3) H1N 0.4883 0.2357 −0.2360 0.051\* C1 0.44938 (19) 0.19657 (18) 0.2069 (2) 0.0494 (4) H1A 0.3929 0.2700 0.1787 0.074\* 0.833 (2) H1B 0.4335 0.1597 0.2840 0.074\* 0.833 (2) H1C 0.4168 0.1428 0.1259 0.074\* 0.833 (2) H1D 0.3692 0.2054 0.2359 0.074\* 0.167 (2) H1E 0.4189 0.1421 0.1267 0.074\* 0.167 (2) H1F 0.4726 0.2735 0.1790 0.074\* 0.167 (2) C2 0.7899 (3) −0.0384 (2) 0.4980 (2) 0.0655 (6) H2A 0.7542 −0.0715 0.5641 0.098\* 0.833 (2) H2B 0.8904 −0.0087 0.5510 0.098\* 0.833 (2) H2C 0.7898 −0.0998 0.4321 0.098\* 0.833 (2) H2D 0.8730 −0.0660 0.5840 0.098\* 0.167 (2) H2E 0.7597 −0.1009 0.4265 0.098\* 0.167 (2) H2F 0.7073 −0.0181 0.5201 0.098\* 0.167 (2) C3 0.72637 (16) 0.04930 (12) 0.07257 (14) 0.0284 (3) C4 0.86253 (19) −0.01539 (16) 0.09550 (19) 0.0442 (4) H4A 0.8863 −0.0020 0.0151 0.066\* H4B 0.8477 −0.0998 0.1041 0.066\* H4C 0.9438 0.0128 0.1825 0.066\* C5 0.63716 (16) 0.11200 (13) −0.03706 (15) 0.0298 (3) H5A 0.5546 0.1478 −0.0310 0.036\* C6 0.65555 (17) 0.13105 (13) −0.16923 (16) 0.0324 (3) C7 0.5494 (3) 0.2307 (3) −0.3968 (2) 0.0675 (7) H7A 0.4682 0.2854 −0.4472 0.101\* H7B 0.5341 0.1580 −0.4518 0.101\* H7C 0.6427 0.2670 −0.3841 0.101\* ------ -------------- --------------- --------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1257 .table-wrap} ------ ------------- ------------- ------------- --------------- -------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ P1 0.0279 (2) 0.0352 (2) 0.0273 (2) −0.00341 (13) 0.01246 (16) −0.00360 (13) O1 0.0347 (8) 0.0594 (11) 0.0381 (8) −0.0165 (8) 0.0151 (6) −0.0108 (7) O2 0.0392 (8) 0.0322 (7) 0.0528 (8) 0.0013 (5) 0.0176 (6) −0.0072 (6) O3 0.0375 (8) 0.0562 (9) 0.0320 (7) 0.0005 (6) 0.0194 (6) 0.0036 (6) O1\' 0.045 (4) 0.034 (4) 0.044 (4) −0.014 (3) 0.027 (4) −0.011 (3) O2\' 0.027 (3) 0.062 (4) 0.039 (4) 0.006 (3) 0.019 (3) −0.006 (3) O3\' 0.038 (4) 0.053 (4) 0.031 (3) −0.004 (3) 0.004 (3) 0.005 (3) O4 0.0373 (6) 0.0325 (5) 0.0290 (5) −0.0056 (4) 0.0172 (4) −0.0023 (4) O5 0.0465 (7) 0.0676 (8) 0.0418 (7) 0.0217 (6) 0.0284 (6) 0.0121 (6) N1 0.0413 (7) 0.0568 (8) 0.0342 (7) 0.0167 (6) 0.0214 (6) 0.0118 (6) C1 0.0347 (8) 0.0538 (10) 0.0550 (11) 0.0079 (7) 0.0149 (7) −0.0083 (8) C2 0.0593 (13) 0.0810 (15) 0.0554 (12) 0.0133 (11) 0.0237 (10) 0.0319 (11) C3 0.0318 (7) 0.0271 (6) 0.0287 (6) −0.0031 (5) 0.0152 (5) −0.0037 (5) C4 0.0429 (9) 0.0498 (9) 0.0429 (9) 0.0172 (7) 0.0214 (7) 0.0102 (7) C5 0.0287 (7) 0.0333 (7) 0.0305 (7) 0.0020 (5) 0.0156 (6) −0.0014 (5) C6 0.0318 (7) 0.0369 (7) 0.0298 (7) 0.0020 (5) 0.0147 (6) 0.0005 (5) C7 0.0618 (13) 0.1063 (19) 0.0439 (10) 0.0368 (13) 0.0317 (10) 0.0331 (11) ------ ------------- ------------- ------------- --------------- -------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1588 .table-wrap} ----------------------- -------------- --------------------- -------------- P1---O1 1.4472 (14) C1---H1D 0.9800 P1---O1\' 1.501 (7) C1---H1E 0.9800 P1---O2\' 1.536 (6) C1---H1F 0.9800 P1---O2 1.5503 (14) C2---H2A 0.9800 P1---O3 1.5536 (13) C2---H2B 0.9800 P1---O4 1.5775 (11) C2---H2C 0.9800 P1---O3\' 1.580 (7) C2---H2D 0.9800 O2---C1 1.439 (2) C2---H2E 0.9800 O3---C2 1.446 (2) C2---H2F 0.9800 O2\'---C1 1.551 (7) C3---C5 1.321 (2) O3\'---C2 1.382 (8) C3---C4 1.479 (2) O4---C3 1.4130 (16) C4---H4A 0.9800 O5---C6 1.2250 (19) C4---H4B 0.9800 N1---C6 1.340 (2) C4---H4C 0.9800 N1---C7 1.442 (2) C5---C6 1.487 (2) N1---H1N 0.8800 C5---H5A 0.9500 C1---H1A 0.9800 C7---H7A 0.9800 C1---H1B 0.9800 C7---H7B 0.9800 C1---H1C 0.9800 C7---H7C 0.9800 O1---P1---O1\' 37.3 (3) H1B---C1---H1F 140.3 O1---P1---O2\' 138.0 (3) H1C---C1---H1F 109.3 O1\'---P1---O2\' 115.2 (4) H1D---C1---H1F 109.5 O1---P1---O2 111.70 (10) H1E---C1---H1F 109.5 O1\'---P1---O2 75.8 (3) O3\'---C2---O3 54.0 (3) O2\'---P1---O2 47.1 (3) O3\'---C2---H2A 148.2 O1---P1---O3 117.47 (9) O3---C2---H2A 109.5 O1\'---P1---O3 139.1 (3) O3\'---C2---H2B 61.9 O2\'---P1---O3 57.3 (3) O3---C2---H2B 109.5 O2---P1---O3 103.86 (8) H2A---C2---H2B 109.5 O1---P1---O4 113.96 (8) O3\'---C2---H2C 102.0 O1\'---P1---O4 117.5 (3) O3---C2---H2C 109.5 O2\'---P1---O4 107.5 (3) H2A---C2---H2C 109.5 O2---P1---O4 106.74 (7) H2B---C2---H2C 109.5 O3---P1---O4 101.93 (7) O3\'---C2---H2D 109.5 O1---P1---O3\' 73.0 (3) O3---C2---H2D 148.9 O1\'---P1---O3\' 107.2 (4) H2A---C2---H2D 69.9 O2\'---P1---O3\' 102.6 (4) H2B---C2---H2D 47.5 O2---P1---O3\' 141.6 (3) H2C---C2---H2D 99.4 O3---P1---O3\' 48.4 (3) O3\'---C2---H2E 109.5 O4---P1---O3\' 105.2 (3) O3---C2---H2E 101.3 C1---O2---P1 123.79 (13) H2A---C2---H2E 100.0 C2---O3---P1 120.71 (13) H2B---C2---H2E 126.0 P1---O2\'---C1 117.4 (5) H2C---C2---H2E 16.6 C2---O3\'---P1 123.3 (5) H2D---C2---H2E 109.5 C3---O4---P1 121.57 (9) O3\'---C2---H2F 109.5 C6---N1---C7 121.65 (15) O3---C2---H2F 62.3 C6---N1---H1N 119.2 H2A---C2---H2F 47.2 C7---N1---H1N 119.2 H2B---C2---H2F 123.9 O2---C1---O2\' 48.6 (3) H2C---C2---H2F 126.0 O2---C1---H1A 109.5 H2D---C2---H2F 109.5 O2\'---C1---H1A 139.2 H2E---C2---H2F 109.5 O2---C1---H1B 109.5 C5---C3---O4 117.41 (13) O2\'---C1---H1B 63.5 C5---C3---C4 130.16 (14) H1A---C1---H1B 109.5 O4---C3---C4 112.32 (12) O2---C1---H1C 109.5 C3---C4---H4A 109.5 O2\'---C1---H1C 110.6 C3---C4---H4B 109.5 H1A---C1---H1C 109.5 H4A---C4---H4B 109.5 H1B---C1---H1C 109.5 C3---C4---H4C 109.5 O2---C1---H1D 141.2 H4A---C4---H4C 109.5 O2\'---C1---H1D 109.5 H4B---C4---H4C 109.5 H1A---C1---H1D 63.8 C3---C5---C6 125.23 (13) H1B---C1---H1D 49.0 C3---C5---H5A 117.4 H1C---C1---H1D 108.5 C6---C5---H5A 117.4 O2---C1---H1E 108.4 O5---C6---N1 122.15 (15) O2\'---C1---H1E 109.5 O5---C6---C5 124.98 (14) H1A---C1---H1E 110.5 N1---C6---C5 112.87 (13) H1B---C1---H1E 109.5 N1---C7---H7A 109.5 H1C---C1---H1E 1.2 N1---C7---H7B 109.5 H1D---C1---H1E 109.5 H7A---C7---H7B 109.5 O2---C1---H1F 64.3 N1---C7---H7C 109.5 O2\'---C1---H1F 109.5 H7A---C7---H7C 109.5 H1A---C1---H1F 48.2 H7B---C7---H7C 109.5 O1---P1---O2---C1 −178.29 (15) O2---P1---O3\'---C2 84.0 (7) O1\'---P1---O2---C1 171.5 (3) O3---P1---O3\'---C2 31.1 (4) O2\'---P1---O2---C1 −42.1 (4) O4---P1---O3\'---C2 −61.4 (6) O3---P1---O2---C1 −50.73 (17) O1---P1---O4---C3 −38.76 (15) O4---P1---O2---C1 56.53 (16) O1\'---P1---O4---C3 2.6 (4) O3\'---P1---O2---C1 −88.6 (5) O2\'---P1---O4---C3 134.5 (3) O1---P1---O3---C2 −54.1 (2) O2---P1---O4---C3 85.04 (12) O1\'---P1---O3---C2 −93.8 (5) O3---P1---O4---C3 −166.34 (11) O2\'---P1---O3---C2 174.5 (4) O3\'---P1---O4---C3 −116.6 (3) O2---P1---O3---C2 −178.02 (16) P1---O2---C1---O2\' 40.5 (4) O4---P1---O3---C2 71.16 (17) P1---O2\'---C1---O2 −37.8 (3) O3\'---P1---O3---C2 −28.7 (4) P1---O3\'---C2---O3 −30.9 (4) O1---P1---O2\'---C1 109.6 (5) P1---O3---C2---O3\' 30.5 (4) O1\'---P1---O2\'---C1 71.9 (6) P1---O4---C3---C5 −85.84 (15) O2---P1---O2\'---C1 35.6 (3) P1---O4---C3---C4 97.63 (14) O3---P1---O2\'---C1 −154.4 (7) O4---C3---C5---C6 −175.23 (13) O4---P1---O2\'---C1 −61.2 (6) C4---C3---C5---C6 0.6 (3) O3\'---P1---O2\'---C1 −171.9 (5) C7---N1---C6---O5 1.7 (3) O1---P1---O3\'---C2 −172.4 (7) C7---N1---C6---C5 −177.96 (19) O1\'---P1---O3\'---C2 172.7 (6) C3---C5---C6---O5 3.9 (3) O2\'---P1---O3\'---C2 51.0 (7) C3---C5---C6---N1 −176.46 (15) ----------------------- -------------- --------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2503 .table-wrap} ------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1N···O1^i^ 0.88 2.03 2.902 (2) 169 C4---H4B···O2^ii^ 0.98 2.43 3.319 (2) 151 ------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) *x*−1/2, −*y*+1/2, *z*−1/2; (ii) −*x*+3/2, *y*−1/2, −*z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------- --------- ------- ----------- ------------- N1---H1*N*⋯O1^i^ 0.88 2.03 2.902 (2) 169 C4---H4*B*⋯O2^ii^ 0.98 2.43 3.319 (2) 151 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.413038

2011-2-09

PMC3051940

Related literature {#sec1} ================== For mono-ketone PCU derivatives, see: Kruger *et al.* (2006)[@bb4]. For examples of the crystal structures of mono-ketone PCU mol­ecules bearing heteroatoms, see: Watson *et al.* (2000)[@bb6]; Karpoormath *et al.* (2010[@bb3]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~25~H~21~NO*M* *~r~* = 351.43Monoclinic,*a* = 6.6117 (3) Å*b* = 16.4344 (7) Å*c* = 17.2331 (8) Åβ = 97.100 (2)°*V* = 1858.18 (14) Å^3^*Z* = 4Cu *K*α radiationμ = 0.59 mm^−1^*T* = 173 K0.43 × 0.33 × 0.25 mm ### Data collection {#sec2.1.2} Bruker Kappa DUO APEXII diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2006[@bb2]) *T* ~min~ = 0.786, *T* ~max~ = 0.86724662 measured reflections3303 independent reflections3240 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.018 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.066*wR*(*F* ^2^) = 0.173*S* = 1.063303 reflections255 parameters24 restraintsH-atom parameters constrainedΔρ~max~ = 0.48 e Å^−3^Δρ~min~ = −0.46 e Å^−3^ {#d5e357} Data collection: *APEX2* (Bruker, 2006[@bb2]); cell refinement: *SAINT* (Bruker, 2006[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb5]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *X-SEED* (Barbour, 2001[@bb1]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S160053681100479X/lx2177sup1.cif](http://dx.doi.org/10.1107/S160053681100479X/lx2177sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S160053681100479X/lx2177Isup2.hkl](http://dx.doi.org/10.1107/S160053681100479X/lx2177Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?lx2177&file=lx2177sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?lx2177sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?lx2177&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [LX2177](http://scripts.iucr.org/cgi-bin/sendsup?lx2177)). The authors would like to thank Dr Hong Su from the University of Capetown for the data collection and structure refinement. Comment ======= We have reported the structures of a number of PCU derivatives including a mono-ketone ethylene acetal (Kruger *et al.*, 2006). We more recently reported the structure of a mono--ketone pentacycloundecane (PCU) (Karpoormath *et al.* 2010), that demonstrated intramolecular hydrogen bonding, a quite uncommon feature hitherto in mono--ketone PCU structures (Watson *et al.*, 2000). In that example the racemate occupied alternative sites in the unit cell. Herein, we report the crystal structure of the title compound (Fig. 1). The C1 methylene group in PCU is disordered over two positions with site--occupancy factors of 0.621 (7) (for atom labelled A) and 0.379 (7) (for atom labelled B) in Fig. 1. Experimental {#experimental} ============ A solution of PCU cage *N*-dibenzyl mono ethylene ketal (0.5 g, 1.25 mmol) in 10 ml of THF was stirred at room temperature for 5 minutes. To this mixture was added 10 ml of 10% HCL solution and stirred overnight at room temperature. THF was removed from the crude product under vacuum using a teflon pump at 80 °C to obtain an aqueous solution with white precipitate. The precipitate was collected by vacuum filtration and washed with water (50 ml) to give a white solid. The yield was 97%. Crystallization of the title compound was carried out by dissolving the compound in ethyl acetate and hexane (1:4) with storage at 20 °C. Melting point: 438--439 K. IR (neat) Vmax cm^-1^: 3376.61, 2978.73, 2961.26, 2794.11, 1721.74, 1602.42, 1494.57, 1342.20, 1131.34, 752.25, 731.39, 696.73, cm^-1^. ^1^H NMR (CDCl~3~, 400 MHz) δ p.p.m.: 1.56 (1.0H, d, J=11.13 Hz), 1.89 (1.0H, d, J=11.13 Hz), 2.52 (1.0H, d, J=4.56 Hz), 2.61 (1.0H, d, J=6.96 Hz), 2.71 (2.0H, d, J=5.96 Hz), 2.90 (1.0H, d, J=5.60 Hz), 2.93 (1.0H, d, J=4.68 Hz), 3.50 (1.0H, d, J=2.28 Hz), 3.51 (2.0H, t, J=12.27 Hz), 3.90 (1.0H, t, J=5.02 Hz), 4.39 (1.0H, d, J=14.65 Hz), 4.52 (2.0H, dd, J=9.87, 14.55 Hz), 4.81 (1.0H, d, J=14.61 Hz), 6.90 (2.0H, d, J=7.24 Hz), 6.99 (2.0H, d, J=7.20 Hz), 7.23 - 7.38 (6.0H, m, J=7.20 Hz). ^13^C NMR (CDCl~3~, 101 MHz) δ p.p.m.: 40.75 (d, *J*=15.71 Hz), 41.28 (d, *J*=14.29 Hz), 43.15 (*s*), 44.18 (*s*), 46.12 (*s*), 50.09 (*s*), 52.72 (*s*), 59.20 (d, *J*=73.03 Hz), 70.28 (*s*), 123.86 (*s*), 129.41 (d, J=10.10 Hz), 129.92 (*s*), 130.45 (d, *J*=24.83 Hz), 131.13 (*s*). HR ESI m/*z*: calcd for C~25~H~25~NO \[*M*+H\]^+^:356.2009 found 356.2014. Refinement {#refinement} ========== All hydrogen atoms were positioned geometrically with C---H = 0.95--1.00 Å and refined as riding on their parent atoms, with *U*~iso~ (H) = 1.2 *U*~eq~ (C). The C1 methylene group was found to be disordered over two positions and modelled with site--occupancy factors, from refinement of 0.621 (7) (C1A) and 0.379 (7) (C1B), respectively. The distance of C2---C1A, C6---C1B and C7---C1A and C11---C1B sets were restrained to 0.001 Å using command SADI and DELU. The displacement ellipsoids of C1A and C1B were restrained using commend ISOR (0.01). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound with atomic numbering scheme. All hydrogen atoms are omitted for clarity. Displacement ellipsoids are drawn at the 25% probability level. The C1 methylene group was found to be disordered over two positions and modelled with site--occupancy factors, from refinement of 0.621 (7) (C1A) and 0.379 (7) (C1B). :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e195 .table-wrap} ------------------------- --------------------------------------- C~25~H~21~NO *F*(000) = 744 *M~r~* = 351.43 *D*~x~ = 1.256 Mg m^−3^ Monoclinic, *P*2~1~/*n* Cu *K*α radiation, λ = 1.54184 Å Hall symbol: -P 2yn Cell parameters from 3299 reflections *a* = 6.6117 (3) Å θ = 5.2--69.2° *b* = 16.4344 (7) Å µ = 0.59 mm^−1^ *c* = 17.2331 (8) Å *T* = 173 K β = 97.100 (2)° Needle, colourless *V* = 1858.18 (14) Å^3^ 0.43 × 0.33 × 0.25 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e320 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker Kappa DUO APEXII diffractometer 3303 independent reflections Radiation source: fine-focus sealed tube 3240 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.018 1.2° φ scans and ω θ~max~ = 69.2°, θ~min~ = 3.7° Absorption correction: multi-scan (*SADABS*; Bruker, 2006) *h* = −7→7 *T*~min~ = 0.786, *T*~max~ = 0.867 *k* = −19→19 24662 measured reflections *l* = −20→20 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e437 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.066 H-atom parameters constrained *wR*(*F*^2^) = 0.173 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.080*P*)^2^ + 1.983*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.06 (Δ/σ)~max~ \< 0.001 3303 reflections Δρ~max~ = 0.48 e Å^−3^ 255 parameters Δρ~min~ = −0.46 e Å^−3^ 24 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.0020 (4) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e618 .table-wrap} ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. Half sphere of data collected using *APEX2* (Bruker, 2006). Crystal to detector distance = 45 mm; combination of φ and ω scans of 1.2°, 50 s per °, 2 iterations. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ \> 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e678 .table-wrap} ------ ------------- --------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) O1 0.1742 (2) 0.13889 (10) 0.19402 (10) 0.0394 (4) N1 −0.2672 (3) 0.05165 (10) 0.14408 (10) 0.0271 (4) C2 −0.4175 (5) 0.27147 (16) 0.1215 (3) 0.0763 (12) C3 −0.3558 (3) 0.19546 (14) 0.17218 (17) 0.0423 (6) H3 −0.4438 0.1857 0.2145 0.051\* C4 −0.3624 (3) 0.12730 (13) 0.11264 (14) 0.0347 (5) H4 −0.5077 0.1160 0.0920 0.042\* C5 −0.2577 (4) 0.16781 (17) 0.04842 (17) 0.0493 (7) H5 −0.2759 0.1387 −0.0029 0.059\* C6 −0.3393 (6) 0.25559 (17) 0.04539 (18) 0.0652 (10) C7 −0.1306 (5) 0.30438 (16) 0.16140 (19) 0.0612 (9) C8 −0.1293 (3) 0.22060 (14) 0.20361 (17) 0.0422 (6) H8 −0.0991 0.2233 0.2619 0.051\* C9 0.0227 (3) 0.17342 (14) 0.16393 (15) 0.0361 (5) C10 −0.0309 (4) 0.19225 (18) 0.07827 (17) 0.0497 (7) H10 0.0730 0.1760 0.0437 0.060\* C11 −0.0792 (5) 0.2836 (2) 0.0801 (2) 0.0775 (12) C12 −0.3867 (3) 0.01601 (13) 0.20230 (13) 0.0311 (5) H12A −0.3795 −0.0440 0.1982 0.037\* H12B −0.5311 0.0318 0.1884 0.037\* C13 −0.3230 (3) 0.03943 (13) 0.28639 (13) 0.0307 (5) C14 −0.4688 (4) 0.04214 (14) 0.33779 (14) 0.0372 (5) H14 −0.6085 0.0347 0.3185 0.045\* C15 −0.4127 (4) 0.05563 (15) 0.41683 (15) 0.0436 (6) H15 −0.5139 0.0568 0.4514 0.052\* C16 −0.2108 (4) 0.06739 (16) 0.44562 (15) 0.0467 (6) H16 −0.1722 0.0761 0.4999 0.056\* C17 −0.0654 (4) 0.06631 (17) 0.39452 (15) 0.0452 (6) H17 0.0736 0.0755 0.4138 0.054\* C18 −0.1200 (4) 0.05196 (15) 0.31545 (14) 0.0384 (6) H18 −0.0184 0.0507 0.2810 0.046\* C19 −0.2474 (4) −0.00746 (14) 0.08166 (13) 0.0349 (5) H19A −0.1791 0.0190 0.0403 0.042\* H19B −0.3851 −0.0244 0.0580 0.042\* C20 −0.1277 (3) −0.08185 (13) 0.11058 (12) 0.0312 (5) C21 0.0737 (3) −0.07388 (14) 0.14401 (14) 0.0381 (5) H21 0.1342 −0.0214 0.1496 0.046\* C22 0.1864 (4) −0.14184 (16) 0.16920 (16) 0.0434 (6) H22 0.3238 −0.1357 0.1921 0.052\* C23 0.1013 (4) −0.21862 (15) 0.16137 (15) 0.0416 (6) H23 0.1796 −0.2652 0.1785 0.050\* C24 −0.0992 (4) −0.22698 (15) 0.12834 (15) 0.0413 (6) H24 −0.1593 −0.2795 0.1228 0.050\* C25 −0.2121 (4) −0.15900 (14) 0.10333 (14) 0.0363 (5) H25 −0.3498 −0.1653 0.0808 0.044\* C1A −0.3205 (6) 0.3417 (2) 0.1498 (2) 0.0414 (11) 0.621 (7) H1A −0.3673 0.3612 0.1989 0.050\* 0.621 (7) H1B −0.3281 0.3860 0.1106 0.050\* 0.621 (7) C1B −0.2299 (8) 0.3246 (3) 0.0321 (4) 0.0458 (19) 0.379 (7) H1D −0.2791 0.3753 0.0546 0.055\* 0.379 (7) H1C −0.2020 0.3321 −0.0225 0.055\* 0.379 (7) ------ ------------- --------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1451 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.0224 (8) 0.0389 (9) 0.0564 (10) 0.0003 (6) 0.0031 (7) 0.0051 (7) N1 0.0261 (9) 0.0239 (9) 0.0310 (9) 0.0000 (7) 0.0019 (7) 0.0019 (7) C2 0.0606 (19) 0.0306 (14) 0.148 (3) 0.0175 (13) 0.055 (2) 0.0285 (18) C3 0.0238 (11) 0.0256 (12) 0.0770 (18) 0.0021 (9) 0.0049 (11) −0.0047 (11) C4 0.0248 (10) 0.0278 (11) 0.0495 (13) 0.0006 (8) −0.0037 (9) 0.0082 (10) C5 0.0439 (14) 0.0489 (16) 0.0522 (15) −0.0049 (12) −0.0061 (12) 0.0247 (12) C6 0.092 (2) 0.0341 (14) 0.0589 (17) −0.0159 (15) −0.0342 (16) 0.0170 (13) C7 0.0715 (19) 0.0268 (13) 0.075 (2) 0.0005 (12) −0.0338 (16) −0.0049 (13) C8 0.0278 (12) 0.0284 (12) 0.0699 (17) −0.0016 (9) 0.0041 (11) −0.0090 (11) C9 0.0243 (11) 0.0292 (11) 0.0549 (14) −0.0052 (9) 0.0055 (10) 0.0056 (10) C10 0.0382 (13) 0.0525 (16) 0.0595 (16) −0.0045 (11) 0.0098 (12) 0.0249 (13) C11 0.066 (2) 0.059 (2) 0.117 (3) 0.0220 (16) 0.050 (2) 0.052 (2) C12 0.0262 (10) 0.0269 (11) 0.0404 (12) −0.0041 (8) 0.0055 (9) 0.0009 (9) C13 0.0311 (11) 0.0240 (10) 0.0378 (12) 0.0013 (8) 0.0069 (9) 0.0060 (9) C14 0.0361 (12) 0.0309 (12) 0.0464 (13) 0.0036 (9) 0.0124 (10) 0.0049 (10) C15 0.0570 (16) 0.0351 (13) 0.0423 (13) 0.0077 (11) 0.0206 (12) 0.0067 (10) C16 0.0684 (18) 0.0373 (13) 0.0338 (12) 0.0072 (12) 0.0040 (12) 0.0047 (10) C17 0.0445 (14) 0.0483 (15) 0.0405 (13) 0.0008 (11) −0.0041 (11) 0.0043 (11) C18 0.0327 (12) 0.0435 (14) 0.0391 (13) 0.0013 (10) 0.0053 (10) 0.0051 (10) C19 0.0376 (12) 0.0351 (12) 0.0301 (11) 0.0035 (9) −0.0027 (9) −0.0024 (9) C20 0.0345 (11) 0.0303 (11) 0.0287 (10) 0.0012 (9) 0.0032 (9) −0.0043 (9) C21 0.0333 (12) 0.0302 (12) 0.0498 (14) −0.0017 (9) 0.0011 (10) −0.0011 (10) C22 0.0316 (12) 0.0429 (14) 0.0542 (15) 0.0035 (10) −0.0005 (11) 0.0025 (11) C23 0.0460 (14) 0.0342 (13) 0.0459 (14) 0.0110 (10) 0.0104 (11) 0.0051 (10) C24 0.0497 (14) 0.0287 (12) 0.0467 (14) −0.0026 (10) 0.0111 (11) −0.0053 (10) C25 0.0351 (12) 0.0348 (12) 0.0384 (12) −0.0025 (9) 0.0020 (9) −0.0085 (10) C1A 0.052 (2) 0.0290 (19) 0.043 (2) 0.0039 (16) 0.0042 (17) 0.0013 (15) C1B 0.062 (4) 0.031 (3) 0.046 (3) 0.002 (3) 0.013 (3) 0.005 (3) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1966 .table-wrap} --------------------- -------------- ----------------------- ------------- O1---C9 1.211 (3) C13---C14 1.388 (3) N1---C4 1.467 (3) C14---C15 1.385 (4) N1---C19 1.467 (3) C14---H14 0.9500 N1---C12 1.473 (3) C15---C16 1.379 (4) C2---C1A 1.380 (4) C15---H15 0.9500 C2---C6 1.491 (5) C16---C17 1.382 (4) C2---C3 1.550 (4) C16---H16 0.9500 C3---C4 1.516 (3) C17---C18 1.386 (4) C3---C8 1.583 (3) C17---H17 0.9500 C3---H3 1.0000 C18---H18 0.9500 C4---C5 1.529 (3) C19---C20 1.507 (3) C4---H4 1.0000 C19---H19A 0.9900 C5---C6 1.539 (4) C19---H19B 0.9900 C5---C10 1.576 (4) C20---C25 1.385 (3) C5---H5 1.0000 C20---C21 1.390 (3) C6---C1B 1.379 (4) C21---C22 1.383 (3) C7---C1A 1.389 (4) C21---H21 0.9500 C7---C11 1.522 (5) C22---C23 1.381 (4) C7---C8 1.557 (4) C22---H22 0.9500 C8---C9 1.500 (3) C23---C24 1.383 (4) C8---H8 1.0000 C23---H23 0.9500 C9---C10 1.507 (4) C24---C25 1.383 (3) C10---C11 1.536 (4) C24---H24 0.9500 C10---H10 1.0000 C25---H25 0.9500 C11---C1B 1.387 (4) C1A---H1A 0.9900 C12---C13 1.508 (3) C1A---H1B 0.9900 C12---H12A 0.9900 C1B---H1D 0.9900 C12---H12B 0.9900 C1B---H1C 0.9900 C13---C18 1.388 (3) C4---N1---C19 111.32 (17) C18---C13---C14 118.8 (2) C4---N1---C12 110.30 (16) C18---C13---C12 121.8 (2) C19---N1---C12 109.88 (17) C14---C13---C12 119.2 (2) C1A---C2---C6 105.1 (3) C15---C14---C13 120.7 (2) C1A---C2---C3 113.4 (3) C15---C14---H14 119.7 C6---C2---C3 105.0 (2) C13---C14---H14 119.7 C4---C3---C2 103.3 (2) C16---C15---C14 120.4 (2) C4---C3---C8 111.81 (19) C16---C15---H15 119.8 C2---C3---C8 98.9 (2) C14---C15---H15 119.8 C4---C3---H3 113.8 C15---C16---C17 119.2 (2) C2---C3---H3 113.8 C15---C16---H16 120.4 C8---C3---H3 113.8 C17---C16---H16 120.4 N1---C4---C3 113.65 (19) C16---C17---C18 120.8 (2) N1---C4---C5 115.1 (2) C16---C17---H17 119.6 C3---C4---C5 101.0 (2) C18---C17---H17 119.6 N1---C4---H4 108.9 C17---C18---C13 120.2 (2) C3---C4---H4 108.9 C17---C18---H18 119.9 C5---C4---H4 108.9 C13---C18---H18 119.9 C4---C5---C6 104.2 (2) N1---C19---C20 112.67 (17) C4---C5---C10 111.9 (2) N1---C19---H19A 109.1 C6---C5---C10 95.0 (2) C20---C19---H19A 109.1 C4---C5---H5 114.6 N1---C19---H19B 109.1 C6---C5---H5 114.6 C20---C19---H19B 109.1 C10---C5---H5 114.6 H19A---C19---H19B 107.8 C1B---C6---C2 104.3 (4) C25---C20---C21 118.6 (2) C1B---C6---C5 126.0 (4) C25---C20---C19 121.6 (2) C2---C6---C5 107.0 (2) C21---C20---C19 119.8 (2) C1A---C7---C11 105.5 (3) C22---C21---C20 120.4 (2) C1A---C7---C8 114.2 (3) C22---C21---H21 119.8 C11---C7---C8 104.1 (2) C20---C21---H21 119.8 C9---C8---C7 102.1 (2) C23---C22---C21 120.6 (2) C9---C8---C3 111.6 (2) C23---C22---H22 119.7 C7---C8---C3 96.9 (2) C21---C22---H22 119.7 C9---C8---H8 114.7 C22---C23---C24 119.3 (2) C7---C8---H8 114.7 C22---C23---H23 120.4 C3---C8---H8 114.7 C24---C23---H23 120.4 O1---C9---C8 127.8 (2) C25---C24---C23 120.1 (2) O1---C9---C10 126.7 (2) C25---C24---H24 120.0 C8---C9---C10 104.5 (2) C23---C24---H24 120.0 C9---C10---C11 101.8 (3) C24---C25---C20 121.0 (2) C9---C10---C5 111.5 (2) C24---C25---H25 119.5 C11---C10---C5 93.7 (2) C20---C25---H25 119.5 C9---C10---H10 115.7 C2---C1A---C7 93.1 (3) C11---C10---H10 115.7 C2---C1A---H1A 113.1 C5---C10---H10 115.7 C7---C1A---H1A 113.1 C1B---C11---C7 102.3 (4) C2---C1A---H1B 113.1 C1B---C11---C10 126.7 (4) C7---C1A---H1B 113.1 C7---C11---C10 108.0 (2) H1A---C1A---H1B 110.5 N1---C12---C13 116.31 (17) C6---C1B---C11 81.7 (3) N1---C12---H12A 108.2 C6---C1B---H1D 115.0 C13---C12---H12A 108.2 C11---C1B---H1D 115.0 N1---C12---H12B 108.2 C6---C1B---H1C 115.0 C13---C12---H12B 108.2 C11---C1B---H1C 115.0 H12A---C12---H12B 107.4 H1D---C1B---H1C 112.1 C1A---C2---C3---C4 −145.8 (3) C4---C5---C10---C11 −107.2 (3) C6---C2---C3---C4 −31.6 (3) C6---C5---C10---C11 0.3 (3) C1A---C2---C3---C8 −30.7 (3) C1A---C7---C11---C1B 10.1 (3) C6---C2---C3---C8 83.4 (3) C8---C7---C11---C1B 130.7 (3) C19---N1---C4---C3 −170.57 (19) C1A---C7---C11---C10 −125.5 (3) C12---N1---C4---C3 67.2 (2) C8---C7---C11---C10 −4.9 (3) C19---N1---C4---C5 −54.8 (3) C9---C10---C11---C1B −142.8 (4) C12---N1---C4---C5 −177.03 (19) C5---C10---C11---C1B −29.9 (5) C2---C3---C4---N1 167.47 (19) C9---C10---C11---C7 −21.3 (3) C8---C3---C4---N1 62.0 (3) C5---C10---C11---C7 91.6 (3) C2---C3---C4---C5 43.6 (2) C4---N1---C12---C13 −92.8 (2) C8---C3---C4---C5 −61.8 (2) C19---N1---C12---C13 144.12 (18) N1---C4---C5---C6 −162.24 (19) N1---C12---C13---C18 −35.2 (3) C3---C4---C5---C6 −39.4 (2) N1---C12---C13---C14 150.2 (2) N1---C4---C5---C10 −60.8 (3) C18---C13---C14---C15 −1.1 (3) C3---C4---C5---C10 62.1 (3) C12---C13---C14---C15 173.7 (2) C1A---C2---C6---C1B −8.8 (3) C13---C14---C15---C16 0.6 (4) C3---C2---C6---C1B −128.7 (3) C14---C15---C16---C17 0.6 (4) C1A---C2---C6---C5 126.6 (3) C15---C16---C17---C18 −1.3 (4) C3---C2---C6---C5 6.7 (3) C16---C17---C18---C13 0.8 (4) C4---C5---C6---C1B 143.1 (4) C14---C13---C18---C17 0.4 (4) C10---C5---C6---C1B 29.1 (5) C12---C13---C18---C17 −174.3 (2) C4---C5---C6---C2 20.3 (3) C4---N1---C19---C20 173.10 (18) C10---C5---C6---C2 −93.7 (3) C12---N1---C19---C20 −64.4 (2) C1A---C7---C8---C9 144.0 (3) N1---C19---C20---C25 120.5 (2) C11---C7---C8---C9 29.5 (3) N1---C19---C20---C21 −60.8 (3) C1A---C7---C8---C3 30.1 (3) C25---C20---C21---C22 0.1 (4) C11---C7---C8---C3 −84.4 (2) C19---C20---C21---C22 −178.6 (2) C4---C3---C8---C9 2.7 (3) C20---C21---C22---C23 0.2 (4) C2---C3---C8---C9 −105.6 (3) C21---C22---C23---C24 −0.4 (4) C4---C3---C8---C7 108.6 (2) C22---C23---C24---C25 0.2 (4) C2---C3---C8---C7 0.3 (3) C23---C24---C25---C20 0.1 (4) C7---C8---C9---O1 124.9 (3) C21---C20---C25---C24 −0.3 (3) C3---C8---C9---O1 −132.5 (3) C19---C20---C25---C24 178.4 (2) C7---C8---C9---C10 −44.2 (2) C6---C2---C1A---C7 −67.4 (3) C3---C8---C9---C10 58.4 (3) C3---C2---C1A---C7 46.7 (4) O1---C9---C10---C11 −128.6 (3) C11---C7---C1A---C2 66.7 (3) C8---C9---C10---C11 40.7 (2) C8---C7---C1A---C2 −46.9 (4) O1---C9---C10---C5 132.6 (3) C2---C6---C1B---C11 83.9 (4) C8---C9---C10---C5 −58.1 (3) C5---C6---C1B---C11 −40.0 (5) C4---C5---C10---C9 −2.9 (3) C7---C11---C1B---C6 −82.9 (4) C6---C5---C10---C9 104.5 (3) C10---C11---C1B---C6 40.9 (5) --------------------- -------------- ----------------------- ------------- :::

PubMed Central

2024-06-05T04:04:17.419550

2011-2-12

PMC3051941

Related literature {#sec1} ================== For a review on the applications and structural chemistry of tin dithio­carbamates, see: Tiekink (2008[@bb8]). For additional structural analysis, see: Addison *et al.* (1984[@bb2]); Spek (2009[@bb7]). For a recently reported related structure, see: Abdul Muthalib *et al.* (2010[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Sn(C~4~H~9~)~2~Cl(C~10~H~12~NS~2~)\]*M* *~r~* = 478.69Triclinic,*a* = 8.6140 (2) Å*b* = 10.9604 (3) Å*c* = 11.4765 (3) Åα = 91.858 (2)°β = 96.193 (2)°γ = 96.011 (2)°*V* = 1070.24 (5) Å^3^*Z* = 2Mo *K*α radiationμ = 1.51 mm^−1^*T* = 150 K0.30 × 0.23 × 0.16 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcaliber Eos Gemini diffractometerAbsorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2010[@bb5]) *T* ~min~ = 0.935, *T* ~max~ = 1.00026998 measured reflections4865 independent reflections4707 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.034 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.018*wR*(*F* ^2^) = 0.046*S* = 1.114865 reflections215 parametersH-atom parameters constrainedΔρ~max~ = 0.29 e Å^−3^Δρ~min~ = −0.50 e Å^−3^ {#d5e533} Data collection: *CrysAlis PRO* (Oxford Diffraction, 2010[@bb5]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb6]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb6]); molecular graphics: *ORTEP-3* (Farrugia, 1997[@bb4]) and *DIAMOND* (Brandenburg, 2006[@bb3]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb9]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811006398/zs2099sup1.cif](http://dx.doi.org/10.1107/S1600536811006398/zs2099sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006398/zs2099Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006398/zs2099Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?zs2099&file=zs2099sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?zs2099sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?zs2099&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [ZS2099](http://scripts.iucr.org/cgi-bin/sendsup?zs2099)). The authors thank Universiti Kebangsaan Malaysia (UKM-GUP-NBT-08--27-111), the Ministry of Higher Education (UKM-ST-06-FRGS0092--2010), Universiti Putra Malaysia and the University of Malaya for supporting this study. Comment ======= Organotin dithiocarbamates attract attention as they exhibit properties suggesting their potential as anti-cancer agents, anti-microbials and insecticides (Tiekink, 2008). Motivated by these and in continuation of structural studies of these systems (Abdul Muthalib *et al.*, 2010), the analysis of the title compound, (I), was undertaken. The Sn^IV^ atom in (I) is five-coordinated, being chelated by an asymmetrically coordinating dithiocarbamate ligand, a Cl and two C atoms of the Sn-bound *tert*-butyl groups (Fig. 1 and Table 1). The asymmetric chelating mode of the non-symmetric dithiocarbamate ligand is reflected in the non-equivalence of the associated C≐S bond distances (Table 1). The coordination geometry is intermediate between square pyramidal and trigonal bi-pyramidal with a leaning towards the former. This assignment is based on the value calculated for τ of 0.45 for the Sn atom, which compares to the τ values of 0.0 and 1.0 for ideal square pyramidal and trigonal bi-pyramidal geometries, respectively (Spek, 2009; Addison *et al.*, 1984). The mode of coordination of the dithiocarbamate ligand, the disposition of the ligand donor set, and the intermediate coordination geometry observed for (I) matches with the literature precedents (Tiekink, 2008). The most prominent feature of the crystal packing is the presence of C--H···π interactions (Table 2). As shown in Fig. 2, these lead to dimeric aggregates. It is also noted that intramolecular C--H···π contacts are present so that the benzene ring participates in two such interactions (Table 2, Fig. 2). The dimeric aggregates stack into columns along the *a* axis (Fig. 3). Experimental {#experimental} ============ The dithiocarbamate ligand was prepared by the addition of carbon disulfide (0.01 mol) to an ethanolic solution (20 ml) of ethylbenzylamine (0.01 mol). The mixture was stirred for 1 h at 277 K, after which the solution was added drop wise to a solution of di-*tert*-butyltin(IV) dichloride (0.005 mol) in ethanol (20 ml). The resulting mixture was stirred for 1 h. The white precipitate was filtered, washed with cold ethanol and dried in a desiccator. Crystallization was carried out by using an ethanol:chloroform (1:2) mixture. Yield 76%; m.p. 451--453 K. Elemental analysis. Found (calculated) for C~18~H~30~ClNS~2~Sn: C, 44.81 (45.16); H 6.27 (6.32), N 2.72 (2.93), S 13.23 (13.40); Sn 23.98 (24.80) %. UV (CHCl~3~) λ~max~ 244 (*L*(π) →*L*(π\*)). IR (KBr): ν(C---H) 2933*m*, 2958*m*; ν(C≐N) 1496*m*; ν(N---C) 1185 s; ν(C≐S) 950 s; ν(Sn---S) 351 s cm^-1^. Refinement {#refinement} ========== Carbon-bound H-atoms were placed in calculated positions (C---H = 0.95 to 0.99 Å) and were included in the refinement in the riding model approximation, with *U*~iso~(H) set to 1.2 to 1.5*U*~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of of (I) showing the atom-labelling scheme and displacement ellipsoids at the 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### A view of the dimeric aggregate in (I) showing the intra- and intermolecular C--H···π contacts as purple dashed lines. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### A view in projection down the a axis of (I) showing columns of dimeric aggregates along a. The intermolecular C--H···π contacts are shown as purple dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e232 .table-wrap} ---------------------------------------- ---------------------------------------- \[Sn(C~4~H~9~)~2~Cl(C~10~H~12~NS~2~)\] *Z* = 2 *M~r~* = 478.69 *F*(000) = 488 Triclinic, *P*1 *D*~x~ = 1.485 Mg m^−3^ Hall symbol: -P 1 Melting point = 451--453 K *a* = 8.6140 (2) Å Mo *K*α radiation, λ = 0.71073 Å *b* = 10.9604 (3) Å Cell parameters from 22888 reflections *c* = 11.4765 (3) Å θ = 2.4--28.8° α = 91.858 (2)° µ = 1.51 mm^−1^ β = 96.193 (2)° *T* = 150 K γ = 96.011 (2)° Block, colourless *V* = 1070.24 (5) Å^3^ 0.30 × 0.23 × 0.16 mm ---------------------------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e377 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction Xcaliber Eos Gemini diffractometer 4865 independent reflections Radiation source: fine-focus sealed tube 4707 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.034 Detector resolution: 16.1952 pixels mm^-1^ θ~max~ = 27.5°, θ~min~ = 2.4° ω scans *h* = −11→11 Absorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2010) *k* = −13→13 *T*~min~ = 0.935, *T*~max~ = 1.000 *l* = −14→14 26998 measured reflections ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e497 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.018 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.046 H-atom parameters constrained *S* = 1.11 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0236*P*)^2^ + 0.279*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4865 reflections (Δ/σ)~max~ = 0.003 215 parameters Δρ~max~ = 0.29 e Å^−3^ 0 restraints Δρ~min~ = −0.50 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------ ::: Special details {#specialdetails} =============== ::: {#d1e654 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Geometry. All s.u.\'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.\'s are taken into account individually in the estimation of s.u.\'s in distances, angles and torsion angles; correlations between s.u.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.\'s is used for estimating s.u.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> 2σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e753 .table-wrap} ------ --------------- --------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Sn 0.908142 (10) 0.227855 (8) 0.757926 (8) 0.01355 (4) Cl1 1.09329 (4) 0.40294 (3) 0.84821 (3) 0.02158 (8) S1 0.88193 (4) 0.35904 (3) 0.58681 (3) 0.01801 (8) S2 0.70139 (5) 0.11432 (3) 0.57914 (3) 0.02180 (8) N1 0.69363 (14) 0.26534 (11) 0.39968 (10) 0.0152 (2) C1 0.74996 (17) 0.24573 (13) 0.50861 (12) 0.0154 (3) C2 0.73841 (18) 0.38150 (14) 0.34275 (13) 0.0192 (3) H2A 0.7233 0.3660 0.2566 0.023\* H2B 0.8514 0.4073 0.3659 0.023\* C3 0.6448 (2) 0.48595 (15) 0.37411 (15) 0.0248 (3) H3A 0.5338 0.4643 0.3450 0.037\* H3B 0.6849 0.5609 0.3380 0.037\* H3C 0.6555 0.4998 0.4595 0.037\* C4 0.58006 (18) 0.17438 (14) 0.32856 (13) 0.0185 (3) H4A 0.5613 0.0996 0.3734 0.022\* H4B 0.6243 0.1508 0.2560 0.022\* C5 0.42662 (17) 0.22668 (13) 0.29687 (13) 0.0162 (3) C6 0.38063 (18) 0.25643 (15) 0.18239 (13) 0.0206 (3) H6 0.4422 0.2374 0.1217 0.025\* C7 0.24535 (19) 0.31377 (15) 0.15584 (14) 0.0248 (3) H7 0.2146 0.3341 0.0775 0.030\* C8 0.15570 (19) 0.34106 (14) 0.24459 (15) 0.0244 (3) H8 0.0644 0.3818 0.2273 0.029\* C9 0.19895 (18) 0.30901 (15) 0.35845 (15) 0.0230 (3) H9 0.1362 0.3265 0.4188 0.028\* C10 0.33337 (17) 0.25166 (14) 0.38442 (13) 0.0185 (3) H10 0.3621 0.2293 0.4624 0.022\* C11 1.08251 (17) 0.09669 (13) 0.75357 (13) 0.0182 (3) C12 1.1743 (2) 0.09891 (18) 0.87481 (16) 0.0344 (4) H12A 1.2538 0.0413 0.8745 0.052\* H12B 1.1022 0.0749 0.9326 0.052\* H12C 1.2258 0.1820 0.8954 0.052\* C13 1.0023 (2) −0.03233 (15) 0.7207 (2) 0.0351 (4) H13A 0.9457 −0.0337 0.6418 0.053\* H13B 0.9280 −0.0558 0.7771 0.053\* H13C 1.0816 −0.0903 0.7221 0.053\* C14 1.1918 (2) 0.13760 (17) 0.66298 (17) 0.0334 (4) H14A 1.2413 0.2211 0.6843 0.050\* H14B 1.1312 0.1364 0.5855 0.050\* H14C 1.2731 0.0816 0.6609 0.050\* C15 0.72963 (18) 0.22899 (15) 0.87978 (13) 0.0210 (3) C16 0.6414 (2) 0.10044 (16) 0.87739 (15) 0.0283 (4) H16A 0.5648 0.0983 0.9347 0.042\* H16B 0.7162 0.0408 0.8971 0.042\* H16C 0.5866 0.0797 0.7988 0.042\* C17 0.8116 (2) 0.2629 (2) 1.00325 (15) 0.0356 (4) H17A 0.8685 0.3453 1.0046 0.053\* H17B 0.8857 0.2034 1.0253 0.053\* H17C 0.7330 0.2618 1.0590 0.053\* C18 0.6177 (2) 0.32236 (19) 0.8403 (2) 0.0390 (5) H18A 0.5717 0.3013 0.7594 0.059\* H18B 0.6756 0.4045 0.8444 0.059\* H18C 0.5339 0.3212 0.8918 0.059\* ------ --------------- --------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1437 .table-wrap} ----- -------------- -------------- -------------- --------------- --------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Sn 0.01353 (6) 0.01384 (6) 0.01283 (6) 0.00071 (4) −0.00031 (4) 0.00204 (4) Cl1 0.02389 (18) 0.01842 (18) 0.01980 (17) −0.00371 (14) −0.00377 (14) 0.00095 (13) S1 0.02071 (18) 0.01593 (17) 0.01529 (16) −0.00302 (13) −0.00340 (13) 0.00330 (13) S2 0.0271 (2) 0.01675 (18) 0.01827 (17) −0.00533 (15) −0.00567 (15) 0.00382 (14) N1 0.0147 (6) 0.0160 (6) 0.0144 (6) 0.0026 (5) −0.0006 (5) 0.0002 (5) C1 0.0146 (6) 0.0164 (7) 0.0150 (6) 0.0026 (5) 0.0005 (5) −0.0010 (5) C2 0.0198 (7) 0.0232 (8) 0.0148 (7) 0.0010 (6) 0.0023 (6) 0.0058 (6) C3 0.0268 (8) 0.0179 (8) 0.0292 (8) 0.0013 (6) 0.0012 (7) 0.0057 (6) C4 0.0196 (7) 0.0188 (7) 0.0160 (7) 0.0042 (6) −0.0031 (6) −0.0051 (5) C5 0.0170 (7) 0.0143 (7) 0.0160 (7) −0.0001 (5) −0.0019 (5) −0.0014 (5) C6 0.0218 (7) 0.0247 (8) 0.0152 (7) 0.0028 (6) 0.0007 (6) −0.0009 (6) C7 0.0262 (8) 0.0254 (8) 0.0210 (8) 0.0038 (6) −0.0069 (6) 0.0033 (6) C8 0.0190 (7) 0.0183 (8) 0.0351 (9) 0.0048 (6) −0.0032 (7) −0.0005 (7) C9 0.0199 (7) 0.0220 (8) 0.0267 (8) −0.0005 (6) 0.0054 (6) −0.0057 (6) C10 0.0198 (7) 0.0197 (7) 0.0151 (7) −0.0009 (6) 0.0008 (6) −0.0003 (5) C11 0.0173 (7) 0.0152 (7) 0.0225 (7) 0.0034 (5) 0.0018 (6) 0.0023 (6) C12 0.0352 (10) 0.0406 (11) 0.0287 (9) 0.0197 (8) −0.0058 (8) 0.0024 (8) C13 0.0275 (9) 0.0155 (8) 0.0613 (13) 0.0039 (7) −0.0013 (9) 0.0013 (8) C14 0.0362 (10) 0.0296 (10) 0.0402 (10) 0.0125 (8) 0.0202 (8) 0.0069 (8) C15 0.0190 (7) 0.0236 (8) 0.0206 (7) −0.0001 (6) 0.0057 (6) 0.0004 (6) C16 0.0277 (9) 0.0297 (9) 0.0263 (8) −0.0070 (7) 0.0070 (7) 0.0042 (7) C17 0.0345 (10) 0.0516 (12) 0.0187 (8) −0.0090 (8) 0.0097 (7) −0.0082 (8) C18 0.0289 (9) 0.0360 (11) 0.0577 (13) 0.0138 (8) 0.0180 (9) 0.0095 (9) ----- -------------- -------------- -------------- --------------- --------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1885 .table-wrap} -------------------- -------------- ---------------------- -------------- Sn---Cl1 2.4847 (4) C9---C10 1.384 (2) Sn---S1 2.4760 (4) C9---H9 0.9500 Sn---S2 2.7409 (4) C10---H10 0.9500 Sn---C11 2.1884 (14) C11---C12 1.522 (2) Sn---C15 2.1879 (15) C11---C14 1.523 (2) S1---C1 1.7470 (15) C11---C13 1.524 (2) S2---C1 1.7109 (15) C12---H12A 0.9800 N1---C1 1.3240 (18) C12---H12B 0.9800 N1---C4 1.4791 (18) C12---H12C 0.9800 N1---C2 1.4839 (19) C13---H13A 0.9800 C2---C3 1.523 (2) C13---H13B 0.9800 C2---H2A 0.9900 C13---H13C 0.9800 C2---H2B 0.9900 C14---H14A 0.9800 C3---H3A 0.9800 C14---H14B 0.9800 C3---H3B 0.9800 C14---H14C 0.9800 C3---H3C 0.9800 C15---C18 1.525 (2) C4---C5 1.509 (2) C15---C16 1.527 (2) C4---H4A 0.9900 C15---C17 1.530 (2) C4---H4B 0.9900 C16---H16A 0.9800 C5---C10 1.390 (2) C16---H16B 0.9800 C5---C6 1.390 (2) C16---H16C 0.9800 C6---C7 1.391 (2) C17---H17A 0.9800 C6---H6 0.9500 C17---H17B 0.9800 C7---C8 1.386 (2) C17---H17C 0.9800 C7---H7 0.9500 C18---H18A 0.9800 C8---C9 1.386 (2) C18---H18B 0.9800 C8---H8 0.9500 C18---H18C 0.9800 C15---Sn---C11 125.79 (6) C9---C10---C5 120.31 (14) C15---Sn---S1 117.55 (4) C9---C10---H10 119.8 C11---Sn---S1 115.59 (4) C5---C10---H10 119.8 C15---Sn---Cl1 98.77 (4) C12---C11---C14 110.27 (15) C11---Sn---Cl1 96.17 (4) C12---C11---C13 109.80 (14) S1---Sn---Cl1 84.342 (12) C14---C11---C13 110.21 (14) C15---Sn---S2 93.43 (4) C12---C11---Sn 108.21 (10) C11---Sn---S2 96.04 (4) C14---C11---Sn 107.78 (10) S1---Sn---S2 68.654 (12) C13---C11---Sn 110.52 (10) Cl1---Sn---S2 152.989 (12) C11---C12---H12A 109.5 C1---S1---Sn 91.00 (5) C11---C12---H12B 109.5 C1---S2---Sn 83.22 (5) H12A---C12---H12B 109.5 C1---N1---C4 122.17 (12) C11---C12---H12C 109.5 C1---N1---C2 121.73 (12) H12A---C12---H12C 109.5 C4---N1---C2 116.09 (11) H12B---C12---H12C 109.5 N1---C1---S2 123.80 (11) C11---C13---H13A 109.5 N1---C1---S1 119.10 (11) C11---C13---H13B 109.5 S2---C1---S1 117.10 (8) H13A---C13---H13B 109.5 N1---C2---C3 113.75 (12) C11---C13---H13C 109.5 N1---C2---H2A 108.8 H13A---C13---H13C 109.5 C3---C2---H2A 108.8 H13B---C13---H13C 109.5 N1---C2---H2B 108.8 C11---C14---H14A 109.5 C3---C2---H2B 108.8 C11---C14---H14B 109.5 H2A---C2---H2B 107.7 H14A---C14---H14B 109.5 C2---C3---H3A 109.5 C11---C14---H14C 109.5 C2---C3---H3B 109.5 H14A---C14---H14C 109.5 H3A---C3---H3B 109.5 H14B---C14---H14C 109.5 C2---C3---H3C 109.5 C18---C15---C16 110.55 (15) H3A---C3---H3C 109.5 C18---C15---C17 111.09 (15) H3B---C3---H3C 109.5 C16---C15---C17 109.57 (14) N1---C4---C5 110.67 (12) C18---C15---Sn 108.38 (11) N1---C4---H4A 109.5 C16---C15---Sn 108.51 (10) C5---C4---H4A 109.5 C17---C15---Sn 108.66 (10) N1---C4---H4B 109.5 C15---C16---H16A 109.5 C5---C4---H4B 109.5 C15---C16---H16B 109.5 H4A---C4---H4B 108.1 H16A---C16---H16B 109.5 C10---C5---C6 119.24 (14) C15---C16---H16C 109.5 C10---C5---C4 119.60 (13) H16A---C16---H16C 109.5 C6---C5---C4 121.08 (14) H16B---C16---H16C 109.5 C5---C6---C7 120.61 (15) C15---C17---H17A 109.5 C5---C6---H6 119.7 C15---C17---H17B 109.5 C7---C6---H6 119.7 H17A---C17---H17B 109.5 C8---C7---C6 119.51 (15) C15---C17---H17C 109.5 C8---C7---H7 120.2 H17A---C17---H17C 109.5 C6---C7---H7 120.2 H17B---C17---H17C 109.5 C9---C8---C7 120.14 (15) C15---C18---H18A 109.5 C9---C8---H8 119.9 C15---C18---H18B 109.5 C7---C8---H8 119.9 H18A---C18---H18B 109.5 C10---C9---C8 120.15 (14) C15---C18---H18C 109.5 C10---C9---H9 119.9 H18A---C18---H18C 109.5 C8---C9---H9 119.9 H18B---C18---H18C 109.5 C15---Sn---S1---C1 −83.40 (7) C8---C9---C10---C5 0.5 (2) C11---Sn---S1---C1 85.49 (6) C6---C5---C10---C9 −2.0 (2) Cl1---Sn---S1---C1 179.64 (5) C4---C5---C10---C9 174.62 (14) S2---Sn---S1---C1 −0.96 (5) C15---Sn---C11---C12 −55.53 (13) C15---Sn---S2---C1 119.28 (6) S1---Sn---C11---C12 136.63 (11) C11---Sn---S2---C1 −114.17 (6) Cl1---Sn---C11---C12 49.96 (11) S1---Sn---S2---C1 0.98 (5) S2---Sn---C11---C12 −154.18 (11) Cl1---Sn---S2---C1 2.29 (6) C15---Sn---C11---C14 −174.77 (11) C4---N1---C1---S2 0.84 (19) S1---Sn---C11---C14 17.39 (12) C2---N1---C1---S2 179.45 (10) Cl1---Sn---C11---C14 −69.28 (11) C4---N1---C1---S1 −179.25 (10) S2---Sn---C11---C14 86.58 (11) C2---N1---C1---S1 −0.64 (18) C15---Sn---C11---C13 64.74 (14) Sn---S2---C1---N1 178.46 (13) S1---Sn---C11---C13 −103.11 (12) Sn---S2---C1---S1 −1.46 (7) Cl1---Sn---C11---C13 170.23 (12) Sn---S1---C1---N1 −178.32 (11) S2---Sn---C11---C13 −33.91 (12) Sn---S1---C1---S2 1.60 (8) C11---Sn---C15---C18 −171.31 (11) C1---N1---C2---C3 −82.33 (17) S1---Sn---C15---C18 −3.68 (13) C4---N1---C2---C3 96.36 (15) Cl1---Sn---C15---C18 84.49 (12) C1---N1---C4---C5 117.52 (15) S2---Sn---C15---C18 −71.34 (12) C2---N1---C4---C5 −61.16 (16) C11---Sn---C15---C16 −51.22 (13) N1---C4---C5---C10 −67.27 (17) S1---Sn---C15---C16 116.41 (10) N1---C4---C5---C6 109.31 (16) Cl1---Sn---C15---C16 −155.42 (10) C10---C5---C6---C7 1.8 (2) S2---Sn---C15---C16 48.75 (11) C4---C5---C6---C7 −174.75 (14) C11---Sn---C15---C17 67.86 (14) C5---C6---C7---C8 −0.2 (2) S1---Sn---C15---C17 −124.51 (11) C6---C7---C8---C9 −1.4 (2) Cl1---Sn---C15---C17 −36.34 (12) C7---C8---C9---C10 1.2 (2) S2---Sn---C15---C17 167.83 (12) -------------------- -------------- ---------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2919 .table-wrap} ------------------------------------------ Cg1 is the centroid of the C5--C10 ring. ------------------------------------------ ::: ::: {#d1e2923 .table-wrap} --------------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C3---H3a···Cg1 0.98 2.78 3.6491 (18) 149 C13---H13b···Cg1^i^ 0.98 2.96 3.5401 (18) 119 --------------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*, −*z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Selected bond lengths (Å) ::: ---------- ------------- Sn---Cl1 2.4847 (4) Sn---S1 2.4760 (4) Sn---S2 2.7409 (4) Sn---C11 2.1884 (14) Sn---C15 2.1879 (15) ---------- ------------- ::: ::: {#table2 .table-wrap} Table 2 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) *Cg*1 is the centroid of the C5--C10 ring. ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ------------- ------------- C3---H3a⋯*Cg*1 0.98 2.78 3.6491 (18) 149 C13---H13b⋯*Cg*1^i^ 0.98 2.96 3.5401 (18) 119 Symmetry code: (i) . ::: [^1]: ‡ Additional correspondence author, e-mail: [email protected].

PubMed Central

2024-06-05T04:04:17.426526

2011-2-26

PMC3051942

Related literature {#sec1} ================== For related structures, see: Wei & Willett (1996[@bb4], 2002[@bb5]); Brammer *et al.* (2002[@bb1]); Zhang *et al.* (2010[@bb6]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} (C~6~H~14~N~2~)\[CuBr~4~\]·H~2~O*M* *~r~* = 515.39Monoclinic,*a* = 9.5171 (19) Å*b* = 9.5341 (19) Å*c* = 14.952 (3) Åβ = 93.93 (3)°*V* = 1353.5 (5) Å^3^*Z* = 4Mo *K*α radiationμ = 13.40 mm^−1^*T* = 298 K0.20 × 0.20 × 0.20 mm ### Data collection {#sec2.1.2} Rigaku SCXmini diffractometerAbsorption correction: multi-scan (*CrystalClear*; Rigaku, 2005[@bb2]) *T* ~min~ = 0.055, *T* ~max~ = 0.08613570 measured reflections3111 independent reflections2285 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.124 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.052*wR*(*F* ^2^) = 0.116*S* = 1.103111 reflections128 parametersH-atom parameters constrainedΔρ~max~ = 1.22 e Å^−3^Δρ~min~ = −1.29 e Å^−3^ {#d5e521} Data collection: *CrystalClear* (Rigaku, 2005[@bb2]); cell refinement: *CrystalClear*; data reduction: *CrystalClear*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb3]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb3]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb3]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005289/rz2552sup1.cif](http://dx.doi.org/10.1107/S1600536811005289/rz2552sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005289/rz2552Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005289/rz2552Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?rz2552&file=rz2552sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?rz2552sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?rz2552&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [RZ2552](http://scripts.iucr.org/cgi-bin/sendsup?rz2552)). This work was supported by the Start-up Projects for Postdoctoral Research Funds (1112000064) and the Major Postdoctoral Research Funds (3212000602) of Southeast University. Comment ======= Ferroelectric materials have attracted intensive interest not only due to their versatile technological applications in the field of electronics and optics, but also for their importance to the fundamental scientific research. Recently, monosalts of 1,4-diazabicyclo\[2.2.2\]octane (dabco) including dabco*HBF~4~*, dabco*HClO~4~* and dabco*HReO~4~* have been reported to have excellent dielectric and ferroelectric properties (Wei & Willett, 1996, 2002; Brammer *et al.*, 2002). Our group has recently reported the compound (dabcoH~2~)~2~Cl~3~\[CuCl~3~(H~2~O)~2~\].H~2~O (Zhang *et al.*, 2010), which also shows good dielectric and ferroelectric properties. Herein we report the synthesis and crystal structure of the title compound, (dabcoH~2~)CuBr~4~.H~2~O. The asymmetric unit of the title compound contains one (dabcoH~2~)^2+^ cation, one \[CuBr~4~\]^2-^ anion and one water molecules (Fig 1). The copper(II) ion has a flattened tetrahedral coordination geometry provided by the four Br^-^ ions, with Cu---Br distances ranging from 2.3598 (12) to 2.4070 (12) Å. Generally, the Cu---Br bond lengths and Br---Cu---Br bond angles in a \[CuBr~4~\]^2-^ anion are not equal to one another but vary with the environment around the Br atoms. As atoms Br1, Br2 and Br4 are involved in hydrogen bonds, the Cu1---Br3 bond length is significantly shorter than the other Cu---Br bonds. The distortion from the ideal tetrahedral geometry is also indicated by the values of the Br---Cu---Br angles, which range from 96.75 (4) to 133.92 (5)°. The H1C and H2C protons of the 1,4-diazoniabicyclo(2.2.2)octane cation and the H1WA hydrogen atom of the water molecule are engaged in bifurcated N---H···Br, N---H···O and O---H···Br hydrogen bonds (Table 1), forming chains parallel to the *b* axis. The chains are further connected by O---H···Br hydrogen bonds into layers parallel to the (011) plane (Fig. 2). Experimental {#experimental} ============ To a concentrated HBr water solution (50 ml) 1,4-diazabicyclo\[2.2.2\]octane (10 mmol, 1.12 g) and of CuBr~2~.2H~2~O (10 mmol, 2.60 g) were added with stirring. Brown single crystals of the title compound suitable for X-ray analysis were obtained by slow evaporation of the solvent over a period of a week at room temperature. The dielectric constant of the compound as a function of temperature indicates that the permittivity is basically temperature-independent (*ε*= C/(T--T~0~)), suggesting that the title compound is not ferroelectric or there may be no distinct phase transition occurring within the measured temperature range between 93 K and 362 K (m. p. 99 °C). Refinement {#refinement} ========== All H atoms were fixed geometrically and treated as riding, with C--H = 0.97 Å, N---H = 0.91 Å, O---H = 0.85 Å, and with *U*~iso~(H) = 1.2 *U*~eq~(C, N) or 1.2 *U*~eq~(O). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound, with the atomic numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Packing diagram of the title compound viewed along the a axis. H atoms not involved in hydrogen bonding (dashed lines) are omitted. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e206 .table-wrap} ---------------------------------- --------------------------------------- (C~6~H~14~N~2~)\[CuBr~4~\]·H~2~O *F*(000) = 972 *M~r~* = 515.39 *D*~x~ = 2.529 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 2622 reflections *a* = 9.5171 (19) Å θ = 3.0--27.5° *b* = 9.5341 (19) Å µ = 13.40 mm^−1^ *c* = 14.952 (3) Å *T* = 298 K β = 93.93 (3)° Polyhedron, brown *V* = 1353.5 (5) Å^3^ 0.20 × 0.20 × 0.20 mm *Z* = 4 ---------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e340 .table-wrap} ------------------------------------------------------------------ -------------------------------------- Rigaku SCXmini diffractometer 3111 independent reflections Radiation source: fine-focus sealed tube 2285 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.124 Detector resolution: 13.6612 pixels mm^-1^ θ~max~ = 27.5°, θ~min~ = 3.0° ω scans *h* = −12→12 Absorption correction: multi-scan (*CrystalClear*; Rigaku, 2005) *k* = −12→12 *T*~min~ = 0.055, *T*~max~ = 0.086 *l* = −19→19 13570 measured reflections ------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e460 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.052 H-atom parameters constrained *wR*(*F*^2^) = 0.116 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0225*P*)^2^ + 2.0506*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.10 (Δ/σ)~max~ \< 0.001 3111 reflections Δρ~max~ = 1.22 e Å^−3^ 128 parameters Δρ~min~ = −1.29 e Å^−3^ 0 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.0204 (7) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e641 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e740 .table-wrap} ------ -------------- ------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Br1 0.13288 (8) 1.07551 (7) −0.32168 (5) 0.0252 (2) Br2 0.47455 (8) 1.29945 (9) −0.17676 (5) 0.0294 (3) Br3 0.24026 (10) 1.44329 (8) −0.35401 (5) 0.0343 (3) Br4 0.12020 (9) 1.24314 (8) −0.10831 (5) 0.0291 (2) C1 0.2071 (9) 0.7578 (7) −0.1967 (5) 0.0250 (18) H1A 0.1136 0.7276 −0.2186 0.030\* H1B 0.2588 0.7837 −0.2479 0.030\* C2 0.2812 (10) 0.6413 (8) −0.1464 (5) 0.039 (2) H2A 0.2182 0.5619 −0.1423 0.046\* H2B 0.3620 0.6113 −0.1776 0.046\* C3 0.1196 (8) 0.8404 (8) −0.0560 (5) 0.0221 (17) H3A 0.0265 0.8058 −0.0751 0.027\* H3B 0.1094 0.9204 −0.0170 0.027\* C4 0.2029 (9) 0.7281 (8) −0.0075 (6) 0.032 (2) H4A 0.2322 0.7602 0.0524 0.039\* H4B 0.1444 0.6456 −0.0023 0.039\* C5 0.3414 (8) 0.9335 (7) −0.1063 (5) 0.0265 (19) H5A 0.3357 1.0120 −0.0654 0.032\* H5B 0.3896 0.9644 −0.1579 0.032\* C6 0.4211 (9) 0.8136 (8) −0.0601 (6) 0.040 (2) H6A 0.5019 0.7893 −0.0932 0.048\* H6B 0.4551 0.8418 −0.0001 0.048\* Cu1 0.24156 (9) 1.27018 (9) −0.24116 (6) 0.0190 (3) N1 0.1962 (6) 0.8822 (6) −0.1354 (4) 0.0164 (13) H1C 0.1478 0.9520 −0.1654 0.020\* N2 0.3277 (6) 0.6913 (6) −0.0552 (4) 0.0204 (14) H2C 0.3753 0.6211 −0.0251 0.024\* O1W 0.6324 (6) 0.5717 (5) −0.0241 (3) 0.0316 (14) H1WA 0.6670 0.5956 0.0276 0.047\* H1WB 0.6832 0.6044 −0.0638 0.047\* ------ -------------- ------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1194 .table-wrap} ----- ------------ ------------ ------------ ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Br1 0.0381 (5) 0.0188 (4) 0.0181 (5) −0.0005 (3) −0.0012 (4) −0.0011 (3) Br2 0.0251 (4) 0.0452 (5) 0.0177 (5) 0.0018 (4) 0.0000 (3) 0.0023 (4) Br3 0.0557 (6) 0.0281 (5) 0.0180 (5) −0.0065 (4) −0.0067 (4) 0.0144 (4) Br4 0.0378 (5) 0.0327 (5) 0.0182 (5) 0.0007 (4) 0.0138 (4) 0.0031 (3) C1 0.037 (5) 0.028 (4) 0.010 (4) −0.003 (4) 0.002 (3) −0.008 (3) C2 0.077 (7) 0.025 (5) 0.015 (5) 0.015 (5) 0.009 (5) −0.004 (4) C3 0.027 (4) 0.029 (4) 0.010 (4) 0.003 (3) 0.003 (3) −0.004 (3) C4 0.046 (5) 0.029 (5) 0.024 (5) 0.009 (4) 0.012 (4) 0.010 (4) C5 0.035 (4) 0.017 (4) 0.026 (5) −0.007 (3) −0.007 (4) 0.006 (3) C6 0.029 (5) 0.035 (5) 0.054 (6) −0.001 (4) −0.011 (4) 0.029 (5) Cu1 0.0288 (5) 0.0193 (5) 0.0087 (5) −0.0016 (4) 0.0003 (4) 0.0041 (4) N1 0.020 (3) 0.019 (3) 0.011 (3) 0.005 (3) −0.002 (2) 0.007 (3) N2 0.037 (4) 0.011 (3) 0.013 (3) 0.006 (3) −0.002 (3) 0.008 (3) O1W 0.045 (3) 0.027 (3) 0.023 (3) 0.000 (3) 0.008 (3) 0.010 (2) ----- ------------ ------------ ------------ ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1482 .table-wrap} ---------------- ------------- ------------------- ------------ Br1---Cu1 2.4070 (12) C4---N2 1.469 (10) Br2---Cu1 2.3726 (13) C4---H4A 0.9700 Br3---Cu1 2.3598 (12) C4---H4B 0.9700 Br4---Cu1 2.3792 (13) C5---N1 1.502 (9) C1---C2 1.492 (10) C5---C6 1.512 (10) C1---N1 1.507 (9) C5---H5A 0.9700 C1---H1A 0.9700 C5---H5B 0.9700 C1---H1B 0.9700 C6---N2 1.471 (9) C2---N2 1.483 (9) C6---H6A 0.9700 C2---H2A 0.9700 C6---H6B 0.9700 C2---H2B 0.9700 N1---H1C 0.9100 C3---N1 1.489 (9) N2---H2C 0.9100 C3---C4 1.490 (10) O1W---H1WA 0.8501 C3---H3A 0.9700 O1W---H1WB 0.8500 C3---H3B 0.9700 C2---C1---N1 109.2 (6) C6---C5---H5B 110.1 C2---C1---H1A 109.8 H5A---C5---H5B 108.4 N1---C1---H1A 109.8 N2---C6---C5 109.6 (6) C2---C1---H1B 109.8 N2---C6---H6A 109.7 N1---C1---H1B 109.8 C5---C6---H6A 109.7 H1A---C1---H1B 108.3 N2---C6---H6B 109.7 N2---C2---C1 109.0 (6) C5---C6---H6B 109.7 N2---C2---H2A 109.9 H6A---C6---H6B 108.2 C1---C2---H2A 109.9 Br3---Cu1---Br2 99.61 (5) N2---C2---H2B 109.9 Br3---Cu1---Br4 133.92 (5) C1---C2---H2B 109.9 Br2---Cu1---Br4 99.64 (5) H2A---C2---H2B 108.3 Br3---Cu1---Br1 101.57 (4) N1---C3---C4 107.9 (6) Br2---Cu1---Br1 130.64 (5) N1---C3---H3A 110.1 Br4---Cu1---Br1 96.75 (4) C4---C3---H3A 110.1 C3---N1---C5 110.3 (5) N1---C3---H3B 110.1 C3---N1---C1 109.4 (5) C4---C3---H3B 110.1 C5---N1---C1 109.4 (6) H3A---C3---H3B 108.4 C3---N1---H1C 109.2 N2---C4---C3 110.9 (6) C5---N1---H1C 109.2 N2---C4---H4A 109.5 C1---N1---H1C 109.2 C3---C4---H4A 109.5 C4---N2---C6 110.2 (6) N2---C4---H4B 109.5 C4---N2---C2 108.8 (6) C3---C4---H4B 109.5 C6---N2---C2 110.7 (6) H4A---C4---H4B 108.1 C4---N2---H2C 109.0 N1---C5---C6 108.0 (6) C6---N2---H2C 109.0 N1---C5---H5A 110.1 C2---N2---H2C 109.0 C6---C5---H5A 110.1 H1WA---O1W---H1WB 109.5 N1---C5---H5B 110.1 ---------------- ------------- ------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1890 .table-wrap} ----------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N2---H2C···O1W 0.91 2.49 3.121 (8) 127 N2---H2C···O1W^i^ 0.91 1.98 2.788 (7) 147 O1W---H1WA···Br4^ii^ 0.85 2.75 3.456 (5) 141 O1W---H1WA···Br2^ii^ 0.85 2.86 3.461 (5) 129 O1W---H1WB···Br1^iii^ 0.85 2.55 3.319 (5) 152 N1---H1C···Br1 0.91 2.61 3.360 (5) 140 N1---H1C···Br4 0.91 2.92 3.546 (6) 127 ----------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*+1, −*z*; (ii) −*x*+1, −*y*+2, −*z*; (iii) −*x*+1, *y*−1/2, −*z*−1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------------- --------- ------- ----------- ------------- N2---H2*C*⋯O1*W* 0.91 2.49 3.121 (8) 127 N2---H2*C*⋯O1*W*^i^ 0.91 1.98 2.788 (7) 147 O1*W*---H1*WA*⋯Br4^ii^ 0.85 2.75 3.456 (5) 141 O1*W*---H1*WA*⋯Br2^ii^ 0.85 2.86 3.461 (5) 129 O1*W*---H1*WB*⋯Br1^iii^ 0.85 2.55 3.319 (5) 152 N1---H1*C*⋯Br1 0.91 2.61 3.360 (5) 140 N1---H1*C*⋯Br4 0.91 2.92 3.546 (6) 127 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.433449

2011-2-23

PMC3051943

Related literature {#sec1} ================== For initiators in ATRP (polymerization by atom transfer radical) processes, see: Matyjaszewski & Xia (2001[@bb4]); Pietrasik & Tsarevsky (2010[@bb6]). For graph-set notation of hydrogen-bond patterns, see: Etter (1990[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~10~H~11~BrN~2~O~3~*M* *~r~* = 287.11Monoclinic,*a* = 24.1245 (12) Å*b* = 5.8507 (3) Å*c* = 15.4723 (8) Åβ = 91.837 (5)°*V* = 2182.72 (19) Å^3^*Z* = 8Mo *K*α radiationμ = 3.76 mm^−1^*T* = 123 K0.60 × 0.05 × 0.05 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcalibur E diffractometerAbsorption correction: analytical (*CrysAlis PRO*; Oxford Diffraction, 2009[@bb5]) *T* ~min~ = 0.444, *T* ~max~ = 1.0005100 measured reflections2633 independent reflections2197 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.032 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.032*wR*(*F* ^2^) = 0.068*S* = 1.062633 reflections151 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.55 e Å^−3^Δρ~min~ = −0.60 e Å^−3^ {#d5e471} Data collection: *CrysAlis CCD* (Oxford Diffraction, 2009[@bb5]); cell refinement: *CrysAlis CCD*; data reduction: *CrysAlis CCD*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb2]) and *Mercury* (Macrae *et al.*, 2006[@bb3]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005320/tk2720sup1.cif](http://dx.doi.org/10.1107/S1600536811005320/tk2720sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005320/tk2720Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005320/tk2720Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?tk2720&file=tk2720sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?tk2720sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?tk2720&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [TK2720](http://scripts.iucr.org/cgi-bin/sendsup?tk2720)). RMF is grateful to the Spanish Research Council (CSIC) for the use of a free-of-charge licence to the Cambridge Structural Database. RMF and FZ also thank the Universidad del Valle, Colombia, and the Instituto de Química de São Carlos, USP, Brasil for partial financial support. RLAH thanks CNPq for partial financial support. Comment ======= The title compound, (I), forms a part of a synthetic programme that the Polymer Research Group of Universidad del Valle is pursuing in order to obtain compounds that act as initiators of reactions in polymerization processes. Compound (I), Fig. 1, belongs to a series of polymeric ATRP (polymerization by atom transfer radical) initiators (Pietrasik & Tsarevsky, 2010); most initiators for ATRP processes are alkyl halides (Matyjaszewski & Xia, 2001). The C4---N1---C5---C6 torsion angle is 12.7 (4)°, indicating a small twist between the benzene ring and the amide. An intramolecular C---H···O interaction is observed (see Table 1). In the crystal structure, weak C---H···O and N---H···O intermolecular interactions are detected (Table 1). In a first substructure (Fig. 2), molecules are linked by C7---H···O1^i^ contacts (i: -x+1/2,-y-1/2,-z) which leads to the formation of dimers with graphs-set notation, R^2^~2~(14) (Etter, 1990). In turn, N---H···O interactions link the dimers running along the *c* axis. The N1 atom acts as hydrogen bond donor to O3^ii^ (ii: -x+1/2,+y-1/2,-z+1/2). In a second substructure, C10---H···Br (Table 1) interactions provide further links between the dimers. Overall, the crystal structure comprises layers in the *bc* plane (Fig. 3). Experimental {#experimental} ============ The initial reagents were purchased from Aldrich Chemical Co. and were used as received. In a 100 mL round bottom flask 4-nitroaniline (3.258 mmol, 0.450 g), triethylamine (0.653 mmol, 0.066 g) were mixed, then a solution of 2-bromo isobuturyl bromide (0.704 g) in anhydrous THF (5 mL) was added drop wise, under an argon stream. The reaction was carried out in a dry bag overnight under magnetic stirring. The solid was filtered off and dichloromethane (20 mL) added to the organic phase which was washed with brine (40 mL) followed by water (10 mL). The solution was concentrated at low pressure affording colourless crystals and recrystalized from a solution of hexane and ethyl acetate (80:20). *M*. pt. 356 (1) K. Refinement {#refinement} ========== The H-atoms were placed geometrically \[C---H = 0.95 Å for aromatic & C---H = 0.98 Å for methyl\], refined in the riding model approximation with U~iso~(H) = 1.2--1.5U~eq~(C). The N-bound H atom was refined freely. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### An ORTEP-3 (Farrugia, 1997) plot of (I) with the atomic labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are shown as spheres of arbitrary radius. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Part of the crystal structure of (I), showing the formation of R22(10) and R44(18) rings, running along \[110\]. Symmetry code: (i) -x+1,-y+1,-z; (ii) -x+2,-y+2,-z. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### Part of the crystal structure of (I), showing the formation of an infinite zig-zag chain of dimers along \[001\] direction. Symmetry code: (iii) x,-y+1/2+1,+z-1/2. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e140 .table-wrap} ------------------------- --------------------------------------- C~10~H~11~BrN~2~O~3~ *F*(000) = 1152 *M~r~* = 287.11 *D*~x~ = 1.747 Mg m^−3^ Monoclinic, *C*2/*c* Melting point: 385(1) K Hall symbol: -C 2yc Mo *K*α radiation, λ = 0.71073 Å *a* = 24.1245 (12) Å Cell parameters from 2722 reflections *b* = 5.8507 (3) Å θ = 3.2--29.3° *c* = 15.4723 (8) Å µ = 3.76 mm^−1^ β = 91.837 (5)° *T* = 123 K *V* = 2182.72 (19) Å^3^ Fragment cut from needle, colourless *Z* = 8 0.60 × 0.05 × 0.05 mm ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e268 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction Xcalibur E diffractometer 2633 independent reflections Radiation source: fine-focus sealed tube 2197 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.032 ω scans θ~max~ = 29.0°, θ~min~ = 3.2° Absorption correction: analytical (*CrysAlis PRO*; Oxford Diffraction, 2009) *h* = −32→18 *T*~min~ = 0.444, *T*~max~ = 1.000 *k* = −6→7 5100 measured reflections *l* = −19→21 ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e382 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.032 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.068 H atoms treated by a mixture of independent and constrained refinement *S* = 1.06 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0213*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2633 reflections (Δ/σ)~max~ \< 0.001 151 parameters Δρ~max~ = 0.55 e Å^−3^ 0 restraints Δρ~min~ = −0.60 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e536 .table-wrap} ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ \> 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e581 .table-wrap} ----- -------------- -------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Br1 0.418223 (9) −0.36757 (5) 0.230618 (14) 0.01800 (9) O1 0.33754 (6) −0.2340 (4) 0.04409 (11) 0.0205 (4) O2 0.09326 (6) 0.3711 (4) 0.06453 (11) 0.0219 (4) O3 0.12126 (7) 0.6341 (3) 0.15486 (11) 0.0224 (4) N1 0.34163 (8) 0.0629 (4) 0.13870 (13) 0.0177 (5) N2 0.12933 (8) 0.4612 (4) 0.11152 (12) 0.0175 (5) C1 0.44903 (10) −0.3344 (5) 0.05532 (15) 0.0205 (6) H1A 0.4520 −0.2507 0.0008 0.031\* H1B 0.4251 −0.4681 0.0461 0.031\* H1C 0.4860 −0.3844 0.0756 0.031\* C2 0.42421 (9) −0.1793 (5) 0.12266 (14) 0.0156 (5) C3 0.46064 (9) 0.0238 (5) 0.14342 (16) 0.0209 (6) H3A 0.4986 −0.0283 0.1564 0.031\* H3B 0.4465 0.1044 0.1937 0.031\* H3C 0.4605 0.1275 0.0937 0.031\* C4 0.36323 (9) −0.1220 (5) 0.09765 (14) 0.0143 (5) C5 0.28757 (9) 0.1555 (5) 0.12844 (14) 0.0133 (5) C6 0.24391 (9) 0.0415 (5) 0.08499 (14) 0.0156 (5) H6 0.2497 −0.1040 0.0595 0.019\* C7 0.19187 (9) 0.1446 (5) 0.07971 (14) 0.0154 (5) H7 0.1618 0.0700 0.0503 0.018\* C8 0.18422 (9) 0.3543 (5) 0.11722 (14) 0.0135 (5) C9 0.22692 (9) 0.4702 (5) 0.16051 (14) 0.0158 (5) H9 0.2208 0.6157 0.1857 0.019\* C10 0.27856 (9) 0.3680 (5) 0.16594 (14) 0.0150 (5) H10 0.3083 0.4438 0.1957 0.018\* H1N 0.3624 (11) 0.132 (5) 0.1742 (17) 0.028 (8)\* ----- -------------- -------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e963 .table-wrap} ----- -------------- -------------- -------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Br1 0.01677 (13) 0.01963 (16) 0.01755 (13) 0.00024 (10) −0.00059 (9) 0.00090 (10) O1 0.0181 (8) 0.0222 (12) 0.0211 (9) 0.0011 (8) −0.0017 (7) −0.0079 (8) O2 0.0143 (8) 0.0292 (13) 0.0218 (9) 0.0013 (8) −0.0029 (7) 0.0000 (8) O3 0.0204 (9) 0.0223 (12) 0.0247 (9) 0.0072 (8) 0.0027 (7) −0.0027 (9) N1 0.0135 (10) 0.0205 (14) 0.0187 (11) 0.0023 (9) −0.0038 (8) −0.0075 (10) N2 0.0183 (10) 0.0190 (14) 0.0152 (10) 0.0039 (9) 0.0026 (8) 0.0028 (9) C1 0.0180 (12) 0.0222 (17) 0.0214 (12) 0.0066 (11) 0.0030 (10) −0.0025 (11) C2 0.0151 (11) 0.0158 (15) 0.0159 (11) 0.0025 (10) 0.0004 (9) −0.0007 (10) C3 0.0141 (11) 0.0220 (17) 0.0265 (13) 0.0001 (11) 0.0008 (10) 0.0007 (12) C4 0.0166 (11) 0.0144 (14) 0.0122 (11) −0.0001 (10) 0.0032 (9) 0.0011 (10) C5 0.0127 (11) 0.0165 (15) 0.0109 (10) −0.0002 (10) 0.0020 (8) 0.0010 (10) C6 0.0176 (11) 0.0145 (15) 0.0148 (11) 0.0015 (10) 0.0005 (9) −0.0023 (10) C7 0.0121 (11) 0.0187 (16) 0.0152 (11) −0.0004 (10) −0.0013 (9) 0.0010 (10) C8 0.0119 (11) 0.0170 (15) 0.0117 (11) 0.0030 (10) 0.0024 (8) 0.0034 (10) C9 0.0200 (12) 0.0120 (14) 0.0155 (11) 0.0010 (10) 0.0030 (9) −0.0018 (10) C10 0.0143 (11) 0.0177 (15) 0.0130 (11) −0.0018 (10) −0.0001 (8) −0.0016 (10) ----- -------------- -------------- -------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1285 .table-wrap} -------------------- ------------- -------------------- ------------ Br1---C2 2.010 (2) C3---H3A 0.9800 O1---C4 1.211 (3) C3---H3B 0.9800 O2---N2 1.234 (3) C3---H3C 0.9800 O3---N2 1.232 (3) C5---C10 1.392 (4) N1---C4 1.366 (3) C5---C6 1.400 (3) N1---C5 1.416 (3) C6---C7 1.393 (3) N1---H1N 0.84 (3) C6---H6 0.9500 N2---C8 1.465 (3) C7---C8 1.373 (4) C1---C2 1.519 (3) C7---H7 0.9500 C1---H1A 0.9800 C8---C9 1.387 (3) C1---H1B 0.9800 C9---C10 1.382 (3) C1---H1C 0.9800 C9---H9 0.9500 C2---C3 1.506 (4) C10---H10 0.9500 C2---C4 1.546 (3) C4---N1---C5 127.9 (2) H3B---C3---H3C 109.5 C4---N1---H1N 117 (2) O1---C4---N1 123.5 (2) C5---N1---H1N 115 (2) O1---C4---C2 121.0 (2) O3---N2---O2 123.4 (2) N1---C4---C2 115.4 (2) O3---N2---C8 118.4 (2) C10---C5---C6 120.1 (2) O2---N2---C8 118.2 (2) C10---C5---N1 116.8 (2) C2---C1---H1A 109.5 C6---C5---N1 123.2 (2) C2---C1---H1B 109.5 C7---C6---C5 119.0 (2) H1A---C1---H1B 109.5 C7---C6---H6 120.5 C2---C1---H1C 109.5 C5---C6---H6 120.5 H1A---C1---H1C 109.5 C8---C7---C6 119.7 (2) H1B---C1---H1C 109.5 C8---C7---H7 120.1 C3---C2---C1 112.2 (2) C6---C7---H7 120.1 C3---C2---C4 115.2 (2) C7---C8---C9 122.2 (2) C1---C2---C4 110.53 (19) C7---C8---N2 119.3 (2) C3---C2---Br1 108.18 (15) C9---C8---N2 118.5 (2) C1---C2---Br1 106.45 (18) C10---C9---C8 118.2 (2) C4---C2---Br1 103.51 (14) C10---C9---H9 120.9 C2---C3---H3A 109.5 C8---C9---H9 120.9 C2---C3---H3B 109.5 C9---C10---C5 120.9 (2) H3A---C3---H3B 109.5 C9---C10---H10 119.6 C2---C3---H3C 109.5 C5---C10---H10 119.6 H3A---C3---H3C 109.5 C5---N1---C4---O1 0.7 (4) C5---C6---C7---C8 −0.3 (3) C5---N1---C4---C2 179.5 (2) C6---C7---C8---C9 0.3 (4) C3---C2---C4---O1 145.0 (2) C6---C7---C8---N2 −179.9 (2) C1---C2---C4---O1 16.6 (3) O3---N2---C8---C7 170.6 (2) Br1---C2---C4---O1 −97.1 (2) O2---N2---C8---C7 −8.3 (3) C3---C2---C4---N1 −33.9 (3) O3---N2---C8---C9 −9.6 (3) C1---C2---C4---N1 −162.3 (2) O2---N2---C8---C9 171.6 (2) Br1---C2---C4---N1 84.0 (2) C7---C8---C9---C10 −0.4 (3) C4---N1---C5---C10 −168.9 (2) N2---C8---C9---C10 179.8 (2) C4---N1---C5---C6 12.7 (4) C8---C9---C10---C5 0.5 (3) C10---C5---C6---C7 0.4 (3) C6---C5---C10---C9 −0.5 (3) N1---C5---C6---C7 178.7 (2) N1---C5---C10---C9 −179.0 (2) -------------------- ------------- -------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1774 .table-wrap} ---------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C6---H6···O1 0.95 2.27 2.862 (3) 120 C7---H7···O1^i^ 0.95 2.45 3.139 (3) 129 N1---H1n···O3^ii^ 0.84 (3) 2.66 (3) 3.316 (3) 136 (2) C10---H10···Br1^iii^ 0.95 2.91 3.812 (2) 160 ---------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1/2, −*y*−1/2, −*z*; (ii) −*x*+1/2, *y*−1/2, −*z*+1/2; (iii) *x*, *y*+1, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- ---------- ---------- ----------- ------------- C6---H6⋯O1 0.95 2.27 2.862 (3) 120 C7---H7⋯O1^i^ 0.95 2.45 3.139 (3) 129 N1---H1n⋯O3^ii^ 0.84 (3) 2.66 (3) 3.316 (3) 136 (2) C10---H10⋯Br1^iii^ 0.95 2.91 3.812 (2) 160 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.437501

2011-2-19

PMC3051944

Related literature {#sec1} ================== For common applications of organic--inorganic hybrid mat­erials, see: Kobel & Hanack (1986[@bb6]); Pierpont & Jung (1994[@bb9]). For a related structure and discussion of geometrical features, see: Sutherland & Harrison (2009[@bb11]). For the coordination around the Cd^II^ cation, see: El Glaoui *et al.* (2009[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} (C~4~H~12~N~2~)\[CdCl~4~\]·H~2~O*M* *~r~* = 360.38Monoclinic,*a* = 6.6204 (2) Å*b* = 12.8772 (3) Å*c* = 14.0961 (4) Åβ = 92.1710 (12)°*V* = 1200.86 (6) Å^3^*Z* = 4Mo *K*α radiationμ = 2.67 mm^−1^*T* = 295 K0.52 × 0.48 × 0.30 mm ### Data collection {#sec2.1.2} Nonius KappaCCD diffractometerAbsorption correction: multi-scan (*SORTAV*; Blessing, 1995[@bb2]) *T* ~min~ = 0.374, *T* ~max~ = 0.4448531 measured reflections3461 independent reflections2903 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.037 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.033*wR*(*F* ^2^) = 0.081*S* = 1.093461 reflections126 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.78 e Å^−3^Δρ~min~ = −1.75 e Å^−3^ {#d5e522} Data collection: *Kappa-CCD Server Software* (Nonius, 1997[@bb7]); cell refinement: *DENZO-SMN* (Otwinowski & Minor, 1997[@bb8]); data reduction: *DENZO-SMN*; program(s) used to solve structure: *SIR97* (Altomare *et al.*, 1999[@bb1]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb10]); molecular graphics: *ORTEPIII* (Burnett & Johnson, 1996[@bb3]); software used to prepare material for publication: *SHELXL97* and *WinGX* (Farrugia, 1999[@bb5]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811005095/zs2095sup1.cif](http://dx.doi.org/10.1107/S1600536811005095/zs2095sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005095/zs2095Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005095/zs2095Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?zs2095&file=zs2095sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?zs2095sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?zs2095&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [ZS2095](http://scripts.iucr.org/cgi-bin/sendsup?zs2095)). We would like to acknowledge the support provided by the Secretary of State for Scientific Research and Technology of Tunisia. Comment ======= Organic-inorganic hybrid materials continue to attract much attention due to their potential applications in various field (Kobel & Hanack, 1986; Pierpont & Jung, 1994). In this work, we report the crystal structure of one such compound, C~4~H~12~N~2~ \[CdCl~4~\] . H~2~O (I), formed from the reaction of piperazine with cadmium chloride. In (I) the asymmetric unit comprises a piperazine-1,4-diium dication, a \[CdCl~4~\]^2-^ anion and a water molecule of solvation (Fig. 1). The atomic arrangement of (I) can be described as built up of corrugated inorganic chains of \[CdCl~4~\]^2-^ tetrahedra and water molecules held together by O---H···Cl hydrogen bonds and extending along the *b* direction of the unit cell. These chains are interconnected by a set of piperazinium N---H···Cl hydrogen bonds to form layers extending along the (1 1 O) planes (Fig. 2, Table 1). Fig 3 shows that two such layers cross the unit cell at *z* = 1/4 and *z* = 3/4 and the bodies of the organic groups are located between these layers and connect them by weak C---H···Cl hydrogen bonds \[C···Cl, 3.535 (3) Å\], giving a three-dimensional framework structure. In the organic entity, the piperazium ring adopts a typical chair conformation and all the geometrical features agree with those found in piperazindiium tetrachlorozincate(II) (Sutherland & Harrison, 2009). It is worth noting that in the anion of (I), the Cd---Cl bond lengths and Cl---Cd---Cl bond angles are not equal, but vary with the environment around the Cl atom. The Cd---Cl bond lengths vary between 2.4418 (6) and 2.4892 (7) Å and the Cl---Cd---Cl angles range from 103.07 (2) to 115.19 (2) °. These values are in good agreement with those reported previously, clearly indicating that the \[CdCl~4~\]^2-^ anion has a slightly distorted tetrahedral stereochemistry (El Glaoui *et al.* (2009). Experimental {#experimental} ============ An aqueous solution of piperazine (4 mmol, 0.344 g), cadmium chloride (4 mmol, 0.732 g) and HCl (10 ml, 0.8 *M*) in a Petri dish was slowly evaporated at room temperature. Single crystals of the title compound, suitable for X-ray diffraction analysis, were obtained after several days (yield 68%). Refinement {#refinement} ========== All N---H hydrogen atoms were found in the difference Fourier map and refined isotropically. The water hydrogen atoms were also found in the difference Fourier but their positions were kept fixed during the refinement and their *U*~iso~ values were given a value equal to 1.2 times *U*~eq~ of the parent oxygen. All C---H atoms were allowed to ride with C---H = 0.97 Å and *U*~iso~(H) = 1.2*U*~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the title compound, showing 50% probability displacement ellipsoids and the atom numbering scheme. Dashed lines indicate N---H···O and N---H···Cl hydrogen bonds. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### A projection along the c axis of the inorganic layer structure at z = 1/4. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### The packing of the title compound viewed down the a axis. Hydrogen bonds are shown as dotted lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e182 .table-wrap} ---------------------------------- --------------------------------------- (C~4~H~12~N~2~)\[CdCl~4~\]·H~2~O *F*(000) = 704 *M~r~* = 360.38 *D*~x~ = 1.993 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 8531 reflections *a* = 6.6204 (2) Å θ = 2.0--30.0° *b* = 12.8772 (3) Å µ = 2.67 mm^−1^ *c* = 14.0961 (4) Å *T* = 295 K β = 92.1710 (12)° Prismatic, colourless *V* = 1200.86 (6) Å^3^ 0.52 × 0.48 × 0.30 mm *Z* = 4 ---------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e316 .table-wrap} -------------------------------------------------------------- -------------------------------------- Nonius KappaCCD diffractometer 3461 independent reflections Radiation source: fine-focus sealed tube 2903 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.037 φ scans and ω scans θ~max~ = 30.0°, θ~min~ = 3.1° Absorption correction: multi-scan (*SORTAV*; Blessing, 1995) *h* = −9→9 *T*~min~ = 0.374, *T*~max~ = 0.444 *k* = −17→17 8531 measured reflections *l* = −19→19 -------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e433 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.033 H atoms treated by a mixture of independent and constrained refinement *wR*(*F*^2^) = 0.081 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0389*P*)^2^ + 0.4362*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.09 (Δ/σ)~max~ \< 0.001 3461 reflections Δρ~max~ = 0.78 e Å^−3^ 126 parameters Δρ~min~ = −1.75 e Å^−3^ 0 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.0778 (19) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e614 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e713 .table-wrap} ----- -------------- ---------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cd1 0.02921 (3) −0.001890 (11) 0.235463 (13) 0.03178 (9) Cl1 0.07520 (10) −0.19208 (5) 0.22725 (4) 0.03972 (16) Cl2 −0.34472 (9) 0.01950 (5) 0.22883 (5) 0.03628 (15) Cl3 0.17473 (9) 0.05843 (5) 0.38740 (5) 0.03822 (15) Cl4 0.13421 (9) 0.09489 (5) 0.09660 (5) 0.03906 (16) N1 0.5582 (3) 0.20385 (16) 0.38723 (15) 0.0312 (4) N2 0.7142 (3) 0.28658 (16) 0.56419 (15) 0.0321 (4) C1 0.4546 (4) 0.29108 (19) 0.43473 (18) 0.0358 (5) H5 0.3509 0.2636 0.4746 0.043\* H6 0.3897 0.3355 0.3871 0.043\* C2 0.6036 (4) 0.35402 (17) 0.49466 (17) 0.0343 (5) H7 0.6991 0.3875 0.4540 0.041\* H8 0.5322 0.4077 0.5281 0.041\* C3 0.8195 (4) 0.20021 (19) 0.51588 (18) 0.0345 (5) H9 0.8879 0.1564 0.5629 0.041\* H10 0.9203 0.2285 0.4749 0.041\* C4 0.6703 (4) 0.13687 (17) 0.45821 (17) 0.0318 (5) H11 0.5752 0.1046 0.4998 0.038\* H12 0.7406 0.0822 0.4255 0.038\* O1W 0.4133 (3) 0.2110 (2) 0.68116 (18) 0.0644 (7) H1 0.646 (5) 0.232 (2) 0.344 (2) 0.038 (8)\* H2 0.461 (5) 0.168 (3) 0.357 (2) 0.053 (9)\* H3 0.632 (5) 0.255 (2) 0.604 (2) 0.040 (8)\* H4 0.803 (5) 0.319 (2) 0.592 (2) 0.041 (8)\* H1W 0.3888 0.1492 0.6962 0.080\* H2W 0.3114 0.2506 0.6752 0.080\* ----- -------------- ---------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1069 .table-wrap} ----- -------------- -------------- -------------- ------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cd1 0.03183 (12) 0.03025 (13) 0.03330 (13) 0.00147 (6) 0.00181 (8) 0.00206 (6) Cl1 0.0483 (4) 0.0303 (3) 0.0411 (3) 0.0064 (2) 0.0091 (3) −0.0011 (2) Cl2 0.0298 (3) 0.0379 (3) 0.0412 (3) 0.0020 (2) 0.0026 (2) −0.0031 (2) Cl3 0.0358 (3) 0.0386 (3) 0.0400 (3) −0.0045 (2) −0.0036 (2) −0.0027 (2) Cl4 0.0327 (3) 0.0419 (3) 0.0433 (3) 0.0050 (2) 0.0105 (2) 0.0109 (3) N1 0.0336 (11) 0.0330 (10) 0.0270 (10) −0.0009 (8) 0.0001 (8) −0.0034 (8) N2 0.0328 (11) 0.0316 (10) 0.0320 (10) −0.0065 (8) 0.0030 (8) −0.0065 (8) C1 0.0362 (13) 0.0354 (12) 0.0361 (13) 0.0073 (10) 0.0022 (10) 0.0015 (10) C2 0.0417 (14) 0.0238 (10) 0.0381 (13) −0.0017 (9) 0.0097 (10) −0.0025 (9) C3 0.0304 (12) 0.0330 (11) 0.0397 (13) 0.0019 (9) −0.0031 (10) −0.0061 (10) C4 0.0366 (12) 0.0252 (10) 0.0333 (12) 0.0016 (9) −0.0009 (9) −0.0026 (9) O1W 0.0435 (13) 0.0692 (14) 0.0818 (18) 0.0050 (11) 0.0183 (12) 0.0334 (13) ----- -------------- -------------- -------------- ------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1325 .table-wrap} ----------------- ------------- ----------------- ------------- Cd1---Cl3 2.4418 (6) C1---C2 1.510 (4) Cd1---Cl4 2.4435 (6) C1---H5 0.9700 Cd1---Cl1 2.4712 (6) C1---H6 0.9700 Cd1---Cl2 2.4891 (7) C2---H7 0.9700 N1---C1 1.488 (3) C2---H8 0.9700 N1---C4 1.497 (3) C3---C4 1.497 (3) N1---H1 0.93 (3) C3---H9 0.9700 N1---H2 0.89 (3) C3---H10 0.9700 N2---C2 1.482 (3) C4---H11 0.9700 N2---C3 1.491 (3) C4---H12 0.9700 N2---H3 0.89 (3) O1W---H1W 0.84 N2---H4 0.81 (3) O1W---H2W 0.85 Cl3---Cd1---Cl4 115.19 (2) C2---C1---H6 109.5 Cl3---Cd1---Cl1 108.13 (2) H5---C1---H6 108.1 Cl4---Cd1---Cl1 115.38 (2) N2---C2---C1 110.57 (19) Cl3---Cd1---Cl2 110.89 (2) N2---C2---H7 109.5 Cl4---Cd1---Cl2 103.07 (2) C1---C2---H7 109.5 Cl1---Cd1---Cl2 103.42 (2) N2---C2---H8 109.5 C1---N1---C4 111.06 (18) C1---C2---H8 109.5 C1---N1---H2 106 (2) H7---C2---H8 108.1 C4---N1---H2 111 (2) N2---C3---C4 110.14 (19) C1---N1---H1 107.8 (18) N2---C3---H9 109.6 C4---N1---H1 111.2 (19) C4---C3---H9 109.6 H1---N1---H2 110 (3) N2---C3---H10 109.6 C2---N2---C3 111.28 (19) C4---C3---H10 109.6 C2---N2---H3 113 (2) H9---C3---H10 108.1 C3---N2---H3 104.5 (18) C3---C4---N1 110.45 (19) C2---N2---H4 110 (2) C3---C4---H11 109.6 C3---N2---H4 106 (2) N1---C4---H11 109.6 H3---N2---H4 112 (3) C3---C4---H12 109.6 N1---C1---C2 110.8 (2) N1---C4---H12 109.6 N1---C1---H5 109.5 H11---C4---H12 108.1 C2---C1---H5 109.5 H1W---O1W---H2W 116 N1---C1---H6 109.5 ----------------- ------------- ----------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1653 .table-wrap} ---------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1···Cl1^i^ 0.93 (3) 2.35 (3) 3.254 (2) 164 (3) N1---H2···Cl3 0.89 (3) 2.41 (4) 3.155 (2) 141 (3) N2---H3···O1W 0.89 (3) 1.93 (3) 2.808 (3) 167 (3) N2---H4···Cl4^ii^ 0.81 (3) 2.46 (3) 3.190 (2) 151 (3) O1W---H1W···Cl2^iii^ 0.84 2.44 3.267 (3) 168 O1W---H2W···Cl4^iv^ 0.85 2.54 3.304 (2) 150 ---------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, *y*+1/2, −*z*+1/2; (ii) *x*+1, −*y*+1/2, *z*+1/2; (iii) −*x*, −*y*, −*z*+1; (iv) *x*, −*y*+1/2, *z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------------ ---------- ---------- ----------- ------------- N1---H1⋯Cl1^i^ 0.93 (3) 2.35 (3) 3.254 (2) 164 (3) N1---H2⋯Cl3 0.89 (3) 2.41 (4) 3.155 (2) 141 (3) N2---H3⋯O1*W* 0.89 (3) 1.93 (3) 2.808 (3) 167 (3) N2---H4⋯Cl4^ii^ 0.81 (3) 2.46 (3) 3.190 (2) 151 (3) O1*W*---H1*W*⋯Cl2^iii^ 0.84 2.44 3.267 (3) 168 O1*W*---H2*W*⋯Cl4^iv^ 0.85 2.54 3.304 (2) 150 Symmetry codes: (i) ; (ii) ; (iii) ; (iv) . :::

PubMed Central

2024-06-05T04:04:17.442048

2011-2-16

PMC3051945

Related literature {#sec1} ================== For general background to ribonucleic acid, see: Franklin (2001[@bb3]); Komiyama *et al.* (1999[@bb4]); Kuzuya *et al.* (2006[@bb5]); Morrow & Iranzo (2004[@bb7]); Nüttymäki & Lönnberg (2006[@bb8]). Some crystal structures of similar mol­ecules have been reported, for instance *N*-salicyloylglycine (Smeets *et al.*, 1985[@bb11]), 2-(*N*-(2-(2-hy­droxy­benzamido)­ethyl­ammonio­eth­yl)amino­carbon­yl) phen­ol­ate (Liu *et al.*, 2006[@bb6]) and *N*-(2-Amino­eth­yl)-2-hy­droxy­benzamide picrate (Yu *et al.*, 2003[@bb12]). More crystal structures of analogs can be found in Cambridge Structural Database (Allen, 2002[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~11~H~14~N~2~O~3~*M* *~r~* = 222.24Monoclinic,*a* = 8.642 (3) Å*b* = 4.9702 (18) Å*c* = 24.972 (3) Åβ = 95.14 (2)°*V* = 1068.3 (6) Å^3^*Z* = 4Mo *K*α radiationμ = 0.10 mm^−1^*T* = 90 K0.3 × 0.2 × 0.15 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcalibur Eos diffractometerAbsorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009[@bb9]) *T* ~min~ = 0.111, *T* ~max~ = 1.0004347 measured reflections2439 independent reflections1504 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.039 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.058*wR*(*F* ^2^) = 0.162*S* = 1.042439 reflections158 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.29 e Å^−3^Δρ~min~ = −0.34 e Å^−3^ {#d5e512} Data collection: *CrysAlis PRO* (Oxford Diffraction, 2009[@bb9]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SIR92* (Altomare *et al.*, 1993[@bb2]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb10]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb10]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811003680/cv5045sup1.cif](http://dx.doi.org/10.1107/S1600536811003680/cv5045sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003680/cv5045Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003680/cv5045Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?cv5045&file=cv5045sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?cv5045sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?cv5045&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [CV5045](http://scripts.iucr.org/cgi-bin/sendsup?cv5045)). This work was supported by the Polish Ministry of Science and Higher Education (grant NN204 0317 33). Comment ======= Ribonucleic acid, which mediates genetic information encoded in DNA, is one of the most important compounds in life. If only one RNA can be chosen from many RNAs in cells and selectively cleaved at desired site, it opens the way to new RNA science (*e.g.* regulation of expression of a specific gene, advanced therapy, RNA manipulation) (Kuzuya *et al.*, 2006). During the past decade, mimics for RNA-cleaving enzymes, ribonucleases, have received special attention (Nüttymäki *et al.*, 2006). The first artificial nucleases capable of cleaving RNA oligonucleotides in a selective manner were DNA conjugates of lanthanide(III) ion complexes (Komiyama *et al.*, 1999; Franklin, 2001; Morrow *et al.*, 2004). The title compound (I, Scheme 1) was isolated during efforts to prepare new synthetic ribonuclease precursors as part of our research program involving the study of the nonselective and selective hydrolysis of RNA by lanthanide complexes. The conformation of the CNCCNCC chain in (I) is *tg^+^tg^-^t* (*t* - *trans*, *g* - *gauche*), as can be seen from the values of the torsion angles. Intramolecular hydrogen bond between hydroxy group and O7 oxygen atom causes closing of the six-membered nearly planar (within 0.022 (13) Å) ring (Fig. 1). This bond is strong and causes the changes in the geometry of involved fragments: lengthening of both O---H (1.11 (4) Å) and C=O (1.255 (3) Å) bonds. This ring is almost coplanar with the phenyl ring plane, the dihedral angle between the two planes is 1.6 (9)°. In the Cambridge Structural Database (Allen, 2002; Version 5.31 of Nov. 2009, updated August 2010) there are 229 fragments of 2-hydroxy-N-monosubstituted- benzamide, and both O---H···O and N---H···O (with hydroxy group as an acceptor) are almost equally represented in the sample. Of course, the different hydrogen bond schemes are connected with the different C1---C2---C7---N8 torsion angles, which are close to 180° for the former and close to 0° for the latter possibility (*cf.* Fig. 2). The overall conformation of the molecule can be described as two almost planar (within 0.022 (2) Å) and nearly parallel (the dihedral angle is 5.65 (16)°) fragments C1···C9 and C10···C13. In the crystal structure, the variety of hydrogen bonds connects the molecules of I into the hydrogen-bonded chains of molecules (*cf.* Table 1). The pairs of almost linear N11---H11···O7(*1 - x,2 - y,1 - z*) and N8---H8···O12(*2 - x,1 - y,1 - z*) hydrogen bonds join the molecules in centrosymmetric dimers, the graph set connected with these interactions are *R*^2^~2~(14). Each of these bonds is accompanied by secondary however still relatively short and directional C---H···O interactions (Table 1). As can be seen in Fig. 3 these bonds in general join two different \"storeys\" of the molecules in alternating manner. Therefore these interactions create the double ribbons of molecules which expand approximately along \[-110\] direction. The interactions between these motifs are only very week. Experimental {#experimental} ============ To a solution of ethylenediamine (0,3972 g, 2 mmol) in THF (7 ml) *O*-acetylsalicyloyl chloride (0,268 ml, 4 mmol) in THF (7 ml) was added dropwise with stirring. The reaction was carried out for 24 h in ambient temperature. The reaction mixture was evaporated to dryness and purified by silica gel column chromatography by elution with CH~2~Cl~2~/methanol (98:2). Crystals suitable for X-ray diffraction analysis were formed by slow evaporation from CH~2~Cl~2~/methanol (1:1) after one week. ESI-MS m/*z* (%) = 221 (100 {C~11~H~13~N~2~O~3~^-^}); 245 (100 {C~11~H~14~N~2~O~3~+Na^+^}). Elemental analysis calculated for C~11~H~14~N~2~O~3~: C, 59.45; H, 6.35; N, 12.60; found C, 58.95; H, 6.00; N, 12.20. ^1^H-NMR p.p.m.: 12.46 (*s*); 7.90 (*s*); 7.48 (*d*); 7.38 (*t*); 6.98 (*d*); 6.89 (*t*); 6.10 (*s*); 3.56 (*t*); 2.05 (*s*). Refinement {#refinement} ========== C-bound H atoms were geometrically positioned (C---H 0.95-0.99 Å) and refined as riding, with Uiso(H) = 1.2-1.5 Ueq(C). The rest H atoms were found in the diffrence Fourier maps and isotropically refined. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### View of I showing the atomic numbering and 50% probability displacement ellipsoids. Hydrogen atoms are depicted as spheres with arbitrary radii. Intramolecular hydrogen bond is shown as dashed line. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Two views: (a) face-on and (b) side-on of the hydrogen-bonded chain of molecules of I. Hydrogen bonds are shown as dashed lines. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### A portion of the crystal packing as seen approximately along b-direction. Hydrogen bonds are shown as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e281 .table-wrap} ------------------------- -------------------------------------- C~11~H~14~N~2~O~3~ *F*(000) = 472 *M~r~* = 222.24 *D*~x~ = 1.38 Mg m^−3^ Monoclinic, *P*2~1~/*n* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2yn Cell parameters from 990 reflections *a* = 8.642 (3) Å θ = 3.0--29.0° *b* = 4.9702 (18) Å µ = 0.10 mm^−1^ *c* = 24.972 (3) Å *T* = 90 K β = 95.14 (2)° Block, yellow *V* = 1068.3 (6) Å^3^ 0.3 × 0.2 × 0.15 mm *Z* = 4 ------------------------- -------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e411 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction Xcalibur Eos diffractometer 2439 independent reflections Radiation source: Enhance (Mo) X-ray Source 1504 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.039 Detector resolution: 16.1544 pixels mm^-1^ θ~max~ = 29.2°, θ~min~ = 3.3° ω scans *h* = −11→6 Absorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009) *k* = −4→6 *T*~min~ = 0.111, *T*~max~ = 1.000 *l* = −28→33 4347 measured reflections ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e531 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.058 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.162 H atoms treated by a mixture of independent and constrained refinement *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0581*P*)^2^ + 0.0266*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2439 reflections (Δ/σ)~max~ \< 0.001 158 parameters Δρ~max~ = 0.29 e Å^−3^ 0 restraints Δρ~min~ = −0.34 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e688 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e787 .table-wrap} ------ -------------- ------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 0.4433 (3) 0.3212 (5) 0.31898 (9) 0.0195 (5) O1 0.3176 (2) 0.4713 (3) 0.32788 (7) 0.0273 (5) H1 0.357 (4) 0.597 (7) 0.3630 (15) 0.078 (12)\* C2 0.5847 (3) 0.3520 (4) 0.34941 (9) 0.0163 (5) C3 0.7073 (3) 0.1857 (5) 0.33760 (10) 0.0211 (6) H3 0.8049 0.2046 0.3579 0.025\* C4 0.6913 (3) −0.0051 (5) 0.29741 (10) 0.0237 (6) H4 0.7763 −0.1170 0.2904 0.028\* C5 0.5507 (3) −0.0306 (5) 0.26766 (10) 0.0239 (6) H5 0.5385 −0.1613 0.2398 0.029\* C6 0.4275 (3) 0.1306 (5) 0.27763 (10) 0.0233 (6) H6 0.3313 0.1127 0.2564 0.028\* C7 0.5993 (3) 0.5583 (4) 0.39258 (9) 0.0165 (5) O7 0.48629 (18) 0.7039 (3) 0.40218 (6) 0.0215 (4) N8 0.7353 (2) 0.5851 (4) 0.42095 (8) 0.0191 (5) H8 0.815 (3) 0.471 (5) 0.4157 (10) 0.030 (8)\* C9 0.7594 (3) 0.7863 (5) 0.46326 (10) 0.0204 (5) H9A 0.7091 0.9568 0.4508 0.024\* H9B 0.8722 0.8209 0.4706 0.024\* C10 0.6929 (3) 0.6963 (5) 0.51550 (9) 0.0214 (6) H10A 0.5782 0.6873 0.5095 0.026\* H10B 0.7316 0.5136 0.5251 0.026\* N11 0.7358 (2) 0.8778 (4) 0.55967 (8) 0.0212 (5) H11 0.666 (3) 0.991 (5) 0.5708 (11) 0.028 (7)\* C12 0.8726 (3) 0.8603 (5) 0.58797 (10) 0.0208 (6) O12 0.97079 (19) 0.6959 (3) 0.57683 (7) 0.0249 (4) C13 0.8981 (3) 1.0561 (5) 0.63381 (11) 0.0296 (6) H13A 0.9890 1.0007 0.6575 0.044\* H13B 0.8062 1.0589 0.6541 0.044\* H13C 0.9157 1.2363 0.6196 0.044\* ------ -------------- ------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1193 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0211 (12) 0.0222 (13) 0.0154 (12) 0.0028 (10) 0.0029 (10) 0.0010 (10) O1 0.0243 (10) 0.0317 (10) 0.0247 (10) 0.0087 (8) −0.0043 (8) −0.0064 (9) C2 0.0225 (12) 0.0153 (11) 0.0117 (11) 0.0012 (10) 0.0051 (10) 0.0011 (10) C3 0.0221 (13) 0.0245 (13) 0.0172 (13) −0.0004 (10) 0.0038 (10) −0.0019 (11) C4 0.0285 (14) 0.0230 (13) 0.0213 (13) 0.0025 (11) 0.0110 (11) −0.0018 (11) C5 0.0318 (15) 0.0245 (13) 0.0164 (13) −0.0070 (12) 0.0081 (11) −0.0029 (11) C6 0.0243 (13) 0.0309 (14) 0.0142 (12) −0.0034 (11) −0.0005 (10) 0.0009 (11) C7 0.0206 (12) 0.0162 (12) 0.0130 (12) 0.0003 (10) 0.0043 (9) 0.0038 (10) O7 0.0210 (9) 0.0265 (9) 0.0170 (9) 0.0046 (7) 0.0022 (7) −0.0016 (7) N8 0.0200 (11) 0.0226 (11) 0.0148 (11) 0.0031 (9) 0.0014 (8) −0.0037 (9) C9 0.0245 (13) 0.0208 (12) 0.0158 (12) −0.0018 (10) 0.0015 (10) −0.0015 (11) C10 0.0220 (12) 0.0261 (13) 0.0164 (13) −0.0029 (11) 0.0024 (10) −0.0027 (11) N11 0.0184 (11) 0.0301 (12) 0.0152 (11) 0.0051 (9) 0.0019 (9) −0.0060 (9) C12 0.0217 (13) 0.0242 (13) 0.0168 (13) −0.0007 (11) 0.0036 (10) 0.0011 (11) O12 0.0212 (9) 0.0308 (10) 0.0228 (10) 0.0061 (8) 0.0021 (7) −0.0068 (8) C13 0.0240 (14) 0.0373 (15) 0.0262 (15) 0.0070 (12) −0.0051 (11) −0.0109 (13) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1519 .table-wrap} ------------------- ------------ ----------------------- ------------- C1---O1 1.352 (3) N8---C9 1.456 (3) C1---C2 1.389 (3) N8---H8 0.91 (3) C1---C6 1.399 (3) C9---C10 1.538 (4) O1---H1 1.11 (4) C9---H9A 0.9900 C2---C3 1.395 (3) C9---H9B 0.9900 C2---C7 1.485 (3) C10---N11 1.447 (3) C3---C4 1.379 (3) C10---H10A 0.9900 C3---H3 0.9500 C10---H10B 0.9900 C4---C5 1.372 (4) N11---C12 1.325 (3) C4---H4 0.9500 N11---H11 0.89 (3) C5---C6 1.373 (3) C12---O12 1.228 (3) C5---H5 0.9500 C12---C13 1.504 (3) C6---H6 0.9500 C13---H13A 0.9800 C7---O7 1.255 (3) C13---H13B 0.9800 C7---N8 1.323 (3) C13---H13C 0.9800 O1---C1---C2 122.0 (2) N8---C9---C10 112.0 (2) O1---C1---C6 117.9 (2) N8---C9---H9A 109.2 C2---C1---C6 120.1 (2) C10---C9---H9A 109.2 C1---O1---H1 104.2 (18) N8---C9---H9B 109.2 C1---C2---C3 117.8 (2) C10---C9---H9B 109.2 C1---C2---C7 119.1 (2) H9A---C9---H9B 107.9 C3---C2---C7 123.1 (2) N11---C10---C9 112.1 (2) C4---C3---C2 122.2 (2) N11---C10---H10A 109.2 C4---C3---H3 118.9 C9---C10---H10A 109.2 C2---C3---H3 118.9 N11---C10---H10B 109.2 C5---C4---C3 118.9 (2) C9---C10---H10B 109.2 C5---C4---H4 120.5 H10A---C10---H10B 107.9 C3---C4---H4 120.5 C12---N11---C10 121.4 (2) C4---C5---C6 120.8 (2) C12---N11---H11 118.2 (17) C4---C5---H5 119.6 C10---N11---H11 120.0 (18) C6---C5---H5 119.6 O12---C12---N11 121.6 (2) C5---C6---C1 120.2 (2) O12---C12---C13 123.1 (2) C5---C6---H6 119.9 N11---C12---C13 115.2 (2) C1---C6---H6 119.9 C12---C13---H13A 109.5 O7---C7---N8 120.6 (2) C12---C13---H13B 109.5 O7---C7---C2 121.3 (2) H13A---C13---H13B 109.5 N8---C7---C2 118.1 (2) C12---C13---H13C 109.5 C7---N8---C9 121.4 (2) H13A---C13---H13C 109.5 C7---N8---H8 120.5 (16) H13B---C13---H13C 109.5 C9---N8---H8 118.1 (17) O1---C1---C2---C3 179.3 (2) C1---C2---C7---O7 0.3 (3) C6---C1---C2---C3 −0.8 (3) C3---C2---C7---O7 −179.8 (2) O1---C1---C2---C7 −0.8 (3) C1---C2---C7---N8 −179.7 (2) C6---C1---C2---C7 179.1 (2) C3---C2---C7---N8 0.2 (3) C1---C2---C3---C4 −0.2 (3) O7---C7---N8---C9 −1.2 (3) C7---C2---C3---C4 179.9 (2) C2---C7---N8---C9 178.81 (19) C2---C3---C4---C5 0.7 (4) C7---N8---C9---C10 78.9 (3) C3---C4---C5---C6 −0.1 (4) N8---C9---C10---N11 171.87 (19) C4---C5---C6---C1 −0.9 (4) C9---C10---N11---C12 −82.2 (3) O1---C1---C6---C5 −178.7 (2) C10---N11---C12---O12 2.5 (4) C2---C1---C6---C5 1.4 (4) C10---N11---C12---C13 −177.9 (2) ------------------- ------------ ----------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2028 .table-wrap} -------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O1---H1···O7 1.11 (4) 1.51 (4) 2.534 (3) 150 (3) N8---H8···O12^i^ 0.91 (3) 2.02 (3) 2.895 (3) 160 (2) N11---H11···O7^ii^ 0.89 (3) 2.16 (3) 3.040 (3) 174 (2) C3---H3···O12^i^ 0.95 2.47 3.404 (4) 169. C6---H6···O1^iii^ 0.95 2.47 3.325 (4) 150. -------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) −*x*+2, −*y*+1, −*z*+1; (ii) −*x*+1, −*y*+2, −*z*+1; (iii) −*x*+1/2, *y*−1/2, −*z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------ ---------- ---------- ----------- ------------- O1---H1⋯O7 1.11 (4) 1.51 (4) 2.534 (3) 150 (3) N8---H8⋯O12^i^ 0.91 (3) 2.02 (3) 2.895 (3) 160 (2) N11---H11⋯O7^ii^ 0.89 (3) 2.16 (3) 3.040 (3) 174 (2) C3---H3⋯O12^i^ 0.95 2.47 3.404 (4) 169 C6---H6⋯O1^iii^ 0.95 2.47 3.325 (4) 150 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.445589

2011-2-05

PMC3051946

Related literature {#sec1} ================== For general background to quinolines see: Kayser & Novak (1987[@bb7]); Rudin *et al.* (1984[@bb11]); Mao *et al.* (2009[@bb9]); Bermudez *et al.* (2004[@bb2]); Jayaprakash *et al.* (2006[@bb6]); Andries *et al.* (2005[@bb1]). For related structures, see: Skörska *et al.* (2005[@bb13]); Devarajegowda *et al.* (2010[@bb3]); Li *et al.* (2005[@bb8]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~13~H~9~ClF~3~N*M* *~r~* = 271.66Monoclinic,*a* = 13.8482 (19) Å*b* = 5.0534 (8) Å*c* = 18.048 (3) Åβ = 107.503 (17)°*V* = 1204.5 (3) Å^3^*Z* = 4Mo *K*α radiationμ = 0.33 mm^−1^*T* = 293 K0.22 × 0.15 × 0.12 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcalibur diffractometerAbsorption correction: multi-scan (*CrysAlis PRO RED*; Oxford Diffraction, 2010[@bb10]) *T* ~min~ = 0.942, *T* ~max~ = 0.96111631 measured reflections2105 independent reflections946 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.092 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.041*wR*(*F* ^2^) = 0.081*S* = 0.782105 reflections164 parametersH-atom parameters constrainedΔρ~max~ = 0.13 e Å^−3^Δρ~min~ = −0.17 e Å^−3^ {#d5e384} Data collection: *CrysAlis PRO CCD* (Oxford Diffraction, 2010[@bb10]); cell refinement: *CrysAlis PRO CCD*; data reduction: *CrysAlis PRO RED* (Oxford Diffraction, 2010[@bb10]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb12]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb12]); molecular graphics: *ORTEP-3* (Farrugia, 1997[@bb4]) and *CAMERON* (Watkin *et al.*, 1993)[@bb14]; software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb5]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811003746/wn2420sup1.cif](http://dx.doi.org/10.1107/S1600536811003746/wn2420sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003746/wn2420Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003746/wn2420Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?wn2420&file=wn2420sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?wn2420sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?wn2420&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [WN2420](http://scripts.iucr.org/cgi-bin/sendsup?wn2420)). The authors thank Professor T. N. Guru Row and Mr Venkatesha R. Hathwar, Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore, for their help with the data collection. Comment ======= 1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)- 3-quinolinecarboxylic acid (ciprofloxacin) is a widely used broad-spectrum antibiotic, which is active against both Gram-positive and Gram-negative bacteria (Kayser & Novak, 1987; Rudin *et al.*, 1984). 2,8-Bis(trifluoromethyl)quinolin-4-yl\]-(2-piperidyl)methanol (mefloquin) is another popular quinoline derivative used in the treatment of malaria. Furthermore, studies have reported that it also possesses important structural features required for antimicrobial activity (Mao *et al.*, 2009; Bermudez *et al.*, 2004; Jayaprakash *et al.*, 2006). Quinoline is the essential structural feature found in these drugs and recently developed antimycobacterial drugs (Andries *et al.*, 2005). Thus, quinoline derivatives are good lead molecules to further develop drug candidates against mycobacterium tuberculosis and as antibacterial agents. On the basis of these observations, we have synthesized a quinoline derivative, with a cyclopropyl group and a trifluoromethyl group as substituents, expecting that the newly designed hybrid molecule would exhibit some antibacterial activity. In this paper we report the crystal structure of 6-chloro-2-cyclopropyl-4-(trifluoromethyl)quinoline. The asymmetric unit of the 6-chloro-2-cyclopropyl-4-(trifluoromethyl) quinoline contains one molecule (Fig. 1). The quinoline ring system makes a dihedral angle of 88.8 (2)° with the cyclopropyl ring. Bond distances and bond angles in the quinoline ring system are in good agreement with those observed in related crystal structures (Skörska *et al.*, 2005; Devarajegowda *et al.*, 2010; Li *et al.*, 2005). The packing of the molecules, when viewed along the *b* axis, is shown in Fig. 2. Experimental {#experimental} ============ A mixture of cyclopropyl acetylene (0.012 mol), anhydrous zinc(II) (0.012 mol), triethylamine (1.67 ml, 0.012 mol), and toluene (25 ml) was stirred at 50°C for 2 h and cooled to 25°C. 4-Chloro- 2-trifluoroacetylaniline (0.01 mol) was added and the reaction mixture was stirred at 25°C for 4 h, then at 50°C for 4 h. After cooling to room temperature, the mixture was added to water (10 ml) and extracted three times with ethyl acetate (20 ml). The combined organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of solvent, the residue was purified by column chromatography on silica gel (hexane/ethyl acetate; 20:1). M.p. 335 K. Refinement {#refinement} ========== All H atoms were placed at calculated positions; C---H = 0.93 Å for aromatic H, C---H = 0.97 Å for methylene H; C---H = 0.98 Å for methine H. They were refined using a riding model with *U*~iso~(H) = 1.2*U*~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms are shown as spheres of arbitrary radius. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The packing of molecules, viewed down the b axis. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e137 .table-wrap} ------------------------- --------------------------------------- C~13~H~9~ClF~3~N *F*(000) = 552 *M~r~* = 271.66 *D*~x~ = 1.498 Mg m^−3^ Monoclinic, *P*2~1~/*c* Melting point: 335 K Hall symbol: -P 2ybc Mo *K*α radiation, λ = 0.71073 Å *a* = 13.8482 (19) Å Cell parameters from 2105 reflections *b* = 5.0534 (8) Å θ = 2.4--25.0° *c* = 18.048 (3) Å µ = 0.33 mm^−1^ β = 107.503 (17)° *T* = 293 K *V* = 1204.5 (3) Å^3^ Plate, colourless *Z* = 4 0.22 × 0.15 × 0.12 mm ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e266 .table-wrap} ---------------------------------------------------------------------------------- ------------------------------------- Oxford Diffraction Xcalibur diffractometer 2105 independent reflections Radiation source: Enhance (Mo) X-ray Source 946 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.092 Detector resolution: 16.0839 pixels mm^-1^ θ~max~ = 25.0°, θ~min~ = 2.4° ω scans *h* = −16→16 Absorption correction: multi-scan (*CrysAlis PRO RED*; Oxford Diffraction, 2010) *k* = −6→6 *T*~min~ = 0.942, *T*~max~ = 0.961 *l* = −21→21 11631 measured reflections ---------------------------------------------------------------------------------- ------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e386 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.041 H-atom parameters constrained *wR*(*F*^2^) = 0.081 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0334*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 0.78 (Δ/σ)~max~ = 0.004 2105 reflections Δρ~max~ = 0.13 e Å^−3^ 164 parameters Δρ~min~ = −0.17 e Å^−3^ 0 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.0045 (8) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e564 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Experimental. *CrysAlis PRO*, Oxford Diffraction Ltd., Version 1.171.33.55 (release 05--01--2010 CrysAlis171. NET) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Geometry. All s.u.\'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.\'s are taken into account individually in the estimation of s.u.\'s in distances, angles and torsion angles; correlations between s.u.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.\'s is used for estimating s.u.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> 2σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e672 .table-wrap} ----- -------------- --------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl1 0.24504 (7) −0.53695 (16) 0.14138 (5) 0.0724 (3) F1 0.53230 (12) 0.2294 (4) 0.43406 (12) 0.1017 (8) F2 0.49335 (13) 0.1618 (4) 0.31203 (13) 0.0964 (7) F3 0.49773 (12) −0.1595 (4) 0.38888 (11) 0.0896 (7) N9 0.15811 (17) 0.2481 (4) 0.35357 (14) 0.0463 (6) C1 0.1215 (2) 0.4767 (6) 0.49521 (17) 0.0629 (9) H1A 0.0846 0.3137 0.4779 0.076\* H1B 0.1300 0.5228 0.5490 0.076\* C2 0.2051 (2) 0.5449 (6) 0.46255 (18) 0.0612 (9) H2 0.2623 0.6398 0.4980 0.073\* C3 0.1078 (2) 0.6908 (6) 0.43962 (19) 0.0695 (10) H3A 0.1077 0.8701 0.4588 0.083\* H3B 0.0624 0.6610 0.3878 0.083\* C4 0.2319 (2) 0.3623 (5) 0.40752 (17) 0.0486 (8) C5 0.3343 (2) 0.3113 (6) 0.41542 (17) 0.0542 (9) H5 0.3843 0.3978 0.4540 0.065\* C6 0.3612 (2) 0.1390 (6) 0.36802 (17) 0.0463 (8) C7 0.2855 (2) 0.0029 (5) 0.30968 (16) 0.0401 (7) C8 0.1844 (2) 0.0691 (5) 0.30551 (16) 0.0405 (7) C10 0.4703 (3) 0.0937 (8) 0.3759 (2) 0.0678 (10) C11 0.3025 (2) −0.1850 (5) 0.25749 (16) 0.0452 (8) H11 0.3683 −0.2290 0.2591 0.054\* C12 0.2229 (2) −0.3017 (5) 0.20490 (16) 0.0456 (8) C13 0.1232 (2) −0.2394 (6) 0.19959 (16) 0.0489 (8) H13 0.0699 −0.3229 0.1630 0.059\* C14 0.1044 (2) −0.0553 (6) 0.24840 (16) 0.0464 (8) H14 0.0378 −0.0105 0.2442 0.056\* ----- -------------- --------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1052 .table-wrap} ----- ------------- ------------- ------------- -------------- ------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.0857 (7) 0.0722 (6) 0.0640 (6) −0.0003 (5) 0.0296 (5) −0.0188 (5) F1 0.0448 (12) 0.1346 (18) 0.1136 (18) −0.0181 (12) 0.0057 (12) −0.0505 (15) F2 0.0542 (13) 0.148 (2) 0.1014 (19) −0.0123 (12) 0.0445 (12) 0.0029 (14) F3 0.0516 (12) 0.0939 (15) 0.1143 (18) 0.0143 (11) 0.0113 (11) −0.0095 (13) N9 0.0436 (15) 0.0528 (16) 0.0448 (16) −0.0020 (14) 0.0165 (13) −0.0026 (14) C1 0.085 (3) 0.058 (2) 0.057 (2) 0.0067 (19) 0.0374 (19) −0.0017 (19) C2 0.049 (2) 0.071 (2) 0.066 (2) −0.0092 (19) 0.0205 (19) −0.024 (2) C3 0.095 (3) 0.051 (2) 0.068 (3) 0.011 (2) 0.032 (2) 0.0001 (19) C4 0.044 (2) 0.055 (2) 0.051 (2) −0.0035 (17) 0.0208 (18) −0.0058 (17) C5 0.044 (2) 0.063 (2) 0.054 (2) −0.0126 (17) 0.0135 (17) −0.0157 (17) C6 0.037 (2) 0.055 (2) 0.049 (2) 0.0002 (16) 0.0153 (17) −0.0012 (16) C7 0.036 (2) 0.0463 (19) 0.0404 (18) −0.0017 (15) 0.0158 (15) 0.0033 (16) C8 0.044 (2) 0.0452 (18) 0.0351 (18) −0.0051 (16) 0.0169 (16) 0.0028 (15) C10 0.051 (3) 0.078 (3) 0.077 (3) −0.003 (2) 0.023 (2) −0.013 (2) C11 0.0381 (19) 0.0523 (19) 0.049 (2) 0.0010 (16) 0.0191 (17) 0.0017 (17) C12 0.053 (2) 0.0478 (19) 0.0413 (19) −0.0054 (17) 0.0221 (17) −0.0045 (15) C13 0.045 (2) 0.055 (2) 0.046 (2) −0.0110 (17) 0.0128 (17) −0.0012 (17) C14 0.0364 (18) 0.056 (2) 0.048 (2) −0.0007 (16) 0.0144 (17) −0.0033 (17) ----- ------------- ------------- ------------- -------------- ------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1420 .table-wrap} --------------------- ------------ ----------------------- -------------- Cl1---C12 1.741 (3) C4---C5 1.406 (4) F1---C10 1.329 (3) C5---C6 1.349 (3) F2---C10 1.330 (4) C5---H5 0.9300 F3---C10 1.335 (3) C6---C7 1.420 (3) N9---C4 1.314 (3) C6---C10 1.492 (4) N9---C8 1.376 (3) C7---C11 1.406 (3) C1---C3 1.449 (4) C7---C8 1.419 (3) C1---C2 1.490 (4) C8---C14 1.413 (3) C1---H1A 0.9700 C11---C12 1.354 (3) C1---H1B 0.9700 C11---H11 0.9300 C2---C3 1.481 (4) C12---C13 1.392 (3) C2---C4 1.482 (4) C13---C14 1.359 (3) C2---H2 0.9800 C13---H13 0.9300 C3---H3A 0.9700 C14---H14 0.9300 C3---H3B 0.9700 C4---N9---C8 117.5 (3) C5---C6---C10 120.2 (3) C3---C1---C2 60.5 (2) C7---C6---C10 119.8 (3) C3---C1---H1A 117.7 C11---C7---C8 119.0 (3) C2---C1---H1A 117.7 C11---C7---C6 126.1 (3) C3---C1---H1B 117.7 C8---C7---C6 114.9 (3) C2---C1---H1B 117.7 N9---C8---C14 117.0 (3) H1A---C1---H1B 114.8 N9---C8---C7 124.4 (3) C3---C2---C4 120.8 (3) C14---C8---C7 118.6 (3) C3---C2---C1 58.35 (19) F1---C10---F2 106.5 (3) C4---C2---C1 120.1 (3) F1---C10---F3 105.9 (3) C3---C2---H2 115.3 F2---C10---F3 105.7 (3) C4---C2---H2 115.3 F1---C10---C6 113.0 (3) C1---C2---H2 115.3 F2---C10---C6 112.2 (3) C1---C3---C2 61.12 (19) F3---C10---C6 113.0 (3) C1---C3---H3A 117.7 C12---C11---C7 119.9 (3) C2---C3---H3A 117.7 C12---C11---H11 120.0 C1---C3---H3B 117.7 C7---C11---H11 120.0 C2---C3---H3B 117.7 C11---C12---C13 122.1 (3) H3A---C3---H3B 114.8 C11---C12---Cl1 119.5 (2) N9---C4---C5 122.0 (3) C13---C12---Cl1 118.5 (2) N9---C4---C2 118.4 (3) C14---C13---C12 119.3 (3) C5---C4---C2 119.6 (3) C14---C13---H13 120.3 C6---C5---C4 121.1 (3) C12---C13---H13 120.3 C6---C5---H5 119.4 C13---C14---C8 121.1 (3) C4---C5---H5 119.4 C13---C14---H14 119.5 C5---C6---C7 120.0 (3) C8---C14---H14 119.5 C3---C1---C2---C4 −109.7 (3) C6---C7---C8---N9 −0.6 (4) C4---C2---C3---C1 108.6 (3) C11---C7---C8---C14 −0.5 (4) C8---N9---C4---C5 1.6 (4) C6---C7---C8---C14 179.3 (2) C8---N9---C4---C2 −176.8 (2) C5---C6---C10---F1 2.5 (5) C3---C2---C4---N9 −27.5 (4) C7---C6---C10---F1 −178.5 (3) C1---C2---C4---N9 41.4 (4) C5---C6---C10---F2 −118.0 (3) C3---C2---C4---C5 154.1 (3) C7---C6---C10---F2 61.0 (4) C1---C2---C4---C5 −137.1 (3) C5---C6---C10---F3 122.6 (3) N9---C4---C5---C6 −0.8 (5) C7---C6---C10---F3 −58.3 (4) C2---C4---C5---C6 177.6 (3) C8---C7---C11---C12 −0.7 (4) C4---C5---C6---C7 −0.9 (4) C6---C7---C11---C12 179.5 (3) C4---C5---C6---C10 178.2 (3) C7---C11---C12---C13 0.9 (4) C5---C6---C7---C11 −178.7 (3) C7---C11---C12---Cl1 −179.23 (19) C10---C6---C7---C11 2.2 (4) C11---C12---C13---C14 0.2 (4) C5---C6---C7---C8 1.5 (4) Cl1---C12---C13---C14 −179.7 (2) C10---C6---C7---C8 −177.6 (3) C12---C13---C14---C8 −1.5 (4) C4---N9---C8---C14 179.1 (2) N9---C8---C14---C13 −178.4 (2) C4---N9---C8---C7 −0.9 (4) C7---C8---C14---C13 1.6 (4) C11---C7---C8---N9 179.5 (2) --------------------- ------------ ----------------------- -------------- :::

PubMed Central

2024-06-05T04:04:17.449814

2011-2-05

PMC3051947

Related literature {#sec1} ================== For hydrogen-bond motifs, see: Bernstein *et al.* (1995[@bb2]). For bond-length data, see: Allen *et al.* (1987[@bb1]). For background to perimidines and their applications, see: Claramunt *et al.* (1995[@bb4]); del Valle *et al.* (1997[@bb11]); Herbert *et al.* (1987[@bb6]); Llamas-Saiz *et al.* (1995[@bb7]); Pozharskii & Dalnikovskaya (1981[@bb8]); Varsha *et al.* (2010[@bb12]). For related structures, see: Llamas-Saiz *et al.* (1995[@bb7]); Varsha *et al.* (2010[@bb12]). For the stability of the temperature controller used in the data collection, see: Cosier & Glazer (1986[@bb5]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~18~H~12~N~2~O~3~*M* *~r~* = 304.30Monoclinic,*a* = 25.4718 (17) Å*b* = 7.0666 (3) Å*c* = 15.0815 (6) Åβ = 94.373 (3)°*V* = 2706.8 (2) Å^3^*Z* = 8Mo *K*α radiationμ = 0.10 mm^−1^*T* = 100 K0.67 × 0.11 × 0.05 mm ### Data collection {#sec2.1.2} Bruker APEX DUO CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2005[@bb3]) *T* ~min~ = 0.933, *T* ~max~ = 0.99442939 measured reflections6529 independent reflections3471 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.072 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.066*wR*(*F* ^2^) = 0.210*S* = 1.026529 reflections255 parametersAll H-atom parameters refinedΔρ~max~ = 0.57 e Å^−3^Δρ~min~ = −0.29 e Å^−3^ {#d5e471} Data collection: *APEX2* (Bruker, 2005[@bb3]); cell refinement: *SAINT* (Bruker, 2005[@bb3]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb9]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL*; software used to prepare material for publication: *SHELXTL* and *PLATON* (Spek, 2009[@bb10]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811006465/sj5107sup1.cif](http://dx.doi.org/10.1107/S1600536811006465/sj5107sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006465/sj5107Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006465/sj5107Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?sj5107&file=sj5107sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?sj5107sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?sj5107&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [SJ5107](http://scripts.iucr.org/cgi-bin/sendsup?sj5107)). KC thanks the Crystal Materials Research Unit (CMRU), Prince of Songkla University, for a research assistance fellowship. Generous support by the Prince of Songkla University is gratefully acknowledged. The authors also thank Universiti Sains Malaysia for the Research University Grant No. 1001/PFIZIK/811160. Comment ======= Perimidines (*peri*-naphtho-fused perimidine ring systems) have received wide interests due to their applications in photophysics (del Valle *et al.*, 1997), usage as coloring materials for polyester fibers (Claramunt *et al.*, 1995) and fluorescent materials (Varsha *et al.*, 2010). They are also noted for their biological activity displaying antiulcer, antifungal, antimicrobial and antitumor properties (Claramunt *et al.*, 1995; Herbert *et al.*, 1987; Pozharskii & Dalnikovskaya, 1981). In an attempt to synthesize a Co(II) Schiff base complex by the reaction of *o*-vanillin, 1,8-diaminonaphthalene and CoCl~2~.6H~2~O, the unexpected product was the perimidine derivative, (I), reported here, Fig 1. In the molecule of the title perimidine derivative (I), C~18~H~12~N~2~O~3~, the perimidine ring system (N1--N2/C7--C17) is planar with an *r.m.s* deviation 0.0126 (11)Å. The whole molecule is essentially planar with the dihedral angle between the perimidine and phenyl rings being 3.25 (5)°. Both the hydroxy and methoxy groups are co-planar with the attached benzene ring with torsion angles O2--C2--C3--C4 = 179.96 (11)° and C18--O3--C3--C2 = -177.96 (12)°. An intramolecular O---H···N interaction generates an S(6) ring motif (Bernstein *et al.*, 1995) and helps to stabilize the planarity of the molecule (Fig. 1). Bond distances are normal (Allen *et al.*, 1987) and are comparable to those found in related structures (Llamas-Saiz *et al.*, 1995; Varsha *et al.*, 2010). In the crystal structure (Fig. 2), the molecules are linked by two C---H···O interactions (Table 1) into dimers which generate S(16) ring motifs. These dimers are arranged into sheets parallel to the *ac* plane and further stacked down the *b* axis by π--π interactions with centroid to centroid distances *Cg*~1~···*Cg*~2~^ii^= 3.7241 (7) Å; *Cg*~2~···*Cg*~3~^ii^= 3.5066 (8) Å; *Cg*~2~···*Cg*~4~^ii^= 3.7055 (8) Å and *Cg*~2~···*Cg*~4~^iii^= 3.5988 (8) Å (symmetry codes (ii) = 2 - *x*, 1 - *y*, 1 - *z* and (iii) = 2 - *x*, 2 - *y*, 2 - *z*). *Cg*1, *Cg*2, *Cg*3, and *Cg*4 are the centroids of the N1--N2/C7--C8/C6--C17, C1--C6, C8--C12/C17, and C12--C17 rings, respectively. Experimental {#experimental} ============ The title compound was synthesized by adding a solution of 1,8-diaminonaphthalene (0.50 g, 3.16 mmol) in ethanol (20 ml) dropwise to a solution of *o*-vanillin (0.96 g, 6.32 mmol) in ethanol (10 ml). The reaction mixture was stirred for 0.5 h at room temperature and a pale-orange precipitate was obtained. After filtration, the pale-orange solid was washed with diethyl ether. A solution of the pale-orange solid (0.20 g, 0.47 mmol) in ethanol (20 ml) was slowly added to a solution of CoCl~2~.6H~2~O (0.11 g, 0.47 mmol) in 10 ml of ethanol followed by triethylamine (0.06 ml, 0.47 mmol). The mixture was refluxed for 3 h. The title compound was obtained as a purple solid and washed with diethyl ether. The purple needle-shaped single crystals of the unexpected perimidine derivative of the title compound suitable for *x*-ray structure determination were recrystallized from ethanol by slow evaporation of the solvent at room temperature over several days, Mp. 507--508 K. Refinement {#refinement} ========== All H atoms (except H13) were located in difference maps and refined isotropically. H13 was refined with *U*~iso~ constrained to be 1.2*U*~eq~ (C13). The highest residual electron density peak is located at 0.68 Å from C16 and the deepest hole is located at 0.48 Å from C16. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound, showing 50% probability displacement ellipsoids and the atom-numbering scheme. An intramolecular hydrogen bond is drawn as a dashed line. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The crystal packing of the title compound viewed down the b axis. Hydrogen bonds were drawn as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e274 .table-wrap} ----------------------- --------------------------------------- C~18~H~12~N~2~O~3~ *F*(000) = 1264 *M~r~* = 304.30 *D*~x~ = 1.493 Mg m^−3^ Monoclinic, *C*2/*c* Melting point = 507--508 K Hall symbol: -C 2yc Mo *K*α radiation, λ = 0.71073 Å *a* = 25.4718 (17) Å Cell parameters from 6529 reflections *b* = 7.0666 (3) Å θ = 1.6--36.3° *c* = 15.0815 (6) Å µ = 0.10 mm^−1^ β = 94.373 (3)° *T* = 100 K *V* = 2706.8 (2) Å^3^ Needle, purple *Z* = 8 0.67 × 0.11 × 0.05 mm ----------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e402 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker APEX DUO CCD area-detector diffractometer 6529 independent reflections Radiation source: sealed tube 3471 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.072 φ and ω scans θ~max~ = 36.3°, θ~min~ = 1.6° Absorption correction: multi-scan (*SADABS*; Bruker, 2005) *h* = −42→34 *T*~min~ = 0.933, *T*~max~ = 0.994 *k* = −11→11 42939 measured reflections *l* = −24→25 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e519 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.066 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.210 All H-atom parameters refined *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.110*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 6529 reflections (Δ/σ)~max~ = 0.001 255 parameters Δρ~max~ = 0.57 e Å^−3^ 0 restraints Δρ~min~ = −0.29 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------ ::: Special details {#specialdetails} =============== ::: {#d1e673 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. The crystal was placed in the cold stream of an Oxford Cryosystems Cobra open-flow nitrogen cryostat (Cosier & Glazer, 1986) operating at 100.0 (1) K. Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e778 .table-wrap} ------ ------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O1 1.20986 (4) 0.86652 (17) 0.36853 (7) 0.0390 (3) O2 0.93604 (4) 0.76137 (15) 0.66009 (7) 0.0305 (2) H1O2 0.9692 (9) 0.784 (3) 0.6441 (15) 0.068 (7)\* O3 0.83728 (4) 0.69274 (15) 0.67439 (7) 0.0307 (2) N1 1.00314 (4) 0.71962 (15) 0.40931 (7) 0.0230 (2) N2 1.01534 (4) 0.77988 (14) 0.56606 (7) 0.0217 (2) C1 0.92971 (5) 0.68964 (16) 0.50224 (9) 0.0213 (2) C2 0.90819 (5) 0.70778 (17) 0.58472 (9) 0.0229 (3) C3 0.85404 (5) 0.66982 (18) 0.59105 (9) 0.0245 (3) C4 0.82297 (5) 0.61425 (18) 0.51641 (10) 0.0269 (3) H4 0.7846 (8) 0.588 (3) 0.5190 (13) 0.053 (5)\* C5 0.84470 (5) 0.59241 (19) 0.43503 (9) 0.0271 (3) H5 0.8242 (6) 0.542 (2) 0.3839 (11) 0.032 (4)\* C6 0.89730 (5) 0.62922 (18) 0.42762 (9) 0.0242 (3) H6 0.9121 (6) 0.608 (3) 0.3716 (12) 0.039 (5)\* C7 0.98576 (5) 0.73220 (16) 0.49261 (9) 0.0208 (2) C8 1.05351 (5) 0.75829 (17) 0.40160 (9) 0.0222 (2) C9 1.07449 (5) 0.7429 (2) 0.31468 (9) 0.0271 (3) H9 1.0495 (6) 0.696 (2) 0.2625 (11) 0.027 (4)\* C10 1.12551 (5) 0.7780 (2) 0.30472 (9) 0.0281 (3) H10 1.1420 (6) 0.761 (2) 0.2446 (11) 0.031 (4)\* C11 1.16293 (5) 0.83502 (19) 0.37912 (9) 0.0269 (3) C12 1.14203 (5) 0.84961 (17) 0.46741 (9) 0.0233 (3) C13 1.17405 (5) 0.89476 (19) 0.54295 (9) 0.0268 (3) H13 1.2155 (6) 0.916 (2) 0.5341 (11) 0.032\* C14 1.15283 (5) 0.90293 (19) 0.62651 (10) 0.0284 (3) H14 1.1753 (6) 0.931 (2) 0.6784 (10) 0.029 (4)\* C15 1.10056 (5) 0.86583 (18) 0.63559 (9) 0.0257 (3) H15 1.0859 (6) 0.865 (2) 0.6931 (12) 0.036 (4)\* C16 1.06736 (5) 0.81935 (16) 0.55893 (9) 0.0218 (2) C17 1.08818 (5) 0.81121 (16) 0.47560 (8) 0.0206 (2) C18 0.78320 (6) 0.6497 (2) 0.68447 (12) 0.0338 (3) H18A 0.7621 (7) 0.737 (3) 0.6464 (12) 0.039 (5)\* H18B 0.7746 (6) 0.521 (3) 0.6683 (10) 0.032 (4)\* H18C 0.7805 (7) 0.666 (2) 0.7467 (12) 0.035 (4)\* ------ ------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1237 .table-wrap} ----- ------------ ------------ ------------ ------------- ------------ ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.0255 (5) 0.0525 (7) 0.0408 (6) −0.0050 (5) 0.0157 (4) 0.0022 (5) O2 0.0225 (5) 0.0393 (6) 0.0313 (5) −0.0060 (4) 0.0121 (4) −0.0095 (4) O3 0.0201 (4) 0.0387 (6) 0.0353 (5) −0.0036 (4) 0.0158 (4) −0.0050 (4) N1 0.0213 (5) 0.0227 (5) 0.0261 (6) 0.0006 (4) 0.0090 (4) 0.0043 (4) N2 0.0189 (5) 0.0195 (5) 0.0278 (6) −0.0018 (4) 0.0099 (4) −0.0012 (4) C1 0.0201 (5) 0.0168 (5) 0.0282 (6) 0.0001 (4) 0.0088 (5) 0.0031 (4) C2 0.0204 (6) 0.0202 (5) 0.0290 (7) −0.0007 (4) 0.0089 (5) −0.0003 (4) C3 0.0222 (6) 0.0220 (5) 0.0309 (7) 0.0002 (4) 0.0112 (5) 0.0011 (5) C4 0.0186 (6) 0.0244 (6) 0.0383 (8) −0.0017 (5) 0.0073 (5) 0.0059 (5) C5 0.0235 (6) 0.0268 (6) 0.0313 (7) −0.0019 (5) 0.0036 (5) 0.0066 (5) C6 0.0245 (6) 0.0234 (6) 0.0254 (6) −0.0002 (4) 0.0066 (5) 0.0054 (5) C7 0.0213 (5) 0.0171 (5) 0.0253 (6) 0.0013 (4) 0.0092 (5) 0.0019 (4) C8 0.0212 (5) 0.0196 (5) 0.0266 (6) 0.0013 (4) 0.0079 (5) 0.0041 (4) C9 0.0265 (6) 0.0316 (6) 0.0244 (6) 0.0006 (5) 0.0096 (5) 0.0042 (5) C10 0.0273 (6) 0.0330 (7) 0.0254 (7) 0.0006 (5) 0.0118 (5) 0.0051 (5) C11 0.0249 (6) 0.0271 (6) 0.0304 (7) 0.0000 (5) 0.0127 (5) 0.0043 (5) C12 0.0204 (5) 0.0213 (5) 0.0297 (6) −0.0008 (4) 0.0109 (5) 0.0026 (5) C13 0.0219 (6) 0.0261 (6) 0.0336 (7) −0.0046 (5) 0.0090 (5) 0.0000 (5) C14 0.0248 (6) 0.0295 (6) 0.0319 (7) −0.0057 (5) 0.0077 (5) −0.0041 (5) C15 0.0245 (6) 0.0263 (6) 0.0273 (7) −0.0051 (5) 0.0100 (5) −0.0033 (5) C16 0.0211 (5) 0.0175 (5) 0.0281 (6) −0.0020 (4) 0.0104 (4) −0.0016 (4) C17 0.0210 (5) 0.0168 (5) 0.0253 (6) 0.0000 (4) 0.0094 (4) 0.0024 (4) C18 0.0192 (6) 0.0437 (9) 0.0405 (9) −0.0047 (6) 0.0145 (6) −0.0017 (7) ----- ------------ ------------ ------------ ------------- ------------ ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1673 .table-wrap} --------------------- -------------- ----------------------- -------------- O1---C11 1.2384 (16) C8---C17 1.4196 (18) O2---C2 1.3474 (16) C8---C9 1.4568 (19) O2---H1O2 0.91 (2) C9---C10 1.3427 (19) O3---C3 1.3676 (16) C9---H9 1.028 (16) O3---C18 1.4301 (16) C10---C11 1.472 (2) N1---C8 1.3256 (16) C10---H10 1.035 (17) N1---C7 1.3663 (17) C11---C12 1.4747 (18) N2---C7 1.3345 (17) C12---C13 1.3868 (19) N2---C16 1.3664 (16) C12---C17 1.4127 (17) C1---C2 1.4030 (18) C13---C14 1.4098 (19) C1---C6 1.4102 (19) C13---H13 1.085 (16) C1---C7 1.4769 (17) C14---C15 1.3739 (18) C2---C3 1.4155 (17) C14---H14 0.955 (15) C3---C4 1.3827 (19) C15---C16 1.4179 (18) C4---C5 1.393 (2) C15---H15 0.970 (17) C4---H4 1.000 (19) C16---C17 1.4019 (18) C5---C6 1.3777 (18) C18---H18A 0.976 (18) C5---H5 0.966 (16) C18---H18B 0.963 (17) C6---H6 0.963 (18) C18---H18C 0.954 (18) C2---O2---H1O2 105.4 (14) C9---C10---C11 122.77 (12) C3---O3---C18 116.32 (11) C9---C10---H10 122.6 (9) C8---N1---C7 116.80 (11) C11---C10---H10 114.6 (9) C7---N2---C16 118.40 (11) O1---C11---C10 121.75 (12) C2---C1---C6 119.38 (11) O1---C11---C12 121.49 (13) C2---C1---C7 120.97 (11) C10---C11---C12 116.75 (11) C6---C1---C7 119.65 (11) C13---C12---C17 119.11 (12) O2---C2---C1 123.88 (11) C13---C12---C11 121.84 (12) O2---C2---C3 116.70 (11) C17---C12---C11 119.03 (12) C1---C2---C3 119.41 (12) C12---C13---C14 120.14 (12) O3---C3---C4 125.62 (12) C12---C13---H13 116.6 (8) O3---C3---C2 114.43 (12) C14---C13---H13 123.2 (8) C4---C3---C2 119.95 (12) C15---C14---C13 121.45 (13) C3---C4---C5 120.50 (12) C15---C14---H14 118.9 (9) C3---C4---H4 121.5 (11) C13---C14---H14 119.6 (9) C5---C4---H4 118.0 (11) C14---C15---C16 119.02 (12) C6---C5---C4 120.32 (13) C14---C15---H15 122.2 (10) C6---C5---H5 118.3 (9) C16---C15---H15 118.7 (10) C4---C5---H5 121.2 (9) N2---C16---C17 119.84 (11) C5---C6---C1 120.42 (12) N2---C16---C15 120.32 (11) C5---C6---H6 119.3 (10) C17---C16---C15 119.84 (11) C1---C6---H6 120.2 (10) C16---C17---C12 120.44 (12) N2---C7---N1 125.29 (11) C16---C17---C8 117.41 (11) N2---C7---C1 117.29 (11) C12---C17---C8 122.12 (11) N1---C7---C1 117.42 (11) O3---C18---H18A 107.1 (10) N1---C8---C17 122.25 (12) O3---C18---H18B 112.2 (9) N1---C8---C9 119.17 (12) H18A---C18---H18B 110.1 (14) C17---C8---C9 118.57 (11) O3---C18---H18C 102.7 (10) C10---C9---C8 120.76 (13) H18A---C18---H18C 115.0 (15) C10---C9---H9 121.4 (9) H18B---C18---H18C 109.5 (14) C8---C9---H9 117.7 (9) C6---C1---C2---O2 178.87 (11) C8---C9---C10---C11 −0.6 (2) C7---C1---C2---O2 −0.90 (19) C9---C10---C11---O1 179.92 (13) C6---C1---C2---C3 −1.62 (18) C9---C10---C11---C12 1.0 (2) C7---C1---C2---C3 178.60 (10) O1---C11---C12---C13 −1.6 (2) C18---O3---C3---C4 1.88 (19) C10---C11---C12---C13 177.40 (12) C18---O3---C3---C2 −177.96 (12) O1---C11---C12---C17 −179.71 (12) O2---C2---C3---O3 −0.19 (17) C10---C11---C12---C17 −0.76 (17) C1---C2---C3---O3 −179.73 (10) C17---C12---C13---C14 −0.32 (19) O2---C2---C3---C4 179.96 (11) C11---C12---C13---C14 −178.48 (12) C1---C2---C3---C4 0.42 (18) C12---C13---C14---C15 0.4 (2) O3---C3---C4---C5 −178.86 (12) C13---C14---C15---C16 −0.3 (2) C2---C3---C4---C5 0.98 (19) C7---N2---C16---C17 0.73 (17) C3---C4---C5---C6 −1.1 (2) C7---N2---C16---C15 −178.36 (11) C4---C5---C6---C1 −0.1 (2) C14---C15---C16---N2 179.33 (12) C2---C1---C6---C5 1.47 (18) C14---C15---C16---C17 0.24 (19) C7---C1---C6---C5 −178.75 (11) N2---C16---C17---C12 −179.29 (10) C16---N2---C7---N1 −0.21 (18) C15---C16---C17---C12 −0.20 (18) C16---N2---C7---C1 179.80 (10) N2---C16---C17---C8 −0.99 (17) C8---N1---C7---N2 −0.03 (18) C15---C16---C17---C8 178.10 (11) C8---N1---C7---C1 179.96 (10) C13---C12---C17---C16 0.24 (18) C2---C1---C7---N2 2.97 (17) C11---C12---C17---C16 178.45 (10) C6---C1---C7---N2 −176.80 (11) C13---C12---C17---C8 −177.98 (11) C2---C1---C7---N1 −177.02 (10) C11---C12---C17---C8 0.23 (18) C6---C1---C7---N1 3.21 (16) N1---C8---C17---C16 0.77 (17) C7---N1---C8---C17 −0.26 (17) C9---C8---C17---C16 −178.10 (11) C7---N1---C8---C9 178.60 (11) N1---C8---C17---C12 179.04 (11) N1---C8---C9---C10 −178.90 (12) C9---C8---C17---C12 0.17 (17) C17---C8---C9---C10 0.01 (19) --------------------- -------------- ----------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2460 .table-wrap} ------------------- ------------ ------------ ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O2---H1O2···N2 0.91 (2) 1.73 (2) 2.5583 (15) 151 (2) C15---H15···O2^i^ 0.970 (18) 2.437 (18) 3.3686 (17) 160.8 (12) ------------------- ------------ ------------ ------------- --------------- ::: Symmetry codes: (i) −*x*+2, *y*, −*z*+3/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ----------------- ------------ ------------ ------------- ------------- O2---H1*O*2⋯N2 0.91 (2) 1.73 (2) 2.5583 (15) 151 (2) C15---H15⋯O2^i^ 0.970 (18) 2.437 (18) 3.3686 (17) 160.8 (12) Symmetry code: (i) . ::: [^1]: ‡ Thomson Reuters ResearcherID: A-3561-2009. [^2]: § Thomson Reuters ResearcherID: A-5085-2009.

PubMed Central

2024-06-05T04:04:17.454170

2011-2-26

PMC3051948

Related literature {#sec1} ================== For the therapeutic properties of sulfonyl­hydrazones, see: Rollas *et al.* (2002[@bb13]); Frlan *et al.* (2008[@bb6]); Lima *et al.* (1999[@bb9]); Sondhi *et al.* (2006[@bb17]) and for their biological activity, see: Kendall *et al.* (2007[@bb8]); Sadek *et al.* (2008[@bb14]). For the anti­cancer activity of naphthalimides, see: Braña & Ramos (2001[@bb3]); Braña *et al.* (2001[@bb2]); Suárez & Sánchez (1992[@bb20]); Ingrassia *et al.* (2009[@bb7]); Wu *et al.* (2009[@bb22]); Norton *et al.* (2008[@bb11]). For the therapeutic properties of cyclic imides, see: Cechinel Filho *et al.* (2003[@bb4]); Walter *et al.* (2002[@bb21]). For background to this study, see: Silva *et al.* (2006[@bb16]); Oliveira & Nunes (2006[@bb12]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~26~H~18~N~4~O~6~S·C~2~H~6~OS*M* *~r~* = 592.63Triclinic,*a* = 9.152 (1) Å*b* = 11.971 (1) Å*c* = 13.910 (1) Åα = 107.268 (7)°β = 101.789 (7)°γ = 96.319 (8)°*V* = 1400.6 (2) Å^3^*Z* = 2Mo *K*α radiationμ = 0.24 mm^−1^*T* = 293 K0.50 × 0.16 × 0.13 mm ### Data collection {#sec2.1.2} Enraf--Nonius CAD-4 diffractometer5055 measured reflections4737 independent reflections3075 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.0173 standard reflections every 200 reflections intensity decay: 1% ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.052*wR*(*F* ^2^) = 0.163*S* = 1.044737 reflections371 parametersH-atom parameters constrainedΔρ~max~ = 0.73 e Å^−3^Δρ~min~ = −0.43 e Å^−3^ {#d5e538} Data collection: *CAD-4 Software* (Enraf--Nonius, 1989[@bb5]); cell refinement: *CAD-4 Software*; data reduction: *HELENA* (Spek, 1996[@bb18]); program(s) used to solve structure: *SIR97* (Altomare *et al.*, 1999[@bb1]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb15]); molecular graphics: *PLATON* (Spek, 2009[@bb19]) and *Mercury* (Macrae *et al.*, 2006[@bb10]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811004697/ff2001sup1.cif](http://dx.doi.org/10.1107/S1600536811004697/ff2001sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004697/ff2001Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004697/ff2001Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?ff2001&file=ff2001sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?ff2001sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?ff2001&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [FF2001](http://scripts.iucr.org/cgi-bin/sendsup?ff2001)). The authors thank CAPES and CNPq for financial support. Comment ======= Sulfonyl-hydrazones are known for their therapeutic properties, such as, antimicrobial (Rollas *et al.* 2002, Frlan *et al.* 2008), analgesic (Lima *et al.* 1999, Sondhi *et al.* 2006), *etc*. Sulfonyl-hydrazones was selective inhibitor of p110α, a phosphoinositide-3-kinase that is over-expressed in 30% of tumors (Kendall *et al.* 2007). In innovative study, the sulfonyl-hydrazones were reported by enhance myocardial repair by stem cells by activating cardiac differentiation in human mobilized peripheral blood mononuclear cells (*M*-PBMCs) (Sadek *et al.* 2008). Cyclic imides have also many therapeutic properties including antibacterial, antitumor, diuretic and antiviral (Cechinel Filho *et al.* 2003). In a previous publication, we reported the synthesis of imidobenzenesulfonyl compounds that showed promising analgesic profiles in the acetic acid- induced mice writhing test. The mechanism of action occurred possibly due to additional non-covalent interactions with the COX active site (Walter *et al.* 2002). The naphthalimides, in special, are known of their high DNA-binding ability and consequently many of them have anticancer property (Braña & Ramos, 2001); Braña *et al.* 2001). Mitonafide and Amonafide are classical examples of naphthalimides derivatives with antitumoral activity (Suárez *et al.* 1992). Recently, many similar compounds have been showed activity against different cancer cell lines (Ingrassia *et al.* 2009, Wu *et al.* 2009, Norton *et al.* 2008). The title compound (I) (Scheme 1) was synthesized as a part of our work to investigate the antitumoral activity of the sulfonyl-hydrazones cyclic imides derivatives (Oliveira *et al.* 2006, Silva *et al.* 2006). The molecular structure of the title compound (Fig. 1) shows E conformation on the hydrazone double bond, which is evidenced by the torsion angle S1--N2--N3--C21 of 165.8 (2)°. The presence of a methylene group among benzo\[*de*\]isoquinoline and benzenesulfonyl moieties allows *p*-nitrophenyl ring and benzo\[*de*\]isoquinoline system to be parallel with respect to each other, so that the molecule adopts an U-shaped spatial conformation. The dihedral angle between mean planes of these planar groups is 4.4 (1)°. This special arrangement enables the neighboring molecule be intercalated by a center of symmetry, forming pairs of molecules in a centrosymmetric structure (Fig. 2). Slipped π--π interaction between *p*-nitrophenyl and benzo\[*de*\]isoquinoline, with centroid--C12 distance of 3.589 Å, and point-to-face C--H···π interaction between benzenesulfonyl and benzo\[*de*\]isoquinoline aromatic systems, with centroid-H8 distance of 2.903 Å, are observed. In addition, crystal packing also shows an intermolecular N2--H···O1S interaction involving amine group and DMSO solvate. Experimental {#experimental} ============ 4-nitrobenzaldehyde (79 mg, 0.52 mmol) was added in a mixture of 4-\[(1,3-dioxo-1*H*-benzo\[*de*\]isoquinolin-2(3*H*)-yl)methyl\] benzenesulfonohydrazide (200 mg, 0.52 mmol) in ethanol (10 ml), with a drop of hydrochloric acid as catalyst, as described for similar compounds (Silva *et al.* 2006, Oliveira *et al.* 2006). The reaction was carried out by stirring at room temperature for one hour. The solid was filtered off with suction. The crystal used for data collection was obtained by dissolving 30 mg of (I) in 10 ml of dimethylsulfoxide and by slow evaporation of the solvent. Refinement {#refinement} ========== All non-H atoms were refined with anisotropic displacement parameters. H atoms were placed at their idealized positions with distances of 0.93 and 0.97 Å and *U*~eq~ fixed at 1.2 times *U*~iso~ of the preceding atom for C--H~Ar~ and C--H~2~, respectively and at 1.5 times *U*~iso~ of the preceding atom for C--H~3~. The H atom of the amino group was found from Fourier map and treated with riding model and its *U*~eq~ was refined freely. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound with the labelling scheme. Displacement ellipsoids are shown at the 40% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Intermolecular interactions observed in (I). :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e233 .table-wrap} -------------------------------- ------------------------------------- C~26~H~18~N~4~O~6~S·C~2~H~6~OS *Z* = 2 *M~r~* = 592.63 *F*(000) = 616 Triclinic, *P*1 *D*~x~ = 1.405 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 9.152 (1) Å Cell parameters from 25 reflections *b* = 11.971 (1) Å θ = 8.5--13.4° *c* = 13.910 (1) Å µ = 0.24 mm^−1^ α = 107.268 (7)° *T* = 293 K β = 101.789 (7)° Prismatic, colourless γ = 96.319 (8)° 0.50 × 0.16 × 0.13 mm *V* = 1400.6 (2) Å^3^ -------------------------------- ------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e377 .table-wrap} ------------------------------------------ ---------------------------------------------- Enraf--Nonius CAD-4 diffractometer *R*~int~ = 0.017 Radiation source: fine-focus sealed tube θ~max~ = 25.1°, θ~min~ = 2.3° graphite *h* = 0→10 ω--2θ scans *k* = −14→14 5055 measured reflections *l* = −16→16 4737 independent reflections 3 standard reflections every 200 reflections 3075 reflections with *I* \> 2σ(*I*) intensity decay: 1% ------------------------------------------ ---------------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e477 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.052 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.163 H-atom parameters constrained *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0792*P*)^2^ + 0.613*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4737 reflections (Δ/σ)~max~ \< 0.001 371 parameters Δρ~max~ = 0.73 e Å^−3^ 0 restraints Δρ~min~ = −0.43 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e636 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ S1 0.34031 (11) 0.73620 (8) 0.53120 (6) 0.0597 (3) N1 0.8354 (3) 1.1992 (2) 0.8805 (2) 0.0571 (7) N2 0.4477 (3) 0.6426 (2) 0.55446 (19) 0.0540 (7) H2N 0.5170 0.6398 0.5273 0.058 (12)\* N3 0.4776 (3) 0.6399 (2) 0.65605 (19) 0.0501 (6) O1 0.6771 (4) 1.2526 (3) 0.9840 (2) 0.1026 (11) O2 0.9903 (3) 1.1379 (3) 0.7756 (2) 0.0987 (10) O3 0.3260 (3) 0.7192 (2) 0.42331 (18) 0.0797 (8) O4 0.2088 (3) 0.7188 (2) 0.5685 (2) 0.0766 (8) C2 0.7994 (4) 1.2237 (3) 0.9760 (3) 0.0626 (9) C3 0.9105 (4) 1.2127 (3) 1.0630 (2) 0.0547 (8) C4 0.8859 (5) 1.2441 (4) 1.1612 (3) 0.0767 (11) H4 0.7994 1.2747 1.1724 0.092\* C5 0.9881 (6) 1.2309 (4) 1.2432 (3) 0.0864 (13) H5 0.9706 1.2547 1.3092 0.104\* C6 1.1117 (6) 1.1846 (4) 1.2296 (3) 0.0803 (13) H6 1.1779 1.1753 1.2858 0.096\* C7 1.1429 (4) 1.1495 (3) 1.1304 (3) 0.0645 (10) C8 1.2697 (5) 1.1010 (4) 1.1103 (5) 0.0918 (15) H8 1.3383 1.0895 1.1643 0.110\* C9 1.2953 (5) 1.0705 (4) 1.0149 (6) 0.1053 (19) H9 1.3799 1.0370 1.0038 0.126\* C10 1.1970 (5) 1.0884 (4) 0.9325 (4) 0.0845 (13) H10 1.2170 1.0683 0.8672 0.101\* C11 1.0701 (4) 1.1359 (3) 0.9479 (3) 0.0547 (8) C12 1.0410 (4) 1.1663 (3) 1.0464 (3) 0.0492 (8) C13 0.9662 (4) 1.1572 (3) 0.8612 (3) 0.0636 (10) C14 0.7269 (5) 1.2149 (3) 0.7930 (3) 0.0737 (11) H14A 0.7827 1.2462 0.7515 0.088\* H14B 0.6660 1.2723 0.8202 0.088\* C15 0.6233 (4) 1.0984 (3) 0.7248 (3) 0.0602 (9) C16 0.6623 (5) 1.0275 (3) 0.6388 (3) 0.0680 (10) H16 0.7496 1.0539 0.6214 0.082\* C17 0.5738 (4) 0.9184 (3) 0.5784 (3) 0.0636 (9) H17 0.6009 0.8715 0.5208 0.076\* C18 0.4443 (4) 0.8797 (3) 0.6049 (2) 0.0535 (8) C19 0.4011 (4) 0.9501 (4) 0.6880 (3) 0.0714 (10) H19 0.3127 0.9246 0.7045 0.086\* C20 0.4909 (5) 1.0596 (4) 0.7469 (3) 0.0765 (11) H20 0.4611 1.1079 0.8027 0.092\* C21 0.5844 (4) 0.5873 (3) 0.6806 (2) 0.0500 (8) H21 0.6372 0.5541 0.6320 0.060\* C22 0.6255 (4) 0.5781 (3) 0.7849 (2) 0.0475 (7) C23 0.7517 (4) 0.5304 (3) 0.8140 (3) 0.0580 (9) H23 0.8057 0.4994 0.7655 0.070\* C24 0.7984 (4) 0.5285 (3) 0.9143 (3) 0.0613 (9) H24 0.8839 0.4973 0.9341 0.074\* C25 0.7162 (4) 0.5734 (3) 0.9838 (2) 0.0550 (8) C26 0.5894 (4) 0.6196 (3) 0.9578 (3) 0.0638 (9) H26 0.5356 0.6495 1.0067 0.077\* C27 0.5431 (4) 0.6209 (3) 0.8576 (3) 0.0615 (9) H27 0.4561 0.6507 0.8382 0.074\* N4 0.7691 (4) 0.5767 (3) 1.0923 (3) 0.0733 (9) O5 0.6974 (4) 0.6209 (4) 1.1535 (2) 0.1111 (12) O6 0.8819 (4) 0.5387 (4) 1.1166 (2) 0.1188 (13) S2 0.74498 (12) 0.64956 (10) 0.39415 (8) 0.0747 (3) O1S 0.7208 (3) 0.6673 (3) 0.5003 (2) 0.0830 (8) C1S 0.8748 (5) 0.5522 (4) 0.3777 (3) 0.0833 (12) H1S1 0.8257 0.4734 0.3689 0.125\* H1S2 0.9591 0.5784 0.4379 0.125\* H1S3 0.9105 0.5515 0.3173 0.125\* C2S 0.8693 (6) 0.7814 (4) 0.4070 (4) 0.1081 (17) H2S1 0.8157 0.8468 0.4170 0.162\* H2S2 0.9049 0.7705 0.3451 0.162\* H2S3 0.9542 0.7979 0.4657 0.162\* ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1457 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.0667 (6) 0.0595 (5) 0.0449 (5) −0.0013 (4) −0.0036 (4) 0.0219 (4) N1 0.0665 (19) 0.0523 (16) 0.0478 (16) 0.0087 (14) 0.0064 (14) 0.0155 (13) N2 0.0696 (19) 0.0552 (16) 0.0371 (14) 0.0016 (14) 0.0122 (14) 0.0193 (12) N3 0.0566 (16) 0.0536 (15) 0.0412 (14) 0.0033 (13) 0.0094 (12) 0.0217 (12) O1 0.084 (2) 0.137 (3) 0.079 (2) 0.060 (2) 0.0151 (16) 0.0140 (19) O2 0.103 (2) 0.127 (3) 0.0623 (18) −0.0099 (19) 0.0389 (17) 0.0240 (17) O3 0.113 (2) 0.0723 (17) 0.0391 (13) −0.0025 (15) −0.0086 (13) 0.0230 (12) O4 0.0539 (15) 0.0878 (19) 0.0830 (19) 0.0021 (13) 0.0062 (13) 0.0319 (15) C2 0.064 (2) 0.062 (2) 0.055 (2) 0.0181 (18) 0.0125 (18) 0.0088 (17) C3 0.059 (2) 0.055 (2) 0.0449 (19) 0.0089 (16) 0.0094 (16) 0.0111 (15) C4 0.077 (3) 0.085 (3) 0.059 (2) 0.014 (2) 0.019 (2) 0.010 (2) C5 0.103 (4) 0.097 (3) 0.046 (2) −0.003 (3) 0.011 (2) 0.019 (2) C6 0.094 (3) 0.068 (3) 0.062 (3) −0.011 (2) −0.012 (2) 0.028 (2) C7 0.058 (2) 0.0424 (18) 0.079 (3) −0.0036 (16) −0.0068 (19) 0.0200 (17) C8 0.062 (3) 0.057 (2) 0.136 (5) 0.007 (2) −0.012 (3) 0.028 (3) C9 0.053 (3) 0.075 (3) 0.170 (6) 0.020 (2) 0.022 (3) 0.015 (3) C10 0.062 (3) 0.068 (3) 0.111 (4) 0.003 (2) 0.038 (3) 0.004 (2) C11 0.0454 (19) 0.0446 (17) 0.066 (2) −0.0026 (15) 0.0159 (17) 0.0083 (16) C12 0.0477 (19) 0.0370 (16) 0.057 (2) −0.0010 (14) 0.0091 (15) 0.0119 (14) C13 0.073 (3) 0.054 (2) 0.058 (2) −0.0128 (18) 0.0226 (19) 0.0129 (17) C14 0.099 (3) 0.054 (2) 0.058 (2) 0.008 (2) −0.003 (2) 0.0214 (17) C15 0.083 (3) 0.0477 (19) 0.0437 (19) 0.0127 (18) −0.0020 (18) 0.0186 (15) C16 0.082 (3) 0.060 (2) 0.059 (2) −0.0055 (19) 0.014 (2) 0.0247 (18) C17 0.080 (3) 0.056 (2) 0.051 (2) 0.0032 (19) 0.0152 (19) 0.0167 (16) C18 0.062 (2) 0.0540 (19) 0.0415 (18) 0.0084 (16) 0.0002 (15) 0.0211 (15) C19 0.067 (2) 0.080 (3) 0.061 (2) 0.007 (2) 0.0146 (19) 0.017 (2) C20 0.080 (3) 0.072 (3) 0.060 (2) 0.009 (2) 0.012 (2) 0.004 (2) C21 0.061 (2) 0.0471 (17) 0.0396 (17) 0.0028 (16) 0.0122 (15) 0.0141 (14) C22 0.0561 (19) 0.0409 (16) 0.0446 (17) 0.0047 (14) 0.0108 (15) 0.0152 (13) C23 0.073 (2) 0.053 (2) 0.051 (2) 0.0212 (17) 0.0210 (17) 0.0152 (16) C24 0.069 (2) 0.062 (2) 0.055 (2) 0.0231 (18) 0.0075 (18) 0.0227 (17) C25 0.064 (2) 0.055 (2) 0.0431 (18) 0.0007 (17) 0.0074 (16) 0.0192 (15) C26 0.068 (2) 0.081 (3) 0.053 (2) 0.017 (2) 0.0235 (18) 0.0292 (19) C27 0.057 (2) 0.083 (3) 0.057 (2) 0.0212 (19) 0.0184 (17) 0.0352 (19) N4 0.080 (2) 0.087 (2) 0.052 (2) 0.0088 (19) 0.0094 (18) 0.0279 (17) O5 0.115 (3) 0.171 (3) 0.0557 (18) 0.032 (2) 0.0289 (19) 0.043 (2) O6 0.121 (3) 0.182 (4) 0.072 (2) 0.070 (3) 0.0121 (19) 0.062 (2) S2 0.0732 (7) 0.1007 (8) 0.0565 (6) 0.0068 (6) 0.0234 (5) 0.0332 (5) O1S 0.103 (2) 0.095 (2) 0.0608 (16) 0.0099 (16) 0.0414 (15) 0.0291 (14) C1S 0.080 (3) 0.094 (3) 0.077 (3) 0.010 (2) 0.028 (2) 0.025 (2) C2S 0.130 (4) 0.101 (4) 0.115 (4) 0.005 (3) 0.060 (3) 0.053 (3) ----- ------------- ------------- ------------- -------------- -------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2153 .table-wrap} ---------------------- ------------- ----------------------- ------------- S1---O4 1.423 (3) C15---C20 1.375 (5) S1---O3 1.429 (2) C15---C16 1.384 (5) S1---N2 1.630 (3) C16---C17 1.381 (5) S1---C18 1.762 (3) C16---H16 0.9300 N1---C2 1.388 (4) C17---C18 1.383 (5) N1---C13 1.394 (5) C17---H17 0.9300 N1---C14 1.478 (4) C18---C19 1.373 (5) N2---N3 1.394 (3) C19---C20 1.383 (5) N2---H2N 0.8006 C19---H19 0.9300 N3---C21 1.263 (4) C20---H20 0.9300 O1---C2 1.224 (4) C21---C22 1.462 (4) O2---C13 1.214 (4) C21---H21 0.9300 C2---C3 1.461 (5) C22---C23 1.383 (4) C3---C4 1.377 (5) C22---C27 1.394 (4) C3---C12 1.404 (5) C23---C24 1.381 (5) C4---C5 1.380 (6) C23---H23 0.9300 C4---H4 0.9300 C24---C25 1.367 (5) C5---C6 1.336 (6) C24---H24 0.9300 C5---H5 0.9300 C25---C26 1.369 (5) C6---C7 1.415 (6) C25---N4 1.474 (4) C6---H6 0.9300 C26---C27 1.377 (5) C7---C8 1.395 (6) C26---H26 0.9300 C7---C12 1.418 (5) C27---H27 0.9300 C8---C9 1.344 (7) N4---O6 1.200 (4) C8---H8 0.9300 N4---O5 1.213 (4) C9---C10 1.391 (7) S2---O1S 1.494 (3) C9---H9 0.9300 S2---C1S 1.755 (4) C10---C11 1.375 (5) S2---C2S 1.781 (5) C10---H10 0.9300 C1S---H1S1 0.9600 C11---C12 1.399 (5) C1S---H1S2 0.9600 C11---C13 1.481 (5) C1S---H1S3 0.9600 C14---C15 1.517 (5) C2S---H2S1 0.9600 C14---H14A 0.9700 C2S---H2S2 0.9600 C14---H14B 0.9700 C2S---H2S3 0.9600 O4---S1---O3 120.25 (16) C20---C15---C14 121.5 (4) O4---S1---N2 108.61 (16) C16---C15---C14 120.0 (4) O3---S1---N2 103.64 (16) C17---C16---C15 121.1 (4) O4---S1---C18 107.94 (17) C17---C16---H16 119.5 O3---S1---C18 109.03 (15) C15---C16---H16 119.5 N2---S1---C18 106.58 (15) C16---C17---C18 119.1 (4) C2---N1---C13 123.8 (3) C16---C17---H17 120.4 C2---N1---C14 118.4 (3) C18---C17---H17 120.4 C13---N1---C14 117.7 (3) C19---C18---C17 120.7 (3) N3---N2---S1 115.3 (2) C19---C18---S1 121.3 (3) N3---N2---H2N 117.1 C17---C18---S1 118.0 (3) S1---N2---H2N 114.1 C18---C19---C20 119.2 (4) C21---N3---N2 115.5 (3) C18---C19---H19 120.4 O1---C2---N1 119.3 (3) C20---C19---H19 120.4 O1---C2---C3 122.8 (3) C15---C20---C19 121.4 (4) N1---C2---C3 117.9 (3) C15---C20---H20 119.3 C4---C3---C12 119.4 (3) C19---C20---H20 119.3 C4---C3---C2 120.4 (3) N3---C21---C22 120.5 (3) C12---C3---C2 120.1 (3) N3---C21---H21 119.7 C3---C4---C5 120.8 (4) C22---C21---H21 119.7 C3---C4---H4 119.6 C23---C22---C27 118.9 (3) C5---C4---H4 119.6 C23---C22---C21 119.9 (3) C6---C5---C4 121.3 (4) C27---C22---C21 121.1 (3) C6---C5---H5 119.4 C24---C23---C22 120.7 (3) C4---C5---H5 119.4 C24---C23---H23 119.6 C5---C6---C7 120.7 (4) C22---C23---H23 119.6 C5---C6---H6 119.6 C25---C24---C23 118.5 (3) C7---C6---H6 119.6 C25---C24---H24 120.7 C8---C7---C6 124.0 (4) C23---C24---H24 120.7 C8---C7---C12 117.6 (4) C24---C25---C26 122.6 (3) C6---C7---C12 118.3 (4) C24---C25---N4 118.9 (3) C9---C8---C7 121.7 (5) C26---C25---N4 118.5 (3) C9---C8---H8 119.1 C25---C26---C27 118.6 (3) C7---C8---H8 119.1 C25---C26---H26 120.7 C8---C9---C10 120.9 (4) C27---C26---H26 120.7 C8---C9---H9 119.6 C26---C27---C22 120.6 (3) C10---C9---H9 119.6 C26---C27---H27 119.7 C11---C10---C9 119.9 (5) C22---C27---H27 119.7 C11---C10---H10 120.1 O6---N4---O5 123.1 (4) C9---C10---H10 120.1 O6---N4---C25 119.1 (4) C10---C11---C12 119.8 (4) O5---N4---C25 117.7 (4) C10---C11---C13 120.2 (4) O1S---S2---C1S 106.61 (19) C12---C11---C13 119.9 (3) O1S---S2---C2S 104.8 (2) C11---C12---C3 120.5 (3) C1S---S2---C2S 97.5 (2) C11---C12---C7 120.1 (3) S2---C1S---H1S1 109.5 C3---C12---C7 119.4 (3) S2---C1S---H1S2 109.5 O2---C13---N1 120.1 (4) H1S1---C1S---H1S2 109.5 O2---C13---C11 122.6 (4) S2---C1S---H1S3 109.5 N1---C13---C11 117.3 (3) H1S1---C1S---H1S3 109.5 N1---C14---C15 111.5 (3) H1S2---C1S---H1S3 109.5 N1---C14---H14A 109.3 S2---C2S---H2S1 109.5 C15---C14---H14A 109.3 S2---C2S---H2S2 109.5 N1---C14---H14B 109.3 H2S1---C2S---H2S2 109.5 C15---C14---H14B 109.3 S2---C2S---H2S3 109.5 H14A---C14---H14B 108.0 H2S1---C2S---H2S3 109.5 C20---C15---C16 118.5 (3) H2S2---C2S---H2S3 109.5 O4---S1---N2---N3 −49.9 (3) C12---C11---C13---O2 176.2 (3) O3---S1---N2---N3 −178.9 (2) C10---C11---C13---N1 176.5 (3) C18---S1---N2---N3 66.1 (3) C12---C11---C13---N1 −4.8 (4) S1---N2---N3---C21 −165.8 (2) C2---N1---C14---C15 −96.1 (4) C13---N1---C2---O1 −175.1 (3) C13---N1---C14---C15 82.0 (4) C14---N1---C2---O1 2.9 (5) N1---C14---C15---C20 86.5 (5) C13---N1---C2---C3 4.6 (5) N1---C14---C15---C16 −92.5 (4) C14---N1---C2---C3 −177.4 (3) C20---C15---C16---C17 −2.3 (5) O1---C2---C3---C4 −5.1 (6) C14---C15---C16---C17 176.8 (3) N1---C2---C3---C4 175.2 (3) C15---C16---C17---C18 −0.1 (5) O1---C2---C3---C12 172.8 (4) C16---C17---C18---C19 2.1 (5) N1---C2---C3---C12 −6.8 (5) C16---C17---C18---S1 −176.1 (3) C12---C3---C4---C5 0.2 (6) O4---S1---C18---C19 5.1 (3) C2---C3---C4---C5 178.1 (4) O3---S1---C18---C19 137.3 (3) C3---C4---C5---C6 −1.7 (7) N2---S1---C18---C19 −111.5 (3) C4---C5---C6---C7 1.1 (7) O4---S1---C18---C17 −176.8 (3) C5---C6---C7---C8 179.7 (4) O3---S1---C18---C17 −44.6 (3) C5---C6---C7---C12 0.8 (5) N2---S1---C18---C17 66.7 (3) C6---C7---C8---C9 −179.1 (4) C17---C18---C19---C20 −1.6 (5) C12---C7---C8---C9 −0.2 (6) S1---C18---C19---C20 176.6 (3) C7---C8---C9---C10 1.2 (7) C16---C15---C20---C19 2.8 (6) C8---C9---C10---C11 −1.2 (7) C14---C15---C20---C19 −176.2 (3) C9---C10---C11---C12 0.2 (5) C18---C19---C20---C15 −0.9 (6) C9---C10---C11---C13 179.0 (4) N2---N3---C21---C22 −179.6 (2) C10---C11---C12---C3 −178.8 (3) N3---C21---C22---C23 −173.8 (3) C13---C11---C12---C3 2.5 (4) N3---C21---C22---C27 3.6 (5) C10---C11---C12---C7 0.7 (5) C27---C22---C23---C24 −2.0 (5) C13---C11---C12---C7 −178.0 (3) C21---C22---C23---C24 175.5 (3) C4---C3---C12---C11 −178.7 (3) C22---C23---C24---C25 0.7 (5) C2---C3---C12---C11 3.3 (5) C23---C24---C25---C26 0.3 (5) C4---C3---C12---C7 1.8 (5) C23---C24---C25---N4 −177.2 (3) C2---C3---C12---C7 −176.2 (3) C24---C25---C26---C27 −0.1 (5) C8---C7---C12---C11 −0.7 (5) N4---C25---C26---C27 177.5 (3) C6---C7---C12---C11 178.2 (3) C25---C26---C27---C22 −1.2 (5) C8---C7---C12---C3 178.8 (3) C23---C22---C27---C26 2.2 (5) C6---C7---C12---C3 −2.3 (5) C21---C22---C27---C26 −175.3 (3) C2---N1---C13---O2 −179.9 (3) C24---C25---N4---O6 −0.8 (5) C14---N1---C13---O2 2.1 (5) C26---C25---N4---O6 −178.5 (4) C2---N1---C13---C11 1.1 (5) C24---C25---N4---O5 177.4 (4) C14---N1---C13---C11 −176.9 (3) C26---C25---N4---O5 −0.3 (5) C10---C11---C13---O2 −2.5 (5) ---------------------- ------------- ----------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3453 .table-wrap} ------------------------------------------------------------ Cg is the centroid of the *p*-nitrophenyl (C22--C27) ring. ------------------------------------------------------------ ::: ::: {#d1e3460 .table-wrap} ----------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N2---H2N···O1S 0.80 1.99 2.764 (4) 163 C8---H8···Cg^i^ 0.93 2.90 3.799 (6) 162 ----------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+2, −*y*+2, −*z*+2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) *Cg* is the centroid of the *p*-nitro­phenyl (C22--C27) ring. ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------ --------- ------- ----------- ------------- N2---H2*N*⋯O1*S* 0.80 1.99 2.764 (4) 163 C8---H8⋯*Cg*^i^ 0.93 2.90 3.799 (6) 162 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.459228

2011-2-12

PMC3051949

Related literature {#sec1} ================== For the applications of complexes with bipyridine and its derivatives in catalysis and visible-light-driven water oxidation, see: Morrow & Trogler (1989[@bb2]) and Duan *et al.* (2010[@bb1]), respectively. Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Cu(NO~3~)(C~10~H~8~N~2~)~2~\]ClO~4~*M* *~r~* = 537.38Triclinic,*a* = 7.5882 (15) Å*b* = 10.473 (2) Å*c* = 14.041 (3) Åα = 76.15 (3)°β = 81.46 (4)°γ = 78.86 (3)°*V* = 1056.9 (4) Å^3^*Z* = 2Mo *K*α radiationμ = 1.22 mm^−1^*T* = 295 K0.24 × 0.20 × 0.18 mm ### Data collection {#sec2.1.2} Rigaku Saturn 724 diffractometerAbsorption correction: multi-scan (*CrystalClear*; Rigaku, 2007[@bb3]) *T* ~min~ = 0.747, *T* ~max~ = 0.80310121 measured reflections4037 independent reflections3579 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.019 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.034*wR*(*F* ^2^) = 0.088*S* = 1.054037 reflections351 parametersH-atom parameters constrainedΔρ~max~ = 0.31 e Å^−3^Δρ~min~ = −0.48 e Å^−3^ {#d5e518} Data collection: *CrystalClear* (Rigaku, 2007[@bb3]); cell refinement: *CrystalClear*; data reduction: *CrystalClear*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb4]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb4]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb4]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811002571/kp2303sup1.cif](http://dx.doi.org/10.1107/S1600536811002571/kp2303sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811002571/kp2303Isup2.hkl](http://dx.doi.org/10.1107/S1600536811002571/kp2303Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?kp2303&file=kp2303sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?kp2303sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?kp2303&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [KP2303](http://scripts.iucr.org/cgi-bin/sendsup?kp2303)). We thank the Social Development Foundation of Jiangsu Province of China (BS2006038) and the Industry High Technology Foundation of Jiangsu (BG2007025). Comment ======= Complexes with bipyridine and its derivatives have been extensively studied because of their potential applications in catalysis (Morrow & Trogler, 1989) and visible light driven water oxidation (Duan *et al.*, 2010). Herein we report the synthesis and structure of the title copper complex with 2, 2\'-bipyridine. The structure of the title complex (Fig. 1)consists of a discrete cation \[Cu(bipy)~2~(NO~3~)\]^+^ and an uncoordinated ClO~4~^-^ anion which is in disorder. The Cu(II) atom is five coordinated by four nitrogen atoms from two bipy ligands and one oxygen atom from one nitrate anion, exhibiting a distorted square pyramidal coordination with the oxygen atom in the axial position (Fig. 1 and Table 1). The uncoordinated perchlorate anion displays the expected tetrahedral geometry. There are weak intermolecular C---H···O hydrogen bonds in the crystal structure(C3---H3···O5^i^, C7---H7···O4^ii^ and C13---H13···O7^iii^; Table 2). Crystal packing is stabilised by the C---H···O hydrogen bonds and π-π interactions between two parallel bipy rings \[centroid (N1, C1---C5)···centroid (N1, C1---C5)^iv^ = 3.77 Å; centroid (N2, C6---C10) ···centroid (N2, C6---C10)^v^= 3.70 Å; centroid (N3, C16---C20)···centroid (N4, C11---C15)^vi^ = 3.75 Å; symmetry codes: (iv)-*x*, 1 - *y*, -*z*; (v) 1 - *x*, -*y*, -*z*; (vi) -*x*, -*y*, 1 - *z*)\](Fig. 2). Experimental {#experimental} ============ 2, 2\'-bipyridine (31.3 mg, 0.2 mmol), Cu(NO~3~)~2~.3H~2~O(42 mg, 0.2 mmol), NaClO~4~ (28 mg, 0.2 mmol), acetone (10 mL) and methanol (6 mL) were stirred for 8 h at 313 K. The solution was then filtered, evaporated in the air and prismatic blue crystals were formed after 2 days (yieled 78%). Refinement {#refinement} ========== All the H atoms were placed in calculated positions and refined using a riding model, with *U*~iso~ (H) =1.2*U*~eq~(C, N) and C--H =0.93 and N--H=0.86 Å. The disorder of \[NO~3~\]^-^ with two locations of O1, O2, and O3 led in the refinement to 1:1 ratio in occupancy for each oxygen atom. However, a slight disorder of \[ClO~4~\]^-^ cannot be described geometrically. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### View of the title complex showing the labeling of the non-H atoms and 30% probability displacement ellipsoids. H atoms are shown as spheres of arbitrary radii. Disorders of the coordinated \[NO3\]- and uncoordinated \[ClO4\]-anions are not shown. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Three dimensional architecture constructed by intermolecular C---H···O hydrogen bonding (dashed lines) and π-π interactions. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e221 .table-wrap} --------------------------------------- --------------------------------------- \[Cu(NO~3~)(C~10~H~8~N~2~)~2~\]ClO~4~ *Z* = 2 *M~r~* = 537.38 *F*(000) = 546 Triclinic, *P*1 *D*~x~ = 1.689 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 7.5882 (15) Å Cell parameters from 4693 reflections *b* = 10.473 (2) Å θ = 3.1--29.0° *c* = 14.041 (3) Å µ = 1.22 mm^−1^ α = 76.15 (3)° *T* = 295 K β = 81.46 (4)° Prism, blue γ = 78.86 (3)° 0.24 × 0.20 × 0.18 mm *V* = 1056.9 (4) Å^3^ --------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e364 .table-wrap} ------------------------------------------------------------------ -------------------------------------- Rigaku Saturn 724 diffractometer 4037 independent reflections Radiation source: fine-focus sealed tube 3579 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.019 ω scans θ~max~ = 26.0°, θ~min~ = 3.1° Absorption correction: multi-scan (*CrystalClear*; Rigaku, 2007) *h* = −8→9 *T*~min~ = 0.747, *T*~max~ = 0.803 *k* = −12→12 10121 measured reflections *l* = −17→17 ------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e478 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.034 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.088 H-atom parameters constrained *S* = 1.05 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0453*P*)^2^ + 0.3686*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4037 reflections (Δ/σ)~max~ \< 0.001 351 parameters Δρ~max~ = 0.31 e Å^−3^ 0 restraints Δρ~min~ = −0.48 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e635 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e734 .table-wrap} ------ ------------- -------------- --------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) Cu1 0.13510 (4) 0.14256 (3) 0.229930 (18) 0.04365 (11) N1 −0.0008 (3) 0.26435 (18) 0.12391 (13) 0.0413 (4) C1 −0.1751 (3) 0.3189 (2) 0.13465 (18) 0.0460 (5) H1 −0.2386 0.3047 0.1972 0.062 (8)\* O1 −0.144 (6) 0.025 (3) 0.2791 (18) 0.072 (5) 0.42 (7) O1\' −0.092 (3) 0.0253 (18) 0.2643 (12) 0.054 (3) 0.58 (7) Cl1 0.40225 (9) 0.48718 (7) 0.29287 (4) 0.05741 (18) N2 0.3386 (2) 0.15087 (18) 0.11680 (13) 0.0405 (4) C2 −0.2638 (4) 0.3950 (2) 0.05677 (19) 0.0526 (6) H2 −0.3832 0.4358 0.0670 0.074 (9)\* O2 −0.165 (6) −0.127 (4) 0.212 (3) 0.093 (7) 0.42 (7) O2\' −0.171 (4) −0.151 (2) 0.2322 (14) 0.071 (3) 0.58 (7) N3 0.0518 (2) 0.23533 (17) 0.34604 (13) 0.0377 (4) C3 −0.1733 (4) 0.4104 (3) −0.03679 (19) 0.0561 (7) H3 −0.2314 0.4605 −0.0909 0.063 (8)\* O3 0.070 (2) −0.033 (3) 0.1678 (19) 0.063 (5) 0.42 (7) O3\' 0.047 (3) −0.0583 (17) 0.1459 (15) 0.082 (3) 0.58 (7) N4 0.2614 (2) 0.00723 (18) 0.33384 (13) 0.0412 (4) C4 0.0043 (4) 0.3504 (2) −0.04923 (17) 0.0514 (6) H4 0.0664 0.3571 −0.1121 0.070 (9)\* O4 0.5696 (3) 0.5366 (3) 0.26537 (19) 0.0918 (7) N5 −0.0741 (3) −0.0584 (2) 0.21550 (15) 0.0465 (5) C5 0.0898 (3) 0.2800 (2) 0.03288 (15) 0.0406 (5) O5 0.2613 (4) 0.5915 (3) 0.25784 (17) 0.1054 (9) C6 0.2824 (3) 0.2197 (2) 0.02926 (15) 0.0398 (5) O6 0.4111 (4) 0.3772 (3) 0.2508 (2) 0.1198 (11) C7 0.4017 (4) 0.2356 (2) −0.05599 (17) 0.0496 (6) H7 0.3614 0.2841 −0.1156 0.055 (7)\* O7 0.3702 (4) 0.4516 (2) 0.39655 (15) 0.0995 (9) C8 0.5801 (4) 0.1788 (3) −0.05135 (19) 0.0534 (6) H8 0.6618 0.1882 −0.1079 0.054 (7)\* C9 0.6372 (3) 0.1078 (3) 0.03760 (19) 0.0516 (6) H9 0.7572 0.0679 0.0420 0.075 (9)\* C10 0.5128 (3) 0.0971 (2) 0.11998 (18) 0.0476 (5) H10 0.5518 0.0505 0.1804 0.053 (7)\* C11 0.3604 (3) −0.1094 (2) 0.32214 (18) 0.0510 (6) H11 0.3782 −0.1292 0.2599 0.062 (8)\* C12 0.4372 (3) −0.2012 (2) 0.3986 (2) 0.0541 (6) H12 0.5064 −0.2812 0.3883 0.065 (8)\* C13 0.4095 (3) −0.1719 (2) 0.4905 (2) 0.0532 (6) H13 0.4616 −0.2316 0.5432 0.059 (8)\* C14 0.3040 (3) −0.0538 (2) 0.50390 (17) 0.0451 (5) H14 0.2812 −0.0342 0.5662 0.052 (7)\* C15 0.2321 (3) 0.0353 (2) 0.42427 (15) 0.0363 (5) C16 0.1165 (3) 0.1643 (2) 0.43096 (15) 0.0356 (4) C17 0.0741 (3) 0.2098 (2) 0.51762 (16) 0.0452 (5) H17 0.1225 0.1607 0.5750 0.055 (7)\* C18 −0.0408 (4) 0.3290 (3) 0.51792 (19) 0.0541 (6) H18 −0.0735 0.3599 0.5759 0.061 (8)\* C19 −0.1059 (3) 0.4013 (3) 0.4320 (2) 0.0541 (6) H19 −0.1838 0.4819 0.4308 0.062 (8)\* C20 −0.0546 (3) 0.3528 (2) 0.34734 (18) 0.0478 (6) H20 −0.0957 0.4039 0.2886 0.051 (7)\* ------ ------------- -------------- --------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1495 .table-wrap} ------ -------------- -------------- -------------- -------------- -------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cu1 0.04732 (18) 0.04701 (18) 0.02684 (15) 0.00769 (13) 0.00054 (11) −0.00424 (11) N1 0.0475 (10) 0.0413 (10) 0.0313 (9) −0.0004 (8) −0.0030 (8) −0.0065 (8) C1 0.0471 (13) 0.0464 (13) 0.0430 (13) −0.0012 (11) −0.0041 (10) −0.0124 (10) O1 0.103 (12) 0.060 (5) 0.036 (5) 0.009 (7) 0.021 (7) −0.012 (4) O1\' 0.068 (5) 0.060 (3) 0.031 (4) −0.014 (4) 0.014 (3) −0.012 (3) Cl1 0.0584 (4) 0.0596 (4) 0.0441 (3) 0.0051 (3) 0.0029 (3) −0.0088 (3) N2 0.0449 (10) 0.0414 (10) 0.0325 (9) −0.0048 (8) 0.0011 (8) −0.0076 (8) C2 0.0539 (15) 0.0484 (14) 0.0573 (15) 0.0009 (12) −0.0205 (12) −0.0135 (12) O2 0.088 (11) 0.054 (8) 0.136 (17) −0.029 (5) −0.030 (12) 0.004 (9) O2\' 0.079 (5) 0.065 (8) 0.074 (5) −0.037 (6) −0.002 (4) −0.008 (5) N3 0.0402 (9) 0.0369 (9) 0.0334 (9) −0.0021 (8) −0.0014 (7) −0.0076 (7) C3 0.0705 (17) 0.0509 (15) 0.0477 (14) −0.0035 (13) −0.0271 (13) −0.0050 (11) O3 0.047 (4) 0.065 (7) 0.064 (7) −0.001 (4) 0.004 (4) −0.006 (4) O3\' 0.065 (4) 0.099 (5) 0.084 (5) −0.022 (4) 0.030 (4) −0.042 (5) N4 0.0443 (10) 0.0405 (10) 0.0328 (9) 0.0020 (8) −0.0006 (8) −0.0059 (8) C4 0.0746 (17) 0.0465 (13) 0.0325 (12) −0.0088 (12) −0.0098 (12) −0.0059 (10) O4 0.0823 (16) 0.0942 (17) 0.0956 (17) −0.0216 (13) 0.0108 (13) −0.0207 (14) N5 0.0438 (12) 0.0518 (13) 0.0397 (11) −0.0028 (11) −0.0084 (9) −0.0034 (10) C5 0.0555 (13) 0.0339 (11) 0.0321 (11) −0.0064 (10) −0.0045 (10) −0.0076 (9) O5 0.1019 (18) 0.125 (2) 0.0643 (14) 0.0473 (16) −0.0261 (13) −0.0138 (14) C6 0.0537 (13) 0.0335 (11) 0.0323 (11) −0.0077 (10) 0.0013 (10) −0.0106 (9) O6 0.1064 (19) 0.111 (2) 0.157 (3) −0.0352 (17) 0.0496 (19) −0.084 (2) C7 0.0662 (16) 0.0484 (13) 0.0329 (12) −0.0125 (12) 0.0050 (11) −0.0104 (10) O7 0.1140 (19) 0.0939 (16) 0.0472 (11) 0.0367 (14) 0.0124 (12) 0.0126 (11) C8 0.0591 (15) 0.0578 (15) 0.0456 (14) −0.0197 (13) 0.0178 (12) −0.0221 (12) C9 0.0467 (14) 0.0554 (15) 0.0536 (15) −0.0114 (12) 0.0077 (11) −0.0192 (12) C10 0.0461 (13) 0.0499 (13) 0.0447 (13) −0.0046 (11) −0.0009 (11) −0.0112 (11) C11 0.0565 (14) 0.0455 (13) 0.0459 (14) 0.0046 (11) −0.0013 (11) −0.0128 (11) C12 0.0505 (14) 0.0396 (13) 0.0657 (17) 0.0041 (11) −0.0075 (12) −0.0071 (11) C13 0.0502 (14) 0.0467 (14) 0.0559 (15) −0.0061 (11) −0.0171 (12) 0.0076 (11) C14 0.0453 (13) 0.0498 (13) 0.0380 (12) −0.0101 (11) −0.0084 (10) −0.0013 (10) C15 0.0344 (10) 0.0401 (11) 0.0330 (11) −0.0086 (9) −0.0013 (9) −0.0047 (9) C16 0.0357 (11) 0.0393 (11) 0.0310 (10) −0.0102 (9) 0.0017 (8) −0.0060 (8) C17 0.0505 (13) 0.0527 (13) 0.0337 (12) −0.0123 (11) 0.0009 (10) −0.0121 (10) C18 0.0565 (15) 0.0630 (16) 0.0495 (14) −0.0128 (13) 0.0057 (12) −0.0298 (13) C19 0.0524 (14) 0.0462 (14) 0.0661 (17) 0.0012 (12) −0.0043 (12) −0.0254 (12) C20 0.0515 (13) 0.0412 (12) 0.0484 (13) 0.0005 (11) −0.0066 (11) −0.0106 (10) ------ -------------- -------------- -------------- -------------- -------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2258 .table-wrap} ------------------------ -------------- ------------------------ -------------- Cu1---N1 1.986 (2) N4---C11 1.338 (3) Cu1---N4 1.9890 (19) N4---C15 1.348 (3) Cu1---N2 2.0426 (19) C4---C5 1.387 (3) Cu1---N3 2.0534 (18) C4---H4 0.9301 Cu1---O1\' 2.233 (15) C5---C6 1.474 (3) Cu1---O3 2.38 (4) C6---C7 1.386 (3) Cu1---O1 2.57 (5) C7---C8 1.374 (4) Cu1---O3\' 2.87 (3) C7---H7 0.9301 N1---C1 1.338 (3) C8---C9 1.375 (4) N1---C5 1.347 (3) C8---H8 0.9300 C1---C2 1.370 (3) C9---C10 1.377 (3) C1---H1 0.9299 C9---H9 0.9300 O1---N5 1.38 (2) C10---H10 0.9299 O1\'---N5 1.213 (19) C11---C12 1.375 (3) Cl1---O6 1.402 (3) C11---H11 0.9300 Cl1---O7 1.410 (2) C12---C13 1.374 (4) Cl1---O5 1.424 (2) C12---H12 0.9300 Cl1---O4 1.429 (2) C13---C14 1.375 (4) N2---C10 1.336 (3) C13---H13 0.9300 N2---C6 1.351 (3) C14---C15 1.380 (3) C2---C3 1.377 (4) C14---H14 0.9300 C2---H2 0.9301 C15---C16 1.477 (3) O2---N5 1.10 (4) C16---C17 1.383 (3) O2\'---N5 1.28 (2) C17---C18 1.378 (4) N3---C20 1.337 (3) C17---H17 0.9300 N3---C16 1.350 (3) C18---C19 1.367 (4) C3---C4 1.378 (4) C18---H18 0.9300 C3---H3 0.9299 C19---C20 1.378 (3) O3---N5 1.231 (16) C19---H19 0.9300 O3\'---N5 1.238 (13) C20---H20 0.9300 N1---Cu1---N4 174.76 (8) C5---C4---H4 120.3 N1---Cu1---N2 81.03 (8) O2---N5---O1\' 130.3 (17) N4---Cu1---N2 99.78 (8) O2---N5---O3 133.1 (18) N1---Cu1---N3 101.94 (8) O1\'---N5---O3 96.5 (13) N4---Cu1---N3 81.12 (7) O2---N5---O3\' 109.6 (16) N2---Cu1---N3 135.94 (7) O1\'---N5---O3\' 119.0 (9) N1---Cu1---O1\' 87.4 (4) O1\'---N5---O2\' 124.5 (11) N4---Cu1---O1\' 88.2 (4) O3---N5---O2\' 138 (2) N2---Cu1---O1\' 130.0 (5) O3\'---N5---O2\' 116.5 (15) N3---Cu1---O1\' 94.0 (5) O2---N5---O1 113 (2) N1---Cu1---O3 85.8 (4) O3---N5---O1 113.3 (9) N4---Cu1---O3 89.1 (4) O3\'---N5---O1 135.0 (10) N2---Cu1---O3 84.1 (4) O2\'---N5---O1 108 (2) N3---Cu1---O3 139.8 (4) N1---C5---C4 120.9 (2) O1\'---Cu1---O3 46.5 (6) N1---C5---C6 114.93 (19) N1---Cu1---O1 86.4 (5) C4---C5---C6 124.1 (2) N4---Cu1---O1 89.5 (5) N2---C6---C7 121.3 (2) N2---Cu1---O1 135.3 (5) N2---C6---C5 115.16 (18) N3---Cu1---O1 88.6 (5) C7---C6---C5 123.5 (2) O1\'---Cu1---O1 5.8 (7) C8---C7---C6 119.2 (2) O3---Cu1---O1 52.1 (6) C8---C7---H7 120.4 N1---Cu1---O3\' 82.6 (3) C6---C7---H7 120.4 N4---Cu1---O3\' 92.3 (3) C7---C8---C9 119.5 (2) N2---Cu1---O3\' 83.3 (2) C7---C8---H8 120.3 N3---Cu1---O3\' 140.7 (3) C9---C8---H8 120.2 O1\'---Cu1---O3\' 46.9 (6) C8---C9---C10 118.6 (2) O3---Cu1---O3\' 3.3 (5) C8---C9---H9 120.7 O1---Cu1---O3\' 52.5 (6) C10---C9---H9 120.7 C1---N1---C5 119.1 (2) N2---C10---C9 122.8 (2) C1---N1---Cu1 125.44 (16) N2---C10---H10 118.6 C5---N1---Cu1 115.08 (15) C9---C10---H10 118.6 N1---C1---C2 122.4 (2) N4---C11---C12 122.5 (2) N1---C1---H1 118.9 N4---C11---H11 118.8 C2---C1---H1 118.8 C12---C11---H11 118.8 N5---O1---Cu1 90 (2) C13---C12---C11 118.5 (2) N5---O1\'---Cu1 113.1 (13) C13---C12---H12 120.8 O6---Cl1---O7 111.08 (19) C11---C12---H12 120.7 O6---Cl1---O5 111.0 (2) C12---C13---C14 119.5 (2) O7---Cl1---O5 108.19 (14) C12---C13---H13 120.2 O6---Cl1---O4 108.65 (16) C14---C13---H13 120.3 O7---Cl1---O4 109.62 (17) C13---C14---C15 119.5 (2) O5---Cl1---O4 108.20 (18) C13---C14---H14 120.2 C10---N2---C6 118.6 (2) C15---C14---H14 120.2 C10---N2---Cu1 128.24 (16) N4---C15---C14 120.9 (2) C6---N2---Cu1 113.12 (15) N4---C15---C16 115.32 (18) C1---C2---C3 119.0 (2) C14---C15---C16 123.7 (2) C1---C2---H2 120.5 N3---C16---C17 121.7 (2) C3---C2---H2 120.5 N3---C16---C15 115.19 (18) C20---N3---C16 118.09 (19) C17---C16---C15 123.1 (2) C20---N3---Cu1 128.80 (16) C18---C17---C16 119.2 (2) C16---N3---Cu1 113.10 (14) C18---C17---H17 120.3 C2---C3---C4 119.1 (2) C16---C17---H17 120.5 C2---C3---H3 120.5 C19---C18---C17 119.3 (2) C4---C3---H3 120.4 C19---C18---H18 120.4 N5---O3---Cu1 104 (2) C17---C18---H18 120.4 N5---O3\'---Cu1 80.4 (14) C18---C19---C20 118.9 (2) C11---N4---C15 119.03 (19) C18---C19---H19 120.5 C11---N4---Cu1 125.60 (16) C20---C19---H19 120.6 C15---N4---Cu1 115.23 (14) N3---C20---C19 122.8 (2) C3---C4---C5 119.4 (2) N3---C20---H20 118.6 C3---C4---H4 120.3 C19---C20---H20 118.6 N2---Cu1---N1---C1 −179.4 (2) O1---Cu1---N4---C11 88.5 (5) N3---Cu1---N1---C1 −44.1 (2) O3\'---Cu1---N4---C11 36.1 (3) O1\'---Cu1---N1---C1 49.5 (6) N2---Cu1---N4---C15 136.89 (16) O3---Cu1---N1---C1 96.0 (4) N3---Cu1---N4---C15 1.56 (15) O1---Cu1---N1---C1 43.7 (5) O1\'---Cu1---N4---C15 −92.8 (6) O3\'---Cu1---N1---C1 96.3 (3) O3---Cu1---N4---C15 −139.3 (4) N2---Cu1---N1---C5 7.62 (15) O1---Cu1---N4---C15 −87.1 (5) N3---Cu1---N1---C5 142.88 (15) O3\'---Cu1---N4---C15 −139.5 (3) O1\'---Cu1---N1---C5 −123.6 (6) C2---C3---C4---C5 −2.3 (4) O3---Cu1---N1---C5 −77.0 (4) Cu1---O1\'---N5---O2 −176 (3) O1---Cu1---N1---C5 −129.3 (5) Cu1---O1\'---N5---O3 −0.6 (10) O3\'---Cu1---N1---C5 −76.7 (3) Cu1---O1\'---N5---O3\' −9.5 (14) C5---N1---C1---C2 −2.7 (3) Cu1---O1\'---N5---O2\' 168.7 (15) Cu1---N1---C1---C2 −175.45 (18) Cu1---O1\'---N5---O1 −172 (6) N1---Cu1---O1---N5 89.4 (10) Cu1---O3---N5---O2 176 (3) N4---Cu1---O1---N5 −87.4 (10) Cu1---O3---N5---O1\' 0.6 (9) N2---Cu1---O1---N5 16.0 (15) Cu1---O3---N5---O3\' 161 (3) N3---Cu1---O1---N5 −168.6 (10) Cu1---O3---N5---O2\' −166.3 (16) O1\'---Cu1---O1---N5 −10 (8) Cu1---O3---N5---O1 3.4 (13) O3---Cu1---O1---N5 1.8 (7) Cu1---O3\'---N5---O2 176 (2) O3\'---Cu1---O1---N5 5.9 (7) Cu1---O3\'---N5---O1\' 6.9 (10) N1---Cu1---O1\'---N5 87.2 (10) Cu1---O3\'---N5---O3 −15 (3) N4---Cu1---O1\'---N5 −90.1 (10) Cu1---O3\'---N5---O2\' −171.4 (13) N2---Cu1---O1\'---N5 11.2 (14) Cu1---O3\'---N5---O1 14.1 (15) N3---Cu1---O1\'---N5 −171.0 (10) Cu1---O1---N5---O2 −177 (2) O3---Cu1---O1\'---N5 0.4 (7) Cu1---O1---N5---O1\' 7(5) O1---Cu1---O1\'---N5 167 (10) Cu1---O1---N5---O3 −3.1 (12) O3\'---Cu1---O1\'---N5 4.9 (7) Cu1---O1---N5---O3\' −15.6 (17) N1---Cu1---N2---C10 175.1 (2) Cu1---O1---N5---O2\' 169.7 (13) N4---Cu1---N2---C10 −10.2 (2) C1---N1---C5---C4 −0.6 (3) N3---Cu1---N2---C10 77.1 (2) Cu1---N1---C5---C4 172.88 (17) O1\'---Cu1---N2---C10 −106.0 (6) C1---N1---C5---C6 178.16 (19) O3---Cu1---N2---C10 −98.2 (4) Cu1---N1---C5---C6 −8.3 (2) O1---Cu1---N2---C10 −109.4 (8) C3---C4---C5---N1 3.1 (3) O3\'---Cu1---N2---C10 −101.4 (4) C3---C4---C5---C6 −175.6 (2) N1---Cu1---N2---C6 −5.48 (15) C10---N2---C6---C7 −0.3 (3) N4---Cu1---N2---C6 169.28 (14) Cu1---N2---C6---C7 −179.83 (17) N3---Cu1---N2---C6 −103.42 (16) C10---N2---C6---C5 −177.82 (19) O1\'---Cu1---N2---C6 73.4 (6) Cu1---N2---C6---C5 2.7 (2) O3---Cu1---N2---C6 81.2 (4) N1---C5---C6---N2 3.6 (3) O1---Cu1---N2---C6 70.1 (8) C4---C5---C6---N2 −177.6 (2) O3\'---Cu1---N2---C6 78.1 (4) N1---C5---C6---C7 −173.8 (2) N1---C1---C2---C3 3.4 (4) C4---C5---C6---C7 4.9 (3) N1---Cu1---N3---C20 −4.9 (2) N2---C6---C7---C8 0.7 (3) N4---Cu1---N3---C20 179.4 (2) C5---C6---C7---C8 178.0 (2) N2---Cu1---N3---C20 84.5 (2) C6---C7---C8---C9 −0.2 (4) O1\'---Cu1---N3---C20 −93.1 (5) C7---C8---C9---C10 −0.6 (4) O3---Cu1---N3---C20 −102.7 (6) C6---N2---C10---C9 −0.6 (3) O1---Cu1---N3---C20 −90.9 (6) Cu1---N2---C10---C9 178.80 (17) O3\'---Cu1---N3---C20 −97.8 (6) C8---C9---C10---N2 1.1 (4) N1---Cu1---N3---C16 175.01 (14) C15---N4---C11---C12 −1.4 (4) N4---Cu1---N3---C16 −0.67 (14) Cu1---N4---C11---C12 −176.91 (19) N2---Cu1---N3---C16 −95.60 (16) N4---C11---C12---C13 0.6 (4) O1\'---Cu1---N3---C16 86.8 (5) C11---C12---C13---C14 1.1 (4) O3---Cu1---N3---C16 77.2 (5) C12---C13---C14---C15 −2.0 (4) O1---Cu1---N3---C16 89.0 (6) C11---N4---C15---C14 0.5 (3) O3\'---Cu1---N3---C16 82.1 (6) Cu1---N4---C15---C14 176.48 (16) C1---C2---C3---C4 −0.8 (4) C11---N4---C15---C16 −178.1 (2) N1---Cu1---O3---N5 −90.8 (8) Cu1---N4---C15---C16 −2.1 (2) N4---Cu1---O3---N5 87.9 (8) C13---C14---C15---N4 1.1 (3) N2---Cu1---O3---N5 −172.2 (8) C13---C14---C15---C16 179.6 (2) N3---Cu1---O3---N5 12.8 (12) C20---N3---C16---C17 0.5 (3) O1\'---Cu1---O3---N5 −0.4 (7) Cu1---N3---C16---C17 −179.47 (16) O1---Cu1---O3---N5 −2.1 (8) C20---N3---C16---C15 179.68 (19) O3\'---Cu1---O3---N5 −96 (11) Cu1---N3---C16---C15 −0.3 (2) N1---Cu1---O3\'---N5 −97.8 (7) N4---C15---C16---N3 1.6 (3) N4---Cu1---O3\'---N5 80.8 (7) C14---C15---C16---N3 −177.00 (19) N2---Cu1---O3\'---N5 −179.6 (8) N4---C15---C16---C17 −179.2 (2) N3---Cu1---O3\'---N5 2.0 (11) C14---C15---C16---C17 2.2 (3) O1\'---Cu1---O3\'---N5 −4.5 (7) N3---C16---C17---C18 1.7 (3) O3---Cu1---O3\'---N5 77 (11) C15---C16---C17---C18 −177.4 (2) O1---Cu1---O3\'---N5 −6.7 (8) C16---C17---C18---C19 −1.9 (4) N2---Cu1---N4---C11 −47.5 (2) C17---C18---C19---C20 −0.1 (4) N3---Cu1---N4---C11 177.2 (2) C16---N3---C20---C19 −2.6 (3) O1\'---Cu1---N4---C11 82.8 (6) Cu1---N3---C20---C19 177.36 (18) O3---Cu1---N4---C11 36.4 (4) C18---C19---C20---N3 2.4 (4) ------------------------ -------------- ------------------------ -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3956 .table-wrap} --------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C3---H3···O5^i^ 0.93 2.58 3.276 (3) 132 C7---H7···O4^ii^ 0.93 2.53 3.322 (4) 144 C13---H13···O7^iii^ 0.93 2.43 3.249 (3) 147 --------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*, −*y*+1, −*z*; (ii) −*x*+1, −*y*+1, −*z*; (iii) −*x*+1, −*y*, −*z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Selected bond lengths (Å) ::: ---------- ------------- Cu1---N1 1.986 (2) Cu1---N4 1.9890 (19) Cu1---N2 2.0426 (19) Cu1---N3 2.0534 (18) Cu1---O3 2.38 (4) ---------- ------------- ::: ::: {#table2 .table-wrap} Table 2 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------- --------- ------- ----------- ------------- C3---H3⋯O5^i^ 0.93 2.58 3.276 (3) 132 C7---H7⋯O4^ii^ 0.93 2.53 3.322 (4) 144 C13---H13⋯O7^iii^ 0.93 2.43 3.249 (3) 147 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.467022

2011-2-05

PMC3051950

Related literature {#sec1} ================== For general background to Schiff bases, see: Hadjoudis *et al.* (1987[@bb7]); Hodnett & Dunn (1970[@bb8]); Misra *et al.* (1981[@bb11]); Agarwal *et al.* (1983[@bb1]); Varma *et al.* (1986[@bb18]); Singh & Dash (1988[@bb16]); Pandeya *et al.* (1999[@bb14]); El-Masry *et al.* (2000[@bb4]); Cohen *et al.* (1964[@bb3]); Moustakali-Mavridis *et al.* (1978[@bb12]) Kaitner & Pavlovic (1996[@bb10]); Yıldız *et al.* (1998[@bb19]). For related structures, see: Odabaşoğlu *et al.* (2003[@bb13]); Hökelek *et al.* (2000[@bb9]); Bingöl Alpaslan *et al.* (2010[@bb2]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~19~H~24~N~2~O~2~*M* *~r~* = 312.40Monoclinic,*a* = 29.4936 (13) Å*b* = 7.8546 (2) Å*c* = 16.7146 (7) Åβ = 115.093 (3)°*V* = 3506.7 (2) Å^3^*Z* = 8Mo *K*α radiationμ = 0.08 mm^−1^*T* = 296 K0.76 × 0.59 × 0.28 mm ### Data collection {#sec2.1.2} Stoe IPDS 2 diffractometerAbsorption correction: integration (*X-RED32*; Stoe & Cie, 2002[@bb17]) *T* ~min~ = 0.944, *T* ~max~ = 0.97922701 measured reflections3625 independent reflections2383 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.073 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.080*wR*(*F* ^2^) = 0.260*S* = 1.103625 reflections208 parameters4 restraintsH-atom parameters constrainedΔρ~max~ = 0.56 e Å^−3^Δρ~min~ = −0.28 e Å^−3^ {#d5e547} Data collection: *X-AREA* (Stoe & Cie, 2002[@bb17]); cell refinement: *X-AREA*; data reduction: *X-RED* (Stoe & Cie, 2002[@bb17]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb15]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb15]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb5]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb6]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004533/fj2390sup1.cif](http://dx.doi.org/10.1107/S1600536811004533/fj2390sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004533/fj2390Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004533/fj2390Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?fj2390&file=fj2390sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?fj2390sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?fj2390&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [FJ2390](http://scripts.iucr.org/cgi-bin/sendsup?fj2390)). The authors wish to acknowledge the Faculty of Arts and Sciences, Ondokuz Mayıs University, Turkey, for the use of the Stoe IPDS 2 diffractometer (purchased under grant No. F279 of the University Research Fund). Comment ======= Schiff bases are used as substrates in the preparation of number of industrial and biologically active compounds *via* ring closure, cycloaddition and replacement reactions. Some Schiff base derivatives are also known to have biological activities such as antimicrobial (El-Masry *et al.*, 2000; Pandeya *et al.*, 1999); antifungal (Singh & Dash 1988; Varma *et al.*, 1986) and antitumor (Hodnett & Dunn 1970; Misra *et al.*, 1981; Agarwal *et al.*, 1983). There are two characteristic properties of Schiff bases, *viz*. photochromism and thermochromism (Cohen *et al.*, 1964; Moustakali-Mavridis *et al.*, 1978). Schiff bases display two possible tautomeric form, namely the phenol-imine (O---H···N) and keto-amine (N---H···O) forms. In the solid state, the keto-amine tautomer has been found in naphthaldimines (Hökelek *et al.*, 2000; Odabaşoğlu *et al.*, 2003), while the phenol-imine form exists in salicylaldimine Schiff bases (Kaitner & Pavlovic, 1996; Yıldız *et al.*, 1998). In the title compound, (I), the phenol-imine tautomer is favoured over the keto-amine form, and there is an intramolecular O---H···N hydrogen bond (Fig. 1 and Table 1). It is known that Schiff bases may exhibit thermochromism or photochromism, depending on the planarity or non-planarity of the molecule, respectively. This planarity of the molecule allows the H atom to be transferred through the hydrogen bond in the ground state with a low energy requirement (Hadjoudis *et al.*, 1987). Therefore, one can expect thermochromic properties in (I) caused by planarity of the molecule: the dihedral angle between rings A (C1---C6) and B (C8---C13) is 17.33 (16)° (Fig. 1). In (I), the C8---C7, C4---N1, C7=N1 and O1---C13 bond lengths of 1.441 (4), 1.417 (3), 1.263 (3) and 1.338 (3) Å, respectively are in good agreement with those observed in (*E*)-2\[(3-Fluoropheng)iminomethy\]-4-(trifluoromethoxy)phenol \[1.447 (4), 1.420 (3), 1.268 (3) and 1.343 (3) Å, Bingöl Alpaslan *et al.*, 2010\]. The C5---C4---N1=C7 and N1=C7---C8---C13 torsion angles are -19.0 (5)° and 1.2 (5)°, respectively. In crystal packing, the interactions \[C2---H2···*Cg*1(*x*, 1 - *y*, *z* - 1/2)\] and \[C17---H17A···*Cg*1(1/2 - *x*, 1/2 + *y*, 3/2 - *z*)\] are effective (Table 1 and Fig. 2.) Experimental {#experimental} ============ The title compound was prepared by refluxing a mixture of a solution containing 5-(diethylamino)-2-hydroxybenzaldehyde (0.5 g, 2.59 mmol) in 20 ml e thanol and a solution containing 4-ethoxyaniline (0.4 g, 2.59 mmol) in 20 ml e thanol. The reaction mixture was stirred for 1 h under reflux. The crystals of (*E*)-5-(diethylamino)-2-\[(4-ethoxyphenylimino)methyl\]phenol suitable for *x*-ray analysis were obtained by slow evaporation from ethyl alcohol (yield % 82;). Refinement {#refinement} ========== All H atoms were refined using a riding model with O---H=0.82 Å and C---H = 0.93 to 0.97 Å, and with *U*~iso~(H) = 1.2--1.5 *U*~eq~ (C,*O*). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### An ORTEP view of (I), with the atom-numbering scheme and 30% probability displacement ellipsoids. The dashed line indicates the intramolecular hydrogen bond. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### A packing diagram for (I). C---H···π interactions are drawn as dashed lines. \[Symmetry codes: (i) x, 1 - y, -1/2 + z; (ii) 1/2 - x, 1/2 + y, 3/2 - z\] :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e213 .table-wrap} ----------------------- ---------------------------------------- C~19~H~24~N~2~O~2~ *F*(000) = 1344 *M~r~* = 312.40 *D*~x~ = 1.183 Mg m^−3^ Monoclinic, *C*2/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -C 2yc Cell parameters from 18643 reflections *a* = 29.4936 (13) Å θ = 1.5--28.0° *b* = 7.8546 (2) Å µ = 0.08 mm^−1^ *c* = 16.7146 (7) Å *T* = 296 K β = 115.093 (3)° Prism, yellow *V* = 3506.7 (2) Å^3^ 0.76 × 0.59 × 0.28 mm *Z* = 8 ----------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e340 .table-wrap} ------------------------------------------------------------------ -------------------------------------- Stoe IPDS 2 diffractometer 3625 independent reflections Radiation source: fine-focus sealed tube 2383 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.073 Detector resolution: 6.67 pixels mm^-1^ θ~max~ = 26.5°, θ~min~ = 1.5° rotation method scans *h* = −36→36 Absorption correction: integration (*X-RED32*; Stoe & Cie, 2002) *k* = −9→9 *T*~min~ = 0.944, *T*~max~ = 0.979 *l* = −20→20 22701 measured reflections ------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e458 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.080 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.260 H-atom parameters constrained *S* = 1.10 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.1257*P*)^2^ + 1.7422*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 3625 reflections (Δ/σ)~max~ \< 0.001 208 parameters Δρ~max~ = 0.56 e Å^−3^ 4 restraints Δρ~min~ = −0.28 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e615 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e714 .table-wrap} ------ -------------- ------------ --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 0.55509 (10) 0.2708 (3) 0.09804 (16) 0.0622 (7) C2 0.59206 (13) 0.3870 (4) 0.14442 (19) 0.0790 (9) H2 0.6032 0.4636 0.1143 0.095\* C3 0.61234 (13) 0.3892 (4) 0.23535 (19) 0.0788 (9) H3 0.6374 0.4677 0.2658 0.095\* C4 0.59672 (10) 0.2789 (4) 0.28250 (17) 0.0633 (7) C5 0.55981 (11) 0.1594 (4) 0.23483 (18) 0.0700 (7) H5 0.5489 0.0815 0.2648 0.084\* C6 0.53963 (10) 0.1569 (4) 0.14410 (17) 0.0688 (7) H6 0.5152 0.0770 0.1133 0.083\* C7 0.60388 (11) 0.2229 (4) 0.42580 (18) 0.0677 (7) H7 0.5730 0.1684 0.3999 0.081\* C8 0.62939 (10) 0.2270 (3) 0.52080 (17) 0.0634 (7) C9 0.60954 (11) 0.1486 (4) 0.57326 (18) 0.0734 (8) H9 0.5786 0.0950 0.5459 0.088\* C10 0.63345 (11) 0.1467 (4) 0.66328 (18) 0.0706 (8) H10 0.6190 0.0904 0.6957 0.085\* C11 0.68015 (11) 0.2300 (4) 0.70765 (17) 0.0663 (7) C12 0.69978 (11) 0.3123 (4) 0.65580 (18) 0.0737 (8) H12 0.7299 0.3706 0.6832 0.088\* C13 0.67567 (11) 0.3099 (4) 0.56443 (17) 0.0668 (7) C14 0.68851 (12) 0.1161 (5) 0.85131 (19) 0.0863 (10) H14A 0.7178 0.0829 0.9037 0.104\* H14B 0.6739 0.0137 0.8179 0.104\* C15 0.65140 (15) 0.1970 (5) 0.8787 (3) 0.1017 (12) H15A 0.6427 0.1182 0.9139 0.153\* H15B 0.6219 0.2272 0.8271 0.153\* H15C 0.6658 0.2975 0.9127 0.153\* C16 0.74589 (14) 0.3596 (6) 0.8467 (2) 0.1112 (14) H16A 0.7407 0.4619 0.8114 0.133\* H16B 0.7453 0.3906 0.9024 0.133\* C17 0.79396 (19) 0.2842 (7) 0.8626 (3) 0.1395 (18) H17A 0.8202 0.3645 0.8931 0.209\* H17B 0.7944 0.2546 0.8073 0.209\* H17C 0.7990 0.1836 0.8981 0.209\* C18 0.54784 (14) 0.3722 (5) −0.04086 (19) 0.0911 (10) H18A 0.5835 0.3629 −0.0240 0.109\* H18B 0.5406 0.4877 −0.0293 0.109\* C19 0.51921 (17) 0.3309 (6) −0.1370 (2) 0.1181 (15) H19A 0.5286 0.4088 −0.1716 0.177\* H19B 0.4840 0.3409 −0.1531 0.177\* H19C 0.5267 0.2167 −0.1478 0.177\* N1 0.62123 (9) 0.2895 (3) 0.37583 (14) 0.0701 (6) N2 0.70399 (10) 0.2291 (4) 0.79754 (15) 0.0912 (9) O1 0.69745 (9) 0.3886 (3) 0.51884 (14) 0.1011 (9) H1 0.6798 0.3787 0.4658 0.152\* O2 0.53303 (8) 0.2546 (3) 0.00831 (12) 0.0780 (6) ------ -------------- ------------ --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1332 .table-wrap} ----- ------------- ------------- ------------- -------------- ------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0630 (15) 0.0717 (16) 0.0496 (13) 0.0059 (13) 0.0218 (11) −0.0012 (11) C2 0.100 (2) 0.0798 (19) 0.0593 (16) −0.0170 (17) 0.0355 (16) 0.0001 (13) C3 0.093 (2) 0.0834 (19) 0.0564 (15) −0.0248 (17) 0.0281 (14) −0.0084 (14) C4 0.0642 (15) 0.0705 (16) 0.0532 (14) 0.0001 (13) 0.0230 (12) −0.0035 (11) C5 0.0692 (16) 0.0829 (18) 0.0597 (15) −0.0066 (14) 0.0291 (13) 0.0031 (13) C6 0.0581 (15) 0.0851 (19) 0.0577 (15) −0.0057 (13) 0.0191 (12) −0.0052 (13) C7 0.0663 (16) 0.0733 (17) 0.0603 (15) −0.0030 (13) 0.0237 (13) −0.0049 (13) C8 0.0670 (16) 0.0653 (15) 0.0553 (14) 0.0001 (12) 0.0232 (12) −0.0032 (11) C9 0.0678 (17) 0.088 (2) 0.0616 (16) −0.0118 (15) 0.0251 (13) −0.0030 (14) C10 0.0711 (17) 0.0843 (19) 0.0556 (14) −0.0087 (14) 0.0260 (13) 0.0004 (13) C11 0.0744 (17) 0.0709 (16) 0.0517 (14) −0.0023 (13) 0.0249 (13) −0.0013 (12) C12 0.0741 (18) 0.0820 (19) 0.0599 (16) −0.0155 (15) 0.0234 (14) −0.0037 (14) C13 0.0798 (18) 0.0651 (15) 0.0578 (15) −0.0106 (13) 0.0315 (14) −0.0003 (12) C14 0.085 (2) 0.109 (2) 0.0555 (15) −0.0049 (18) 0.0209 (15) 0.0098 (16) C15 0.124 (3) 0.105 (3) 0.089 (2) −0.011 (2) 0.058 (2) 0.000 (2) C16 0.088 (2) 0.166 (4) 0.0653 (19) −0.036 (2) 0.0193 (17) 0.011 (2) C17 0.133 (4) 0.130 (4) 0.129 (4) 0.008 (3) 0.030 (3) 0.023 (3) C18 0.109 (3) 0.106 (2) 0.0574 (16) −0.002 (2) 0.0342 (17) 0.0046 (16) C19 0.136 (3) 0.154 (4) 0.0554 (18) −0.009 (3) 0.031 (2) 0.001 (2) N1 0.0841 (16) 0.0725 (14) 0.0520 (12) −0.0050 (12) 0.0273 (12) −0.0018 (10) N2 0.0797 (16) 0.137 (2) 0.0484 (13) −0.0196 (15) 0.0187 (11) 0.0094 (13) O1 0.1140 (18) 0.1272 (19) 0.0608 (12) −0.0550 (16) 0.0358 (12) −0.0062 (12) O2 0.0849 (14) 0.0925 (14) 0.0498 (10) −0.0046 (11) 0.0220 (9) 0.0006 (9) ----- ------------- ------------- ------------- -------------- ------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1786 .table-wrap} ----------------------- ------------ ---------------------- ------------ C1---O2 1.364 (3) C12---H12 0.9300 C1---C6 1.378 (4) C13---O1 1.338 (3) C1---C2 1.381 (4) C14---N2 1.467 (4) C2---C3 1.377 (4) C14---C15 1.495 (5) C2---H2 0.9300 C14---H14A 0.9700 C3---C4 1.375 (4) C14---H14B 0.9700 C3---H3 0.9300 C15---H15A 0.9600 C4---C5 1.402 (4) C15---H15B 0.9600 C4---N1 1.417 (3) C15---H15C 0.9600 C5---C6 1.374 (4) C16---C17 1.453 (5) C5---H5 0.9300 C16---N2 1.547 (5) C6---H6 0.9300 C16---H16A 0.9700 C7---N1 1.263 (4) C16---H16B 0.9700 C7---C8 1.441 (4) C17---H17A 0.9600 C7---H7 0.9300 C17---H17B 0.9600 C8---C9 1.388 (4) C17---H17C 0.9600 C8---C13 1.405 (4) C18---O2 1.423 (4) C9---C10 1.364 (4) C18---C19 1.499 (4) C9---H9 0.9300 C18---H18A 0.9700 C10---C11 1.417 (4) C18---H18B 0.9700 C10---H10 0.9300 C19---H19A 0.9600 C11---N2 1.362 (3) C19---H19B 0.9600 C11---C12 1.389 (4) C19---H19C 0.9600 C12---C13 1.385 (4) O1---H1 0.8200 O2---C1---C6 115.9 (2) C15---C14---H14A 109.0 O2---C1---C2 125.0 (3) N2---C14---H14B 109.0 C6---C1---C2 119.0 (2) C15---C14---H14B 109.0 C3---C2---C1 119.9 (3) H14A---C14---H14B 107.8 C3---C2---H2 120.1 C14---C15---H15A 109.5 C1---C2---H2 120.1 C14---C15---H15B 109.5 C4---C3---C2 122.0 (3) H15A---C15---H15B 109.5 C4---C3---H3 119.0 C14---C15---H15C 109.5 C2---C3---H3 119.0 H15A---C15---H15C 109.5 C3---C4---C5 117.7 (2) H15B---C15---H15C 109.5 C3---C4---N1 117.1 (2) C17---C16---N2 109.0 (4) C5---C4---N1 125.2 (3) C17---C16---H16A 109.9 C6---C5---C4 120.4 (3) N2---C16---H16A 109.9 C6---C5---H5 119.8 C17---C16---H16B 109.9 C4---C5---H5 119.8 N2---C16---H16B 109.9 C5---C6---C1 121.1 (3) H16A---C16---H16B 108.3 C5---C6---H6 119.5 C16---C17---H17A 109.5 C1---C6---H6 119.5 C16---C17---H17B 109.5 N1---C7---C8 123.4 (3) H17A---C17---H17B 109.5 N1---C7---H7 118.3 C16---C17---H17C 109.5 C8---C7---H7 118.3 H17A---C17---H17C 109.5 C9---C8---C13 117.1 (2) H17B---C17---H17C 109.5 C9---C8---C7 121.6 (3) O2---C18---C19 107.9 (3) C13---C8---C7 121.4 (3) O2---C18---H18A 110.1 C10---C9---C8 122.8 (3) C19---C18---H18A 110.1 C10---C9---H9 118.6 O2---C18---H18B 110.1 C8---C9---H9 118.6 C19---C18---H18B 110.1 C9---C10---C11 120.3 (3) H18A---C18---H18B 108.4 C9---C10---H10 119.8 C18---C19---H19A 109.5 C11---C10---H10 119.8 C18---C19---H19B 109.5 N2---C11---C12 122.3 (3) H19A---C19---H19B 109.5 N2---C11---C10 120.5 (3) C18---C19---H19C 109.5 C12---C11---C10 117.3 (2) H19A---C19---H19C 109.5 C13---C12---C11 121.8 (3) H19B---C19---H19C 109.5 C13---C12---H12 119.1 C7---N1---C4 122.9 (3) C11---C12---H12 119.1 C11---N2---C14 122.0 (3) O1---C13---C12 118.4 (3) C11---N2---C16 120.3 (3) O1---C13---C8 120.9 (2) C14---N2---C16 117.5 (2) C12---C13---C8 120.7 (3) C13---O1---H1 109.5 N2---C14---C15 112.9 (3) C1---O2---C18 117.0 (2) N2---C14---H14A 109.0 O2---C1---C2---C3 −178.6 (3) C11---C12---C13---C8 1.7 (5) C6---C1---C2---C3 −1.0 (5) C9---C8---C13---O1 179.9 (3) C1---C2---C3---C4 −0.4 (5) C7---C8---C13---O1 0.3 (4) C2---C3---C4---C5 1.5 (5) C9---C8---C13---C12 −0.2 (4) C2---C3---C4---N1 178.2 (3) C7---C8---C13---C12 −179.8 (3) C3---C4---C5---C6 −1.3 (4) C8---C7---N1---C4 177.4 (3) N1---C4---C5---C6 −177.8 (3) C3---C4---N1---C7 164.5 (3) C4---C5---C6---C1 0.0 (5) C5---C4---N1---C7 −19.0 (5) O2---C1---C6---C5 179.0 (3) C12---C11---N2---C14 −167.9 (3) C2---C1---C6---C5 1.1 (4) C10---C11---N2---C14 12.7 (5) N1---C7---C8---C9 −178.4 (3) C12---C11---N2---C16 17.2 (5) N1---C7---C8---C13 1.2 (5) C10---C11---N2---C16 −162.2 (3) C13---C8---C9---C10 −1.4 (4) C15---C14---N2---C11 −92.0 (4) C7---C8---C9---C10 178.3 (3) C15---C14---N2---C16 83.0 (4) C8---C9---C10---C11 1.4 (5) C17---C16---N2---C11 −93.3 (4) C9---C10---C11---N2 179.6 (3) C17---C16---N2---C14 91.6 (4) C9---C10---C11---C12 0.2 (4) C6---C1---O2---C18 179.2 (3) N2---C11---C12---C13 178.9 (3) C2---C1---O2---C18 −3.1 (4) C10---C11---C12---C13 −1.7 (5) C19---C18---O2---C1 179.9 (3) C11---C12---C13---O1 −178.4 (3) ----------------------- ------------ ---------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2614 .table-wrap} -------------------------------------- Cg1 is the centroid of C8--C13 ring. -------------------------------------- ::: ::: {#d1e2618 .table-wrap} ---------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O1---H1···N1 0.82 1.88 2.610 (3) 148 C2---H2···Cg1^i^ 0.93 2.85 3.681 (4) 149 C17---H17A···Cg1^ii^ 0.96 2.97 3.763 (6) 140 ---------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) *x*, −*y*+1, *z*−1/2; (ii) −*x*+1/2, *y*+1/2, −*z*+3/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) *Cg*1 is the centroid of C8--C13 ring. ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------------ --------- ------- ----------- ------------- O1---H1⋯N1 0.82 1.88 2.610 (3) 148 C2---H2⋯*Cg*1^i^ 0.93 2.85 3.681 (4) 149 C17---H17*A*⋯*Cg*1^ii^ 0.96 2.97 3.763 (6) 140 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.475798

2011-2-12

PMC3051951

Related literature {#sec1} ================== For the original synthesis of glycerol menthonides, see: Greenberg (1999[@bb3]). For general background to glycerol menthonides, see: Kiessling *et al.* (2009*b* [@bb5]). For a related structure, see: Kiessling *et al.* (2009*a* [@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~20~H~27~BrO~4~*M* *~r~* = 411.33Monoclinic,*a* = 42.976 (7) Å*b* = 5.5763 (9) Å*c* = 16.072 (3) Åβ = 92.618 (2)°*V* = 3847.5 (11) Å^3^*Z* = 8Mo *K*α radiationμ = 2.16 mm^−1^*T* = 100 K0.50 × 0.05 × 0.03 mm ### Data collection {#sec2.1.2} Bruker SMART APEX CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2009[@bb1]) *T* ~min~ = 0.588, *T* ~max~ = 0.74617537 measured reflections9230 independent reflections6765 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.043 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.058*wR*(*F* ^2^) = 0.148*S* = 1.029230 reflections457 parameters1 restraintH-atom parameters constrainedΔρ~max~ = 4.00 e Å^−3^Δρ~min~ = −0.75 e Å^−3^Absolute structure: Flack (1983[@bb2]), 3965 Friedel pairsFlack parameter: 0.000 (13) {#d5e570} Data collection: *APEX2* (Bruker, 2009[@bb1]); cell refinement: *SAINT* (Bruker, 2009[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *Mercury* (Macrae *et al.*, 2008[@bb6]); software used to prepare material for publication: *SHELXTL* and *Mercury*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811006428/tk2718sup1.cif](http://dx.doi.org/10.1107/S1600536811006428/tk2718sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006428/tk2718Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006428/tk2718Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?tk2718&file=tk2718sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?tk2718sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?tk2718&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [TK2718](http://scripts.iucr.org/cgi-bin/sendsup?tk2718)). The diffractometer was funded by NSF grant 0087210, Ohio Board of Regents grant CAP-491 and YSU. Comment ======= The title structure was synthesized as part of a study of 3-carbon stereochemical moieties, specifically tri-substituted glycerol. Here menthone serves as a chiral auxiliary, freezing two carbons into a specific stereochemistry and influencing the stereochemistry of the third owing to the steric bulk of the menthone (Kiessling *et al.*, 2009*b*). Previously a different stereoisomer was isolated as the 3,5-dinitrobenzoate derivative and its crystal structure was published (Kiessling *et al.*, 2009*a*). The starting material, glycerol menthonide, was originally prepared as an additive to spearmint gum by reaction of menthone with glycerol under acid catalysis (Greenberg, 1999). No further chemical analysis of the menthonide had been reported in the literature at that time. Later analysis revealed that glycerol menthonide exists in as many as six isomers, which proved to be difficult to separate (Kiessling *et al.* 2009*b*). However, conversion of the hydroxy group to an ester by reaction with 4-bromobenzoyl chloride yields a mixture of esters out of which the title compound crystallizes. Isolation of the crystals followed by sequential recrystallization from methanol/water yielded the title compound in \> 97% purity in the form of colorless needles. The title compound crystallizes with two crystallographically independent molecules in a monoclinic setting in the space group *C*2, Fig. 1. The two molecules, molecule A and B, are chemically identical and differ only in one on the torsion angles around the ester oxygen atom, C9---C8---O2---C1, which is -106.5 (7) ° in molecule A, and 146.1 (6) ° in molecule B. All other bonds, angles and torsion angles in both molecules are virtually identical, as can be seen in the overlay of the two molecules as shown in Fig. 2, and are within their expected ranges. The two molecules are not only very similar with respect to each other, they are also crystallographically related by a pseudotranslation found along the (0 1 1) diagonal of the unit cell (Fig. 3.). The glycerol menthonide of the two molecules are transformed into each other by a translation of half a unit cell along this direction. The *p*-bromo benzoate moieties, however, do not obey the pseudotranslation, thus causing a doubling of the unit cell with respect to a theoretical smaller primitive monoclinic cell with the dimensions a = 22.5949, b = 5.5763, c = 16.0718 and β = 108.193. Packing in the structure of the title molecule is dominated by a combination weak interactions and van der Waals interactions. Via pairs of bifurcated C---H···O interactions between phenyl H atoms and the ester carbonyl O atoms molecules A and B form dimers (Fig. 4, Table 1). The dimers have local non-crystallographic inversion symmetry with the *p*-bromo benzoate moieties of the A and B molecules related by a pseudo inversion center in the middle of each dimer. The glycerol menthonide sections of the molecules are also interacting with each other with both oxygen atoms of the gylcerol units acting as acceptors for weak C---H···O interactions from aliphatic C---H and CH~2~ groups of neighboring glycerol menthonide moieties (Table 1). The connections are between like molecules and to both sides of the molecules, which leads to the formation of chains of molecules of either A or B that stretch parallel to the (0 1 0) direction. The combination of both types of C---H···O interactions leads to the formation of column shaped double chains as shown in Fig. 4. The outside of these columns is dominated by methyl, methylene and aromatic H atoms and the bromine atoms, and interactions between neighboring columns are limited to van der Waals interactions. The refined Flack parameter of 0.000 (13) confirms the compound as a chiral and enantiopure molecule. The crystallographic assignment of the absolute stereochemistry is consistent with having started with (-)-menthone, and provides the stereochemistry of the acetal carbon and the esterified secondary alcohol of the glycerol chain. Specifically, the acetal carbon, C5, is *R* and the secondary alcohol, C2, is also *R*. This brings the bromobenzoate into approximately the same plane as the menthyl ring and *cis* to the isopropyl group. Experimental {#experimental} ============ All chemicals were purchased through ThermoFisher Inc. and used without further purification. Glycerol menthonide was prepared according to the published procedure (Greenberg 1999). GC/MS data was obtained using a Varian CP 3800 with Saturn 2000 ion trap MS. Column: Varian CP 5860, WCOT fused silica 30 m × 0.25 mm, coating CP-Sil. Carrier gas: He 1.2 ml/min. Temperature Program: initial temperature 473 K, ramp 20 K/min to 533 K hold 14.5 min. NMR data were obtained at Bucknell University using a Varian 600 MHz instrument and CDCl~3~, data are reported as p.p.m. from TMS and coupling constants are in Hz. Melting points were obtained on a MelTemp and are uncorrected. TLC was done with Analtech 2520 plates. In a 50-ml round-bottom flask were placed glycerol menthonide (5.02 g, 22.0 mmol), 4-bromobenzoyl chloride (4.96 g, 23.0 mmol) and pyridine (10 ml). The flask was fitted with an air reflux condenser, drying tube and a magnetic stir bar. The flask was heated to reflux of the solvent while stirring for 2 h. The contents of the flask were then added to water (30 ml) and methyl *tert*-butyl ether (MTBE, 20 ml) and separated. The aqueous layer was extracted twice with MTBE (20 ml). The combined organic layers were washed with 10% HCl (2 × 15 ml), 10% Na~2~CO~3~ (2 × 15 ml) and saturated NaCl (15 ml), dried over MgSO~4~ and the solvent removed under vacuum to yield the crude product as an oil. To the oil was added methanol (10 ml) and the solution placed in a freezer for 72 hr. Vacuum filtration yielded the product as a white solid (1.19 g) which was 72% pure by GC/MS analysis. A portion of this solid was further purified by recrystallization from methanol/water to yield white needles, mp 353.5 -- 354 K. TLC: *R*~f~ = 0.54 in 7% ethyl acetate/petroleum ether. GC: *R*~t~ = 12.11 min. IR: 2952, 1718, 1589, 1269, 1095, 1008, 849, 753. MS: 412 (18), 410 (18), 397 (34), 395 (35), 355 (48), 353 (48), 327 (100), 325 (86), 185 (36), 183 (32), 69 (45), expected for C~20~H~27~BrO~4~ 410.10. ^13^C NMR: 165.7, 131.7 (2), 131.3 (2), 128.7, 128.3, 113.1, 77.5, 65.9, 64.7, 48.3, 44.1, 33.5, 30.3, 24.1, 23.4, 23.2, 22.1, 18.1. ^1^H NMR: 7.92 (dt, J = 8.4, 1.8 Hz, 2H), 7.59 (dt, J = 9.0, 1.8 Hz, 2H), 4.53 (m, 1H), 4.48 (dd, J = 11.4, 4.2 Hz, 1H), 4.40 (dd, J = 11.4, 5.1 Hz, 1H), 4.09 (dd, J = 7.8, 6.9 Hz, 1H), 3.75 (dd, J = 7.8, 6.6 Hz, 1H), 2.24 (sept, J = 6.9 Hz, 1H)1.86 (ddd, J = 13.2, 2.4, 1.2 Hz, 1H), 1.71 - 1.77 (m, 1H), 1.56 - 1.68 (m, 2H), 1.34 - 1.46 (m, 2H), 1.01 (t, j = 12.9 Hz, 1H), 0.89 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 7.2 Hz, 3H), 0.83 (d, J = 7.2 Hz, 3H), 0.86 - 0.90 (m, 1H). Refinement {#refinement} ========== Reflection 2 0 0 was obstructed by the beam stop and was omitted from the refinement. The structure shows pseudotranslation along the (0 1 1) diagonal. The *p*-bromo benzoate moieties do not obey the pseudotranslation and cause the doubling of the unit cell. The largest residual electron density peaks are located close to the bromine atoms, 0.84 Å from Br1 and 0.82 Å from Br2. The relatively large residual electron densities found (4.00 and 3.78 e Å^-3^) are associated with correlation effects due to the pseudotranslation exhibited by the structure. Q1, located close to Br1, is at a position that agrees with the position of Br2 translated along the direction of the pseudotranslation. Q2, on the other hand, reflects Br1 translated by half a unit cell along (0 1 1) (Fig. 5). H atoms attached to carbon atoms were positioned geometrically and constrained to ride on their parent atoms, with C---H distances of 0.95 (CH~ar~), 0.99 (CH~2~), 0.98 (CH~3~) or 1.00 Å (C---H) and with *U*~iso~(H) = 1.2 *U*~eq~(C) or 1.5 *U*~eq~(C~methyl~) for methyl H. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Displacement ellipsoid style view of the two molecules A and B of the title compound. Ellipsoid probability is at the 50% level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Overlay of the two crystallographically independent molecules. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### Packing view of the title compound, view down the (0 1 1) diagonal showing the pseudotranslation. Molecules A are shown in red, molecules B in blue. :::  ::: ::: {#Fap4 .fig} Fig. 4. ::: {.caption} ###### Packing view of the title compound with intermolecular C---H···O interactions shown (blue dashed lines). Molecules A are shown in red, molecules B in blue. :::  ::: ::: {#Fap5 .fig} Fig. 5. ::: {.caption} ###### Q-peaks (yellow spheres) caused by correlation effects due to pseudo-translation and their positions with respect to the Br atoms (green smaller spheres). Q1, located close to Br1, is created by translation of Br2 and Q2 by translation of Br1 by half a unit cell along the (0 1 1) direction. View is down the direction of the pseudotranslation as in Fig. 3. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e246 .table-wrap} ------------------------ --------------------------------------- C~20~H~27~BrO~4~ *F*(000) = 1712 *M~r~* = 411.33 *D*~x~ = 1.420 Mg m^−3^ Monoclinic, *C*2 Mo *K*α radiation, λ = 0.71073 Å Hall symbol: C 2y Cell parameters from 3693 reflections *a* = 42.976 (7) Å θ = 2.5--27.6° *b* = 5.5763 (9) Å µ = 2.16 mm^−1^ *c* = 16.072 (3) Å *T* = 100 K β = 92.618 (2)° Needle, colourless *V* = 3847.5 (11) Å^3^ 0.50 × 0.05 × 0.03 mm *Z* = 8 ------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e368 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEX CCD diffractometer 9230 independent reflections Radiation source: fine-focus sealed tube 6765 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.043 ω scans θ~max~ = 28.3°, θ~min~ = 1.3° Absorption correction: multi-scan (*SADABS*; Bruker, 2009) *h* = −57→56 *T*~min~ = 0.588, *T*~max~ = 0.746 *k* = −7→7 17537 measured reflections *l* = −21→21 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e482 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.058 H-atom parameters constrained *wR*(*F*^2^) = 0.148 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0759*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.02 (Δ/σ)~max~ = 0.001 9230 reflections Δρ~max~ = 4.00 e Å^−3^ 457 parameters Δρ~min~ = −0.75 e Å^−3^ 1 restraint Absolute structure: Flack (1983), 3965 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: 0.000 (13) ---------------------------------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e641 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e740 .table-wrap} ------ --------------- -------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Br1A 0.677987 (16) 0.69491 (10) 0.98525 (5) 0.02577 (19) Br1B 0.822411 (16) 0.57423 (10) 0.51465 (5) 0.02449 (18) C1A 0.79543 (14) 0.4707 (12) 0.7970 (4) 0.0172 (14) C2A 0.76758 (14) 0.5328 (11) 0.8445 (4) 0.0141 (12) C3A 0.74302 (14) 0.3702 (11) 0.8413 (4) 0.0165 (13) H3A 0.7448 0.2269 0.8099 0.020\* C4A 0.71634 (15) 0.4125 (12) 0.8826 (4) 0.0167 (13) H4A 0.6998 0.2990 0.8814 0.020\* C5A 0.71416 (17) 0.6295 (9) 0.9266 (5) 0.0119 (18) C6A 0.73825 (16) 0.7922 (11) 0.9304 (4) 0.0195 (14) H6A 0.7365 0.9360 0.9615 0.023\* C7A 0.76521 (14) 0.7446 (12) 0.8881 (4) 0.0188 (14) H7A 0.7818 0.8571 0.8894 0.023\* C8A 0.84603 (15) 0.6051 (12) 0.7615 (5) 0.0151 (15) H8A1 0.8517 0.7596 0.7359 0.018\* H8A2 0.8419 0.4871 0.7163 0.018\* C9A 0.87254 (10) 0.5184 (8) 0.8185 (3) 0.0130 (9) H9A 0.8746 0.6223 0.8691 0.016\* C10A 0.86975 (11) 0.2539 (9) 0.8437 (3) 0.0169 (10) H10A 0.8786 0.2267 0.9009 0.020\* H10B 0.8478 0.2005 0.8404 0.020\* C11A 0.91262 (10) 0.2894 (9) 0.7673 (3) 0.0139 (9) C12A 0.93969 (12) 0.2590 (10) 0.8319 (3) 0.0172 (11) H12A 0.9557 0.3822 0.8221 0.021\* H12B 0.9320 0.2852 0.8883 0.021\* C13A 0.95462 (12) 0.0102 (10) 0.8282 (3) 0.0201 (11) H13A 0.9388 −0.1127 0.8423 0.024\* C14A 0.96479 (11) −0.0364 (10) 0.7392 (3) 0.0201 (11) H14A 0.9817 0.0764 0.7263 0.024\* H14B 0.9731 −0.2014 0.7357 0.024\* C15A 0.93810 (12) −0.0064 (10) 0.6753 (3) 0.0172 (11) H15A 0.9220 −0.1289 0.6850 0.021\* H15B 0.9458 −0.0324 0.6189 0.021\* C16A 0.92351 (11) 0.2444 (9) 0.6798 (3) 0.0127 (10) H16A 0.9408 0.3608 0.6715 0.015\* C17A 0.89885 (11) 0.2924 (9) 0.6090 (3) 0.0151 (9) H17A 0.8856 0.4287 0.6270 0.018\* C18A 0.87701 (16) 0.0784 (15) 0.5892 (5) 0.0263 (15) H18A 0.8662 0.0337 0.6394 0.039\* H18B 0.8893 −0.0582 0.5707 0.039\* H18C 0.8616 0.1237 0.5450 0.039\* C19A 0.91434 (13) 0.3708 (10) 0.5304 (3) 0.0234 (11) H19A 0.8983 0.4080 0.4869 0.035\* H19B 0.9276 0.2411 0.5112 0.035\* H19C 0.9271 0.5137 0.5422 0.035\* C20A 0.98250 (12) −0.0095 (12) 0.8913 (3) 0.0289 (13) H20A 0.9986 0.1052 0.8766 0.043\* H20B 0.9910 −0.1725 0.8902 0.043\* H20C 0.9757 0.0265 0.9473 0.043\* C1B 0.70385 (15) 0.7839 (11) 0.6994 (4) 0.0161 (13) C2B 0.73214 (14) 0.7265 (13) 0.6536 (4) 0.0182 (13) C3B 0.75673 (15) 0.8902 (13) 0.6586 (4) 0.0199 (14) H3B 0.7550 1.0339 0.6898 0.024\* C4B 0.78383 (15) 0.8412 (12) 0.6174 (4) 0.0174 (14) H4B 0.8008 0.9506 0.6204 0.021\* C5B 0.78569 (19) 0.6330 (10) 0.5726 (5) 0.0149 (19) C6B 0.76197 (14) 0.4659 (12) 0.5682 (4) 0.0163 (13) H6B 0.7641 0.3207 0.5381 0.020\* C7B 0.73489 (14) 0.5156 (11) 0.6091 (4) 0.0142 (13) H7B 0.7182 0.4042 0.6064 0.017\* C8B 0.65383 (17) 0.6320 (10) 0.7341 (5) 0.0187 (18) H8B1 0.6496 0.8006 0.7493 0.022\* H8B2 0.6560 0.5358 0.7858 0.022\* C9B 0.62768 (10) 0.5353 (8) 0.6779 (3) 0.0136 (9) H9B 0.6255 0.6337 0.6259 0.016\* C10B 0.63120 (11) 0.2705 (9) 0.6557 (3) 0.0163 (10) H10C 0.6230 0.2379 0.5982 0.020\* H10D 0.6533 0.2198 0.6611 0.020\* C11B 0.58757 (10) 0.3063 (9) 0.7291 (3) 0.0137 (9) C12B 0.56128 (12) 0.2708 (10) 0.6640 (3) 0.0168 (10) H12C 0.5693 0.2956 0.6079 0.020\* H12D 0.5449 0.3919 0.6724 0.020\* C13B 0.54689 (11) 0.0148 (10) 0.6691 (3) 0.0157 (11) H13B 0.5631 −0.1054 0.6551 0.019\* C14B 0.53697 (11) −0.0327 (9) 0.7582 (3) 0.0175 (10) H14C 0.5192 0.0726 0.7701 0.021\* H14D 0.5299 −0.2010 0.7625 0.021\* C15B 0.56317 (12) 0.0115 (10) 0.8228 (3) 0.0153 (11) H15C 0.5800 −0.1063 0.8149 0.018\* H15D 0.5553 −0.0133 0.8791 0.018\* C16B 0.57645 (11) 0.2651 (9) 0.8171 (3) 0.0124 (10) H16B 0.5584 0.3760 0.8231 0.015\* C17B 0.60009 (12) 0.3292 (9) 0.8881 (3) 0.0180 (10) H17B 0.6117 0.4749 0.8707 0.022\* C18B 0.6239 (2) 0.1343 (11) 0.9093 (5) 0.028 (2) H18D 0.6132 −0.0096 0.9282 0.042\* H18E 0.6385 0.1913 0.9537 0.042\* H18F 0.6354 0.0959 0.8598 0.042\* C19B 0.58304 (13) 0.3940 (11) 0.9663 (3) 0.0257 (12) H19D 0.5983 0.4311 1.0117 0.039\* H19E 0.5701 0.2583 0.9824 0.039\* H19F 0.5698 0.5342 0.9550 0.039\* C20B 0.51938 (12) −0.0086 (11) 0.6060 (3) 0.0262 (12) H20D 0.5032 0.1069 0.6195 0.039\* H20E 0.5109 −0.1716 0.6082 0.039\* H20F 0.5264 0.0237 0.5500 0.039\* O1A 0.79755 (11) 0.2908 (9) 0.7548 (3) 0.0252 (11) O2A 0.81834 (12) 0.6356 (6) 0.8087 (3) 0.0151 (13) O3A 0.90037 (7) 0.5265 (6) 0.7737 (2) 0.0152 (7) O4A 0.88748 (12) 0.1333 (6) 0.7838 (3) 0.0165 (13) O1B 0.70079 (11) 0.9560 (8) 0.7431 (3) 0.0222 (10) O2B 0.68186 (12) 0.6166 (8) 0.6883 (4) 0.0186 (13) O3B 0.59946 (7) 0.5436 (6) 0.7213 (2) 0.0158 (7) O4B 0.61311 (12) 0.1522 (7) 0.7151 (3) 0.0132 (12) ------ --------------- -------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e2067 .table-wrap} ------ ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Br1A 0.0183 (4) 0.0367 (4) 0.0226 (4) 0.0055 (4) 0.0042 (3) −0.0042 (4) Br1B 0.0170 (4) 0.0360 (4) 0.0207 (4) 0.0008 (4) 0.0030 (3) −0.0012 (4) C1A 0.013 (3) 0.023 (3) 0.015 (3) 0.002 (2) 0.000 (2) 0.004 (3) C2A 0.022 (3) 0.009 (3) 0.012 (3) 0.003 (2) −0.001 (2) −0.002 (3) C3A 0.021 (3) 0.008 (3) 0.020 (3) −0.001 (2) −0.001 (3) −0.001 (2) C4A 0.020 (3) 0.013 (3) 0.017 (3) −0.005 (2) −0.002 (3) −0.002 (3) C5A 0.009 (4) 0.017 (4) 0.009 (4) 0.0005 (19) 0.000 (3) 0.005 (2) C6A 0.034 (4) 0.004 (3) 0.020 (3) 0.001 (3) −0.002 (3) 0.000 (2) C7A 0.015 (3) 0.015 (4) 0.026 (4) −0.001 (3) 0.001 (3) 0.006 (3) C8A 0.015 (3) 0.017 (3) 0.014 (3) −0.001 (2) 0.005 (3) 0.002 (2) C9A 0.015 (2) 0.014 (2) 0.010 (2) −0.0014 (17) 0.0048 (17) 0.0005 (18) C10A 0.017 (2) 0.017 (3) 0.016 (2) 0.0037 (18) 0.0025 (18) 0.0067 (19) C11A 0.011 (2) 0.016 (2) 0.015 (2) 0.0002 (18) −0.0002 (17) 0.0033 (19) C12A 0.011 (2) 0.024 (3) 0.016 (2) −0.002 (2) −0.002 (2) −0.002 (2) C13A 0.015 (2) 0.031 (3) 0.014 (2) −0.006 (2) −0.008 (2) 0.007 (2) C14A 0.014 (2) 0.029 (3) 0.018 (2) 0.009 (2) 0.0013 (19) 0.004 (2) C15A 0.019 (3) 0.021 (3) 0.012 (2) 0.001 (2) 0.001 (2) 0.004 (2) C16A 0.012 (2) 0.015 (3) 0.011 (2) −0.002 (2) 0.0002 (19) 0.0048 (18) C17A 0.018 (2) 0.015 (2) 0.012 (2) −0.0008 (19) −0.0034 (18) 0.0032 (19) C18A 0.029 (4) 0.027 (3) 0.021 (3) −0.010 (3) −0.014 (3) 0.010 (3) C19A 0.034 (3) 0.023 (3) 0.013 (2) −0.003 (2) 0.002 (2) 0.006 (2) C20A 0.021 (3) 0.052 (4) 0.013 (2) 0.005 (3) −0.001 (2) 0.006 (2) C1B 0.025 (3) 0.008 (3) 0.014 (3) −0.005 (2) −0.003 (3) 0.000 (2) C2B 0.018 (3) 0.018 (4) 0.018 (3) −0.001 (3) −0.002 (3) 0.005 (3) C3B 0.029 (4) 0.021 (3) 0.009 (3) 0.000 (3) −0.002 (3) 0.004 (3) C4B 0.018 (3) 0.020 (3) 0.014 (3) 0.001 (2) −0.001 (3) 0.009 (3) C5B 0.019 (4) 0.015 (4) 0.012 (4) 0.005 (2) 0.005 (4) 0.003 (2) C6B 0.013 (3) 0.024 (3) 0.011 (3) 0.000 (2) −0.003 (2) −0.003 (3) C7B 0.026 (3) 0.007 (3) 0.009 (3) −0.004 (2) −0.006 (2) 0.000 (2) C8B 0.018 (4) 0.020 (4) 0.018 (4) −0.001 (2) 0.003 (3) −0.002 (2) C9B 0.015 (2) 0.014 (3) 0.012 (2) −0.0012 (17) 0.0026 (17) −0.0013 (18) C10B 0.017 (2) 0.017 (2) 0.015 (2) −0.0012 (19) 0.0045 (18) −0.0056 (19) C11B 0.010 (2) 0.012 (2) 0.019 (2) 0.0002 (17) 0.0004 (17) −0.0055 (19) C12B 0.015 (2) 0.021 (3) 0.015 (2) −0.002 (2) −0.003 (2) −0.001 (2) C13B 0.011 (2) 0.020 (3) 0.017 (2) 0.001 (2) −0.002 (2) −0.002 (2) C14B 0.016 (2) 0.018 (3) 0.018 (2) −0.0035 (18) 0.0007 (19) −0.003 (2) C15B 0.015 (2) 0.017 (3) 0.014 (2) 0.000 (2) 0.005 (2) −0.0024 (19) C16B 0.011 (2) 0.015 (2) 0.011 (2) 0.003 (2) 0.0034 (18) −0.0021 (18) C17B 0.025 (3) 0.017 (2) 0.012 (2) 0.001 (2) −0.0023 (19) −0.0071 (19) C18B 0.034 (4) 0.029 (4) 0.020 (4) 0.004 (2) −0.007 (3) −0.006 (2) C19B 0.032 (3) 0.032 (3) 0.013 (2) −0.001 (2) 0.001 (2) −0.009 (2) C20B 0.020 (3) 0.039 (3) 0.019 (3) −0.005 (2) −0.001 (2) −0.009 (2) O1A 0.026 (2) 0.022 (2) 0.028 (3) −0.006 (2) 0.008 (2) −0.011 (2) O2A 0.017 (3) 0.012 (3) 0.016 (3) 0.0001 (14) 0.003 (2) −0.0024 (14) O3A 0.0153 (16) 0.0121 (18) 0.0187 (17) 0.0002 (12) 0.0058 (13) 0.0006 (14) O4A 0.017 (3) 0.011 (3) 0.022 (3) −0.0002 (14) 0.006 (2) 0.0029 (15) O1B 0.025 (2) 0.020 (2) 0.022 (2) −0.0031 (18) 0.0022 (19) −0.008 (2) O2B 0.013 (3) 0.018 (3) 0.025 (3) −0.0051 (15) 0.004 (2) −0.0064 (17) O3B 0.0175 (16) 0.0105 (18) 0.0198 (17) 0.0008 (13) 0.0047 (13) 0.0000 (14) O4B 0.016 (3) 0.008 (2) 0.016 (3) 0.0006 (14) 0.002 (2) −0.0016 (15) ------ ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e3008 .table-wrap} --------------------------- ------------ --------------------------- ------------ Br1A---C5A 1.889 (7) C20A---H20C 0.9800 Br1B---C5B 1.897 (8) C1B---O1B 1.199 (8) C1A---O1A 1.217 (8) C1B---O2B 1.334 (7) C1A---O2A 1.354 (8) C1B---C2B 1.485 (9) C1A---C2A 1.489 (8) C2B---C7B 1.385 (10) C2A---C7A 1.380 (10) C2B---C3B 1.396 (9) C2A---C3A 1.391 (9) C3B---C4B 1.393 (9) C3A---C4A 1.371 (9) C3B---H3B 0.9500 C3A---H3A 0.9500 C4B---C5B 1.370 (9) C4A---C5A 1.408 (9) C4B---H4B 0.9500 C4A---H4A 0.9500 C5B---C6B 1.381 (9) C5A---C6A 1.376 (9) C6B---C7B 1.390 (8) C6A---C7A 1.395 (9) C6B---H6B 0.9500 C6A---H6A 0.9500 C7B---H7B 0.9500 C7A---H7A 0.9500 C8B---O2B 1.443 (9) C8A---O2A 1.450 (8) C8B---C9B 1.509 (8) C8A---C9A 1.508 (8) C8B---H8B1 0.9900 C8A---H8A1 0.9900 C8B---H8B2 0.9900 C8A---H8A2 0.9900 C9B---O3B 1.427 (5) C9A---O3A 1.424 (5) C9B---C10B 1.528 (6) C9A---C10A 1.536 (6) C9B---H9B 1.0000 C9A---H9A 1.0000 C10B---O4B 1.421 (6) C10A---O4A 1.423 (7) C10B---H10C 0.9900 C10A---H10A 0.9900 C10B---H10D 0.9900 C10A---H10B 0.9900 C11B---O4B 1.420 (6) C11A---O4A 1.422 (6) C11B---O3B 1.426 (6) C11A---O3A 1.429 (6) C11B---C12B 1.517 (7) C11A---C16A 1.524 (6) C11B---C16B 1.530 (6) C11A---C12A 1.533 (7) C12B---C13B 1.559 (8) C12A---C13A 1.531 (8) C12B---H12C 0.9900 C12A---H12A 0.9900 C12B---H12D 0.9900 C12A---H12B 0.9900 C13B---C20B 1.527 (7) C13A---C20A 1.537 (7) C13B---C14B 1.536 (7) C13A---C14A 1.538 (7) C13B---H13B 1.0000 C13A---H13A 1.0000 C14B---C15B 1.517 (7) C14A---C15A 1.513 (7) C14B---H14C 0.9900 C14A---H14A 0.9900 C14B---H14D 0.9900 C14A---H14B 0.9900 C15B---C16B 1.529 (8) C15A---C16A 1.535 (7) C15B---H15C 0.9900 C15A---H15A 0.9900 C15B---H15D 0.9900 C15A---H15B 0.9900 C16B---C17B 1.535 (7) C16A---C17A 1.542 (7) C16B---H16B 1.0000 C16A---H16A 1.0000 C17B---C18B 1.522 (9) C17A---C19A 1.520 (6) C17B---C19B 1.527 (7) C17A---C18A 1.543 (9) C17B---H17B 1.0000 C17A---H17A 1.0000 C18B---H18D 0.9800 C18A---H18A 0.9800 C18B---H18E 0.9800 C18A---H18B 0.9800 C18B---H18F 0.9800 C18A---H18C 0.9800 C19B---H19D 0.9800 C19A---H19A 0.9800 C19B---H19E 0.9800 C19A---H19B 0.9800 C19B---H19F 0.9800 C19A---H19C 0.9800 C20B---H20D 0.9800 C20A---H20A 0.9800 C20B---H20E 0.9800 C20A---H20B 0.9800 C20B---H20F 0.9800 O1A---C1A---O2A 124.4 (6) C7B---C2B---C3B 120.2 (6) O1A---C1A---C2A 124.0 (6) C7B---C2B---C1B 122.1 (6) O2A---C1A---C2A 111.6 (6) C3B---C2B---C1B 117.7 (6) C7A---C2A---C3A 120.2 (6) C4B---C3B---C2B 119.5 (7) C7A---C2A---C1A 122.6 (6) C4B---C3B---H3B 120.3 C3A---C2A---C1A 117.1 (6) C2B---C3B---H3B 120.3 C4A---C3A---C2A 121.3 (6) C5B---C4B---C3B 119.1 (7) C4A---C3A---H3A 119.3 C5B---C4B---H4B 120.5 C2A---C3A---H3A 119.3 C3B---C4B---H4B 120.5 C3A---C4A---C5A 117.9 (6) C4B---C5B---C6B 122.6 (7) C3A---C4A---H4A 121.0 C4B---C5B---Br1B 118.3 (6) C5A---C4A---H4A 121.0 C6B---C5B---Br1B 119.1 (5) C6A---C5A---C4A 121.4 (7) C5B---C6B---C7B 118.2 (6) C6A---C5A---Br1A 119.1 (5) C5B---C6B---H6B 120.9 C4A---C5A---Br1A 119.5 (5) C7B---C6B---H6B 120.9 C5A---C6A---C7A 119.6 (6) C2B---C7B---C6B 120.5 (6) C5A---C6A---H6A 120.2 C2B---C7B---H7B 119.8 C7A---C6A---H6A 120.2 C6B---C7B---H7B 119.8 C2A---C7A---C6A 119.5 (6) O2B---C8B---C9B 106.8 (6) C2A---C7A---H7A 120.3 O2B---C8B---H8B1 110.4 C6A---C7A---H7A 120.3 C9B---C8B---H8B1 110.4 O2A---C8A---C9A 109.6 (6) O2B---C8B---H8B2 110.4 O2A---C8A---H8A1 109.8 C9B---C8B---H8B2 110.4 C9A---C8A---H8A1 109.8 H8B1---C8B---H8B2 108.6 O2A---C8A---H8A2 109.8 O3B---C9B---C8B 108.8 (4) C9A---C8A---H8A2 109.8 O3B---C9B---C10B 103.9 (4) H8A1---C8A---H8A2 108.2 C8B---C9B---C10B 113.9 (4) O3A---C9A---C8A 108.2 (4) O3B---C9B---H9B 110.0 O3A---C9A---C10A 104.0 (4) C8B---C9B---H9B 110.0 C8A---C9A---C10A 113.7 (4) C10B---C9B---H9B 110.0 O3A---C9A---H9A 110.3 O4B---C10B---C9B 103.2 (4) C8A---C9A---H9A 110.3 O4B---C10B---H10C 111.1 C10A---C9A---H9A 110.3 C9B---C10B---H10C 111.1 O4A---C10A---C9A 103.0 (4) O4B---C10B---H10D 111.1 O4A---C10A---H10A 111.2 C9B---C10B---H10D 111.1 C9A---C10A---H10A 111.2 H10C---C10B---H10D 109.1 O4A---C10A---H10B 111.2 O4B---C11B---O3B 105.4 (4) C9A---C10A---H10B 111.2 O4B---C11B---C12B 111.7 (4) H10A---C10A---H10B 109.1 O3B---C11B---C12B 108.6 (4) O4A---C11A---O3A 105.5 (3) O4B---C11B---C16B 109.4 (4) O4A---C11A---C16A 109.9 (4) O3B---C11B---C16B 110.4 (4) O3A---C11A---C16A 110.4 (4) C12B---C11B---C16B 111.3 (4) O4A---C11A---C12A 111.5 (4) C11B---C12B---C13B 111.6 (4) O3A---C11A---C12A 108.9 (4) C11B---C12B---H12C 109.3 C16A---C11A---C12A 110.6 (4) C13B---C12B---H12C 109.3 C13A---C12A---C11A 112.4 (4) C11B---C12B---H12D 109.3 C13A---C12A---H12A 109.1 C13B---C12B---H12D 109.3 C11A---C12A---H12A 109.1 H12C---C12B---H12D 108.0 C13A---C12A---H12B 109.1 C20B---C13B---C14B 111.4 (4) C11A---C12A---H12B 109.1 C20B---C13B---C12B 109.9 (4) H12A---C12A---H12B 107.9 C14B---C13B---C12B 109.5 (4) C12A---C13A---C20A 110.8 (5) C20B---C13B---H13B 108.7 C12A---C13A---C14A 109.0 (4) C14B---C13B---H13B 108.7 C20A---C13A---C14A 110.8 (4) C12B---C13B---H13B 108.7 C12A---C13A---H13A 108.7 C15B---C14B---C13B 112.4 (4) C20A---C13A---H13A 108.7 C15B---C14B---H14C 109.1 C14A---C13A---H13A 108.7 C13B---C14B---H14C 109.1 C15A---C14A---C13A 112.0 (4) C15B---C14B---H14D 109.1 C15A---C14A---H14A 109.2 C13B---C14B---H14D 109.1 C13A---C14A---H14A 109.2 H14C---C14B---H14D 107.9 C15A---C14A---H14B 109.2 C14B---C15B---C16B 112.1 (4) C13A---C14A---H14B 109.2 C14B---C15B---H15C 109.2 H14A---C14A---H14B 107.9 C16B---C15B---H15C 109.2 C14A---C15A---C16A 111.5 (4) C14B---C15B---H15D 109.2 C14A---C15A---H15A 109.3 C16B---C15B---H15D 109.2 C16A---C15A---H15A 109.3 H15C---C15B---H15D 107.9 C14A---C15A---H15B 109.3 C15B---C16B---C11B 109.2 (4) C16A---C15A---H15B 109.3 C15B---C16B---C17B 114.0 (4) H15A---C15A---H15B 108.0 C11B---C16B---C17B 115.3 (4) C11A---C16A---C15A 109.7 (4) C15B---C16B---H16B 105.8 C11A---C16A---C17A 115.0 (4) C11B---C16B---H16B 105.8 C15A---C16A---C17A 113.1 (4) C17B---C16B---H16B 105.8 C11A---C16A---H16A 106.1 C18B---C17B---C19B 109.1 (5) C15A---C16A---H16A 106.1 C18B---C17B---C16B 114.6 (5) C17A---C16A---H16A 106.1 C19B---C17B---C16B 110.0 (4) C19A---C17A---C16A 110.6 (4) C18B---C17B---H17B 107.6 C19A---C17A---C18A 109.7 (5) C19B---C17B---H17B 107.6 C16A---C17A---C18A 114.1 (5) C16B---C17B---H17B 107.6 C19A---C17A---H17A 107.4 C17B---C18B---H18D 109.5 C16A---C17A---H17A 107.4 C17B---C18B---H18E 109.5 C18A---C17A---H17A 107.4 H18D---C18B---H18E 109.5 C17A---C18A---H18A 109.5 C17B---C18B---H18F 109.5 C17A---C18A---H18B 109.5 H18D---C18B---H18F 109.5 H18A---C18A---H18B 109.5 H18E---C18B---H18F 109.5 C17A---C18A---H18C 109.5 C17B---C19B---H19D 109.5 H18A---C18A---H18C 109.5 C17B---C19B---H19E 109.5 H18B---C18A---H18C 109.5 H19D---C19B---H19E 109.5 C17A---C19A---H19A 109.5 C17B---C19B---H19F 109.5 C17A---C19A---H19B 109.5 H19D---C19B---H19F 109.5 H19A---C19A---H19B 109.5 H19E---C19B---H19F 109.5 C17A---C19A---H19C 109.5 C13B---C20B---H20D 109.5 H19A---C19A---H19C 109.5 C13B---C20B---H20E 109.5 H19B---C19A---H19C 109.5 H20D---C20B---H20E 109.5 C13A---C20A---H20A 109.5 C13B---C20B---H20F 109.5 C13A---C20A---H20B 109.5 H20D---C20B---H20F 109.5 H20A---C20A---H20B 109.5 H20E---C20B---H20F 109.5 C13A---C20A---H20C 109.5 C1A---O2A---C8A 117.1 (5) H20A---C20A---H20C 109.5 C9A---O3A---C11A 109.1 (3) H20B---C20A---H20C 109.5 C11A---O4A---C10A 105.8 (4) O1B---C1B---O2B 122.8 (6) C1B---O2B---C8B 119.5 (5) O1B---C1B---C2B 125.2 (6) C11B---O3B---C9B 109.2 (3) O2B---C1B---C2B 111.9 (6) C11B---O4B---C10B 106.0 (4) O1A---C1A---C2A---C7A −176.4 (7) C1B---C2B---C7B---C6B −178.8 (6) O2A---C1A---C2A---C7A 5.4 (9) C5B---C6B---C7B---C2B −0.7 (10) O1A---C1A---C2A---C3A 1.6 (10) O2B---C8B---C9B---O3B 179.1 (4) O2A---C1A---C2A---C3A −176.6 (6) O2B---C8B---C9B---C10B 63.7 (6) C7A---C2A---C3A---C4A −1.5 (10) O3B---C9B---C10B---O4B −22.7 (5) C1A---C2A---C3A---C4A −179.6 (6) C8B---C9B---C10B---O4B 95.5 (5) C2A---C3A---C4A---C5A 1.7 (10) O4B---C11B---C12B---C13B 64.6 (5) C3A---C4A---C5A---C6A −1.7 (10) O3B---C11B---C12B---C13B −179.6 (4) C3A---C4A---C5A---Br1A −179.5 (5) C16B---C11B---C12B---C13B −57.9 (5) C4A---C5A---C6A---C7A 1.5 (10) C11B---C12B---C13B---C20B 176.8 (4) Br1A---C5A---C6A---C7A 179.3 (5) C11B---C12B---C13B---C14B 54.1 (6) C3A---C2A---C7A---C6A 1.3 (10) C20B---C13B---C14B---C15B −174.8 (4) C1A---C2A---C7A---C6A 179.2 (6) C12B---C13B---C14B---C15B −53.0 (6) C5A---C6A---C7A---C2A −1.2 (10) C13B---C14B---C15B---C16B 55.9 (6) O2A---C8A---C9A---O3A −170.9 (4) C14B---C15B---C16B---C11B −56.9 (5) O2A---C8A---C9A---C10A 74.2 (6) C14B---C15B---C16B---C17B 172.5 (4) O3A---C9A---C10A---O4A −23.3 (5) O4B---C11B---C16B---C15B −65.8 (5) C8A---C9A---C10A---O4A 94.1 (5) O3B---C11B---C16B---C15B 178.7 (4) O4A---C11A---C12A---C13A 65.0 (5) C12B---C11B---C16B---C15B 58.0 (5) O3A---C11A---C12A---C13A −179.0 (4) O4B---C11B---C16B---C17B 64.0 (5) C16A---C11A---C12A---C13A −57.5 (6) O3B---C11B---C16B---C17B −51.5 (5) C11A---C12A---C13A---C20A 177.6 (4) C12B---C11B---C16B---C17B −172.1 (4) C11A---C12A---C13A---C14A 55.4 (6) C15B---C16B---C17B---C18B 44.4 (7) C12A---C13A---C14A---C15A −55.0 (6) C11B---C16B---C17B---C18B −83.1 (6) C20A---C13A---C14A---C15A −177.2 (5) C15B---C16B---C17B---C19B −79.0 (5) C13A---C14A---C15A---C16A 57.1 (6) C11B---C16B---C17B---C19B 153.6 (4) O4A---C11A---C16A---C15A −66.9 (5) O1A---C1A---O2A---C8A 5.8 (10) O3A---C11A---C16A---C15A 177.2 (4) C2A---C1A---O2A---C8A −176.0 (5) C12A---C11A---C16A---C15A 56.5 (5) C9A---C8A---O2A---C1A −106.5 (6) O4A---C11A---C16A---C17A 61.9 (5) C8A---C9A---O3A---C11A −118.0 (4) O3A---C11A---C16A---C17A −54.1 (5) C10A---C9A---O3A---C11A 3.2 (5) C12A---C11A---C16A---C17A −174.7 (4) O4A---C11A---O3A---C9A 18.3 (5) C14A---C15A---C16A---C11A −57.0 (5) C16A---C11A---O3A---C9A 137.0 (4) C14A---C15A---C16A---C17A 173.2 (4) C12A---C11A---O3A---C9A −101.4 (4) C11A---C16A---C17A---C19A 150.3 (4) O3A---C11A---O4A---C10A −34.0 (5) C15A---C16A---C17A---C19A −82.6 (5) C16A---C11A---O4A---C10A −153.0 (4) C11A---C16A---C17A---C18A −85.5 (6) C12A---C11A---O4A---C10A 84.2 (5) C15A---C16A---C17A---C18A 41.6 (6) C9A---C10A---O4A---C11A 35.1 (5) O1B---C1B---C2B---C7B 175.2 (7) O1B---C1B---O2B---C8B −4.0 (10) O2B---C1B---C2B---C7B −3.2 (9) C2B---C1B---O2B---C8B 174.5 (6) O1B---C1B---C2B---C3B −2.9 (10) C9B---C8B---O2B---C1B 146.1 (6) O2B---C1B---C2B---C3B 178.7 (6) O4B---C11B---O3B---C9B 18.4 (5) C7B---C2B---C3B---C4B 1.0 (10) C12B---C11B---O3B---C9B −101.4 (4) C1B---C2B---C3B---C4B 179.1 (6) C16B---C11B---O3B---C9B 136.4 (4) C2B---C3B---C4B---C5B 0.2 (10) C8B---C9B---O3B---C11B −119.0 (4) C3B---C4B---C5B---C6B −1.7 (10) C10B---C9B---O3B---C11B 2.8 (5) C3B---C4B---C5B---Br1B 178.4 (5) O3B---C11B---O4B---C10B −33.6 (5) C4B---C5B---C6B---C7B 1.9 (10) C12B---C11B---O4B---C10B 84.1 (5) Br1B---C5B---C6B---C7B −178.1 (5) C16B---C11B---O4B---C10B −152.3 (4) C3B---C2B---C7B---C6B −0.7 (10) C9B---C10B---O4B---C11B 34.6 (5) --------------------------- ------------ --------------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e5002 .table-wrap} ---------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C3A---H3A···O1B^i^ 0.95 2.61 3.295 (8) 129. C13B---H13B···O3B^i^ 1.00 2.69 3.541 (6) 143. C15B---H15C···O3B^i^ 0.99 2.62 3.484 (6) 145. C8A---H8A1···O4A^ii^ 0.99 2.68 3.452 (8) 135. C15A---H15A···O3A^i^ 0.99 2.59 3.486 (6) 150. C3B---H3B···O1A^ii^ 0.95 2.51 3.195 (8) 129. C8B---H8B1···O4B^ii^ 0.99 2.56 3.394 (8) 143. ---------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) *x*, *y*−1, *z*; (ii) *x*, *y*+1, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------------- --------- ------- ----------- ------------- C3*A*---H3*A*⋯O1*B*^i^ 0.95 2.61 3.295 (8) 129 C13*B*---H13*B*⋯O3*B*^i^ 1.00 2.69 3.541 (6) 143 C15*B*---H15*C*⋯O3*B*^i^ 0.99 2.62 3.484 (6) 145 C8*A*---H8*A*1⋯O4*A*^ii^ 0.99 2.68 3.452 (8) 135 C15*A*---H15*A*⋯O3*A*^i^ 0.99 2.59 3.486 (6) 150 C3*B*---H3*B*⋯O1*A*^ii^ 0.95 2.51 3.195 (8) 129 C8*B*---H8*B*1⋯O4*B*^ii^ 0.99 2.56 3.394 (8) 143 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.483213

2011-2-26

PMC3051952

Related literature {#sec1} ================== For background details and the biological activity of quinolines, see: Markees *et al.* (1970[@bb3]); Campbell *et al.* (1998[@bb2]); Bhat *et al.* (2005[@bb1]). For the biological activity of chalcones, see: Wu *et al.* (2006[@bb6]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~25~H~18~ClNO*M* *~r~* = 383.85Triclinic,*a* = 6.5376 (2) Å*b* = 10.0345 (4) Å*c* = 15.6545 (6) Åα = 90.845 (3)°β = 95.521 (3)°γ = 107.035 (3)°*V* = 976.36 (6) Å^3^*Z* = 2Cu *K*α radiationμ = 1.84 mm^−1^*T* = 295 K0.52 × 0.18 × 0.12 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcalibur Ruby Gemini diffractometerAbsorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009[@bb4]) *T* ~min~ = 0.544, *T* ~max~ = 1.0007607 measured reflections4065 independent reflections3402 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.019 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.049*wR*(*F* ^2^) = 0.160*S* = 1.044065 reflections254 parametersH-atom parameters constrainedΔρ~max~ = 0.29 e Å^−3^Δρ~min~ = −0.24 e Å^−3^ {#d5e362} Data collection: *CrysAlis PRO* (Oxford Diffraction, 2009[@bb4]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb5]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb5]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004661/ez2231sup1.cif](http://dx.doi.org/10.1107/S1600536811004661/ez2231sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004661/ez2231Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004661/ez2231Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?ez2231&file=ez2231sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?ez2231sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?ez2231&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [EZ2231](http://scripts.iucr.org/cgi-bin/sendsup?ez2231)). RJB wishes to acknowledge the NSF--MRI program (grant CHE-0619278) for funds to purchase the diffractometer. Comment ======= Quinoline derivatives are very important compounds because of their wide occurrence in natural products and biologically active compounds (Markees *et al.*, 1970; Campbell *et al.*, 1998). Additionally, chalcone derivatives are attracting the increasing interest of many researchers, because of their bioactivity such as antimicrobial, antimalarial, anticancer, antiviral, antitumor activities (Bhat *et al.*, 2005). Introduction of the quinoline scaffold into chalcone compounds can bring about significant changes in biological effects (Wu *et al.*, 2006). The crystal structure of the title compound shows that the molecules are isolated and not involved in intermolecular interactions. However, both the phenyl ring and the quinoline rings are involved in π--π interactions (centroid to centroid distances of 3.428 (2) and 3.770 (2) Å, respectively). Experimental {#experimental} ============ A mixture of 3-acetyl-2-methyl-4-phenylquinoline (2.61 g, 0.01 M), 4-chlorobenzaldehyde (1.40 g, 0.01 M) and KOH (1.12 g, 0.02 M ) in distilled ethanol (20 ml) was stirred for 12 h at room temperature. The resulting mixture was neutralized with dilute acetic acid. The resultant solid was filtered, dried and purified by column chromatography using 1:1 mixture of ethyl acetate and hexane. Re-crystallization was by slow evaporation of acetone solution of (I) which yielded colourless needle type crystals. M.pt. 453-455 K. Yield: 72%. Refinement {#refinement} ========== H atoms were placed in geometrically idealized positions and constrained to ride on their parent atoms with a C---H distances of 0.93 and 0.96 Å *U*~iso~(H) = 1.2*U*~eq~(C) and 0.98 Å for CH~3~ \[*U*~iso~(H) = 1.5*U*~eq~(C)\]. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Diagram of the title compound, C25H18ClNO, showing atom labeling. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The molecular packing for C25H18ClNO viewed down the a axis. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e154 .table-wrap} ----------------------- --------------------------------------- C~25~H~18~ClNO *Z* = 2 *M~r~* = 383.85 *F*(000) = 400 Triclinic, *P*1 *D*~x~ = 1.306 Mg m^−3^ Hall symbol: -P 1 Cu *K*α radiation, λ = 1.54184 Å *a* = 6.5376 (2) Å Cell parameters from 4929 reflections *b* = 10.0345 (4) Å θ = 5.3--77.1° *c* = 15.6545 (6) Å µ = 1.84 mm^−1^ α = 90.845 (3)° *T* = 295 K β = 95.521 (3)° Needle, colorless γ = 107.035 (3)° 0.52 × 0.18 × 0.12 mm *V* = 976.36 (6) Å^3^ ----------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e285 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction Xcalibur Ruby Gemini diffractometer 4065 independent reflections Radiation source: Enhance (Cu) X-ray Source 3402 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.019 Detector resolution: 10.5081 pixels mm^-1^ θ~max~ = 77.4°, θ~min~ = 5.3° ω scans *h* = −3→8 Absorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009) *k* = −12→12 *T*~min~ = 0.544, *T*~max~ = 1.000 *l* = −19→19 7607 measured reflections ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e405 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.049 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.160 H-atom parameters constrained *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.1125*P*)^2^ + 0.0628*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4065 reflections (Δ/σ)~max~ = 0.001 254 parameters Δρ~max~ = 0.29 e Å^−3^ 0 restraints Δρ~min~ = −0.24 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e562 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e661 .table-wrap} ------ --------------- --------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl −0.41045 (10) −0.24622 (7) 0.99317 (4) 0.1004 (3) O 0.6524 (2) 0.15628 (12) 0.65464 (9) 0.0678 (3) N 0.22876 (19) 0.41447 (12) 0.55076 (8) 0.0485 (3) C1 0.0479 (2) 0.02060 (15) 0.82219 (9) 0.0505 (3) C2 0.0750 (3) −0.10510 (17) 0.85056 (12) 0.0603 (4) H2A 0.1889 −0.1338 0.8340 0.072\* C3 −0.0651 (3) −0.18756 (18) 0.90290 (12) 0.0671 (4) H3A −0.0465 −0.2714 0.9212 0.081\* C4 −0.2326 (3) −0.14364 (19) 0.92754 (11) 0.0638 (4) C5 −0.2633 (3) −0.0196 (2) 0.90095 (13) 0.0696 (4) H5A −0.3765 0.0092 0.9181 0.083\* C6 −0.1218 (3) 0.06090 (18) 0.84822 (12) 0.0620 (4) H6A −0.1416 0.1444 0.8299 0.074\* C7 0.1907 (3) 0.11066 (14) 0.76588 (10) 0.0515 (3) H7A 0.1646 0.1949 0.7532 0.062\* C8 0.3530 (3) 0.08465 (14) 0.73113 (10) 0.0543 (4) H8A 0.3797 0.0001 0.7420 0.065\* C9 0.4934 (2) 0.18093 (14) 0.67652 (10) 0.0488 (3) C10 0.4416 (2) 0.31192 (13) 0.64783 (8) 0.0434 (3) C11 0.2682 (2) 0.30333 (14) 0.58322 (9) 0.0463 (3) C12 0.1198 (3) 0.16483 (16) 0.54764 (11) 0.0588 (4) H12A 0.0640 0.1744 0.4898 0.088\* H12B 0.0030 0.1345 0.5824 0.088\* H12C 0.1978 0.0973 0.5480 0.088\* C13 0.3573 (2) 0.54308 (14) 0.58070 (8) 0.0447 (3) C14 0.3076 (3) 0.66120 (16) 0.54642 (10) 0.0547 (4) H14A 0.1939 0.6494 0.5037 0.066\* C15 0.4265 (3) 0.79222 (17) 0.57609 (12) 0.0622 (4) H15A 0.3928 0.8693 0.5535 0.075\* C16 0.5992 (3) 0.81211 (15) 0.64035 (12) 0.0596 (4) H16A 0.6782 0.9020 0.6602 0.072\* C17 0.6522 (3) 0.70013 (15) 0.67399 (10) 0.0511 (3) H17A 0.7675 0.7145 0.7162 0.061\* C18 0.5324 (2) 0.56215 (13) 0.64491 (8) 0.0422 (3) C19 0.5751 (2) 0.44052 (13) 0.67829 (8) 0.0414 (3) C20 0.7569 (2) 0.45328 (13) 0.74642 (8) 0.0437 (3) C21 0.9681 (3) 0.50871 (19) 0.72893 (11) 0.0599 (4) H21A 0.9977 0.5393 0.6744 0.072\* C22 1.1357 (3) 0.5186 (2) 0.79260 (14) 0.0710 (5) H22A 1.2772 0.5567 0.7807 0.085\* C23 1.0937 (3) 0.4725 (2) 0.87317 (12) 0.0673 (5) H23A 1.2066 0.4777 0.9153 0.081\* C24 0.8847 (3) 0.41878 (18) 0.89139 (11) 0.0623 (4) H24A 0.8563 0.3886 0.9461 0.075\* C25 0.7164 (2) 0.40945 (15) 0.82857 (9) 0.0512 (3) H25A 0.5753 0.3736 0.8414 0.061\* ------ --------------- --------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1283 .table-wrap} ----- ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl 0.0863 (4) 0.1060 (5) 0.0916 (4) −0.0055 (3) 0.0264 (3) 0.0365 (3) O 0.0731 (7) 0.0532 (6) 0.0893 (8) 0.0308 (6) 0.0285 (6) 0.0164 (6) N 0.0481 (6) 0.0462 (6) 0.0503 (6) 0.0133 (5) 0.0028 (5) 0.0012 (5) C1 0.0537 (8) 0.0416 (7) 0.0515 (7) 0.0073 (6) 0.0036 (6) 0.0039 (5) C2 0.0624 (9) 0.0487 (8) 0.0697 (10) 0.0146 (7) 0.0107 (7) 0.0116 (7) C3 0.0731 (11) 0.0506 (8) 0.0718 (10) 0.0093 (7) 0.0057 (8) 0.0178 (7) C4 0.0599 (9) 0.0639 (9) 0.0542 (8) −0.0025 (7) 0.0051 (7) 0.0109 (7) C5 0.0627 (10) 0.0746 (11) 0.0719 (11) 0.0178 (8) 0.0168 (8) 0.0097 (8) C6 0.0667 (10) 0.0536 (8) 0.0677 (9) 0.0189 (7) 0.0126 (7) 0.0111 (7) C7 0.0600 (8) 0.0358 (6) 0.0576 (8) 0.0121 (6) 0.0061 (6) 0.0067 (5) C8 0.0636 (9) 0.0368 (6) 0.0634 (8) 0.0146 (6) 0.0107 (7) 0.0104 (6) C9 0.0551 (8) 0.0377 (6) 0.0540 (7) 0.0135 (6) 0.0082 (6) 0.0043 (5) C10 0.0478 (7) 0.0374 (6) 0.0460 (6) 0.0120 (5) 0.0112 (5) 0.0043 (5) C11 0.0475 (7) 0.0404 (6) 0.0497 (7) 0.0102 (5) 0.0079 (5) −0.0003 (5) C12 0.0581 (8) 0.0442 (7) 0.0668 (9) 0.0065 (6) −0.0008 (7) −0.0035 (6) C13 0.0488 (7) 0.0419 (6) 0.0454 (6) 0.0152 (5) 0.0093 (5) 0.0047 (5) C14 0.0580 (8) 0.0511 (8) 0.0578 (8) 0.0214 (6) 0.0024 (6) 0.0100 (6) C15 0.0742 (10) 0.0447 (7) 0.0734 (10) 0.0255 (7) 0.0080 (8) 0.0132 (7) C16 0.0712 (10) 0.0368 (7) 0.0684 (9) 0.0124 (6) 0.0065 (7) 0.0008 (6) C17 0.0579 (8) 0.0413 (7) 0.0522 (7) 0.0121 (6) 0.0040 (6) 0.0016 (5) C18 0.0492 (7) 0.0374 (6) 0.0411 (6) 0.0127 (5) 0.0099 (5) 0.0036 (5) C19 0.0466 (6) 0.0390 (6) 0.0403 (6) 0.0134 (5) 0.0099 (5) 0.0039 (5) C20 0.0491 (7) 0.0386 (6) 0.0454 (6) 0.0153 (5) 0.0068 (5) 0.0021 (5) C21 0.0529 (8) 0.0722 (10) 0.0563 (8) 0.0185 (7) 0.0134 (6) 0.0028 (7) C22 0.0461 (8) 0.0879 (13) 0.0803 (12) 0.0219 (8) 0.0073 (8) −0.0080 (9) C23 0.0642 (10) 0.0716 (10) 0.0683 (10) 0.0301 (8) −0.0129 (8) −0.0077 (8) C24 0.0742 (10) 0.0602 (9) 0.0508 (8) 0.0198 (8) −0.0021 (7) 0.0065 (6) C25 0.0544 (8) 0.0476 (7) 0.0488 (7) 0.0108 (6) 0.0058 (6) 0.0060 (5) ----- ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1768 .table-wrap} ----------------------- -------------- ----------------------- -------------- Cl---C4 1.7399 (17) C12---H12C 0.9600 O---C9 1.2149 (19) C13---C18 1.4149 (19) N---C11 1.3147 (18) C13---C14 1.4173 (19) N---C13 1.3646 (18) C14---C15 1.365 (2) C1---C6 1.380 (2) C14---H14A 0.9300 C1---C2 1.397 (2) C15---C16 1.403 (2) C1---C7 1.467 (2) C15---H15A 0.9300 C2---C3 1.384 (2) C16---C17 1.367 (2) C2---H2A 0.9300 C16---H16A 0.9300 C3---C4 1.379 (3) C17---C18 1.4196 (19) C3---H3A 0.9300 C17---H17A 0.9300 C4---C5 1.381 (3) C18---C19 1.4253 (17) C5---C6 1.385 (2) C19---C20 1.4929 (18) C5---H5A 0.9300 C20---C21 1.385 (2) C6---H6A 0.9300 C20---C25 1.390 (2) C7---C8 1.326 (2) C21---C22 1.388 (2) C7---H7A 0.9300 C21---H21A 0.9300 C8---C9 1.471 (2) C22---C23 1.375 (3) C8---H8A 0.9300 C22---H22A 0.9300 C9---C10 1.5142 (18) C23---C24 1.374 (3) C10---C19 1.3770 (18) C23---H23A 0.9300 C10---C11 1.4267 (19) C24---C25 1.384 (2) C11---C12 1.5053 (19) C24---H24A 0.9300 C12---H12A 0.9600 C25---H25A 0.9300 C12---H12B 0.9600 C11---N---C13 118.73 (12) N---C13---C18 122.82 (12) C6---C1---C2 118.20 (15) N---C13---C14 117.62 (13) C6---C1---C7 118.85 (14) C18---C13---C14 119.55 (13) C2---C1---C7 122.95 (14) C15---C14---C13 120.05 (14) C3---C2---C1 120.99 (16) C15---C14---H14A 120.0 C3---C2---H2A 119.5 C13---C14---H14A 120.0 C1---C2---H2A 119.5 C14---C15---C16 120.79 (14) C4---C3---C2 119.06 (16) C14---C15---H15A 119.6 C4---C3---H3A 120.5 C16---C15---H15A 119.6 C2---C3---H3A 120.5 C17---C16---C15 120.43 (14) C3---C4---C5 121.40 (16) C17---C16---H16A 119.8 C3---C4---Cl 119.65 (14) C15---C16---H16A 119.8 C5---C4---Cl 118.96 (15) C16---C17---C18 120.51 (14) C4---C5---C6 118.56 (17) C16---C17---H17A 119.7 C4---C5---H5A 120.7 C18---C17---H17A 119.7 C6---C5---H5A 120.7 C13---C18---C17 118.66 (12) C1---C6---C5 121.79 (16) C13---C18---C19 117.70 (12) C1---C6---H6A 119.1 C17---C18---C19 123.63 (13) C5---C6---H6A 119.1 C10---C19---C18 118.40 (12) C8---C7---C1 126.86 (13) C10---C19---C20 121.16 (12) C8---C7---H7A 116.6 C18---C19---C20 120.42 (11) C1---C7---H7A 116.6 C21---C20---C25 118.93 (14) C7---C8---C9 124.21 (13) C21---C20---C19 120.71 (13) C7---C8---H8A 117.9 C25---C20---C19 120.37 (13) C9---C8---H8A 117.9 C20---C21---C22 120.14 (16) O---C9---C8 120.17 (13) C20---C21---H21A 119.9 O---C9---C10 119.62 (13) C22---C21---H21A 119.9 C8---C9---C10 120.21 (12) C23---C22---C21 120.37 (16) C19---C10---C11 119.78 (12) C23---C22---H22A 119.8 C19---C10---C9 119.63 (12) C21---C22---H22A 119.8 C11---C10---C9 120.30 (12) C24---C23---C22 119.90 (16) N---C11---C10 122.56 (12) C24---C23---H23A 120.1 N---C11---C12 116.00 (13) C22---C23---H23A 120.1 C10---C11---C12 121.44 (13) C23---C24---C25 120.18 (16) C11---C12---H12A 109.5 C23---C24---H24A 119.9 C11---C12---H12B 109.5 C25---C24---H24A 119.9 H12A---C12---H12B 109.5 C24---C25---C20 120.47 (15) C11---C12---H12C 109.5 C24---C25---H25A 119.8 H12A---C12---H12C 109.5 C20---C25---H25A 119.8 H12B---C12---H12C 109.5 C6---C1---C2---C3 0.4 (3) C13---C14---C15---C16 0.2 (3) C7---C1---C2---C3 −179.28 (15) C14---C15---C16---C17 0.4 (3) C1---C2---C3---C4 −0.5 (3) C15---C16---C17---C18 −0.5 (3) C2---C3---C4---C5 0.1 (3) N---C13---C18---C17 −177.84 (13) C2---C3---C4---Cl 179.88 (13) C14---C13---C18---C17 0.8 (2) C3---C4---C5---C6 0.2 (3) N---C13---C18---C19 0.69 (19) Cl---C4---C5---C6 −179.55 (14) C14---C13---C18---C19 179.30 (12) C2---C1---C6---C5 −0.1 (3) C16---C17---C18---C13 −0.1 (2) C7---C1---C6---C5 179.63 (16) C16---C17---C18---C19 −178.57 (13) C4---C5---C6---C1 −0.2 (3) C11---C10---C19---C18 1.17 (19) C6---C1---C7---C8 −176.02 (16) C9---C10---C19---C18 174.99 (11) C2---C1---C7---C8 3.7 (3) C11---C10---C19---C20 179.45 (11) C1---C7---C8---C9 −178.63 (14) C9---C10---C19---C20 −6.74 (19) C7---C8---C9---O 172.12 (16) C13---C18---C19---C10 −1.45 (18) C7---C8---C9---C10 −7.4 (2) C17---C18---C19---C10 177.00 (13) O---C9---C10---C19 −67.03 (19) C13---C18---C19---C20 −179.74 (11) C8---C9---C10---C19 112.49 (15) C17---C18---C19---C20 −1.3 (2) O---C9---C10---C11 106.75 (17) C10---C19---C20---C21 114.65 (16) C8---C9---C10---C11 −73.73 (18) C18---C19---C20---C21 −67.11 (18) C13---N---C11---C10 −0.7 (2) C10---C19---C20---C25 −65.29 (17) C13---N---C11---C12 179.73 (13) C18---C19---C20---C25 112.95 (15) C19---C10---C11---N −0.1 (2) C25---C20---C21---C22 0.6 (2) C9---C10---C11---N −173.84 (13) C19---C20---C21---C22 −179.32 (15) C19---C10---C11---C12 179.44 (13) C20---C21---C22---C23 0.6 (3) C9---C10---C11---C12 5.7 (2) C21---C22---C23---C24 −1.3 (3) C11---N---C13---C18 0.4 (2) C22---C23---C24---C25 0.8 (3) C11---N---C13---C14 −178.23 (13) C23---C24---C25---C20 0.5 (2) N---C13---C14---C15 177.86 (15) C21---C20---C25---C24 −1.2 (2) C18---C13---C14---C15 −0.8 (2) C19---C20---C25---C24 178.80 (13) ----------------------- -------------- ----------------------- -------------- :::

PubMed Central

2024-06-05T04:04:17.495524

2011-2-12

PMC3051953

Related literature {#sec1} ================== For general background to the Wittig reaction, see: Wittig & Schöllkopf (1954[@bb13]); Wittig & Haag (1955[@bb12]). For the synthesis, applications and biological activity of triphenyl­phospho­nium compounds, see: Rideout *et al.* (1989[@bb8]); Cooper *et al.* (2001[@bb2]); Dubios & Lin (1978[@bb4]); Lou & Shang (2000[@bb7]); Calderon *et al.* (2008[@bb1]). For related structures, see: Shafiq *et al.* (2008[@bb9]); Wu *et al.* (2007[@bb3]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~20~H~20~OP^+^·Cl^−^*M* *~r~* = 342.78Monoclinic,*a* = 14.1988 (4) Å*b* = 12.5743 (3) Å*c* = 19.7098 (6) Åβ = 92.510 (2)°*V* = 3515.61 (17) Å^3^*Z* = 8Mo *K*α radiationμ = 0.31 mm^−1^*T* = 296 K0.76 × 0.71 × 0.60 mm ### Data collection {#sec2.1.2} Stoe IPDS 2 diffractometerAbsorption correction: integration (*X-RED32*; Stoe & Cie, 2002[@bb11]) *T* ~min~ = 0.599, *T* ~max~ = 0.90526668 measured reflections3725 independent reflections3317 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.046 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.036*wR*(*F* ^2^) = 0.101*S* = 1.073725 reflections230 parameters35 restraintsH-atom parameters constrainedΔρ~max~ = 0.42 e Å^−3^Δρ~min~ = −0.24 e Å^−3^ {#d5e510} Data collection: *X-AREA* (Stoe & Cie, 2002[@bb11]); cell refinement: *X-AREA*; data reduction: *X-RED32* (Stoe & Cie, 2002[@bb11]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb10]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb10]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb5]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb6]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S160053681100482X/rz2551sup1.cif](http://dx.doi.org/10.1107/S160053681100482X/rz2551sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S160053681100482X/rz2551Isup2.hkl](http://dx.doi.org/10.1107/S160053681100482X/rz2551Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?rz2551&file=rz2551sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?rz2551sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?rz2551&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [RZ2551](http://scripts.iucr.org/cgi-bin/sendsup?rz2551)). This work was financially supported by the BAP Selcuk University in Turkey. The authors acknowledge the Faculty of Arts and Sciences, Ondokuz Mayıs University, Turkey, for the use of the Stoe IPDS 2 diffractometer (purchased under grant No. F279 of the University Research Fund). Comment ======= Triphenylphosphonium compounds and their various derivatives are key reagents in the Wittig reactions and are used to convert aldehydes and ketones into alkenes (Wittig & Schöllkopf, 1954; Wittig & Haag, 1955), specifically in applications ranging from the synthesis of simple alkenes to the construction of complex biologically active molecules in the pharmaceutical research (Rideout *et al.*, 1989; Cooper *et al.*, 2001). They are also an important class of isoaromatic compounds and have widespread applications for their antimicrobial and anticancer activities (Dubios & Lin, 1978; Lou & Shang, 2000). In addition, phosphonium compounds enhance flame retardancy mainly in textile industry (Calderon *et al.*, 2008). The title compound crystallizes with one cation and anion in the asymmetric unit (Fig. 1). In the molecule, the hydroxyethyl group (C19---C20---O1) is disordered over two orientations with site occupancy factors of 0.554 (4) and 0.446 (4), respectively. The dihedral angles between rings A (C1---C6), B (C7---C12) and C (C13---C18) are A/B = 73.79 (1)°, A/C = 67.88 (1)° and B/C = 70.96 (1)°. All the geometric parameters are in agreement with those observed in related compounds (Shafiq *et al.*, 2008; Wu *et al.*, 2007). The minimum separation between the P^+^ and Cl^-^ centres is 4.211 (1)Å. In the crystal structure, intermolecular C---H···Cl and C---H···O hydrogen bonds (Table 1) link the ions to form chains parallel to the *b* axis (Fig. 2). Experimental {#experimental} ============ (2-Hydroxyethyl)triphenylphosphonium chloride powder was purchased from Merck. Single crystals suitable for X-ray ananlysis were grown by slow evaporation of a concentrated acetonitrile solution. Refinement {#refinement} ========== H atoms were positioned geometrically and treated using a riding model, fixing the bond lengths at 0.93, 0.97 and 0.82 Å for aromatic CH, CH~2~, and OH groups, respectively. The displacement parameters of the H atoms were constrained as *U*~iso~(H) = 1.2*U*~eq~(C) or 1.5*U*~eq~(O). In the molecule, the hydroxyethyl group, (C19---C20---O1) is disordered over two orientations with site occupancy factors of 0.554 (4) and 0.446 (4). The disordered atoms were refined using the following restraints: SIMU, DELU and SADI (*SHELXL*; Sheldrick, 2008). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The structure of the title compound, with 30% probability displacement ellipsoids and the atom-numbering scheme. The H atoms are omitted for clarity. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The crystal packing of the title compound. Intermolecular hydrogen bonds are drawn as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e143 .table-wrap} ------------------------- ---------------------------------------- C~20~H~20~OP^+^·Cl^−^ *F*(000) = 1440 *M~r~* = 342.78 *D*~x~ = 1.295 Mg m^−3^ Monoclinic, *C*2/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -C 2yc Cell parameters from 36925 reflections *a* = 14.1988 (4) Å θ = 2.1--27.3° *b* = 12.5743 (3) Å µ = 0.31 mm^−1^ *c* = 19.7098 (6) Å *T* = 296 K β = 92.510 (2)° Prism, colorless *V* = 3515.61 (17) Å^3^ 0.76 × 0.71 × 0.60 mm *Z* = 8 ------------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e271 .table-wrap} ------------------------------------------------------------------ -------------------------------------- Stoe IPDS 2 diffractometer 3725 independent reflections Radiation source: fine-focus sealed tube 3317 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.046 Detector resolution: 6.67 pixels mm^-1^ θ~max~ = 26.8°, θ~min~ = 2.1° rotation method scans *h* = −17→17 Absorption correction: integration (*X-RED32*; Stoe & Cie, 2002) *k* = −15→15 *T*~min~ = 0.599, *T*~max~ = 0.905 *l* = −24→24 26668 measured reflections ------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e389 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.036 H-atom parameters constrained *wR*(*F*^2^) = 0.101 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0495*P*)^2^ + 1.6584*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.07 (Δ/σ)~max~ = 0.001 3725 reflections Δρ~max~ = 0.42 e Å^−3^ 230 parameters Δρ~min~ = −0.24 e Å^−3^ 35 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.0106 (6) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e570 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. 360 frames, detector distance = 120 mm Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e675 .table-wrap} ------ -------------- -------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) Cl1 0.25807 (3) 0.74387 (4) 0.18184 (2) 0.06015 (16) P1 0.22348 (3) 0.60936 (3) 0.37482 (2) 0.04301 (14) C1 0.34518 (11) 0.64165 (12) 0.39231 (8) 0.0449 (3) C2 0.39771 (12) 0.68183 (14) 0.33985 (9) 0.0545 (4) H2 0.3690 0.6949 0.2973 0.065\* C3 0.49228 (13) 0.70205 (16) 0.35142 (11) 0.0633 (5) H3 0.5273 0.7292 0.3166 0.076\* C4 0.53530 (13) 0.68242 (17) 0.41386 (11) 0.0655 (5) H4 0.5994 0.6958 0.4210 0.079\* C5 0.48442 (14) 0.64332 (17) 0.46574 (10) 0.0652 (5) H5 0.5140 0.6305 0.5080 0.078\* C6 0.38882 (12) 0.62269 (15) 0.45550 (9) 0.0543 (4) H6 0.3542 0.5963 0.4908 0.065\* C7 0.18175 (11) 0.54012 (13) 0.44737 (8) 0.0457 (3) C8 0.21070 (14) 0.43627 (15) 0.46028 (9) 0.0606 (5) H8 0.2449 0.3994 0.4287 0.073\* C9 0.18823 (16) 0.38821 (15) 0.52053 (10) 0.0665 (5) H9 0.2087 0.3193 0.5298 0.080\* C10 0.13605 (13) 0.44101 (16) 0.56677 (9) 0.0608 (5) H10 0.1221 0.4082 0.6074 0.073\* C11 0.10449 (13) 0.54206 (17) 0.55326 (9) 0.0617 (5) H11 0.0675 0.5769 0.5841 0.074\* C12 0.12762 (12) 0.59252 (14) 0.49368 (9) 0.0527 (4) H12 0.1068 0.6615 0.4848 0.063\* C13 0.15396 (11) 0.72717 (13) 0.36117 (8) 0.0450 (3) C14 0.05633 (12) 0.71654 (16) 0.34952 (10) 0.0581 (4) H14 0.0288 0.6494 0.3490 0.070\* C15 0.00133 (13) 0.80521 (18) 0.33882 (10) 0.0667 (5) H15 −0.0634 0.7980 0.3308 0.080\* C16 0.04150 (15) 0.90428 (17) 0.33992 (10) 0.0677 (5) H16 0.0037 0.9640 0.3329 0.081\* C17 0.13779 (15) 0.91629 (15) 0.35143 (10) 0.0629 (5) H17 0.1646 0.9838 0.3522 0.076\* C18 0.19394 (12) 0.82728 (13) 0.36184 (9) 0.0510 (4) H18 0.2587 0.8349 0.3693 0.061\* C19 0.22152 (13) 0.52738 (14) 0.29984 (8) 0.0548 (4) H19A 0.2554 0.5656 0.2658 0.066\* 0.554 (4) H19B 0.2580 0.4641 0.3111 0.066\* 0.554 (4) H19C 0.2453 0.5679 0.2624 0.066\* 0.446 (4) H19D 0.2628 0.4668 0.3078 0.066\* 0.446 (4) O1A 0.0805 (2) 0.4345 (3) 0.31380 (16) 0.0879 (10) 0.554 (4) H1A 0.1117 0.3827 0.3265 0.132\* 0.554 (4) C20A 0.1293 (4) 0.4906 (5) 0.2660 (4) 0.0667 (14) 0.554 (4) H20A 0.0926 0.5514 0.2500 0.080\* 0.554 (4) H20B 0.1414 0.4454 0.2275 0.080\* 0.554 (4) O1B 0.1262 (3) 0.4096 (3) 0.23172 (16) 0.0766 (11) 0.446 (4) H1B 0.1513 0.3564 0.2483 0.115\* 0.446 (4) C20B 0.1230 (4) 0.4883 (6) 0.2807 (6) 0.0672 (17) 0.446 (4) H20C 0.0940 0.4603 0.3206 0.081\* 0.446 (4) H20D 0.0848 0.5471 0.2634 0.081\* 0.446 (4) ------ -------------- -------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1332 .table-wrap} ------ ------------- ------------- ------------- --------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.0621 (3) 0.0621 (3) 0.0561 (3) 0.0009 (2) 0.0013 (2) 0.00363 (19) P1 0.0439 (2) 0.0434 (2) 0.0418 (2) −0.00118 (16) 0.00250 (15) 0.00225 (15) C1 0.0427 (8) 0.0448 (8) 0.0472 (8) 0.0022 (6) 0.0027 (6) −0.0008 (6) C2 0.0510 (9) 0.0598 (10) 0.0529 (9) −0.0018 (8) 0.0037 (7) 0.0069 (7) C3 0.0509 (10) 0.0718 (12) 0.0680 (11) −0.0066 (9) 0.0106 (8) 0.0017 (9) C4 0.0458 (9) 0.0720 (12) 0.0784 (13) −0.0019 (8) 0.0006 (9) −0.0108 (10) C5 0.0562 (10) 0.0778 (13) 0.0604 (11) 0.0042 (9) −0.0114 (8) −0.0055 (9) C6 0.0543 (9) 0.0613 (10) 0.0471 (8) 0.0014 (8) 0.0019 (7) −0.0021 (7) C7 0.0487 (8) 0.0458 (8) 0.0426 (7) −0.0049 (6) 0.0026 (6) 0.0010 (6) C8 0.0772 (12) 0.0519 (10) 0.0536 (9) 0.0067 (9) 0.0128 (9) 0.0036 (8) C9 0.0862 (14) 0.0535 (10) 0.0602 (11) 0.0025 (9) 0.0076 (10) 0.0128 (8) C10 0.0636 (11) 0.0698 (12) 0.0495 (9) −0.0113 (9) 0.0074 (8) 0.0110 (8) C11 0.0621 (10) 0.0727 (12) 0.0513 (9) −0.0048 (9) 0.0144 (8) −0.0046 (8) C12 0.0568 (9) 0.0496 (9) 0.0522 (9) −0.0016 (7) 0.0067 (7) −0.0014 (7) C13 0.0438 (8) 0.0482 (8) 0.0432 (7) 0.0017 (6) 0.0033 (6) 0.0035 (6) C14 0.0468 (9) 0.0621 (10) 0.0654 (11) −0.0026 (8) 0.0017 (8) 0.0010 (8) C15 0.0475 (10) 0.0838 (14) 0.0683 (12) 0.0128 (9) −0.0026 (8) −0.0017 (10) C16 0.0713 (12) 0.0689 (12) 0.0626 (11) 0.0249 (10) 0.0007 (9) 0.0045 (9) C17 0.0767 (13) 0.0480 (9) 0.0644 (11) 0.0044 (9) 0.0073 (9) 0.0040 (8) C18 0.0495 (9) 0.0510 (9) 0.0528 (9) −0.0004 (7) 0.0043 (7) 0.0021 (7) C19 0.0666 (10) 0.0499 (9) 0.0476 (8) −0.0022 (8) 0.0013 (7) −0.0016 (7) O1A 0.0844 (19) 0.087 (2) 0.091 (2) −0.0292 (16) −0.0075 (15) 0.0052 (17) C20A 0.080 (2) 0.0603 (19) 0.058 (3) −0.0002 (17) −0.0162 (18) −0.0101 (17) O1B 0.086 (2) 0.075 (2) 0.067 (2) −0.0013 (17) −0.0132 (16) −0.0231 (16) C20B 0.073 (2) 0.064 (2) 0.063 (4) 0.003 (2) −0.018 (2) −0.014 (2) ------ ------------- ------------- ------------- --------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1816 .table-wrap} ---------------------- -------------- ------------------------- -------------- P1---C1 1.7938 (16) C13---C18 1.381 (2) P1---C13 1.7939 (16) C13---C14 1.401 (2) P1---C7 1.7968 (15) C14---C15 1.372 (3) P1---C19 1.8009 (17) C14---H14 0.9300 C1---C6 1.387 (2) C15---C16 1.370 (3) C1---C2 1.396 (2) C15---H15 0.9300 C2---C3 1.376 (2) C16---C17 1.384 (3) C2---H2 0.9300 C16---H16 0.9300 C3---C4 1.372 (3) C17---C18 1.384 (2) C3---H3 0.9300 C17---H17 0.9300 C4---C5 1.369 (3) C18---H18 0.9300 C4---H4 0.9300 C19---C20A 1.515 (4) C5---C6 1.388 (3) C19---C20B 1.516 (4) C5---H5 0.9300 C19---H19A 0.9700 C6---H6 0.9300 C19---H19B 0.9700 C7---C12 1.385 (2) C19---H19C 0.9700 C7---C8 1.389 (2) C19---H19D 0.9700 C8---C9 1.382 (2) O1A---C20A 1.386 (8) C8---H8 0.9300 O1A---H1A 0.8200 C9---C10 1.371 (3) C20A---H20A 0.9700 C9---H9 0.9300 C20A---H20B 0.9700 C10---C11 1.370 (3) O1B---C20B 1.383 (8) C10---H10 0.9300 O1B---H1B 0.8200 C11---C12 1.387 (2) C20B---H20C 0.9700 C11---H11 0.9300 C20B---H20D 0.9700 C12---H12 0.9300 C1---P1---C13 111.16 (7) C15---C14---H14 120.0 C1---P1---C7 107.77 (7) C13---C14---H14 120.0 C13---P1---C7 108.73 (7) C16---C15---C14 120.17 (18) C1---P1---C19 105.51 (8) C16---C15---H15 119.9 C13---P1---C19 111.16 (8) C14---C15---H15 119.9 C7---P1---C19 112.45 (8) C15---C16---C17 120.62 (18) C6---C1---C2 119.68 (15) C15---C16---H16 119.7 C6---C1---P1 121.49 (12) C17---C16---H16 119.7 C2---C1---P1 118.76 (12) C18---C17---C16 119.63 (18) C3---C2---C1 119.56 (17) C18---C17---H17 120.2 C3---C2---H2 120.2 C16---C17---H17 120.2 C1---C2---H2 120.2 C13---C18---C17 120.12 (16) C4---C3---C2 120.56 (18) C13---C18---H18 119.9 C4---C3---H3 119.7 C17---C18---H18 119.9 C2---C3---H3 119.7 C20A---C19---P1 121.2 (4) C5---C4---C3 120.38 (18) C20B---C19---P1 111.8 (4) C5---C4---H4 119.8 C20A---C19---H19A 107.0 C3---C4---H4 119.8 C20B---C19---H19A 118.0 C4---C5---C6 120.22 (18) P1---C19---H19A 107.0 C4---C5---H5 119.9 C20A---C19---H19B 107.0 C6---C5---H5 119.9 C20B---C19---H19B 105.6 C1---C6---C5 119.60 (17) P1---C19---H19B 107.0 C1---C6---H6 120.2 H19A---C19---H19B 106.8 C5---C6---H6 120.2 C20A---C19---H19C 98.6 C12---C7---C8 119.65 (15) C20B---C19---H19C 109.3 C12---C7---P1 120.38 (13) P1---C19---H19C 109.3 C8---C7---P1 119.74 (12) H19B---C19---H19C 113.9 C9---C8---C7 119.39 (17) C20A---C19---H19D 109.6 C9---C8---H8 120.3 C20B---C19---H19D 109.3 C7---C8---H8 120.3 P1---C19---H19D 109.3 C10---C9---C8 120.75 (18) H19A---C19---H19D 100.8 C10---C9---H9 119.6 H19C---C19---H19D 107.9 C8---C9---H9 119.6 O1A---C20A---C19 107.7 (5) C11---C10---C9 120.12 (16) O1A---C20A---H20A 110.2 C11---C10---H10 119.9 C19---C20A---H20A 110.2 C9---C10---H10 119.9 O1A---C20A---H20B 110.2 C10---C11---C12 120.10 (17) C19---C20A---H20B 110.2 C10---C11---H11 120.0 H20A---C20A---H20B 108.5 C12---C11---H11 120.0 C20B---O1B---H1B 109.5 C7---C12---C11 119.94 (17) O1B---C20B---C19 110.3 (6) C7---C12---H12 120.0 O1B---C20B---H20C 109.6 C11---C12---H12 120.0 C19---C20B---H20C 109.6 C18---C13---C14 119.46 (16) O1B---C20B---H20D 109.6 C18---C13---P1 121.88 (12) C19---C20B---H20D 109.6 C14---C13---P1 118.66 (13) H20C---C20B---H20D 108.1 C15---C14---C13 120.00 (18) C13---P1---C1---C6 112.88 (14) P1---C7---C12---C11 −172.90 (14) C7---P1---C1---C6 −6.17 (16) C10---C11---C12---C7 0.8 (3) C19---P1---C1---C6 −126.51 (14) C1---P1---C13---C18 2.53 (16) C13---P1---C1---C2 −70.32 (15) C7---P1---C13---C18 121.01 (14) C7---P1---C1---C2 170.63 (13) C19---P1---C13---C18 −114.68 (15) C19---P1---C1---C2 50.29 (15) C1---P1---C13---C14 −177.47 (13) C6---C1---C2---C3 0.1 (3) C7---P1---C13---C14 −58.99 (15) P1---C1---C2---C3 −176.77 (14) C19---P1---C13---C14 65.32 (15) C1---C2---C3---C4 0.4 (3) C18---C13---C14---C15 0.1 (3) C2---C3---C4---C5 −0.6 (3) P1---C13---C14---C15 −179.91 (15) C3---C4---C5---C6 0.3 (3) C13---C14---C15---C16 −0.4 (3) C2---C1---C6---C5 −0.4 (3) C14---C15---C16---C17 0.3 (3) P1---C1---C6---C5 176.39 (14) C15---C16---C17---C18 0.1 (3) C4---C5---C6---C1 0.2 (3) C14---C13---C18---C17 0.3 (2) C1---P1---C7---C12 101.87 (14) P1---C13---C18---C17 −179.67 (13) C13---P1---C7---C12 −18.72 (16) C16---C17---C18---C13 −0.4 (3) C19---P1---C7---C12 −142.27 (14) C1---P1---C19---C20A −175.4 (3) C1---P1---C7---C8 −72.50 (16) C13---P1---C19---C20A −54.8 (3) C13---P1---C7---C8 166.91 (14) C7---P1---C19---C20A 67.4 (3) C19---P1---C7---C8 43.36 (17) C1---P1---C19---C20B 176.9 (4) C12---C7---C8---C9 −2.6 (3) C13---P1---C19---C20B −62.5 (4) P1---C7---C8---C9 171.81 (16) C7---P1---C19---C20B 59.6 (4) C7---C8---C9---C10 1.5 (3) C20B---C19---C20A---O1A −20 (2) C8---C9---C10---C11 0.8 (3) P1---C19---C20A---O1A −57.9 (5) C9---C10---C11---C12 −2.0 (3) C20A---C19---C20B---O1B 47 (2) C8---C7---C12---C11 1.5 (3) P1---C19---C20B---O1B −168.2 (5) ---------------------- -------------- ------------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2779 .table-wrap} --------------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C2---H2···Cl1 0.93 2.78 3.7009 (19) 171 C19---H19C···Cl1 0.97 2.73 3.6325 (18) 154 O1B---H1B···Cl1^i^ 0.82 2.32 3.115 (4) 162 O1A---H1A···Cl1^i^ 0.82 2.55 3.314 (4) 155 C19---H19B···Cl1^i^ 0.97 2.78 3.5935 (19) 142 --------------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) −*x*+1/2, *y*−1/2, −*z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ---------------------- --------- ------- ------------- ------------- C2---H2⋯Cl1 0.93 2.78 3.7009 (19) 171 C19---H19*C*⋯Cl1 0.97 2.73 3.6325 (18) 154 O1*B*---H1*B*⋯Cl1^i^ 0.82 2.32 3.115 (4) 162 O1*A*---H1*A*⋯Cl1^i^ 0.82 2.55 3.314 (4) 155 C19---H19*B*⋯Cl1^i^ 0.97 2.78 3.5935 (19) 142 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.503604

2011-2-16

PMC3051954

Related literature {#sec1} ================== For the preparation of the title compound, an inter­mediate from the synthesis of a fluorinated docetaxel analog, see: Lu *et al.* (2009[@bb4]). For the absolute configuration of the title compound, see: Kingston *et al.* (1982[@bb3]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~35~H~37~Cl~6~FO~14~·C~4~H~8~O~2~·H~2~O*M* *~r~* = 1019.47Orthorhombic,*a* = 14.7037 (11) Å*b* = 16.6601 (12) Å*c* = 18.9258 (14) Å*V* = 4636.2 (6) Å^3^*Z* = 4Mo *K*α radiationμ = 0.44 mm^−1^*T* = 293 K0.40 × 0.31 × 0.29 mm ### Data collection {#sec2.1.2} Bruker SMART CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2001[@bb1]) *T* ~min~ = 0.604, *T* ~max~ = 1.00025522 measured reflections9094 independent reflections6096 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.053 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.051*wR*(*F* ^2^) = 0.115*S* = 0.919094 reflections628 parameters101 restraintsH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.64 e Å^−3^Δρ~min~ = −0.32 e Å^−3^Absolute structure: Flack (1983[@bb2]), 4052 Friedel pairsFlack parameter: 0.03 (6) {#d5e567} Data collection: *SMART* (Bruker, 2001[@bb1]); cell refinement: *SAINT* (Bruker, 2001[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb5]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb5]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811002790/zs2080sup1.cif](http://dx.doi.org/10.1107/S1600536811002790/zs2080sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811002790/zs2080Isup2.hkl](http://dx.doi.org/10.1107/S1600536811002790/zs2080Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?zs2080&file=zs2080sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?zs2080sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?zs2080&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [ZS2080](http://scripts.iucr.org/cgi-bin/sendsup?zs2080)). The work was supported financially by the National Natural Science Foundation of China (No. 20772017), the National Drug Innovative Program (No. 2009ZX09301--011) and the Shanghai Municipal Committee of Science and Technology (No. 07DZ19713). We would like to thank Dr Jie Sun for the single-crystal X-ray determination. Comment ======= In our research on the synthesis of a series of novel fluorinated docetaxel analogs, one of the key intermediate products, the title compound 7,10-di- (2,2,2-trichloroethyloxycarbonyl)-2-debenzoyl- 2-(3-fluorobenzoyl)-10-deacetylbaccatin III monohydrate ethyl acetate monosolvate, C~35~H~37~Cl~6~FO~14~. C~4~H~8~O~2~. H~2~O (I) (Fig. 1) was obtained from 10-deacetylbaccatin III (Kingston *et al.*,1982). The reaction scheme (Lu *et al.*, 2009) is shown in Fig.2. Absolute configuration(1*S*,2S,3*R*,4S,5*R*,7S,8*S*,10*R*,13*S*) for the nine chiral centres of the molecule has been determined. In the crystal structure, molecules are linked by hydroxy and water O---H···O hydrogen bonds (Table 1). Experimental {#experimental} ============ To a solution of 2-debenzoyl-2-(*m*-fluorobenzoyl)-10-deacetylbaccatin III (1.03 g, 1.84 mmol) in anhydrous pyridine (20 ml) was added 2,2,2-trichloroethylchloroformate (0.85 ml, 6.17 mmol) dropwise at 273 K. The reaction mixture was then warmed to room temperature and further stirred for 30 min. The reaction mixture was then quenched with water and the solvent was removed under reduced pressure. The residue was dissolved in DCM, and washed with dilute HCl and brine. The organic layer was dried with anhydrous Na~2~SO~4~, filtered, and concentrated *in vacuo*. The crude residue was purified by flash column chromatography (petroleum ether/ ethyl acetate 2/1) to give the title compound (1.58 g, 94% yield) as a white solid. Suitable crystals were obtained by recrystallization from hexane and DCM (m.p. 495--497 K). ^1^H NMR (300 MHz, CDCl~3~): d 1.12 (s, 3H), 1.15 (s, 3H), 1.85 (s, 3H), 2.17 (s, 3H), 2.30 (m, 2H), 2.31 (s, 3H), 2.05 and 2.65 (2 m, 2H), 3.98 (d, 1H, J = 6.6 Hz), 4.14 and 4.33 (2 d, 2H, J = 8.4 Hz), 4.61 and 4.92 (2 d, 2H, J=12.0 Hz), 4.78 (d, 2H, J = 12.0 Hz), 4.90 (m, 1H), 5.00 (d, 1H, J = 7.8 Hz), 5.59 (m, 1H), 5.62 (d, 1H, J = 7.5 Hz), 6.27 (s, 1H), 7.33 (m, 1H), 7.48 (m, 1H), 7.79 (m, 1H), 7.90 (d, 1H, J = 7.5 Hz); ^13^C NMR (100 MHz, CDCl3): d 10.6, 15.4, 20.1, 22.5, 26.6, 33.3, 38.4, 42.6, 47.4, 56.3, 67.8, 74.6, 76.2, 76.6, 77.1, 77.4, 78.7, 79.7, 80.4, 83.7, 94.2, 94.3, 116.9, 120.9, 125.9, 130.4, 130.8, 131.4, 146.6, 153.2, 153.3, 162.6 (d, J~C---F~ = 246.4 Hz), 165.7, 170.8, 201.1; ESIMS m/*z* 933.0 \[*M* + Na^+^\]; HRMS (MALDI) m/*z* calcd for C~35~H~37~Cl~6~FO~14~Na^+^ \[*M* + Na^+^\]: 933.0215, found: 933.01908. Refinement {#refinement} ========== Hydrogen atoms of the hydroxy groups and the water molecule were located by difference methods and both positional and isotropic displacement parameters were refined. Other H atoms were positioned geometrically and treated as riding with C---H = 0.96--0.98 Å and *U*~iso~ = 1.2 or 1.5*U*eq(C). The F atom was significantly disordered and was subsequently refined isotropically. The absolute configuration for the nine chiral centres in the molecule have been assigned C1(S), C2(S), C3(*R*), C4(S), C5(*R*), C7(S), C8(S), C10(*R*), C13(S) on the basis of the Flack structure parameter \[0.03 (6)\] (Flack,1983) (atom mames are those arbitrarily assigned in this crystallographic study). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Molecular configuration and atom numbering scheme for (I) with probaility ellipsoids drawn at the 40% probability level???. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Reaction scheme for the synthesis of (I) :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e222 .table-wrap} ------------------------------------------ --------------------------------------- C~35~H~37~Cl~6~FO~14~·C~4~H~8~O~2~·H~2~O *D*~x~ = 1.461 Mg m^−3^ *M~r~* = 1019.47 Melting point = 495--497 K Orthorhombic, *P*2~1~2~1~2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2ac 2ab Cell parameters from 4411 reflections *a* = 14.7037 (11) Å θ = 5.0--38.3° *b* = 16.6601 (12) Å µ = 0.44 mm^−1^ *c* = 18.9258 (14) Å *T* = 293 K *V* = 4636.2 (6) Å^3^ Prismatic, colorless *Z* = 4 0.40 × 0.31 × 0.29 mm *F*(000) = 2112 ------------------------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e367 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART CCD area-detector diffractometer 9094 independent reflections Radiation source: fine-focus sealed tube 6096 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.053 φ and ω scans θ~max~ = 26.0°, θ~min~ = 1.6° Absorption correction: multi-scan (*SADABS*; Bruker, 2001) *h* = −13→18 *T*~min~ = 0.604, *T*~max~ = 1.000 *k* = −19→20 25522 measured reflections *l* = −22→23 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e484 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.051 H atoms treated by a mixture of independent and constrained refinement *wR*(*F*^2^) = 0.115 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0513*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 0.91 (Δ/σ)~max~ = 0.013 9094 reflections Δρ~max~ = 0.64 e Å^−3^ 628 parameters Δρ~min~ = −0.32 e Å^−3^ 101 restraints Absolute structure: Flack (1983), 4052 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: 0.03 (6) ---------------------------------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e643 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e742 .table-wrap} ------- -------------- --------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) Cl1 0.32716 (9) 0.01873 (8) 1.04792 (7) 0.0699 (4) Cl2 0.48384 (11) 0.04791 (9) 1.13542 (6) 0.0841 (5) Cl3 0.45947 (9) −0.10584 (7) 1.06832 (6) 0.0652 (4) Cl4 0.08093 (10) 0.25135 (9) 0.93518 (9) 0.0931 (5) Cl5 0.21962 (10) 0.36674 (7) 0.96872 (8) 0.0782 (5) Cl6 0.17098 (13) 0.24496 (9) 1.06934 (8) 0.1047 (6) O1 0.3735 (2) 0.16138 (19) 0.49241 (15) 0.0514 (8) O2 0.48084 (18) 0.03348 (15) 0.50337 (12) 0.0380 (6) O3 0.3511 (2) −0.02415 (19) 0.46551 (17) 0.0642 (9) O4 0.64110 (17) 0.00931 (15) 0.57227 (13) 0.0385 (6) O5 0.7005 (2) 0.05200 (18) 0.67458 (16) 0.0538 (8) O6 0.5595 (2) −0.15701 (15) 0.62706 (14) 0.0488 (8) O7 0.47088 (17) −0.02112 (15) 0.82322 (12) 0.0365 (6) O8 0.5838 (2) 0.0466 (2) 0.87704 (15) 0.0664 (10) O9 0.46637 (18) −0.00885 (15) 0.93540 (12) 0.0408 (7) O10 0.30922 (18) 0.05437 (17) 0.75999 (15) 0.0470 (7) O11 0.34759 (18) 0.20512 (15) 0.78236 (12) 0.0378 (6) O12 0.3935 (2) 0.14650 (18) 0.88410 (14) 0.0578 (9) O13 0.2698 (2) 0.22498 (16) 0.87740 (14) 0.0498 (8) O14 0.6592 (2) 0.2433 (2) 0.59204 (18) 0.0644 (9) O15 0.4525 (4) 0.2095 (4) 0.3655 (2) 0.163 (2) O16 0.5049 (3) 0.1760 (3) 0.2632 (2) 0.1125 (16) O17 0.7215 (3) 0.4008 (3) 0.6057 (3) 0.0948 (13) C1 0.4306 (3) 0.1568 (2) 0.55338 (18) 0.0352 (9) C2 0.4391 (3) 0.0639 (2) 0.56755 (18) 0.0338 (9) H2 0.3779 0.0411 0.5718 0.041\* C3 0.4974 (2) 0.0350 (2) 0.63144 (17) 0.0275 (8) H3 0.5330 0.0818 0.6464 0.033\* C4 0.5681 (3) −0.0301 (2) 0.61001 (18) 0.0309 (8) C5 0.6021 (3) −0.0914 (2) 0.66434 (18) 0.0356 (9) H5 0.6684 −0.0962 0.6615 0.043\* C6 0.5727 (3) −0.0846 (2) 0.74108 (19) 0.0396 (10) H6A 0.6263 −0.0832 0.7709 0.047\* H6B 0.5377 −0.1318 0.7538 0.047\* C7 0.5157 (3) −0.0099 (2) 0.75516 (17) 0.0312 (8) H7 0.5562 0.0367 0.7583 0.037\* C8 0.4412 (2) 0.0076 (2) 0.69925 (18) 0.0290 (8) C9 0.3801 (3) 0.0733 (2) 0.73402 (18) 0.0304 (8) C10 0.4163 (3) 0.1582 (2) 0.74474 (18) 0.0314 (9) H10 0.4702 0.1547 0.7750 0.038\* C11 0.4436 (3) 0.1997 (2) 0.67764 (18) 0.0325 (9) C12 0.5294 (3) 0.2261 (2) 0.6700 (2) 0.0373 (9) C13 0.5632 (3) 0.2488 (2) 0.5977 (2) 0.0455 (11) H13 0.5451 0.3043 0.5881 0.055\* C14 0.5237 (3) 0.1953 (2) 0.54023 (19) 0.0460 (11) H14A 0.5669 0.1525 0.5313 0.055\* H14B 0.5194 0.2268 0.4973 0.055\* C15 0.3795 (3) 0.2012 (2) 0.61382 (19) 0.0356 (9) C16 0.3599 (3) 0.2890 (2) 0.5920 (2) 0.0498 (11) H16A 0.3268 0.3154 0.6289 0.075\* H16B 0.3246 0.2895 0.5493 0.075\* H16C 0.4164 0.3165 0.5841 0.075\* C17 0.2842 (3) 0.1642 (2) 0.6257 (2) 0.0449 (10) H17A 0.2906 0.1090 0.6395 0.067\* H17B 0.2499 0.1672 0.5826 0.067\* H17C 0.2532 0.1933 0.6622 0.067\* C18 0.5361 (3) −0.1049 (2) 0.5696 (2) 0.0400 (10) H18A 0.4715 −0.1045 0.5592 0.048\* H18B 0.5710 −0.1153 0.5271 0.048\* C19 0.3806 (3) −0.0650 (2) 0.6853 (2) 0.0377 (9) H19A 0.4176 −0.1099 0.6717 0.057\* H19B 0.3386 −0.0527 0.6480 0.057\* H19C 0.3474 −0.0781 0.7274 0.057\* C20 0.5979 (3) 0.2312 (3) 0.7288 (2) 0.0522 (12) H20A 0.5668 0.2361 0.7732 0.078\* H20B 0.6361 0.2772 0.7217 0.078\* H20C 0.6345 0.1835 0.7291 0.078\* C21 0.4298 (4) −0.0068 (2) 0.4567 (2) 0.0463 (11) F1 0.4305 (8) −0.1272 (5) 0.2284 (3) 0.198 (3) 0.70 C22 0.4730 (5) −0.0350 (5) 0.3940 (3) 0.026 (2) 0.526 (16) C23 0.4227 (6) −0.0638 (5) 0.3372 (3) 0.041 (3) 0.526 (16) H23 0.3595 −0.0655 0.3398 0.049\* 0.526 (16) C24 0.4667 (8) −0.0900 (5) 0.2764 (3) 0.064 (3) 0.526 (16) C25 0.5611 (8) −0.0874 (5) 0.2725 (3) 0.083 (5) 0.526 (16) H25 0.5906 −0.1049 0.2319 0.099\* 0.526 (16) C26 0.6114 (6) −0.0587 (6) 0.3293 (4) 0.073 (4) 0.526 (16) H26 0.6745 −0.0570 0.3267 0.087\* 0.526 (16) C27 0.5673 (5) −0.0325 (5) 0.3901 (3) 0.042 (3) 0.526 (16) H27 0.6010 −0.0133 0.4281 0.050\* 0.526 (16) F1\' 0.5191 (10) −0.1369 (6) 0.2353 (4) 0.197 (9) 0.30 C22\' 0.5049 (9) −0.0223 (7) 0.3965 (5) 0.061 (4) 0.474 (16) C23\' 0.4661 (9) −0.0641 (7) 0.3405 (6) 0.081 (5) 0.474 (16) H23\' 0.4035 −0.0716 0.3388 0.097\* 0.474 (16) C24\' 0.5210 (11) −0.0946 (6) 0.2871 (5) 0.066 (4) 0.474 (16) C25\' 0.6146 (10) −0.0835 (6) 0.2897 (5) 0.093 (5) 0.474 (16) H25\' 0.6513 −0.1039 0.2540 0.112\* 0.474 (16) C26\' 0.6534 (8) −0.0417 (7) 0.3457 (6) 0.112 (6) 0.474 (16) H26\' 0.7160 −0.0342 0.3475 0.135\* 0.474 (16) C27\' 0.5985 (9) −0.0112 (8) 0.3992 (5) 0.083 (5) 0.474 (16) H27\' 0.6244 0.0168 0.4366 0.100\* 0.474 (16) C28 0.7039 (3) 0.0475 (2) 0.6126 (3) 0.0469 (11) C29 0.7772 (3) 0.0835 (3) 0.5674 (3) 0.0630 (13) H29A 0.7614 0.1378 0.5557 0.094\* H29B 0.7833 0.0526 0.5248 0.094\* H29C 0.8338 0.0830 0.5927 0.094\* C30 0.5148 (3) 0.0097 (2) 0.8779 (2) 0.0387 (9) C31 0.4976 (3) 0.0306 (3) 0.99812 (19) 0.0468 (11) H31A 0.4888 0.0881 0.9940 0.056\* H31B 0.5619 0.0203 1.0050 0.056\* C32 0.4442 (3) −0.0013 (2) 1.0595 (2) 0.0462 (11) C33 0.3432 (3) 0.1873 (2) 0.8512 (2) 0.0440 (11) C34 0.2589 (4) 0.2100 (3) 0.9515 (2) 0.0605 (14) H34A 0.3157 0.2198 0.9761 0.073\* H34B 0.2414 0.1545 0.9592 0.073\* C35 0.1856 (4) 0.2657 (3) 0.9791 (2) 0.0627 (14) C36 0.3518 (5) 0.1838 (7) 0.2640 (5) 0.167 (4) H36A 0.3408 0.1283 0.2535 0.250\* H36B 0.3562 0.2137 0.2208 0.250\* H36C 0.3025 0.2045 0.2919 0.250\* C37 0.4357 (7) 0.1913 (5) 0.3031 (4) 0.129 (3) C38 0.5947 (6) 0.1783 (5) 0.2986 (4) 0.137 (3) H38A 0.6089 0.2330 0.3124 0.164\* H38B 0.5931 0.1455 0.3409 0.164\* C39 0.6630 (5) 0.1490 (6) 0.2517 (5) 0.147 (3) H39A 0.6456 0.0970 0.2345 0.220\* H39B 0.7198 0.1449 0.2764 0.220\* H39C 0.6695 0.1853 0.2126 0.220\* H1 0.391 (4) 0.187 (3) 0.4583 (18) 0.08 (2)\* H14 0.689 (3) 0.2851 (17) 0.593 (2) 0.050 (14)\* H17D 0.749 (4) 0.376 (4) 0.569 (2) 0.13 (3)\* H17E 0.690 (7) 0.440 (5) 0.585 (4) 0.21 (7)\* ------- -------------- --------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e2348 .table-wrap} ------- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.0532 (7) 0.0841 (9) 0.0724 (8) 0.0076 (7) 0.0175 (7) 0.0100 (7) Cl2 0.1221 (13) 0.0941 (10) 0.0360 (6) −0.0281 (9) −0.0002 (7) −0.0152 (6) Cl3 0.0857 (10) 0.0550 (7) 0.0548 (7) 0.0017 (7) 0.0015 (7) 0.0104 (6) Cl4 0.0709 (10) 0.0803 (10) 0.1283 (13) −0.0074 (8) 0.0329 (10) −0.0173 (10) Cl5 0.0888 (10) 0.0376 (6) 0.1083 (11) −0.0080 (7) 0.0518 (9) −0.0079 (7) Cl6 0.1549 (16) 0.0884 (11) 0.0707 (9) −0.0151 (10) 0.0685 (10) −0.0060 (8) O1 0.066 (2) 0.0535 (19) 0.0343 (17) 0.0101 (17) −0.0127 (16) 0.0037 (15) O2 0.0474 (17) 0.0383 (15) 0.0284 (13) 0.0033 (13) 0.0035 (13) −0.0035 (11) O3 0.065 (2) 0.061 (2) 0.066 (2) −0.0042 (19) −0.0187 (19) −0.0175 (17) O4 0.0352 (15) 0.0419 (15) 0.0383 (14) 0.0036 (13) 0.0098 (13) 0.0014 (13) O5 0.0481 (19) 0.062 (2) 0.0513 (19) −0.0068 (16) −0.0071 (15) −0.0079 (17) O6 0.070 (2) 0.0274 (14) 0.0491 (16) 0.0024 (14) −0.0006 (16) 0.0016 (13) O7 0.0407 (16) 0.0424 (15) 0.0265 (12) −0.0062 (13) 0.0011 (12) 0.0014 (12) O8 0.052 (2) 0.108 (3) 0.0388 (16) −0.0339 (19) 0.0029 (15) −0.0104 (18) O9 0.0460 (17) 0.0527 (17) 0.0236 (12) −0.0109 (14) 0.0009 (13) 0.0019 (12) O10 0.0385 (17) 0.0447 (16) 0.0578 (18) −0.0026 (14) 0.0187 (15) −0.0051 (15) O11 0.0459 (17) 0.0351 (15) 0.0325 (14) 0.0119 (13) 0.0032 (13) −0.0053 (12) O12 0.079 (2) 0.0545 (19) 0.0405 (16) 0.0324 (18) 0.0049 (16) 0.0056 (15) O13 0.062 (2) 0.0432 (17) 0.0440 (16) 0.0147 (15) 0.0193 (16) 0.0019 (14) O14 0.055 (2) 0.056 (2) 0.082 (2) −0.0113 (18) 0.0204 (18) −0.0080 (19) O15 0.196 (5) 0.232 (6) 0.061 (3) −0.054 (5) 0.022 (3) −0.007 (3) O16 0.079 (3) 0.176 (5) 0.082 (3) −0.019 (3) 0.013 (3) −0.039 (3) O17 0.072 (3) 0.077 (3) 0.136 (4) −0.010 (2) 0.009 (3) 0.024 (3) C1 0.045 (2) 0.034 (2) 0.0270 (19) 0.0055 (19) −0.0045 (18) 0.0021 (16) C2 0.035 (2) 0.034 (2) 0.0324 (19) 0.0007 (17) 0.0024 (18) −0.0057 (17) C3 0.030 (2) 0.0246 (19) 0.0283 (18) −0.0001 (16) 0.0029 (16) −0.0019 (15) C4 0.038 (2) 0.027 (2) 0.0278 (18) 0.0017 (17) 0.0034 (17) 0.0009 (16) C5 0.039 (2) 0.031 (2) 0.037 (2) 0.0076 (18) 0.0047 (19) 0.0002 (17) C6 0.050 (3) 0.034 (2) 0.035 (2) 0.008 (2) −0.001 (2) 0.0082 (18) C7 0.036 (2) 0.033 (2) 0.0249 (17) −0.0037 (17) 0.0041 (17) 0.0022 (16) C8 0.030 (2) 0.0247 (19) 0.0321 (19) −0.0005 (16) 0.0017 (16) 0.0025 (15) C9 0.030 (2) 0.033 (2) 0.0282 (19) 0.0034 (17) −0.0001 (17) 0.0001 (16) C10 0.028 (2) 0.032 (2) 0.034 (2) 0.0094 (17) 0.0032 (17) −0.0054 (17) C11 0.041 (2) 0.0205 (19) 0.036 (2) 0.0052 (17) 0.0018 (19) −0.0040 (16) C12 0.043 (2) 0.0212 (19) 0.048 (2) 0.0007 (18) −0.002 (2) −0.0060 (17) C13 0.048 (3) 0.029 (2) 0.060 (3) −0.006 (2) 0.012 (2) −0.001 (2) C14 0.063 (3) 0.037 (2) 0.038 (2) −0.003 (2) 0.009 (2) 0.0048 (19) C15 0.041 (2) 0.029 (2) 0.037 (2) 0.0072 (18) −0.0038 (19) 0.0001 (18) C16 0.056 (3) 0.041 (2) 0.052 (2) 0.015 (2) −0.009 (2) −0.004 (2) C17 0.045 (3) 0.042 (2) 0.048 (2) 0.005 (2) −0.010 (2) −0.006 (2) C18 0.053 (3) 0.028 (2) 0.039 (2) 0.0057 (19) 0.004 (2) −0.0037 (18) C19 0.038 (2) 0.034 (2) 0.041 (2) −0.0032 (19) 0.0051 (19) 0.0015 (18) C20 0.045 (3) 0.043 (3) 0.069 (3) −0.004 (2) −0.007 (2) −0.014 (2) C21 0.071 (3) 0.038 (2) 0.030 (2) 0.004 (2) −0.009 (2) −0.0035 (18) F1 0.288 (8) 0.198 (6) 0.107 (4) −0.049 (6) −0.005 (5) −0.044 (5) C22 0.055 (5) 0.014 (4) 0.008 (4) −0.014 (4) 0.002 (3) −0.005 (3) C23 0.061 (6) 0.041 (5) 0.019 (4) −0.018 (4) −0.014 (4) −0.004 (3) C24 0.106 (8) 0.062 (6) 0.023 (4) −0.015 (6) −0.024 (5) −0.021 (4) C25 0.096 (10) 0.087 (8) 0.066 (7) −0.007 (7) 0.029 (7) −0.013 (6) C26 0.120 (8) 0.080 (7) 0.018 (5) 0.027 (6) 0.015 (5) −0.020 (5) C27 0.042 (6) 0.055 (6) 0.028 (4) 0.007 (5) 0.007 (4) −0.012 (4) F1\' 0.198 (12) 0.197 (12) 0.197 (12) −0.005 (9) −0.010 (9) −0.015 (9) C22\' 0.078 (8) 0.054 (7) 0.051 (6) −0.022 (7) −0.004 (6) −0.004 (5) C23\' 0.075 (8) 0.079 (8) 0.089 (8) −0.011 (7) 0.000 (7) 0.016 (7) C24\' 0.099 (9) 0.071 (7) 0.029 (5) −0.020 (7) −0.010 (6) −0.018 (5) C25\' 0.116 (9) 0.090 (8) 0.073 (8) −0.004 (7) 0.044 (7) −0.001 (7) C26\' 0.176 (11) 0.091 (9) 0.070 (8) −0.017 (8) −0.047 (8) 0.001 (7) C27\' 0.091 (9) 0.094 (9) 0.065 (7) −0.023 (7) 0.010 (7) −0.014 (6) C28 0.040 (3) 0.037 (2) 0.064 (3) 0.006 (2) 0.003 (2) −0.001 (2) C29 0.047 (3) 0.056 (3) 0.086 (4) 0.000 (2) 0.022 (3) 0.001 (3) C30 0.039 (2) 0.042 (2) 0.035 (2) −0.002 (2) −0.004 (2) −0.0008 (19) C31 0.047 (3) 0.057 (3) 0.037 (2) −0.003 (2) 0.002 (2) −0.003 (2) C32 0.053 (3) 0.054 (3) 0.032 (2) −0.003 (2) 0.003 (2) −0.003 (2) C33 0.059 (3) 0.035 (2) 0.038 (2) 0.009 (2) 0.009 (2) −0.006 (2) C34 0.085 (4) 0.043 (3) 0.054 (3) 0.012 (3) 0.033 (3) 0.003 (2) C35 0.085 (4) 0.036 (3) 0.068 (3) −0.006 (2) 0.043 (3) −0.008 (2) C36 0.063 (5) 0.275 (13) 0.162 (8) −0.039 (6) 0.010 (6) −0.044 (8) C37 0.139 (8) 0.163 (8) 0.086 (5) −0.033 (6) 0.034 (6) −0.006 (5) C38 0.127 (7) 0.123 (6) 0.161 (8) −0.010 (6) −0.071 (7) −0.028 (6) C39 0.081 (5) 0.173 (9) 0.187 (9) −0.011 (6) −0.012 (6) −0.039 (7) ------- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e3671 .table-wrap} ----------------------- ------------ ------------------------------- ------------- Cl1---C32 1.766 (4) C14---H14A 0.9700 Cl2---C32 1.754 (4) C14---H14B 0.9700 Cl3---C32 1.764 (4) C15---C17 1.546 (5) Cl4---C35 1.765 (6) C15---C16 1.547 (5) Cl5---C35 1.766 (4) C16---H16A 0.9600 Cl6---C35 1.756 (5) C16---H16B 0.9600 O1---C1 1.429 (4) C16---H16C 0.9600 O1---H1 0.82 (2) C17---H17A 0.9600 O2---C21 1.340 (5) C17---H17B 0.9600 O2---C2 1.452 (4) C17---H17C 0.9600 O3---C21 1.203 (5) C18---H18A 0.9700 O4---C28 1.358 (5) C18---H18B 0.9700 O4---C4 1.447 (4) C19---H19A 0.9600 O5---C28 1.176 (5) C19---H19B 0.9600 O6---C18 1.433 (4) C19---H19C 0.9600 O6---C5 1.444 (4) C20---H20A 0.9600 O7---C30 1.323 (4) C20---H20B 0.9600 O7---C7 1.459 (4) C20---H20C 0.9600 O8---C30 1.187 (5) C21---C22 1.425 (6) O9---C30 1.337 (4) C21---C22\' 1.607 (9) O9---C31 1.432 (4) F1---C24 1.223 (8) O10---C9 1.194 (4) C22---C23 1.3900 O11---C33 1.337 (5) C22---C27 1.3900 O11---C10 1.463 (4) C23---C24 1.3900 O12---C33 1.182 (5) C23---H23 0.9300 O13---C33 1.344 (5) C24---C25 1.3900 O13---C34 1.433 (5) C25---C26 1.3900 O14---C13 1.419 (5) C25---H25 0.9300 O14---H14 0.83 (2) C26---C27 1.3900 O15---C37 1.244 (8) C26---H26 0.9300 O16---C37 1.292 (9) C27---H27 0.9300 O16---C38 1.480 (8) F1\'---C24\' 1.208 (9) O17---H17D 0.91 (2) C22\'---C23\' 1.3900 O17---H17E 0.89 (2) C22\'---C27\' 1.3900 C1---C14 1.532 (6) C23\'---C24\' 1.3900 C1---C15 1.556 (5) C23\'---H23\' 0.9300 C1---C2 1.576 (5) C24\'---C25\' 1.3900 C2---C3 1.559 (5) C25\'---C26\' 1.3900 C2---H2 0.9800 C25\'---H25\' 0.9300 C3---C4 1.556 (5) C26\'---C27\' 1.3900 C3---C8 1.594 (5) C26\'---H26\' 0.9300 C3---H3 0.9800 C27\'---H27\' 0.9300 C4---C5 1.533 (5) C28---C29 1.501 (6) C4---C18 1.537 (5) C29---H29A 0.9600 C5---C6 1.520 (5) C29---H29B 0.9600 C5---H5 0.9800 C29---H29C 0.9600 C6---C7 1.523 (5) C31---C32 1.499 (5) C6---H6A 0.9700 C31---H31A 0.9700 C6---H6B 0.9700 C31---H31B 0.9700 C7---C8 1.550 (5) C34---C35 1.516 (6) C7---H7 0.9800 C34---H34A 0.9700 C8---C19 1.525 (5) C34---H34B 0.9700 C8---C9 1.562 (5) C36---C37 1.444 (10) C9---C10 1.526 (5) C36---H36A 0.9600 C10---C11 1.500 (5) C36---H36B 0.9600 C10---H10 0.9800 C36---H36C 0.9600 C11---C12 1.344 (5) C38---C39 1.427 (9) C11---C15 1.532 (5) C38---H38A 0.9700 C12---C20 1.504 (5) C38---H38B 0.9700 C12---C13 1.504 (5) C39---H39A 0.9600 C13---C14 1.522 (5) C39---H39B 0.9600 C13---H13 0.9800 C39---H39C 0.9600 C1---O1---H1 119 (4) H19A---C19---H19B 109.5 C21---O2---C2 119.3 (3) C8---C19---H19C 109.5 C28---O4---C4 116.1 (3) H19A---C19---H19C 109.5 C18---O6---C5 91.0 (2) H19B---C19---H19C 109.5 C30---O7---C7 114.9 (3) C12---C20---H20A 109.5 C30---O9---C31 113.5 (3) C12---C20---H20B 109.5 C33---O11---C10 112.8 (3) H20A---C20---H20B 109.5 C33---O13---C34 111.7 (3) C12---C20---H20C 109.5 C13---O14---H14 118 (3) H20A---C20---H20C 109.5 C37---O16---C38 115.7 (6) H20B---C20---H20C 109.5 H17D---O17---H17E 103 (3) O3---C21---O2 124.5 (4) O1---C1---C14 111.8 (3) O3---C21---C22 117.7 (5) O1---C1---C15 106.5 (3) O2---C21---C22 117.7 (5) C14---C1---C15 110.6 (3) O3---C21---C22\' 136.0 (6) O1---C1---C2 103.7 (3) O2---C21---C22\' 99.4 (6) C14---C1---C2 111.6 (3) C22---C21---C22\' 18.4 (4) C15---C1---C2 112.4 (3) C23---C22---C27 120.0 O2---C2---C3 108.0 (3) C23---C22---C21 121.4 (4) O2---C2---C1 103.5 (3) C27---C22---C21 118.6 (4) C3---C2---C1 118.6 (3) C22---C23---C24 120.0 O2---C2---H2 108.8 C22---C23---H23 120.0 C3---C2---H2 108.8 C24---C23---H23 120.0 C1---C2---H2 108.8 F1---C24---C25 114.2 (7) C4---C3---C2 112.4 (3) F1---C24---C23 124.8 (7) C4---C3---C8 110.9 (3) C25---C24---C23 120.0 C2---C3---C8 115.3 (3) C26---C25---C24 120.0 C4---C3---H3 105.8 C26---C25---H25 120.0 C2---C3---H3 105.8 C24---C25---H25 120.0 C8---C3---H3 105.8 C27---C26---C25 120.0 O4---C4---C5 113.0 (3) C27---C26---H26 120.0 O4---C4---C18 110.5 (3) C25---C26---H26 120.0 C5---C4---C18 83.9 (3) C26---C27---C22 120.0 O4---C4---C3 107.9 (3) C26---C27---H27 120.0 C5---C4---C3 120.5 (3) C22---C27---H27 120.0 C18---C4---C3 119.4 (3) C23\'---C22\'---C27\' 120.0 O6---C5---C6 113.6 (3) C23\'---C22\'---C21 109.8 (7) O6---C5---C4 92.0 (3) C27\'---C22\'---C21 129.3 (7) C6---C5---C4 119.9 (3) C24\'---C23\'---C22\' 120.0 O6---C5---H5 110.0 C24\'---C23\'---H23\' 120.0 C6---C5---H5 110.0 C22\'---C23\'---H23\' 120.0 C4---C5---H5 110.0 F1\'---C24\'---C23\' 142.2 (8) C5---C6---C7 112.6 (3) F1\'---C24\'---C25\' 97.5 (8) C5---C6---H6A 109.1 C23\'---C24\'---C25\' 120.0 C7---C6---H6A 109.1 C26\'---C25\'---C24\' 120.0 C5---C6---H6B 109.1 C26\'---C25\'---H25\' 120.0 C7---C6---H6B 109.1 C24\'---C25\'---H25\' 120.0 H6A---C6---H6B 107.8 C27\'---C26\'---C25\' 120.0 O7---C7---C6 107.4 (3) C27\'---C26\'---H26\' 120.0 O7---C7---C8 107.9 (3) C25\'---C26\'---H26\' 120.0 C6---C7---C8 115.0 (3) C26\'---C27\'---C22\' 120.0 O7---C7---H7 108.8 C26\'---C27\'---H27\' 120.0 C6---C7---H7 108.8 C22\'---C27\'---H27\' 120.0 C8---C7---H7 108.8 O5---C28---O4 124.2 (4) C19---C8---C7 112.5 (3) O5---C28---C29 125.1 (4) C19---C8---C9 107.0 (3) O4---C28---C29 110.7 (4) C7---C8---C9 104.5 (3) C28---C29---H29A 109.5 C19---C8---C3 113.0 (3) C28---C29---H29B 109.5 C7---C8---C3 103.7 (3) H29A---C29---H29B 109.5 C9---C8---C3 115.9 (3) C28---C29---H29C 109.5 O10---C9---C10 119.6 (3) H29A---C29---H29C 109.5 O10---C9---C8 119.4 (3) H29B---C29---H29C 109.5 C10---C9---C8 120.3 (3) O8---C30---O7 127.4 (4) O11---C10---C11 110.5 (3) O8---C30---O9 125.9 (4) O11---C10---C9 108.6 (3) O7---C30---O9 106.7 (3) C11---C10---C9 114.1 (3) O9---C31---C32 108.2 (3) O11---C10---H10 107.8 O9---C31---H31A 110.1 C11---C10---H10 107.8 C32---C31---H31A 110.1 C9---C10---H10 107.8 O9---C31---H31B 110.1 C12---C11---C10 119.5 (3) C32---C31---H31B 110.1 C12---C11---C15 119.1 (3) H31A---C31---H31B 108.4 C10---C11---C15 120.7 (3) C31---C32---Cl2 107.2 (3) C11---C12---C20 124.6 (4) C31---C32---Cl3 110.9 (3) C11---C12---C13 119.4 (4) Cl2---C32---Cl3 110.0 (2) C20---C12---C13 115.9 (3) C31---C32---Cl1 110.3 (3) O14---C13---C12 112.5 (4) Cl2---C32---Cl1 109.7 (2) O14---C13---C14 106.8 (3) Cl3---C32---Cl1 108.8 (2) C12---C13---C14 112.1 (3) O12---C33---O11 127.7 (4) O14---C13---H13 108.5 O12---C33---O13 125.2 (4) C12---C13---H13 108.5 O11---C33---O13 107.1 (4) C14---C13---H13 108.5 O13---C34---C35 108.0 (4) C13---C14---C1 118.1 (3) O13---C34---H34A 110.1 C13---C14---H14A 107.8 C35---C34---H34A 110.1 C1---C14---H14A 107.8 O13---C34---H34B 110.1 C13---C14---H14B 107.8 C35---C34---H34B 110.1 C1---C14---H14B 107.8 H34A---C34---H34B 108.4 H14A---C14---H14B 107.1 C34---C35---Cl6 107.5 (3) C11---C15---C17 115.9 (3) C34---C35---Cl4 112.0 (3) C11---C15---C16 109.9 (3) Cl6---C35---Cl4 109.0 (3) C17---C15---C16 104.3 (3) C34---C35---Cl5 110.1 (3) C11---C15---C1 106.0 (3) Cl6---C35---Cl5 109.3 (3) C17---C15---C1 110.8 (3) Cl4---C35---Cl5 108.9 (3) C16---C15---C1 110.1 (3) C37---C36---H36A 109.5 C15---C16---H16A 109.5 C37---C36---H36B 109.5 C15---C16---H16B 109.5 H36A---C36---H36B 109.5 H16A---C16---H16B 109.5 C37---C36---H36C 109.5 C15---C16---H16C 109.5 H36A---C36---H36C 109.5 H16A---C16---H16C 109.5 H36B---C36---H36C 109.5 H16B---C16---H16C 109.5 O15---C37---O16 116.5 (9) C15---C17---H17A 109.5 O15---C37---C36 132.5 (9) C15---C17---H17B 109.5 O16---C37---C36 111.0 (7) H17A---C17---H17B 109.5 C39---C38---O16 109.7 (6) C15---C17---H17C 109.5 C39---C38---H38A 109.7 H17A---C17---H17C 109.5 O16---C38---H38A 109.7 H17B---C17---H17C 109.5 C39---C38---H38B 109.7 O6---C18---C4 92.3 (3) O16---C38---H38B 109.7 O6---C18---H18A 113.2 H38A---C38---H38B 108.2 C4---C18---H18A 113.2 C38---C39---H39A 109.5 O6---C18---H18B 113.2 C38---C39---H39B 109.5 C4---C18---H18B 113.2 H39A---C39---H39B 109.5 H18A---C18---H18B 110.6 C38---C39---H39C 109.5 C8---C19---H19A 109.5 H39A---C39---H39C 109.5 C8---C19---H19B 109.5 H39B---C39---H39C 109.5 C21---O2---C2---C3 128.3 (3) C12---C11---C15---C17 175.8 (3) C21---O2---C2---C1 −105.2 (3) C10---C11---C15---C17 4.9 (5) O1---C1---C2---O2 60.6 (3) C12---C11---C15---C16 −66.3 (4) C14---C1---C2---O2 −59.9 (4) C10---C11---C15---C16 122.8 (4) C15---C1---C2---O2 175.2 (3) C12---C11---C15---C1 52.6 (4) O1---C1---C2---C3 −179.9 (3) C10---C11---C15---C1 −118.3 (3) C14---C1---C2---C3 59.6 (4) O1---C1---C15---C11 −177.1 (3) C15---C1---C2---C3 −65.3 (4) C14---C1---C15---C11 −55.4 (4) O2---C2---C3---C4 −11.9 (4) C2---C1---C15---C11 70.0 (4) C1---C2---C3---C4 −129.0 (3) O1---C1---C15---C17 56.6 (4) O2---C2---C3---C8 −140.3 (3) C14---C1---C15---C17 178.2 (3) C1---C2---C3---C8 102.6 (4) C2---C1---C15---C17 −56.4 (4) C28---O4---C4---C5 −56.2 (4) O1---C1---C15---C16 −58.3 (4) C28---O4---C4---C18 −148.2 (3) C14---C1---C15---C16 63.4 (4) C28---O4---C4---C3 79.6 (4) C2---C1---C15---C16 −171.2 (3) C2---C3---C4---O4 74.7 (4) C5---O6---C18---C4 −7.2 (3) C8---C3---C4---O4 −154.6 (3) O4---C4---C18---O6 119.2 (3) C2---C3---C4---C5 −153.4 (3) C5---C4---C18---O6 6.9 (3) C8---C3---C4---C5 −22.7 (4) C3---C4---C18---O6 −114.8 (3) C2---C3---C4---C18 −52.4 (4) C2---O2---C21---O3 −4.2 (6) C8---C3---C4---C18 78.3 (4) C2---O2---C21---C22 179.4 (4) C18---O6---C5---C6 131.3 (3) C2---O2---C21---C22\' 177.5 (5) C18---O6---C5---C4 7.3 (3) O3---C21---C22---C23 15.6 (7) O4---C4---C5---O6 −116.5 (3) O2---C21---C22---C23 −167.8 (4) C18---C4---C5---O6 −6.8 (3) C22\'---C21---C22---C23 −162 (3) C3---C4---C5---O6 113.9 (3) O3---C21---C22---C27 −165.1 (5) O4---C4---C5---C6 124.7 (4) O2---C21---C22---C27 11.5 (7) C18---C4---C5---C6 −125.7 (4) C22\'---C21---C22---C27 18 (2) C3---C4---C5---C6 −5.0 (5) C27---C22---C23---C24 0.0 O6---C5---C6---C7 −111.6 (4) C21---C22---C23---C24 179.2 (7) C4---C5---C6---C7 −4.4 (5) C22---C23---C24---F1 168.3 (10) C30---O7---C7---C6 94.0 (4) C22---C23---C24---C25 0.0 C30---O7---C7---C8 −141.5 (3) F1---C24---C25---C26 −169.4 (9) C5---C6---C7---O7 164.3 (3) C23---C24---C25---C26 0.0 C5---C6---C7---C8 44.2 (4) C24---C25---C26---C27 0.0 O7---C7---C8---C19 −68.0 (4) C25---C26---C27---C22 0.0 C6---C7---C8---C19 51.8 (4) C23---C22---C27---C26 0.0 O7---C7---C8---C9 47.7 (3) C21---C22---C27---C26 −179.3 (7) C6---C7---C8---C9 167.5 (3) O3---C21---C22\'---C23\' 2.6 (11) O7---C7---C8---C3 169.6 (3) O2---C21---C22\'---C23\' −179.5 (5) C6---C7---C8---C3 −70.6 (4) C22---C21---C22\'---C23\' 5.9 (19) C4---C3---C8---C19 −66.2 (4) O3---C21---C22\'---C27\' −166.8 (7) C2---C3---C8---C19 62.9 (4) O2---C21---C22\'---C27\' 11.2 (9) C4---C3---C8---C7 55.9 (3) C22---C21---C22\'---C27\' −163 (3) C2---C3---C8---C7 −175.0 (3) C27\'---C22\'---C23\'---C24\' 0.0 C4---C3---C8---C9 169.8 (3) C21---C22\'---C23\'---C24\' −170.5 (9) C2---C3---C8---C9 −61.1 (4) C22\'---C23\'---C24\'---F1\' 172 (2) C19---C8---C9---O10 18.4 (4) C22\'---C23\'---C24\'---C25\' 0.0 C7---C8---C9---O10 −101.1 (4) F1\'---C24\'---C25\'---C26\' −175.2 (13) C3---C8---C9---O10 145.4 (3) C23\'---C24\'---C25\'---C26\' 0.0 C19---C8---C9---C10 −170.8 (3) C24\'---C25\'---C26\'---C27\' 0.0 C7---C8---C9---C10 69.7 (4) C25\'---C26\'---C27\'---C22\' 0.0 C3---C8---C9---C10 −43.8 (4) C23\'---C22\'---C27\'---C26\' 0.0 C33---O11---C10---C11 −158.6 (3) C21---C22\'---C27\'---C26\' 168.4 (11) C33---O11---C10---C9 75.6 (4) C4---O4---C28---O5 −2.3 (6) O10---C9---C10---O11 −5.4 (5) C4---O4---C28---C29 178.2 (3) C8---C9---C10---O11 −176.2 (3) C7---O7---C30---O8 2.3 (6) O10---C9---C10---C11 −129.2 (4) C7---O7---C30---O9 −177.5 (3) C8---C9---C10---C11 60.0 (4) C31---O9---C30---O8 9.1 (6) O11---C10---C11---C12 115.7 (4) C31---O9---C30---O7 −171.1 (3) C9---C10---C11---C12 −121.6 (4) C30---O9---C31---C32 −174.4 (3) O11---C10---C11---C15 −73.5 (4) O9---C31---C32---Cl2 180.0 (3) C9---C10---C11---C15 49.2 (4) O9---C31---C32---Cl3 59.9 (4) C10---C11---C12---C20 −11.8 (5) O9---C31---C32---Cl1 −60.7 (4) C15---C11---C12---C20 177.3 (3) C10---O11---C33---O12 9.0 (6) C10---C11---C12---C13 165.0 (3) C10---O11---C33---O13 −171.1 (3) C15---C11---C12---C13 −6.0 (5) C34---O13---C33---O12 0.0 (6) C11---C12---C13---O14 −155.7 (3) C34---O13---C33---O11 −179.8 (3) C20---C12---C13---O14 21.3 (5) C33---O13---C34---C35 170.1 (4) C11---C12---C13---C14 −35.3 (5) O13---C34---C35---Cl6 178.6 (3) C20---C12---C13---C14 141.6 (4) O13---C34---C35---Cl4 58.9 (4) O14---C13---C14---C1 151.0 (3) O13---C34---C35---Cl5 −62.5 (5) C12---C13---C14---C1 27.4 (5) C38---O16---C37---O15 3.0 (11) O1---C1---C14---C13 136.6 (4) C38---O16---C37---C36 −177.4 (8) C15---C1---C14---C13 18.1 (5) C37---O16---C38---C39 171.4 (8) C2---C1---C14---C13 −107.8 (4) ----------------------- ------------ ------------------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e6103 .table-wrap} --------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O17---H17E···Cl1^i^ 0.89 (2) 2.85 (6) 3.582 (5) 141 (6) O17---H17E···O9^i^ 0.89 (2) 2.48 (7) 3.241 (6) 143 (9) O14---H14···O17 0.83 (2) 2.00 (2) 2.791 (6) 161 (4) O1---H1···O15 0.82 (2) 2.01 (3) 2.786 (6) 158 (5) O17---H17D···O1^ii^ 0.91 (2) 2.25 (4) 3.085 (6) 152 (6) --------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, *y*+1/2, −*z*+3/2; (ii) *x*+1/2, −*y*+1/2, −*z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- ---------- ---------- ----------- ------------- O17---H17*E*⋯Cl1^i^ 0.89 (2) 2.85 (6) 3.582 (5) 141 (6) O17---H17*E*⋯O9^i^ 0.89 (2) 2.48 (7) 3.241 (6) 143 (9) O14---H14⋯O17 0.83 (2) 2.00 (2) 2.791 (6) 161 (4) O1---H1⋯O15 0.82 (2) 2.01 (3) 2.786 (6) 158 (5) O17---H17*D*⋯O1^ii^ 0.91 (2) 2.25 (4) 3.085 (6) 152 (6) Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.511272

2011-2-02

PMC3051955

Related literature {#sec1} ================== For general background to the synthesis of benzothia­zines, see: Harmata *et al.* (2005[@bb3]). For the pharmacological activity of benzothia­zine derivatives, see: Lopatina *et al.* (1982[@bb4]). For related structures, see: Saeed *et al.* (2010[@bb6]); Aouine *et al.* (2010[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~11~H~11~NO~3~S*M* *~r~* = 237.27Monoclinic,*a* = 17.347 (5) Å*b* = 8.724 (2) Å*c* = 7.274 (1) Åβ = 98.71 (2)°*V* = 1088.1 (4) Å^3^*Z* = 4Cu *K*α radiationμ = 2.59 mm^−1^*T* = 296 K0.20 × 0.15 × 0.15 mm ### Data collection {#sec2.1.2} Enraf--Nonius CAD-4 diffractometerAbsorption correction: ψ scan (North *et al.*, 1968[@bb5]) *T* ~min~ = 0.625, *T* ~max~ = 0.6971852 measured reflections1852 independent reflections1654 reflections with *I* \> 2σ(*I*)2 standard reflections every 90 min intensity decay: none ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.043*wR*(*F* ^2^) = 0.123*S* = 1.031852 reflections147 parametersH-atom parameters constrainedΔρ~max~ = 0.31 e Å^−3^Δρ~min~ = −0.28 e Å^−3^ {#d5e417} Data collection: *CAD-4 Software* (Enraf--Nonius, 1989[@bb2]); cell refinement: *CAD-4 Software*; data reduction: *CAD-4 Software*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *PLATON* (Spek, 2009[@bb8]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb9]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811006477/bt5472sup1.cif](http://dx.doi.org/10.1107/S1600536811006477/bt5472sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006477/bt5472Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006477/bt5472Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?bt5472&file=bt5472sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?bt5472sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?bt5472&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BT5472](http://scripts.iucr.org/cgi-bin/sendsup?bt5472)). Comment ======= Several derivatives of benzothiazines, particularly those carrying a keto group on the thiazine part of the molecule, show stimulant and antidepressant activity. \[Lopatina *et al.* 1982\]. The goal of the present work was the synthesis, the crystal structure determination and the biological teste of the methyl (3-oxo-2,3-dihydro-4*H*-1,4-benzothiazin-4-yl)acetate. \[Harmata *et al.* 2005\]. In the crystal structure of the title compound (Fig. 1), the molecules exhibit C···H---O intermolecular H-bonds interactions (Fig. 2). The heterocyclic thiazine ring adopt half-chair conformation with the S and N atoms displaced by 0.357 (5) and 0.304 (15) Å, respectively, on the opposite sides from the mean plane formed by the remaining ring atoms. The methyl acetate group, which is almost planar with the r. m.s deviaton of 0.042 (14) Å, is iclined at dihedral angle of 88.31 (9)° and 74.67 (9)° with respect to the thiazine and benzene ring respectively. The dihedral angle between the aromatic benzene ring C1--C6 and thiazine ring C5/C6/N7/C8/C9/S10 is 17.02 (9)° while the methyl acetate group C12/C13/O14/O15/C16 is oriented at dihedral angle of 81.30 (8)° with respect to the benzothiazine ring. In the title compound (Fig. 1), the bond distances and angles agree with the cortresponding bond distances and angles reported in related compounds \[Saeed *et al.* 2010 and Aouine *et al.* 2010\]. Experimental {#experimental} ============ To 1,4-benzithiazin-3-one (0.25 g, 1.5 mmol), potassium carbonate (0.41 g, 3 mmol), in ketone (15 ml) was added methyl chloroacetate (0.32 g, 3 mmol). The mixture was heated to reflux for 48 h. The salts were removed by filtration and the filtrate concentrated under reduced pressure. The residue was separated by chromatography on a column of silica gel with dichloromethane/diethyl ether (9/1) as eluent. Crystals were isolated when the solvent was allowed to evaporate. Refinement {#refinement} ========== All H atoms were fixed geometrically and treated as riding with C---H = 0.97 Å (methyne) and 0.93Å (aromatic) with U iso (H) = 1.2Ueq(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Molecular view of the title compound showing the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented as small spheres of arbitrary radii. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Partial packing view showing the chain formed by C---H···O hydrogen bondings. H atoms not involved in hydrogen bonds have been omitted for clarity. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e118 .table-wrap} ------------------------- ------------------------------------- C~11~H~11~NO~3~S *F*(000) = 496 *M~r~* = 237.27 *D*~x~ = 1.448 Mg m^−3^ Monoclinic, *P*2~1~/*c* Cu *K*α radiation, λ = 1.54180 Å Hall symbol: -P 2ybc Cell parameters from 25 reflections *a* = 17.347 (5) Å θ = 25.0--35.0° *b* = 8.724 (2) Å µ = 2.59 mm^−1^ *c* = 7.274 (1) Å *T* = 296 K β = 98.71 (2)° Prism, colourless *V* = 1088.1 (4) Å^3^ 0.20 × 0.15 × 0.15 mm *Z* = 4 ------------------------- ------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e246 .table-wrap} ------------------------------------------------------ -------------------------------------- Enraf--Nonius CAD-4 diffractometer 1654 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.000 graphite θ~max~ = 64.9°, θ~min~ = 2.6° ω--2θ scans *h* = −20→20 Absorption correction: ψ scan (North *et al.*, 1968) *k* = 0→10 *T*~min~ = 0.625, *T*~max~ = 0.697 *l* = 0→8 1852 measured reflections 2 standard reflections every 90 min 1852 independent reflections intensity decay: none ------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e365 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.043 H-atom parameters constrained *wR*(*F*^2^) = 0.123 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0891*P*)^2^ + 0.2952*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.03 (Δ/σ)~max~ \< 0.001 1852 reflections Δρ~max~ = 0.31 e Å^−3^ 147 parameters Δρ~min~ = −0.28 e Å^−3^ 0 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.025 (2) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e546 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e645 .table-wrap} ------ -------------- -------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 0.06412 (11) 1.0010 (2) −0.1876 (3) 0.0408 (5) C12 0.34845 (11) 0.9981 (2) −0.1202 (3) 0.0425 (5) C13 0.38184 (11) 1.1551 (2) −0.0708 (3) 0.0385 (5) C16 0.48971 (13) 1.3152 (3) −0.0896 (3) 0.0523 (6) C2 0.06020 (13) 1.0995 (2) −0.3366 (3) 0.0462 (5) C3 0.12837 (14) 1.1575 (2) −0.3843 (3) 0.0477 (5) C4 0.19978 (12) 1.1181 (2) −0.2852 (3) 0.0411 (5) C5 0.13542 (10) 0.9596 (2) −0.0860 (2) 0.0342 (4) C6 0.20474 (10) 1.0183 (2) −0.1350 (2) 0.0325 (4) C8 0.29001 (11) 0.9244 (2) 0.1449 (3) 0.0424 (5) C9 0.22014 (12) 0.9212 (3) 0.2432 (3) 0.0480 (5) H1 0.0183 0.9615 −0.1545 0.049\* H12A 0.3363 0.9889 −0.2544 0.051\* H12B 0.3870 0.9207 −0.0761 0.051\* H16A 0.4570 1.3905 −0.1589 0.078\* H16B 0.5394 1.3128 −0.1325 0.078\* H16C 0.4970 1.3413 0.0401 0.078\* H2 0.0122 1.1265 −0.4041 0.055\* H3 0.1262 1.2242 −0.4847 0.057\* H4 0.2451 1.1588 −0.3192 0.049\* H9A 0.2064 1.0251 0.2730 0.058\* H9B 0.2327 0.8649 0.3589 0.058\* N7 0.27801 (9) 0.97159 (18) −0.0378 (2) 0.0371 (4) O11 0.35438 (9) 0.8896 (2) 0.2240 (2) 0.0645 (5) O14 0.34929 (8) 1.25486 (18) −0.0003 (2) 0.0561 (5) O15 0.45320 (8) 1.16608 (16) −0.1160 (2) 0.0454 (4) S10 0.13827 (3) 0.83215 (6) 0.10137 (7) 0.0470 (3) ------ -------------- -------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1047 .table-wrap} ----- ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0361 (10) 0.0407 (10) 0.0462 (11) −0.0021 (8) 0.0082 (8) −0.0077 (8) C2 0.0487 (11) 0.0415 (11) 0.0450 (11) 0.0044 (9) −0.0043 (9) −0.0055 (9) C3 0.0651 (14) 0.0391 (11) 0.0370 (10) −0.0035 (9) 0.0012 (9) 0.0033 (8) C4 0.0502 (11) 0.0370 (10) 0.0385 (10) −0.0082 (9) 0.0144 (8) 0.0011 (8) C5 0.0378 (9) 0.0294 (9) 0.0373 (10) −0.0026 (7) 0.0121 (7) −0.0040 (7) C6 0.0359 (9) 0.0287 (9) 0.0343 (9) −0.0022 (7) 0.0098 (7) −0.0042 (7) N7 0.0312 (8) 0.0376 (8) 0.0447 (9) −0.0005 (6) 0.0128 (6) 0.0019 (7) C8 0.0408 (10) 0.0393 (10) 0.0471 (11) 0.0024 (8) 0.0071 (8) 0.0026 (8) C9 0.0509 (11) 0.0567 (13) 0.0379 (10) 0.0024 (10) 0.0116 (9) 0.0121 (9) S10 0.0442 (4) 0.0470 (4) 0.0529 (4) −0.0048 (2) 0.0170 (2) 0.0152 (2) O11 0.0449 (9) 0.0783 (12) 0.0667 (11) 0.0108 (8) −0.0030 (7) 0.0096 (9) C12 0.0334 (9) 0.0418 (11) 0.0560 (12) 0.0009 (8) 0.0185 (8) −0.0028 (9) C13 0.0295 (9) 0.0454 (11) 0.0419 (10) −0.0017 (8) 0.0098 (7) −0.0010 (8) O14 0.0455 (9) 0.0543 (10) 0.0735 (11) −0.0063 (7) 0.0257 (8) −0.0220 (8) O15 0.0317 (7) 0.0491 (8) 0.0579 (9) −0.0035 (5) 0.0147 (6) 0.0000 (6) C16 0.0405 (11) 0.0562 (13) 0.0605 (13) −0.0111 (9) 0.0085 (10) 0.0037 (11) ----- ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1373 .table-wrap} ----------------- ------------- ------------------- ----------- S10---C5 1.7538 (17) C5---C6 1.402 (2) S10---C9 1.800 (2) C8---C9 1.498 (3) O11---C8 1.215 (3) C12---C13 1.509 (3) O14---C13 1.195 (2) C1---H1 0.9300 O15---C13 1.332 (2) C2---H2 0.9300 O15---C16 1.447 (3) C3---H3 0.9300 N7---C6 1.418 (2) C4---H4 0.9300 N7---C8 1.377 (3) C9---H9A 0.9700 N7---C12 1.459 (3) C9---H9B 0.9700 C1---C2 1.377 (3) C12---H12A 0.9700 C1---C5 1.389 (3) C12---H12B 0.9700 C2---C3 1.378 (3) C16---H16A 0.9600 C3---C4 1.379 (3) C16---H16B 0.9600 C4---C6 1.390 (3) C16---H16C 0.9600 C5---S10---C9 95.67 (10) C5---C1---H1 120.00 C13---O15---C16 115.88 (16) C1---C2---H2 120.00 C6---N7---C8 124.10 (15) C3---C2---H2 121.00 C6---N7---C12 119.55 (15) C2---C3---H3 120.00 C8---N7---C12 115.50 (16) C4---C3---H3 120.00 C2---C1---C5 121.00 (18) C3---C4---H4 120.00 C1---C2---C3 119.0 (2) C6---C4---H4 120.00 C2---C3---C4 120.93 (19) S10---C9---H9A 109.00 C3---C4---C6 120.73 (19) S10---C9---H9B 109.00 S10---C5---C1 119.76 (14) C8---C9---H9A 109.00 S10---C5---C6 120.32 (13) C8---C9---H9B 109.00 C1---C5---C6 119.92 (15) H9A---C9---H9B 108.00 N7---C6---C4 121.09 (16) N7---C12---H12A 109.00 N7---C6---C5 120.47 (14) N7---C12---H12B 109.00 C4---C6---C5 118.39 (16) C13---C12---H12A 109.00 O11---C8---N7 121.72 (18) C13---C12---H12B 109.00 O11---C8---C9 121.43 (19) H12A---C12---H12B 108.00 N7---C8---C9 116.83 (17) O15---C16---H16A 109.00 S10---C9---C8 111.08 (15) O15---C16---H16B 109.00 N7---C12---C13 111.18 (16) O15---C16---H16C 109.00 O14---C13---O15 124.83 (17) H16A---C16---H16B 109.00 O14---C13---C12 125.04 (18) H16A---C16---H16C 109.00 O15---C13---C12 110.13 (16) H16B---C16---H16C 109.00 C2---C1---H1 119.00 ----------------- ------------- ------------------- ----------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1737 .table-wrap} ------------------ --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C4---H4···O14^i^ 0.93 2.51 3.411 (3) 164 ------------------ --------- --------- ----------- --------------- ::: Symmetry codes: (i) . ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------- --------- ------- ----------- ------------- C4---H4⋯O14 0.93 2.51 3.411 (3) 164 :::

PubMed Central

2024-06-05T04:04:17.524481

2011-2-26

PMC3051956

Related literature {#sec1} ================== For the pharmacological properties and applications of Mannich bases, see: Joshi *et al.* (2004[@bb3]); Holla *et al.* (2003[@bb2]); Negm *et al.* (2005[@bb4]). For a related structure, see: Wang *et al.* (2011[@bb7]). For standard bond lengths, see: Allen *et al.* (1987[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~34~H~26~N~4~O~2~S*M* *~r~* = 554.65Monoclinic,*a* = 13.142 (3) Å*b* = 21.563 (4) Å*c* = 10.097 (2) Åβ = 99.22 (3)°*V* = 2824.4 (10) Å^3^*Z* = 4Mo *K*α radiationμ = 0.15 mm^−1^*T* = 113 K0.20 × 0.18 × 0.10 mm ### Data collection {#sec2.1.2} Rigaku Saturn CCD area-detector diffractometerAbsorption correction: multi-scan (*CrystalClear*; Rigaku/MSC, 2005[@bb5]) *T* ~min~ = 0.970, *T* ~max~ = 0.98523204 measured reflections4960 independent reflections4082 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.054 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.045*wR*(*F* ^2^) = 0.142*S* = 1.114960 reflections372 parametersH-atom parameters constrainedΔρ~max~ = 0.34 e Å^−3^Δρ~min~ = −0.31 e Å^−3^ {#d5e466} Data collection: *CrystalClear* (Rigaku/MSC, 2005[@bb5]); cell refinement: *CrystalClear*; data reduction: *CrystalClear*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb6]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb6]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb6]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811005721/cv5051sup1.cif](http://dx.doi.org/10.1107/S1600536811005721/cv5051sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005721/cv5051Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005721/cv5051Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?cv5051&file=cv5051sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?cv5051sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?cv5051&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [CV5051](http://scripts.iucr.org/cgi-bin/sendsup?cv5051)). We gratefully acknowledge support from the Key Laboratory Project of Liaoning Province (grant No. 2008S127) and the Doctoral Starting Foundation of Liaoning Province (grant No. 20071103). Comment ======= We are paying attention to the synthesis and applications of Mannich base due to their comprehensive biological activities (Joshi *et al.*, 2004; Holla *et al.*, 2003; Negm *et al.*, 2005). Recently, we have reported a crystal structure of Mannich base modified by the triazole thione (Wang *et al.*, 2011). Herewith we present the crystal structure of the title compound (I), which is a new Mannich base. In (I) (Fig. 1), all bond lengths and angles are normal (Allen *et al.*, 1987). An intramolecular O---H···N hydrogen bond (Table 1) results in the formation of a planar (r.m.s. deviation = 0.0094 (2) Å) six-membered ring. This six-membered ring forms a dihedral angle of 36.3 (3)° with the triazole ring. The naphthyl system and central triazole ring form a dihedral angle of 37.8 (1)°. The weak intermolecular C---H···O and C---H···π interactions (Table 1) contribute to the crystal packing stabilisation. Experimental {#experimental} ============ The title compound was synthesized by the reaction of the chalcone (2.0 mmol) with its corresponding Schiff base, which was inturn obtained by refluxing 4-amino-1-methyl-4*H*-1,2,4-triazole-5-thiol (2.0 mmol), 2-hydroxynaphthalene-1 -carbaldehyde (2.0 mmol) in ethanol. A mixture of Schiff base and chalcone in ethanol was stirring for 24 h.The reaction progress was monitored *via* TLC. The resulting precipitate was filtered off, washed with cold ethanol, dried and purified to give the target product as colorless solid in 84% yield. Crystals of (I) suitable for single-crystal X-ray analysis were grown by slow evaporation of a solution in chloroform-ethanol (1:1). Refinement {#refinement} ========== The hydroxy H atom was located in a differency map, but placed in idealized position with O---H 0.84 Å. C-bound H atoms were positioned geometrically (C---H = 0.95--0.99 Å). All H atoms were refined as riding, with *U*~iso~(H) = 1.2-1.5 *U*~eq~ of the parent atom. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### View of (I) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 60% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e126 .table-wrap} ------------------------- --------------------------------------- C~34~H~26~N~4~O~2~S *F*(000) = 1160 *M~r~* = 554.65 *D*~x~ = 1.304 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 7260 reflections *a* = 13.142 (3) Å θ = 1.6--28.0° *b* = 21.563 (4) Å µ = 0.15 mm^−1^ *c* = 10.097 (2) Å *T* = 113 K β = 99.22 (3)° Prism, colorless *V* = 2824.4 (10) Å^3^ 0.20 × 0.18 × 0.10 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e257 .table-wrap} ---------------------------------------------------------------------- -------------------------------------- Rigaku Saturn CCD area-detector diffractometer 4960 independent reflections Radiation source: rotating anode 4082 reflections with *I* \> 2σ(*I*) confocal *R*~int~ = 0.054 Detector resolution: 7.31 pixels mm^-1^ θ~max~ = 25.0°, θ~min~ = 1.6° φ and ω scans *h* = −15→15 Absorption correction: multi-scan (*CrystalClear*; Rigaku/MSC, 2005) *k* = −25→25 *T*~min~ = 0.970, *T*~max~ = 0.985 *l* = −12→11 23204 measured reflections ---------------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e380 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.045 H-atom parameters constrained *wR*(*F*^2^) = 0.142 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0813*P*)^2^ + 0.4421*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.11 (Δ/σ)~max~ = 0.001 4960 reflections Δρ~max~ = 0.34 e Å^−3^ 372 parameters Δρ~min~ = −0.31 e Å^−3^ 0 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.0240 (19) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e561 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e660 .table-wrap} ----- --------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ S1 0.16625 (4) 0.42969 (3) 0.53137 (5) 0.02488 (19) O1 0.08098 (12) 0.59528 (7) 0.32929 (16) 0.0304 (4) O2 0.56113 (11) 0.45741 (7) 0.40769 (15) 0.0256 (4) H2 0.4993 0.4598 0.3708 0.038\* N1 0.10577 (13) 0.46429 (8) 0.27235 (17) 0.0199 (4) N2 0.14223 (13) 0.47373 (8) 0.15336 (17) 0.0218 (4) N3 0.26474 (13) 0.43820 (8) 0.30946 (16) 0.0185 (4) N4 0.36713 (13) 0.43073 (8) 0.37079 (17) 0.0195 (4) C1 −0.00280 (15) 0.47524 (10) 0.2847 (2) 0.0201 (5) H1 −0.0055 0.4847 0.3810 0.024\* C2 −0.06940 (16) 0.41850 (9) 0.2465 (2) 0.0217 (5) C3 −0.06416 (17) 0.38507 (11) 0.1301 (2) 0.0285 (5) H3 −0.0143 0.3957 0.0754 0.034\* C4 −0.13163 (19) 0.33608 (11) 0.0934 (2) 0.0339 (6) H4 −0.1275 0.3132 0.0140 0.041\* C5 −0.20463 (18) 0.32055 (11) 0.1720 (2) 0.0336 (6) H5 −0.2514 0.2875 0.1458 0.040\* C6 −0.20963 (19) 0.35305 (11) 0.2889 (3) 0.0351 (6) H6 −0.2596 0.3423 0.3433 0.042\* C7 −0.14105 (17) 0.40157 (10) 0.3265 (2) 0.0279 (5) H7 −0.1435 0.4233 0.4078 0.034\* C8 −0.04660 (15) 0.53104 (9) 0.2024 (2) 0.0200 (5) H8A −0.0383 0.5241 0.1078 0.024\* H8B −0.1214 0.5336 0.2053 0.024\* C9 0.00226 (16) 0.59267 (10) 0.2479 (2) 0.0220 (5) C10 −0.04771 (17) 0.65007 (10) 0.1847 (2) 0.0258 (5) C11 −0.14383 (19) 0.64937 (11) 0.1051 (3) 0.0436 (7) H11 −0.1822 0.6119 0.0939 0.052\* C12 −0.1845 (2) 0.70293 (13) 0.0417 (4) 0.0623 (10) H12 −0.2502 0.7019 −0.0133 0.075\* C13 −0.1304 (2) 0.75742 (12) 0.0580 (4) 0.0585 (9) H13 −0.1582 0.7939 0.0135 0.070\* C14 −0.0359 (2) 0.75920 (12) 0.1386 (3) 0.0514 (8) H14 0.0014 0.7970 0.1507 0.062\* C15 0.00491 (19) 0.70596 (11) 0.2024 (3) 0.0388 (6) H15 0.0699 0.7077 0.2592 0.047\* C16 0.17801 (16) 0.44309 (9) 0.3722 (2) 0.0191 (5) C17 0.24002 (15) 0.45884 (9) 0.1792 (2) 0.0193 (5) C18 0.31025 (15) 0.45953 (9) 0.0795 (2) 0.0194 (5) C19 0.29602 (16) 0.50478 (10) −0.0206 (2) 0.0222 (5) H19 0.2473 0.5371 −0.0175 0.027\* C20 0.35328 (17) 0.50241 (11) −0.1249 (2) 0.0269 (5) H20 0.3431 0.5329 −0.1936 0.032\* C21 0.42476 (17) 0.45594 (10) −0.1289 (2) 0.0282 (5) H21 0.4633 0.4543 −0.2008 0.034\* C22 0.44066 (18) 0.41152 (10) −0.0284 (2) 0.0273 (5) H22 0.4906 0.3799 −0.0313 0.033\* C23 0.38430 (17) 0.41304 (10) 0.0757 (2) 0.0234 (5) H23 0.3957 0.3827 0.1446 0.028\* C24 0.38344 (16) 0.39135 (9) 0.4677 (2) 0.0203 (5) H24 0.3278 0.3674 0.4899 0.024\* C25 0.48594 (15) 0.38324 (9) 0.5431 (2) 0.0176 (4) C26 0.50280 (16) 0.33939 (9) 0.6524 (2) 0.0207 (5) C27 0.42351 (17) 0.30223 (10) 0.6923 (2) 0.0269 (5) H27 0.3546 0.3065 0.6473 0.032\* C28 0.4453 (2) 0.26033 (11) 0.7947 (2) 0.0343 (6) H28 0.3911 0.2359 0.8196 0.041\* C29 0.5456 (2) 0.25274 (11) 0.8635 (3) 0.0362 (6) H29 0.5598 0.2230 0.9336 0.043\* C30 0.62286 (19) 0.28835 (11) 0.8292 (2) 0.0302 (5) H30 0.6908 0.2838 0.8772 0.036\* C31 0.60419 (16) 0.33192 (9) 0.7236 (2) 0.0219 (5) C32 0.68548 (17) 0.36873 (11) 0.6870 (2) 0.0263 (5) H32 0.7530 0.3644 0.7363 0.032\* C33 0.66934 (17) 0.40962 (10) 0.5842 (2) 0.0240 (5) H33 0.7251 0.4333 0.5615 0.029\* C34 0.56926 (16) 0.41697 (9) 0.5107 (2) 0.0198 (5) ----- --------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1572 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.0264 (3) 0.0314 (3) 0.0177 (3) 0.0045 (2) 0.0061 (2) 0.0032 (2) O1 0.0231 (9) 0.0351 (9) 0.0309 (9) −0.0044 (7) −0.0023 (7) 0.0010 (7) O2 0.0212 (8) 0.0302 (8) 0.0252 (8) −0.0010 (7) 0.0030 (7) 0.0093 (6) N1 0.0171 (9) 0.0269 (9) 0.0164 (9) 0.0009 (7) 0.0042 (7) 0.0027 (7) N2 0.0191 (10) 0.0273 (10) 0.0191 (9) −0.0007 (7) 0.0034 (7) 0.0012 (7) N3 0.0155 (9) 0.0240 (9) 0.0161 (9) 0.0012 (7) 0.0025 (7) 0.0015 (7) N4 0.0157 (10) 0.0243 (9) 0.0179 (9) 0.0026 (7) 0.0006 (7) −0.0005 (7) C1 0.0145 (11) 0.0259 (11) 0.0203 (11) 0.0023 (9) 0.0041 (9) 0.0010 (8) C2 0.0189 (11) 0.0220 (11) 0.0228 (11) 0.0028 (9) −0.0006 (9) 0.0065 (8) C3 0.0274 (13) 0.0348 (13) 0.0236 (12) −0.0045 (10) 0.0050 (10) 0.0019 (10) C4 0.0367 (15) 0.0356 (13) 0.0284 (13) −0.0017 (11) 0.0022 (11) −0.0063 (10) C5 0.0302 (13) 0.0289 (12) 0.0394 (14) −0.0082 (10) −0.0012 (11) −0.0017 (11) C6 0.0322 (14) 0.0309 (13) 0.0449 (15) −0.0064 (10) 0.0143 (12) −0.0007 (11) C7 0.0291 (13) 0.0257 (12) 0.0308 (13) −0.0022 (10) 0.0099 (10) −0.0018 (9) C8 0.0153 (11) 0.0251 (11) 0.0203 (11) 0.0016 (9) 0.0047 (9) 0.0014 (8) C9 0.0175 (12) 0.0288 (12) 0.0205 (11) −0.0014 (9) 0.0052 (10) −0.0013 (9) C10 0.0228 (12) 0.0243 (11) 0.0295 (12) −0.0005 (9) 0.0019 (10) −0.0032 (9) C11 0.0357 (15) 0.0201 (12) 0.0666 (19) −0.0040 (11) −0.0176 (13) 0.0025 (12) C12 0.0496 (18) 0.0281 (14) 0.094 (3) 0.0010 (13) −0.0344 (17) 0.0071 (15) C13 0.056 (2) 0.0201 (13) 0.089 (2) 0.0032 (12) −0.0187 (17) 0.0064 (14) C14 0.0482 (18) 0.0201 (13) 0.080 (2) −0.0075 (12) −0.0076 (16) −0.0020 (13) C15 0.0307 (14) 0.0249 (12) 0.0572 (17) −0.0034 (10) −0.0032 (12) −0.0045 (11) C16 0.0194 (11) 0.0160 (10) 0.0222 (11) −0.0004 (8) 0.0045 (9) 0.0004 (8) C17 0.0170 (11) 0.0203 (10) 0.0202 (11) −0.0019 (8) 0.0018 (9) 0.0014 (8) C18 0.0152 (11) 0.0236 (11) 0.0190 (11) −0.0027 (8) 0.0013 (9) −0.0013 (8) C19 0.0185 (11) 0.0252 (11) 0.0219 (11) 0.0002 (9) 0.0006 (9) 0.0010 (9) C20 0.0273 (12) 0.0318 (12) 0.0212 (12) −0.0027 (10) 0.0026 (10) 0.0023 (9) C21 0.0289 (13) 0.0355 (13) 0.0217 (12) −0.0049 (10) 0.0087 (10) −0.0037 (10) C22 0.0257 (12) 0.0309 (12) 0.0264 (12) 0.0018 (10) 0.0072 (10) −0.0049 (9) C23 0.0228 (12) 0.0244 (11) 0.0219 (12) 0.0010 (9) 0.0002 (9) 0.0007 (9) C24 0.0206 (12) 0.0198 (10) 0.0209 (11) 0.0002 (8) 0.0047 (9) −0.0021 (8) C25 0.0183 (11) 0.0181 (10) 0.0168 (10) 0.0027 (8) 0.0040 (8) −0.0023 (8) C26 0.0240 (12) 0.0199 (11) 0.0186 (11) 0.0009 (9) 0.0048 (9) −0.0002 (8) C27 0.0260 (13) 0.0278 (12) 0.0268 (12) −0.0034 (9) 0.0035 (10) 0.0048 (9) C28 0.0408 (15) 0.0279 (12) 0.0360 (14) −0.0050 (11) 0.0113 (12) 0.0096 (10) C29 0.0446 (16) 0.0325 (13) 0.0318 (14) 0.0051 (11) 0.0068 (12) 0.0150 (10) C30 0.0313 (13) 0.0322 (13) 0.0264 (12) 0.0093 (10) 0.0020 (10) 0.0062 (10) C31 0.0225 (12) 0.0228 (11) 0.0204 (11) 0.0056 (9) 0.0032 (9) −0.0012 (8) C32 0.0200 (12) 0.0322 (12) 0.0252 (12) 0.0034 (9) −0.0010 (9) −0.0008 (9) C33 0.0189 (12) 0.0287 (12) 0.0250 (12) 0.0003 (9) 0.0057 (9) −0.0007 (9) C34 0.0235 (12) 0.0210 (10) 0.0153 (10) −0.0003 (9) 0.0036 (9) −0.0015 (8) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2333 .table-wrap} ----------------------- -------------- ----------------------- -------------- S1---C16 1.665 (2) C13---C14 1.372 (4) O1---C9 1.215 (3) C13---H13 0.9500 O2---C34 1.349 (2) C14---C15 1.382 (4) O2---H2 0.8400 C14---H14 0.9500 N1---C16 1.349 (3) C15---H15 0.9500 N1---N2 1.378 (2) C17---C18 1.471 (3) N1---C1 1.471 (3) C18---C19 1.396 (3) N2---C17 1.310 (3) C18---C23 1.402 (3) N3---C17 1.377 (3) C19---C20 1.390 (3) N3---C16 1.394 (3) C19---H19 0.9500 N3---N4 1.397 (2) C20---C21 1.379 (3) N4---C24 1.287 (3) C20---H20 0.9500 C1---C2 1.518 (3) C21---C22 1.387 (3) C1---C8 1.522 (3) C21---H21 0.9500 C1---H1 1.0000 C22---C23 1.380 (3) C2---C7 1.384 (3) C22---H22 0.9500 C2---C3 1.390 (3) C23---H23 0.9500 C3---C4 1.391 (3) C24---C25 1.448 (3) C3---H3 0.9500 C24---H24 0.9500 C4---C5 1.381 (3) C25---C34 1.396 (3) C4---H4 0.9500 C25---C26 1.444 (3) C5---C6 1.383 (3) C26---C31 1.418 (3) C5---H5 0.9500 C26---C27 1.423 (3) C6---C7 1.393 (3) C27---C28 1.369 (3) C6---H6 0.9500 C27---H27 0.9500 C7---H7 0.9500 C28---C29 1.398 (4) C8---C9 1.515 (3) C28---H28 0.9500 C8---H8A 0.9900 C29---C30 1.361 (3) C8---H8B 0.9900 C29---H29 0.9500 C9---C10 1.495 (3) C30---C31 1.412 (3) C10---C11 1.384 (3) C30---H30 0.9500 C10---C15 1.387 (3) C31---C32 1.426 (3) C11---C12 1.385 (3) C32---C33 1.353 (3) C11---H11 0.9500 C32---H32 0.9500 C12---C13 1.370 (4) C33---C34 1.411 (3) C12---H12 0.9500 C33---H33 0.9500 C34---O2---H2 109.5 C10---C15---H15 119.6 C16---N1---N2 113.59 (16) N1---C16---N3 102.42 (16) C16---N1---C1 124.56 (17) N1---C16---S1 128.11 (16) N2---N1---C1 121.84 (17) N3---C16---S1 129.41 (16) C17---N2---N1 104.91 (17) N2---C17---N3 110.08 (18) C17---N3---C16 108.93 (16) N2---C17---C18 124.36 (19) C17---N3---N4 121.57 (16) N3---C17---C18 125.38 (18) C16---N3---N4 127.36 (16) C19---C18---C23 119.5 (2) C24---N4---N3 116.37 (17) C19---C18---C17 118.47 (18) N1---C1---C2 112.14 (16) C23---C18---C17 121.73 (19) N1---C1---C8 111.58 (16) C20---C19---C18 119.8 (2) C2---C1---C8 110.26 (17) C20---C19---H19 120.1 N1---C1---H1 107.5 C18---C19---H19 120.1 C2---C1---H1 107.5 C21---C20---C19 120.2 (2) C8---C1---H1 107.5 C21---C20---H20 119.9 C7---C2---C3 119.2 (2) C19---C20---H20 119.9 C7---C2---C1 118.89 (19) C20---C21---C22 120.3 (2) C3---C2---C1 121.87 (19) C20---C21---H21 119.9 C2---C3---C4 120.2 (2) C22---C21---H21 119.9 C2---C3---H3 119.9 C23---C22---C21 120.3 (2) C4---C3---H3 119.9 C23---C22---H22 119.8 C5---C4---C3 120.2 (2) C21---C22---H22 119.8 C5---C4---H4 119.9 C22---C23---C18 119.8 (2) C3---C4---H4 119.9 C22---C23---H23 120.1 C4---C5---C6 120.0 (2) C18---C23---H23 120.1 C4---C5---H5 120.0 N4---C24---C25 120.45 (19) C6---C5---H5 120.0 N4---C24---H24 119.8 C5---C6---C7 119.7 (2) C25---C24---H24 119.8 C5---C6---H6 120.1 C34---C25---C26 119.34 (19) C7---C6---H6 120.1 C34---C25---C24 120.85 (18) C2---C7---C6 120.7 (2) C26---C25---C24 119.80 (18) C2---C7---H7 119.7 C31---C26---C27 117.64 (19) C6---C7---H7 119.7 C31---C26---C25 118.60 (19) C9---C8---C1 115.01 (18) C27---C26---C25 123.76 (19) C9---C8---H8A 108.5 C28---C27---C26 120.8 (2) C1---C8---H8A 108.5 C28---C27---H27 119.6 C9---C8---H8B 108.5 C26---C27---H27 119.6 C1---C8---H8B 108.5 C27---C28---C29 121.3 (2) H8A---C8---H8B 107.5 C27---C28---H28 119.4 O1---C9---C10 121.2 (2) C29---C28---H28 119.4 O1---C9---C8 121.3 (2) C30---C29---C28 119.3 (2) C10---C9---C8 117.44 (19) C30---C29---H29 120.3 C11---C10---C15 118.3 (2) C28---C29---H29 120.3 C11---C10---C9 122.4 (2) C29---C30---C31 121.4 (2) C15---C10---C9 119.2 (2) C29---C30---H30 119.3 C10---C11---C12 120.5 (2) C31---C30---H30 119.3 C10---C11---H11 119.8 C30---C31---C26 119.6 (2) C12---C11---H11 119.8 C30---C31---C32 121.3 (2) C13---C12---C11 120.4 (3) C26---C31---C32 119.16 (19) C13---C12---H12 119.8 C33---C32---C31 122.0 (2) C11---C12---H12 119.8 C33---C32---H32 119.0 C12---C13---C14 119.9 (3) C31---C32---H32 119.0 C12---C13---H13 120.1 C32---C33---C34 119.7 (2) C14---C13---H13 120.1 C32---C33---H33 120.2 C13---C14---C15 120.0 (2) C34---C33---H33 120.2 C13---C14---H14 120.0 O2---C34---C25 123.30 (19) C15---C14---H14 120.0 O2---C34---C33 115.47 (18) C14---C15---C10 120.9 (2) C25---C34---C33 121.22 (19) C14---C15---H15 119.6 C16---N1---N2---C17 −0.8 (2) N1---N2---C17---C18 177.69 (18) C1---N1---N2---C17 −179.26 (17) C16---N3---C17---N2 −3.0 (2) C17---N3---N4---C24 −154.97 (19) N4---N3---C17---N2 −167.49 (16) C16---N3---N4---C24 43.5 (3) C16---N3---C17---C18 −178.37 (19) C16---N1---C1---C2 −90.8 (2) N4---N3---C17---C18 17.1 (3) N2---N1---C1---C2 87.5 (2) N2---C17---C18---C19 34.5 (3) C16---N1---C1---C8 144.92 (19) N3---C17---C18---C19 −150.7 (2) N2---N1---C1---C8 −36.7 (3) N2---C17---C18---C23 −139.8 (2) N1---C1---C2---C7 136.1 (2) N3---C17---C18---C23 35.0 (3) C8---C1---C2---C7 −98.9 (2) C23---C18---C19---C20 1.7 (3) N1---C1---C2---C3 −47.3 (3) C17---C18---C19---C20 −172.70 (19) C8---C1---C2---C3 77.7 (2) C18---C19---C20---C21 −0.7 (3) C7---C2---C3---C4 1.3 (3) C19---C20---C21---C22 −0.5 (3) C1---C2---C3---C4 −175.3 (2) C20---C21---C22---C23 0.7 (3) C2---C3---C4---C5 0.4 (4) C21---C22---C23---C18 0.3 (3) C3---C4---C5---C6 −1.1 (4) C19---C18---C23---C22 −1.5 (3) C4---C5---C6---C7 0.3 (4) C17---C18---C23---C22 172.7 (2) C3---C2---C7---C6 −2.2 (3) N3---N4---C24---C25 −176.06 (16) C1---C2---C7---C6 174.5 (2) N4---C24---C25---C34 −1.2 (3) C5---C6---C7---C2 1.4 (4) N4---C24---C25---C26 179.30 (18) N1---C1---C8---C9 −64.8 (2) C34---C25---C26---C31 −0.2 (3) C2---C1---C8---C9 169.89 (17) C24---C25---C26---C31 179.34 (18) C1---C8---C9---O1 11.4 (3) C34---C25---C26---C27 −179.18 (19) C1---C8---C9---C10 −170.98 (18) C24---C25---C26---C27 0.3 (3) O1---C9---C10---C11 −171.5 (2) C31---C26---C27---C28 −0.8 (3) C8---C9---C10---C11 10.9 (3) C25---C26---C27---C28 178.3 (2) O1---C9---C10---C15 10.5 (3) C26---C27---C28---C29 0.1 (4) C8---C9---C10---C15 −167.1 (2) C27---C28---C29---C30 0.9 (4) C15---C10---C11---C12 2.0 (4) C28---C29---C30---C31 −1.3 (4) C9---C10---C11---C12 −175.9 (3) C29---C30---C31---C26 0.6 (3) C10---C11---C12---C13 −0.6 (5) C29---C30---C31---C32 −179.4 (2) C11---C12---C13---C14 −0.7 (6) C27---C26---C31---C30 0.4 (3) C12---C13---C14---C15 0.6 (5) C25---C26---C31---C30 −178.68 (19) C13---C14---C15---C10 0.9 (5) C27---C26---C31---C32 −179.57 (19) C11---C10---C15---C14 −2.2 (4) C25---C26---C31---C32 1.4 (3) C9---C10---C15---C14 175.8 (2) C30---C31---C32---C33 178.4 (2) N2---N1---C16---N3 −1.0 (2) C26---C31---C32---C33 −1.6 (3) C1---N1---C16---N3 177.48 (17) C31---C32---C33---C34 0.6 (3) N2---N1---C16---S1 176.44 (15) C26---C25---C34---O2 177.88 (18) C1---N1---C16---S1 −5.1 (3) C24---C25---C34---O2 −1.6 (3) C17---N3---C16---N1 2.3 (2) C26---C25---C34---C33 −0.9 (3) N4---N3---C16---N1 165.67 (17) C24---C25---C34---C33 179.63 (18) C17---N3---C16---S1 −175.07 (16) C32---C33---C34---O2 −178.16 (19) N4---N3---C16---S1 −11.7 (3) C32---C33---C34---C25 0.7 (3) N1---N2---C17---N3 2.2 (2) ----------------------- -------------- ----------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3715 .table-wrap} ----------------------------------------- Cg1 is the centroid of the C2--C7 ring. ----------------------------------------- ::: ::: {#d1e3719 .table-wrap} --------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O2---H2···N4 0.84 1.85 2.582 (2) 145 C32---H32···O1^i^ 0.95 2.53 3.196 (2) 127 C14---H14···Cg1^ii^ 0.95 2.60 3.465 (2) 151 --------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*+1, −*z*+1; (ii) −*x*, *y*+1/2, −*z*−1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) *Cg*1 is the centroid of the C2--C7 ring. ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ----------- ------------- O2---H2⋯N4 0.84 1.85 2.582 (2) 145 C32---H32⋯O1^i^ 0.95 2.53 3.196 (2) 127 C14---H14⋯*Cg*1^ii^ 0.95 2.60 3.465 (2) 151 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.528999

2011-2-19

PMC3051957

Related literature {#sec1} ================== For information on industrial chemicals, see: Chloro­nitro­toluenes (2010[@bb2]). For the use of the title compound as a starting material in the synthesis of 7-chlorovasicine (pyrrolo\[2,1-*b*\]quinazolin-3-ol, 8-chloro-1,2,3,9-tetrahydro), see: Southwick & Cremer (1959[@bb8]). For the toxic effects of the title compound on *D. magna*, see: Ramos *et al.* (2001[@bb5]) and on *T. pyriformis*, see: Schultz (1999[@bb6]); Katritzky *et al.* (2003[@bb3]). For a related structure, see: Liu & Du (2008[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~7~H~6~ClNO~2~*M* *~r~* = 171.58Orthorhombic,*a* = 7.3061 (5) Å*b* = 13.8392 (9) Å*c* = 14.6799 (10) Å*V* = 1484.29 (17) Å^3^*Z* = 8Mo *K*α radiationμ = 0.46 mm^−1^*T* = 125 K0.32 × 0.20 × 0.10 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2007[@bb1]) *T* ~min~ = 0.868, *T* ~max~ = 0.95622310 measured reflections2271 independent reflections1963 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.038 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.031*wR*(*F* ^2^) = 0.090*S* = 1.052271 reflections101 parametersH-atom parameters constrainedΔρ~max~ = 0.35 e Å^−3^Δρ~min~ = −0.38 e Å^−3^ {#d5e326} Data collection: *APEX2* (Bruker, 2007[@bb1]); cell refinement: *SAINT* (Bruker, 2007[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb7]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004466/jj2075sup1.cif](http://dx.doi.org/10.1107/S1600536811004466/jj2075sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004466/jj2075Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004466/jj2075Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?jj2075&file=jj2075sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?jj2075sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?jj2075&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [JJ2075](http://scripts.iucr.org/cgi-bin/sendsup?jj2075)). This work was supported by Vassar College. X-ray facilities were provided by the US National Science Foundation (grant No. 0521237 to JMT). Comment ======= The title compound, C~7~H~6~ClNO~2~, also known as 2-chloro-6-nitrotoluene, is a common intermediate in the synthesis of industrial chemicals (Chloronitrotoluenes, 2010), as well as in pharmaceuticals such as the bronchodilatory compound vasicine (Southwick *et al.*, 1959). 1-chloro-2-methyl-3-nitrobenzene is relatively toxic to biological species such as the freashwater flea *D. magna* and freshwater protozoa *T. pyriformis*, which suggests that this compound could become a harmful pollutant (Katritzky *et al.*, 2003; Schultz, 1999; Ramos *et al.*, 2001; Chloronitrotoluenes, 2010). C~7~H~6~ClNO~2~, (I), contains an aromatic ring with chloro, methyl and nitro substituents arranged in this order next to one another, The C---Cl and C---N bond lengths and angles in (I) are very close to those found in a similar structure (Liu & Du, 2008). The central methyl group interacts sterically with the neighboring chloro and nitro groups, as evidenced by the N---C3---C4 and Cl---C1---C6 angles of 115.0 (1)° and 116.78 (8)°, respectively. These angles are compressed from the ideal *sp*^2^ - hybridized carbon atom. The mean plane of the nitro group is twisted away from the mean plane of the aromatic ring by 38.81 (5)°. Experimental {#experimental} ============ Crystalline1-chloro-2-methyl-3-nitrobenzene was purchase from Aldrich Chemical Company, USA. Refinement {#refinement} ========== All non-hydrogen atoms were refined anisotropically. Hydrogen atoms on carbon were included in calculated positions and refined using a riding model at C--H = 0.95 or 0.98 Å and *U*~iso~(H) = 1.2 or 1.5 × *U*~eq~(C) of the aryl and methyl C-atoms, respectively. The extinction parameter (EXTI) refined to zero and was removed from the refinement. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the title compound, with displacement ellipsoids shown at the 50% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e139 .table-wrap} ------------------------- --------------------------------------- C~7~H~6~ClNO~2~ *F*(000) = 704 *M~r~* = 171.58 *D*~x~ = 1.536 Mg m^−3^ Orthorhombic, *Pbca* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ac 2ab Cell parameters from 9979 reflections *a* = 7.3061 (5) Å θ = 2.8--30.5° *b* = 13.8392 (9) Å µ = 0.46 mm^−1^ *c* = 14.6799 (10) Å *T* = 125 K *V* = 1484.29 (17) Å^3^ Block, colorless *Z* = 8 0.32 × 0.20 × 0.10 mm ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e260 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker APEXII CCD diffractometer 2271 independent reflections Radiation source: fine-focus sealed tube 1963 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.038 φ and ω scans θ~max~ = 30.5°, θ~min~ = 2.8° Absorption correction: multi-scan (*SADABS*; Bruker, 2007) *h* = −10→10 *T*~min~ = 0.868, *T*~max~ = 0.956 *k* = −19→19 22310 measured reflections *l* = −20→20 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e377 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.031 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.090 H-atom parameters constrained *S* = 1.05 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0501*P*)^2^ + 0.4184*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2271 reflections (Δ/σ)~max~ = 0.001 101 parameters Δρ~max~ = 0.35 e Å^−3^ 0 restraints Δρ~min~ = −0.38 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e534 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e633 .table-wrap} ----- -------------- ------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl 0.02248 (4) 0.79411 (2) 0.19541 (2) 0.02921 (10) O1 0.18412 (16) 0.46030 (7) 0.46513 (7) 0.0383 (2) O2 0.27741 (17) 0.60583 (8) 0.49519 (6) 0.0414 (3) N 0.21538 (15) 0.54450 (7) 0.44328 (7) 0.0269 (2) C1 0.09994 (14) 0.68212 (7) 0.23325 (8) 0.0200 (2) C2 0.11332 (14) 0.66404 (7) 0.32692 (7) 0.0202 (2) C3 0.18229 (14) 0.57217 (8) 0.34792 (7) 0.0198 (2) C4 0.22965 (15) 0.50274 (8) 0.28388 (8) 0.0207 (2) H4A 0.2734 0.4412 0.3026 0.025\* C5 0.21212 (15) 0.52466 (8) 0.19236 (7) 0.0218 (2) H5A 0.2439 0.4783 0.1474 0.026\* C6 0.14754 (15) 0.61522 (8) 0.16681 (7) 0.0218 (2) H6A 0.1360 0.6313 0.1041 0.026\* C7 0.05257 (18) 0.73682 (9) 0.39679 (9) 0.0294 (3) H7A −0.0502 0.7744 0.3725 0.044\* H7B 0.1544 0.7804 0.4111 0.044\* H7C 0.0139 0.7032 0.4523 0.044\* ----- -------------- ------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e876 .table-wrap} ---- -------------- -------------- -------------- -------------- --------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl 0.02669 (16) 0.01774 (15) 0.04320 (19) −0.00006 (9) −0.00430 (11) 0.00518 (11) O1 0.0576 (6) 0.0269 (5) 0.0303 (5) −0.0020 (4) 0.0027 (4) 0.0077 (4) O2 0.0613 (7) 0.0399 (6) 0.0232 (4) −0.0141 (5) −0.0070 (4) −0.0023 (4) N 0.0321 (5) 0.0269 (5) 0.0218 (4) −0.0029 (4) 0.0012 (4) 0.0015 (4) C1 0.0176 (4) 0.0150 (4) 0.0274 (5) −0.0011 (4) −0.0013 (4) 0.0010 (4) C2 0.0185 (5) 0.0174 (5) 0.0248 (5) −0.0030 (4) 0.0024 (4) −0.0032 (4) C3 0.0208 (5) 0.0197 (5) 0.0189 (5) −0.0033 (4) 0.0009 (4) 0.0007 (4) C4 0.0207 (5) 0.0159 (4) 0.0256 (5) −0.0006 (4) 0.0003 (4) −0.0015 (4) C5 0.0221 (5) 0.0202 (5) 0.0232 (5) −0.0012 (4) 0.0013 (4) −0.0054 (4) C6 0.0222 (5) 0.0226 (5) 0.0207 (5) −0.0027 (4) −0.0013 (4) −0.0003 (4) C7 0.0326 (6) 0.0234 (5) 0.0324 (6) −0.0011 (5) 0.0074 (5) −0.0095 (5) ---- -------------- -------------- -------------- -------------- --------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1129 .table-wrap} ------------------- -------------- ------------------- -------------- Cl---C1 1.7410 (11) C4---C5 1.3832 (16) O1---N 1.2300 (13) C4---H4A 0.9500 O2---N 1.2275 (14) C5---C6 1.3907 (16) N---C3 1.4713 (14) C5---H5A 0.9500 C1---C6 1.3891 (15) C6---H6A 0.9500 C1---C2 1.4010 (15) C7---H7A 0.9800 C2---C3 1.4018 (15) C7---H7B 0.9800 C2---C7 1.5045 (15) C7---H7C 0.9800 C3---C4 1.3882 (15) O2---N---O1 124.17 (11) C3---C4---H4A 120.6 O2---N---C3 118.13 (10) C4---C5---C6 119.41 (10) O1---N---C3 117.66 (10) C4---C5---H5A 120.3 C6---C1---C2 123.55 (10) C6---C5---H5A 120.3 C6---C1---Cl 116.78 (8) C1---C6---C5 119.74 (10) C2---C1---Cl 119.66 (8) C1---C6---H6A 120.1 C1---C2---C3 113.76 (10) C5---C6---H6A 120.1 C1---C2---C7 121.93 (10) C2---C7---H7A 109.5 C3---C2---C7 124.29 (10) C2---C7---H7B 109.5 C4---C3---C2 124.64 (10) H7A---C7---H7B 109.5 C4---C3---N 115.04 (10) C2---C7---H7C 109.5 C2---C3---N 120.29 (10) H7A---C7---H7C 109.5 C5---C4---C3 118.87 (10) H7B---C7---H7C 109.5 C5---C4---H4A 120.6 C6---C1---C2---C3 0.94 (15) O1---N---C3---C4 −38.35 (15) Cl---C1---C2---C3 −178.30 (7) O2---N---C3---C2 −38.54 (16) C6---C1---C2---C7 −177.26 (11) O1---N---C3---C2 143.61 (12) Cl---C1---C2---C7 3.50 (15) C2---C3---C4---C5 1.31 (17) C1---C2---C3---C4 −1.68 (15) N---C3---C4---C5 −176.63 (10) C7---C2---C3---C4 176.46 (11) C3---C4---C5---C6 −0.09 (17) C1---C2---C3---N 176.17 (9) C2---C1---C6---C5 0.13 (17) C7---C2---C3---N −5.69 (16) Cl---C1---C6---C5 179.39 (8) O2---N---C3---C4 139.50 (12) C4---C5---C6---C1 −0.59 (17) ------------------- -------------- ------------------- -------------- :::

PubMed Central

2024-06-05T04:04:17.537022

2011-2-12

PMC3051958

Related literature {#sec1} ================== For general background to and details of the biological activity of phenanthrene derivatives, see: Wang *et al.* (2010[@bb10]); Li & Wang (2009[@bb7]); Gao & Wong (2010[@bb5]); Zhan & Jiang (2010[@bb11]); Becker & Dettbarn (2009[@bb2]); Jones & Mathews (1997[@bb6]). For ring conformations, see: Cremer & Pople (1975[@bb4]). For bond-length data, see: Allen *et al.* (1987[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~22~H~16~O~2~*M* *~r~* = 312.35Monoclinic,*a* = 12.1831 (3) Å*b* = 5.4674 (1) Å*c* = 24.6064 (7) Åβ = 106.005 (2)°*V* = 1575.50 (7) Å^3^*Z* = 4Mo *K*α radiationμ = 0.08 mm^−1^*T* = 296 K0.49 × 0.41 × 0.13 mm ### Data collection {#sec2.1.2} Bruker SMART APEXII CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2009[@bb3]) *T* ~min~ = 0.960, *T* ~max~ = 0.98917018 measured reflections4613 independent reflections2927 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.030 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.049*wR*(*F* ^2^) = 0.145*S* = 1.044613 reflections217 parametersH-atom parameters constrainedΔρ~max~ = 0.13 e Å^−3^Δρ~min~ = −0.18 e Å^−3^ {#d5e359} Data collection: *APEX2* (Bruker, 2009[@bb3]); cell refinement: *SAINT* (Bruker, 2009[@bb3]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL*; software used to prepare material for publication: *SHELXTL* and *PLATON* (Spek, 2009[@bb9]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811003904/sj5097sup1.cif](http://dx.doi.org/10.1107/S1600536811003904/sj5097sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003904/sj5097Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003904/sj5097Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?sj5097&file=sj5097sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?sj5097sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?sj5097&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [SJ5097](http://scripts.iucr.org/cgi-bin/sendsup?sj5097)). HKF and CKQ thank Universiti Sains Malaysia for the Research University Grant (No. 1001/PFIZIK/811160). Financial support from the National Science Foundation of China (20702024) is also acknowledged. Comment ======= Phenanthrene is a major structural component of many natural products that play important roles in pharmaceutical and biological fields. For example, phenanthrene-based tylophorine derivatives could serve as potential antiviral agents against the tobacco mosaic virus in vitro (Wang *et al.*, 2010). In addition, phenanthrene-based alkaloids are found to possess antitumor activities (Li & Wang, 2009) and other important bioactivities. Gao & Wong reported that phenanthrene has important effect on rice cultivation by degrading the bacterium affecting the rice plants (Gao & Wong, 2010). In a phenanthrene-contaminated soil, the activity of urease and catalase may be decreased while polyphenol oxidase was stimulated (Zhan & Jiang, 2010). The importance of 9,10-disubstituted phenanthrene in biochemistry also has been reported. Phenanthrene 9,10-dihydrodiol could be used as a biomarker for ETS-exposure of children and the derivatives of pyrrolo(9, 10b)-phenanthrene were good templates for DNA intercalating drug delivery system (Becker & Dettbarn, 2009; Jones & Mathews, 1997). Due to the importance of the 9, 10-disubstituted phenanthrene derivatives, herewith, we report the crystal structure of the title compound. The title compound (Fig. 1) is made up of a phenanthrene (C9-C22) ring system, a phenyl (C1-C6) ring and a 1,4-dioxane (O1/O2/C7-C9/C22) ring. The phenanthrene ring system is essentially planar, with a maximum deviation of 0.058 (1) Å at atom C21, and is inclined at an angle of 58.39 (6) ° with the phenyl ring. The 1,4-dioxane ring is in chair conformation, puckering parameters (Cremer & Pople, 1975) Q = 0.4811 (14) Å; Θ = 51.41 (16)° and φ = 79.22 (18)°. Bond lengths (Allen *et al.*, 1987) and angles are within normal ranges. In the crystal (Fig.2), molecules are stacked along the *b*-axis but no significant hydrogen bonds are observed. Experimental {#experimental} ============ The title compound is a product of the photoreaction between phenanthrenequinone and styrene. The compound was purified by flash column chromatography with ethyl acetate/petroleum ether (1:10) as eluents. Good quality crystals of the title compound were obtained from slow evaporation of an acetone and petroleum ether solution (1:10). Refinement {#refinement} ========== All H atoms were positioned geometrically and refined using a riding model with C--H = 0.93 -0.98 Å and *U*~iso~(H) = 1.2 *U*~eq~(C). The highest residual electron density peak is located at 0.74 Å from H1A and the deepest hole is located at 1.33 Å from C14. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of the title compound showing 30% probability displacement ellipsoids for non-H atoms. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The crystal structure of the title compound, viewed along the b axis. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e125 .table-wrap} ------------------------- --------------------------------------- C~22~H~16~O~2~ *F*(000) = 656 *M~r~* = 312.35 *D*~x~ = 1.317 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 4055 reflections *a* = 12.1831 (3) Å θ = 2.8--28.1° *b* = 5.4674 (1) Å µ = 0.08 mm^−1^ *c* = 24.6064 (7) Å *T* = 296 K β = 106.005 (2)° Plate, colourless *V* = 1575.50 (7) Å^3^ 0.49 × 0.41 × 0.13 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e252 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEXII CCD area-detector diffractometer 4613 independent reflections Radiation source: fine-focus sealed tube 2927 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.030 φ and ω scans θ~max~ = 30.1°, θ~min~ = 2.1° Absorption correction: multi-scan (*SADABS*; Bruker, 2009) *h* = −17→17 *T*~min~ = 0.960, *T*~max~ = 0.989 *k* = −7→7 17018 measured reflections *l* = −34→34 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e369 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.049 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.145 H-atom parameters constrained *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0666*P*)^2^ + 0.1135*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4613 reflections (Δ/σ)~max~ = 0.001 217 parameters Δρ~max~ = 0.13 e Å^−3^ 0 restraints Δρ~min~ = −0.18 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e526 .table-wrap} ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ \> 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e571 .table-wrap} ------ -------------- -------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O1 0.69332 (7) 0.38054 (17) 0.93970 (4) 0.0546 (2) O2 0.88773 (8) 0.39205 (19) 0.89709 (4) 0.0634 (3) C1 0.70209 (14) −0.0387 (3) 1.00451 (6) 0.0650 (4) H1A 0.6455 −0.0275 0.9704 0.078\* C2 0.69661 (18) −0.2210 (3) 1.04270 (7) 0.0778 (5) H2A 0.6366 −0.3325 1.0340 0.093\* C3 0.77931 (18) −0.2381 (3) 1.09335 (7) 0.0790 (5) H3A 0.7755 −0.3612 1.1189 0.095\* C4 0.86718 (15) −0.0739 (3) 1.10617 (7) 0.0779 (5) H4A 0.9232 −0.0854 1.1405 0.093\* C5 0.87316 (13) 0.1090 (3) 1.06854 (6) 0.0643 (4) H5A 0.9327 0.2215 1.0778 0.077\* C6 0.79093 (11) 0.1262 (2) 1.01686 (5) 0.0502 (3) C7 0.80427 (11) 0.3130 (2) 0.97448 (5) 0.0504 (3) H7A 0.8427 0.4579 0.9944 0.060\* C8 0.87275 (12) 0.2128 (3) 0.93669 (6) 0.0590 (3) H8A 0.9470 0.1598 0.9598 0.071\* H8B 0.8338 0.0716 0.9164 0.071\* C9 0.79160 (10) 0.5302 (2) 0.87464 (5) 0.0501 (3) C10 0.79662 (11) 0.6914 (2) 0.82942 (5) 0.0505 (3) C11 0.89116 (12) 0.6902 (3) 0.80716 (6) 0.0619 (4) H11A 0.9501 0.5790 0.8208 0.074\* C12 0.89711 (14) 0.8519 (3) 0.76553 (6) 0.0706 (4) H12A 0.9596 0.8491 0.7507 0.085\* C13 0.81042 (15) 1.0190 (3) 0.74551 (6) 0.0706 (4) H13A 0.8158 1.1311 0.7179 0.085\* C14 0.71683 (14) 1.0214 (3) 0.76584 (6) 0.0639 (4) H14A 0.6590 1.1344 0.7516 0.077\* C15 0.70603 (11) 0.8569 (2) 0.80781 (5) 0.0511 (3) C16 0.60599 (11) 0.8495 (2) 0.82931 (5) 0.0500 (3) C17 0.51242 (13) 1.0099 (3) 0.81093 (6) 0.0629 (4) H17A 0.5139 1.1283 0.7840 0.075\* C18 0.41948 (13) 0.9955 (3) 0.83177 (6) 0.0669 (4) H18A 0.3593 1.1047 0.8192 0.080\* C19 0.41436 (12) 0.8191 (3) 0.87158 (6) 0.0626 (4) H19A 0.3503 0.8082 0.8850 0.075\* C20 0.50375 (11) 0.6612 (3) 0.89093 (6) 0.0545 (3) H20A 0.5000 0.5429 0.9175 0.065\* C21 0.60128 (10) 0.6763 (2) 0.87100 (5) 0.0473 (3) C22 0.69876 (10) 0.5239 (2) 0.89464 (5) 0.0479 (3) ------ -------------- -------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1106 .table-wrap} ----- ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.0505 (5) 0.0640 (5) 0.0521 (5) 0.0110 (4) 0.0191 (4) 0.0106 (4) O2 0.0592 (6) 0.0747 (6) 0.0649 (6) 0.0212 (5) 0.0314 (5) 0.0178 (5) C1 0.0845 (10) 0.0617 (8) 0.0518 (7) −0.0079 (7) 0.0238 (7) −0.0085 (7) C2 0.1138 (13) 0.0596 (8) 0.0736 (10) −0.0131 (9) 0.0484 (10) −0.0079 (8) C3 0.1175 (15) 0.0642 (9) 0.0705 (10) 0.0252 (10) 0.0512 (10) 0.0158 (8) C4 0.0789 (11) 0.0925 (12) 0.0645 (9) 0.0307 (10) 0.0234 (8) 0.0236 (9) C5 0.0577 (8) 0.0761 (9) 0.0595 (8) 0.0153 (7) 0.0166 (6) 0.0094 (7) C6 0.0571 (7) 0.0507 (7) 0.0471 (6) 0.0110 (6) 0.0216 (6) −0.0017 (5) C7 0.0521 (7) 0.0520 (7) 0.0476 (7) 0.0079 (5) 0.0147 (5) 0.0002 (5) C8 0.0630 (8) 0.0620 (8) 0.0576 (8) 0.0183 (6) 0.0258 (6) 0.0086 (7) C9 0.0507 (7) 0.0542 (7) 0.0468 (6) 0.0081 (5) 0.0160 (5) −0.0011 (6) C10 0.0575 (7) 0.0538 (7) 0.0424 (6) −0.0003 (6) 0.0173 (5) −0.0052 (5) C11 0.0644 (9) 0.0720 (9) 0.0546 (8) 0.0038 (7) 0.0255 (6) 0.0002 (7) C12 0.0743 (10) 0.0852 (11) 0.0600 (8) −0.0074 (8) 0.0315 (7) 0.0007 (8) C13 0.0871 (11) 0.0733 (9) 0.0535 (8) −0.0100 (9) 0.0229 (8) 0.0090 (7) C14 0.0744 (9) 0.0633 (8) 0.0523 (7) 0.0020 (7) 0.0147 (7) 0.0060 (7) C15 0.0603 (8) 0.0519 (7) 0.0394 (6) −0.0017 (6) 0.0108 (5) −0.0051 (5) C16 0.0543 (7) 0.0515 (7) 0.0410 (6) 0.0038 (5) 0.0078 (5) −0.0060 (5) C17 0.0700 (9) 0.0598 (8) 0.0545 (8) 0.0120 (7) 0.0098 (7) 0.0025 (7) C18 0.0609 (9) 0.0694 (9) 0.0664 (9) 0.0197 (7) 0.0106 (7) −0.0024 (8) C19 0.0508 (8) 0.0738 (9) 0.0620 (8) 0.0089 (7) 0.0136 (6) −0.0084 (7) C20 0.0506 (7) 0.0608 (8) 0.0518 (7) 0.0042 (6) 0.0139 (6) −0.0028 (6) C21 0.0477 (7) 0.0501 (6) 0.0425 (6) 0.0027 (5) 0.0095 (5) −0.0068 (5) C22 0.0522 (7) 0.0505 (6) 0.0419 (6) 0.0048 (5) 0.0147 (5) 0.0002 (5) ----- ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1547 .table-wrap} ----------------------- -------------- ----------------------- -------------- O1---C22 1.3742 (14) C10---C11 1.4053 (19) O1---C7 1.4347 (15) C10---C15 1.4130 (18) O2---C9 1.3749 (15) C11---C12 1.370 (2) O2---C8 1.4285 (16) C11---H11A 0.9300 C1---C6 1.376 (2) C12---C13 1.381 (2) C1---C2 1.384 (2) C12---H12A 0.9300 C1---H1A 0.9300 C13---C14 1.366 (2) C2---C3 1.373 (3) C13---H13A 0.9300 C2---H2A 0.9300 C14---C15 1.4027 (18) C3---C4 1.366 (3) C14---H14A 0.9300 C3---H3A 0.9300 C15---C16 1.4570 (19) C4---C5 1.378 (2) C16---C21 1.4086 (18) C4---H4A 0.9300 C16---C17 1.4103 (18) C5---C6 1.3882 (19) C17---C18 1.368 (2) C5---H5A 0.9300 C17---H17A 0.9300 C6---C7 1.5002 (18) C18---C19 1.388 (2) C7---C8 1.5128 (18) C18---H18A 0.9300 C7---H7A 0.9800 C19---C20 1.3680 (18) C8---H8A 0.9700 C19---H19A 0.9300 C8---H8B 0.9700 C20---C21 1.4074 (18) C9---C22 1.3527 (17) C20---H20A 0.9300 C9---C10 1.4337 (17) C21---C22 1.4361 (17) C22---O1---C7 112.41 (9) C15---C10---C9 119.32 (11) C9---O2---C8 113.33 (10) C12---C11---C10 120.44 (14) C6---C1---C2 120.25 (15) C12---C11---H11A 119.8 C6---C1---H1A 119.9 C10---C11---H11A 119.8 C2---C1---H1A 119.9 C11---C12---C13 120.06 (14) C3---C2---C1 120.32 (17) C11---C12---H12A 120.0 C3---C2---H2A 119.8 C13---C12---H12A 120.0 C1---C2---H2A 119.8 C14---C13---C12 120.62 (14) C4---C3---C2 119.81 (15) C14---C13---H13A 119.7 C4---C3---H3A 120.1 C12---C13---H13A 119.7 C2---C3---H3A 120.1 C13---C14---C15 121.39 (14) C3---C4---C5 120.33 (16) C13---C14---H14A 119.3 C3---C4---H4A 119.8 C15---C14---H14A 119.3 C5---C4---H4A 119.8 C14---C15---C10 117.76 (12) C4---C5---C6 120.40 (16) C14---C15---C16 122.88 (12) C4---C5---H5A 119.8 C10---C15---C16 119.36 (11) C6---C5---H5A 119.8 C21---C16---C17 117.38 (12) C1---C6---C5 118.87 (13) C21---C16---C15 119.29 (11) C1---C6---C7 121.44 (12) C17---C16---C15 123.32 (12) C5---C6---C7 119.58 (13) C18---C17---C16 121.56 (14) O1---C7---C6 108.98 (10) C18---C17---H17A 119.2 O1---C7---C8 108.36 (10) C16---C17---H17A 119.2 C6---C7---C8 111.39 (10) C17---C18---C19 120.48 (13) O1---C7---H7A 109.4 C17---C18---H18A 119.8 C6---C7---H7A 109.4 C19---C18---H18A 119.8 C8---C7---H7A 109.4 C20---C19---C18 119.84 (14) O2---C8---C7 111.52 (11) C20---C19---H19A 120.1 O2---C8---H8A 109.3 C18---C19---H19A 120.1 C7---C8---H8A 109.3 C19---C20---C21 120.61 (13) O2---C8---H8B 109.3 C19---C20---H20A 119.7 C7---C8---H8B 109.3 C21---C20---H20A 119.7 H8A---C8---H8B 108.0 C20---C21---C16 120.07 (11) C22---C9---O2 123.01 (11) C20---C21---C22 120.54 (11) C22---C9---C10 121.12 (11) C16---C21---C22 119.33 (11) O2---C9---C10 115.82 (11) C9---C22---O1 122.63 (11) C11---C10---C15 119.68 (12) C9---C22---C21 121.26 (11) C11---C10---C9 120.98 (12) O1---C22---C21 116.06 (10) C6---C1---C2---C3 0.4 (2) C11---C10---C15---C14 −2.33 (19) C1---C2---C3---C4 0.2 (2) C9---C10---C15---C14 176.42 (11) C2---C3---C4---C5 0.0 (2) C11---C10---C15---C16 177.24 (12) C3---C4---C5---C6 −0.9 (2) C9---C10---C15---C16 −4.02 (18) C2---C1---C6---C5 −1.3 (2) C14---C15---C16---C21 179.16 (12) C2---C1---C6---C7 175.03 (13) C10---C15---C16---C21 −0.38 (17) C4---C5---C6---C1 1.5 (2) C14---C15---C16---C17 −1.50 (19) C4---C5---C6---C7 −174.83 (13) C10---C15---C16---C17 178.96 (12) C22---O1---C7---C6 −171.11 (9) C21---C16---C17---C18 −1.3 (2) C22---O1---C7---C8 −49.75 (14) C15---C16---C17---C18 179.35 (13) C1---C6---C7---O1 31.63 (16) C16---C17---C18---C19 −0.7 (2) C5---C6---C7---O1 −152.09 (11) C17---C18---C19---C20 1.2 (2) C1---C6---C7---C8 −87.87 (15) C18---C19---C20---C21 0.2 (2) C5---C6---C7---C8 88.41 (15) C19---C20---C21---C16 −2.18 (19) C9---O2---C8---C7 −40.45 (16) C19---C20---C21---C22 174.94 (12) O1---C7---C8---O2 61.41 (15) C17---C16---C21---C20 2.68 (18) C6---C7---C8---O2 −178.73 (11) C15---C16---C21---C20 −177.94 (11) C8---O2---C9---C22 10.01 (18) C17---C16---C21---C22 −174.49 (11) C8---O2---C9---C10 −172.32 (11) C15---C16---C21---C22 4.90 (17) C22---C9---C10---C11 −177.33 (12) O2---C9---C22---O1 0.8 (2) O2---C9---C10---C11 4.95 (18) C10---C9---C22---O1 −176.74 (11) C22---C9---C10---C15 3.94 (19) O2---C9---C22---C21 178.22 (11) O2---C9---C10---C15 −173.77 (11) C10---C9---C22---C21 0.67 (19) C15---C10---C11---C12 1.4 (2) C7---O1---C22---C9 21.05 (16) C9---C10---C11---C12 −177.34 (13) C7---O1---C22---C21 −156.48 (10) C10---C11---C12---C13 0.6 (2) C20---C21---C22---C9 177.71 (12) C11---C12---C13---C14 −1.6 (2) C16---C21---C22---C9 −5.14 (18) C12---C13---C14---C15 0.6 (2) C20---C21---C22---O1 −4.72 (17) C13---C14---C15---C10 1.4 (2) C16---C21---C22---O1 172.42 (10) C13---C14---C15---C16 −178.18 (13) ----------------------- -------------- ----------------------- -------------- ::: [^1]: ‡ Thomson Reuters ResearcherID: A-3561-2009. [^2]: § Thomson Reuters ResearcherID: A-5525-2009.

PubMed Central

2024-06-05T04:04:17.540356

2011-2-05

PMC3051959

Related literature {#sec1} ================== For background to polynuclear complexes, see: Liu *et al.* (2008[@bb3]). For transition metals bridged by mixed formate and azide anions, see: Liu *et al.* (2006[@bb2]). For related nickel(II) complexes, see: Wang *et al.* (2008[@bb6]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Ni~6~(C~13~H~10~NO~2~)~4~(N~3~)~8~(CH~4~O)~8~\]·6CH~4~O*M* *~r~* = 1985.97Monoclinic,*a* = 11.8230 (1) Å*b* = 14.6051 (2) Å*c* = 26.3997 (4) Åβ = 105.368 (1)°*V* = 4395.6 (1) Å^3^*Z* = 2Mo *K*α radiationμ = 1.34 mm^−1^*T* = 293 K0.6 × 0.5 × 0.4 mm ### Data collection {#sec2.1.2} Rigaku Saturn CCD diffractometerAbsorption correction: multi-scan (*REQAB*; Jacobson, 1998[@bb1]) *T* ~min~ = 0.461, *T* ~max~ = 0.59751748 measured reflections7789 independent reflections4991 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.095 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.046*wR*(*F* ^2^) = 0.127*S* = 1.027789 reflections557 parameters1 restraintH-atom parameters constrainedΔρ~max~ = 0.84 e Å^−3^Δρ~min~ = −0.63 e Å^−3^ {#d5e662} Data collection: *CrystalClear* (Rigaku/MSC, 2006[@bb4]); cell refinement: *CrystalClear*; data reduction: *CrystalClear*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb5]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb5]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb7]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811003473/wm2438sup1.cif](http://dx.doi.org/10.1107/S1600536811003473/wm2438sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003473/wm2438Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003473/wm2438Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?wm2438&file=wm2438sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?wm2438sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?wm2438&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [WM2438](http://scripts.iucr.org/cgi-bin/sendsup?wm2438)). This study was supported by the Doctoral Research Fund of Henan Chinese Medicine (BSJJ2009--38) and the Science and Technology Department of Henan Province (082102330003). Comment ======= The design and synthesis of new polynuclear metal complexes for single molecule magnets have attracted great interest in coordination chemsitry, because single molecule magnets not only show fascinating physical properties, but also have potential application in information storage and quantum computing at the molecular level (Liu *et al.*, 2008). To date, although it is difficult to predict which kind of topology and structure will lead to high-nuclearity compounds in advance, many synthetic approaches have been employed to obtain well-isolated polynuclear complexes, e.g. by using new blocking ligands with short bridges. Many single molecule magnets are based on Mn^III^, Fe^III^, and Ni^II^. In most of these compounds, magnetic exchange interactions are mainly propagated by bridging OH^-^, O*R*^-^, O^2-^, or *R*CO^2-^ groups, which often transmit antiferromagnetic interactions. An attractive strategy to facilitate the formation of ferromagnetic coupled clusters is to utilize azide and carboxalate-containing ligands simultaneously (Liu *et al.*, 2006). Herein, we report the synthesis and structure of the hexanuclear Ni(II) complex, \[Ni~6~(C~13~H~10~NO~2~)~4~(N~3~)~8~(CH~3~OH)~8~\]^.^6CH~3~OH. The structure of the title compound consists of neutral hexanuclear \[Ni^II^~6~(C~13~H~10~NO~2~)~4~(N~3~)~8~(CH~3~OH)~8~\] molecules and six methanol solvate molecules situated between the hexanuclear units. The complete molecule has inversion symmetry. In the neutral hexanuclear unit, six octahedrally coordinated Ni^II^ atoms are linked by four µ~1,1,1~-azido and four µ~1,1~-azido bridges, forming face-sharing tetracubane units with four missing corners based on the Ni~6~N~8~ core. The Ni^II^ atoms are further bridged by four µ~1,2~-carboxalate ligands (Fig. 1). The Ni---O distances range between 2.000 (3)--2.094 (3) Å, and the Ni---N distances between 2.052 (4)--2.165 (3) Å. These bond lengths indicate that the Ni^II^ ions are in the divalent state, and are in agreement with other Ni^II^ complexes (Wang *et al.*, 2008). The hexanuclear units are connected *via* N---H···O hydrogen bonding into a three-dimensional structure (Fig. 2). The N---H···O hydrogen bonding (Table 2) is accomplished through the N atoms of 2-phenylamino-benzoate and O atoms of carboxylate groups, with the N···O distances being 2.667···2.676 Å. Although the H atoms of the methanol OH groups could not be located, short O···N/O contacts suggest that these molecules participate in hydrogen bonding between O atoms of methanol as donors and acceptors, and between O atoms of methanol and N atoms of azido bridges, with O···O distances in the range of 2.65···2.72 Å, and O···N distances in the range of 2.79···2.86 Å. Experimental {#experimental} ============ Under stirring, 2.0 mmol 2-phenylamino-benzoic acid, 4.0 mmol NaN~3~ were added, one after another, into a 20 ml methanol solution containing 1.0 mol Ni(ClO~4~)~2~^.^6H~2~O. The resulting solution was kept stirred for another hour, and then filtered off. The filtered solution was allowed to stand undisturbed in a sealed vessel. Crystallization took one week and gave block-shaped green crystals in a yield of 40% based on Ni(ClO~4~)~2~^.^6H~2~O. The product was washed with methanol and dried in air. Refinement {#refinement} ========== Hydrogen atoms bonded to C and N atoms were added geometrically and were refined using a riding model, with C---H = 0.96 Å (CH~3~), C---H = 0.93 Å (C---H) and N---H = 0.86 Å. The hydrogen atoms of the OH group of the methanol molecules could not be derived from Fourier maps and were eventually not included in the refinement. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The hexanuclear unit of the title structure. The non-C atoms are labelled; all atoms are shown with displacement ellipsoids at the 30% probability level. H atoms have been omitted for clarity. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### A view of the crystal packing along the b axis. Hydrogen bonding is indicated with dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e262 .table-wrap} ----------------------------------------------------------- ---------------------------------------- \[Ni~6~(C~13~H~10~NO~2~)~4~(N~3~)~8~(CH~4~O)~8~\]·6CH~4~O *F*(000) = 2064 *M~r~* = 1985.97 *D*~x~ = 1.500 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 62970 reflections *a* = 11.8230 (1) Å θ = 3.4--25.0° *b* = 14.6051 (2) Å µ = 1.34 mm^−1^ *c* = 26.3997 (4) Å *T* = 293 K β = 105.368 (1)° Block, green *V* = 4395.6 (1) Å^3^ 0.6 × 0.5 × 0.4 mm *Z* = 2 ----------------------------------------------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e412 .table-wrap} ------------------------------------------------------------- -------------------------------------- Rigaku Saturn CCD diffractometer 7789 independent reflections Radiation source: fine-focus sealed tube 4991 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.095 Detector resolution: 0.76 pixels mm^-1^ θ~max~ = 25.1°, θ~min~ = 3.5° ω and φ scans *h* = −14→13 Absorption correction: multi-scan (*REQAB*; Jacobson, 1998) *k* = −17→17 *T*~min~ = 0.461, *T*~max~ = 0.597 *l* = −31→31 51748 measured reflections ------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e535 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.046 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.127 H-atom parameters constrained *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0602*P*)^2^ + 3.7541*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 7789 reflections (Δ/σ)~max~ = 0.001 557 parameters Δρ~max~ = 0.84 e Å^−3^ 1 restraint Δρ~min~ = −0.63 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e692 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e791 .table-wrap} ------ ------------- -------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Ni1 0.03270 (4) −0.41612 (4) −0.45991 (2) 0.02905 (16) Ni2 0.12781 (5) −0.42241 (4) −0.56219 (2) 0.03106 (16) Ni3 0.21549 (5) −0.26552 (4) −0.45100 (2) 0.03523 (17) O1 0.0920 (3) −0.2905 (2) −0.58242 (11) 0.0373 (8) O2 0.2149 (3) −0.2093 (2) −0.52023 (12) 0.0451 (8) O3 0.2404 (3) −0.3091 (2) −0.37703 (11) 0.0441 (8) O4 0.1078 (2) −0.4196 (2) −0.38032 (11) 0.0349 (7) O5 0.0386 (3) −0.4489 (2) −0.64055 (11) 0.0460 (8) O6 0.2908 (3) −0.4162 (2) −0.57582 (13) 0.0519 (9) O7 0.3963 (3) −0.2654 (2) −0.43819 (12) 0.0455 (8) O8 0.2376 (3) −0.1355 (2) −0.41891 (13) 0.0499 (9) N1 −0.0332 (3) −0.2038 (3) −0.66782 (14) 0.0429 (10) H1 −0.0360 −0.2487 −0.6471 0.051\* N2 0.2946 (4) −0.2152 (3) −0.28674 (15) 0.0506 (11) H2 0.2625 −0.2080 −0.3198 0.061\* N3 0.1967 (3) −0.4019 (2) −0.48097 (13) 0.0303 (8) N4 0.2806 (3) −0.4517 (3) −0.46086 (15) 0.0410 (10) N5 0.3583 (4) −0.4983 (3) −0.44295 (19) 0.0636 (13) N6 −0.0316 (3) −0.4379 (2) −0.54194 (13) 0.0261 (8) N7 −0.1158 (3) −0.3975 (3) −0.57064 (14) 0.0364 (9) N8 −0.1899 (4) −0.3606 (3) −0.59810 (19) 0.0667 (14) N9 0.0354 (3) −0.2757 (3) −0.46261 (15) 0.0368 (9) N10 −0.0368 (4) −0.2270 (3) −0.49112 (17) 0.0455 (10) N11 −0.1037 (5) −0.1781 (4) −0.5168 (2) 0.0810 (17) N12 0.1322 (3) −0.5651 (2) −0.55169 (14) 0.0347 (9) N13 0.2120 (4) −0.6185 (3) −0.54439 (15) 0.0413 (10) N14 0.2878 (4) −0.6697 (3) −0.53838 (18) 0.0626 (13) C1 0.1398 (4) −0.2160 (3) −0.56424 (17) 0.0356 (11) C2 0.1097 (4) −0.1303 (3) −0.59541 (17) 0.0349 (11) C3 0.1651 (4) −0.0493 (3) −0.57447 (18) 0.0425 (12) H3 0.2198 −0.0512 −0.5418 0.051\* C4 0.1424 (5) 0.0327 (3) −0.5999 (2) 0.0486 (13) H4 0.1809 0.0856 −0.5849 0.058\* C5 0.0605 (5) 0.0357 (3) −0.6486 (2) 0.0492 (13) H5 0.0447 0.0910 −0.6666 0.059\* C6 0.0031 (4) −0.0419 (3) −0.67024 (18) 0.0415 (12) H6 −0.0535 −0.0380 −0.7022 0.050\* C7 0.0274 (4) −0.1275 (3) −0.64536 (17) 0.0379 (11) C8 −0.0906 (4) −0.2160 (3) −0.72137 (17) 0.0376 (11) C9 −0.0428 (4) −0.1844 (3) −0.76057 (18) 0.0430 (12) H9 0.0283 −0.1532 −0.7519 0.052\* C10 −0.1013 (5) −0.1993 (3) −0.81294 (18) 0.0481 (13) H10 −0.0695 −0.1772 −0.8392 0.058\* C11 −0.2053 (5) −0.2463 (3) −0.82626 (19) 0.0479 (13) H11 −0.2442 −0.2558 −0.8614 0.057\* C12 −0.2517 (4) −0.2792 (3) −0.7873 (2) 0.0478 (13) H12 −0.3221 −0.3114 −0.7960 0.057\* C13 −0.1938 (4) −0.2645 (3) −0.73482 (19) 0.0419 (12) H13 −0.2252 −0.2876 −0.7086 0.050\* C14 0.1895 (4) −0.3668 (3) −0.35553 (17) 0.0333 (11) C15 0.2289 (4) −0.3742 (3) −0.29743 (16) 0.0310 (10) C16 0.2167 (4) −0.4573 (3) −0.27362 (18) 0.0367 (11) H16 0.1856 −0.5072 −0.2947 0.044\* C17 0.2492 (4) −0.4680 (3) −0.21992 (19) 0.0424 (12) H17 0.2433 −0.5247 −0.2048 0.051\* C18 0.2909 (4) −0.3924 (3) −0.18871 (18) 0.0464 (13) H18 0.3091 −0.3979 −0.1523 0.056\* C19 0.3054 (4) −0.3103 (3) −0.21058 (17) 0.0437 (12) H19 0.3333 −0.2607 −0.1887 0.052\* C20 0.2793 (4) −0.2985 (3) −0.26533 (17) 0.0353 (11) C21 0.3580 (4) −0.1407 (3) −0.25939 (17) 0.0386 (11) C22 0.4703 (4) −0.1507 (4) −0.2265 (2) 0.0516 (13) H22 0.5039 −0.2087 −0.2208 0.062\* C23 0.5326 (5) −0.0757 (4) −0.2021 (2) 0.0607 (15) H23 0.6073 −0.0836 −0.1798 0.073\* C24 0.4856 (6) 0.0093 (4) −0.2105 (2) 0.0637 (16) H24 0.5287 0.0598 −0.1948 0.076\* C25 0.3750 (6) 0.0205 (4) −0.2420 (2) 0.0659 (17) H25 0.3423 0.0788 −0.2471 0.079\* C26 0.3105 (5) −0.0539 (4) −0.2668 (2) 0.0521 (14) H26 0.2352 −0.0452 −0.2883 0.062\* C27 0.0697 (4) −0.4277 (4) −0.68775 (18) 0.0486 (13) H27A 0.1157 −0.3726 −0.6828 0.073\* H27B −0.0001 −0.4189 −0.7158 0.073\* H27C 0.1147 −0.4772 −0.6965 0.073\* C28 0.3410 (5) −0.4747 (4) −0.6070 (2) 0.0701 (17) H28A 0.2869 −0.5229 −0.6215 0.105\* H28B 0.4123 −0.5007 −0.5856 0.105\* H28C 0.3579 −0.4400 −0.6350 0.105\* C29 0.4840 (4) −0.2829 (4) −0.3909 (2) 0.0619 (16) H29A 0.4721 −0.2436 −0.3637 0.093\* H29B 0.5599 −0.2714 −0.3963 0.093\* H29C 0.4793 −0.3457 −0.3809 0.093\* C30 0.1425 (5) −0.0758 (4) −0.4257 (3) 0.0737 (19) H30A 0.1067 −0.0674 −0.4625 0.111\* H30B 0.1694 −0.0177 −0.4099 0.111\* H30C 0.0862 −0.1010 −0.4093 0.111\* O9 0.4740 (3) −0.1887 (3) −0.02231 (14) 0.0596 (10) C32 0.4755 (8) −0.2635 (6) −0.0553 (3) 0.119 (3) H32A 0.3989 −0.2907 −0.0656 0.178\* H32B 0.5313 −0.3079 −0.0369 0.178\* H32C 0.4972 −0.2431 −0.0860 0.178\* O10 0.6812 (4) −0.3749 (3) −0.08285 (19) 0.0796 (12) C31 0.6724 (7) −0.3549 (5) −0.1353 (3) 0.101 (2) H31A 0.6486 −0.2923 −0.1423 0.151\* H31B 0.6153 −0.3945 −0.1574 0.151\* H31C 0.7472 −0.3641 −0.1423 0.151\* O11 0.6012 (4) −0.5314 (3) −0.05491 (19) 0.0812 (13) C33 0.4822 (6) −0.5423 (5) −0.0710 (4) 0.118 (3) H33A 0.4586 −0.5532 −0.1082 0.178\* H33B 0.4446 −0.4879 −0.0631 0.178\* H33C 0.4599 −0.5935 −0.0530 0.178\* ------ ------------- -------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e2490 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Ni1 0.0226 (3) 0.0415 (3) 0.0211 (3) −0.0032 (2) 0.0023 (2) −0.0025 (3) Ni2 0.0255 (3) 0.0447 (4) 0.0219 (3) −0.0044 (3) 0.0043 (2) −0.0013 (3) Ni3 0.0307 (3) 0.0489 (4) 0.0232 (3) −0.0095 (3) 0.0020 (2) −0.0018 (3) O1 0.0361 (18) 0.0427 (19) 0.0277 (17) −0.0090 (15) −0.0010 (14) 0.0033 (14) O2 0.0383 (19) 0.063 (2) 0.0272 (18) −0.0167 (16) −0.0030 (15) 0.0032 (15) O3 0.0429 (19) 0.063 (2) 0.0241 (17) −0.0212 (17) 0.0039 (15) −0.0002 (16) O4 0.0302 (16) 0.0460 (19) 0.0260 (16) −0.0083 (15) 0.0033 (13) −0.0039 (14) O5 0.051 (2) 0.068 (2) 0.0181 (16) −0.0173 (17) 0.0072 (15) −0.0042 (15) O6 0.0385 (19) 0.075 (2) 0.048 (2) −0.0122 (18) 0.0223 (17) −0.0148 (19) O7 0.0293 (17) 0.067 (2) 0.0338 (19) −0.0079 (16) −0.0031 (15) 0.0019 (16) O8 0.050 (2) 0.052 (2) 0.048 (2) −0.0080 (18) 0.0133 (17) −0.0119 (17) N1 0.048 (2) 0.048 (2) 0.025 (2) −0.0151 (19) −0.0039 (18) 0.0071 (18) N2 0.070 (3) 0.047 (3) 0.024 (2) −0.019 (2) −0.006 (2) 0.0023 (18) N3 0.0187 (18) 0.046 (2) 0.025 (2) −0.0004 (16) 0.0027 (15) 0.0002 (17) N4 0.031 (2) 0.056 (3) 0.035 (2) −0.010 (2) 0.0063 (19) −0.003 (2) N5 0.035 (3) 0.070 (3) 0.074 (3) 0.010 (2) −0.008 (2) 0.013 (3) N6 0.0207 (18) 0.036 (2) 0.0190 (18) −0.0001 (16) 0.0009 (15) 0.0011 (15) N7 0.030 (2) 0.049 (2) 0.026 (2) −0.0042 (19) 0.0006 (19) 0.0003 (18) N8 0.046 (3) 0.078 (3) 0.064 (3) 0.006 (3) −0.008 (3) 0.014 (3) N9 0.029 (2) 0.042 (2) 0.037 (2) −0.0021 (18) 0.0050 (18) −0.0025 (19) N10 0.040 (2) 0.044 (3) 0.050 (3) −0.009 (2) 0.008 (2) −0.011 (2) N11 0.065 (3) 0.060 (3) 0.094 (4) 0.011 (3) −0.020 (3) 0.013 (3) N12 0.026 (2) 0.041 (2) 0.037 (2) 0.0000 (18) 0.0088 (18) −0.0004 (18) N13 0.034 (2) 0.052 (3) 0.038 (2) −0.005 (2) 0.010 (2) −0.0036 (19) N14 0.044 (3) 0.069 (3) 0.072 (3) 0.023 (3) 0.010 (2) 0.001 (3) C1 0.031 (3) 0.049 (3) 0.029 (3) −0.007 (2) 0.012 (2) 0.001 (2) C2 0.030 (2) 0.048 (3) 0.029 (3) −0.005 (2) 0.010 (2) 0.002 (2) C3 0.045 (3) 0.053 (3) 0.030 (3) −0.012 (2) 0.010 (2) −0.004 (2) C4 0.061 (4) 0.041 (3) 0.049 (3) −0.011 (3) 0.023 (3) −0.009 (3) C5 0.063 (4) 0.043 (3) 0.051 (3) 0.000 (3) 0.030 (3) 0.002 (3) C6 0.041 (3) 0.050 (3) 0.032 (3) 0.004 (2) 0.007 (2) 0.005 (2) C7 0.042 (3) 0.042 (3) 0.031 (3) −0.002 (2) 0.014 (2) 0.001 (2) C8 0.036 (3) 0.039 (3) 0.030 (3) −0.001 (2) −0.004 (2) 0.003 (2) C9 0.039 (3) 0.053 (3) 0.035 (3) −0.006 (2) 0.006 (2) 0.005 (2) C10 0.060 (3) 0.053 (3) 0.030 (3) −0.001 (3) 0.008 (3) 0.003 (2) C11 0.051 (3) 0.051 (3) 0.032 (3) 0.009 (3) −0.006 (2) 0.001 (2) C12 0.036 (3) 0.047 (3) 0.050 (3) −0.001 (2) −0.007 (2) −0.001 (2) C13 0.037 (3) 0.047 (3) 0.037 (3) −0.003 (2) 0.003 (2) 0.005 (2) C14 0.029 (2) 0.043 (3) 0.026 (2) −0.001 (2) 0.003 (2) −0.002 (2) C15 0.024 (2) 0.043 (3) 0.025 (2) −0.001 (2) 0.0047 (19) −0.003 (2) C16 0.030 (2) 0.042 (3) 0.038 (3) −0.001 (2) 0.008 (2) −0.003 (2) C17 0.042 (3) 0.044 (3) 0.042 (3) −0.002 (2) 0.013 (2) 0.012 (2) C18 0.049 (3) 0.060 (3) 0.024 (3) −0.004 (3) −0.001 (2) 0.009 (2) C19 0.050 (3) 0.052 (3) 0.024 (3) −0.011 (2) 0.000 (2) −0.009 (2) C20 0.033 (2) 0.046 (3) 0.025 (2) −0.006 (2) 0.003 (2) 0.001 (2) C21 0.044 (3) 0.047 (3) 0.024 (2) −0.009 (2) 0.007 (2) −0.002 (2) C22 0.045 (3) 0.055 (3) 0.052 (3) −0.001 (3) 0.006 (3) −0.003 (3) C23 0.043 (3) 0.081 (5) 0.055 (4) −0.017 (3) 0.007 (3) −0.011 (3) C24 0.071 (4) 0.065 (4) 0.056 (4) −0.029 (3) 0.019 (3) −0.018 (3) C25 0.091 (5) 0.043 (3) 0.064 (4) −0.001 (3) 0.021 (4) −0.008 (3) C26 0.053 (3) 0.053 (3) 0.046 (3) 0.001 (3) 0.006 (3) −0.003 (3) C27 0.052 (3) 0.066 (4) 0.029 (3) −0.003 (3) 0.012 (2) 0.001 (2) C28 0.045 (3) 0.095 (5) 0.077 (4) −0.001 (3) 0.029 (3) −0.009 (4) C29 0.035 (3) 0.098 (5) 0.043 (3) 0.001 (3) −0.006 (3) 0.004 (3) C30 0.055 (4) 0.071 (4) 0.102 (5) −0.012 (3) 0.031 (4) −0.038 (4) O9 0.043 (2) 0.087 (3) 0.049 (2) 0.0074 (19) 0.0117 (18) −0.007 (2) C32 0.113 (7) 0.132 (7) 0.111 (7) 0.041 (5) 0.030 (5) −0.032 (6) O10 0.067 (3) 0.081 (3) 0.087 (3) −0.007 (2) 0.014 (2) −0.002 (3) C31 0.089 (6) 0.118 (6) 0.084 (6) −0.008 (5) 0.005 (4) 0.005 (5) O11 0.059 (3) 0.074 (3) 0.115 (4) 0.019 (2) 0.030 (3) 0.009 (3) C33 0.070 (5) 0.079 (5) 0.202 (10) 0.013 (4) 0.028 (6) 0.012 (6) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e3637 .table-wrap} ---------------------- ------------- ------------------- ----------- Ni1---N9 2.052 (4) C9---C10 1.390 (6) Ni1---O4 2.054 (3) C9---H9 0.9300 Ni1---N12^i^ 2.071 (4) C10---C11 1.370 (7) Ni1---N6 2.120 (3) C10---H10 0.9300 Ni1---N6^i^ 2.133 (3) C11---C12 1.375 (7) Ni1---N3 2.165 (3) C11---H11 0.9300 Ni2---O1 2.014 (3) C12---C13 1.389 (6) Ni2---O6 2.054 (3) C12---H12 0.9300 Ni2---O5 2.094 (3) C13---H13 0.9300 Ni2---N12 2.102 (4) C14---C15 1.484 (6) Ni2---N6 2.103 (3) C15---C16 1.392 (6) Ni2---N3 2.104 (3) C15---C20 1.424 (6) Ni3---O3 2.000 (3) C16---C17 1.376 (6) Ni3---O2 2.002 (3) C16---H16 0.9300 Ni3---O8 2.068 (3) C17---C18 1.387 (6) Ni3---O7 2.074 (3) C17---H17 0.9300 Ni3---N9 2.075 (4) C18---C19 1.362 (6) Ni3---N3 2.133 (4) C18---H18 0.9300 O1---C1 1.262 (5) C19---C20 1.406 (6) O2---C1 1.265 (5) C19---H19 0.9300 O3---C14 1.255 (5) C21---C26 1.379 (7) O4---C14 1.273 (5) C21---C22 1.388 (6) O5---C27 1.424 (5) C22---C23 1.380 (7) O6---C28 1.422 (6) C22---H22 0.9300 O7---C29 1.418 (5) C23---C24 1.354 (8) O8---C30 1.396 (6) C23---H23 0.9300 N1---C7 1.371 (6) C24---C25 1.360 (8) N1---C8 1.408 (5) C24---H24 0.9300 N1---H1 0.8601 C25---C26 1.387 (7) N2---C20 1.373 (6) C25---H25 0.9300 N2---C21 1.408 (6) C26---H26 0.9300 N2---H2 0.8602 C27---H27A 0.9600 N3---N4 1.231 (5) C27---H27B 0.9600 N4---N5 1.140 (5) C27---H27C 0.9600 N6---N7 1.231 (5) C28---H28A 0.9600 N6---Ni1^i^ 2.133 (3) C28---H28B 0.9600 N7---N8 1.116 (5) C28---H28C 0.9600 N9---N10 1.209 (5) C29---H29A 0.9600 N10---N11 1.145 (6) C29---H29B 0.9600 N12---N13 1.199 (5) C29---H29C 0.9600 N12---Ni1^i^ 2.071 (4) C30---H30A 0.9600 N13---N14 1.146 (5) C30---H30B 0.9600 C1---C2 1.488 (6) C30---H30C 0.9600 C2---C3 1.394 (6) O9---C32 1.399 (7) C2---C7 1.417 (6) C32---H32A 0.9600 C3---C4 1.364 (7) C32---H32B 0.9600 C3---H3 0.9300 C32---H32C 0.9600 C4---C5 1.391 (7) O10---C31 1.391 (8) C4---H4 0.9300 C31---H31A 0.9600 C5---C6 1.366 (7) C31---H31B 0.9600 C5---H5 0.9300 C31---H31C 0.9600 C6---C7 1.406 (6) O11---C33 1.367 (8) C6---H6 0.9300 C33---H33A 0.9600 C8---C13 1.373 (6) C33---H33B 0.9600 C8---C9 1.384 (6) C33---H33C 0.9600 N9---Ni1---O4 93.08 (13) C6---C7---C2 117.7 (4) N9---Ni1---N12^i^ 99.26 (15) C13---C8---C9 119.3 (4) O4---Ni1---N12^i^ 90.83 (13) C13---C8---N1 119.0 (4) N9---Ni1---N6 96.84 (14) C9---C8---N1 121.6 (4) O4---Ni1---N6 169.12 (12) C8---C9---C10 119.8 (5) N12^i^---Ni1---N6 91.98 (13) C8---C9---H9 120.1 N9---Ni1---N6^i^ 179.03 (14) C10---C9---H9 120.1 O4---Ni1---N6^i^ 87.46 (12) C11---C10---C9 120.7 (5) N12^i^---Ni1---N6^i^ 81.53 (14) C11---C10---H10 119.6 N6---Ni1---N6^i^ 82.56 (13) C9---C10---H10 119.6 N9---Ni1---N3 82.65 (14) C10---C11---C12 119.5 (5) O4---Ni1---N3 95.22 (12) C10---C11---H11 120.3 N12^i^---Ni1---N3 173.55 (14) C12---C11---H11 120.3 N6---Ni1---N3 81.66 (12) C11---C12---C13 120.2 (5) N6^i^---Ni1---N3 96.51 (13) C11---C12---H12 119.9 O1---Ni2---O6 93.00 (13) C13---C12---H12 119.9 O1---Ni2---O5 84.23 (12) C8---C13---C12 120.5 (5) O6---Ni2---O5 94.91 (13) C8---C13---H13 119.8 O1---Ni2---N12 168.48 (13) C12---C13---H13 119.8 O6---Ni2---N12 94.32 (14) O3---C14---O4 124.3 (4) O5---Ni2---N12 86.29 (14) O3---C14---C15 117.3 (4) O1---Ni2---N6 91.76 (13) O4---C14---C15 118.3 (4) O6---Ni2---N6 174.19 (14) C16---C15---C20 119.0 (4) O5---Ni2---N6 88.87 (12) C16---C15---C14 119.2 (4) N12---Ni2---N6 81.51 (13) C20---C15---C14 121.7 (4) O1---Ni2---N3 97.55 (13) C17---C16---C15 122.0 (4) O6---Ni2---N3 92.54 (13) C17---C16---H16 119.0 O5---Ni2---N3 172.24 (13) C15---C16---H16 119.0 N12---Ni2---N3 91.00 (14) C16---C17---C18 118.7 (4) N6---Ni2---N3 83.53 (13) C16---C17---H17 120.6 O3---Ni3---O2 170.33 (12) C18---C17---H17 120.6 O3---Ni3---O8 85.53 (13) C19---C18---C17 120.9 (4) O2---Ni3---O8 88.09 (13) C19---C18---H18 119.5 O3---Ni3---O7 87.85 (13) C17---C18---H18 119.5 O2---Ni3---O7 84.40 (13) C18---C19---C20 121.7 (4) O8---Ni3---O7 85.37 (13) C18---C19---H19 119.1 O3---Ni3---N9 90.07 (14) C20---C19---H19 119.1 O2---Ni3---N9 98.02 (14) N2---C20---C19 121.0 (4) O8---Ni3---N9 98.04 (14) N2---C20---C15 121.5 (4) O7---Ni3---N9 175.86 (14) C19---C20---C15 117.4 (4) O3---Ni3---N3 92.25 (13) C26---C21---C22 118.1 (4) O2---Ni3---N3 93.99 (13) C26---C21---N2 119.8 (4) O8---Ni3---N3 177.59 (14) C22---C21---N2 122.1 (5) O7---Ni3---N3 93.61 (13) C23---C22---C21 120.8 (5) N9---Ni3---N3 82.89 (14) C23---C22---H22 119.6 C1---O1---Ni2 133.1 (3) C21---C22---H22 119.6 C1---O2---Ni3 129.7 (3) C24---C23---C22 120.4 (5) C14---O3---Ni3 133.7 (3) C24---C23---H23 119.8 C14---O4---Ni1 125.1 (3) C22---C23---H23 119.8 C27---O5---Ni2 130.1 (3) C23---C24---C25 119.8 (5) C28---O6---Ni2 129.1 (3) C23---C24---H24 120.1 C29---O7---Ni3 128.7 (3) C25---C24---H24 120.1 C30---O8---Ni3 120.7 (3) C24---C25---C26 120.8 (6) C7---N1---C8 126.5 (4) C24---C25---H25 119.6 C7---N1---H1 116.7 C26---C25---H25 119.6 C8---N1---H1 116.8 C21---C26---C25 120.1 (5) C20---N2---C21 125.7 (4) C21---C26---H26 120.0 C20---N2---H2 117.1 C25---C26---H26 120.0 C21---N2---H2 117.2 O5---C27---H27A 109.5 N4---N3---Ni2 113.9 (3) O5---C27---H27B 109.5 N4---N3---Ni3 113.6 (3) H27A---C27---H27B 109.5 Ni2---N3---Ni3 119.03 (16) O5---C27---H27C 109.5 N4---N3---Ni1 120.4 (3) H27A---C27---H27C 109.5 Ni2---N3---Ni1 96.71 (13) H27B---C27---H27C 109.5 Ni3---N3---Ni1 90.38 (13) O6---C28---H28A 109.5 N5---N4---N3 179.0 (5) O6---C28---H28B 109.5 N7---N6---Ni2 115.2 (3) H28A---C28---H28B 109.5 N7---N6---Ni1 124.7 (3) O6---C28---H28C 109.5 Ni2---N6---Ni1 98.09 (13) H28A---C28---H28C 109.5 N7---N6---Ni1^i^ 119.0 (3) H28B---C28---H28C 109.5 Ni2---N6---Ni1^i^ 97.17 (13) O7---C29---H29A 109.5 Ni1---N6---Ni1^i^ 97.44 (13) O7---C29---H29B 109.5 N8---N7---N6 177.4 (5) H29A---C29---H29B 109.5 N10---N9---Ni1 126.5 (3) O7---C29---H29C 109.5 N10---N9---Ni3 125.2 (3) H29A---C29---H29C 109.5 Ni1---N9---Ni3 95.24 (16) H29B---C29---H29C 109.5 N11---N10---N9 177.3 (5) O8---C30---H30A 109.5 N13---N12---Ni1^i^ 128.4 (3) O8---C30---H30B 109.5 N13---N12---Ni2 131.1 (3) H30A---C30---H30B 109.5 Ni1^i^---N12---Ni2 99.16 (16) O8---C30---H30C 109.5 N14---N13---N12 178.7 (5) H30A---C30---H30C 109.5 O1---C1---O2 123.4 (4) H30B---C30---H30C 109.5 O1---C1---C2 119.9 (4) O9---C32---H32A 109.5 O2---C1---C2 116.7 (4) O9---C32---H32B 109.5 C3---C2---C7 118.7 (4) H32A---C32---H32B 109.5 C3---C2---C1 118.4 (4) O9---C32---H32C 109.5 C7---C2---C1 122.9 (4) H32A---C32---H32C 109.5 C4---C3---C2 122.7 (5) H32B---C32---H32C 109.5 C4---C3---H3 118.7 O10---C31---H31A 109.5 C2---C3---H3 118.7 O10---C31---H31B 109.5 C3---C4---C5 118.7 (5) H31A---C31---H31B 109.5 C3---C4---H4 120.6 O10---C31---H31C 109.5 C5---C4---H4 120.6 H31A---C31---H31C 109.5 C6---C5---C4 120.5 (5) H31B---C31---H31C 109.5 C6---C5---H5 119.8 O11---C33---H33A 109.5 C4---C5---H5 119.8 O11---C33---H33B 109.5 C5---C6---C7 121.7 (5) H33A---C33---H33B 109.5 C5---C6---H6 119.2 O11---C33---H33C 109.5 C7---C6---H6 119.2 H33A---C33---H33C 109.5 N1---C7---C6 120.1 (4) H33B---C33---H33C 109.5 N1---C7---C2 122.0 (4) ---------------------- ------------- ------------------- ----------- ::: Symmetry codes: (i) −*x*, −*y*−1, −*z*−1. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e5130 .table-wrap} --------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1···O1 0.86 2.05 2.666 (5) 128 N2---H2···O3 0.86 2.08 2.677 (5) 126 --------------- --------- --------- ----------- --------------- ::: ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Selected bond lengths (Å) ::: -------------- ----------- Ni1---N9 2.052 (4) Ni1---O4 2.054 (3) Ni1---N12^i^ 2.071 (4) Ni1---N6 2.120 (3) Ni1---N6^i^ 2.133 (3) Ni1---N3 2.165 (3) Ni2---O1 2.014 (3) Ni2---O6 2.054 (3) Ni2---O5 2.094 (3) Ni2---N12 2.102 (4) Ni2---N6 2.103 (3) Ni2---N3 2.104 (3) Ni3---O3 2.000 (3) Ni3---O2 2.002 (3) Ni3---O8 2.068 (3) Ni3---O7 2.074 (3) Ni3---N9 2.075 (4) Ni3---N3 2.133 (4) -------------- ----------- Symmetry code: (i) . ::: ::: {#table2 .table-wrap} Table 2 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------- --------- ------- ----------- ------------- N1---H1⋯O1 0.86 2.05 2.666 (5) 128 N2---H2⋯O3 0.86 2.08 2.677 (5) 126 :::

PubMed Central

2024-06-05T04:04:17.546302

2011-2-05

PMC3051960

Related literature {#sec1} ================== Pyridine-2,5-dicarb­oxy­lic acid (2,5-pydcH~2~) can coordinate to metal centers (Pasdar *et al.*, 2011[@bb7]) or form hydrogen-bonded networks (Zeng *et al.*, 2005[@bb10]). For work by our group on the synthesis of proton-transfer compounds containing different proton donor and acceptor groups, see: Eshtiagh-Hosseini *et al.* (2010*a* [@bb3],*b* [@bb4]); Aghabozorg *et al.* (2008[@bb1], 2011[@bb2]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~3~H~12~N~2~ ^2+^·C~7~H~3~NO~4~ ^2−^·C~2~H~6~OS*M* *~r~* = 319.39Monoclinic,*a* = 11.984 (2) Å*b* = 10.346 (2) Å*c* = 12.942 (3) Åβ = 111.63 (3)°*V* = 1491.6 (6) Å^3^*Z* = 4Mo *K*α radiationμ = 0.24 mm^−1^*T* = 120 K0.4 × 0.3 × 0.3 mm ### Data collection {#sec2.1.2} STOE IPDS 2T diffractometer12249 measured reflections4010 independent reflections3380 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.035 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.041*wR*(*F* ^2^) = 0.095*S* = 1.074010 reflections216 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.43 e Å^−3^Δρ~min~ = −0.34 e Å^−3^ {#d5e611} Data collection: *X-AREA* (Stoe & Cie, 2005[@bb9]); cell refinement: *X-AREA*; data reduction: *X-AREA*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb8]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb5]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb6]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004545/jj2074sup1.cif](http://dx.doi.org/10.1107/S1600536811004545/jj2074sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004545/jj2074Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004545/jj2074Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?jj2074&file=jj2074sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?jj2074sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?jj2074&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [JJ2074](http://scripts.iucr.org/cgi-bin/sendsup?jj2074)). We are grateful to the Islamic Azad University, North Tehran Branch, for financial support. Comment ======= Pyridine-2,5-dicarboxylic acid (2,5-pydcH~2~) can coordinate to metal centers (Pasdar *et al.*, 2011) or form hydrogen-bonded networks (Zeng *et al.*, 2005). Our research group has been focused on synthesis of proton transfer compounds containing different proton donor and acceptor groups (Eshtiagh-Hosseini *et al.*, 2010*a*; Eshtiagh-Hosseini *et al.*, 2010*b*; Aghabozorg *et al.*, 2008, 2011). We report here the synthesis and crystal structure of the title proton transfer compound, \[pdaH2\]^2+^.\[2,5-pydc\]^2-^.(DMSO). The asymmetric unit contains deprotonated pyridine-2,5-dicarboxylic acid, diprotonated propane-1,3-diamine, and one DMSO solvent molecule (Fig. 1). Crystal packing is stabilized by N---H···O hydrogen bonds and weak C---H···O intermolecular interactions (Fig. 2 & Table 1). Experimental {#experimental} ============ Propane-1,3-diamine (0.07 g, 0.29 ml, 1 mmol) was added to a DMSO/H~2~O solution of pyridine-2,5-dicarboxylic acid (0.17 g, 1 mmol) (13 ml) at room temperature. The suitable crystals for X-ray diffraction experiment were isolated by slow evaporation of the solvent after two months. Refinement {#refinement} ========== Nitrogen-bound H atoms were found in difference Fourier map and refined isotropically without restraint. Carbon-bound H atoms were positioned geometrically and refined as riding atoms with C---H distances of 0.93 Å (aromatic) and 0.97 Å (CH~2~) and were refined with *U*iso(H) = 1.2 *Ueq*(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of title compound with displacement ellipsoids drawn at 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The packing diagram of the title compound, viewed down the a axis, showing N---H···O hydrogen bonds and weak C---H···O intermolecular interactions (dashed lines). :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e143 .table-wrap} ------------------------------------------------ --------------------------------------- C~3~H~12~N~2~^2+^·C~7~H~3~NO~4~^2−^·C~2~H~6~OS *F*(000) = 680 *M~r~* = 319.39 *D*~x~ = 1.422 Mg m^−3^ Monoclinic, *P*2~1~/*n* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2yn Cell parameters from 4010 reflections *a* = 11.984 (2) Å θ = 2.6--29.2° *b* = 10.346 (2) Å µ = 0.24 mm^−1^ *c* = 12.942 (3) Å *T* = 120 K β = 111.63 (3)° Block, colorless *V* = 1491.6 (6) Å^3^ 0.4 × 0.3 × 0.3 mm *Z* = 4 ------------------------------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e294 .table-wrap} ------------------------------------------ -------------------------------------- STOE IPDS 2T diffractometer 3380 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.035 graphite θ~max~ = 29.2°, θ~min~ = 2.6° Detector resolution: 0.15 pixels mm^-1^ *h* = −16→14 rotation method scans *k* = −14→14 12249 measured reflections *l* = −17→17 4010 independent reflections ------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e393 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.041 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.095 H atoms treated by a mixture of independent and constrained refinement *S* = 1.07 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0447*P*)^2^ + 0.6814*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4010 reflections (Δ/σ)~max~ \< 0.001 216 parameters Δρ~max~ = 0.43 e Å^−3^ 0 restraints Δρ~min~ = −0.34 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e550 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e649 .table-wrap} ------ --------------- -------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ S1 0.25330 (3) 0.98812 (3) 0.01042 (3) 0.01677 (10) O1 0.89632 (10) 0.63514 (12) 0.26504 (10) 0.0237 (2) O2 0.87767 (10) 0.45057 (12) 0.17030 (11) 0.0271 (3) O3 0.28902 (9) 0.63320 (10) 0.16349 (8) 0.0147 (2) O4 0.28589 (9) 0.41856 (10) 0.13819 (8) 0.0145 (2) O5 0.26031 (11) 1.00924 (11) 0.12737 (9) 0.0216 (2) N1 0.52969 (11) 0.63725 (11) 0.20599 (10) 0.0136 (2) N2 −0.08584 (11) 0.67039 (12) −0.18378 (10) 0.0120 (2) H2A −0.1484 (18) 0.6233 (18) −0.1797 (15) 0.018 (5)\* H2B −0.1114 (17) 0.7160 (19) −0.2439 (16) 0.019 (5)\* H2C −0.0253 (19) 0.619 (2) −0.1876 (16) 0.024 (5)\* N3 0.09589 (11) 0.71239 (12) 0.22640 (10) 0.0122 (2) H3A 0.0361 (18) 0.6692 (19) 0.2400 (15) 0.020 (5)\* H3B 0.1526 (17) 0.6583 (18) 0.2240 (14) 0.013 (4)\* H3C 0.1289 (18) 0.768 (2) 0.2777 (16) 0.021 (5)\* C1 0.83737 (12) 0.54143 (14) 0.20910 (12) 0.0143 (3) C2 0.70396 (12) 0.53745 (13) 0.18810 (11) 0.0116 (2) C3 0.63536 (13) 0.43090 (13) 0.13750 (12) 0.0151 (3) H3 0.6694 0.3631 0.1122 0.018\* C4 0.51512 (13) 0.42656 (13) 0.12501 (12) 0.0144 (3) H4 0.4682 0.3550 0.0929 0.017\* C5 0.46609 (11) 0.53089 (13) 0.16125 (11) 0.0108 (2) C6 0.33590 (12) 0.52826 (13) 0.15352 (10) 0.0111 (2) C7 0.64639 (12) 0.63845 (13) 0.21994 (11) 0.0133 (3) H7 0.6915 0.7109 0.2528 0.016\* C8 −0.03989 (13) 0.75898 (13) −0.08677 (11) 0.0144 (3) H8A −0.1022 0.8202 −0.0896 0.017\* H8B 0.0278 0.8073 −0.0907 0.017\* C9 −0.00090 (12) 0.68569 (13) 0.02247 (11) 0.0134 (3) H9A 0.0622 0.6249 0.0264 0.016\* H9B −0.0682 0.6374 0.0272 0.016\* C10 0.04461 (13) 0.78090 (13) 0.11828 (11) 0.0139 (3) H10A 0.1056 0.8357 0.1084 0.017\* H10B −0.0210 0.8357 0.1183 0.017\* C11 0.37246 (17) 0.88029 (16) 0.02034 (14) 0.0256 (3) H11A 0.4460 0.9123 0.0744 0.038\* H11B 0.3803 0.8739 −0.0507 0.038\* H11C 0.3553 0.7965 0.0427 0.038\* C12 0.31441 (17) 1.13018 (16) −0.02737 (15) 0.0264 (3) H12A 0.2650 1.2033 −0.0275 0.040\* H12B 0.3167 1.1191 −0.1002 0.040\* H12C 0.3943 1.1444 0.0253 0.040\* ------ --------------- -------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1232 .table-wrap} ----- -------------- -------------- -------------- --------------- -------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.01593 (17) 0.01708 (17) 0.01747 (17) −0.00372 (13) 0.00635 (13) −0.00230 (13) O1 0.0141 (5) 0.0294 (6) 0.0311 (6) −0.0076 (5) 0.0125 (5) −0.0101 (5) O2 0.0145 (5) 0.0236 (6) 0.0466 (7) 0.0026 (5) 0.0151 (5) −0.0072 (5) O3 0.0106 (4) 0.0155 (5) 0.0186 (5) 0.0014 (4) 0.0061 (4) −0.0011 (4) O4 0.0103 (4) 0.0146 (5) 0.0187 (5) −0.0015 (4) 0.0054 (4) 0.0018 (4) O5 0.0245 (6) 0.0222 (5) 0.0223 (5) −0.0018 (4) 0.0137 (4) −0.0039 (4) N1 0.0118 (5) 0.0126 (5) 0.0174 (5) 0.0001 (4) 0.0065 (4) −0.0009 (4) N2 0.0098 (5) 0.0133 (5) 0.0133 (5) −0.0003 (4) 0.0046 (4) −0.0006 (4) N3 0.0092 (5) 0.0134 (5) 0.0133 (5) −0.0004 (5) 0.0035 (4) 0.0003 (4) C1 0.0103 (6) 0.0176 (6) 0.0164 (6) 0.0004 (5) 0.0064 (5) 0.0038 (5) C2 0.0099 (6) 0.0131 (6) 0.0131 (6) 0.0005 (5) 0.0057 (5) 0.0017 (5) C3 0.0139 (6) 0.0126 (6) 0.0208 (6) 0.0015 (5) 0.0087 (5) −0.0021 (5) C4 0.0122 (6) 0.0118 (6) 0.0195 (6) −0.0013 (5) 0.0063 (5) −0.0021 (5) C5 0.0085 (6) 0.0121 (6) 0.0124 (5) 0.0006 (5) 0.0044 (5) 0.0022 (5) C6 0.0082 (6) 0.0152 (6) 0.0101 (5) 0.0001 (5) 0.0035 (4) 0.0008 (5) C7 0.0116 (6) 0.0114 (6) 0.0172 (6) −0.0021 (5) 0.0056 (5) −0.0021 (5) C8 0.0166 (7) 0.0125 (6) 0.0144 (6) −0.0006 (5) 0.0059 (5) −0.0008 (5) C9 0.0121 (6) 0.0132 (6) 0.0145 (6) −0.0004 (5) 0.0047 (5) 0.0000 (5) C10 0.0149 (6) 0.0127 (6) 0.0137 (6) 0.0001 (5) 0.0049 (5) 0.0007 (5) C11 0.0380 (10) 0.0197 (7) 0.0261 (8) 0.0078 (7) 0.0201 (7) 0.0009 (6) C12 0.0351 (9) 0.0171 (7) 0.0315 (8) −0.0015 (7) 0.0175 (7) 0.0028 (6) ----- -------------- -------------- -------------- --------------- -------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1637 .table-wrap} ------------------- -------------- -------------------- -------------- S1---O5 1.5007 (12) C3---C4 1.3904 (19) S1---C11 1.7791 (17) C3---H3 0.9300 S1---C12 1.7888 (17) C4---C5 1.3905 (18) O1---C1 1.2594 (18) C4---H4 0.9300 O2---C1 1.2442 (19) C5---C6 1.5265 (18) O3---C6 1.2508 (17) C7---H7 0.9300 O4---C6 1.2645 (17) C8---C9 1.5182 (19) N1---C5 1.3423 (17) C8---H8A 0.9700 N1---C7 1.3427 (18) C8---H8B 0.9700 N2---C8 1.4866 (18) C9---C10 1.5189 (19) N2---H2A 0.91 (2) C9---H9A 0.9700 N2---H2B 0.86 (2) C9---H9B 0.9700 N2---H2C 0.92 (2) C10---H10A 0.9700 N3---C10 1.4847 (18) C10---H10B 0.9700 N3---H3A 0.91 (2) C11---H11A 0.9600 N3---H3B 0.890 (19) C11---H11B 0.9600 N3---H3C 0.86 (2) C11---H11C 0.9600 C1---C2 1.5204 (19) C12---H12A 0.9600 C2---C3 1.3867 (19) C12---H12B 0.9600 C2---C7 1.3955 (18) C12---H12C 0.9600 O5---S1---C11 105.87 (8) N1---C7---C2 123.87 (13) O5---S1---C12 106.25 (7) N1---C7---H7 118.1 C11---S1---C12 97.83 (8) C2---C7---H7 118.1 C5---N1---C7 117.60 (12) N2---C8---C9 111.69 (11) C8---N2---H2A 109.7 (12) N2---C8---H8A 109.3 C8---N2---H2B 108.8 (13) C9---C8---H8A 109.3 H2A---N2---H2B 108.5 (17) N2---C8---H8B 109.3 C8---N2---H2C 110.5 (12) C9---C8---H8B 109.3 H2A---N2---H2C 112.2 (17) H8A---C8---H8B 107.9 H2B---N2---H2C 107.1 (17) C8---C9---C10 109.33 (12) C10---N3---H3A 109.5 (12) C8---C9---H9A 109.8 C10---N3---H3B 108.8 (11) C10---C9---H9A 109.8 H3A---N3---H3B 111.2 (17) C8---C9---H9B 109.8 C10---N3---H3C 108.6 (13) C10---C9---H9B 109.8 H3A---N3---H3C 110.5 (17) H9A---C9---H9B 108.3 H3B---N3---H3C 108.1 (17) N3---C10---C9 111.05 (11) O2---C1---O1 126.50 (14) N3---C10---H10A 109.4 O2---C1---C2 116.52 (13) C9---C10---H10A 109.4 O1---C1---C2 116.98 (13) N3---C10---H10B 109.4 C3---C2---C7 117.59 (12) C9---C10---H10B 109.4 C3---C2---C1 120.48 (12) H10A---C10---H10B 108.0 C7---C2---C1 121.92 (12) S1---C11---H11A 109.5 C2---C3---C4 119.29 (13) S1---C11---H11B 109.5 C2---C3---H3 120.4 H11A---C11---H11B 109.5 C4---C3---H3 120.4 S1---C11---H11C 109.5 C3---C4---C5 118.97 (13) H11A---C11---H11C 109.5 C3---C4---H4 120.5 H11B---C11---H11C 109.5 C5---C4---H4 120.5 S1---C12---H12A 109.5 N1---C5---C4 122.59 (12) S1---C12---H12B 109.5 N1---C5---C6 116.55 (11) H12A---C12---H12B 109.5 C4---C5---C6 120.85 (12) S1---C12---H12C 109.5 O3---C6---O4 126.18 (12) H12A---C12---H12C 109.5 O3---C6---C5 117.70 (12) H12B---C12---H12C 109.5 O4---C6---C5 116.11 (12) O2---C1---C2---C3 6.0 (2) C3---C4---C5---C6 −177.55 (12) O1---C1---C2---C3 −173.18 (13) N1---C5---C6---O3 16.67 (17) O2---C1---C2---C7 −175.04 (14) C4---C5---C6---O3 −164.35 (13) O1---C1---C2---C7 5.8 (2) N1---C5---C6---O4 −162.89 (12) C7---C2---C3---C4 −2.7 (2) C4---C5---C6---O4 16.09 (18) C1---C2---C3---C4 176.36 (13) C5---N1---C7---C2 1.7 (2) C2---C3---C4---C5 1.6 (2) C3---C2---C7---N1 1.1 (2) C7---N1---C5---C4 −2.97 (19) C1---C2---C7---N1 −177.95 (13) C7---N1---C5---C6 175.99 (11) N2---C8---C9---C10 −179.79 (11) C3---C4---C5---N1 1.4 (2) C8---C9---C10---N3 −173.86 (11) ------------------- -------------- -------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2263 .table-wrap} --------------------- ------------ ------------ ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N2---H2A···O4^i^ 0.91 (2) 1.96 (2) 2.8260 (16) 157.8 (17) N2---H2B···O3^ii^ 0.86 (2) 2.06 (2) 2.8461 (17) 151.0 (18) N2---H2C···O2^iii^ 0.92 (2) 1.84 (2) 2.7385 (17) 164.4 (18) N3---H3A···O1^iv^ 0.91 (2) 1.85 (2) 2.7369 (17) 161.6 (18) N3---H3B···O3 0.890 (19) 2.073 (19) 2.8427 (16) 144.2 (16) N3---H3C···O4^v^ 0.86 (2) 1.96 (2) 2.7925 (17) 164.2 (18) C8---H8A···O5^vi^ 0.97 2.50 3.4614 (19) 170 C10---H10A···O5 0.97 2.53 3.4718 (19) 165 C11---H11B···O1^ii^ 0.96 2.46 3.424 (2) 178 --------------------- ------------ ------------ ------------- --------------- ::: Symmetry codes: (i) −*x*, −*y*+1, −*z*; (ii) *x*−1/2, −*y*+3/2, *z*−1/2; (iii) −*x*+1, −*y*+1, −*z*; (iv) *x*−1, *y*, *z*; (v) −*x*+1/2, *y*+1/2, −*z*+1/2; (vi) −*x*, −*y*+2, −*z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- ------------ ------------ ------------- ------------- N2---H2*A*⋯O4^i^ 0.91 (2) 1.96 (2) 2.8260 (16) 157.8 (17) N2---H2*B*⋯O3^ii^ 0.86 (2) 2.06 (2) 2.8461 (17) 151.0 (18) N2---H2*C*⋯O2^iii^ 0.92 (2) 1.84 (2) 2.7385 (17) 164.4 (18) N3---H3*A*⋯O1^iv^ 0.91 (2) 1.85 (2) 2.7369 (17) 161.6 (18) N3---H3*B*⋯O3 0.890 (19) 2.073 (19) 2.8427 (16) 144.2 (16) N3---H3*C*⋯O4^v^ 0.86 (2) 1.96 (2) 2.7925 (17) 164.2 (18) C8---H8*A*⋯O5^vi^ 0.97 2.50 3.4614 (19) 170 C10---H10*A*⋯O5 0.97 2.53 3.4718 (19) 165 C11---H11*B*⋯O1^ii^ 0.96 2.46 3.424 (2) 178 Symmetry codes: (i) ; (ii) ; (iii) ; (iv) ; (v) ; (vi) . :::

PubMed Central

2024-06-05T04:04:17.558635

2011-2-12

PMC3051961

Related literature {#sec1} ================== For related compounds, see: Li *et al.* (2011[@bb3]) and references therein. Di\[tris­(trifluoro­meth­yl)phen­yl\]phosphine chloride was prepared according to Batsanov *et al.* (2002[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Pd(CH~3~)(C~24~H~10~F~18~NOP)(C~2~H~3~N)\]\[SbF~6~\]·0.5CH~2~Cl~2~*M* *~r~* = 1142.00Triclinic,*a* = 8.6993 (4) Å*b* = 11.8120 (5) Å*c* = 18.1494 (8) Åα = 78.557 (2)°β = 82.007 (2)°γ = 79.526 (2)°*V* = 1787.14 (14) Å^3^*Z* = 2Cu *K*α radiationμ = 12.64 mm^−1^*T* = 100 K0.38 × 0.13 × 0.11 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: numerical (*SADABS*; Bruker, 2007[@bb2]) *T* ~min~ = 0.086, *T* ~max~ = 0.34819130 measured reflections6422 independent reflections5830 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.035 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.036*wR*(*F* ^2^) = 0.093*S* = 1.056422 reflections534 parameters3 restraintsH-atom parameters constrainedΔρ~max~ = 1.46 e Å^−3^Δρ~min~ = −0.88 e Å^−3^ {#d5e491} Data collection: *APEX2* (Bruker, 2007[@bb2]); cell refinement: *SAINT* (Bruker, 2007[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb4]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb4]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb4]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005757/cv5046sup1.cif](http://dx.doi.org/10.1107/S1600536811005757/cv5046sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005757/cv5046Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005757/cv5046Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?cv5046&file=cv5046sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?cv5046sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?cv5046&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [CV5046](http://scripts.iucr.org/cgi-bin/sendsup?cv5046)). We thank Professor Maurice S. Brookhart for helpful discussions. Comment ======= In continuation of our structural study of Pd complexes with phosphine-imine ligands (Li *et al.*, 2011), we present here the title compound (I). In (I) (Fig. 1), each Pd center has a distorted square-planar environment being coordinated by acetonitrile \[Pd---N 2.079 (3) Å\], methyl \[Pd---C 2.047 (4) Å\] and bidentate ligand *L*. The solvent molecule has been treated as disordered between two positions related by inversion center with occupancies fixed to 0.5 each. The crystal packing exhibits weak intermolecular C---H···F contacts (Table 1). Experimental {#experimental} ============ All manipulations of air- and/or moisture-sensitive compounds were conducted using standard Schlenk techniques. Argon was purified by passage through columns of BASF R3--11 catalyst (Chemalog) and 4Å molecular sieves. All solvents were deoxygenated, dried and distilled using common techniques. Di\[tris(trifluoromethyl)phenyl\]phosphine chloride were prepared according to the literature procedures(Batsanov *et al.*, 2002). A flame-dried Schlenk flask was charged with purified 2-pyridyl-carbinal (138 mg, 1.27 mmol) and dried THF (5 ml). The solution was cooled to -78°C and stirred for 30 min, 1.6 mol/l n-BuLi in hexane (0.8 ml, 1.28 mmol) was added slowly. After stirring of 1.0 hrs at -78°C, 800 mg of di\[tris(trifluoromethyl)phenyl\]phosphine chloride in THF(2 ml) was added slowly. Stirring for 1 day at -78°C, and brought it to room temperature and stirred overnight. 3.0 ml degassed saturated NaCl solution was charged for hydrolysis. After separation, dry and column purification, the ligand of 2- methoxy(di(2,4,6-tris(trifluoromethyl) phenyl)phosphino)\] pyridine(0.45 g) was obtained. The yield is 50%. The neutral complex was prepared by reaction of the above ligand (1.0 equiv.) and (COD)PdMeCl (1.0 equiv.) at RT, and the cationic complex was obtained by reacting the neutral complex(1.0 equiv) with AgSbF~6~ (1.0 equiv.) at RT. Single crystal of the cationic complex was cultivated by recrystallization of CH~2~Cl~2~ and pentane. Anal. Calcd for C27H16F24N2OPPdSb: C, 29.49; H, 1.47; N, 2.55. Found: C, 29.52; H, 1.30; N, 2.27. Refinement {#refinement} ========== C-bound H atoms were geometrically positioned (C---H 0.95-0.99 Å) and refined as riding, with Uiso(H) = 1.2-1.5 Ueq(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of (I) showing the atom-numbering scheme and 50% probabilty displacement ellipsoids. The H atoms and solvent molecules are omitted for clarity :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e106 .table-wrap} ---------------------------------------------------------------------- --------------------------------------- \[Pd(CH~3~)(C~24~H~10~F~18~NOP)(C~2~H~3~N)\]\[SbF~6~\]·0.5CH~2~Cl~2~ *Z* = 2 *M~r~* = 1142.00 *F*(000) = 1098 Triclinic, *P*1 *D*~x~ = 2.122 Mg m^−3^ Hall symbol: -P 1 Cu *K*α radiation, λ = 1.54178 Å *a* = 8.6993 (4) Å Cell parameters from 8055 reflections *b* = 11.8120 (5) Å θ = 2.5--69.1° *c* = 18.1494 (8) Å µ = 12.64 mm^−1^ α = 78.557 (2)° *T* = 100 K β = 82.007 (2)° Block, colourless γ = 79.526 (2)° 0.38 × 0.13 × 0.11 mm *V* = 1787.14 (14) Å^3^ ---------------------------------------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e258 .table-wrap} ---------------------------------------------------------- -------------------------------------- Bruker APEXII CCD diffractometer 6422 independent reflections Radiation source: fine-focus sealed tube 5830 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.035 φ and ω scans θ~max~ = 69.7°, θ~min~ = 2.5° Absorption correction: numerical (*SAINT*; Bruker, 2007) *h* = −10→10 *T*~min~ = 0.086, *T*~max~ = 0.348 *k* = −14→14 19130 measured reflections *l* = −21→21 ---------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e375 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.036 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.093 H-atom parameters constrained *S* = 1.05 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0539*P*)^2^ + 2.2192*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 6422 reflections (Δ/σ)~max~ = 0.043 534 parameters Δρ~max~ = 1.46 e Å^−3^ 3 restraints Δρ~min~ = −0.88 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e532 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e631 .table-wrap} ------ ------------- -------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) Pd1 0.88403 (6) 0.79572 (4) 0.19133 (3) 0.02224 (17) P1 0.7299 (2) 0.67699 (15) 0.26210 (10) 0.0200 (4) C1 0.8178 (10) 0.9157 (7) 0.2617 (5) 0.0305 (17) H1A 0.9104 0.9464 0.2697 0.046\* H1B 0.7698 0.8781 0.3103 0.046\* H1C 0.7415 0.9801 0.2387 0.046\* N2 1.0136 (8) 0.9151 (6) 0.1220 (4) 0.0279 (14) C3 1.0826 (9) 0.9841 (7) 0.0885 (4) 0.0251 (15) C4 1.1735 (10) 1.0729 (7) 0.0447 (5) 0.0316 (17) H4A 1.1014 1.1415 0.0232 0.047\* H4B 1.2423 1.0406 0.0039 0.047\* H4C 1.2374 1.0960 0.0780 0.047\* N5 0.9618 (7) 0.6603 (6) 0.1231 (3) 0.0251 (13) C6 1.1173 (9) 0.6238 (7) 0.1095 (4) 0.0283 (16) H6 1.1877 0.6752 0.1122 0.034\* C7 1.1789 (10) 0.5154 (8) 0.0918 (4) 0.0318 (17) H7 1.2893 0.4931 0.0820 0.038\* C8 1.0768 (10) 0.4392 (8) 0.0886 (5) 0.0322 (17) H8 1.1161 0.3626 0.0788 0.039\* C9 0.9161 (10) 0.4774 (7) 0.0999 (4) 0.0295 (16) H9 0.8441 0.4278 0.0962 0.035\* C10 0.8615 (9) 0.5875 (7) 0.1165 (4) 0.0253 (15) C11 0.6888 (9) 0.6356 (7) 0.1274 (4) 0.0266 (16) H11A 0.6704 0.7160 0.0980 0.032\* H11B 0.6292 0.5872 0.1068 0.032\* O12 0.6279 (6) 0.6381 (4) 0.2067 (3) 0.0228 (10) C13 0.5605 (8) 0.7290 (6) 0.3291 (4) 0.0207 (14) C14 0.4259 (9) 0.7999 (6) 0.2991 (4) 0.0225 (14) C15 0.2888 (9) 0.8282 (6) 0.3458 (4) 0.0255 (15) H15 0.1999 0.8755 0.3243 0.031\* C16 0.2801 (9) 0.7889 (7) 0.4226 (4) 0.0272 (16) C17 0.4112 (9) 0.7274 (6) 0.4540 (4) 0.0259 (15) H17 0.4076 0.7050 0.5074 0.031\* C18 0.5494 (9) 0.6975 (6) 0.4090 (4) 0.0243 (15) C19 0.4112 (9) 0.8531 (7) 0.2163 (4) 0.0259 (15) F20 0.3435 (5) 0.7874 (4) 0.1823 (2) 0.0305 (10) F21 0.5456 (5) 0.8716 (4) 0.1750 (2) 0.0297 (10) F22 0.3187 (6) 0.9577 (4) 0.2110 (3) 0.0355 (11) C23 0.1304 (10) 0.8149 (8) 0.4732 (5) 0.0348 (18) F24 0.0112 (6) 0.8704 (6) 0.4348 (3) 0.0530 (15) F25 0.1458 (8) 0.8773 (8) 0.5225 (5) 0.084 (3) F26 0.0838 (7) 0.7169 (6) 0.5117 (4) 0.0626 (18) C27 0.6838 (10) 0.6287 (7) 0.4516 (4) 0.0306 (17) F28 0.6692 (6) 0.6487 (5) 0.5223 (3) 0.0436 (13) F29 0.6908 (6) 0.5127 (4) 0.4572 (3) 0.0388 (11) F30 0.8222 (5) 0.6545 (4) 0.4194 (3) 0.0348 (10) C31 0.8327 (8) 0.5257 (6) 0.2986 (4) 0.0207 (14) C32 0.7605 (9) 0.4264 (7) 0.2976 (4) 0.0260 (15) C33 0.8487 (10) 0.3176 (7) 0.2930 (5) 0.0304 (17) H33 0.7981 0.2540 0.2903 0.036\* C34 1.0100 (10) 0.3012 (7) 0.2922 (5) 0.0338 (19) C35 1.0823 (9) 0.3903 (7) 0.3014 (5) 0.0318 (17) H35 1.1921 0.3765 0.3054 0.038\* C36 0.9955 (9) 0.5019 (7) 0.3047 (4) 0.0263 (15) C37 0.5854 (9) 0.4261 (7) 0.3027 (4) 0.0275 (16) F38 0.4982 (5) 0.5129 (4) 0.3348 (2) 0.0268 (9) F39 0.5506 (6) 0.3264 (4) 0.3475 (3) 0.0340 (10) F40 0.5333 (5) 0.4294 (4) 0.2367 (3) 0.0334 (10) C41 1.1054 (12) 0.1834 (8) 0.2817 (6) 0.047 (2) F42 1.0618 (9) 0.0980 (5) 0.3320 (4) 0.076 (2) F43 1.0811 (9) 0.1564 (6) 0.2159 (4) 0.074 (2) F44 1.2567 (7) 0.1820 (6) 0.2777 (5) 0.076 (2) C45 1.1009 (9) 0.5837 (7) 0.3185 (5) 0.0292 (16) F46 1.1596 (5) 0.5423 (4) 0.3843 (3) 0.0351 (11) F47 1.2226 (5) 0.5887 (5) 0.2645 (3) 0.0364 (11) F48 1.0343 (5) 0.6941 (4) 0.3209 (3) 0.0317 (10) Sb1 0.60710 (6) 0.23126 (4) 0.07962 (3) 0.02735 (18) F11 0.5822 (6) 0.3936 (4) 0.0756 (3) 0.0385 (11) F12 0.6312 (8) 0.2064 (5) 0.1830 (3) 0.0544 (15) F13 0.6346 (8) 0.0698 (5) 0.0829 (4) 0.0577 (17) F14 0.5886 (7) 0.2566 (6) −0.0242 (3) 0.0483 (14) F15 0.8255 (6) 0.2283 (5) 0.0575 (3) 0.0467 (13) F16 0.3891 (6) 0.2383 (5) 0.0997 (4) 0.0528 (15) Cl1 0.5356 (9) 0.0251 (5) 0.4168 (5) 0.153 (3) C50 0.390 (4) 0.059 (2) 0.481 (2) 0.106 (13) 0.50 H50A 0.2931 0.0323 0.4729 0.127\* 0.50 H50B 0.3670 0.1448 0.4795 0.127\* 0.50 ------ ------------- -------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1604 .table-wrap} ----- ------------ ------------ ------------ -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Pd1 0.0200 (3) 0.0197 (3) 0.0254 (3) −0.0038 (2) −0.0024 (2) 0.0004 (2) P1 0.0169 (8) 0.0179 (8) 0.0230 (8) −0.0007 (6) −0.0016 (6) −0.0008 (7) C1 0.035 (4) 0.022 (4) 0.035 (4) −0.004 (3) −0.006 (3) −0.004 (3) N2 0.025 (3) 0.027 (3) 0.030 (3) −0.006 (3) −0.003 (3) 0.000 (3) C3 0.023 (4) 0.025 (4) 0.027 (4) −0.002 (3) −0.004 (3) −0.004 (3) C4 0.033 (4) 0.028 (4) 0.033 (4) −0.011 (3) 0.000 (3) 0.000 (3) N5 0.025 (3) 0.025 (3) 0.023 (3) −0.005 (3) 0.001 (2) 0.000 (3) C6 0.024 (4) 0.033 (4) 0.026 (4) −0.006 (3) 0.003 (3) −0.001 (3) C7 0.023 (4) 0.039 (5) 0.029 (4) −0.003 (3) 0.005 (3) −0.003 (3) C8 0.034 (4) 0.030 (4) 0.030 (4) 0.000 (3) 0.002 (3) −0.007 (3) C9 0.030 (4) 0.033 (4) 0.026 (4) −0.008 (3) 0.003 (3) −0.007 (3) C10 0.026 (4) 0.030 (4) 0.020 (3) −0.007 (3) 0.002 (3) −0.004 (3) C11 0.024 (4) 0.034 (4) 0.021 (3) −0.006 (3) −0.002 (3) −0.002 (3) O12 0.018 (2) 0.025 (3) 0.024 (2) −0.003 (2) −0.0003 (19) −0.004 (2) C13 0.017 (3) 0.016 (3) 0.027 (3) −0.001 (3) −0.001 (3) −0.003 (3) C14 0.024 (4) 0.015 (3) 0.029 (4) −0.003 (3) −0.006 (3) −0.003 (3) C15 0.024 (4) 0.019 (4) 0.033 (4) 0.000 (3) −0.006 (3) −0.005 (3) C16 0.028 (4) 0.020 (4) 0.034 (4) −0.004 (3) 0.003 (3) −0.010 (3) C17 0.033 (4) 0.019 (4) 0.025 (3) −0.003 (3) −0.002 (3) −0.003 (3) C18 0.025 (4) 0.020 (4) 0.028 (4) −0.003 (3) −0.003 (3) −0.004 (3) C19 0.023 (4) 0.024 (4) 0.028 (4) 0.001 (3) −0.003 (3) −0.003 (3) F20 0.028 (2) 0.036 (3) 0.028 (2) −0.0051 (19) −0.0070 (18) −0.0070 (19) F21 0.025 (2) 0.029 (2) 0.030 (2) −0.0036 (18) −0.0027 (18) 0.0046 (19) F22 0.038 (3) 0.028 (2) 0.035 (2) 0.011 (2) −0.007 (2) −0.002 (2) C23 0.027 (4) 0.039 (5) 0.035 (4) 0.003 (4) 0.001 (3) −0.008 (4) F24 0.029 (3) 0.067 (4) 0.046 (3) 0.014 (3) 0.006 (2) 0.001 (3) F25 0.046 (4) 0.136 (7) 0.091 (5) −0.017 (4) 0.020 (4) −0.085 (6) F26 0.043 (3) 0.057 (4) 0.065 (4) 0.003 (3) 0.024 (3) 0.012 (3) C27 0.032 (4) 0.028 (4) 0.026 (4) 0.005 (3) −0.004 (3) 0.000 (3) F28 0.043 (3) 0.057 (3) 0.026 (2) 0.013 (2) −0.010 (2) −0.008 (2) F29 0.039 (3) 0.028 (2) 0.040 (3) 0.006 (2) −0.004 (2) 0.006 (2) F30 0.025 (2) 0.043 (3) 0.036 (2) −0.002 (2) −0.0054 (19) −0.006 (2) C31 0.018 (3) 0.019 (3) 0.021 (3) 0.000 (3) 0.002 (3) 0.001 (3) C32 0.022 (4) 0.025 (4) 0.027 (4) −0.003 (3) 0.005 (3) −0.002 (3) C33 0.030 (4) 0.023 (4) 0.034 (4) −0.004 (3) 0.010 (3) −0.002 (3) C34 0.027 (4) 0.024 (4) 0.042 (5) 0.003 (3) 0.011 (3) 0.000 (4) C35 0.020 (4) 0.028 (4) 0.039 (4) 0.002 (3) 0.004 (3) 0.004 (3) C36 0.023 (4) 0.025 (4) 0.027 (4) −0.001 (3) 0.001 (3) 0.001 (3) C37 0.026 (4) 0.022 (4) 0.034 (4) −0.005 (3) 0.004 (3) −0.006 (3) F38 0.019 (2) 0.025 (2) 0.035 (2) −0.0022 (17) 0.0041 (17) −0.0083 (19) F39 0.030 (2) 0.025 (2) 0.044 (3) −0.0108 (19) 0.010 (2) −0.004 (2) F40 0.031 (2) 0.037 (3) 0.035 (2) −0.010 (2) −0.0001 (19) −0.012 (2) C41 0.037 (5) 0.028 (5) 0.062 (6) 0.007 (4) 0.020 (4) −0.005 (4) F42 0.086 (5) 0.026 (3) 0.089 (5) 0.013 (3) 0.036 (4) 0.006 (3) F43 0.087 (5) 0.050 (4) 0.076 (5) 0.019 (4) 0.004 (4) −0.028 (4) F44 0.034 (3) 0.043 (3) 0.148 (8) 0.012 (3) 0.005 (4) −0.033 (4) C45 0.019 (4) 0.031 (4) 0.032 (4) −0.002 (3) −0.003 (3) 0.005 (3) F46 0.029 (2) 0.040 (3) 0.033 (2) −0.002 (2) −0.0103 (19) 0.004 (2) F47 0.023 (2) 0.048 (3) 0.037 (3) −0.012 (2) 0.0014 (19) −0.002 (2) F48 0.026 (2) 0.025 (2) 0.043 (3) −0.0037 (18) −0.0132 (19) 0.002 (2) Sb1 0.0290 (3) 0.0234 (3) 0.0279 (3) −0.0051 (2) 0.0026 (2) −0.0033 (2) F11 0.035 (3) 0.024 (2) 0.056 (3) −0.004 (2) −0.004 (2) −0.005 (2) F12 0.083 (4) 0.045 (3) 0.028 (3) 0.007 (3) −0.006 (3) −0.004 (2) F13 0.083 (5) 0.024 (3) 0.063 (4) −0.013 (3) 0.017 (3) −0.013 (3) F14 0.050 (3) 0.068 (4) 0.030 (3) −0.013 (3) −0.007 (2) −0.010 (3) F15 0.025 (3) 0.049 (3) 0.060 (3) 0.001 (2) −0.001 (2) −0.004 (3) F16 0.029 (3) 0.055 (3) 0.074 (4) −0.018 (3) 0.015 (3) −0.018 (3) Cl1 0.147 (5) 0.104 (4) 0.221 (8) −0.059 (4) −0.011 (5) −0.035 (5) C50 0.09 (2) 0.044 (14) 0.19 (4) −0.035 (15) 0.02 (2) −0.05 (2) ----- ------------ ------------ ------------ -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2761 .table-wrap} ----------------------- ------------- ----------------------- ------------- Pd1---C1 2.047 (8) C19---F21 1.327 (9) Pd1---N2 2.079 (7) C19---F20 1.336 (9) Pd1---N5 2.170 (6) C19---F22 1.340 (9) Pd1---P1 2.2146 (18) C23---F25 1.301 (11) P1---O12 1.609 (5) C23---F26 1.328 (11) P1---C13 1.870 (7) C23---F24 1.328 (10) P1---C31 1.883 (7) C27---F30 1.324 (10) C1---H1A 0.9800 C27---F28 1.335 (9) C1---H1B 0.9800 C27---F29 1.344 (10) C1---H1C 0.9800 C31---C36 1.408 (11) N2---C3 1.128 (10) C31---C32 1.432 (10) C3---C4 1.467 (11) C32---C33 1.383 (11) C4---H4A 0.9800 C32---C37 1.513 (11) C4---H4B 0.9800 C33---C34 1.379 (12) C4---H4C 0.9800 C33---H33 0.9500 N5---C6 1.347 (10) C34---C35 1.367 (12) N5---C10 1.363 (10) C34---C41 1.517 (11) C6---C7 1.377 (12) C35---C36 1.403 (11) C6---H6 0.9500 C35---H35 0.9500 C7---C8 1.388 (12) C36---C45 1.523 (11) C7---H7 0.9500 C37---F40 1.329 (9) C8---C9 1.388 (12) C37---F38 1.341 (9) C8---H8 0.9500 C37---F39 1.349 (9) C9---C10 1.378 (11) C41---F42 1.294 (11) C9---H9 0.9500 C41---F44 1.305 (12) C10---C11 1.507 (11) C41---F43 1.347 (14) C11---O12 1.467 (8) C45---F46 1.332 (9) C11---H11A 0.9900 C45---F48 1.334 (9) C11---H11B 0.9900 C45---F47 1.340 (9) C13---C14 1.418 (10) Sb1---F13 1.868 (5) C13---C18 1.418 (10) Sb1---F16 1.870 (5) C14---C15 1.394 (11) Sb1---F14 1.873 (5) C14---C19 1.523 (10) Sb1---F12 1.876 (5) C15---C16 1.374 (11) Sb1---F11 1.879 (5) C15---H15 0.9500 Sb1---F11 1.879 (5) C16---C17 1.367 (11) Sb1---F15 1.881 (5) C16---C23 1.506 (11) Cl1---C50 1.65 (2) C17---C18 1.388 (11) C50---H50A 0.9900 C17---H17 0.9500 C50---H50B 0.9900 C18---C27 1.510 (11) C1---Pd1---N2 87.5 (3) F25---C23---F24 107.8 (8) C1---Pd1---N5 176.1 (3) F26---C23---F24 105.3 (7) N2---Pd1---N5 94.4 (2) F25---C23---C16 112.5 (7) C1---Pd1---P1 91.4 (2) F26---C23---C16 111.1 (7) N2---Pd1---P1 175.69 (19) F24---C23---C16 112.6 (7) N5---Pd1---P1 86.99 (17) F30---C27---F28 106.8 (7) O12---P1---C13 96.7 (3) F30---C27---F29 107.1 (6) O12---P1---C31 96.4 (3) F28---C27---F29 106.2 (7) C13---P1---C31 112.8 (3) F30---C27---C18 112.7 (7) O12---P1---Pd1 107.5 (2) F28---C27---C18 111.7 (6) C13---P1---Pd1 122.6 (2) F29---C27---C18 112.0 (7) C31---P1---Pd1 115.0 (2) C36---C31---C32 115.5 (7) Pd1---C1---H1A 109.5 C36---C31---P1 122.0 (6) Pd1---C1---H1B 109.5 C32---C31---P1 119.5 (6) H1A---C1---H1B 109.5 C33---C32---C31 121.6 (7) Pd1---C1---H1C 109.5 C33---C32---C37 112.9 (7) H1A---C1---H1C 109.5 C31---C32---C37 125.5 (7) H1B---C1---H1C 109.5 C34---C33---C32 120.3 (8) C3---N2---Pd1 175.1 (6) C34---C33---H33 119.9 N2---C3---C4 179.5 (9) C32---C33---H33 119.9 C3---C4---H4A 109.5 C35---C34---C33 120.0 (8) C3---C4---H4B 109.5 C35---C34---C41 120.6 (8) H4A---C4---H4B 109.5 C33---C34---C41 119.3 (8) C3---C4---H4C 109.5 C34---C35---C36 120.5 (8) H4A---C4---H4C 109.5 C34---C35---H35 119.8 H4B---C4---H4C 109.5 C36---C35---H35 119.8 C6---N5---C10 118.0 (7) C35---C36---C31 121.4 (7) C6---N5---Pd1 118.4 (5) C35---C36---C45 110.3 (7) C10---N5---Pd1 119.8 (5) C31---C36---C45 128.2 (7) N5---C6---C7 123.0 (7) F40---C37---F38 108.0 (6) N5---C6---H6 118.5 F40---C37---F39 106.2 (6) C7---C6---H6 118.5 F38---C37---F39 105.4 (6) C6---C7---C8 118.8 (7) F40---C37---C32 114.0 (6) C6---C7---H7 120.6 F38---C37---C32 113.5 (6) C8---C7---H7 120.6 F39---C37---C32 109.1 (7) C9---C8---C7 118.6 (8) F42---C41---F44 111.0 (9) C9---C8---H8 120.7 F42---C41---F43 103.6 (9) C7---C8---H8 120.7 F44---C41---F43 105.5 (8) C10---C9---C8 119.8 (7) F42---C41---C34 112.8 (7) C10---C9---H9 120.1 F44---C41---C34 112.9 (8) C8---C9---H9 120.1 F43---C41---C34 110.3 (9) N5---C10---C9 121.5 (7) F46---C45---F48 106.3 (7) N5---C10---C11 115.9 (7) F46---C45---F47 107.4 (6) C9---C10---C11 122.5 (7) F48---C45---F47 106.3 (6) O12---C11---C10 113.5 (6) F46---C45---C36 109.5 (6) O12---C11---H11A 108.9 F48---C45---C36 116.7 (6) C10---C11---H11A 108.9 F47---C45---C36 110.2 (7) O12---C11---H11B 108.9 F13---Sb1---F16 91.2 (3) C10---C11---H11B 108.9 F13---Sb1---F14 90.0 (3) H11A---C11---H11B 107.7 F16---Sb1---F14 89.7 (3) C11---O12---P1 120.4 (4) F13---Sb1---F12 90.2 (3) C14---C13---C18 115.7 (6) F16---Sb1---F12 91.8 (3) C14---C13---P1 118.6 (5) F14---Sb1---F12 178.5 (3) C18---C13---P1 125.5 (5) F13---Sb1---F11 179.2 (3) C15---C14---C13 121.0 (7) F16---Sb1---F11 89.6 (2) C15---C14---C19 112.6 (6) F14---Sb1---F11 89.8 (3) C13---C14---C19 126.3 (7) F12---Sb1---F11 90.0 (2) C16---C15---C14 121.0 (7) F13---Sb1---F11 179.2 (3) C16---C15---H15 119.5 F16---Sb1---F11 89.6 (2) C14---C15---H15 119.5 F14---Sb1---F11 89.8 (3) C17---C16---C15 119.4 (7) F12---Sb1---F11 90.0 (2) C17---C16---C23 119.1 (7) F11---Sb1---F11 0.0 (3) C15---C16---C23 121.5 (7) F13---Sb1---F15 90.1 (3) C16---C17---C18 120.8 (7) F16---Sb1---F15 178.4 (3) C16---C17---H17 119.6 F14---Sb1---F15 89.3 (3) C18---C17---H17 119.6 F12---Sb1---F15 89.2 (3) C17---C18---C13 121.7 (7) F11---Sb1---F15 89.1 (2) C17---C18---C27 114.9 (7) F11---Sb1---F15 89.1 (2) C13---C18---C27 123.4 (7) F11---F11---Sb1 0(10) F21---C19---F20 107.6 (6) C50---Cl1---C50^i^ 74.4 (19) F21---C19---F22 105.9 (6) Cl1---C50---Cl1^i^ 105.6 (19) F20---C19---F22 106.3 (6) Cl1---C50---H50A 110.6 F21---C19---C14 114.9 (6) Cl1^i^---C50---H50A 110.6 F20---C19---C14 111.7 (6) Cl1---C50---H50B 110.6 F22---C19---C14 109.8 (6) Cl1^i^---C50---H50B 110.6 F25---C23---F26 107.0 (8) H50A---C50---H50B 108.7 C1---Pd1---P1---O12 130.9 (3) C15---C14---C19---F21 153.5 (6) N2---Pd1---P1---O12 57 (3) C13---C14---C19---F21 −26.5 (10) N5---Pd1---P1---O12 −52.7 (3) C15---C14---C19---F20 −83.6 (8) C1---Pd1---P1---C13 20.6 (4) C13---C14---C19---F20 96.5 (8) N2---Pd1---P1---C13 −54 (3) C15---C14---C19---F22 34.2 (9) N5---Pd1---P1---C13 −163.0 (3) C13---C14---C19---F22 −145.7 (7) C1---Pd1---P1---C31 −123.1 (3) C17---C16---C23---F25 60.7 (11) N2---Pd1---P1---C31 163 (3) C15---C16---C23---F25 −117.5 (9) N5---Pd1---P1---C31 53.3 (3) C17---C16---C23---F26 −59.3 (10) C1---Pd1---N2---C3 15 (8) C15---C16---C23---F26 122.5 (8) N5---Pd1---N2---C3 −162 (8) C17---C16---C23---F24 −177.2 (7) P1---Pd1---N2---C3 89 (8) C15---C16---C23---F24 4.6 (11) Pd1---N2---C3---C4 132 (100) C17---C18---C27---F30 −145.4 (7) C1---Pd1---N5---C6 −62 (4) C13---C18---C27---F30 35.2 (10) N2---Pd1---N5---C6 56.6 (6) C17---C18---C27---F28 −25.3 (10) P1---Pd1---N5---C6 −127.5 (6) C13---C18---C27---F28 155.4 (7) C1---Pd1---N5---C10 96 (4) C17---C18---C27---F29 93.7 (8) N2---Pd1---N5---C10 −145.5 (6) C13---C18---C27---F29 −85.6 (9) P1---Pd1---N5---C10 30.4 (5) O12---P1---C31---C36 134.8 (6) C10---N5---C6---C7 −2.2 (11) C13---P1---C31---C36 −125.2 (6) Pd1---N5---C6---C7 156.1 (6) Pd1---P1---C31---C36 22.1 (7) N5---C6---C7---C8 −0.7 (12) O12---P1---C31---C32 −25.0 (6) C6---C7---C8---C9 2.9 (12) C13---P1---C31---C32 75.1 (6) C7---C8---C9---C10 −2.1 (12) Pd1---P1---C31---C32 −137.7 (5) C6---N5---C10---C9 3.0 (11) C36---C31---C32---C33 −8.2 (11) Pd1---N5---C10---C9 −155.0 (6) P1---C31---C32---C33 152.8 (6) C6---N5---C10---C11 −176.2 (6) C36---C31---C32---C37 170.7 (7) Pd1---N5---C10---C11 25.8 (8) P1---C31---C32---C37 −28.2 (10) C8---C9---C10---N5 −0.8 (12) C31---C32---C33---C34 2.7 (12) C8---C9---C10---C11 178.3 (7) C37---C32---C33---C34 −176.4 (7) N5---C10---C11---O12 −75.3 (8) C32---C33---C34---C35 4.6 (13) C9---C10---C11---O12 105.5 (8) C32---C33---C34---C41 −175.9 (8) C10---C11---O12---P1 40.9 (8) C33---C34---C35---C36 −5.8 (13) C13---P1---O12---C11 154.3 (5) C41---C34---C35---C36 174.7 (8) C31---P1---O12---C11 −91.7 (6) C34---C35---C36---C31 −0.3 (12) Pd1---P1---O12---C11 27.0 (6) C34---C35---C36---C45 177.6 (7) O12---P1---C13---C14 −45.0 (6) C32---C31---C36---C35 7.0 (11) C31---P1---C13---C14 −144.8 (5) P1---C31---C36---C35 −153.5 (6) Pd1---P1---C13---C14 70.7 (6) C32---C31---C36---C45 −170.4 (7) O12---P1---C13---C18 130.7 (6) P1---C31---C36---C45 29.1 (11) C31---P1---C13---C18 30.9 (7) C33---C32---C37---F40 −79.3 (9) Pd1---P1---C13---C18 −113.5 (6) C31---C32---C37---F40 101.7 (9) C18---C13---C14---C15 −4.7 (10) C33---C32---C37---F38 156.4 (7) P1---C13---C14---C15 171.4 (5) C31---C32---C37---F38 −22.6 (11) C18---C13---C14---C19 175.2 (7) C33---C32---C37---F39 39.2 (9) P1---C13---C14---C19 −8.6 (9) C31---C32---C37---F39 −139.8 (7) C13---C14---C15---C16 0.4 (11) C35---C34---C41---F42 122.7 (11) C19---C14---C15---C16 −179.5 (7) C33---C34---C41---F42 −56.8 (14) C14---C15---C16---C17 4.3 (11) C35---C34---C41---F44 −4.1 (14) C14---C15---C16---C23 −177.5 (7) C33---C34---C41---F44 176.3 (9) C15---C16---C17---C18 −4.5 (11) C35---C34---C41---F43 −121.9 (10) C23---C16---C17---C18 177.2 (7) C33---C34---C41---F43 58.5 (11) C16---C17---C18---C13 0.0 (11) C35---C36---C45---F46 −61.1 (8) C16---C17---C18---C27 −179.4 (7) C31---C36---C45---F46 116.6 (8) C14---C13---C18---C17 4.5 (10) C35---C36---C45---F48 178.2 (7) P1---C13---C18---C17 −171.3 (6) C31---C36---C45---F48 −4.2 (12) C14---C13---C18---C27 −176.1 (7) C35---C36---C45---F47 56.8 (8) P1---C13---C18---C27 8.0 (10) C31---C36---C45---F47 −125.5 (8) ----------------------- ------------- ----------------------- ------------- ::: Symmetry codes: (i) −*x*+1, −*y*, −*z*+1. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e4502 .table-wrap} -------------------- --------- --------- ------------ --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C4---H4C···F16^ii^ 0.98 2.44 3.310 (10) 148 C11---H11B···F11 0.99 2.58 3.489 (9) 154 C9---H9···F11 0.95 2.47 3.345 (9) 152 -------------------- --------- --------- ------------ --------------- ::: Symmetry codes: (ii) *x*+1, *y*+1, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------- --------- ------- ------------ ------------- C4---H4*C*⋯F16^i^ 0.98 2.44 3.310 (10) 148 C11---H11*B*⋯F11 0.99 2.58 3.489 (9) 154 C9---H9⋯F11 0.95 2.47 3.345 (9) 152 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.564936

2011-2-23

PMC3051962

Related literature {#sec1} ================== For the application of benzothia­zoles as biologically active compounds, see: Leong *et al.* (2004[@bb7]); Yildiz-Oren *et al.* (2004[@bb18]); Lockhart *et al.* (2005[@bb8]); Sheng *et al.* (2007[@bb16]). For the synthesis of the title compound, see: Racané *et al.* (2006[@bb14], 2011[@bb13]). For related 1,3-benzothia­zole structures, see: Matković-Čalogović *et al.* (2003[@bb10]); Pavlović *et al.* (2009[@bb12]); Đaković *et al.* (2009[@bb4]); Čičak *et al.* (2010[@bb3]). For graph-set theory, see: Etter (1990[@bb5]); Bernstein *et al.* (1995[@bb2]). For a description of the Cambridge Structural Database, see: Allen (2002[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~8~H~6~INS*M* *~r~* = 275.11Monoclinic,*a* = 8.3255 (3) Å*b* = 7.6967 (3) Å*c* = 13.8083 (5) Åβ = 90.686 (4)°*V* = 884.76 (6) Å^3^*Z* = 4Mo *K*α radiationμ = 3.79 mm^−1^*T* = 296 K0.47 × 0.38 × 0.14 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcalibur diffractometer with a Saphire-3 CCD detectorAbsorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009[@bb11]) *T* ~min~ = 0.253, *T* ~max~ = 0.65813190 measured reflections1928 independent reflections1729 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.027 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.024*wR*(*F* ^2^) = 0.064*S* = 1.061928 reflections101 parametersH-atom parameters constrainedΔρ~max~ = 0.84 e Å^−3^Δρ~min~ = −0.72 e Å^−3^ {#d5e416} Data collection: *CrysAlis PRO* (Oxford Diffraction, 2009[@bb11]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb15]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb15]); molecular graphics: *ORTEP-3* (Farrugia, 1997[@bb6]) and *Mercury* (Macrae *et al.*, 2006[@bb9]); software used to prepare material for publication: *SHELXL97* and *PLATON* (Spek, 2009[@bb17]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811004570/fj2389sup1.cif](http://dx.doi.org/10.1107/S1600536811004570/fj2389sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004570/fj2389Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004570/fj2389Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?fj2389&file=fj2389sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?fj2389sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?fj2389&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [FJ2389](http://scripts.iucr.org/cgi-bin/sendsup?fj2389)). This research was supported by the Ministry of Science, Education and Sports of the Republic of Croatia, Zagreb (grant Nos. 119--1193079--1332 and 119--1191342--1339). Comment ======= This work was a part of our preparative, structural, mechanistic and computational investigation of a series of substituted benzothiazoles (bta), which attract considerable interest due to their biological activities. The molecule is almost ideally planar (r.m.s. deviation = 0.009 Å), with the largest deviation from the plane being that of atom I1 \[0.075 (3) Å\] (Fig.1). The geometry of the benzothiazole rings is consistent with other 1,3-benzothiazoles listed in the CSD base (Allen *et al.*, 2002). The two S---C bonds of the thiazole ring \[S1---C1 and S1---C2\] differ with respect to each other, but both are within two bortherline cases, single S---C \[1.82 Å\] and double S=C \[1.56 Å\], while the endocyclic C---N bond is dominantly double in character. The differences in C---C bonds within benzene ring are common for such fused rings. In the crystal structure halogen bonds are the principal specific interactions responsible for the crystal packing. There is only one short and directional C---I···N contact \[C---I = 2.103 (3) Å\] (see Table 1) that link the molecules into antiparallel zigzag C(7) chains (Etter, 1990; Bernstein *et al.*, 1995) in \[1 0 - 1\] direction (Figs. 2 and 3). Relatively short off-set π--π contacts \[*C*g···*C*g = 3.758 (2) Å\] between the thiazole rings, belonging to the molecules that are related by an inversion centre, link the neighboring supramolecular chains and provide the secondary interactions for building the crystal structure. The structure of the title compound is one more example showing that halogen bonding is also as effective and reliable tool for assembling molecules into supramolecular architectures. Experimental {#experimental} ============ Colourless single crystals of the title compound were obtained by slow evaporation of a dichloromethane solution. Refinement {#refinement} ========== All H atoms were placed in geometrically idealized positions and constrained to ride on their parent C atom at distances of 0.93 or 0.96 Å for aromatic or methyl H atoms, respectively, and with *U*~iso~(H) = 1.2*U*~eq~(C) (for aromatic H) or *U*~iso~(H) = 1.5*U*~eq~(C) (for methyl group). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Molecular structure of the title compound with the atom labeling scheme. Displacement ellipsoids for non-H atoms are drawn at the 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Crystal packing of the title compound viewed down the b axis showing halogen bonds as dashed lines. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### Spacefill representaton of a zigzag halogen bonding chain running in \[1 0 - 1\]. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e152 .table-wrap} ------------------------- ---------------------------------------- C~8~H~6~INS *F*(000) = 520 *M~r~* = 275.11 *D*~x~ = 2.065 Mg m^−3^ Monoclinic, *P*2~1~/*n* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2yn Cell parameters from 10010 reflections *a* = 8.3255 (3) Å θ = 4.4--32.6° *b* = 7.6967 (3) Å µ = 3.79 mm^−1^ *c* = 13.8083 (5) Å *T* = 296 K β = 90.686 (4)° Plate, colourless *V* = 884.76 (6) Å^3^ 0.47 × 0.38 × 0.14 mm *Z* = 4 ------------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e277 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction Xcalibur diffractometer with a Saphire-3 CCD detector 1928 independent reflections Radiation source: Enhance (Mo) X-ray Source 1729 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.027 Detector resolution: 16.3426 pixels mm^-1^ θ~max~ = 27.0°, θ~min~ = 4.6° CCD scans *h* = −10→10 Absorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009) *k* = −9→9 *T*~min~ = 0.253, *T*~max~ = 0.658 *l* = −17→17 13190 measured reflections ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e395 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.024 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.064 H-atom parameters constrained *S* = 1.06 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0397*P*)^2^ + 0.4162*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 1928 reflections (Δ/σ)~max~ = 0.001 101 parameters Δρ~max~ = 0.84 e Å^−3^ 0 restraints Δρ~min~ = −0.72 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e552 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Experimental. Solvent used: CH~2~Cl~2~ Crystal mount: glued on a glass fibre Mosaicity (°): 1.1 (1) Frames collected: 892 Seconds exposure per frame: 5 Degree rotation per frame: 1.0 Crystal-Detector distance (mm): 50.0. Geometry. Bond distances, angles *etc*. have been calculated using the rounded fractional coordinates. All su\'s are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.\'s are taken into account in the estimation of distances, angles and torsion angles Refinement. Refinement on *F*^2^ for ALL reflections except those flagged by the user for potential systematic errors. Weighted *R*-factors *wR* and all goodnesses of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The observed criterion of *F*^2^ \> σ(*F*^2^) is used only for calculating -*R*-factor-obs *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*-factors based on ALL data will be even larger. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e666 .table-wrap} ----- -------------- ------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ I1 0.96733 (2) 0.14994 (3) 0.30624 (1) 0.0485 (1) S1 0.66879 (11) 0.75187 (9) 0.49021 (6) 0.0518 (3) N1 0.6453 (3) 0.5615 (3) 0.64355 (18) 0.0447 (8) C1 0.6117 (4) 0.7135 (4) 0.6097 (2) 0.0457 (9) C2 0.7440 (3) 0.5425 (3) 0.4842 (2) 0.0392 (8) C3 0.8155 (3) 0.4585 (4) 0.40718 (19) 0.0430 (8) C4 0.8633 (3) 0.2887 (4) 0.42068 (19) 0.0399 (8) C5 0.8427 (4) 0.2058 (4) 0.5097 (2) 0.0452 (9) C6 0.7728 (4) 0.2900 (4) 0.5857 (2) 0.0467 (9) C7 0.7211 (3) 0.4614 (3) 0.5734 (2) 0.0386 (7) C8 0.5343 (5) 0.8546 (4) 0.6669 (3) 0.0600 (11) H3 0.83070 0.51470 0.34840 0.0520\* H5 0.87710 0.09160 0.51740 0.0540\* H6 0.75980 0.23380 0.64480 0.0560\* H8A 0.46780 0.80420 0.71580 0.0900\* H8B 0.46950 0.92540 0.62460 0.0900\* H8C 0.61580 0.92510 0.69710 0.0900\* ----- -------------- ------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e907 .table-wrap} ---- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ I1 0.0488 (1) 0.0567 (2) 0.0402 (1) 0.0012 (1) 0.0048 (1) −0.0055 (1) S1 0.0658 (5) 0.0376 (4) 0.0518 (4) 0.0063 (3) −0.0035 (3) 0.0058 (3) N1 0.0487 (13) 0.0419 (13) 0.0437 (13) −0.0022 (10) 0.0082 (10) −0.0014 (10) C1 0.0416 (14) 0.0411 (14) 0.0543 (17) −0.0019 (12) −0.0027 (12) −0.0054 (12) C2 0.0424 (14) 0.0345 (12) 0.0407 (13) −0.0029 (11) −0.0035 (11) 0.0049 (11) C3 0.0482 (15) 0.0457 (14) 0.0351 (13) −0.0040 (12) −0.0001 (11) 0.0075 (12) C4 0.0393 (14) 0.0457 (14) 0.0347 (13) −0.0025 (11) 0.0025 (11) −0.0027 (11) C5 0.0536 (16) 0.0347 (13) 0.0474 (16) 0.0044 (12) 0.0043 (13) 0.0030 (11) C6 0.0593 (18) 0.0394 (13) 0.0415 (15) −0.0005 (13) 0.0114 (13) 0.0073 (12) C7 0.0396 (13) 0.0364 (12) 0.0399 (13) −0.0035 (11) 0.0037 (10) 0.0013 (10) C8 0.062 (2) 0.0511 (19) 0.067 (2) 0.0089 (15) −0.0004 (17) −0.0108 (15) ---- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1152 .table-wrap} ------------------- ------------- ------------------- ------------- I1---C4 2.103 (3) C4---C5 1.397 (4) S1---C1 1.748 (3) C5---C6 1.369 (4) S1---C2 1.731 (2) C6---C7 1.397 (4) N1---C1 1.289 (4) C3---H3 0.9300 N1---C7 1.395 (4) C5---H5 0.9300 C1---C8 1.494 (5) C6---H6 0.9300 C2---C3 1.385 (4) C8---H8A 0.9600 C2---C7 1.396 (4) C8---H8B 0.9600 C3---C4 1.378 (4) C8---H8C 0.9600 I1···C1^i^ 3.826 (3) H3···H8A^vii^ 2.5800 I1···N1^ii^ 3.158 (2) H5···S1^viii^ 3.1600 I1···H5^iii^ 3.3100 H5···I1^iii^ 3.3100 S1···H5^iv^ 3.1600 H5···H5^iii^ 2.5400 S1···H8B^v^ 3.1600 H8A···H3^ix^ 2.5800 N1···I1^vi^ 3.158 (2) H8B···S1^v^ 3.1600 C1···I1^i^ 3.826 (3) C1---S1---C2 89.46 (14) N1---C7---C6 125.3 (2) C1---N1---C7 110.3 (2) C2---C7---C6 119.0 (2) S1---C1---N1 115.8 (2) C2---C3---H3 121.00 S1---C1---C8 120.0 (2) C4---C3---H3 121.00 N1---C1---C8 124.1 (3) C4---C5---H5 119.00 S1---C2---C3 129.1 (2) C6---C5---H5 120.00 S1---C2---C7 108.70 (19) C5---C6---H6 120.00 C3---C2---C7 122.2 (2) C7---C6---H6 120.00 C2---C3---C4 117.7 (2) C1---C8---H8A 110.00 I1---C4---C3 120.06 (19) C1---C8---H8B 110.00 I1---C4---C5 119.0 (2) C1---C8---H8C 109.00 C3---C4---C5 120.9 (3) H8A---C8---H8B 109.00 C4---C5---C6 121.1 (3) H8A---C8---H8C 109.00 C5---C6---C7 119.1 (3) H8B---C8---H8C 109.00 N1---C7---C2 115.7 (2) C2---S1---C1---N1 0.5 (3) S1---C2---C7---C6 180.0 (2) C2---S1---C1---C8 178.5 (3) C3---C2---C7---N1 −179.1 (2) C1---S1---C2---C3 179.0 (3) C3---C2---C7---C6 0.4 (4) C1---S1---C2---C7 −0.6 (2) C2---C3---C4---I1 178.41 (19) C7---N1---C1---S1 −0.3 (3) C2---C3---C4---C5 −1.1 (4) C7---N1---C1---C8 −178.2 (3) I1---C4---C5---C6 −178.8 (2) C1---N1---C7---C2 −0.2 (3) C3---C4---C5---C6 0.8 (5) C1---N1---C7---C6 −179.6 (3) C4---C5---C6---C7 0.2 (5) S1---C2---C3---C4 −179.0 (2) C5---C6---C7---N1 178.6 (3) C7---C2---C3---C4 0.6 (4) C5---C6---C7---C2 −0.8 (4) S1---C2---C7---N1 0.5 (3) ------------------- ------------- ------------------- ------------- ::: Symmetry codes: (i) −*x*+2, −*y*+1, −*z*+1; (ii) *x*+1/2, −*y*+1/2, *z*−1/2; (iii) −*x*+2, −*y*, −*z*+1; (iv) *x*, *y*+1, *z*; (v) −*x*+1, −*y*+2, −*z*+1; (vi) *x*−1/2, −*y*+1/2, *z*+1/2; (vii) *x*+1/2, −*y*+3/2, *z*−1/2; (viii) *x*, *y*−1, *z*; (ix) *x*−1/2, −*y*+3/2, *z*+1/2. Table 1 Halogen-bond geometry (Å, °) {#d1e1692} ==================================== ::: {#d1e1704 .table-wrap} ------------------- ----------- ------------ -------------- ----------------- C4---I1 I1···N1^i^ C4···N1*^i^* C4---I1···N1^i^ C4---I1···N1*^i^* 2.103 (3) 3.158 (2) 5.257 (4) 175.99 (9) ------------------- ----------- ------------ -------------- ----------------- ::: Symmetry code: (i) 1/2 + *x*, 1/2--*y*, --1/2 + *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Halogen-bond geometry (Å, °) :::   C4---I1 I1⋯N1^i^ C4⋯N1^*i*^ C4---I1⋯N1^i^ ----------------- ----------- ----------- ------------ --------------- C4---I1⋯N1^*i*^ 2.103 (3) 3.158 (2) 5.257 (4) 175.99 (9) Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.575048

2011-2-12

PMC3051963

Related literature {#sec1} ================== For the double Mannich condensation reaction, see: Guthmann *et al.* (2009[@bb4]); Coates *et al.* (1994[@bb2]); Barker *et al.* (2002[@bb1]). For the methyl­ation of the β-keto ester in the synthesis of the title compound, see: Weiler (1970[@bb7]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~18~H~21~NO~3~*M* *~r~* = 299.36Orthorhombic,*a* = 10.795 (2) Å*b* = 14.386 (3) Å*c* = 9.797 (2) Å*V* = 1521.5 (5) Å^3^*Z* = 4Mo *K*α radiationμ = 0.09 mm^−1^*T* = 293 K0.20 × 0.20 × 0.20 mm ### Data collection {#sec2.1.2} Rigaku Saturn 724 diffractometer10268 measured reflections1584 independent reflections1546 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.045 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.067*wR*(*F* ^2^) = 0.167*S* = 1.161584 reflections200 parameters1 restraintH-atom parameters constrainedΔρ~max~ = 0.15 e Å^−3^Δρ~min~ = −0.16 e Å^−3^ {#d5e383} Data collection: *CrystalClear* (Rigaku/MSC, 2005[@bb5]); cell refinement: *CrystalClear*; data reduction: *CrystalClear*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb6]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb6]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb3]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S160053681100300X/xu5143sup1.cif](http://dx.doi.org/10.1107/S160053681100300X/xu5143sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S160053681100300X/xu5143Isup2.hkl](http://dx.doi.org/10.1107/S160053681100300X/xu5143Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?xu5143&file=xu5143sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?xu5143sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?xu5143&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [XU5143](http://scripts.iucr.org/cgi-bin/sendsup?xu5143)). The work was supported by the National Natural Science Foundation of China (grant No. 30873147). Comment ======= The AE rings of diterpenoid alkaloids have received much attention as key intermediate in the total syntheses of diterpenoid alkaloids. Double Mannich condensation (Guthmann *et al.*, 2009; Coates *et al.*, 1994; Barker *et al.*, 2002) is an efficient method to append the E ring to the A ring. Therefore, we have designed and synthesized the racemic 1-substituted AE-bicyclic analogue by double Mannich condensation. Herein, we report the structure of the title compound. As illustrated in Fig. 1, the molecule of the title compound is constructed from the fusion of a cyclohexanone ring, a piperidine ring and a furanone ring. The two six-membered rings are in standard chair conformations. The furanone ring is *cis*-fused with the cyclohexanone ring and adopts envelope conformation. The bond angles around C4 and C5 are indicative of *sp*^2^ hybridization for the two atoms. And the strain in the furanone ring is illustrated by the much distorted triangular geometry of C4 atom and the bond angles around C4 range between 109.7 (4) and 128.6 (5)°. Experimental {#experimental} ============ The intermediate, 6-methyltetrahydroisobenzofuran-1,7(3H,7aH)-dione (1b), was synthesized according to the procedure described by Weiler (1970). A solution of tetrahydroisobenzofuran-1,7(3H,7aH)-dione (1.00 g, 6.49 mmol) in THF (10 mL) was added to 1M lithium diisopropylamide solution in THF (14.2 ml, 14.2 mmol) at 273 K. After 30 min, CH~3~I (0.48 ml, 7.71 mmol) was added dropwise in the mixture. Then the mixture was stirred at the same temperature for 2 h. H~2~O (20 mL) was added and the solution was extracted with CH~2~Cl~2~ (60 mL). The organic layer was dried over anhydrous Na~2~SO~4~ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate/hexane, v:v, 1:2) to give 1b. (0.382 g, yield 35%) as a colourless oil. To a solution of 1b (200 mg, 1.19 mmol) in EtOH (300 mL) was added 37% CH~2~O solution (0.29 mL, 3.57 mmol) and phenylmethanamine (195 µL, 1.79 mmol). The reaction mixture was refluxing for 48 h and then concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate/hexane, v:v, 1:4) to give the title compound (107 mg, yield 30%) as a white solid. Crystallization from a ethyl acetate-petroleum ether system yielded colourless crystals suitable for single-crystal structure determination. Refinement {#refinement} ========== H atoms were fixed geometrically and treated as riding, with C---H = 0.98 (methine), 0.97 (methylene), 0.96 (methyl) or 0.93 Å (aromatic) and *U*~iso~(H) = 1.5*U*~eq~(C) for methyl groups and *U*~iso~(H) = 1.2*U*~eq~(C) for the others. A total of 1163 Friedel pairs were merged before final refinement as there is no significant anomalous dispersion for the determination of the absolute configuration. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound, showing the atom-numbering scheme with displacement ellipsoids at 30% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e152 .table-wrap} ------------------------- --------------------------------------- C~18~H~21~NO~3~ *F*(000) = 640 *M~r~* = 299.36 *D*~x~ = 1.307 Mg m^−3^ Orthorhombic, *Pna*2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2c -2n Cell parameters from 3565 reflections *a* = 10.795 (2) Å θ = 2.5--27.5° *b* = 14.386 (3) Å µ = 0.09 mm^−1^ *c* = 9.797 (2) Å *T* = 293 K *V* = 1521.5 (5) Å^3^ Prism, colourless *Z* = 4 0.20 × 0.20 × 0.20 mm ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e274 .table-wrap} ------------------------------------------ -------------------------------------- Rigaku Saturn 724 diffractometer 1546 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.045 graphite θ~max~ = 26.0°, θ~min~ = 2.5° ω scans *h* = −12→13 10268 measured reflections *k* = −17→17 1584 independent reflections *l* = −10→12 ------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e369 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.067 H-atom parameters constrained *wR*(*F*^2^) = 0.167 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0752*P*)^2^ + 0.8271*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.16 (Δ/σ)~max~ \< 0.001 1584 reflections Δρ~max~ = 0.15 e Å^−3^ 200 parameters Δρ~min~ = −0.16 e Å^−3^ 1 restraint Absolute structure: unk Primary atom site location: structure-invariant direct methods ---------------------------------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e530 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. For 6-methyltetrahydroisobenzofuran-1,7(3H, 7aH)-dione (1b), ^1^H NMR (400 MHz, CDCl~3~): δ 4.28 (dd, J = 9.2, 4.8 Hz, 1H), 4.15 (d, J = 9.2 Hz, 1H), 3.46(d, J = 7.2 Hz,1H), 2.97--2.91 (m, 1H), 2.40--2.34 (m, 1H), 2.07--2.03 (m, 2H), 1.79--1.69 (m, 1H), 1.49--1.40 (m, 1H), 1.09(d, J = 6.0 Hz, 3H); ^13^C NMR (100 MHz CDCl~3~): δ 204.3, 172.2, 72.1, 54.4, 44.0, 40.7, 32.5, 26.9, 14.2.For 5-benzyl-7-methylhexahydro-1H-3a,7-methanofuro \[3,4-c\]azocine- 3,10(4H)-dione (1), ^1^H NMR (400 MHz, CDCl~3~): δ 7.37--7.27(m, 5H), 4.29 (t, J = 9.2 Hz, 1H), 3.83 (dd, J =9.2, 10.4 Hz, 1H), 3.61, 3.51 (ABq, J = 13.0 Hz, 2H), 3.14--3.12(m, 1H), 3.07, 2.85 (ABq, J = 11.2 Hz, 2H), 3.05, 2.38 (ABx, J = 2.4, 12.0 Hz, 2H), 2.81--2.75 (m, 1H), 2.26--2.20 (m, 1H), 1.92--1.87 (m, 1H), 1.44--1.38 (m, 1H), 0.99 (s, 3H); ^13^C NMR (100 MHz, CDC~l3~): δ 210.7, 173.4, 137.7, 128.7, 128.5, 127.5, 69.2, 65.8, 61.5, 59.8, 58.6, 47.5, 46.1, 39.2, 22.0, 20.7 Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e675 .table-wrap} ------ ------------ ------------ ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O1 0.4992 (4) 1.0732 (2) 0.3736 (5) 0.0579 (10) O2 0.6479 (3) 0.9870 (3) 0.2802 (5) 0.0630 (11) O3 0.5495 (4) 0.8809 (3) 0.5463 (4) 0.0635 (11) N1 0.3480 (3) 0.7803 (3) 0.2454 (4) 0.0389 (9) C1 0.3691 (5) 1.0624 (4) 0.4104 (7) 0.0556 (14) H1B 0.3216 1.1164 0.3825 0.067\* H1A 0.3601 1.0542 0.5082 0.067\* C2 0.3259 (4) 0.9760 (3) 0.3343 (5) 0.0424 (11) H2 0.3083 0.9938 0.2398 0.051\* C3 0.4465 (4) 0.9178 (3) 0.3349 (5) 0.0346 (10) C4 0.5441 (5) 0.9930 (4) 0.3236 (5) 0.0443 (11) C5 0.4612 (4) 0.8689 (3) 0.4713 (5) 0.0371 (11) C6 0.3570 (4) 0.8020 (3) 0.4992 (5) 0.0405 (11) C7 0.2386 (4) 0.8628 (4) 0.5110 (6) 0.0483 (12) H7A 0.1679 0.8219 0.5225 0.058\* H7B 0.2452 0.9004 0.5929 0.058\* C8 0.2129 (4) 0.9273 (4) 0.3903 (6) 0.0465 (12) H8A 0.1754 0.8912 0.3176 0.056\* H8B 0.1532 0.9739 0.4186 0.056\* C9 0.3758 (6) 0.7484 (4) 0.6313 (6) 0.0606 (15) H9B 0.4532 0.7157 0.6276 0.091\* H9A 0.3094 0.7046 0.6428 0.091\* H9C 0.3765 0.7909 0.7068 0.091\* C10 0.3545 (5) 0.7331 (3) 0.3766 (6) 0.0442 (11) H10B 0.4286 0.6950 0.3792 0.053\* H10A 0.2835 0.6923 0.3858 0.053\* C11 0.4512 (4) 0.8433 (3) 0.2246 (5) 0.0401 (11) H11B 0.4455 0.8718 0.1350 0.048\* H11A 0.5289 0.8096 0.2300 0.048\* C12 0.3250 (5) 0.7190 (4) 0.1294 (6) 0.0476 (12) H12B 0.3046 0.7575 0.0513 0.057\* H12A 0.2523 0.6819 0.1500 0.057\* C13 0.4275 (4) 0.6538 (3) 0.0878 (5) 0.0386 (11) C14 0.5080 (6) 0.6763 (4) −0.0179 (6) 0.0583 (15) H14 0.4984 0.7322 −0.0644 0.070\* C15 0.6027 (6) 0.6160 (5) −0.0545 (7) 0.0690 (19) H15 0.6555 0.6315 −0.1260 0.083\* C16 0.6189 (6) 0.5334 (5) 0.0141 (7) 0.0663 (18) H16 0.6829 0.4934 −0.0098 0.080\* C17 0.5400 (6) 0.5112 (4) 0.1175 (7) 0.0635 (17) H17 0.5504 0.4554 0.1641 0.076\* C18 0.4448 (5) 0.5703 (3) 0.1542 (6) 0.0470 (12) H18 0.3916 0.5535 0.2246 0.056\* ------ ------------ ------------ ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1240 .table-wrap} ----- ----------- ------------- ----------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.071 (2) 0.0449 (19) 0.058 (2) −0.0122 (18) 0.002 (2) −0.005 (2) O2 0.045 (2) 0.072 (3) 0.072 (3) −0.0190 (19) 0.010 (2) −0.007 (2) O3 0.052 (2) 0.083 (3) 0.056 (3) −0.010 (2) −0.0164 (19) 0.003 (2) N1 0.038 (2) 0.040 (2) 0.039 (2) 0.0011 (17) −0.0009 (17) −0.0094 (17) C1 0.059 (3) 0.043 (3) 0.065 (4) 0.010 (2) 0.010 (3) −0.006 (3) C2 0.041 (2) 0.045 (3) 0.042 (3) 0.011 (2) −0.004 (2) −0.001 (2) C3 0.032 (2) 0.035 (2) 0.037 (2) −0.0028 (18) 0.0027 (18) −0.0030 (18) C4 0.053 (3) 0.044 (3) 0.037 (3) −0.007 (2) −0.007 (2) −0.005 (2) C5 0.031 (2) 0.043 (2) 0.038 (3) 0.0065 (19) −0.0019 (19) −0.009 (2) C6 0.044 (2) 0.038 (2) 0.040 (3) −0.002 (2) 0.002 (2) 0.001 (2) C7 0.038 (2) 0.055 (3) 0.052 (3) 0.000 (2) 0.010 (2) −0.009 (3) C8 0.034 (2) 0.056 (3) 0.050 (3) 0.015 (2) 0.002 (2) −0.005 (3) C9 0.077 (4) 0.059 (3) 0.045 (3) 0.002 (3) 0.003 (3) 0.007 (3) C10 0.044 (2) 0.037 (2) 0.052 (3) −0.004 (2) 0.002 (2) −0.012 (2) C11 0.042 (2) 0.038 (2) 0.040 (3) 0.000 (2) 0.000 (2) −0.005 (2) C12 0.040 (2) 0.053 (3) 0.050 (3) −0.001 (2) −0.007 (2) −0.013 (2) C13 0.037 (2) 0.040 (2) 0.039 (3) −0.009 (2) −0.006 (2) −0.013 (2) C14 0.075 (4) 0.055 (3) 0.045 (3) −0.012 (3) 0.010 (3) −0.011 (3) C15 0.058 (3) 0.084 (5) 0.065 (4) −0.018 (3) 0.021 (3) −0.033 (4) C16 0.052 (3) 0.078 (4) 0.068 (4) 0.012 (3) −0.004 (3) −0.041 (4) C17 0.069 (4) 0.051 (3) 0.070 (4) 0.014 (3) −0.022 (4) −0.022 (3) C18 0.055 (3) 0.042 (3) 0.044 (3) −0.004 (2) −0.001 (2) −0.010 (2) ----- ----------- ------------- ----------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1699 .table-wrap} ---------------------- ------------ ----------------------- ------------ O1---C1 1.458 (7) C8---H8A 0.9700 O1---C4 1.344 (6) C8---H8B 0.9700 O2---C4 1.202 (6) C9---H9B 0.9600 O3---C5 1.216 (6) C9---H9A 0.9600 N1---C10 1.455 (7) C9---H9C 0.9600 N1---C11 1.451 (6) C10---H10B 0.9700 N1---C12 1.460 (6) C10---H10A 0.9700 C1---H1B 0.9700 C11---H11B 0.9700 C1---H1A 0.9700 C11---H11A 0.9700 C1---C2 1.523 (7) C12---H12B 0.9700 C2---H2 0.9800 C12---H12A 0.9700 C2---C3 1.548 (6) C12---C13 1.507 (7) C2---C8 1.509 (7) C13---C14 1.389 (8) C3---C4 1.513 (7) C13---C18 1.380 (7) C3---C5 1.519 (7) C14---H14 0.9300 C3---C11 1.523 (6) C14---C15 1.388 (9) C5---C6 1.505 (7) C15---H15 0.9300 C6---C7 1.552 (7) C15---C16 1.376 (10) C6---C9 1.520 (8) C16---H16 0.9300 C6---C10 1.558 (7) C16---C17 1.362 (10) C7---H7A 0.9700 C17---H17 0.9300 C7---H7B 0.9700 C17---C18 1.382 (8) C7---C8 1.529 (8) C18---H18 0.9300 O1---C1---H1B 110.7 C6---C10---H10A 109.1 O1---C1---H1A 110.7 C7---C6---C10 113.7 (4) O1---C1---C2 105.2 (4) C7---C8---H8A 108.6 O1---C4---C3 109.7 (4) C7---C8---H8B 108.6 O2---C4---O1 121.8 (5) H7A---C7---H7B 107.4 O2---C4---C3 128.6 (5) C8---C2---C1 116.7 (4) O3---C5---C3 123.2 (4) C8---C2---H2 107.9 O3---C5---C6 124.5 (5) C8---C2---C3 115.3 (4) N1---C10---C6 112.7 (4) C8---C7---C6 115.7 (4) N1---C10---H10B 109.1 C8---C7---H7A 108.4 N1---C10---H10A 109.1 C8---C7---H7B 108.4 N1---C11---C3 108.4 (4) H8A---C8---H8B 107.6 N1---C11---H11B 110.0 C9---C6---C7 109.4 (4) N1---C11---H11A 110.0 C9---C6---C10 109.6 (4) N1---C12---H12B 107.9 H9B---C9---H9A 109.5 N1---C12---H12A 107.9 H9B---C9---H9C 109.5 N1---C12---C13 117.5 (4) H9A---C9---H9C 109.5 C1---C2---H2 107.9 C10---N1---C12 114.5 (4) C1---C2---C3 100.4 (4) H10B---C10---H10A 107.8 H1B---C1---H1A 108.8 C11---N1---C10 112.2 (4) C2---C1---H1B 110.7 C11---N1---C12 113.5 (4) C2---C1---H1A 110.7 C11---C3---C2 113.9 (4) C2---C8---C7 114.6 (4) H11B---C11---H11A 108.4 C2---C8---H8A 108.6 H12B---C12---H12A 107.2 C2---C8---H8B 108.6 C13---C12---H12B 107.9 C3---C2---H2 107.9 C13---C12---H12A 107.9 C3---C11---H11B 110.0 C13---C14---H14 119.8 C3---C11---H11A 110.0 C13---C18---C17 120.9 (6) C4---O1---C1 110.2 (4) C13---C18---H18 119.5 C4---C3---C2 101.5 (4) C14---C13---C12 121.1 (5) C4---C3---C5 108.9 (4) C14---C15---H15 119.8 C4---C3---C11 115.3 (4) C15---C14---C13 120.5 (6) C5---C3---C2 109.9 (4) C15---C14---H14 119.8 C5---C3---C11 107.1 (4) C15---C16---H16 120.4 C5---C6---C7 105.6 (4) C16---C15---C14 120.5 (6) C5---C6---C9 112.3 (4) C16---C15---H15 119.8 C5---C6---C10 106.2 (4) C16---C17---H17 119.5 C6---C5---C3 112.2 (4) C16---C17---C18 120.9 (7) C6---C7---H7A 108.4 C17---C16---C15 119.1 (6) C6---C7---H7B 108.4 C17---C16---H16 120.4 C6---C9---H9B 109.5 C17---C18---H18 119.5 C6---C9---H9A 109.5 C18---C13---C12 120.9 (5) C6---C9---H9C 109.5 C18---C13---C14 118.0 (5) C6---C10---H10B 109.1 C18---C17---H17 119.5 O1---C1---C2---C3 32.6 (5) C5---C6---C7---C8 54.1 (6) O1---C1---C2---C8 158.1 (4) C5---C6---C10---N1 −53.3 (5) O3---C5---C6---C7 117.6 (5) C6---C7---C8---C2 −41.8 (6) O3---C5---C6---C9 −1.6 (7) C7---C6---C10---N1 62.4 (5) O3---C5---C6---C10 −121.3 (5) C8---C2---C3---C4 −160.5 (4) N1---C12---C13---C14 −97.1 (6) C8---C2---C3---C5 −45.4 (5) N1---C12---C13---C18 82.4 (6) C8---C2---C3---C11 74.9 (6) C1---O1---C4---O2 176.2 (5) C9---C6---C7---C8 175.2 (5) C1---O1---C4---C3 −4.9 (6) C9---C6---C10---N1 −174.8 (4) C1---C2---C3---C4 −34.2 (5) C10---N1---C11---C3 −61.7 (5) C1---C2---C3---C5 80.9 (5) C10---N1---C12---C13 −69.9 (6) C1---C2---C3---C11 −158.8 (4) C10---C6---C7---C8 −62.0 (6) C1---C2---C8---C7 −81.1 (6) C11---N1---C10---C6 58.3 (5) C2---C3---C4---O1 25.5 (5) C11---N1---C12---C13 60.8 (6) C2---C3---C4---O2 −155.7 (6) C11---C3---C4---O1 149.2 (4) C2---C3---C5---O3 −120.4 (5) C11---C3---C4---O2 −32.0 (8) C2---C3---C5---C6 61.7 (5) C11---C3---C5---O3 115.3 (5) C2---C3---C11---N1 −59.9 (5) C11---C3---C5---C6 −62.6 (4) C3---C2---C8---C7 36.4 (6) C12---N1---C10---C6 −170.3 (4) C3---C5---C6---C7 −64.6 (5) C12---N1---C11---C3 166.5 (4) C3---C5---C6---C9 176.2 (4) C12---C13---C14---C15 179.5 (5) C3---C5---C6---C10 56.5 (5) C12---C13---C18---C17 −179.0 (5) C4---O1---C1---C2 −18.5 (6) C13---C14---C15---C16 −0.6 (9) C4---C3---C5---O3 −10.1 (6) C14---C13---C18---C17 0.6 (7) C4---C3---C5---C6 172.1 (4) C14---C15---C16---C17 0.7 (9) C4---C3---C11---N1 −176.7 (4) C15---C16---C17---C18 −0.2 (9) C5---C3---C4---O1 −90.4 (5) C16---C17---C18---C13 −0.5 (8) C5---C3---C4---O2 88.4 (6) C18---C13---C14---C15 0.0 (7) C5---C3---C11---N1 61.9 (5) ---------------------- ------------ ----------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2655 .table-wrap} ---------------------------------------- Cg is the centroid of the phenyl ring. ---------------------------------------- ::: ::: {#d1e2659 .table-wrap} ------------------ --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C8---H8B···Cg^i^ 0.97 2.87 3.833 (6) 169 ------------------ --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1/2, *y*+1/2, *z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) *Cg* is the centroid of the phenyl ring. ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- --------- ------- ----------- ------------- C8---H8*B*⋯*Cg*^i^ 0.97 2.87 3.833 (6) 169 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.579542

2011-2-05

PMC3051964

Related literature {#sec1} ================== For coordination polymers, see: He *et al.* (2010[@bb5]). For related structures, see: Gou *et al.* (2010[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~12~H~20~N~3~ ^+^·Cl^−^*M* *~r~* = 241.76Orthorhombic,*a* = 5.5256 (10) Å*b* = 13.928 (2) Å*c* = 16.685 (3) Å*V* = 1284.1 (4) Å^3^*Z* = 4Mo *K*α radiationμ = 0.28 mm^−1^*T* = 291 K0.25 × 0.20 × 0.18 mm ### Data collection {#sec2.1.2} Bruker SMART APEX CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1995[@bb6]) *T* ~min~ = 0.934, *T* ~max~ = 0.9525296 measured reflections2516 independent reflections2259 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.019 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.041*wR*(*F* ^2^) = 0.102*S* = 1.062516 reflections145 parametersH-atom parameters constrainedΔρ~max~ = 0.26 e Å^−3^Δρ~min~ = −0.24 e Å^−3^Absolute structure: Flack (1983[@bb3]), 1031 Friedel pairsFlack parameter: −0.04 (8) {#d5e479} Data collection: *SMART* (Bruker, 2000[@bb1]); cell refinement: *SAINT-Plus* (Bruker, 2000[@bb1]); data reduction: *SAINT-Plus*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *ORTEPIII* (Burnett & Johnson, 1996[@bb2]) and *PLATON* (Spek, 2009[@bb8]); software used to prepare material for publication: *SHELXTL* (Sheldrick, 2008[@bb7]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005526/bt5470sup1.cif](http://dx.doi.org/10.1107/S1600536811005526/bt5470sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005526/bt5470Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005526/bt5470Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?bt5470&file=bt5470sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?bt5470sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?bt5470&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BT5470](http://scripts.iucr.org/cgi-bin/sendsup?bt5470)). The authors thank the Program for Young Excellent Talents in Southeast University for financial support. Comment ======= Recent years have witnessed an explosion of great interest in chiral coordination polymers because of their potential utility in enantiomerically selective catalysis and separations, second-order nonlinearoptical (NLO) applications and magnetism (He *et al.* 2010). We tried to synthesize such polymers by use of chiral (1*R*,2*R*)-(pyridin-4-ylmethyl)cyclohexane-1,2-diamine ligand and zinc chloride. However, Zn(II) ions weren\'t ligated to the chiral ligands and the hydrochloride of the ligand has been obtained in the reaction conditions. Herein, we report the structure of this hydrochloride, 1.HCl \[1 = (1*R*,2*R*)-(pyridin-4-ylmethyl)cyclohexane-1,2-diamine\]. The asymmetric unit of the title compound contains a protonated (1*R*,2*R*)-(pyridin-4-ylmethyl)cyclohexane-1,2-diamine and a chloride ion. In the molecule, the distances of the C---N bonds of the pyridine ring are 1.331 (3) and 1.338 (3) Å, which are shorter than those of C---N bonds (1.452 (3), 1.478 (2) and 1.498 (2) Å) of cyclohexane-1,2-diamine. The protonated (1*R*,2*R*)-(pyridin-4-ylmethyl)cyclohexane-1,2-diamine cations and chloride anions are linked to each other, *via* N---H···N (N1···N3a 2.926 (2) Å, symmetry code: a, -1/2 + *x*, -3/2 - *y*, -1 - *z*) and N---H···Cl (N1···Cl1 3.201 (2) Å, N1···Cl1b 3.158 (2) Å, symmetry code: b, -1 + *x*, *y*, *z*) hydrogen bonds between the N atoms of aminium and the N atoms of adjacent pyridine rings, as well as the N atoms of aminium and chloride anions into a one-dimensional hydrogen bonding chain along the *a* axis (Fig.2), which are further constructed into a three-dimensional supramolecular network by interchain N---H···Cl hydrogen-bonds (N2···Cl1c 3.554 (2) Å, symmetry code: c, 1 - *x*, -1/2 + *y*, -1/2 - *z*) between secondary amines and chloride anions. Experimental {#experimental} ============ 1*R*,2*R*)-(pyridin-4-ylmethyl)cyclohexane-1,2-diamine (0.021 g, 0.1 mmol) dissolved in water (5 ml) was added to a methanol solution (10 ml) ZnCl~2~ (0.019 g, 0.1 mmol). The mixture solution was stirred for 2 h at room temperature and then filtered. The filtrate was allowed to evaporate slowly at room temperature. After 2 weeks, colorless block crystals were obtained in 33.1% yield (0.008 g). Refinement {#refinement} ========== All H atoms attached to C atoms were fixed geometrically and treated as riding with C---H = 0.93--0.97 Å with *U*~iso~(H) = 1.2 *U*~eq~(C). H atoms attached to N atoms were located in difference Fourier maps and included in the subsequent refinement using restraints (N---H= 0.89 (1) Å) with *U*~iso~(H) = 1.5 *U*~eq~(N). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### View of the asymmetric unit of the title compoundcompound with the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. H atoms are represented as small spheres of arbitrary radii. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### View of the one-dimesional hydrogen bonding chain along the a axis. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### View of the three-dimensional supramolecular network along the bc plane. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e209 .table-wrap} ------------------------------- -------------------------------------- C~12~H~20~N~3~^+^·Cl^−^ *F*(000) = 520 *M~r~* = 241.76 *D*~x~ = 1.251 Mg m^−3^ Orthorhombic, *P*2~1~2~1~2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2ac 2ab Cell parameters from 780 reflections *a* = 5.5256 (10) Å θ = 2.5--28.0° *b* = 13.928 (2) Å µ = 0.28 mm^−1^ *c* = 16.685 (3) Å *T* = 291 K *V* = 1284.1 (4) Å^3^ Block, colorless *Z* = 4 0.25 × 0.20 × 0.18 mm ------------------------------- -------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e339 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker SMART APEX CCD diffractometer 2516 independent reflections Radiation source: fine-focus sealed tube 2259 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.019 φ and ω scans θ~max~ = 26.0°, θ~min~ = 1.9° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1995) *h* = −6→6 *T*~min~ = 0.934, *T*~max~ = 0.952 *k* = −17→16 5296 measured reflections *l* = −6→20 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e456 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.041 H-atom parameters constrained *wR*(*F*^2^) = 0.102 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0552*P*)^2^ + 0.1405*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.06 (Δ/σ)~max~ \< 0.001 2516 reflections Δρ~max~ = 0.26 e Å^−3^ 145 parameters Δρ~min~ = −0.24 e Å^−3^ 0 restraints Absolute structure: Flack (1983), 1031 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: −0.04 (8) ---------------------------------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e621 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e720 .table-wrap} ------ -------------- --------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl1 0.80278 (10) −0.57398 (4) −0.18879 (4) 0.05595 (19) C1 0.2910 (4) −0.76369 (13) −0.19230 (10) 0.0334 (4) H1A 0.1413 −0.7975 −0.2063 0.040\* C2 0.2862 (4) −0.74096 (15) −0.10296 (10) 0.0411 (5) H2A 0.4249 −0.7015 −0.0894 0.049\* H2B 0.1410 −0.7048 −0.0905 0.049\* C3 0.2912 (5) −0.83212 (16) −0.05335 (12) 0.0500 (6) H3A 0.2945 −0.8158 0.0032 0.060\* H3B 0.1459 −0.8692 −0.0636 0.060\* C4 0.5108 (5) −0.89136 (16) −0.07397 (12) 0.0489 (6) H4A 0.5090 −0.9502 −0.0429 0.059\* H4B 0.6559 −0.8560 −0.0599 0.059\* C5 0.5163 (5) −0.91576 (15) −0.16282 (12) 0.0464 (5) H5A 0.3803 −0.9571 −0.1754 0.056\* H5B 0.6636 −0.9509 −0.1746 0.056\* C6 0.5051 (4) −0.82635 (13) −0.21600 (10) 0.0341 (4) H6A 0.6531 −0.7892 −0.2067 0.041\* C7 0.7097 (5) −0.89100 (19) −0.33387 (12) 0.0534 (6) H7A 0.7163 −0.9575 −0.3168 0.064\* H7B 0.8493 −0.8583 −0.3116 0.064\* C8 0.7219 (4) −0.88678 (13) −0.42405 (11) 0.0371 (5) C9 0.9147 (4) −0.84386 (15) −0.46266 (14) 0.0439 (5) H9A 1.0437 −0.8198 −0.4330 0.053\* C10 0.9160 (5) −0.83668 (16) −0.54485 (14) 0.0476 (6) H10A 1.0495 −0.8084 −0.5693 0.057\* C11 0.5538 (4) −0.91212 (16) −0.55406 (12) 0.0447 (5) H11A 0.4288 −0.9367 −0.5852 0.054\* C12 0.5397 (4) −0.92329 (16) −0.47230 (12) 0.0432 (5) H12A 0.4087 −0.9551 −0.4495 0.052\* N1 0.2983 (3) −0.67078 (11) −0.23746 (9) 0.0377 (4) H1B 0.3011 −0.6827 −0.2899 0.057\* H1C 0.4305 −0.6382 −0.2237 0.057\* H1D 0.1676 −0.6362 −0.2256 0.057\* N2 0.4907 (3) −0.84717 (12) −0.30272 (9) 0.0380 (4) H2C 0.3781 −0.8927 −0.3056 0.057\* N3 0.7369 (4) −0.86795 (12) −0.59140 (10) 0.0447 (5) ------ -------------- --------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1333 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.0377 (3) 0.0491 (3) 0.0811 (4) 0.0058 (3) −0.0025 (3) 0.0005 (3) C1 0.0329 (9) 0.0365 (9) 0.0309 (9) 0.0019 (8) 0.0000 (9) 0.0007 (7) C2 0.0437 (12) 0.0489 (11) 0.0308 (9) 0.0119 (11) 0.0016 (9) −0.0052 (8) C3 0.0536 (13) 0.0626 (14) 0.0340 (10) 0.0020 (13) 0.0029 (10) 0.0052 (10) C4 0.0653 (16) 0.0475 (12) 0.0340 (10) 0.0102 (12) −0.0032 (11) 0.0073 (9) C5 0.0638 (15) 0.0375 (11) 0.0379 (10) 0.0082 (12) −0.0023 (10) −0.0008 (9) C6 0.0363 (11) 0.0359 (10) 0.0301 (9) 0.0041 (9) −0.0018 (8) −0.0026 (7) C7 0.0519 (13) 0.0710 (15) 0.0372 (10) 0.0208 (13) 0.0009 (10) −0.0047 (10) C8 0.0406 (12) 0.0354 (10) 0.0353 (9) 0.0088 (9) 0.0034 (9) −0.0056 (8) C9 0.0408 (12) 0.0395 (11) 0.0514 (12) −0.0010 (10) −0.0041 (10) −0.0065 (10) C10 0.0457 (13) 0.0437 (12) 0.0532 (13) −0.0009 (10) 0.0117 (11) 0.0075 (10) C11 0.0435 (12) 0.0491 (12) 0.0414 (11) −0.0011 (11) −0.0022 (9) −0.0093 (10) C12 0.0382 (11) 0.0475 (12) 0.0439 (11) −0.0031 (11) 0.0072 (9) −0.0033 (10) N1 0.0384 (9) 0.0403 (9) 0.0344 (8) 0.0069 (8) −0.0010 (7) −0.0009 (7) N2 0.0415 (10) 0.0421 (9) 0.0304 (8) 0.0065 (8) 0.0013 (8) −0.0049 (7) N3 0.0506 (12) 0.0458 (10) 0.0377 (8) 0.0048 (9) 0.0064 (8) −0.0002 (7) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1663 .table-wrap} ---------------- ------------- ------------------ ------------- C1---N1 1.498 (2) C7---N2 1.452 (3) C1---C6 1.523 (3) C7---C8 1.507 (3) C1---C2 1.524 (2) C7---H7A 0.9700 C1---H1A 0.9800 C7---H7B 0.9700 C2---C3 1.516 (3) C8---C9 1.381 (3) C2---H2A 0.9700 C8---C12 1.386 (3) C2---H2B 0.9700 C9---C10 1.375 (3) C3---C4 1.507 (3) C9---H9A 0.9300 C3---H3A 0.9700 C10---N3 1.331 (3) C3---H3B 0.9700 C10---H10A 0.9300 C4---C5 1.521 (3) C11---N3 1.338 (3) C4---H4A 0.9700 C11---C12 1.375 (3) C4---H4B 0.9700 C11---H11A 0.9300 C5---C6 1.530 (3) C12---H12A 0.9300 C5---H5A 0.9700 N1---H1B 0.8900 C5---H5B 0.9700 N1---H1C 0.8900 C6---N2 1.478 (2) N1---H1D 0.8900 C6---H6A 0.9800 N2---H2C 0.8899 N1---C1---C6 110.08 (15) C1---C6---H6A 107.7 N1---C1---C2 108.24 (14) C5---C6---H6A 107.7 C6---C1---C2 112.74 (16) N2---C7---C8 112.22 (19) N1---C1---H1A 108.6 N2---C7---H7A 109.2 C6---C1---H1A 108.6 C8---C7---H7A 109.2 C2---C1---H1A 108.6 N2---C7---H7B 109.2 C3---C2---C1 111.09 (16) C8---C7---H7B 109.2 C3---C2---H2A 109.4 H7A---C7---H7B 107.9 C1---C2---H2A 109.4 C9---C8---C12 116.63 (18) C3---C2---H2B 109.4 C9---C8---C7 121.1 (2) C1---C2---H2B 109.4 C12---C8---C7 122.2 (2) H2A---C2---H2B 108.0 C10---C9---C8 120.1 (2) C4---C3---C2 110.41 (19) C10---C9---H9A 120.0 C4---C3---H3A 109.6 C8---C9---H9A 120.0 C2---C3---H3A 109.6 N3---C10---C9 123.6 (2) C4---C3---H3B 109.6 N3---C10---H10A 118.2 C2---C3---H3B 109.6 C9---C10---H10A 118.2 H3A---C3---H3B 108.1 N3---C11---C12 123.8 (2) C3---C4---C5 111.15 (19) N3---C11---H11A 118.1 C3---C4---H4A 109.4 C12---C11---H11A 118.1 C5---C4---H4A 109.4 C11---C12---C8 119.6 (2) C3---C4---H4B 109.4 C11---C12---H12A 120.2 C5---C4---H4B 109.4 C8---C12---H12A 120.2 H4A---C4---H4B 108.0 C1---N1---H1B 109.5 C4---C5---C6 112.48 (16) C1---N1---H1C 109.5 C4---C5---H5A 109.1 H1B---N1---H1C 109.5 C6---C5---H5A 109.1 C1---N1---H1D 109.5 C4---C5---H5B 109.1 H1B---N1---H1D 109.5 C6---C5---H5B 109.1 H1C---N1---H1D 109.5 H5A---C5---H5B 107.8 C7---N2---C6 112.84 (16) N2---C6---C1 108.96 (15) C7---N2---H2C 105.3 N2---C6---C5 114.22 (15) C6---N2---H2C 103.3 C1---C6---C5 110.31 (16) C10---N3---C11 116.16 (17) N2---C6---H6A 107.7 ---------------- ------------- ------------------ ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2154 .table-wrap} --------------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1B···N3^i^ 0.89 2.13 2.926 (2) 148 N1---H1C···Cl1 0.89 2.32 3.201 (2) 172 N1---H1D···Cl1^ii^ 0.89 2.28 3.1583 (19) 170 N2---H2C···Cl1^iii^ 0.89 2.72 3.5538 (19) 157 --------------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) *x*−1/2, −*y*−3/2, −*z*−1; (ii) *x*−1, *y*, *z*; (iii) −*x*+1, *y*−1/2, −*z*−1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ------------- ------------- N1---H1*B*⋯N3^i^ 0.89 2.13 2.926 (2) 148 N1---H1*C*⋯Cl1 0.89 2.32 3.201 (2) 172 N1---H1*D*⋯Cl1^ii^ 0.89 2.28 3.1583 (19) 170 N2---H2*C*⋯Cl1^iii^ 0.89 2.72 3.5538 (19) 157 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.585965

2011-2-19

PMC3051965

Related literature {#sec1} ================== For background to diimine complexes and related structures, see: Dehghanpour *et al.* (2007[@bb4]); Mahmoudi *et al.* (2009[@bb3]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Hg~2~Cl~4~(C~12~H~9~N~3~O~2~)~2~\]*M* *~r~* = 997.42Monoclinic,*a* = 8.9731 (2) Å*b* = 7.8439 (3) Å*c* = 20.1403 (7) Åβ = 98.155 (2)°*V* = 1403.22 (8) Å^3^*Z* = 2Mo *K*α radiationμ = 11.35 mm^−1^*T* = 150 K0.18 × 0.16 × 0.14 mm ### Data collection {#sec2.1.2} Nonius KappaCCD diffractometerAbsorption correction: multi-scan (*SORTAV*; Blessing, 1995[@bb2]) *T* ~min~ = 0.115, *T* ~max~ = 0.22211428 measured reflections3197 independent reflections2639 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.055 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.028*wR*(*F* ^2^) = 0.064*S* = 1.063197 reflections181 parametersH-atom parameters constrainedΔρ~max~ = 0.94 e Å^−3^Δρ~min~ = −1.56 e Å^−3^ {#d5e446} Data collection: *COLLECT* (Nonius, 2002[@bb5]); cell refinement: *DENZO-SMN* (Otwinowski & Minor, 1997[@bb6]); data reduction: *DENZO-SMN*; program(s) used to solve structure: *SIR92* (Altomare *et al.*, 1994[@bb1]); program(s) used to refine structure: *SHELXTL* (Sheldrick, 2008[@bb7]); molecular graphics: *PLATON* (Spek, 2009[@bb8]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004703/gk2347sup1.cif](http://dx.doi.org/10.1107/S1600536811004703/gk2347sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004703/gk2347Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004703/gk2347Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?gk2347&file=gk2347sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?gk2347sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?gk2347&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [GK2347](http://scripts.iucr.org/cgi-bin/sendsup?gk2347)). We are grateful to Bu-Ali Sina and Alzahra Universities for financial support. Comment ======= In our ongoing studies on the synthesis, structural and spectroscopic characterization of transition metal complexes with diimine ligands (Dehghanpour *et al.,* 2007; Mahmoudi *et al.,* 2009), we report herein the crystal structure of the title complex. The title compound was prepared by the reaction of HgCl~2~ with (4-nitrophenyl)pyridin-2-ylmethyleneamine. The molecluar structure of the title complex is shown in Fig. 1. The unique Hg^II^ ion in is in a distorted square pyramidal coordination environment formed by a bis-chelating ligand, two bridging Cl atoms and one terminal Cl atom. Experimental {#experimental} ============ The title complex was prepared by the reaction of HgCl~2~ (22.7 mg, 0.1 mmol) and (4-nitrophenyl)pyridin-2-ylmethyleneamine (27.2 mg, 0.1mmol) in 15 ml acetonitrile at room temperature. The solution was then concentrated under vacuum, and diffusion of diethyl ether vapor into the concentrated solution gave yellow crystals of the title compound in 60% yield. Refinement {#refinement} ========== The H- atom positions were calculated and refined in a riding model approximatiom with *U*~iso~(H) = 1.2*U*~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the structure of the title complex, with displacement ellipsoids drawn at the 50% probability level. Symmetry code: (a) -x + 1, -y + 1, -z + 1. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e127 .table-wrap} -------------------------------------- --------------------------------------- \[Hg~2~Cl~4~(C~12~H~9~N~3~O~2~)~2~\] *F*(000) = 928 *M~r~* = 997.42 *D*~x~ = 2.361 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 6448 reflections *a* = 8.9731 (2) Å θ = 2.6--27.5° *b* = 7.8439 (3) Å µ = 11.35 mm^−1^ *c* = 20.1403 (7) Å *T* = 150 K β = 98.155 (2)° Block, colourless *V* = 1403.22 (8) Å^3^ 0.18 × 0.16 × 0.14 mm *Z* = 2 -------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e268 .table-wrap} -------------------------------------------------------------- -------------------------------------- Nonius KappaCCD diffractometer 3197 independent reflections Radiation source: fine-focus sealed tube 2639 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.055 Detector resolution: 9 pixels mm^-1^ θ~max~ = 27.6°, θ~min~ = 2.8° φ scans and ω scans with κ offsets *h* = −11→11 Absorption correction: multi-scan (*SORTAV*; Blessing, 1995) *k* = −9→10 *T*~min~ = 0.115, *T*~max~ = 0.222 *l* = −25→26 11428 measured reflections -------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e394 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.028 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.064 H-atom parameters constrained *S* = 1.06 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0234*P*)^2^ + 1.6835*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 3197 reflections (Δ/σ)~max~ = 0.001 181 parameters Δρ~max~ = 0.94 e Å^−3^ 0 restraints Δρ~min~ = −1.56 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e551 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e650 .table-wrap} ------ --------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Hg1 0.641245 (19) 0.62356 (2) 0.448116 (9) 0.02542 (8) Cl1 0.83299 (13) 0.45830 (16) 0.40698 (7) 0.0314 (3) Cl2 0.60508 (13) 0.60053 (14) 0.56941 (6) 0.0270 (3) O1 1.0314 (4) 1.2850 (5) 0.72381 (19) 0.0428 (9) O2 1.1963 (4) 1.0918 (5) 0.7078 (2) 0.0440 (10) N1 0.5013 (4) 0.7782 (5) 0.36266 (19) 0.0238 (8) N2 0.6929 (4) 0.9273 (5) 0.4652 (2) 0.0216 (8) N3 1.0753 (5) 1.1652 (5) 0.6919 (2) 0.0319 (10) C1 0.4077 (5) 0.7090 (6) 0.3123 (2) 0.0265 (10) H1A 0.3985 0.5884 0.3101 0.032\* C2 0.3234 (5) 0.8064 (7) 0.2632 (3) 0.0308 (11) H2A 0.2589 0.7531 0.2277 0.037\* C3 0.3344 (5) 0.9808 (7) 0.2663 (3) 0.0312 (11) H3A 0.2769 1.0502 0.2335 0.037\* C4 0.4315 (5) 1.0539 (6) 0.3187 (2) 0.0275 (10) H4A 0.4404 1.1744 0.3222 0.033\* C5 0.5152 (5) 0.9497 (6) 0.3657 (2) 0.0212 (9) C6 0.6209 (5) 1.0210 (6) 0.4202 (3) 0.0228 (10) H6A 0.6364 1.1408 0.4221 0.027\* C7 0.7901 (5) 0.9952 (6) 0.5209 (2) 0.0206 (9) C8 0.7776 (5) 1.1611 (6) 0.5433 (2) 0.0239 (10) H8A 0.7039 1.2351 0.5203 0.029\* C9 0.8717 (5) 1.2189 (6) 0.5988 (2) 0.0265 (10) H9A 0.8641 1.3324 0.6145 0.032\* C10 0.9778 (5) 1.1072 (6) 0.6314 (2) 0.0242 (10) C11 0.9934 (5) 0.9425 (6) 0.6092 (2) 0.0257 (10) H11A 1.0688 0.8696 0.6316 0.031\* C12 0.8981 (5) 0.8855 (6) 0.5542 (2) 0.0241 (10) H12A 0.9058 0.7717 0.5388 0.029\* ------ --------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1036 .table-wrap} ----- -------------- -------------- -------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Hg1 0.03088 (12) 0.01758 (11) 0.02789 (12) 0.00384 (7) 0.00446 (8) 0.00096 (8) Cl1 0.0311 (6) 0.0273 (6) 0.0363 (7) 0.0085 (5) 0.0069 (5) −0.0012 (5) Cl2 0.0332 (6) 0.0244 (6) 0.0233 (6) −0.0052 (4) 0.0035 (5) −0.0015 (5) O1 0.037 (2) 0.046 (2) 0.043 (2) −0.0073 (18) 0.0020 (17) −0.017 (2) O2 0.0277 (19) 0.055 (3) 0.045 (2) 0.0031 (17) −0.0075 (16) −0.0044 (19) N1 0.0249 (19) 0.022 (2) 0.025 (2) 0.0021 (16) 0.0057 (16) 0.0018 (17) N2 0.0210 (18) 0.0192 (19) 0.025 (2) 0.0007 (15) 0.0039 (15) 0.0047 (16) N3 0.026 (2) 0.037 (3) 0.033 (3) −0.0090 (18) 0.0047 (18) −0.003 (2) C1 0.029 (2) 0.026 (3) 0.024 (3) −0.003 (2) 0.0052 (19) 0.001 (2) C2 0.029 (2) 0.035 (3) 0.026 (3) −0.004 (2) −0.004 (2) −0.004 (2) C3 0.033 (3) 0.036 (3) 0.023 (3) 0.012 (2) 0.000 (2) 0.006 (2) C4 0.035 (3) 0.021 (2) 0.026 (3) 0.004 (2) 0.003 (2) 0.001 (2) C5 0.026 (2) 0.021 (2) 0.017 (2) 0.0034 (19) 0.0048 (18) 0.0020 (19) C6 0.027 (2) 0.013 (2) 0.029 (3) 0.0024 (18) 0.0064 (19) −0.001 (2) C7 0.019 (2) 0.019 (2) 0.024 (3) 0.0006 (17) 0.0067 (18) 0.0006 (19) C8 0.025 (2) 0.022 (2) 0.024 (3) 0.0018 (18) 0.0044 (19) 0.0039 (19) C9 0.025 (2) 0.020 (2) 0.035 (3) −0.0029 (19) 0.009 (2) −0.006 (2) C10 0.020 (2) 0.026 (3) 0.027 (3) −0.0062 (18) 0.0036 (18) −0.002 (2) C11 0.024 (2) 0.023 (2) 0.030 (3) 0.004 (2) 0.0027 (19) 0.004 (2) C12 0.022 (2) 0.020 (2) 0.031 (3) −0.0005 (18) 0.0053 (19) −0.001 (2) ----- -------------- -------------- -------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1422 .table-wrap} ----------------------------- ------------- ---------------------- ------------ Hg1---N1 2.323 (4) C3---C4 1.392 (7) Hg1---Cl1 2.3940 (11) C3---H3A 0.9500 Hg1---N2 2.442 (4) C4---C5 1.388 (6) Hg1---Cl2 2.5161 (12) C4---H4A 0.9500 Hg1---Cl2^i^ 2.8068 (11) C5---C6 1.457 (6) Cl2---Hg1^i^ 2.8068 (11) C6---H6A 0.9500 O1---N3 1.233 (5) C7---C8 1.387 (6) O2---N3 1.231 (5) C7---C12 1.394 (6) N1---C1 1.337 (6) C8---C9 1.380 (7) N1---C5 1.352 (6) C8---H8A 0.9500 N2---C6 1.272 (6) C9---C10 1.388 (7) N2---C7 1.423 (6) C9---H9A 0.9500 N3---C10 1.468 (6) C10---C11 1.381 (6) C1---C2 1.386 (7) C11---C12 1.375 (7) C1---H1A 0.9500 C11---H11A 0.9500 C2---C3 1.372 (7) C12---H12A 0.9500 C2---H2A 0.9500 N1---Hg1---Cl1 111.46 (10) C4---C3---H3A 120.7 N1---Hg1---N2 70.57 (13) C5---C4---C3 119.6 (5) Cl1---Hg1---N2 116.47 (9) C5---C4---H4A 120.2 N1---Hg1---Cl2 128.76 (9) C3---C4---H4A 120.2 Cl1---Hg1---Cl2 119.68 (4) N1---C5---C4 121.2 (4) N2---Hg1---Cl2 88.91 (9) N1---C5---C6 117.6 (4) N1---Hg1---Cl2^i^ 84.28 (9) C4---C5---C6 121.3 (4) Cl1---Hg1---Cl2^i^ 102.07 (4) N2---C6---C5 121.8 (4) N2---Hg1---Cl2^i^ 139.38 (9) N2---C6---H6A 119.1 Cl2---Hg1---Cl2^i^ 82.50 (4) C5---C6---H6A 119.1 Hg1---Cl2---Hg1^i^ 97.50 (4) C8---C7---C12 120.4 (4) C1---N1---C5 118.8 (4) C8---C7---N2 122.6 (4) C1---N1---Hg1 124.5 (3) C12---C7---N2 117.0 (4) C5---N1---Hg1 116.7 (3) C9---C8---C7 120.2 (4) C6---N2---C7 122.6 (4) C9---C8---H8A 119.9 C6---N2---Hg1 113.3 (3) C7---C8---H8A 119.9 C7---N2---Hg1 124.0 (3) C8---C9---C10 118.4 (4) O2---N3---O1 123.8 (4) C8---C9---H9A 120.8 O2---N3---C10 118.1 (4) C10---C9---H9A 120.8 O1---N3---C10 118.1 (4) C11---C10---C9 122.2 (4) N1---C1---C2 122.6 (5) C11---C10---N3 118.9 (4) N1---C1---H1A 118.7 C9---C10---N3 119.0 (4) C2---C1---H1A 118.7 C12---C11---C10 119.0 (4) C3---C2---C1 119.2 (5) C12---C11---H11A 120.5 C3---C2---H2A 120.4 C10---C11---H11A 120.5 C1---C2---H2A 120.4 C11---C12---C7 119.8 (4) C2---C3---C4 118.6 (4) C11---C12---H12A 120.1 C2---C3---H3A 120.7 C7---C12---H12A 120.1 N1---Hg1---Cl2---Hg1^i^ 76.43 (12) C1---N1---C5---C6 −178.4 (4) Cl1---Hg1---Cl2---Hg1^i^ −99.66 (5) Hg1---N1---C5---C6 2.7 (5) N2---Hg1---Cl2---Hg1^i^ 140.20 (9) C3---C4---C5---N1 −1.8 (7) Cl2^i^---Hg1---Cl2---Hg1^i^ 0.0 C3---C4---C5---C6 178.4 (4) Cl1---Hg1---N1---C1 68.2 (4) C7---N2---C6---C5 −176.3 (4) N2---Hg1---N1---C1 179.9 (4) Hg1---N2---C6---C5 1.9 (5) Cl2---Hg1---N1---C1 −108.1 (3) N1---C5---C6---N2 −3.2 (6) Cl2^i^---Hg1---N1---C1 −32.5 (3) C4---C5---C6---N2 176.7 (4) Cl1---Hg1---N1---C5 −112.9 (3) C6---N2---C7---C8 22.2 (7) N2---Hg1---N1---C5 −1.3 (3) Hg1---N2---C7---C8 −155.9 (3) Cl2---Hg1---N1---C5 70.7 (3) C6---N2---C7---C12 −159.7 (4) Cl2^i^---Hg1---N1---C5 146.3 (3) Hg1---N2---C7---C12 22.3 (5) N1---Hg1---N2---C6 −0.3 (3) C12---C7---C8---C9 −0.2 (7) Cl1---Hg1---N2---C6 104.6 (3) N2---C7---C8---C9 177.9 (4) Cl2---Hg1---N2---C6 −132.5 (3) C7---C8---C9---C10 −0.2 (7) Cl2^i^---Hg1---N2---C6 −55.3 (4) C8---C9---C10---C11 1.2 (7) N1---Hg1---N2---C7 177.8 (3) C8---C9---C10---N3 −177.9 (4) Cl1---Hg1---N2---C7 −77.2 (3) O2---N3---C10---C11 23.7 (6) Cl2---Hg1---N2---C7 45.7 (3) O1---N3---C10---C11 −156.4 (4) Cl2^i^---Hg1---N2---C7 122.8 (3) O2---N3---C10---C9 −157.1 (4) C5---N1---C1---C2 −0.4 (7) O1---N3---C10---C9 22.7 (6) Hg1---N1---C1---C2 178.4 (3) C9---C10---C11---C12 −1.8 (7) N1---C1---C2---C3 −0.8 (7) N3---C10---C11---C12 177.3 (4) C1---C2---C3---C4 0.7 (7) C10---C11---C12---C7 1.4 (7) C2---C3---C4---C5 0.5 (7) C8---C7---C12---C11 −0.5 (7) C1---N1---C5---C4 1.7 (6) N2---C7---C12---C11 −178.7 (4) Hg1---N1---C5---C4 −177.2 (3) ----------------------------- ------------- ---------------------- ------------ ::: Symmetry codes: (i) −*x*+1, −*y*+1, −*z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Selected bond lengths (Å) ::: -------------- ------------- Hg1---N1 2.323 (4) Hg1---Cl1 2.3940 (11) Hg1---N2 2.442 (4) Hg1---Cl2 2.5161 (12) Hg1---Cl2^i^ 2.8068 (11) -------------- ------------- Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.590519

2011-2-12

PMC3051966

Related literature {#sec1} ================== For the crystal structure of (*S*)-3-amino-4,4,4-trifluoro­butane­carb­oxy­lic acid, see: Soloshonok *et al.* (1993[@bb7]). For the graph-set analysis of hydrogen bonds, see: Etter *et al.* (1990[@bb3]); Bernstein *et al.* (1995[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~5~H~4~F~6~O~3~*M* *~r~* = 226.08Monoclinic,*a* = 5.5031 (2) Å*b* = 20.5490 (8) Å*c* = 14.0342 (6) Åβ = 98.4543 (14)°*V* = 1569.79 (11) Å^3^*Z* = 8Mo *K*α radiationμ = 0.24 mm^−1^*T* = 200 K0.59 × 0.45 × 0.33 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometer25936 measured reflections3897 independent reflections3469 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.014 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.038*wR*(*F* ^2^) = 0.100*S* = 1.043897 reflections257 parametersH-atom parameters constrainedΔρ~max~ = 0.42 e Å^−3^Δρ~min~ = −0.38 e Å^−3^ {#d5e494} Data collection: *APEX2* (Bruker, 2010[@bb2]); cell refinement: *SAINT* (Bruker, 2010[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb6]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb6]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb4]) and *Mercury* (Macrae *et al.*, 2006[@bb5]); software used to prepare material for publication: *SHELXL97* and *PLATON* (Spek, 2009[@bb8]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004764/gk2344sup1.cif](http://dx.doi.org/10.1107/S1600536811004764/gk2344sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004764/gk2344Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004764/gk2344Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?gk2344&file=gk2344sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?gk2344sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?gk2344&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [GK2344](http://scripts.iucr.org/cgi-bin/sendsup?gk2344)). The authors thank Mr Eddie Nelson for helpful discussions. Comment ======= Chelate ligands have found widespread use in coordination chemistry due to the increased stability of coordination compounds they can form in comparison to monodentate ligands. Most work in this field has been done with chelate ligands capable of forming five-, six- and seven-membered chelate rings. The coordination behaviour of such ligands with respect to reaction products formed (*e.g.* the coordination number of the central atom) is a function of electronic as well as steric factors. In a larger study aimed at elucidating the coordination chemistry of multiply-fluorinated carboxylic acid derivatives, the structure of the title compound was determined to enable comparisons with reaction products obtained. The title compound is a symmetric, polyhalogenated derivative of β-hydroxypropanecarboxylic acid which bears two trifluoromethyl-groups at the alcoholic carbon atom. The asymmetric unit (Fig. 1) comprises two molecules of the title compound. In the crystal structure, intra- as well as intermolecular hydrogen bonds are present. While the intramolecular hydrogen bonds are formed between the alcoholic hydroxyl group and the carbonylic O-atom of the carboxylic group, intermolecular hydrogen bonds can be observed between the carboxylic acid groups\' OH-groups and carbonylic O-atoms. The latter interaction connects both molecules of the asymmetric unit to dimers. In terms of graph-set analysis, the descriptor for the intramolecular hydrogen bonds is *S*(6)*S*(6) on the unitary level while the intermolecular hydrogen bonds necessitate a *R*^2^~2~(8) descriptor on the binary level. For the intramolecular hydrogen bond, a bifurcation could be discussed applying the O-atom of another hydroxyl group as acceptor. This would render it a mixed intra-intermolecular hydrogen bond, however, the D--H···A angle of only around 120° for the intermolecular hydrogen bond is comparatively small. Apart from these hydrogen bonds, C--H···O contacts are present in the crystal structure whose ranges fall more than 0.2 Å below the sum of van-der-Waals radii of the respective atoms. These contacts can be observed between one of the H-atoms of the methylene group and the O-atom of a neighbouring hydroxyl group. Like the possible, bifurcated hydrogen bond mentioned above, these C--H···O contacts connect the molecules to infinite strands along the crystallographic *a* axis (Fig. 3). The descriptor for the C--H···O contacts on the unitary level is *C*^1^~1~(4)*C*^1^~1~(4). Experimental {#experimental} ============ The structural analysis was done on a single-crystal taken from a commercially obtained (Fluorochem) batch of the title compound. Refinement {#refinement} ========== Carbon-bound H-atoms were placed in calculated positions (C---H 0.99 Å) and were included in the refinement in the riding model approximation, with *U*(H) set to 1.2*U*~eq~(C). The H-atoms of the carboxylic acid group as well as of the hydroxyl groups were allowed to rotate with a fixed angle around the C---O bond to best fit the experimental electron density (HFIX 147 in the *SHELX* program suite (Sheldrick, 2008)), their *U*(H) invariably set to 1.5*U*~eq~(C) Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of the title compound with anisotropic displacement ellipsoids drawn at the 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Intermolecular C--H···O contacts and hydrogen bonds in the title compound, viewed along \[0 0 - 1\]. Intramolecular hydrogen bonds are indicated with green, intermolecular hydrogen bonds with blue dotted lines. The C--H···O contacts are illustrated with yellow dotted lines. Symmetry operators: i -1 + x, y, z; ii = 1 + x, y, z. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e182 .table-wrap} ------------------------- --------------------------------------- C~5~H~4~F~6~O~3~ *F*(000) = 896 *M~r~* = 226.08 *D*~x~ = 1.913 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 9089 reflections *a* = 5.5031 (2) Å θ = 2.9--28.3° *b* = 20.5490 (8) Å µ = 0.24 mm^−1^ *c* = 14.0342 (6) Å *T* = 200 K β = 98.4543 (14)° Rod, colourless *V* = 1569.79 (11) Å^3^ 0.59 × 0.45 × 0.33 mm *Z* = 8 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e312 .table-wrap} ------------------------------------------ -------------------------------------- Bruker APEXII CCD diffractometer 3469 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.014 graphite θ~max~ = 28.3°, θ~min~ = 2.5° φ and ω scans *h* = −7→7 25936 measured reflections *k* = −27→27 3897 independent reflections *l* = −18→18 ------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e410 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.038 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.100 H-atom parameters constrained *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0438*P*)^2^ + 0.8289*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 3897 reflections (Δ/σ)~max~ \< 0.001 257 parameters Δρ~max~ = 0.42 e Å^−3^ 0 restraints Δρ~min~ = −0.38 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e569 .table-wrap} ----- -------------- ------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O1 0.86328 (18) 0.71888 (5) 0.08430 (10) 0.0429 (3) H1 0.8645 0.6811 0.1073 0.064\* O2 0.45964 (17) 0.70927 (5) 0.08404 (8) 0.0326 (2) O3 0.17625 (19) 0.80005 (7) −0.02218 (11) 0.0520 (4) H3 0.2000 0.7657 0.0103 0.078\* O4 0.47274 (16) 0.59040 (4) 0.16029 (7) 0.0285 (2) H4 0.4717 0.6280 0.1367 0.043\* O5 0.87553 (17) 0.59872 (5) 0.15635 (8) 0.0337 (2) O6 1.13316 (16) 0.48391 (5) 0.18383 (8) 0.0316 (2) H6 1.1185 0.5241 0.1733 0.047\* C1 0.6381 (2) 0.74043 (6) 0.06831 (9) 0.0261 (2) C2 0.6189 (2) 0.80980 (6) 0.03285 (10) 0.0281 (3) H2A 0.7714 0.8211 0.0069 0.034\* H2B 0.6071 0.8389 0.0882 0.034\* C3 0.3986 (2) 0.82251 (7) −0.04523 (10) 0.0301 (3) C4 0.3661 (3) 0.89678 (8) −0.05702 (13) 0.0431 (4) C5 0.4440 (4) 0.79138 (8) −0.14087 (12) 0.0477 (4) C6 0.6980 (2) 0.56870 (6) 0.17642 (9) 0.0233 (2) C7 0.7220 (2) 0.50386 (6) 0.22712 (9) 0.0246 (2) H7A 0.5583 0.4829 0.2201 0.030\* H7B 0.7761 0.5113 0.2967 0.030\* C8 0.9032 (2) 0.45714 (6) 0.18926 (9) 0.0237 (2) C9 0.9528 (3) 0.40037 (7) 0.26098 (11) 0.0343 (3) C10 0.7933 (3) 0.43236 (7) 0.08834 (10) 0.0333 (3) F1 0.1814 (3) 0.91197 (7) −0.12449 (13) 0.0885 (5) F2 0.5634 (2) 0.92505 (5) −0.08100 (10) 0.0611 (3) F3 0.3264 (3) 0.92357 (6) 0.02449 (11) 0.0842 (5) F4 0.2561 (3) 0.79879 (8) −0.21017 (9) 0.0852 (5) F5 0.6404 (2) 0.81581 (6) −0.17319 (8) 0.0595 (3) F6 0.4835 (4) 0.72803 (6) −0.12768 (9) 0.0885 (5) F7 0.74664 (19) 0.36955 (5) 0.27353 (8) 0.0483 (2) F8 1.1068 (2) 0.35676 (5) 0.23401 (9) 0.0582 (3) F9 1.05355 (19) 0.42287 (5) 0.34686 (7) 0.0486 (3) F10 0.75894 (18) 0.48279 (5) 0.02779 (6) 0.0430 (2) F11 0.9385 (2) 0.39072 (6) 0.05224 (8) 0.0601 (3) F12 0.57504 (19) 0.40413 (5) 0.08745 (7) 0.0503 (3) ----- -------------- ------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1058 .table-wrap} ----- ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.0233 (5) 0.0342 (5) 0.0710 (8) 0.0020 (4) 0.0066 (5) 0.0233 (5) O2 0.0239 (4) 0.0293 (5) 0.0446 (6) 0.0004 (4) 0.0053 (4) 0.0128 (4) O3 0.0223 (5) 0.0557 (7) 0.0775 (9) −0.0007 (5) 0.0055 (5) 0.0399 (7) O4 0.0201 (4) 0.0232 (4) 0.0421 (5) 0.0019 (3) 0.0042 (4) 0.0057 (4) O5 0.0215 (4) 0.0276 (5) 0.0525 (6) 0.0005 (4) 0.0068 (4) 0.0101 (4) O6 0.0181 (4) 0.0299 (5) 0.0474 (6) 0.0013 (3) 0.0061 (4) 0.0051 (4) C1 0.0243 (6) 0.0250 (6) 0.0284 (6) −0.0002 (5) 0.0021 (5) 0.0039 (5) C2 0.0260 (6) 0.0232 (6) 0.0343 (6) −0.0023 (5) 0.0020 (5) 0.0039 (5) C3 0.0252 (6) 0.0282 (6) 0.0368 (7) −0.0012 (5) 0.0042 (5) 0.0117 (5) C4 0.0451 (8) 0.0333 (7) 0.0536 (9) 0.0100 (6) 0.0162 (7) 0.0177 (7) C5 0.0688 (11) 0.0382 (8) 0.0333 (8) −0.0069 (8) −0.0022 (7) 0.0056 (6) C6 0.0215 (5) 0.0224 (5) 0.0258 (6) 0.0009 (4) 0.0026 (4) −0.0009 (4) C7 0.0223 (5) 0.0241 (6) 0.0284 (6) 0.0026 (4) 0.0069 (4) 0.0039 (5) C8 0.0205 (5) 0.0223 (5) 0.0284 (6) 0.0016 (4) 0.0042 (4) 0.0024 (4) C9 0.0363 (7) 0.0283 (6) 0.0384 (7) 0.0067 (5) 0.0058 (6) 0.0077 (5) C10 0.0377 (7) 0.0301 (7) 0.0320 (7) −0.0014 (5) 0.0050 (5) −0.0032 (5) F1 0.0713 (9) 0.0650 (8) 0.1198 (13) 0.0159 (7) −0.0168 (8) 0.0530 (8) F2 0.0698 (7) 0.0310 (5) 0.0890 (9) −0.0065 (5) 0.0329 (6) 0.0162 (5) F3 0.1413 (14) 0.0428 (6) 0.0828 (9) 0.0398 (7) 0.0640 (9) 0.0165 (6) F4 0.0932 (10) 0.1107 (12) 0.0420 (6) −0.0324 (9) −0.0229 (6) 0.0152 (7) F5 0.0693 (7) 0.0685 (7) 0.0459 (6) 0.0097 (6) 0.0255 (5) 0.0052 (5) F6 0.1863 (17) 0.0330 (6) 0.0454 (6) −0.0033 (8) 0.0140 (8) −0.0057 (5) F7 0.0554 (6) 0.0367 (5) 0.0539 (6) −0.0085 (4) 0.0122 (5) 0.0157 (4) F8 0.0696 (7) 0.0405 (5) 0.0674 (7) 0.0310 (5) 0.0197 (6) 0.0141 (5) F9 0.0552 (6) 0.0490 (6) 0.0369 (5) 0.0086 (5) −0.0084 (4) 0.0121 (4) F10 0.0524 (5) 0.0473 (5) 0.0275 (4) −0.0056 (4) 0.0000 (4) 0.0059 (4) F11 0.0746 (8) 0.0577 (7) 0.0495 (6) 0.0186 (6) 0.0140 (5) −0.0199 (5) F12 0.0496 (6) 0.0501 (6) 0.0485 (6) −0.0230 (5) −0.0022 (4) −0.0053 (4) ----- ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1568 .table-wrap} --------------------- -------------- --------------------- -------------- O1---C1 1.3042 (16) C7---C8 1.5347 (16) O1---H1 0.8400 C7---H7A 0.9900 O2---C1 1.2192 (16) C7---H7B 0.9900 O3---C3 1.3896 (16) C8---C9 1.5387 (18) O3---H3 0.8400 C8---C10 1.5425 (19) O4---C6 1.3055 (15) F1---C4 1.321 (2) O4---H4 0.8400 F2---C4 1.3183 (19) O5---C6 1.2228 (15) F3---C4 1.316 (2) O6---C8 1.3920 (14) F4---C5 1.320 (2) O6---H6 0.8400 F5---C5 1.330 (2) C1---C2 1.5084 (17) F6---C5 1.328 (2) C2---C3 1.5325 (18) F7---C9 1.3336 (18) C2---H2A 0.9900 F8---C9 1.3259 (17) C2---H2B 0.9900 F9---C9 1.3330 (19) C3---C5 1.540 (2) F10---C10 1.3359 (17) C3---C4 1.543 (2) F11---C10 1.3213 (17) C7---C6 1.5073 (17) F12---C10 1.3323 (17) O1---C1---C2 113.34 (11) C8---C7---H7A 108.8 O2---C1---O1 124.10 (12) C8---C7---H7B 108.8 O2---C1---C2 122.48 (11) C9---C8---C10 111.00 (11) O3---C3---C2 114.09 (11) F1---C4---C3 112.06 (16) O3---C3---C4 105.15 (12) F2---C4---C3 112.11 (13) O3---C3---C5 109.04 (13) F2---C4---F1 106.79 (14) O4---C6---C7 113.50 (10) F3---C4---C3 110.61 (13) O5---C6---O4 123.94 (11) F3---C4---F1 108.40 (16) O5---C6---C7 122.50 (11) F3---C4---F2 106.61 (16) O6---C8---C7 114.46 (10) F4---C5---C3 112.59 (17) O6---C8---C9 105.08 (10) F4---C5---F5 107.03 (14) O6---C8---C10 108.49 (10) F4---C5---F6 108.05 (16) C1---O1---H1 109.5 F5---C5---C3 112.62 (14) C1---C2---C3 113.99 (11) F6---C5---C3 109.26 (13) C1---C2---H2A 108.8 F6---C5---F5 107.04 (18) C1---C2---H2B 108.8 F7---C9---C8 111.95 (11) C2---C3---C4 108.21 (12) F8---C9---C8 112.64 (12) C2---C3---C5 109.85 (12) F8---C9---F7 107.96 (13) C3---O3---H3 109.5 F8---C9---F9 107.12 (12) C3---C2---H2A 108.8 F9---C9---C8 109.80 (12) C3---C2---H2B 108.8 F9---C9---F7 107.10 (12) C5---C3---C4 110.40 (12) F10---C10---C8 109.13 (11) C6---O4---H4 109.5 F11---C10---C8 112.85 (12) C6---C7---C8 113.94 (10) F11---C10---F10 107.19 (12) C6---C7---H7A 108.8 F11---C10---F12 108.03 (13) C6---C7---H7B 108.8 F12---C10---C8 112.56 (11) C7---C8---C9 108.03 (10) F12---C10---F10 106.78 (12) C7---C8---C10 109.71 (10) H2A---C2---H2B 107.6 C8---O6---H6 109.5 H7A---C7---H7B 107.7 O1---C1---C2---C3 140.99 (13) C4---C3---C5---F4 −63.00 (18) O2---C1---C2---C3 −41.98 (19) C4---C3---C5---F5 58.14 (18) O3---C3---C4---F1 −58.76 (18) C4---C3---C5---F6 176.95 (16) O3---C3---C4---F2 −178.84 (14) C5---C3---C4---F1 58.71 (18) O3---C3---C4---F3 62.33 (18) C5---C3---C4---F2 −61.37 (19) O3---C3---C5---F4 52.05 (17) C5---C3---C4---F3 179.80 (15) O3---C3---C5---F5 173.18 (13) C6---C7---C8---O6 50.77 (14) O3---C3---C5---F6 −68.01 (19) C6---C7---C8---C9 167.43 (11) O6---C8---C9---F7 −179.87 (11) C6---C7---C8---C10 −71.45 (13) O6---C8---C9---F8 −57.98 (15) C7---C8---C9---F7 57.53 (15) O6---C8---C9---F9 61.31 (14) C7---C8---C9---F8 179.43 (12) O6---C8---C10---F10 −63.45 (14) C7---C8---C9---F9 −61.29 (14) O6---C8---C10---F11 55.60 (15) C7---C8---C10---F10 62.26 (14) O6---C8---C10---F12 178.20 (11) C7---C8---C10---F11 −178.69 (12) C1---C2---C3---O3 50.06 (17) C7---C8---C10---F12 −56.09 (15) C1---C2---C3---C5 −72.71 (15) C8---C7---C6---O4 139.87 (11) C1---C2---C3---C4 166.70 (12) C8---C7---C6---O5 −42.93 (17) C2---C3---C4---F1 178.96 (14) C9---C8---C10---F10 −178.42 (11) C2---C3---C4---F2 58.88 (18) C9---C8---C10---F11 −59.37 (15) C2---C3---C4---F3 −59.96 (18) C9---C8---C10---F12 63.22 (15) C2---C3---C5---F4 177.75 (13) C10---C8---C9---F7 −62.79 (15) C2---C3---C5---F5 −61.12 (17) C10---C8---C9---F8 59.10 (16) C2---C3---C5---F6 57.69 (19) C10---C8---C9---F9 178.39 (11) --------------------- -------------- --------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2262 .table-wrap} ------------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O1---H1···O5 0.84 1.83 2.6653 (14) 178 O3---H3···O2 0.84 2.01 2.7296 (14) 144 O3---H3···O1^i^ 0.84 2.45 2.9561 (15) 120 O4---H4···O2 0.84 1.82 2.6635 (13) 178 O6---H6···O5 0.84 2.03 2.7502 (13) 144 O6---H6···O4^ii^ 0.84 2.41 2.9276 (13) 121 C2---H2A···O3^ii^ 0.99 2.36 3.2773 (16) 153 C7---H7A···O6^i^ 0.99 2.32 3.2340 (14) 153 ------------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) *x*−1, *y*, *z*; (ii) *x*+1, *y*, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------- --------- ------- ------------- ------------- O1---H1⋯O5 0.84 1.83 2.6653 (14) 178 O3---H3⋯O2 0.84 2.01 2.7296 (14) 144 O3---H3⋯O1^i^ 0.84 2.45 2.9561 (15) 120 O4---H4⋯O2 0.84 1.82 2.6635 (13) 178 O6---H6⋯O5 0.84 2.03 2.7502 (13) 144 O6---H6⋯O4^ii^ 0.84 2.41 2.9276 (13) 121 C2---H2*A*⋯O3^ii^ 0.99 2.36 3.2773 (16) 153 C7---H7*A*⋯O6^i^ 0.99 2.32 3.2340 (14) 153 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.595973

2011-2-12

PMC3051967

Related literature {#sec1} ================== For the synthesis and biological properties of the title compound and analogues, see: Bischoff (1907[@bb2]); Kaeriyama *et al.* (1976[@bb8]). For the use of the title compound in organic synthesis, see: Haddleton & Waterson (1999[@bb7]); Edeleva *et al.* (2009[@bb4]); Guillaneuf *et al.* (2007[@bb6]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~10~H~10~BrNO~4~*M* *~r~* = 288.10Orthorhombic,*a* = 11.4128 (16) Å*b* = 14.450 (2) Å*c* = 14.539 (2) Å*V* = 2397.7 (6) Å^3^*Z* = 8Mo *K*α radiationμ = 3.43 mm^−1^*T* = 295 K0.45 × 0.15 × 0.14 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2008[@bb3]) *T* ~min~ = 0.625, *T* ~max~ = 0.72018926 measured reflections2177 independent reflections1086 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.049 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.046*wR*(*F* ^2^) = 0.132*S* = 1.002177 reflections145 parametersH-atom parameters constrainedΔρ~max~ = 0.84 e Å^−3^Δρ~min~ = −0.51 e Å^−3^ {#d5e401} Data collection: *APEX2* (Bruker, 2008[@bb3]); cell refinement: *SAINT* (Bruker, 2008[@bb3]); data reduction: *SAINT*; program(s) used to solve structure: *SIR97* (Altomare *et al.*, 1999[@bb1]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb11]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb5]) and *SCHAKAL97* (Keller, 1997[@bb9]); software used to prepare material for publication: *SHELXL97* and *PARST95* (Nardelli, 1995[@bb10]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811005988/tk2722sup1.cif](http://dx.doi.org/10.1107/S1600536811005988/tk2722sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005988/tk2722Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005988/tk2722Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?tk2722&file=tk2722sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?tk2722sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?tk2722&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [TK2722](http://scripts.iucr.org/cgi-bin/sendsup?tk2722)). Financial support from the Universitá Politecnica delle Marche and the Universitá degli Studi di Parma is gratefully acknowledged. Comment ======= The synthesis of the title compound and analogues was originally reported in the early part of last century (Bischoff, 1907), and in the seventies several of these compounds were found to possess useful miticidal, insecticidal, nematocidal or fungicidal activities (Kaeriyama *et al.*, 1976). More recently, the title compound was prepared (Haddleton & Waterson, 1999) and used as initiator for H-atom transfer polymerization. The same compound was also used in the preparation of new alkoxyamines derived from imadaziline-, imidazoline- and pyrrolidine-1-oxyl nitroxides (Edeleva *et al.*, 2009) and, within our group, for the synthesis of phenyl- and 4-nitrophenyl- 2-(2,2-diphenyl-3-(phenylimino)-indolin-1-yloxy)-2-methylpropionate (Guillaneuf *et al.*, 2007). In order to obtain structural parameters for molecular mechanics calculations for the above mentioned alkoxyamines, the X-ray crystal structure of the title compound has been determined and the results are reported herein. In the molecule of the title compound (Fig. 1), the plane of the nitro group is approximately coplanar with the benzene ring (dihedral angle 6.4 (3) °), whereas the plane of the carboxylic group is tilted by 60.53 (13) °. All bond lengths and angles are unexceptional. In the crystal structure (Fig. 2), the molecules are linked by intermolecular C---H···O hydrogen bonds (Table 1) into zigzag chains running parallel to the *c* axis. Experimental {#experimental} ============ The title compound was prepared according to the literature method (Haddleton & Waterson, 1999). Crystals suitable for X-ray analysis were obtained by slow evaporation of its *n*-pentane solution (m. p. 342--343 K). IR data, ν, cm^-1^: 1753 (C═O), 1615 and 1592 (benzene ring), 1521 (NO~2~). ^1^H NMR spectrum, δ in CDCl~3~: 2.08 (s, 6H); 7.3 (2*H*, d, *J* = 9.2 Hz); 8.31 (2*H*, d, *J* = 9.2 Hz). The ESI-MS obtained with 3200 QTRAP spectrometer does not give the molecular ion peak. The melting point was measured by an electrothermal apparatus and is uncorrected. The ^1^H NMR spectrum was recorded with a Varian 400 MHz spectrometer. The IR spectrum was recorded with a Perkin-Elmer MGX1 spectrophotometer. Refinement {#refinement} ========== All H atoms were placed in geometrically idealized positions and treated as riding atoms, with C---H = 0.93--0.96 Å, and *U*~iso~(H) = 1.2 *U*~eq~(C) or 1.5 *U*~eq~(C) for methyl H atoms. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound, with displacement ellipsoids drawn at the 40% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Partial crystal packing of the title compound viewed approximately along the a axis. Intermolecular C---H···O hydrogen bonds are shown as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e168 .table-wrap} ------------------------ -------------------------------------- C~10~H~10~BrNO~4~ *F*(000) = 1152 *M~r~* = 288.10 *D*~x~ = 1.596 Mg m^−3^ Orthorhombic, *Pbcn* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2n 2ab Cell parameters from 877 reflections *a* = 11.4128 (16) Å θ = 5.6--21.3° *b* = 14.450 (2) Å µ = 3.43 mm^−1^ *c* = 14.539 (2) Å *T* = 295 K *V* = 2397.7 (6) Å^3^ Needle, colourless *Z* = 8 0.45 × 0.15 × 0.14 mm ------------------------ -------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e289 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker APEXII CCD diffractometer 2177 independent reflections Radiation source: fine-focus sealed tube 1086 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.049 ω scans θ~max~ = 25.3°, θ~min~ = 2.3° Absorption correction: multi-scan (*SADABS*; Bruker, 2008) *h* = −13→13 *T*~min~ = 0.625, *T*~max~ = 0.720 *k* = −15→17 18926 measured reflections *l* = −17→17 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e403 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.046 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.132 H-atom parameters constrained *S* = 1.00 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0685*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2177 reflections (Δ/σ)~max~ \< 0.001 145 parameters Δρ~max~ = 0.84 e Å^−3^ 0 restraints Δρ~min~ = −0.51 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e557 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e650 .table-wrap} ----- -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Br1 −0.00330 (6) 0.10818 (4) 0.62160 (4) 0.1233 (3) O1 −0.0531 (2) 0.33291 (18) 0.53800 (18) 0.0757 (8) O2 0.1275 (2) 0.30016 (16) 0.58917 (16) 0.0639 (7) O3 0.1600 (3) 0.6175 (2) 0.8793 (2) 0.1042 (11) O4 0.1583 (4) 0.6983 (2) 0.7567 (2) 0.1188 (13) N1 0.1583 (3) 0.6243 (3) 0.7961 (3) 0.0724 (9) C1 0.0266 (3) 0.1820 (2) 0.5074 (2) 0.0603 (10) C2 0.1417 (3) 0.1512 (2) 0.4701 (3) 0.0783 (12) H2A 0.2016 0.1614 0.5154 0.117\* H2B 0.1597 0.1859 0.4156 0.117\* H2C 0.1380 0.0865 0.4554 0.117\* C3 −0.0733 (4) 0.1656 (3) 0.4429 (4) 0.1049 (17) H3A −0.1451 0.1849 0.4714 0.157\* H3B −0.0777 0.1009 0.4283 0.157\* H3C −0.0612 0.2005 0.3875 0.157\* C4 0.0267 (3) 0.2799 (3) 0.5452 (2) 0.0603 (10) C5 0.1339 (3) 0.3821 (2) 0.6389 (3) 0.0551 (9) C6 0.1295 (3) 0.4663 (3) 0.5954 (2) 0.0628 (10) H6 0.1207 0.4695 0.5319 0.075\* C8 0.1531 (3) 0.5392 (3) 0.7411 (2) 0.0556 (9) C7 0.1381 (3) 0.5461 (3) 0.6467 (3) 0.0626 (10) H7 0.1339 0.6038 0.6184 0.075\* C9 0.1598 (3) 0.4549 (3) 0.7842 (2) 0.0618 (10) H9 0.1699 0.4515 0.8476 0.074\* C10 0.1515 (3) 0.3756 (3) 0.7324 (3) 0.0623 (10) H10 0.1576 0.3179 0.7604 0.075\* ----- -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1012 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Br1 0.1760 (7) 0.0961 (5) 0.0979 (5) −0.0278 (3) 0.0319 (3) 0.0105 (3) O1 0.0642 (16) 0.0717 (18) 0.091 (2) 0.0147 (14) −0.0123 (15) −0.0147 (15) O2 0.0549 (15) 0.0642 (17) 0.0727 (16) 0.0074 (13) −0.0079 (13) −0.0145 (14) O3 0.153 (3) 0.095 (2) 0.064 (2) −0.023 (2) −0.0036 (18) −0.0151 (16) O4 0.198 (4) 0.061 (2) 0.097 (2) −0.017 (2) −0.004 (2) −0.0031 (19) N1 0.084 (2) 0.071 (3) 0.062 (2) −0.0081 (19) 0.0088 (19) −0.009 (2) C1 0.058 (2) 0.062 (2) 0.061 (2) 0.0014 (18) −0.0044 (18) −0.0028 (19) C2 0.080 (3) 0.062 (3) 0.093 (3) 0.014 (2) 0.012 (2) −0.005 (2) C3 0.097 (3) 0.087 (3) 0.131 (4) 0.018 (3) −0.043 (3) −0.047 (3) C4 0.053 (2) 0.070 (3) 0.058 (2) 0.006 (2) −0.0084 (19) −0.007 (2) C5 0.0414 (19) 0.060 (2) 0.064 (2) 0.0041 (17) 0.0010 (17) −0.006 (2) C6 0.069 (2) 0.075 (3) 0.045 (2) −0.001 (2) 0.0076 (18) −0.001 (2) C8 0.046 (2) 0.064 (3) 0.056 (2) −0.0086 (18) 0.0046 (16) −0.007 (2) C7 0.071 (2) 0.059 (3) 0.057 (2) −0.003 (2) 0.0135 (19) 0.003 (2) C9 0.062 (2) 0.073 (3) 0.050 (2) −0.002 (2) −0.0102 (18) 0.005 (2) C10 0.058 (2) 0.055 (2) 0.074 (3) 0.0015 (19) −0.0109 (19) 0.0033 (19) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1356 .table-wrap} ---------------- ----------- ---------------- ----------- Br1---C1 2.002 (4) C3---H3A 0.9600 O1---C4 1.195 (4) C3---H3B 0.9600 O2---C4 1.348 (4) C3---H3C 0.9600 O2---C5 1.390 (4) C5---C6 1.372 (5) O3---N1 1.214 (4) C5---C10 1.378 (5) O4---N1 1.214 (4) C6---C7 1.376 (5) N1---C8 1.467 (5) C6---H6 0.9300 C1---C2 1.489 (5) C8---C9 1.372 (5) C1---C3 1.496 (5) C8---C7 1.388 (5) C1---C4 1.518 (5) C7---H7 0.9300 C2---H2A 0.9600 C9---C10 1.375 (5) C2---H2B 0.9600 C9---H9 0.9300 C2---H2C 0.9600 C10---H10 0.9300 C4---O2---C5 118.5 (3) O1---C4---O2 123.6 (4) O4---N1---O3 122.8 (4) O1---C4---C1 124.4 (3) O4---N1---C8 118.8 (3) O2---C4---C1 112.0 (3) O3---N1---C8 118.4 (4) C6---C5---C10 121.4 (4) C2---C1---C3 113.4 (3) C6---C5---O2 121.0 (3) C2---C1---C4 114.2 (3) C10---C5---O2 117.6 (3) C3---C1---C4 112.0 (3) C5---C6---C7 119.4 (3) C2---C1---Br1 107.1 (2) C5---C6---H6 120.3 C3---C1---Br1 107.8 (3) C7---C6---H6 120.3 C4---C1---Br1 101.3 (2) C9---C8---C7 121.5 (3) C1---C2---H2A 109.5 C9---C8---N1 119.5 (4) C1---C2---H2B 109.5 C7---C8---N1 118.9 (3) H2A---C2---H2B 109.5 C6---C7---C8 119.0 (4) C1---C2---H2C 109.5 C6---C7---H7 120.5 H2A---C2---H2C 109.5 C8---C7---H7 120.5 H2B---C2---H2C 109.5 C8---C9---C10 119.1 (4) C1---C3---H3A 109.5 C8---C9---H9 120.4 C1---C3---H3B 109.5 C10---C9---H9 120.4 H3A---C3---H3B 109.5 C9---C10---C5 119.5 (4) C1---C3---H3C 109.5 C9---C10---H10 120.2 H3A---C3---H3C 109.5 C5---C10---H10 120.2 H3B---C3---H3C 109.5 ---------------- ----------- ---------------- ----------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1693 .table-wrap} ----------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C6---H6···O3^i^ 0.93 2.59 3.385 (4) 144 ----------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) *x*, −*y*+1, *z*−1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------- --------- ------- ----------- ------------- C6---H6⋯O3^i^ 0.93 2.59 3.385 (4) 144 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.602268

2011-2-23

PMC3051968

Related literature {#sec1} ================== For standard bond lengths, see Allen *et al.* (1987[@bb1]). For background to and applications of quaternary ammonium compounds, see: Chanawanno *et al.* (2010[@bb3]); Fun *et al.* (2010[@bb4]); Massi *et al.* (2003[@bb6]); Soprey & Maxcy (1968[@bb8]); Yabuhara *et al.* (2004[@bb10]). For related structures, see: Chanawanno *et al.* (2010[@bb3]); Kaewmanee *et al.* (2010[@bb5]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~18~H~23~N~2~ ^+^·C~6~H~5~O~3~S^−^·H~2~O*M* *~r~* = 442.57Monoclinic,*a* = 9.9393 (5) Å*b* = 17.9047 (9) Å*c* = 13.2532 (7) Åβ = 100.715 (1)°*V* = 2317.4 (2) Å^3^*Z* = 4Mo *K*α radiationμ = 0.17 mm^−1^*T* = 297 K0.47 × 0.28 × 0.27 mm ### Data collection {#sec2.1.2} Bruker SMART APEXII CCD area-detector. diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2009[@bb2]) *T* ~min~ = 0.924, *T* ~max~ = 0.95523078 measured reflections6105 independent reflections3770 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.030 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.057*wR*(*F* ^2^) = 0.173*S* = 1.046105 reflections293 parametersH-atom parameters constrainedΔρ~max~ = 0.37 e Å^−3^Δρ~min~ = −0.34 e Å^−3^ {#d5e607} Data collection: *APEX2* (Bruker, 2009[@bb2]); cell refinement: *SAINT* (Bruker, 2009[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL*; software used to prepare material for publication: *SHELXTL* and *PLATON* (Spek, 2009[@bb9]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811004156/sj5101sup1.cif](http://dx.doi.org/10.1107/S1600536811004156/sj5101sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004156/sj5101Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004156/sj5101Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?sj5101&file=sj5101sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?sj5101sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?sj5101&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [SJ5101](http://scripts.iucr.org/cgi-bin/sendsup?sj5101)). Financial support by the Prince of Songkla University is gratefully acknowledged. KC thanks the Crystal Materials Research Unit (CMRU), Prince of Songkla University, for the research assistance fellowship. The authors also thank Universiti Sains Malaysia for the Research University Grant No. 1001/PFIZIK/811160. Comment ======= Quaternary ammonium compounds (QACs) are relatively low toxicity and wide-ranging antimicrobial agents that are commonly used for water treatment, food industry additives and hygienic care for both medical and domestic purposes (Yabuhara *et al.*, 2004). However, due to the long-term usage of common QACs such as benzalkonium chloride and cetylpridinium chloride, QAC resistant microorganisms have appeared. It was reported that some *Staphylococcus* spp. contain genes conveying resistance to this type of disinfectant (Massi *et al.*, 2003; Soprey *et al.*, 1968; Yabuhara *et al.*, 2004). Therefore, we have developed the novel pyridinium QACs which can overcome this *Staphylococcus*-resistant phenomenon by exhibiting strong anti-methicillin-resistant *Staphylococcus aureus* activity and reported this discovery in our previous work (Chanawanno *et al.*, 2010; Fun *et al.*, 2010). The title compound was the one among many pyridinium QACs which was synthesized in our laboratory hoping for a new antibacterial drug candidate. The antibacterial activity of this compound is under investigation and its crystal structure is reported here. Fig. 1 shows the asymmetric unit of the title compound (I) which consists of the C~18~H~23~N~2~^+^ cation, C~6~H~5~O~3~S^-^ anion and one H~2~O molecule. The cation exists in the *E* configuration with respect to the C6═C7 double bond \[1.337 (2) Å\]. The π-conjugated system of cation (N1/C1--C13) is planar with an *r.m.s* deviation of 0.0215 (2) Å and the dihedral angle between the C1--C5/N1 pyridinium and the C8--C13 benzene rings is 0.82 (10)° with the torsion angle C5--C6--C7--C8 = -179.19 (17)°. One ethyl unit of the diethylamino moiety is disordered over two positions; the major component *A* and the minor component *B* (Fig. 1), with a refined site-occupancy ratio of 0.73789 (9)/0.26211 (9). The diethylamino group deviates from the attached C8--C13 ring and its conformation can be indicated by the torsion angles C11--N2--C14--C15 = 83.8 (4)°, C11--N2--C16--C17 = -95.3 (4)° for the major component *A* and 106.1 (7)° for the minor component *B*. The cation and anion are inclined to each other as indicated by the dihedral angle between the π-conjugated system of cation (N1/C1--C13) and the C19--C24 benzene ring of anion being 86.71 (10)°. The bond lengths (Allen *et al.*, 1987) and angles in (I) are in normal ranges and comparable with those for related structures (Chanawanno *et al.*, 2010; Kaewmanee *et al.*, 2010). In the crystal packing, the cations, anions and water molecules are arranged into individual chains along the \[001\] direction (Fig. 2). The cations are linked to the anions and water molecules in neighboring chains by C---H···O weak interactions (Table 1 and Fig. 2) whereas the anions are linked to water molecule by O---H···O hydrogen bonds (Table 1). A C---H···π interaction involving the benzenesulfonate anion was observed (Table 1). Experimental {#experimental} ============ (*E*)-2-(4-(diethylamino)styryl)-1-methylpyridinium iodide (compound A, 0.14 g, 0.37 mmol) was prepared by a literature method (Kaewmanee *et al.*, 2010) and then was mixed with silver (I) benzenesulfonate (Chanawanno *et al.*, 2010) (0.10 g, 0.37 mmol) in methanol (100 ml). The mixture immediately yielded a grey precipitate of silver iodide. After stirring the mixture for 30 min, the precipitate of silver iodide was removed and the resulting solution was evaporated yielding the title compound as an orange solid. Orange block-shaped single crystals of the title compound suitable for *x*-ray structure determination was recrystallized from methanol by slow evaporation of the solvent at room temperature after a few weeks, Mp. 466--468 K. Refinement {#refinement} ========== All H atoms were placed in calculated positions to ride on their parent atoms, with d(O---H) = 0.97 and 1.07 Å, d(C---H) = 0.93 Å for aromatic and CH, 0.97 Å for CH~2~ and 0.96 Å for CH~3~ atoms. The *U*~iso~ values were constrained to be 1.5*U*~eq~ of the carrier atom for methyl H atoms and 1.2*U*~eq~ for the remaining H atoms. A rotating group model was used for the methyl groups. The highest residual electron density peak is located at 1.09 Å from H14B and the deepest hole is located at 0.72 Å from S1. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of (I) showing 40% probability displacement ellipsoids and the atom-numbering scheme. Atoms of the minor disorder component are linked by open bonds. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The crystal packing of the major component viewed along the b axis. The O---H···O hydrogen bonds and weak C---H···O interactions are drawn as dashed lines. Only the major component is shown. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e232 .table-wrap} ------------------------------------------ --------------------------------------- C~18~H~23~N~2~^+^·C~6~H~5~O~3~S^−^·H~2~O *F*(000) = 944 *M~r~* = 442.57 *D*~x~ = 1.268 Mg m^−3^ Monoclinic, *P*2~1~/*c* Melting point = 566--468 K Hall symbol: -P 2ybc Mo *K*α radiation, λ = 0.71073 Å *a* = 9.9393 (5) Å Cell parameters from 6105 reflections *b* = 17.9047 (9) Å θ = 1.9--29.0° *c* = 13.2532 (7) Å µ = 0.17 mm^−1^ β = 100.715 (1)° *T* = 297 K *V* = 2317.4 (2) Å^3^ Block, orange *Z* = 4 0.47 × 0.28 × 0.27 mm ------------------------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e380 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEXII CCD area-detector. diffractometer 6105 independent reflections Radiation source: sealed tube 3770 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.030 φ and ω scans θ~max~ = 29.0°, θ~min~ = 1.9° Absorption correction: multi-scan (*SADABS*; Bruker, 2009) *h* = −13→13 *T*~min~ = 0.924, *T*~max~ = 0.955 *k* = −24→24 23078 measured reflections *l* = −17→18 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e497 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.057 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.173 H-atom parameters constrained *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0718*P*)^2^ + 0.6034*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 6105 reflections (Δ/σ)~max~ = 0.001 293 parameters Δρ~max~ = 0.37 e Å^−3^ 0 restraints Δρ~min~ = −0.34 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e654 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e753 .table-wrap} ------ -------------- --------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) N1 0.37923 (17) 0.19719 (9) 0.60635 (12) 0.0544 (4) N2 0.5404 (2) −0.11253 (14) 0.11672 (19) 0.0943 (7) C1 0.3917 (3) 0.24752 (13) 0.68435 (19) 0.0749 (7) H1A 0.3134 0.2636 0.7070 0.090\* C2 0.5133 (3) 0.27431 (15) 0.7291 (2) 0.0861 (8) H2A 0.5193 0.3085 0.7826 0.103\* C3 0.6310 (3) 0.25112 (14) 0.69564 (19) 0.0779 (7) H3A 0.7163 0.2697 0.7260 0.093\* C4 0.6188 (2) 0.20033 (12) 0.61701 (16) 0.0601 (5) H4A 0.6970 0.1843 0.5943 0.072\* C5 0.49121 (19) 0.17222 (10) 0.57031 (14) 0.0466 (4) C6 0.47237 (18) 0.12106 (10) 0.48520 (14) 0.0478 (4) H6A 0.3837 0.1055 0.4583 0.057\* C7 0.57404 (18) 0.09435 (10) 0.44222 (14) 0.0470 (4) H7A 0.6621 0.1100 0.4708 0.056\* C8 0.56174 (17) 0.04385 (9) 0.35634 (14) 0.0447 (4) C9 0.67804 (19) 0.02127 (12) 0.31950 (16) 0.0602 (5) H9A 0.7627 0.0407 0.3498 0.072\* C10 0.6720 (2) −0.02858 (13) 0.24028 (17) 0.0677 (6) H10A 0.7524 −0.0421 0.2185 0.081\* C11 0.5480 (2) −0.05947 (12) 0.19157 (16) 0.0602 (5) C12 0.4306 (2) −0.03423 (12) 0.22563 (17) 0.0630 (5) H12A 0.3453 −0.0516 0.1932 0.076\* C13 0.43791 (19) 0.01503 (11) 0.30494 (16) 0.0568 (5) H13A 0.3574 0.0298 0.3253 0.068\* C14 0.4085 (3) −0.14535 (16) 0.0674 (2) 0.0988 (10) H14A 0.4247 −0.1945 0.0412 0.119\* H14B 0.3509 −0.1514 0.1184 0.119\* C15 0.3368 (4) −0.09968 (19) −0.0164 (3) 0.1244 (12) H15A 0.2533 −0.1241 −0.0475 0.187\* H15B 0.3938 −0.0929 −0.0667 0.187\* H15C 0.3159 −0.0519 0.0098 0.187\* C16A 0.6609 (5) −0.1534 (2) 0.0964 (3) 0.0785 (14) 0.738 (9) H16A 0.6350 −0.2045 0.0777 0.094\* 0.738 (9) H16B 0.7302 −0.1546 0.1585 0.094\* 0.738 (9) C17A 0.7198 (5) −0.1177 (2) 0.0113 (4) 0.0975 (17) 0.738 (9) H17A 0.7939 −0.1477 −0.0033 0.146\* 0.738 (9) H17B 0.7530 −0.0687 0.0321 0.146\* 0.738 (9) H17C 0.6499 −0.1140 −0.0492 0.146\* 0.738 (9) C16B 0.6536 (13) −0.1042 (7) 0.0426 (10) 0.080 (4)\* 0.262 (9) H16C 0.6142 −0.1116 −0.0293 0.096\* 0.262 (9) H16D 0.7013 −0.0567 0.0518 0.096\* 0.262 (9) C17B 0.7432 (15) −0.1684 (7) 0.0869 (10) 0.090 (4)\* 0.262 (9) H17D 0.8044 −0.1811 0.0414 0.135\* 0.262 (9) H17E 0.6870 −0.2108 0.0949 0.135\* 0.262 (9) H17F 0.7953 −0.1544 0.1526 0.135\* 0.262 (9) S1 0.04707 (5) 0.15726 (4) 0.24744 (4) 0.0654 (2) O1 0.0265 (2) 0.18007 (11) 0.14137 (14) 0.0980 (6) O2 −0.0623 (2) 0.18000 (11) 0.29822 (16) 0.0985 (6) O3 0.18028 (17) 0.17776 (11) 0.30344 (15) 0.0916 (6) C19 0.0540 (2) 0.02197 (16) 0.3415 (2) 0.0776 (7) H19A 0.0560 0.0495 0.4013 0.093\* C20 0.0584 (3) −0.0546 (2) 0.3458 (3) 0.1078 (11) H20A 0.0638 −0.0787 0.4085 0.129\* C21 0.0549 (3) −0.0958 (2) 0.2577 (5) 0.1239 (16) H21A 0.0578 −0.1477 0.2608 0.149\* C22 0.0472 (3) −0.0597 (2) 0.1643 (3) 0.1092 (11) H22A 0.0446 −0.0874 0.1047 0.131\* C23 0.0431 (2) 0.01794 (17) 0.1597 (2) 0.0815 (7) H23A 0.0381 0.0423 0.0972 0.098\* C24 0.04664 (18) 0.05846 (14) 0.24854 (17) 0.0618 (5) C18 0.2404 (2) 0.17099 (14) 0.56214 (19) 0.0718 (6) H18A 0.2365 0.1176 0.5682 0.108\* H18B 0.2185 0.1848 0.4910 0.108\* H18C 0.1757 0.1934 0.5984 0.108\* O1W 0.8847 (2) 0.20924 (15) 0.49628 (17) 0.1225 (8) H1W1 0.9246 0.2080 0.4349 0.147\* H2W1 0.9407 0.2522 0.5417 0.147\* ------ -------------- --------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1706 .table-wrap} ------ ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ N1 0.0629 (10) 0.0548 (9) 0.0489 (9) 0.0076 (7) 0.0193 (8) 0.0020 (7) N2 0.0730 (13) 0.1111 (17) 0.0977 (17) 0.0068 (12) 0.0129 (12) −0.0540 (14) C1 0.1001 (19) 0.0667 (14) 0.0643 (14) 0.0145 (13) 0.0324 (14) −0.0063 (12) C2 0.126 (2) 0.0707 (15) 0.0626 (15) −0.0013 (16) 0.0201 (16) −0.0207 (13) C3 0.0946 (18) 0.0713 (15) 0.0622 (14) −0.0176 (13) 0.0001 (13) −0.0076 (12) C4 0.0608 (12) 0.0635 (12) 0.0542 (12) −0.0035 (9) 0.0060 (9) −0.0027 (10) C5 0.0511 (10) 0.0446 (9) 0.0452 (10) 0.0039 (7) 0.0121 (8) 0.0037 (8) C6 0.0438 (9) 0.0507 (10) 0.0494 (10) −0.0008 (7) 0.0096 (8) −0.0008 (8) C7 0.0417 (9) 0.0503 (10) 0.0479 (10) 0.0036 (7) 0.0053 (7) 0.0022 (8) C8 0.0415 (9) 0.0446 (9) 0.0478 (10) 0.0047 (7) 0.0082 (7) 0.0028 (8) C9 0.0391 (9) 0.0771 (13) 0.0641 (13) 0.0035 (9) 0.0083 (9) −0.0135 (11) C10 0.0471 (11) 0.0884 (15) 0.0693 (14) 0.0122 (10) 0.0149 (10) −0.0182 (12) C11 0.0587 (12) 0.0614 (12) 0.0602 (12) 0.0083 (9) 0.0099 (10) −0.0118 (10) C12 0.0474 (11) 0.0695 (13) 0.0704 (14) −0.0030 (9) 0.0066 (9) −0.0172 (11) C13 0.0429 (10) 0.0630 (12) 0.0660 (13) 0.0021 (8) 0.0139 (9) −0.0100 (10) C14 0.116 (2) 0.0828 (18) 0.088 (2) 0.0180 (16) −0.0052 (17) −0.0326 (16) C15 0.157 (3) 0.102 (2) 0.104 (3) 0.030 (2) −0.003 (2) −0.008 (2) C16A 0.083 (3) 0.065 (2) 0.091 (3) 0.0100 (17) 0.027 (2) −0.0236 (19) C17A 0.106 (3) 0.096 (3) 0.100 (3) −0.007 (2) 0.042 (3) −0.022 (2) S1 0.0521 (3) 0.0842 (4) 0.0600 (4) −0.0066 (3) 0.0107 (2) 0.0051 (3) O1 0.1207 (16) 0.1058 (14) 0.0630 (11) 0.0042 (12) 0.0051 (10) 0.0237 (10) O2 0.0845 (13) 0.1046 (14) 0.1157 (16) 0.0043 (10) 0.0427 (12) −0.0098 (12) O3 0.0688 (11) 0.1090 (14) 0.0908 (13) −0.0309 (10) −0.0008 (9) 0.0101 (11) C19 0.0459 (11) 0.1011 (19) 0.0840 (17) −0.0052 (11) 0.0073 (11) 0.0224 (15) C20 0.0568 (16) 0.111 (3) 0.151 (3) −0.0014 (16) 0.0091 (18) 0.052 (2) C21 0.0538 (16) 0.085 (2) 0.229 (5) 0.0030 (14) 0.016 (2) 0.023 (3) C22 0.0698 (18) 0.098 (2) 0.161 (3) 0.0011 (16) 0.022 (2) −0.028 (2) C23 0.0588 (14) 0.100 (2) 0.0860 (18) −0.0017 (13) 0.0138 (12) −0.0064 (15) C24 0.0338 (9) 0.0847 (15) 0.0659 (13) −0.0028 (9) 0.0066 (8) 0.0094 (12) C18 0.0523 (12) 0.0903 (17) 0.0775 (16) 0.0081 (11) 0.0242 (11) 0.0007 (13) O1W 0.1150 (17) 0.157 (2) 0.1059 (16) −0.0526 (15) 0.0468 (13) −0.0250 (15) ------ ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2288 .table-wrap} ----------------------- -------------- ------------------------- -------------- N1---C1 1.360 (3) C15---H15B 0.9600 N1---C5 1.365 (2) C15---H15C 0.9600 N1---C18 1.472 (3) C16A---C17A 1.506 (7) N2---C11 1.365 (3) C16A---H16A 0.9700 N2---C16A 1.471 (4) C16A---H16B 0.9700 N2---C14 1.474 (4) C17A---H17A 0.9600 N2---C16B 1.632 (14) C17A---H17B 0.9600 C1---C2 1.333 (4) C17A---H17C 0.9600 C1---H1A 0.9300 C16B---C17B 1.51 (2) C2---C3 1.389 (4) C16B---H16C 0.9700 C2---H2A 0.9300 C16B---H16D 0.9700 C3---C4 1.371 (3) C17B---H17D 0.9600 C3---H3A 0.9300 C17B---H17E 0.9600 C4---C5 1.397 (3) C17B---H17F 0.9600 C4---H4A 0.9300 S1---O2 1.4395 (18) C5---C6 1.438 (3) S1---O3 1.4398 (17) C6---C7 1.337 (2) S1---O1 1.4414 (18) C6---H6A 0.9300 S1---C24 1.769 (2) C7---C8 1.441 (2) C19---C20 1.372 (4) C7---H7A 0.9300 C19---C24 1.384 (3) C8---C13 1.390 (3) C19---H19A 0.9300 C8---C9 1.396 (2) C20---C21 1.376 (5) C9---C10 1.371 (3) C20---H20A 0.9300 C9---H9A 0.9300 C21---C22 1.385 (5) C10---C11 1.396 (3) C21---H21A 0.9300 C10---H10A 0.9300 C22---C23 1.391 (4) C11---C12 1.401 (3) C22---H22A 0.9300 C12---C13 1.364 (3) C23---C24 1.377 (3) C12---H12A 0.9300 C23---H23A 0.9300 C13---H13A 0.9300 C18---H18A 0.9600 C14---C15 1.454 (4) C18---H18B 0.9600 C14---H14A 0.9700 C18---H18C 0.9600 C14---H14B 0.9700 O1W---H1W1 0.9693 C15---H15A 0.9600 O1W---H2W1 1.0669 C1---N1---C5 121.22 (19) C14---C15---H15B 109.5 C1---N1---C18 117.38 (19) H15A---C15---H15B 109.5 C5---N1---C18 121.40 (17) C14---C15---H15C 109.5 C11---N2---C16A 122.8 (2) H15A---C15---H15C 109.5 C11---N2---C14 121.6 (2) H15B---C15---H15C 109.5 C16A---N2---C14 114.1 (2) N2---C16A---C17A 111.7 (4) C11---N2---C16B 115.0 (5) N2---C16A---H16A 109.3 C14---N2---C16B 115.2 (5) C17A---C16A---H16A 109.3 C2---C1---N1 121.5 (2) N2---C16A---H16B 109.3 C2---C1---H1A 119.2 C17A---C16A---H16B 109.3 N1---C1---H1A 119.2 H16A---C16A---H16B 108.0 C1---C2---C3 119.9 (2) C17B---C16B---N2 96.9 (10) C1---C2---H2A 120.0 C17B---C16B---H16C 112.4 C3---C2---H2A 120.0 N2---C16B---H16C 112.4 C4---C3---C2 118.7 (2) C17B---C16B---H16D 112.4 C4---C3---H3A 120.7 N2---C16B---H16D 112.4 C2---C3---H3A 120.7 H16C---C16B---H16D 109.9 C3---C4---C5 121.3 (2) C16B---C17B---H17D 109.5 C3---C4---H4A 119.3 C16B---C17B---H17E 109.5 C5---C4---H4A 119.3 H17D---C17B---H17E 109.5 N1---C5---C4 117.31 (17) C16B---C17B---H17F 109.5 N1---C5---C6 119.16 (17) H17D---C17B---H17F 109.5 C4---C5---C6 123.50 (17) H17E---C17B---H17F 109.5 C7---C6---C5 124.29 (17) O2---S1---O3 112.89 (13) C7---C6---H6A 117.9 O2---S1---O1 113.17 (13) C5---C6---H6A 117.9 O3---S1---O1 112.36 (12) C6---C7---C8 126.94 (17) O2---S1---C24 106.01 (11) C6---C7---H7A 116.5 O3---S1---C24 104.71 (11) C8---C7---H7A 116.5 O1---S1---C24 106.92 (12) C13---C8---C9 115.87 (17) C20---C19---C24 120.3 (3) C13---C8---C7 123.87 (16) C20---C19---H19A 119.9 C9---C8---C7 120.26 (16) C24---C19---H19A 119.9 C10---C9---C8 122.39 (18) C19---C20---C21 120.3 (3) C10---C9---H9A 118.8 C19---C20---H20A 119.8 C8---C9---H9A 118.8 C21---C20---H20A 119.8 C9---C10---C11 121.40 (18) C20---C21---C22 119.7 (4) C9---C10---H10A 119.3 C20---C21---H21A 120.1 C11---C10---H10A 119.3 C22---C21---H21A 120.1 N2---C11---C10 122.44 (19) C21---C22---C23 120.1 (4) N2---C11---C12 121.4 (2) C21---C22---H22A 119.9 C10---C11---C12 116.11 (19) C23---C22---H22A 119.9 C13---C12---C11 121.91 (19) C24---C23---C22 119.5 (3) C13---C12---H12A 119.0 C24---C23---H23A 120.2 C11---C12---H12A 119.0 C22---C23---H23A 120.2 C12---C13---C8 122.21 (17) C23---C24---C19 120.0 (3) C12---C13---H13A 118.9 C23---C24---S1 121.29 (19) C8---C13---H13A 118.9 C19---C24---S1 118.6 (2) C15---C14---N2 112.6 (3) N1---C18---H18A 109.5 C15---C14---H14A 109.1 N1---C18---H18B 109.5 N2---C14---H14A 109.1 H18A---C18---H18B 109.5 C15---C14---H14B 109.1 N1---C18---H18C 109.5 N2---C14---H14B 109.1 H18A---C18---H18C 109.5 H14A---C14---H14B 107.8 H18B---C18---H18C 109.5 C14---C15---H15A 109.5 H1W1---O1W---H2W1 103.8 C5---N1---C1---C2 −0.3 (3) C10---C11---C12---C13 −2.9 (4) C18---N1---C1---C2 180.0 (2) C11---C12---C13---C8 0.6 (4) N1---C1---C2---C3 0.4 (4) C9---C8---C13---C12 2.1 (3) C1---C2---C3---C4 −0.4 (4) C7---C8---C13---C12 −178.2 (2) C2---C3---C4---C5 0.3 (3) C11---N2---C14---C15 83.8 (4) C1---N1---C5---C4 0.2 (3) C16A---N2---C14---C15 −109.7 (3) C18---N1---C5---C4 179.92 (18) C16B---N2---C14---C15 −63.0 (6) C1---N1---C5---C6 −177.75 (18) C11---N2---C16A---C17A −95.3 (4) C18---N1---C5---C6 2.0 (3) C14---N2---C16A---C17A 98.4 (4) C3---C4---C5---N1 −0.2 (3) C16B---N2---C16A---C17A −3.2 (7) C3---C4---C5---C6 177.6 (2) C11---N2---C16B---C17B 106.1 (7) N1---C5---C6---C7 178.44 (17) C16A---N2---C16B---C17B −6.1 (5) C4---C5---C6---C7 0.7 (3) C14---N2---C16B---C17B −104.8 (7) C5---C6---C7---C8 −179.19 (17) C24---C19---C20---C21 −0.3 (4) C6---C7---C8---C13 −0.1 (3) C19---C20---C21---C22 0.1 (4) C6---C7---C8---C9 179.54 (19) C20---C21---C22---C23 0.1 (4) C13---C8---C9---C10 −2.6 (3) C21---C22---C23---C24 −0.1 (4) C7---C8---C9---C10 177.8 (2) C22---C23---C24---C19 0.0 (3) C8---C9---C10---C11 0.2 (4) C22---C23---C24---S1 178.04 (19) C16A---N2---C11---C10 13.7 (4) C20---C19---C24---C23 0.3 (3) C14---N2---C11---C10 179.0 (3) C20---C19---C24---S1 −177.88 (18) C16B---N2---C11---C10 −34.1 (6) O2---S1---C24---C23 127.83 (19) C16A---N2---C11---C12 −164.7 (3) O3---S1---C24---C23 −112.59 (18) C14---N2---C11---C12 0.6 (4) O1---S1---C24---C23 6.8 (2) C16B---N2---C11---C12 147.5 (5) O2---S1---C24---C19 −54.06 (19) C9---C10---C11---N2 −176.0 (2) O3---S1---C24---C19 65.52 (19) C9---C10---C11---C12 2.5 (4) O1---S1---C24---C19 −175.08 (17) N2---C11---C12---C13 175.6 (2) ----------------------- -------------- ------------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3414 .table-wrap} --------------------------------------------- *Cg*1 is the centroid of the C19--C24 ring. --------------------------------------------- ::: ::: {#d1e3420 .table-wrap} --------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O1W---H1W1···O2^i^ 0.97 1.91 2.821 (3) 156 O1W---H2W1···O1^ii^ 1.07 1.88 2.933 (3) 170 C1---H1A···O3^iii^ 0.93 2.26 3.151 (3) 160 C3---H3A···O2^ii^ 0.93 2.41 3.335 (4) 178 C4---H4A···O1W 0.93 2.50 3.338 (3) 149 C18---H18B···O3 0.96 2.45 3.371 (3) 162 C10---H10A···Cg1^i^ 0.93 2.95 3.741 (2) 144 --------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) *x*+1, *y*, *z*; (ii) *x*+1, −*y*+1/2, *z*+1/2; (iii) *x*, −*y*+1/2, *z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) *Cg*1 is the centroid of the C19--C24 ring. ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ----------------------- --------- ------- ----------- ------------- O1*W*---H1*W*1⋯O2^i^ 0.97 1.91 2.821 (3) 156 O1*W*---H2*W*1⋯O1^ii^ 1.07 1.88 2.933 (3) 170 C1---H1*A*⋯O3^iii^ 0.93 2.26 3.151 (3) 160 C3---H3*A*⋯O2^ii^ 0.93 2.41 3.335 (4) 178 C4---H4*A*⋯O1*W* 0.93 2.50 3.338 (3) 149 C18---H18*B*⋯O3 0.96 2.45 3.371 (3) 162 C10---H10*A*⋯*Cg*1^i^ 0.93 2.95 3.741 (2) 144 Symmetry codes: (i) ; (ii) ; (iii) . ::: [^1]: ‡ Thomson Reuters ResearcherID: A-3561-2009. [^2]: § Additional correspondence author, e-mail: [email protected]. Thomson Reuters ResearcherID: A-5085-2009.

PubMed Central

2024-06-05T04:04:17.605658

2011-2-09

PMC3051969

Related literature {#sec1} ================== For the biological and pharmaceutical properties of benzimidazole derivatives, see: Koči *et al.* (2002[@bb5]); Matsuno *et al.* (2000[@bb6]); Garuti *et al.* (1999[@bb4]). For related structures, see: Rashid *et al.* (2006[@bb9], 2007[@bb8]). For the aryl­sulfonyl­ation of benzimidazole derivatives, see: Abdireimov *et al.* (2010[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~17~H~18~N~2~O~2~S*M* *~r~* = 314.39Monoclinic,*a* = 12.142 (2) Å*b* = 8.8940 (18) Å*c* = 15.324 (3) Åβ = 96.78 (3)°*V* = 1643.3 (6) Å^3^*Z* = 4Cu *K*α radiationμ = 1.82 mm^−1^*T* = 302 K0.60 × 0.25 × 0.22 mm ### Data collection {#sec2.1.2} Stoe Stadi-4 four-circle diffractometerAbsorption correction: ψ scan (North *et al.*, 1968[@bb7]) *T* ~min~ = 0.609, *T* ~max~ = 0.6702727 measured reflections2429 independent reflections1813 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.044θ~max~ = 60.0°3 standard reflections every 60 min intensity decay: 5.2% ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.058*wR*(*F* ^2^) = 0.150*S* = 1.122429 reflections234 parametersH-atom parameters constrainedΔρ~max~ = 0.15 e Å^−3^Δρ~min~ = −0.27 e Å^−3^ {#d5e469} Data collection: *STADI4* (Stoe & Cie, 1997[@bb11]); cell refinement: *STADI4*; data reduction: *X-RED* (Stoe & Cie, 1997[@bb11]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb10]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb10]); molecular graphics: *XP* (Bruker, 1998[@bb3]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb12]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005551/cv5052sup1.cif](http://dx.doi.org/10.1107/S1600536811005551/cv5052sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005551/cv5052Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005551/cv5052Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?cv5052&file=cv5052sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?cv5052sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?cv5052&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [CV5052](http://scripts.iucr.org/cgi-bin/sendsup?cv5052)). We thank the Academy of Sciences of the Republic of Uzbekistan for supporting this study (grant Nos. FA-F3-T045 & FA-A6-T114). Comment ======= Benzimidazole derivatives are important heteroaromatic compounds which have attracted great attention due to their biological and pharmaceutical activities (Koči *et al.*, 2002; Matsuno *et al.*, 2000; Garuti *et al.*, 1999). The title compound has been obtained by the reaction of hydroxymethyl-1*H*-benzimidazole with 4-*tert*-butilbenzolsulfochlorid in the presence of triethylamine (Abdireimov *et al.*, 2010; see also Fig. 1), where occurs deformylation of oxymethyl groups. The structure of the final product was investigated by ^1^H NMR-spectroscopy and X-ray diffraction. The molecule (Fig. 2) consist of two flat fragments - benzimidazolic (N1/C2/N3/C3A--C7A) and benzolic (C8--C13) (r.m.s. deviation = 0.0082 and 0.0017 Å) ones, which form a dihedral angle of 84.1 (1)°. All bond lengths and angles are normal and comparable with those in related structures (Rashid *et al.*, 2006, 2007). The *tert*-butyl group was rotationally disordered over two orientations with occupancies refined to 0.51 (2) and 0.49 (2), respectively. In the crystal structure, weak intermolecular C---H···O hydrogen bonds (Table 1) link the molecules into chains propagated in direction \[010\]. Experimental {#experimental} ============ To three-necked flask supplied with a mixer, containing solution of 2.32 g (10 mmol) 4-*tert*-butilbenzolsulfochloride in 15 ml acetone is added mixture of 1.48 g (10 mmol) 1-hydroxymethyl-1*H*benzimidazole and 1.01 g (10 mmol) triethylamine in 30 ml of acetone. The reaction mixture is mixed at room temperature for 4 h and acetone is evaporated. The rest of mass is washed by 100 ml of water and filtered, and recrystallized from benzine and received 2.61 g (76%) of title compound, m.p. 395--396 K. The colorless crystals suitable for *x*-ray analysis have been grown from absolutized ethanol at room temperature. ^1^H NMR (400 MHz, CDCl~3~): 8.33 (1*H*,s, H-2), 7.85 (3*H*, m, H-4, 5, 6,), 7.71 (1*H*, dd, J═2.1, J═8.2 Hz H-7), 7.45 (2*H*, m, H-9, 13), 7.32 (2*H*, m, H-10, 12), 1.20 (9*H*, s, C(CH~3~)~3~). Refinement {#refinement} ========== The C15, C16 and C17 methyl carbon atoms of a *tert*-butyl group were treated as rotationally disordered over two orientations with site occupancy factors refined to 0.51 (2) and 0.49 (2), respectively. All H atoms were positioned geometrically and treated as riding atoms, with C---H distances of 0.96 Å for CH~3~, 0.93 Å for C~ar~ and included in the refinement in a riding motion approximation, with *U*~iso~=1.2*U*~eq~(C) or *U*~iso~=1.5*U*~eq~(C) for methyl H atoms. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Reaction sequence. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The molecular structure of the title compound, showing the atomic numbering scheme. The displacement ellipsoids are drawn at the 30% probability level. Minor parts of the disordered atoms were omitted for clarity. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e208 .table-wrap} ------------------------- ------------------------------------- C~17~H~18~N~2~O~2~S *F*(000) = 664 *M~r~* = 314.39 *D*~x~ = 1.271 Mg m^−3^ Monoclinic, *P*2~1~/*n* Melting point: 395(1) K Hall symbol: -P 2yn Cu *K*α radiation, λ = 1.54184 Å *a* = 12.142 (2) Å Cell parameters from 14 reflections *b* = 8.8940 (18) Å θ = 10--20° *c* = 15.324 (3) Å µ = 1.82 mm^−1^ β = 96.78 (3)° *T* = 302 K *V* = 1643.3 (6) Å^3^ Prism, colourless *Z* = 4 0.60 × 0.25 × 0.22 mm ------------------------- ------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e340 .table-wrap} ------------------------------------------------------------------------------------------------------------------- -------------------------------------- Stoe Stadi-4 four-circle diffractometer 1813 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.044 graphite θ~max~ = 60.0°, θ~min~ = 4.4° Scan width (ω) = 1.56 -- 1.80, scan ratio 2θ:ω = 1.00 I(Net) and sigma(I) calculated according to Blessing (1987) *h* = −13→13 Absorption correction: ψ scan (North *et al.*, 1968) *k* = 0→9 *T*~min~ = 0.609, *T*~max~ = 0.670 *l* = 0→17 2727 measured reflections 3 standard reflections every 60 min 2429 independent reflections intensity decay: 5.2% ------------------------------------------------------------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e463 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.058 H-atom parameters constrained *wR*(*F*^2^) = 0.150 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0478*P*)^2^ + 1.1618*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.12 (Δ/σ)~max~ \< 0.001 2429 reflections Δρ~max~ = 0.15 e Å^−3^ 234 parameters Δρ~min~ = −0.27 e Å^−3^ 0 restraints Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.0054 (4) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e644 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e743 .table-wrap} ------ -------------- -------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) S1 0.15656 (9) 0.56256 (13) 0.30146 (7) 0.0817 (4) O1 0.2287 (3) 0.6147 (4) 0.24143 (18) 0.1059 (11) O2 0.0939 (3) 0.4275 (3) 0.2866 (2) 0.1116 (11) N1 0.2366 (2) 0.5318 (4) 0.39620 (19) 0.0695 (8) N3 0.2705 (3) 0.4528 (4) 0.5352 (3) 0.0882 (11) C2 0.2092 (4) 0.4382 (5) 0.4623 (3) 0.0855 (12) H2B 0.1509 0.3700 0.4542 0.103\* C3A 0.3453 (3) 0.5650 (4) 0.5199 (3) 0.0678 (10) C4 0.4313 (4) 0.6232 (5) 0.5767 (3) 0.0857 (12) H4A 0.4460 0.5875 0.6340 0.103\* C5 0.4939 (4) 0.7339 (6) 0.5467 (4) 0.0924 (13) H5A 0.5514 0.7757 0.5845 0.111\* C6 0.4741 (4) 0.7862 (5) 0.4611 (4) 0.0907 (13) H6A 0.5189 0.8618 0.4425 0.109\* C7 0.3901 (3) 0.7286 (4) 0.4032 (3) 0.0764 (11) H7A 0.3773 0.7625 0.3455 0.092\* C7A 0.3259 (3) 0.6188 (4) 0.4344 (2) 0.0621 (9) C8 0.0676 (3) 0.7078 (4) 0.3232 (2) 0.0593 (9) C9 −0.0313 (3) 0.6758 (4) 0.3528 (2) 0.0639 (9) H9A −0.0507 0.5766 0.3627 0.077\* C10 −0.1020 (3) 0.7904 (4) 0.3678 (2) 0.0635 (9) H10A −0.1696 0.7674 0.3875 0.076\* C11 −0.0760 (3) 0.9392 (4) 0.3545 (2) 0.0542 (8) C12 0.0251 (3) 0.9681 (4) 0.3244 (2) 0.0673 (10) H12A 0.0450 1.0670 0.3146 0.081\* C13 0.0966 (3) 0.8541 (4) 0.3086 (2) 0.0672 (10) H13A 0.1640 0.8759 0.2883 0.081\* C14 −0.1562 (3) 1.0652 (5) 0.3703 (3) 0.0709 (10) C15 −0.2610 (16) 1.044 (3) 0.3059 (11) 0.131 (7) 0.51 (2) H15A −0.3100 1.1275 0.3104 0.197\* 0.51 (2) H15B −0.2974 0.9526 0.3196 0.197\* 0.51 (2) H15C −0.2413 1.0382 0.2471 0.197\* 0.51 (2) C16 −0.113 (2) 1.2215 (18) 0.361 (3) 0.234 (18) 0.51 (2) H16A −0.0440 1.2326 0.3985 0.351\* 0.51 (2) H16B −0.1658 1.2926 0.3788 0.351\* 0.51 (2) H16C −0.1015 1.2394 0.3015 0.351\* 0.51 (2) C17 −0.1958 (18) 1.047 (2) 0.4597 (8) 0.142 (10) 0.51 (2) H17A −0.1330 1.0447 0.5041 0.214\* 0.51 (2) H17B −0.2367 0.9549 0.4613 0.214\* 0.51 (2) H17C −0.2428 1.1302 0.4706 0.214\* 0.51 (2) C15A −0.0948 (12) 1.1855 (16) 0.4249 (10) 0.093 (5) 0.49 (2) H15D −0.1469 1.2544 0.4454 0.140\* 0.49 (2) H15E −0.0470 1.2386 0.3899 0.140\* 0.49 (2) H15F −0.0511 1.1403 0.4743 0.140\* 0.49 (2) C16A −0.248 (2) 1.013 (2) 0.415 (3) 0.233 (19) 0.49 (2) H16D −0.2963 1.0962 0.4239 0.350\* 0.49 (2) H16E −0.2204 0.9706 0.4708 0.350\* 0.49 (2) H16F −0.2894 0.9380 0.3797 0.350\* 0.49 (2) C17A −0.192 (3) 1.141 (3) 0.2816 (11) 0.150 (10) 0.49 (2) H17D −0.2465 1.2174 0.2891 0.226\* 0.49 (2) H17E −0.2240 1.0676 0.2403 0.226\* 0.49 (2) H17F −0.1290 1.1865 0.2600 0.226\* 0.49 (2) ------ -------------- -------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1492 .table-wrap} ------ ------------- ------------ ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.0854 (7) 0.0894 (8) 0.0698 (6) 0.0210 (6) 0.0072 (5) −0.0219 (6) O1 0.112 (2) 0.145 (3) 0.0660 (17) 0.044 (2) 0.0306 (16) −0.0054 (18) O2 0.116 (2) 0.087 (2) 0.126 (3) 0.0087 (19) −0.012 (2) −0.0552 (19) N1 0.0673 (19) 0.069 (2) 0.0716 (19) 0.0118 (16) 0.0044 (16) 0.0041 (16) N3 0.083 (2) 0.086 (3) 0.096 (3) 0.001 (2) 0.014 (2) 0.026 (2) C2 0.080 (3) 0.067 (3) 0.112 (4) 0.000 (2) 0.020 (3) 0.016 (3) C3A 0.061 (2) 0.068 (2) 0.075 (2) 0.0119 (19) 0.0132 (19) 0.008 (2) C4 0.082 (3) 0.095 (3) 0.079 (3) 0.012 (3) 0.007 (2) 0.006 (2) C5 0.071 (3) 0.094 (3) 0.111 (4) 0.004 (3) 0.003 (3) −0.015 (3) C6 0.073 (3) 0.075 (3) 0.128 (4) −0.003 (2) 0.023 (3) 0.006 (3) C7 0.075 (3) 0.070 (3) 0.087 (3) 0.012 (2) 0.024 (2) 0.019 (2) C7A 0.059 (2) 0.059 (2) 0.070 (2) 0.0141 (18) 0.0141 (17) 0.0043 (18) C8 0.057 (2) 0.070 (2) 0.0502 (19) 0.0035 (18) 0.0041 (15) −0.0080 (17) C9 0.060 (2) 0.058 (2) 0.071 (2) −0.0046 (18) 0.0000 (18) −0.0060 (18) C10 0.050 (2) 0.071 (2) 0.069 (2) −0.0058 (18) 0.0079 (16) −0.0093 (19) C11 0.0482 (18) 0.062 (2) 0.0502 (18) −0.0012 (16) −0.0024 (14) −0.0048 (16) C12 0.067 (2) 0.059 (2) 0.076 (2) −0.0038 (19) 0.0100 (19) 0.0078 (19) C13 0.058 (2) 0.081 (3) 0.065 (2) −0.002 (2) 0.0149 (17) 0.005 (2) C14 0.063 (2) 0.074 (3) 0.074 (2) 0.011 (2) 0.0002 (18) −0.006 (2) C15 0.100 (10) 0.177 (19) 0.106 (11) 0.076 (11) −0.037 (8) −0.032 (11) C16 0.17 (2) 0.069 (9) 0.49 (6) 0.027 (10) 0.14 (3) 0.05 (2) C17 0.20 (2) 0.153 (18) 0.071 (8) 0.102 (16) 0.023 (8) −0.007 (8) C15A 0.095 (7) 0.057 (8) 0.122 (9) 0.014 (7) −0.010 (7) −0.037 (7) C16A 0.157 (18) 0.104 (11) 0.48 (5) −0.015 (13) 0.23 (3) −0.07 (2) C17A 0.18 (2) 0.153 (18) 0.105 (10) 0.096 (16) −0.050 (13) −0.022 (11) ------ ------------- ------------ ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1966 .table-wrap} --------------------- ------------- ------------------------ ------------- S1---O1 1.421 (3) C12---C13 1.375 (5) S1---O2 1.426 (3) C12---H12A 0.9300 S1---N1 1.671 (3) C13---H13A 0.9300 S1---C8 1.742 (3) C14---C16A 1.455 (17) N1---C2 1.381 (5) C14---C16 1.498 (17) N1---C7A 1.402 (5) C14---C15A 1.501 (12) N3---C2 1.274 (5) C14---C17 1.513 (15) N3---C3A 1.387 (5) C14---C15 1.527 (15) C2---H2B 0.9300 C14---C17A 1.535 (18) C3A---C4 1.379 (5) C15---H15A 0.9600 C3A---C7A 1.389 (5) C15---H15B 0.9600 C4---C5 1.357 (6) C15---H15C 0.9600 C4---H4A 0.9300 C16---H16A 0.9600 C5---C6 1.386 (6) C16---H16B 0.9600 C5---H5A 0.9300 C16---H16C 0.9600 C6---C7 1.369 (6) C17---H17A 0.9600 C6---H6A 0.9300 C17---H17B 0.9600 C7---C7A 1.371 (5) C17---H17C 0.9600 C7---H7A 0.9300 C15A---H15D 0.9600 C8---C9 1.363 (5) C15A---H15E 0.9600 C8---C13 1.373 (5) C15A---H15F 0.9600 C9---C10 1.369 (5) C16A---H16D 0.9600 C9---H9A 0.9300 C16A---H16E 0.9600 C10---C11 1.381 (5) C16A---H16F 0.9600 C10---H10A 0.9300 C17A---H17D 0.9600 C11---C12 1.385 (5) C17A---H17E 0.9600 C11---C14 1.523 (5) C17A---H17F 0.9600 O1---S1---O2 122.0 (2) C13---C12---H12A 119.2 O1---S1---N1 106.03 (18) C11---C12---H12A 119.2 O2---S1---N1 104.21 (19) C8---C13---C12 119.4 (3) O1---S1---C8 109.00 (19) C8---C13---H13A 120.3 O2---S1---C8 108.89 (18) C12---C13---H13A 120.3 N1---S1---C8 105.39 (15) C16A---C14---C15A 109.0 (13) C2---N1---C7A 105.5 (3) C16---C14---C17 109.4 (14) C2---N1---S1 124.7 (3) C16A---C14---C11 112.5 (8) C7A---N1---S1 127.9 (3) C16---C14---C11 115.5 (8) C2---N3---C3A 104.6 (4) C15A---C14---C11 109.1 (6) N3---C2---N1 114.5 (4) C17---C14---C11 110.1 (7) N3---C2---H2B 122.7 C16---C14---C15 109.3 (12) N1---C2---H2B 122.7 C17---C14---C15 104.1 (10) C4---C3A---N3 128.7 (4) C11---C14---C15 107.8 (7) C4---C3A---C7A 119.9 (4) C16A---C14---C17A 113.7 (12) N3---C3A---C7A 111.4 (4) C15A---C14---C17A 104.5 (10) C5---C4---C3A 118.1 (4) C11---C14---C17A 107.7 (7) C5---C4---H4A 120.9 C14---C15---H15A 109.5 C3A---C4---H4A 120.9 C14---C15---H15B 109.5 C4---C5---C6 121.5 (4) C14---C15---H15C 109.5 C4---C5---H5A 119.2 C14---C16---H16A 109.5 C6---C5---H5A 119.2 C14---C16---H16B 109.5 C7---C6---C5 121.4 (4) C14---C16---H16C 109.5 C7---C6---H6A 119.3 C14---C17---H17A 109.5 C5---C6---H6A 119.3 C14---C17---H17B 109.5 C6---C7---C7A 116.8 (4) C14---C17---H17C 109.5 C6---C7---H7A 121.6 C14---C15A---H15D 109.5 C7A---C7---H7A 121.6 C14---C15A---H15E 109.5 C7---C7A---C3A 122.3 (4) H15D---C15A---H15E 109.5 C7---C7A---N1 133.7 (4) C14---C15A---H15F 109.5 C3A---C7A---N1 104.0 (3) H15D---C15A---H15F 109.5 C9---C8---C13 120.4 (3) H15E---C15A---H15F 109.5 C9---C8---S1 120.0 (3) C14---C16A---H16D 109.5 C13---C8---S1 119.7 (3) C14---C16A---H16E 109.5 C8---C9---C10 119.6 (3) H16D---C16A---H16E 109.5 C8---C9---H9A 120.2 C14---C16A---H16F 109.5 C10---C9---H9A 120.2 H16D---C16A---H16F 109.5 C9---C10---C11 122.0 (3) H16E---C16A---H16F 109.5 C9---C10---H10A 119.0 C14---C17A---H17D 109.5 C11---C10---H10A 119.0 C14---C17A---H17E 109.5 C10---C11---C12 117.0 (3) H17D---C17A---H17E 109.5 C10---C11---C14 121.3 (3) C14---C17A---H17F 109.5 C12---C11---C14 121.7 (3) H17D---C17A---H17F 109.5 C13---C12---C11 121.7 (3) H17E---C17A---H17F 109.5 O1---S1---N1---C2 −158.3 (3) O2---S1---C8---C9 22.1 (3) O2---S1---N1---C2 −28.4 (4) N1---S1---C8---C9 −89.2 (3) C8---S1---N1---C2 86.2 (3) O1---S1---C8---C13 −21.3 (3) O1---S1---N1---C7A 39.6 (4) O2---S1---C8---C13 −156.6 (3) O2---S1---N1---C7A 169.5 (3) N1---S1---C8---C13 92.1 (3) C8---S1---N1---C7A −75.9 (3) C13---C8---C9---C10 0.2 (5) C3A---N3---C2---N1 0.6 (5) S1---C8---C9---C10 −178.5 (3) C7A---N1---C2---N3 −1.4 (5) C8---C9---C10---C11 −0.5 (5) S1---N1---C2---N3 −166.9 (3) C9---C10---C11---C12 0.5 (5) C2---N3---C3A---C4 −178.8 (4) C9---C10---C11---C14 179.2 (3) C2---N3---C3A---C7A 0.5 (5) C10---C11---C12---C13 −0.2 (5) N3---C3A---C4---C5 −179.9 (4) C14---C11---C12---C13 −178.8 (3) C7A---C3A---C4---C5 0.8 (6) C9---C8---C13---C12 0.1 (5) C3A---C4---C5---C6 −1.2 (7) S1---C8---C13---C12 178.8 (3) C4---C5---C6---C7 0.3 (7) C11---C12---C13---C8 −0.1 (5) C5---C6---C7---C7A 0.9 (6) C10---C11---C14---C16A 10.7 (19) C6---C7---C7A---C3A −1.2 (5) C12---C11---C14---C16A −170.7 (19) C6---C7---C7A---N1 −178.1 (4) C10---C11---C14---C16 174 (2) C4---C3A---C7A---C7 0.4 (6) C12---C11---C14---C16 −7(2) N3---C3A---C7A---C7 −179.0 (3) C10---C11---C14---C15A 131.8 (8) C4---C3A---C7A---N1 178.0 (3) C12---C11---C14---C15A −49.7 (8) N3---C3A---C7A---N1 −1.3 (4) C10---C11---C14---C17 49.9 (10) C2---N1---C7A---C7 178.8 (4) C12---C11---C14---C17 −131.5 (10) S1---N1---C7A---C7 −16.3 (6) C10---C11---C14---C15 −63.0 (13) C2---N1---C7A---C3A 1.6 (4) C12---C11---C14---C15 115.6 (13) S1---N1---C7A---C3A 166.4 (3) C10---C11---C14---C17A −115.3 (15) O1---S1---C8---C9 157.3 (3) C12---C11---C14---C17A 63.2 (15) --------------------- ------------- ------------------------ ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2937 .table-wrap} -------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C7---H7A···O2^i^ 0.93 2.56 3.430 (5) 156 C13---H13A···O1^i^ 0.93 2.56 3.292 (5) 136 -------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1/2, *y*+1/2, −*z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- --------- ------- ----------- ------------- C7---H7*A*⋯O2^i^ 0.93 2.56 3.430 (5) 156 C13---H13*A*⋯O1^i^ 0.93 2.56 3.292 (5) 136 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.614040

2011-2-26

PMC3051970

Related literature {#sec1} ================== For related structures, see: Bouacida (2008[@bb2]); Bouacida *et al.* (2005[@bb4], 2009[@bb3]); Casellato *et al.* (1995[@bb7]); Cherouana *et al.* (2003[@bb8]). For standard bond lengths see: Allen *et al.* (1987[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} (C~4~H~6~N~3~O)~2~\[InCl~5~(H~2~O)\]*M* *~r~* = 534.32Triclinic,*a* = 6.863 (1) Å*b* = 10.487 (2) Å*c* = 12.765 (2) Åα = 104.608 (1)°β = 97.998 (1)°γ = 98.121 (1)°*V* = 865.3 (2) Å^3^*Z* = 2Mo *K*α radiationμ = 2.16 mm^−1^*T* = 295 K0.18 × 0.09 × 0.07 mm ### Data collection {#sec2.1.2} Nonius KappaCCD diffractometer18109 measured reflections3933 independent reflections3572 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.032 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.020*wR*(*F* ^2^) = 0.048*S* = 1.073929 reflections214 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.35 e Å^−3^Δρ~min~ = −0.61 e Å^−3^ {#d5e676} Data collection: *COLLECT* (Nonius, 1998[@bb10]); cell refinement: *SCALEPACK* (Otwinowski & Minor, 1997[@bb11]); data reduction: *DENZO* (Otwinowski & Minor, 1997[@bb11]) and *SCALEPACK*; program(s) used to solve structure: *SIR2002* (Burla *et al.*, 2003[@bb6]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb12]); molecular graphics: *PLATON* (Spek, 2009[@bb13]) and *DIAMOND* (Brandenburg *et al.*, 2001[@bb5]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb9]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811004235/lh5204sup1.cif](http://dx.doi.org/10.1107/S1600536811004235/lh5204sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004235/lh5204Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004235/lh5204Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?lh5204&file=lh5204sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?lh5204sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?lh5204&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [LH5204](http://scripts.iucr.org/cgi-bin/sendsup?lh5204)). This work was supported by the Unité de Recherche de Chimie de l'Environnement et Moléculaire Structurale, CHEMS, Université Mentouri-Constantine, Algeria. Comment ======= The title compound, was prepared as part of our ongoing studies of hydrogen-bonding interaction in the crystal structures of protonated amines (Bouacida, 2008; Bouacida *et al.*, 2009). The asymmetric unit of the title compound (I) is shown in Fig. 1. The bond distances (Allen *et al.* 1987) and angles are within the ranges of accepted values. In the title compound the imine N atom is protonated as in other related structures (Bouacida *et al.*, 2005; Casellato, *et al.* 1995; Cherouana *et al.*, 2003). The In atom is six-coordinated (by five chlorine atoms and one water molecule) forming a slightly-distorted octahedral geometry. In the crystal structure alternating layers of cations and anions are arranged along \[010\] and are linked *via* intermolecular N---H···O, O---H···Cl and N---H···Cl hydrogen bonds to form a two-dimensional sheets parallel to (001) (see Fig. 2). Additional stabilization within these sheeets is provided by weak intermolecular C---H···O interactions. Experimental {#experimental} ============ A solution of 1 mmol InCl~3~ and 2 mmol cytosine in hydrochloric acid was slowly evaporated to dryness over a period of two weeks yielding red crystals suitable for X-ray diffraction. Refinement {#refinement} ========== All H atoms were visible in differnce Fourier maps but were introduced in calculated positions and treated as riding on C and N atoms with C---H = 0.93Å and N---H = 0.86Å and *U*~iso~(H) = 1.2(C,N). The water H atoms were located in a difference Fourier map and their positions were refined with *U*~iso~(H) =1.5 *U*~eq~(O). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of the title compound with displacement ellipsoids drawn at the 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Part of the crystal structure with hydrogen bonds shown as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e132 .table-wrap} ------------------------------------ --------------------------------------- (C~4~H~6~N~3~O)~2~\[InCl~5~(H2O)\] *Z* = 2 *M~r~* = 534.32 *F*(000) = 524 Triclinic, *P*1 *D*~x~ = 2.051 Mg m^−3^ *a* = 6.863 (1) Å Mo *K*α radiation, λ = 0.71073 Å *b* = 10.487 (2) Å Cell parameters from 8762 reflections *c* = 12.765 (2) Å θ = 3.1--27.5° α = 104.608 (1)° µ = 2.16 mm^−1^ β = 97.998 (1)° *T* = 295 K γ = 98.121 (1)° Needle, red *V* = 865.3 (2) Å^3^ 0.18 × 0.09 × 0.07 mm ------------------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e267 .table-wrap} ----------------------------------------- ------------------------------- Nonius KappaCCD diffractometer *R*~int~ = 0.032 graphite θ~max~ = 27.6°, θ~min~ = 1.7° CCD rotation images, thick slices scans *h* = −8→8 18109 measured reflections *k* = −13→13 3933 independent reflections *l* = −16→16 3572 reflections with *I* \> 2σ(*I*) ----------------------------------------- ------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e359 .table-wrap} ------------------------------------ ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.02 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.048 H atoms treated by a mixture of independent and constrained refinement *S* = 1.07 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0229*P*)^2^ + 0.0464*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 3929 reflections (Δ/σ)~max~ = 0.002 214 parameters Δρ~max~ = 0.35 e Å^−3^ 0 restraints Δρ~min~ = −0.61 e Å^−3^ ------------------------------------ ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e516 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger.4 bad reflections were omitted from the refinement ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e617 .table-wrap} ------ --------------- --------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ In1 0.550968 (18) 0.423292 (12) 0.265050 (10) 0.02044 (5) Cl2 0.68990 (8) 0.33651 (5) 0.42094 (4) 0.03022 (11) Cl3 0.35973 (7) 0.19643 (4) 0.16412 (4) 0.02749 (11) Cl4 0.36901 (7) 0.51814 (5) 0.13047 (4) 0.03375 (12) Cl5 0.68860 (8) 0.65285 (5) 0.38414 (5) 0.03400 (12) Cl1 0.84669 (8) 0.39953 (6) 0.17617 (5) 0.03882 (13) N2B 0.6503 (2) −0.06652 (16) 0.62369 (13) 0.0249 (4) H2B 0.5921 −0.1469 0.6175 0.03\* O1B 0.3547 (2) 0.00633 (15) 0.63256 (14) 0.0405 (4) N6A 0.3443 (2) 0.01389 (16) 0.88504 (14) 0.0282 (4) H6A 0.411 −0.0502 0.8804 0.034\* O1A 0.6221 (2) 0.16293 (15) 0.89141 (15) 0.0455 (4) N6B 0.6325 (2) 0.15524 (17) 0.63714 (15) 0.0316 (4) H6B 0.5662 0.2195 0.641 0.038\* N7B 0.9460 (2) −0.14472 (16) 0.62174 (14) 0.0304 (4) H71B 0.8827 −0.2227 0.619 0.037\* H72B 1.0728 −0.1321 0.6225 0.037\* C4B 0.9437 (3) 0.08585 (19) 0.63066 (16) 0.0264 (4) H4B 1.08 0.1051 0.6303 0.032\* C3B 0.8491 (3) −0.04516 (19) 0.62486 (15) 0.0227 (4) C4A 0.0348 (3) 0.08195 (19) 0.89372 (16) 0.0258 (4) H4A −0.1012 0.0624 0.8951 0.031\* C5B 0.8318 (3) 0.1819 (2) 0.63676 (17) 0.0302 (5) H5B 0.8922 0.2685 0.6408 0.036\* C1B 0.5332 (3) 0.0312 (2) 0.63174 (16) 0.0266 (4) C3A 0.1280 (3) 0.21374 (18) 0.90100 (15) 0.0234 (4) O1W 0.2642 (2) 0.42641 (16) 0.35025 (13) 0.0319 (3) H1W 0.166 (4) 0.433 (2) 0.312 (2) 0.048\* H2W 0.272 (4) 0.487 (3) 0.402 (2) 0.048\* C5A 0.1454 (3) −0.01407 (19) 0.88486 (16) 0.0267 (4) H3A 0.0849 −0.1015 0.8785 0.032\* C1A 0.4435 (3) 0.1381 (2) 0.89219 (17) 0.0284 (4) N7A 0.0296 (3) 0.31296 (17) 0.90638 (15) 0.0354 (4) H72A 0.091 0.3911 0.9082 0.042\* H71A −0.0963 0.2999 0.9081 0.042\* N2A 0.3263 (2) 0.23531 (16) 0.89832 (14) 0.0258 (4) H2A 0.3828 0.3148 0.9006 0.031\* ------ --------------- --------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1122 .table-wrap} ----- ------------- ------------- ------------- -------------- ------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ In1 0.01960 (8) 0.01626 (7) 0.02516 (8) 0.00200 (5) 0.00384 (5) 0.00607 (5) Cl2 0.0331 (3) 0.0272 (2) 0.0304 (3) 0.0062 (2) 0.0002 (2) 0.0106 (2) Cl3 0.0290 (3) 0.0184 (2) 0.0310 (3) 0.00087 (18) 0.0023 (2) 0.00312 (19) Cl4 0.0287 (3) 0.0312 (3) 0.0428 (3) 0.0015 (2) −0.0020 (2) 0.0198 (2) Cl5 0.0313 (3) 0.0185 (2) 0.0444 (3) −0.0001 (2) −0.0013 (2) 0.0017 (2) Cl1 0.0277 (3) 0.0490 (3) 0.0454 (3) 0.0106 (2) 0.0166 (2) 0.0159 (3) N2B 0.0211 (8) 0.0216 (8) 0.0346 (9) 0.0037 (6) 0.0062 (7) 0.0118 (7) O1B 0.0207 (8) 0.0379 (9) 0.0675 (11) 0.0080 (7) 0.0129 (7) 0.0187 (8) N6A 0.0253 (9) 0.0235 (8) 0.0384 (10) 0.0089 (7) 0.0066 (8) 0.0101 (7) O1A 0.0206 (8) 0.0371 (9) 0.0813 (13) 0.0066 (7) 0.0145 (8) 0.0175 (9) N6B 0.0244 (9) 0.0256 (9) 0.0501 (11) 0.0096 (7) 0.0088 (8) 0.0162 (8) N7B 0.0255 (9) 0.0268 (9) 0.0386 (10) 0.0071 (7) 0.0055 (8) 0.0072 (8) C4B 0.0183 (9) 0.0304 (11) 0.0312 (11) 0.0022 (8) 0.0048 (8) 0.0113 (9) C3B 0.0229 (10) 0.0257 (10) 0.0193 (9) 0.0051 (8) 0.0034 (7) 0.0060 (8) C4A 0.0180 (9) 0.0301 (11) 0.0288 (11) 0.0011 (8) 0.0043 (8) 0.0093 (8) C5B 0.0268 (11) 0.0241 (10) 0.0402 (12) −0.0012 (8) 0.0051 (9) 0.0135 (9) C1B 0.0215 (10) 0.0310 (11) 0.0306 (11) 0.0079 (8) 0.0062 (8) 0.0122 (9) C3A 0.0212 (9) 0.0230 (9) 0.0243 (10) 0.0035 (8) 0.0038 (8) 0.0041 (8) O1W 0.0262 (8) 0.0365 (9) 0.0297 (8) 0.0082 (7) 0.0045 (6) 0.0022 (6) C5A 0.0263 (10) 0.0246 (10) 0.0276 (11) −0.0005 (8) 0.0041 (8) 0.0079 (8) C1A 0.0219 (10) 0.0284 (10) 0.0353 (11) 0.0061 (8) 0.0069 (9) 0.0078 (9) N7A 0.0239 (9) 0.0265 (9) 0.0529 (12) 0.0052 (7) 0.0076 (8) 0.0054 (8) N2A 0.0191 (8) 0.0216 (8) 0.0372 (10) 0.0015 (6) 0.0062 (7) 0.0095 (7) ----- ------------- ------------- ------------- -------------- ------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1524 .table-wrap} ----------------------- -------------- ----------------------- -------------- In1---O1W 2.3776 (15) N7B---H71B 0.86 In1---Cl1 2.4718 (6) N7B---H72B 0.86 In1---Cl5 2.4720 (6) C4B---C5B 1.344 (3) In1---Cl4 2.4730 (6) C4B---C3B 1.413 (3) In1---Cl3 2.4787 (6) C4B---H4B 0.93 In1---Cl2 2.5155 (6) C4A---C5A 1.337 (3) N2B---C3B 1.349 (2) C4A---C3A 1.413 (3) N2B---C1B 1.381 (2) C4A---H4A 0.93 N2B---H2B 0.86 C5B---H5B 0.93 O1B---C1B 1.218 (2) C3A---N7A 1.311 (2) N6A---C5A 1.354 (2) C3A---N2A 1.355 (2) N6A---C1A 1.356 (3) O1W---H1W 0.80 (2) N6A---H6A 0.86 O1W---H2W 0.78 (3) O1A---C1A 1.218 (2) C5A---H3A 0.93 N6B---C5B 1.357 (2) C1A---N2A 1.379 (2) N6B---C1B 1.361 (2) N7A---H72A 0.86 N6B---H6B 0.86 N7A---H71A 0.86 N7B---C3B 1.310 (2) N2A---H2A 0.86 O1W---In1---Cl1 175.07 (4) N7B---C3B---N2B 119.31 (17) O1W---In1---Cl5 88.65 (4) N7B---C3B---C4B 123.05 (17) Cl1---In1---Cl5 95.26 (2) N2B---C3B---C4B 117.64 (17) O1W---In1---Cl4 86.45 (4) C5A---C4A---C3A 118.82 (17) Cl1---In1---Cl4 96.55 (2) C5A---C4A---H4A 120.6 Cl5---In1---Cl4 89.56 (2) C3A---C4A---H4A 120.6 O1W---In1---Cl3 80.65 (4) C4B---C5B---N6B 121.53 (18) Cl1---In1---Cl3 95.42 (2) C4B---C5B---H5B 119.2 Cl5---In1---Cl3 169.296 (17) N6B---C5B---H5B 119.2 Cl4---In1---Cl3 89.95 (2) O1B---C1B---N6B 123.31 (18) O1W---In1---Cl2 83.91 (4) O1B---C1B---N2B 121.90 (18) Cl1---In1---Cl2 93.21 (2) N6B---C1B---N2B 114.78 (16) Cl5---In1---Cl2 88.07 (2) N7A---C3A---N2A 119.53 (17) Cl4---In1---Cl2 170.125 (18) N7A---C3A---C4A 122.86 (18) Cl3---In1---Cl2 90.60 (2) N2A---C3A---C4A 117.57 (17) C3B---N2B---C1B 124.87 (16) In1---O1W---H1W 114.4 (18) C3B---N2B---H2B 117.6 In1---O1W---H2W 115.7 (19) C1B---N2B---H2B 117.6 H1W---O1W---H2W 101 (2) C5A---N6A---C1A 123.24 (17) C4A---C5A---N6A 121.06 (18) C5A---N6A---H6A 118.4 C4A---C5A---H3A 119.5 C1A---N6A---H6A 118.4 N6A---C5A---H3A 119.5 C5B---N6B---C1B 122.77 (17) O1A---C1A---N6A 123.22 (18) C5B---N6B---H6B 118.6 O1A---C1A---N2A 121.78 (18) C1B---N6B---H6B 118.6 N6A---C1A---N2A 114.99 (17) C3B---N7B---H71B 120 C3A---N7A---H72A 120 C3B---N7B---H72B 120 C3A---N7A---H71A 120 H71B---N7B---H72B 120 H72A---N7A---H71A 120 C5B---C4B---C3B 118.37 (18) C3A---N2A---C1A 124.27 (16) C5B---C4B---H4B 120.8 C3A---N2A---H2A 117.9 C3B---C4B---H4B 120.8 C1A---N2A---H2A 117.9 C1B---N2B---C3B---N7B 176.87 (18) C5A---C4A---C3A---N7A 177.79 (19) C1B---N2B---C3B---C4B −2.5 (3) C5A---C4A---C3A---N2A 0.1 (3) C5B---C4B---C3B---N7B −178.07 (19) C3A---C4A---C5A---N6A 1.3 (3) C5B---C4B---C3B---N2B 1.2 (3) C1A---N6A---C5A---C4A −1.1 (3) C3B---C4B---C5B---N6B −0.2 (3) C5A---N6A---C1A---O1A −179.4 (2) C1B---N6B---C5B---C4B 0.2 (3) C5A---N6A---C1A---N2A −0.6 (3) C5B---N6B---C1B---O1B 179.6 (2) N7A---C3A---N2A---C1A −179.71 (19) C5B---N6B---C1B---N2B −1.2 (3) C4A---C3A---N2A---C1A −2.0 (3) C3B---N2B---C1B---O1B −178.40 (19) O1A---C1A---N2A---C3A −179.1 (2) C3B---N2B---C1B---N6B 2.4 (3) N6A---C1A---N2A---C3A 2.2 (3) ----------------------- -------------- ----------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2099 .table-wrap} ----------------------- ---------- ---------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O1W---H1W···Cl1^i^ 0.80 (3) 2.52 (3) 3.3033 (17) 167 (2) N2A---H2A···Cl4^ii^ 0.86 2.41 3.2185 (18) 156 N2B---H2B···Cl2^iii^ 0.86 2.47 3.2774 (18) 157 O1W---H2W···Cl2^ii^ 0.78 (3) 2.49 (3) 3.2667 (18) 174 (3) N6A---H6A···Cl3^iii^ 0.86 2.37 3.2104 (17) 164 N6B---H6B···Cl5^ii^ 0.86 2.38 3.2160 (18) 163 N7A---H71A···O1A^i^ 0.86 2.19 2.965 (3) 150 N7B---H71B···O1W^iii^ 0.86 2.38 3.226 (3) 168 N7A---H72A···Cl1^ii^ 0.86 2.69 3.471 (2) 152 N7B---H72B···O1B^iv^ 0.86 2.22 2.987 (3) 149 C4A---H4A···O1A^i^ 0.93 2.30 3.068 (3) 140 C4B---H4B···O1B^iv^ 0.93 2.28 3.051 (3) 140 ----------------------- ---------- ---------- ------------- --------------- ::: Symmetry codes: (i) *x*−1, *y*, *z*; (ii) −*x*+1, −*y*+1, −*z*+1; (iii) −*x*+1, −*y*, −*z*+1; (iv) *x*+1, *y*, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------------- ---------- ---------- ------------- ------------- O1*W*---H1*W*⋯Cl1^i^ 0.80 (3) 2.52 (3) 3.3033 (17) 167 (2) N2*A*---H2*A*⋯Cl4^ii^ 0.86 2.41 3.2185 (18) 156 N2*B*---H2*B*⋯Cl2^iii^ 0.86 2.47 3.2774 (18) 157 O1*W*---H2*W*⋯Cl2^ii^ 0.78 (3) 2.49 (3) 3.2667 (18) 174 (3) N6*A*---H6*A*⋯Cl3^iii^ 0.86 2.37 3.2104 (17) 164 N6*B*---H6*B*⋯Cl5^ii^ 0.86 2.38 3.2160 (18) 163 N7*A*---H71*A*⋯O1*A*^i^ 0.86 2.19 2.965 (3) 150 N7*B*---H71*B*⋯O1*W*^iii^ 0.86 2.38 3.226 (3) 168 N7*A*---H72*A*⋯Cl1^ii^ 0.86 2.69 3.471 (2) 152 N7*B*---H72*B*⋯O1*B*^iv^ 0.86 2.22 2.987 (3) 149 C4*A*---H4*A*⋯O1*A*^i^ 0.93 2.30 3.068 (3) 140 C4*B*---H4*B*⋯O1*B*^iv^ 0.93 2.28 3.051 (3) 140 Symmetry codes: (i) ; (ii) ; (iii) ; (iv) . ::: [^1]: ‡ Current address: Département Sciences de la Matière, Facult des Sciences Exactes et Sciences de la Nature et de la Vie, Universit Larbi Ben M'hidi, Oum El Bouaghi 04000, Algeria.

PubMed Central

2024-06-05T04:04:17.620452

2011-2-12

PMC3051971

Related literature {#sec1} ================== For the only reported crystal structure of a compound possessing a propylyl­amino unit, see: Steiner *et al.* (1999[@bb5]). For the structure of 1,4-bis­(4-amino­phenoxl)benzene, see: Shemsi *et al.* (2008[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~30~H~24~N~2~O~2~*M* *~r~* = 444.51Triclinic,*a* = 9.8766 (7) Å*b* = 11.1635 (6) Å*c* = 12.1531 (9) Åα = 68.687 (6)°β = 69.601 (7)°γ = 88.529 (5)°*V* = 1162.19 (13) Å^3^*Z* = 2Mo *K*α radiationμ = 0.08 mm^−1^*T* = 100 K0.30 × 0.10 × 0.05 mm ### Data collection {#sec2.1.2} Agilent SuperNova Dual diffractometer with an Atlas detectorAbsorption correction: multi-scan (*CrysAlis PRO*; Agilent, 2010[@bb1]) *T* ~min~ = 0.712, *T* ~max~ = 1.0009192 measured reflections5142 independent reflections3245 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.051 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.063*wR*(*F* ^2^) = 0.172*S* = 1.065142 reflections323 parameters4 restraintsH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.24 e Å^−3^Δρ~min~ = −0.33 e Å^−3^ {#d5e353} Data collection: *CrysAlis PRO* (Agilent, 2010[@bb1]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb3]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb3]); molecular graphics: *X-SEED* (Barbour, 2001[@bb2]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb6]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811003862/jh2263sup1.cif](http://dx.doi.org/10.1107/S1600536811003862/jh2263sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003862/jh2263Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003862/jh2263Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?jh2263&file=jh2263sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?jh2263sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?jh2263&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [JH2263](http://scripts.iucr.org/cgi-bin/sendsup?jh2263)). We thank the Higher Education Commission of Pakistan and the University of Malaya for supporting this study. Comment ======= 1,4-Bis(4-aminophenoxy)benzene is a precusor for the synthesis of polyamides owing the functional amino --NH~2~ group that will condense with carboxylic acids (Shemsi *et al.*, 2008). The amino group can be also converted to a dialkylamino group by reaction with an alkyl halide in the presence of potassium carbonate. This strategy is used for the synthesis of the nitrogen--propargyl bond. The unit cell has two independent molecules of C~30~H~24~N~2~O~2~ (Scheme I) that both lie on a center-of-inversion (Fig. 1). The central phenylene ring is aligned at 61.4 (2) ° with respect to the flanking aromatic ring (the dihedral angle is 70.7 (3) ° for the second molecule). There is only one reported example of the nitrogen-parpargyl bond (Steiner *et al.*, 1999). Experimental {#experimental} ============ 1,4-Bis(4-aminophenoxy)benzene (1 g, 2.2 mmol) was dissolved in ethanl (30 ml) followed by the addition of potassium carbonate (3 g, 21 mmol). The mixture was heated for 1 h. Propargyl bromide (1.5 ml, 15 mmol) was added and the heating was continued for another 8 h. The solvent was evaporated under reduced pressure and the residue was dissolved in a mixture of water (50 ml) and dichloromethane (50 ml). The aqueous layer was extracted three times with dichloromethane and concentrated. The product was recrystallized from ethanol; yield 60%. Refinement {#refinement} ========== Carbon-bound H-atoms were placed in calculated positions \[C---H 0.95 to 0.99 Å, *U*~iso~(H) 1.2*U*~eq~(C)\] and were included in the refinement in the riding model approximation. The acetylenic H-atoms were located in a difference Fourier map, and were refined with a distance restraint of C--H 0.95±0.01 Å; their temperature factors were refined. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Thermal ellipsoid plot (Barbour, 2001) of C30H24N2O2 at the 70% probability level; hydrogen atoms are drawn as spheres of arbitrary radius. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e134 .table-wrap} ------------------------- --------------------------------------- C~30~H~24~N~2~O~2~ *Z* = 2 *M~r~* = 444.51 *F*(000) = 468 Triclinic, *P*1 *D*~x~ = 1.270 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 9.8766 (7) Å Cell parameters from 2448 reflections *b* = 11.1635 (6) Å θ = 2.2--29.2° *c* = 12.1531 (9) Å µ = 0.08 mm^−1^ α = 68.687 (6)° *T* = 100 K β = 69.601 (7)° Prism, colorless γ = 88.529 (5)° 0.30 × 0.10 × 0.05 mm *V* = 1162.19 (13) Å^3^ ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e270 .table-wrap} ------------------------------------------------------------------- -------------------------------------- Agilent SuperNova Dual diffractometer with an Atlas detector 5142 independent reflections Radiation source: SuperNova (Mo) X-ray Source 3245 reflections with *I* \> 2σ(*I*) Mirror *R*~int~ = 0.051 Detector resolution: 10.4041 pixels mm^-1^ θ~max~ = 27.5°, θ~min~ = 2.2° ω scans *h* = −12→12 Absorption correction: multi-scan (*CrysAlis PRO*; Agilent, 2010) *k* = −12→14 *T*~min~ = 0.712, *T*~max~ = 1.000 *l* = −13→15 9192 measured reflections ------------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e390 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.063 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.172 H atoms treated by a mixture of independent and constrained refinement *S* = 1.06 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0626*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 5142 reflections (Δ/σ)~max~ = 0.001 323 parameters Δρ~max~ = 0.24 e Å^−3^ 4 restraints Δρ~min~ = −0.33 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e546 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O1 0.51131 (17) 0.20860 (14) 0.78479 (13) 0.0252 (4) O2 1.00539 (17) 0.19216 (14) 0.77617 (13) 0.0247 (4) N1 0.7243 (2) 0.72196 (18) 0.64767 (16) 0.0242 (5) N2 1.2235 (2) 0.70018 (18) 0.65456 (17) 0.0240 (5) C1 0.6093 (2) −0.0128 (2) 1.0493 (2) 0.0223 (5) H1 0.6838 −0.0217 1.0835 0.027\* C2 0.6174 (2) 0.0957 (2) 0.9431 (2) 0.0243 (5) H2 0.6977 0.1611 0.9038 0.029\* C3 0.5073 (2) 0.1073 (2) 0.89530 (19) 0.0211 (5) C4 0.5691 (2) 0.3332 (2) 0.7564 (2) 0.0212 (5) C5 0.6303 (2) 0.4110 (2) 0.6295 (2) 0.0220 (5) H5 0.6387 0.3760 0.5671 0.026\* C6 0.6796 (2) 0.5397 (2) 0.5924 (2) 0.0216 (5) H6 0.7206 0.5927 0.5047 0.026\* C7 0.6698 (2) 0.5927 (2) 0.68269 (19) 0.0205 (5) C8 0.6062 (2) 0.5121 (2) 0.8109 (2) 0.0225 (5) H8 0.5976 0.5460 0.8739 0.027\* C9 0.5554 (2) 0.3838 (2) 0.8474 (2) 0.0232 (5) H9 0.5114 0.3308 0.9348 0.028\* C10 0.7819 (3) 0.8070 (2) 0.5142 (2) 0.0249 (5) H10A 0.8515 0.7620 0.4663 0.030\* H10B 0.8367 0.8851 0.5052 0.030\* C11 0.6713 (3) 0.8483 (2) 0.4560 (2) 0.0257 (5) C12 0.5809 (3) 0.8773 (3) 0.4114 (2) 0.0346 (6) C13 0.6654 (3) 0.7857 (2) 0.7376 (2) 0.0264 (6) H13A 0.5603 0.7558 0.7841 0.032\* H13B 0.6760 0.8803 0.6901 0.032\* C14 0.7383 (3) 0.7593 (2) 0.8296 (2) 0.0280 (6) C15 0.7930 (3) 0.7348 (3) 0.9058 (3) 0.0416 (7) C16 1.0318 (2) −0.1219 (2) 1.0003 (2) 0.0219 (5) H16 1.0540 −0.2052 1.0006 0.026\* C17 1.0369 (2) −0.0226 (2) 0.8889 (2) 0.0231 (5) H17 1.0618 −0.0381 0.8128 0.028\* C18 1.0058 (2) 0.0986 (2) 0.88900 (19) 0.0212 (5) C19 1.0600 (2) 0.3185 (2) 0.74796 (19) 0.0212 (5) C20 0.9869 (2) 0.4191 (2) 0.69923 (19) 0.0236 (5) H20 0.9004 0.4016 0.6876 0.028\* C21 1.0402 (2) 0.5458 (2) 0.6673 (2) 0.0244 (5) H21 0.9900 0.6148 0.6333 0.029\* C22 1.1676 (2) 0.5732 (2) 0.68473 (19) 0.0204 (5) C23 1.2417 (2) 0.4694 (2) 0.73047 (19) 0.0220 (5) H23 1.3296 0.4859 0.7406 0.026\* C24 1.1894 (2) 0.3433 (2) 0.76112 (19) 0.0222 (5) H24 1.2416 0.2740 0.7910 0.027\* C25 1.1369 (3) 0.8061 (2) 0.6209 (2) 0.0268 (6) H25A 1.1674 0.8791 0.6381 0.032\* H25B 1.0332 0.7765 0.6748 0.032\* C26 1.1529 (2) 0.8513 (2) 0.4870 (2) 0.0239 (5) C27 1.1667 (3) 0.8879 (2) 0.3791 (2) 0.0323 (6) C28 1.3208 (3) 0.7176 (2) 0.7156 (2) 0.0273 (6) H28A 1.3485 0.8115 0.6881 0.033\* H28B 1.4106 0.6782 0.6865 0.033\* C29 1.2574 (3) 0.6603 (2) 0.8560 (2) 0.0308 (6) C30 1.2069 (4) 0.6076 (3) 0.9671 (3) 0.0454 (8) H12 0.506 (2) 0.895 (3) 0.377 (2) 0.055 (9)\* H15 0.838 (3) 0.720 (3) 0.966 (2) 0.055 (9)\* H27 1.177 (3) 0.911 (3) 0.2929 (12) 0.059 (9)\* H30 1.167 (3) 0.570 (3) 1.0577 (10) 0.075 (11)\* ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1295 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.0315 (9) 0.0200 (8) 0.0219 (9) 0.0000 (7) −0.0140 (7) −0.0015 (6) O2 0.0334 (9) 0.0205 (9) 0.0209 (9) 0.0019 (7) −0.0148 (7) −0.0039 (6) N1 0.0316 (11) 0.0219 (10) 0.0180 (10) 0.0034 (9) −0.0101 (8) −0.0054 (8) N2 0.0283 (11) 0.0203 (10) 0.0230 (10) 0.0053 (9) −0.0135 (9) −0.0039 (8) C1 0.0214 (12) 0.0224 (12) 0.0256 (12) 0.0055 (10) −0.0126 (10) −0.0082 (9) C2 0.0210 (12) 0.0222 (12) 0.0249 (13) −0.0025 (10) −0.0069 (10) −0.0049 (9) C3 0.0226 (12) 0.0210 (12) 0.0184 (12) 0.0029 (10) −0.0088 (10) −0.0046 (9) C4 0.0198 (11) 0.0215 (12) 0.0211 (12) 0.0029 (10) −0.0100 (9) −0.0043 (9) C5 0.0223 (12) 0.0249 (13) 0.0209 (12) 0.0063 (10) −0.0095 (10) −0.0099 (9) C6 0.0223 (12) 0.0245 (12) 0.0153 (11) 0.0063 (10) −0.0068 (9) −0.0049 (9) C7 0.0195 (11) 0.0203 (12) 0.0197 (12) 0.0059 (10) −0.0094 (9) −0.0035 (9) C8 0.0222 (12) 0.0275 (13) 0.0201 (12) 0.0089 (10) −0.0105 (10) −0.0094 (9) C9 0.0209 (12) 0.0263 (13) 0.0169 (12) 0.0039 (10) −0.0061 (9) −0.0029 (9) C10 0.0272 (13) 0.0220 (12) 0.0232 (12) 0.0003 (10) −0.0094 (10) −0.0057 (9) C11 0.0305 (14) 0.0217 (12) 0.0215 (12) 0.0025 (11) −0.0099 (10) −0.0038 (9) C12 0.0382 (16) 0.0354 (15) 0.0340 (15) 0.0100 (13) −0.0195 (13) −0.0115 (12) C13 0.0298 (13) 0.0209 (12) 0.0283 (13) 0.0044 (11) −0.0116 (11) −0.0081 (10) C14 0.0234 (13) 0.0341 (14) 0.0246 (13) −0.0012 (11) −0.0039 (10) −0.0135 (11) C15 0.0351 (16) 0.061 (2) 0.0308 (15) −0.0072 (14) −0.0113 (13) −0.0200 (14) C16 0.0236 (12) 0.0189 (12) 0.0252 (12) 0.0062 (10) −0.0110 (10) −0.0090 (9) C17 0.0234 (12) 0.0268 (13) 0.0193 (12) 0.0038 (10) −0.0070 (10) −0.0099 (10) C18 0.0179 (11) 0.0254 (13) 0.0193 (12) 0.0019 (10) −0.0088 (9) −0.0051 (9) C19 0.0246 (12) 0.0211 (12) 0.0148 (11) −0.0003 (10) −0.0057 (9) −0.0045 (9) C20 0.0198 (12) 0.0291 (13) 0.0184 (12) 0.0035 (10) −0.0086 (9) −0.0036 (9) C21 0.0241 (12) 0.0255 (13) 0.0194 (12) 0.0085 (10) −0.0092 (10) −0.0032 (9) C22 0.0213 (12) 0.0215 (12) 0.0135 (11) 0.0029 (10) −0.0054 (9) −0.0021 (9) C23 0.0193 (12) 0.0278 (13) 0.0195 (12) 0.0056 (10) −0.0096 (9) −0.0073 (9) C24 0.0232 (12) 0.0254 (13) 0.0180 (12) 0.0072 (10) −0.0099 (9) −0.0061 (9) C25 0.0311 (14) 0.0238 (13) 0.0223 (12) 0.0069 (11) −0.0085 (10) −0.0065 (10) C26 0.0216 (12) 0.0218 (12) 0.0269 (13) 0.0054 (10) −0.0092 (10) −0.0074 (10) C27 0.0332 (15) 0.0343 (15) 0.0312 (16) 0.0047 (12) −0.0151 (12) −0.0114 (12) C28 0.0250 (13) 0.0241 (13) 0.0332 (14) 0.0040 (10) −0.0126 (11) −0.0093 (10) C29 0.0367 (14) 0.0318 (14) 0.0358 (16) 0.0162 (12) −0.0211 (12) −0.0193 (12) C30 0.067 (2) 0.0478 (18) 0.0350 (18) 0.0323 (16) −0.0280 (16) −0.0231 (14) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1996 .table-wrap} ---------------------- -------------- --------------------------- -------------- O1---C4 1.391 (3) C13---C14 1.472 (3) O1---C3 1.395 (2) C13---H13A 0.9900 O2---C18 1.391 (2) C13---H13B 0.9900 O2---C19 1.399 (3) C14---C15 1.175 (3) N1---C7 1.410 (3) C15---H15 0.95 (1) N1---C10 1.457 (3) C16---C18^ii^ 1.384 (3) N1---C13 1.463 (3) C16---C17 1.389 (3) N2---C22 1.404 (3) C16---H16 0.9500 N2---C28 1.458 (3) C17---C18 1.380 (3) N2---C25 1.461 (3) C17---H17 0.9500 C1---C3^i^ 1.378 (3) C18---C16^ii^ 1.384 (3) C1---C2 1.391 (3) C19---C20 1.380 (3) C1---H1 0.9500 C19---C24 1.388 (3) C2---C3 1.384 (3) C20---C21 1.388 (3) C2---H2 0.9500 C20---H20 0.9500 C3---C1^i^ 1.378 (3) C21---C22 1.405 (3) C4---C5 1.379 (3) C21---H21 0.9500 C4---C9 1.381 (3) C22---C23 1.399 (3) C5---C6 1.385 (3) C23---C24 1.382 (3) C5---H5 0.9500 C23---H23 0.9500 C6---C7 1.399 (3) C24---H24 0.9500 C6---H6 0.9500 C25---C26 1.467 (3) C7---C8 1.400 (3) C25---H25A 0.9900 C8---C9 1.385 (3) C25---H25B 0.9900 C8---H8 0.9500 C26---C27 1.181 (3) C9---H9 0.9500 C27---H27 0.950 (10) C10---C11 1.477 (3) C28---C29 1.481 (3) C10---H10A 0.9900 C28---H28A 0.9900 C10---H10B 0.9900 C28---H28B 0.9900 C11---C12 1.180 (3) C29---C30 1.178 (4) C12---H12 0.96 (1) C30---H30 0.956 (10) C4---O1---C3 120.48 (16) C14---C13---H13B 109.1 C18---O2---C19 116.42 (16) H13A---C13---H13B 107.8 C7---N1---C10 119.60 (18) C15---C14---C13 177.7 (3) C7---N1---C13 118.73 (18) C14---C15---H15 177.1 (18) C10---N1---C13 115.86 (18) C18^ii^---C16---C17 119.6 (2) C22---N2---C28 117.61 (17) C18^ii^---C16---H16 120.2 C22---N2---C25 119.25 (19) C17---C16---H16 120.2 C28---N2---C25 116.15 (19) C18---C17---C16 119.9 (2) C3^i^---C1---C2 119.6 (2) C18---C17---H17 120.0 C3^i^---C1---H1 120.2 C16---C17---H17 120.0 C2---C1---H1 120.2 C17---C18---C16^ii^ 120.50 (19) C3---C2---C1 119.4 (2) C17---C18---O2 117.25 (19) C3---C2---H2 120.3 C16^ii^---C18---O2 122.1 (2) C1---C2---H2 120.3 C20---C19---C24 120.5 (2) C1^i^---C3---C2 121.0 (2) C20---C19---O2 118.4 (2) C1^i^---C3---O1 115.80 (19) C24---C19---O2 121.0 (2) C2---C3---O1 123.04 (19) C19---C20---C21 119.8 (2) C5---C4---C9 120.1 (2) C19---C20---H20 120.1 C5---C4---O1 116.31 (19) C21---C20---H20 120.1 C9---C4---O1 123.34 (19) C20---C21---C22 120.8 (2) C4---C5---C6 120.4 (2) C20---C21---H21 119.6 C4---C5---H5 119.8 C22---C21---H21 119.6 C6---C5---H5 119.8 C23---C22---N2 119.9 (2) C5---C6---C7 120.7 (2) C23---C22---C21 118.0 (2) C5---C6---H6 119.7 N2---C22---C21 122.11 (19) C7---C6---H6 119.7 C24---C23---C22 121.2 (2) C6---C7---C8 117.8 (2) C24---C23---H23 119.4 C6---C7---N1 121.92 (19) C22---C23---H23 119.4 C8---C7---N1 120.2 (2) C23---C24---C19 119.6 (2) C9---C8---C7 121.2 (2) C23---C24---H24 120.2 C9---C8---H8 119.4 C19---C24---H24 120.2 C7---C8---H8 119.4 N2---C25---C26 112.17 (19) C4---C9---C8 119.8 (2) N2---C25---H25A 109.2 C4---C9---H9 120.1 C26---C25---H25A 109.2 C8---C9---H9 120.1 N2---C25---H25B 109.2 N1---C10---C11 114.87 (19) C26---C25---H25B 109.2 N1---C10---H10A 108.5 H25A---C25---H25B 107.9 C11---C10---H10A 108.5 C27---C26---C25 179.6 (3) N1---C10---H10B 108.5 C26---C27---H27 175.8 (18) C11---C10---H10B 108.5 N2---C28---C29 113.99 (19) H10A---C10---H10B 107.5 N2---C28---H28A 108.8 C12---C11---C10 177.9 (3) C29---C28---H28A 108.8 C11---C12---H12 176.0 (17) N2---C28---H28B 108.8 N1---C13---C14 112.7 (2) C29---C28---H28B 108.8 N1---C13---H13A 109.1 H28A---C28---H28B 107.6 C14---C13---H13A 109.1 C30---C29---C28 176.1 (3) N1---C13---H13B 109.1 C29---C30---H30 177 (2) C3^i^---C1---C2---C3 0.5 (4) C18^ii^---C16---C17---C18 0.6 (4) C1---C2---C3---C1^i^ −0.5 (4) C16---C17---C18---C16^ii^ −0.6 (4) C1---C2---C3---O1 −175.8 (2) C16---C17---C18---O2 −176.80 (19) C4---O1---C3---C1^i^ 146.9 (2) C19---O2---C18---C17 −142.9 (2) C4---O1---C3---C2 −37.5 (3) C19---O2---C18---C16^ii^ 41.0 (3) C3---O1---C4---C5 151.1 (2) C18---O2---C19---C20 −138.0 (2) C3---O1---C4---C9 −35.0 (3) C18---O2---C19---C24 45.9 (3) C9---C4---C5---C6 0.6 (3) C24---C19---C20---C21 −2.3 (3) O1---C4---C5---C6 174.64 (18) O2---C19---C20---C21 −178.41 (18) C4---C5---C6---C7 0.8 (3) C19---C20---C21---C22 −0.4 (3) C5---C6---C7---C8 −1.3 (3) C28---N2---C22---C23 −23.4 (3) C5---C6---C7---N1 177.5 (2) C25---N2---C22---C23 −173.04 (19) C10---N1---C7---C6 5.2 (3) C28---N2---C22---C21 158.4 (2) C13---N1---C7---C6 157.2 (2) C25---N2---C22---C21 8.8 (3) C10---N1---C7---C8 −176.13 (19) C20---C21---C22---C23 2.4 (3) C13---N1---C7---C8 −24.1 (3) C20---C21---C22---N2 −179.4 (2) C6---C7---C8---C9 0.5 (3) N2---C22---C23---C24 179.92 (19) N1---C7---C8---C9 −178.26 (19) C21---C22---C23---C24 −1.8 (3) C5---C4---C9---C8 −1.3 (3) C22---C23---C24---C19 −0.8 (3) O1---C4---C9---C8 −174.98 (19) C20---C19---C24---C23 2.9 (3) C7---C8---C9---C4 0.8 (3) O2---C19---C24---C23 178.92 (18) C7---N1---C10---C11 72.2 (3) C22---N2---C25---C26 −82.9 (2) C13---N1---C10---C11 −80.6 (3) C28---N2---C25---C26 127.0 (2) C7---N1---C13---C14 85.2 (2) C22---N2---C28---C29 −56.4 (3) C10---N1---C13---C14 −121.7 (2) C25---N2---C28---C29 94.1 (2) ---------------------- -------------- --------------------------- -------------- ::: Symmetry codes: (i) −*x*+1, −*y*, −*z*+2; (ii) −*x*+2, −*y*, −*z*+2. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3079 .table-wrap} --------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C12---H12···O1^iii^ 0.96 (1) 2.66 (3) 3.263 (3) 121 (2) C27---H27···O2^iv^ 0.95 (1) 2.68 (2) 3.285 (3) 122 (2) --------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (iii) −*x*+1, −*y*+1, −*z*+1; (iv) −*x*+2, −*y*+1, −*z*+1.

PubMed Central

2024-06-05T04:04:17.625060

2011-2-05

PMC3051972

Related literature {#sec1} ================== For general background to mol­ecular-based magnetic materials, see: Jones (1997[@bb3]); Akutagawa *et al.* (2009[@bb1]). For the role played by the size and shape of the counter-cations in determining the ground-state properties of the resulting materials, see: Ren *et al.* (2003[@bb4]). For related structures, see: Sellmann *et al.* (1991[@bb6]); Xie *et al.* (2002[@bb9], 2003[@bb8]); Ren *et al.* (2002[@bb5]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} (C~15~H~15~N~2~)\[Ni(C~6~H~4~S~2~)~2~\]*M* *~r~* = 562.42Triclinic,*a* = 7.1517 (7) Å*b* = 12.8190 (13) Å*c* = 15.3294 (16) Åα = 69.774 (1)°β = 77.740 (1)°γ = 87.721 (1)°*V* = 1287.8 (2) Å^3^*Z* = 2Mo *K*α radiationμ = 1.10 mm^−1^*T* = 296 K0.36 × 0.30 × 0.28 mm ### Data collection {#sec2.1.2} Bruker SMART APEX CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2000[@bb2]) *T* ~min~ = 0.694, *T* ~max~ = 0.7496530 measured reflections4530 independent reflections3728 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.042 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.036*wR*(*F* ^2^) = 0.098*S* = 1.024530 reflections312 parametersH-atom parameters constrainedΔρ~max~ = 0.25 e Å^−3^Δρ~min~ = −0.39 e Å^−3^ {#d5e394} Data collection: *SMART* (Bruker, 2000[@bb2]); cell refinement: *SAINT* (Bruker, 2000[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb7]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004971/rz2554sup1.cif](http://dx.doi.org/10.1107/S1600536811004971/rz2554sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004971/rz2554Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004971/rz2554Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?rz2554&file=rz2554sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?rz2554sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?rz2554&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [RZ2554](http://scripts.iucr.org/cgi-bin/sendsup?rz2554)). This work was supported by the National Natural Science Foundation of China (No. 20971004), the Key Project of Chinese Ministry of Education (No. 210102) and the Natural Science Foundation of Anhui Province (No. 11040606M45). Comment ======= Molecular solids with particular functionality are continuously paid much attention by chemists and physicists in the field of materials science (Jones, 1997). The preparation of new molecular based spin-bearing systems, among others, has been pursued from the viewpoint of materials/physical organic chemistry to develop novel molecular-based magnetic materials (Akutagawa *et al.*, 2009). In our previous research using benzylpyridinium derivatives (\[RBzPy\]^+^) as the counter-cation of \[*M*(mnt)~2~\]^-^ (where *M* = Ni, Pd and Pt and mnt^2-^ = maleodinitriledithiolate), a series of ion-pair compounds with segregated columnar stacks of cations and anions has been prepared (Ren *et al.*, 2002; Ren *et al.*, 2003; Xie *et al.*, 2002). The quasi one-dimensional magnetic nature of these compounds was attributed to intermolecular orbital interactions within the anionic columns. As an extension of our work on this series of complexes, we report here the crystal structure of the title compound, (I). The asymmetric unit of (I) contains half each of two independent centrosymmetric \[Ni(C~6~H~4~S~2~)~2~\]^-^ anions and one (C~15~H~15~N~2~)^+^ cation. In the anions, the nickel(III) ions are coordinated by four S atoms in a square-planar geometry; the Ni---S bonds and S---Ni---S angles are in agreement with the corresponding values found in analogous complexes (Sellmann *et al.*, 1991; Xie *et al.*, 2003). The centrosymmetric \[Ni(C~6~H~4~S~2~)~2~\]^-^ anions are almost planar. The dihedral angle between the two benzene rings of the cation is 86.49 (6)°. In the crystal structure, the packing of the two anions is different (Fig. 2). The Ni1-containing anions stack in a side-by-side fashion, forming one-dimensional ribbons parallel to (011); the shortest distance between the adjacent nickel(III) ions is 7.152 (6) Å. The Ni2-containing anions stack in a face-to-face fashion along the *a* axis with an alternating arrangement of \[Ni(C~6~H~4~S~2~)~2~\]^-^ anions and \[C~15~H~15~N~2~\]^+^ cations such that the pyridine ring of the cation lies above the benzene ring of the anion. The shortest distance between adjacent nickel(III) ions is also 7.152 (6) Å. A Ni···Ni distance of 8.155 (9)Å is found between adjacent Ni1-containing and Ni2-containing anions. Experimental {#experimental} ============ Benzene-1,2-dithiol (142 mg, 1.0 mmol) was added to a solution of sodium metal (46 mg, 2.0 mmol) in absolute ethanol (25 ml), under a nitrogen atmosphere at room temperature. A solution of NiCl~2~.6H~2~O (120 mg, 0.5 mmol) in ethanol (25 ml) was added, resulting in the mixture turning a muddy red-brown colour. Following this, \[CNBzPy(CH~3~)~2~\]Br (304 mg, 1.0 mmol) was added and the mixture allowed to stand with stirring for 1 h, and then stirred for an additional 24 h in air. The colour of the mixture gradually turned green, indicating oxidation from a dianionic species to the more stable monoanionic form. The precipitate was washed with absolute ethanol and diethyl ether and then dried. The crude product was recrystallized twice from dichloromethane to give the title compound (yield 198 mg, 54%). Refinement {#refinement} ========== All H atoms were placed in calculated positions and refined using a riding model, with C--H = 0.93--0.97 Å, and with *U*~iso~(H) = 1.2 *U*~eq~(C) or 1.5 *U*~eq~(C) for methyl H atoms. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of (I) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. Symmetry codes: (A) 1-x, 1-y, 1-z; (B) 1-x, 2-y, -z. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Packing diagram of (I) viewed along the a axis. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e240 .table-wrap} ----------------------------------------- --------------------------------------- (C~15~H~15~N~2~)\[Ni(C~6~H~4~S~2~)~2~\] *Z* = 2 *M~r~* = 562.42 *F*(000) = 582 Triclinic, *P*1 *D*~x~ = 1.450 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 7.1517 (7) Å Cell parameters from 3577 reflections *b* = 12.8190 (13) Å θ = 2.6--27.0° *c* = 15.3294 (16) Å µ = 1.10 mm^−1^ α = 69.774 (1)° *T* = 296 K β = 77.740 (1)° Block, dark green γ = 87.721 (1)° 0.36 × 0.30 × 0.28 mm *V* = 1287.8 (2) Å^3^ ----------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e387 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEX CCD area-detector diffractometer 4530 independent reflections Radiation source: sealed tube 3728 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.042 φ and ω scans θ~max~ = 25.1°, θ~min~ = 1.5° Absorption correction: multi-scan (*SADABS*; Bruker, 2000) *h* = −8→8 *T*~min~ = 0.694, *T*~max~ = 0.749 *k* = −12→15 6530 measured reflections *l* = −18→15 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e504 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.036 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.098 H-atom parameters constrained *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0581*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4530 reflections (Δ/σ)~max~ = 0.001 312 parameters Δρ~max~ = 0.25 e Å^−3^ 0 restraints Δρ~min~ = −0.39 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e658 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e757 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Ni1 0.5000 0.5000 0.5000 0.05051 (14) Ni2 0.5000 1.0000 0.0000 0.06279 (16) S1 0.38833 (9) 0.43210 (6) 0.41084 (5) 0.06354 (19) S2 0.78410 (8) 0.44650 (5) 0.45826 (4) 0.05774 (17) S3 0.52163 (10) 0.85288 (5) 0.11833 (6) 0.0751 (2) S4 0.44027 (9) 1.09946 (6) 0.09034 (6) 0.0758 (2) C1 0.5817 (3) 0.3696 (2) 0.36074 (16) 0.0563 (6) C2 0.5622 (4) 0.3134 (2) 0.29922 (18) 0.0710 (7) H2 0.4429 0.3068 0.2862 0.085\* C3 0.7171 (4) 0.2681 (3) 0.2582 (2) 0.0800 (8) H3 0.7024 0.2306 0.2177 0.096\* C4 0.8974 (4) 0.2777 (2) 0.2765 (2) 0.0779 (8) H4 1.0026 0.2472 0.2480 0.093\* C5 0.9189 (4) 0.3322 (2) 0.33656 (18) 0.0674 (7) H5 1.0394 0.3392 0.3482 0.081\* C6 0.7616 (3) 0.37727 (19) 0.38061 (15) 0.0544 (5) C7 0.4721 (4) 0.8937 (2) 0.2174 (2) 0.0750 (8) C8 0.4671 (4) 0.8185 (3) 0.3089 (3) 0.0933 (10) H8 0.4884 0.7438 0.3178 0.112\* C9 0.4315 (5) 0.8526 (4) 0.3851 (3) 0.1155 (14) H9 0.4298 0.8014 0.4456 0.139\* C10 0.3978 (5) 0.9626 (5) 0.3733 (3) 0.1139 (14) H10 0.3753 0.9851 0.4261 0.137\* C11 0.3969 (4) 1.0402 (3) 0.2847 (3) 0.0971 (10) H11 0.3712 1.1140 0.2779 0.116\* C12 0.4356 (3) 1.0061 (2) 0.2045 (2) 0.0734 (7) C13 0.7251 (6) 0.5985 (3) −0.0472 (2) 0.0964 (10) C14 0.8167 (5) 0.6096 (2) 0.0246 (2) 0.0708 (7) C15 1.0079 (5) 0.6423 (2) 0.0003 (2) 0.0809 (8) H15 1.0773 0.6544 −0.0612 0.097\* C16 1.0958 (4) 0.6572 (2) 0.06717 (19) 0.0723 (7) H16 1.2245 0.6796 0.0505 0.087\* C17 0.9938 (4) 0.63901 (18) 0.15919 (17) 0.0571 (6) C18 0.8028 (4) 0.60457 (19) 0.18304 (18) 0.0614 (6) H18 0.7338 0.5916 0.2447 0.074\* C19 0.7138 (4) 0.5892 (2) 0.1172 (2) 0.0713 (7) H19 0.5858 0.5654 0.1343 0.086\* C20 1.0872 (4) 0.65782 (19) 0.23205 (18) 0.0632 (6) H20A 1.0577 0.5944 0.2906 0.076\* H20B 1.2250 0.6635 0.2093 0.076\* C21 0.9853 (4) 0.7593 (2) 0.34242 (17) 0.0622 (6) H21 0.9952 0.6936 0.3918 0.075\* C22 0.9338 (4) 0.8545 (2) 0.36168 (17) 0.0648 (7) C23 0.9208 (3) 0.9501 (2) 0.28705 (17) 0.0597 (6) H23 0.8853 1.0150 0.2995 0.072\* C24 0.9592 (3) 0.95288 (18) 0.19364 (15) 0.0512 (5) C25 1.0102 (3) 0.85467 (18) 0.17933 (15) 0.0509 (5) H25 1.0374 0.8532 0.1177 0.061\* C26 0.8910 (5) 0.8506 (3) 0.46412 (19) 0.0950 (10) H26A 0.8574 0.9231 0.4661 0.142\* H26B 1.0023 0.8277 0.4907 0.142\* H26C 0.7864 0.7985 0.5004 0.142\* C27 0.9439 (3) 1.0558 (2) 0.11151 (17) 0.0617 (6) H27A 1.0669 1.0761 0.0692 0.093\* H27B 0.9012 1.1153 0.1346 0.093\* H27C 0.8536 1.0422 0.0781 0.093\* N1 0.6563 (6) 0.5905 (3) −0.1048 (2) 0.1353 (14) N2 1.0217 (3) 0.76078 (14) 0.25195 (12) 0.0528 (5) ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1500 .table-wrap} ----- ------------- ------------- ------------- --------------- --------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Ni1 0.0451 (2) 0.0580 (3) 0.0509 (2) −0.00616 (18) −0.01511 (17) −0.01801 (19) Ni2 0.0386 (2) 0.0489 (3) 0.0962 (4) 0.00137 (17) −0.0198 (2) −0.0160 (2) S1 0.0478 (3) 0.0842 (4) 0.0722 (4) −0.0036 (3) −0.0202 (3) −0.0387 (3) S2 0.0473 (3) 0.0721 (4) 0.0593 (3) −0.0029 (3) −0.0192 (3) −0.0244 (3) S3 0.0622 (4) 0.0528 (4) 0.1011 (5) 0.0018 (3) −0.0223 (4) −0.0121 (3) S4 0.0527 (4) 0.0594 (4) 0.1193 (6) 0.0036 (3) −0.0267 (4) −0.0308 (4) C1 0.0559 (14) 0.0622 (14) 0.0501 (12) −0.0090 (11) −0.0119 (10) −0.0171 (11) C2 0.0641 (16) 0.0864 (18) 0.0730 (16) −0.0116 (14) −0.0170 (13) −0.0376 (15) C3 0.083 (2) 0.090 (2) 0.0773 (18) −0.0109 (16) −0.0060 (15) −0.0465 (16) C4 0.0702 (18) 0.088 (2) 0.0779 (18) 0.0033 (15) −0.0050 (14) −0.0381 (16) C5 0.0548 (15) 0.0792 (18) 0.0669 (15) 0.0004 (12) −0.0127 (12) −0.0235 (14) C6 0.0538 (13) 0.0553 (13) 0.0505 (12) −0.0052 (10) −0.0133 (10) −0.0118 (10) C7 0.0439 (14) 0.0775 (19) 0.095 (2) −0.0151 (12) −0.0167 (13) −0.0157 (16) C8 0.0681 (19) 0.099 (2) 0.095 (2) −0.0250 (17) −0.0201 (17) −0.006 (2) C9 0.082 (2) 0.150 (4) 0.098 (3) −0.045 (3) −0.019 (2) −0.018 (3) C10 0.077 (2) 0.165 (4) 0.102 (3) −0.036 (3) −0.007 (2) −0.052 (3) C11 0.0607 (18) 0.113 (3) 0.129 (3) −0.0204 (17) −0.0139 (19) −0.057 (3) C12 0.0415 (13) 0.0823 (19) 0.096 (2) −0.0117 (12) −0.0158 (13) −0.0276 (16) C13 0.131 (3) 0.077 (2) 0.090 (2) 0.0043 (19) −0.047 (2) −0.0267 (18) C14 0.095 (2) 0.0486 (14) 0.0756 (17) 0.0042 (13) −0.0351 (16) −0.0201 (13) C15 0.113 (3) 0.0626 (17) 0.0636 (16) −0.0043 (16) −0.0130 (16) −0.0199 (13) C16 0.0724 (18) 0.0616 (16) 0.0770 (18) −0.0079 (13) −0.0066 (14) −0.0209 (14) C17 0.0669 (15) 0.0398 (12) 0.0625 (14) 0.0040 (10) −0.0202 (12) −0.0113 (10) C18 0.0655 (15) 0.0529 (14) 0.0629 (14) 0.0007 (11) −0.0178 (12) −0.0137 (11) C19 0.0727 (17) 0.0596 (15) 0.0846 (19) −0.0003 (13) −0.0283 (15) −0.0213 (14) C20 0.0626 (15) 0.0515 (14) 0.0749 (16) 0.0057 (11) −0.0262 (13) −0.0145 (12) C21 0.0633 (15) 0.0659 (16) 0.0537 (14) −0.0124 (12) −0.0227 (11) −0.0084 (12) C22 0.0615 (15) 0.0786 (18) 0.0563 (14) −0.0147 (13) −0.0149 (12) −0.0226 (14) C23 0.0522 (14) 0.0626 (15) 0.0682 (15) −0.0056 (11) −0.0131 (11) −0.0265 (13) C24 0.0393 (11) 0.0540 (13) 0.0609 (13) −0.0056 (9) −0.0159 (10) −0.0168 (11) C25 0.0479 (12) 0.0544 (13) 0.0508 (12) −0.0033 (10) −0.0187 (10) −0.0132 (10) C26 0.114 (3) 0.114 (3) 0.0588 (16) −0.019 (2) −0.0142 (16) −0.0323 (17) C27 0.0556 (14) 0.0527 (13) 0.0729 (15) 0.0009 (10) −0.0198 (12) −0.0130 (12) N1 0.186 (4) 0.134 (3) 0.112 (2) −0.004 (3) −0.083 (3) −0.044 (2) N2 0.0505 (11) 0.0507 (11) 0.0562 (11) −0.0044 (8) −0.0207 (9) −0.0109 (9) ----- ------------- ------------- ------------- --------------- --------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2261 .table-wrap} ------------------------- -------------- ----------------------- -------------- Ni1---S1 2.1459 (6) C13---C14 1.443 (4) Ni1---S1^i^ 2.1459 (6) C14---C15 1.380 (4) Ni1---S2 2.1560 (6) C14---C19 1.392 (4) Ni1---S2^i^ 2.1560 (6) C15---C16 1.379 (4) Ni2---S3^ii^ 2.1451 (7) C15---H15 0.9300 Ni2---S3 2.1451 (7) C16---C17 1.388 (4) Ni2---S4^ii^ 2.1569 (8) C16---H16 0.9300 Ni2---S4 2.1569 (8) C17---C18 1.385 (3) S1---C1 1.741 (3) C17---C20 1.506 (3) S2---C6 1.747 (2) C18---C19 1.372 (3) S3---C7 1.735 (3) C18---H18 0.9300 S4---C12 1.739 (3) C19---H19 0.9300 C1---C6 1.399 (3) C20---N2 1.491 (3) C1---C2 1.400 (3) C20---H20A 0.9700 C2---C3 1.366 (4) C20---H20B 0.9700 C2---H2 0.9300 C21---N2 1.349 (3) C3---C4 1.395 (4) C21---C22 1.370 (4) C3---H3 0.9300 C21---H21 0.9300 C4---C5 1.368 (4) C22---C23 1.373 (4) C4---H4 0.9300 C22---C26 1.518 (4) C5---C6 1.397 (4) C23---C24 1.388 (3) C5---H5 0.9300 C23---H23 0.9300 C7---C8 1.395 (4) C24---C25 1.374 (3) C7---C12 1.407 (4) C24---C27 1.496 (3) C8---C9 1.356 (5) C25---N2 1.341 (3) C8---H8 0.9300 C25---H25 0.9300 C9---C10 1.377 (6) C26---H26A 0.9600 C9---H9 0.9300 C26---H26B 0.9600 C10---C11 1.379 (5) C26---H26C 0.9600 C10---H10 0.9300 C27---H27A 0.9600 C11---C12 1.414 (4) C27---H27B 0.9600 C11---H11 0.9300 C27---H27C 0.9600 C13---N1 1.133 (4) S1---Ni1---S1^i^ 180.00 (3) C15---C14---C13 119.2 (3) S1---Ni1---S2 92.04 (2) C19---C14---C13 120.8 (3) S1^i^---Ni1---S2 87.97 (2) C16---C15---C14 119.9 (3) S1---Ni1---S2^i^ 87.97 (2) C16---C15---H15 120.0 S1^i^---Ni1---S2^i^ 92.03 (2) C14---C15---H15 120.0 S2---Ni1---S2^i^ 180.0 C15---C16---C17 120.5 (3) S3^ii^---Ni2---S3 180.00 (4) C15---C16---H16 119.8 S3^ii^---Ni2---S4^ii^ 91.75 (3) C17---C16---H16 119.8 S3---Ni2---S4^ii^ 88.25 (3) C18---C17---C16 119.0 (2) S3^ii^---Ni2---S4 88.25 (3) C18---C17---C20 120.1 (2) S3---Ni2---S4 91.75 (3) C16---C17---C20 120.9 (2) S4^ii^---Ni2---S4 180.00 (2) C19---C18---C17 121.1 (2) C1---S1---Ni1 104.89 (8) C19---C18---H18 119.5 C6---S2---Ni1 104.81 (8) C17---C18---H18 119.5 C7---S3---Ni2 105.49 (11) C18---C19---C14 119.5 (3) C12---S4---Ni2 104.82 (11) C18---C19---H19 120.3 C6---C1---C2 119.0 (2) C14---C19---H19 120.3 C6---C1---S1 119.51 (18) N2---C20---C17 112.08 (18) C2---C1---S1 121.47 (19) N2---C20---H20A 109.2 C3---C2---C1 120.5 (3) C17---C20---H20A 109.2 C3---C2---H2 119.7 N2---C20---H20B 109.2 C1---C2---H2 119.7 C17---C20---H20B 109.2 C2---C3---C4 120.5 (3) H20A---C20---H20B 107.9 C2---C3---H3 119.8 N2---C21---C22 120.2 (2) C4---C3---H3 119.8 N2---C21---H21 119.9 C5---C4---C3 119.7 (3) C22---C21---H21 119.9 C5---C4---H4 120.1 C21---C22---C23 118.4 (2) C3---C4---H4 120.1 C21---C22---C26 119.2 (3) C4---C5---C6 120.7 (2) C23---C22---C26 122.3 (3) C4---C5---H5 119.7 C22---C23---C24 122.0 (2) C6---C5---H5 119.7 C22---C23---H23 119.0 C5---C6---C1 119.5 (2) C24---C23---H23 119.0 C5---C6---S2 121.75 (19) C25---C24---C23 116.6 (2) C1---C6---S2 118.69 (19) C25---C24---C27 120.6 (2) C8---C7---C12 119.3 (3) C23---C24---C27 122.8 (2) C8---C7---S3 122.0 (3) N2---C25---C24 121.7 (2) C12---C7---S3 118.7 (2) N2---C25---H25 119.1 C9---C8---C7 121.0 (4) C24---C25---H25 119.1 C9---C8---H8 119.5 C22---C26---H26A 109.5 C7---C8---H8 119.5 C22---C26---H26B 109.5 C8---C9---C10 120.2 (4) H26A---C26---H26B 109.5 C8---C9---H9 119.9 C22---C26---H26C 109.5 C10---C9---H9 119.9 H26A---C26---H26C 109.5 C9---C10---C11 121.3 (4) H26B---C26---H26C 109.5 C9---C10---H10 119.4 C24---C27---H27A 109.5 C11---C10---H10 119.4 C24---C27---H27B 109.5 C10---C11---C12 119.1 (4) H27A---C27---H27B 109.5 C10---C11---H11 120.4 C24---C27---H27C 109.5 C12---C11---H11 120.4 H27A---C27---H27C 109.5 C7---C12---C11 119.0 (3) H27B---C27---H27C 109.5 C7---C12---S4 119.2 (2) C25---N2---C21 121.1 (2) C11---C12---S4 121.8 (3) C25---N2---C20 119.51 (19) N1---C13---C14 178.7 (4) C21---N2---C20 119.3 (2) C15---C14---C19 120.0 (2) S2---Ni1---S1---C1 2.24 (8) C8---C7---C12---S4 −179.55 (19) S2^i^---Ni1---S1---C1 −177.76 (8) S3---C7---C12---S4 0.3 (3) S1---Ni1---S2---C6 −1.49 (8) C10---C11---C12---C7 0.6 (4) S1^i^---Ni1---S2---C6 178.51 (8) C10---C11---C12---S4 −179.1 (2) S4^ii^---Ni2---S3---C7 −177.93 (9) Ni2---S4---C12---C7 1.4 (2) S4---Ni2---S3---C7 2.07 (9) Ni2---S4---C12---C11 −179.0 (2) S3^ii^---Ni2---S4---C12 178.07 (8) C19---C14---C15---C16 −1.4 (4) S3---Ni2---S4---C12 −1.93 (8) C13---C14---C15---C16 177.7 (3) Ni1---S1---C1---C6 −2.8 (2) C14---C15---C16---C17 0.3 (4) Ni1---S1---C1---C2 178.49 (18) C15---C16---C17---C18 0.7 (4) C6---C1---C2---C3 −0.9 (4) C15---C16---C17---C20 −178.4 (2) S1---C1---C2---C3 177.8 (2) C16---C17---C18---C19 −0.5 (4) C1---C2---C3---C4 −0.4 (4) C20---C17---C18---C19 178.6 (2) C2---C3---C4---C5 0.5 (5) C17---C18---C19---C14 −0.6 (4) C3---C4---C5---C6 0.7 (4) C15---C14---C19---C18 1.5 (4) C4---C5---C6---C1 −2.0 (4) C13---C14---C19---C18 −177.5 (3) C4---C5---C6---S2 179.6 (2) C18---C17---C20---N2 −72.8 (3) C2---C1---C6---C5 2.1 (3) C16---C17---C20---N2 106.3 (3) S1---C1---C6---C5 −176.67 (18) N2---C21---C22---C23 −0.1 (3) C2---C1---C6---S2 −179.45 (18) N2---C21---C22---C26 179.2 (2) S1---C1---C6---S2 1.8 (3) C21---C22---C23---C24 −0.3 (3) Ni1---S2---C6---C5 178.62 (18) C26---C22---C23---C24 −179.7 (2) Ni1---S2---C6---C1 0.16 (19) C22---C23---C24---C25 0.3 (3) Ni2---S3---C7---C8 178.04 (19) C22---C23---C24---C27 179.3 (2) Ni2---S3---C7---C12 −1.8 (2) C23---C24---C25---N2 0.2 (3) C12---C7---C8---C9 −1.4 (4) C27---C24---C25---N2 −178.85 (19) S3---C7---C8---C9 178.8 (2) C24---C25---N2---C21 −0.7 (3) C7---C8---C9---C10 0.6 (5) C24---C25---N2---C20 −177.0 (2) C8---C9---C10---C11 0.8 (6) C22---C21---N2---C25 0.6 (3) C9---C10---C11---C12 −1.4 (5) C22---C21---N2---C20 176.9 (2) C8---C7---C12---C11 0.8 (4) C17---C20---N2---C25 −44.8 (3) S3---C7---C12---C11 −179.4 (2) C17---C20---N2---C21 138.9 (2) ------------------------- -------------- ----------------------- -------------- ::: Symmetry codes: (i) −*x*+1, −*y*+1, −*z*+1; (ii) −*x*+1, −*y*+2, −*z*.

PubMed Central

2024-06-05T04:04:17.631859

2011-2-16

PMC3051973

Related literature {#sec1} ================== For general background to azo compounds, see: Catino & Farris (1985[@bb5]); Gregory (1991[@bb10]). For bond-length data, see: Allen *et al.* (1987[@bb2]); Deveci *et al.* (2005[@bb6]); Özdemir *et al.* (2006[@bb13]); Albayrak *et al.* (2009[@bb1]); Karabıyık *et al.* (2009[@bb11]); Yazıcı *et al.* (2011[@bb17]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~14~H~11~FN~2~O~2~*M* *~r~* = 258.25Triclinic,*a* = 6.7632 (3) Å*b* = 12.5906 (6) Å*c* = 13.8769 (6) Åα = 85.641 (4)°β = 89.337 (3)°γ = 84.254 (4)°*V* = 1172.31 (9) Å^3^*Z* = 4Mo *K*α radiationμ = 0.11 mm^−1^*T* = 150 K0.64 × 0.40 × 0.12 mm ### Data collection {#sec2.1.2} Stoe IPDS II diffractometerAbsorption correction: integration (*X-RED32*; Stoe & Cie, 2002[@bb16]) *T* ~min~ = 0.941, *T* ~max~ = 0.98720279 measured reflections4870 independent reflections3825 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.034 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.036*wR*(*F* ^2^) = 0.104*S* = 1.044870 reflections351 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.20 e Å^−3^Δρ~min~ = −0.26 e Å^−3^ {#d5e467} Data collection: *X-AREA* (Stoe & Cie, 2002[@bb16]); cell refinement: *X-AREA*; data reduction: *X-RED32* (Stoe & Cie, 2002[@bb16]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb15]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb15]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb7]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb8]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004909/bh2334sup1.cif](http://dx.doi.org/10.1107/S1600536811004909/bh2334sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004909/bh2334Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004909/bh2334Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?bh2334&file=bh2334sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?bh2334sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?bh2334&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BH2334](http://scripts.iucr.org/cgi-bin/sendsup?bh2334)). The authors thank Professor Magnus Rueping of RWTH Aachen University, Germany, for helpful discussions. They also acknowledge the Faculty of Arts and Sciences, Ondokuz Mayıs University, Turkey, for the use of the Stoe IPDS II diffractometer (purchased under grant F.279 of the University Research Fund). Comment ======= Azo dyes have been most widely used class of dyes due to its versatile applications in various fields, such as dyeing textile fibres, colouring different materials, plastics, biological-medical studies, electro-optical devices and ink-jet printers in high technology areas (Catino & Farris, 1985; Gregory, 1991). The molecule of the title compound, with the atom numbering scheme, is shown in Fig. 1. The asymmetric unit contains two independent molecules (labelled *A* and *B*) with no significant differences in their structures. The conformations of the two molecules in the asymmetric unit are *trans* with respect to azo bridge. The dihedral angles between the aromatic rings are 17.21 (2)° for molecule *A* and 19.06 (2)° for molecule *B*. All bond lengths are in agreement with those reported for other azo compounds (Allen *et al.*, 1987; Deveci *et al.*, 2005; Özdemir *et al.*, 2006; Albayrak *et al.*, 2009; Karabıyık *et al.*, 2009; Yazıcı *et al.*, 2011). Each of the independent molecules has a strong intra-molecular O---H···O hydrogen bond which generates an *S*(6) ring motif. The crystal packing is stabilized by weak van der Waals interactions and molecules are stacked along crystallographic \[100\] direction. Experimental {#experimental} ============ A mixture of 2-fluoroaniline (0.86 g, 7.8 mmol), water (20 ml) and concentrated hydrochloric acid (1.97 ml, 23.4 mmol) was stirred until a clear solution was obtained. This solution was cooled down to 0--5 °C and a solution of sodium nitrite (0.75 g, 7.8 mmol) in water was added dropwise while the temperature was maintained below 5 °C. The resulting mixture was stirred for 30 min in an ice bath. 2-Hydroxyacetophenone (1.067 g, 7.8 mmol) solution (pH 9) was gradually added to a cooled solution of 2-fluorobenzenediazonium chloride, prepared as described above, and the resulting mixture was stirred at 0--5 °C for 2 h in an ice bath. The product was recrystallized from acetic acid to obtain solid (*E*)-2-acetyl-4-(2-fluorophenyldiazenyl)phenol. Crystals were obtained after one day by slow evaporation from benzene (yield 84%, m.p.= 414--416 K). Refinement {#refinement} ========== All C-bonded H atoms were placed in calculated positions and constrained to ride on their parents atoms, with C---H = 0.93--0.96 Å, and *U*~iso~(H) = 1.2*U*~eq~(C) or 1.5*U*~eq~(C). Hydroxyl H atoms were found in a difference map and refined freely (coordinates and isotropic displacement parameters). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the asymmetric unit of the title compound, with the atomic numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e146 .table-wrap} ------------------------ ---------------------------------------- C~14~H~11~FN~2~O~2~ *Z* = 4 *M~r~* = 258.25 *F*(000) = 536 Triclinic, *P*1 *D*~x~ = 1.463 Mg m^−3^ Hall symbol: -P 1 Melting point: 414 K *a* = 6.7632 (3) Å Mo *K*α radiation, λ = 0.71073 Å *b* = 12.5906 (6) Å Cell parameters from 26377 reflections *c* = 13.8769 (6) Å θ = 2.1--28.0° α = 85.641 (4)° µ = 0.11 mm^−1^ β = 89.337 (3)° *T* = 150 K γ = 84.254 (4)° Prism, yellow *V* = 1172.31 (9) Å^3^ 0.64 × 0.40 × 0.12 mm ------------------------ ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e283 .table-wrap} ------------------------------------------------------------------ -------------------------------------- Stoe IPDS II diffractometer 4870 independent reflections Radiation source: fine-focus sealed tube 3825 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.034 rotation method scans θ~max~ = 26.5°, θ~min~ = 2.1° Absorption correction: integration (*X-RED32*; Stoe & Cie, 2002) *h* = −8→8 *T*~min~ = 0.941, *T*~max~ = 0.987 *k* = −15→15 20279 measured reflections *l* = −17→17 ------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e395 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.036 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.104 H atoms treated by a mixture of independent and constrained refinement *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.063*P*)^2^ + 0.1104*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4870 reflections (Δ/σ)~max~ \< 0.001 351 parameters Δρ~max~ = 0.20 e Å^−3^ 0 restraints Δρ~min~ = −0.26 e Å^−3^ 0 constraints ------------------------------------- ------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e558 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C7B 0.29323 (18) 0.16314 (9) 0.29768 (8) 0.0257 (3) C8B 0.3302 (2) 0.12570 (10) 0.19883 (9) 0.0330 (3) H8G 0.3581 0.0492 0.2033 0.049\* H8H 0.4417 0.1579 0.1701 0.049\* H8I 0.2146 0.1460 0.1596 0.049\* F1B 0.19877 (12) 0.84085 (6) 0.20031 (5) 0.0356 (2) O1B 0.23372 (14) 0.24319 (8) 0.48420 (6) 0.0301 (2) O2B 0.30636 (15) 0.09721 (7) 0.36845 (6) 0.0377 (2) C1B 0.18273 (16) 0.46248 (9) 0.24684 (8) 0.0211 (2) C2B 0.15586 (17) 0.49461 (9) 0.34147 (8) 0.0228 (2) H2B 0.1256 0.5667 0.3513 0.027\* C3B 0.17401 (17) 0.42033 (10) 0.41916 (8) 0.0248 (2) H3B 0.1573 0.4424 0.4815 0.030\* C4B 0.21747 (17) 0.31175 (9) 0.40529 (8) 0.0230 (2) C5B 0.24380 (16) 0.27757 (9) 0.31097 (8) 0.0220 (2) C6B 0.22510 (16) 0.35533 (9) 0.23235 (8) 0.0213 (2) H6B 0.2415 0.3342 0.1697 0.026\* C9B 0.15918 (16) 0.70366 (9) 0.09673 (8) 0.0207 (2) C10B 0.13857 (17) 0.67548 (9) 0.00216 (8) 0.0232 (2) H10B 0.1198 0.6053 −0.0089 0.028\* C11B 0.14587 (18) 0.75119 (10) −0.07505 (8) 0.0258 (3) H11B 0.1340 0.7313 −0.1378 0.031\* C12B 0.17078 (18) 0.85670 (10) −0.05954 (8) 0.0264 (3) H12B 0.1764 0.9070 −0.1119 0.032\* C13B 0.18720 (18) 0.88725 (9) 0.03347 (9) 0.0269 (3) H13B 0.2022 0.9579 0.0445 0.032\* C14B 0.18075 (17) 0.81039 (9) 0.10957 (8) 0.0241 (2) N1B 0.17444 (14) 0.53478 (8) 0.16294 (7) 0.0216 (2) N2B 0.16196 (14) 0.63179 (8) 0.18110 (7) 0.0223 (2) H1A 0.666 (3) 0.8198 (18) 0.0400 (15) 0.068 (6)\* H1B 0.264 (3) 0.1779 (18) 0.4624 (15) 0.067 (6)\* C1A 0.67173 (16) 0.53945 (9) 0.25268 (8) 0.0211 (2) C2A 0.65490 (17) 0.50686 (9) 0.15876 (8) 0.0231 (2) H2A 0.6472 0.4350 0.1496 0.028\* C3A 0.64973 (17) 0.58043 (10) 0.08049 (8) 0.0241 (2) H3A 0.6396 0.5581 0.0185 0.029\* C4A 0.65968 (16) 0.68882 (9) 0.09347 (8) 0.0224 (2) C5A 0.67659 (16) 0.72345 (9) 0.18736 (8) 0.0219 (2) C6A 0.68203 (16) 0.64637 (9) 0.26628 (8) 0.0212 (2) H6A 0.6927 0.6676 0.3286 0.025\* C7A 0.69267 (17) 0.83745 (9) 0.19921 (8) 0.0249 (3) C8A 0.7238 (2) 0.87475 (10) 0.29742 (9) 0.0336 (3) H8D 0.7310 0.9507 0.2922 0.050\* H8E 0.8455 0.8394 0.3241 0.050\* H8F 0.6148 0.8580 0.3389 0.050\* C9A 0.71928 (16) 0.29896 (9) 0.40370 (8) 0.0209 (2) C10A 0.69207 (17) 0.32845 (9) 0.49868 (8) 0.0239 (2) H10A 0.6558 0.3997 0.5099 0.029\* C11A 0.71875 (18) 0.25244 (10) 0.57564 (8) 0.0268 (3) H11A 0.7033 0.2731 0.6384 0.032\* C12A 0.76851 (19) 0.14535 (10) 0.56014 (9) 0.0282 (3) H12A 0.7863 0.0947 0.6125 0.034\* C13A 0.79162 (19) 0.11398 (10) 0.46700 (9) 0.0289 (3) H13A 0.8229 0.0423 0.4559 0.035\* C14A 0.76734 (18) 0.19117 (9) 0.39089 (8) 0.0256 (3) F1A 0.79319 (13) 0.16003 (6) 0.29986 (5) 0.0370 (2) N1A 0.68463 (14) 0.46776 (8) 0.33713 (7) 0.0217 (2) N2A 0.70257 (14) 0.37066 (8) 0.31933 (7) 0.0220 (2) O1A 0.65338 (13) 0.75669 (7) 0.01410 (6) 0.0286 (2) O2A 0.68122 (14) 0.90317 (7) 0.12833 (6) 0.0340 (2) ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1329 .table-wrap} ------ ------------ ------------ ------------ ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C7B 0.0285 (6) 0.0206 (6) 0.0279 (6) −0.0049 (4) −0.0044 (5) 0.0035 (5) C8B 0.0463 (8) 0.0207 (6) 0.0305 (6) 0.0038 (5) −0.0045 (5) −0.0012 (5) F1B 0.0615 (5) 0.0232 (4) 0.0223 (4) −0.0040 (3) −0.0014 (3) −0.0036 (3) O1B 0.0421 (5) 0.0268 (5) 0.0208 (4) −0.0070 (4) −0.0022 (3) 0.0075 (3) O2B 0.0598 (7) 0.0212 (5) 0.0309 (5) −0.0048 (4) −0.0045 (4) 0.0072 (4) C1B 0.0206 (5) 0.0213 (6) 0.0211 (5) −0.0039 (4) −0.0013 (4) 0.0026 (4) C2B 0.0258 (6) 0.0199 (5) 0.0228 (5) −0.0034 (4) 0.0003 (4) −0.0009 (4) C3B 0.0261 (6) 0.0282 (6) 0.0204 (5) −0.0047 (5) 0.0015 (4) −0.0018 (4) C4B 0.0224 (6) 0.0255 (6) 0.0209 (5) −0.0069 (4) −0.0022 (4) 0.0058 (4) C5B 0.0227 (6) 0.0199 (6) 0.0233 (5) −0.0046 (4) −0.0019 (4) 0.0019 (4) C6B 0.0235 (6) 0.0216 (6) 0.0190 (5) −0.0045 (4) −0.0011 (4) 0.0004 (4) C9B 0.0195 (5) 0.0197 (6) 0.0216 (5) 0.0007 (4) 0.0020 (4) 0.0023 (4) C10B 0.0262 (6) 0.0191 (5) 0.0239 (5) −0.0005 (4) 0.0000 (4) −0.0002 (4) C11B 0.0291 (6) 0.0262 (6) 0.0211 (5) 0.0002 (5) −0.0005 (4) 0.0003 (4) C12B 0.0291 (6) 0.0223 (6) 0.0257 (6) 0.0006 (5) 0.0015 (4) 0.0068 (4) C13B 0.0331 (7) 0.0169 (6) 0.0300 (6) −0.0010 (4) 0.0004 (5) 0.0014 (5) C14B 0.0288 (6) 0.0213 (6) 0.0216 (5) 0.0012 (4) 0.0001 (4) −0.0020 (4) N1B 0.0242 (5) 0.0182 (5) 0.0219 (5) −0.0011 (4) 0.0000 (4) 0.0013 (4) N2B 0.0236 (5) 0.0197 (5) 0.0229 (5) −0.0012 (4) 0.0009 (4) 0.0016 (4) C1A 0.0206 (5) 0.0207 (5) 0.0211 (5) −0.0009 (4) 0.0009 (4) 0.0025 (4) C2A 0.0251 (6) 0.0190 (5) 0.0248 (6) −0.0012 (4) 0.0000 (4) −0.0008 (4) C3A 0.0255 (6) 0.0264 (6) 0.0198 (5) 0.0001 (4) −0.0003 (4) −0.0015 (4) C4A 0.0192 (6) 0.0246 (6) 0.0216 (5) 0.0008 (4) 0.0013 (4) 0.0057 (4) C5A 0.0213 (6) 0.0194 (6) 0.0240 (5) −0.0003 (4) 0.0014 (4) 0.0018 (4) C6A 0.0228 (6) 0.0208 (6) 0.0196 (5) −0.0008 (4) 0.0012 (4) −0.0004 (4) C7A 0.0256 (6) 0.0208 (6) 0.0274 (6) −0.0016 (4) 0.0020 (4) 0.0030 (5) C8A 0.0492 (8) 0.0218 (6) 0.0306 (7) −0.0081 (5) −0.0015 (5) −0.0002 (5) C9A 0.0219 (6) 0.0198 (5) 0.0211 (5) −0.0053 (4) −0.0023 (4) 0.0023 (4) C10A 0.0282 (6) 0.0191 (6) 0.0246 (6) −0.0041 (4) 0.0006 (4) −0.0003 (4) C11A 0.0334 (7) 0.0263 (6) 0.0212 (5) −0.0073 (5) 0.0000 (5) −0.0001 (5) C12A 0.0359 (7) 0.0233 (6) 0.0249 (6) −0.0072 (5) −0.0049 (5) 0.0073 (5) C13A 0.0404 (7) 0.0171 (6) 0.0291 (6) −0.0041 (5) −0.0042 (5) 0.0012 (5) C14A 0.0338 (7) 0.0220 (6) 0.0217 (6) −0.0064 (5) −0.0016 (4) −0.0017 (4) F1A 0.0663 (6) 0.0224 (4) 0.0221 (4) −0.0024 (3) −0.0016 (3) −0.0040 (3) N1A 0.0239 (5) 0.0192 (5) 0.0217 (5) −0.0027 (4) −0.0002 (4) 0.0015 (4) N2A 0.0245 (5) 0.0191 (5) 0.0221 (5) −0.0034 (4) −0.0011 (4) 0.0016 (4) O1A 0.0372 (5) 0.0261 (5) 0.0208 (4) −0.0005 (4) 0.0009 (3) 0.0064 (3) O2A 0.0500 (6) 0.0209 (4) 0.0298 (5) −0.0046 (4) −0.0003 (4) 0.0071 (4) ------ ------------ ------------ ------------ ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2076 .table-wrap} --------------------------- -------------- --------------------------- -------------- C7B---O2B 1.2348 (14) C1A---C6A 1.3822 (16) C7B---C5B 1.4711 (16) C1A---C2A 1.4051 (16) C7B---C8B 1.4944 (17) C1A---N1A 1.4217 (14) C8B---H8G 0.9600 C2A---C3A 1.3712 (16) C8B---H8H 0.9600 C2A---H2A 0.9300 C8B---H8I 0.9600 C3A---C4A 1.3984 (17) F1B---C14B 1.3542 (13) C3A---H3A 0.9300 O1B---C4B 1.3403 (13) C4A---O1A 1.3400 (13) O1B---H1B 0.90 (2) C4A---C5A 1.4144 (16) C1B---C6B 1.3802 (16) C5A---C6A 1.4054 (15) C1B---C2B 1.4076 (15) C5A---C7A 1.4719 (16) C1B---N1B 1.4203 (14) C6A---H6A 0.9300 C2B---C3B 1.3707 (16) C7A---O2A 1.2341 (14) C2B---H2B 0.9300 C7A---C8A 1.4986 (17) C3B---C4B 1.3966 (17) C8A---H8D 0.9600 C3B---H3B 0.9300 C8A---H8E 0.9600 C4B---C5B 1.4125 (16) C8A---H8F 0.9600 C5B---C6B 1.4074 (15) C9A---C14A 1.3879 (16) C6B---H6B 0.9300 C9A---C10A 1.4015 (16) C9B---C14B 1.3911 (16) C9A---N2A 1.4214 (14) C9B---C10B 1.3974 (15) C10A---C11A 1.3796 (16) C9B---N2B 1.4234 (14) C10A---H10A 0.9300 C10B---C11B 1.3827 (16) C11A---C12A 1.3889 (17) C10B---H10B 0.9300 C11A---H11A 0.9300 C11B---C12B 1.3887 (17) C12A---C13A 1.3825 (17) C11B---H11B 0.9300 C12A---H12A 0.9300 C12B---C13B 1.3833 (17) C13A---C14A 1.3795 (16) C12B---H12B 0.9300 C13A---H13A 0.9300 C13B---C14B 1.3804 (16) C14A---F1A 1.3551 (13) C13B---H13B 0.9300 N1A---N2A 1.2593 (14) N1B---N2B 1.2603 (14) O1A---H1A 0.91 (2) O2B---C7B---C5B 120.13 (11) C6A---C1A---C2A 119.80 (10) O2B---C7B---C8B 119.40 (11) C6A---C1A---N1A 116.42 (10) C5B---C7B---C8B 120.47 (10) C2A---C1A---N1A 123.76 (10) C7B---C8B---H8G 109.5 C3A---C2A---C1A 120.38 (11) C7B---C8B---H8H 109.5 C3A---C2A---H2A 119.8 H8G---C8B---H8H 109.5 C1A---C2A---H2A 119.8 C7B---C8B---H8I 109.5 C2A---C3A---C4A 120.28 (10) H8G---C8B---H8I 109.5 C2A---C3A---H3A 119.9 H8H---C8B---H8I 109.5 C4A---C3A---H3A 119.9 C4B---O1B---H1B 105.8 (13) O1A---C4A---C3A 117.37 (10) C6B---C1B---C2B 119.67 (10) O1A---C4A---C5A 122.32 (11) C6B---C1B---N1B 116.49 (10) C3A---C4A---C5A 120.32 (10) C2B---C1B---N1B 123.81 (10) C6A---C5A---C4A 118.24 (10) C3B---C2B---C1B 120.40 (11) C6A---C5A---C7A 122.30 (10) C3B---C2B---H2B 119.8 C4A---C5A---C7A 119.44 (10) C1B---C2B---H2B 119.8 C1A---C6A---C5A 120.98 (10) C2B---C3B---C4B 120.37 (11) C1A---C6A---H6A 119.5 C2B---C3B---H3B 119.8 C5A---C6A---H6A 119.5 C4B---C3B---H3B 119.8 O2A---C7A---C5A 120.32 (11) O1B---C4B---C3B 117.47 (10) O2A---C7A---C8A 119.38 (11) O1B---C4B---C5B 122.31 (11) C5A---C7A---C8A 120.30 (10) C3B---C4B---C5B 120.22 (10) C7A---C8A---H8D 109.5 C6B---C5B---C4B 118.39 (10) C7A---C8A---H8E 109.5 C6B---C5B---C7B 122.06 (10) H8D---C8A---H8E 109.5 C4B---C5B---C7B 119.54 (10) C7A---C8A---H8F 109.5 C1B---C6B---C5B 120.95 (10) H8D---C8A---H8F 109.5 C1B---C6B---H6B 119.5 H8E---C8A---H8F 109.5 C5B---C6B---H6B 119.5 C14A---C9A---C10A 117.45 (10) C14B---C9B---C10B 117.45 (10) C14A---C9A---N2A 117.30 (10) C14B---C9B---N2B 117.23 (10) C10A---C9A---N2A 125.26 (10) C10B---C9B---N2B 125.31 (10) C11A---C10A---C9A 120.39 (11) C11B---C10B---C9B 120.50 (11) C11A---C10A---H10A 119.8 C11B---C10B---H10B 119.7 C9A---C10A---H10A 119.8 C9B---C10B---H10B 119.7 C10A---C11A---C12A 120.57 (11) C10B---C11B---C12B 120.42 (11) C10A---C11A---H11A 119.7 C10B---C11B---H11B 119.8 C12A---C11A---H11A 119.7 C12B---C11B---H11B 119.8 C13A---C12A---C11A 120.07 (11) C13B---C12B---C11B 120.26 (11) C13A---C12A---H12A 120.0 C13B---C12B---H12B 119.9 C11A---C12A---H12A 120.0 C11B---C12B---H12B 119.9 C14A---C13A---C12A 118.64 (11) C14B---C13B---C12B 118.46 (11) C14A---C13A---H13A 120.7 C14B---C13B---H13B 120.8 C12A---C13A---H13A 120.7 C12B---C13B---H13B 120.8 F1A---C14A---C13A 118.30 (11) F1B---C14B---C13B 118.04 (11) F1A---C14A---C9A 118.85 (10) F1B---C14B---C9B 119.08 (10) C13A---C14A---C9A 122.85 (11) C13B---C14B---C9B 122.87 (11) N2A---N1A---C1A 113.45 (9) N2B---N1B---C1B 113.68 (9) N1A---N2A---C9A 113.47 (9) N1B---N2B---C9B 113.37 (9) C4A---O1A---H1A 101.3 (13) C6B---C1B---C2B---C3B 0.82 (17) C6A---C1A---C2A---C3A 0.36 (17) N1B---C1B---C2B---C3B −177.35 (10) N1A---C1A---C2A---C3A −177.85 (10) C1B---C2B---C3B---C4B −0.62 (17) C1A---C2A---C3A---C4A −0.48 (17) C2B---C3B---C4B---O1B 179.85 (10) C2A---C3A---C4A---O1A −179.82 (10) C2B---C3B---C4B---C5B 0.22 (17) C2A---C3A---C4A---C5A 0.46 (17) O1B---C4B---C5B---C6B −179.62 (10) O1A---C4A---C5A---C6A 179.99 (10) C3B---C4B---C5B---C6B −0.01 (17) C3A---C4A---C5A---C6A −0.30 (16) O1B---C4B---C5B---C7B −0.76 (17) O1A---C4A---C5A---C7A −1.47 (16) C3B---C4B---C5B---C7B 178.86 (10) C3A---C4A---C5A---C7A 178.24 (10) O2B---C7B---C5B---C6B −179.27 (11) C2A---C1A---C6A---C5A −0.21 (17) C8B---C7B---C5B---C6B 1.43 (17) N1A---C1A---C6A---C5A 178.13 (10) O2B---C7B---C5B---C4B 1.91 (17) C4A---C5A---C6A---C1A 0.18 (16) C8B---C7B---C5B---C4B −177.39 (11) C7A---C5A---C6A---C1A −178.31 (10) C2B---C1B---C6B---C5B −0.62 (17) C6A---C5A---C7A---O2A −177.81 (11) N1B---C1B---C6B---C5B 177.68 (10) C4A---C5A---C7A---O2A 3.72 (17) C4B---C5B---C6B---C1B 0.21 (17) C6A---C5A---C7A---C8A 2.39 (17) C7B---C5B---C6B---C1B −178.62 (10) C4A---C5A---C7A---C8A −176.08 (11) C14B---C9B---C10B---C11B 1.95 (16) C14A---C9A---C10A---C11A 1.94 (17) N2B---C9B---C10B---C11B −177.37 (10) N2A---C9A---C10A---C11A −177.74 (10) C9B---C10B---C11B---C12B −0.98 (17) C9A---C10A---C11A---C12A −1.46 (18) C10B---C11B---C12B---C13B −0.44 (18) C10A---C11A---C12A---C13A −0.06 (19) C11B---C12B---C13B---C14B 0.81 (18) C11A---C12A---C13A---C14A 1.01 (19) C12B---C13B---C14B---F1B 179.40 (10) C12A---C13A---C14A---F1A 179.01 (11) C12B---C13B---C14B---C9B 0.23 (18) C12A---C13A---C14A---C9A −0.48 (19) C10B---C9B---C14B---F1B 179.24 (10) C10A---C9A---C14A---F1A 179.53 (10) N2B---C9B---C14B---F1B −1.38 (16) N2A---C9A---C14A---F1A −0.77 (16) C10B---C9B---C14B---C13B −1.59 (17) C10A---C9A---C14A---C13A −0.98 (18) N2B---C9B---C14B---C13B 177.78 (11) N2A---C9A---C14A---C13A 178.72 (11) C6B---C1B---N1B---N2B −170.98 (10) C6A---C1A---N1A---N2A −170.56 (10) C2B---C1B---N1B---N2B 7.24 (16) C2A---C1A---N1A---N2A 7.71 (16) C1B---N1B---N2B---C9B 178.39 (9) C1A---N1A---N2A---C9A 178.87 (9) C14B---C9B---N2B---N1B −169.03 (10) C14A---C9A---N2A---N1A −171.20 (10) C10B---C9B---N2B---N1B 10.29 (16) C10A---C9A---N2A---N1A 8.47 (16) --------------------------- -------------- --------------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3187 .table-wrap} ----------------- ---------- ---------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O1A---H1A···O2A 0.91 (2) 1.68 (2) 2.5437 (12) 157 (2) O1B---H1B···O2B 0.90 (2) 1.72 (2) 2.5395 (13) 150 (2) ----------------- ---------- ---------- ------------- --------------- ::: ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- ---------- ---------- ------------- ------------- O1*A*---H1*A*⋯O2*A* 0.91 (2) 1.68 (2) 2.5437 (12) 157 (2) O1*B*---H1*B*⋯O2*B* 0.90 (2) 1.72 (2) 2.5395 (13) 150 (2) :::

PubMed Central

2024-06-05T04:04:17.639413

2011-2-16

PMC3051974

Related literature {#sec1} ================== For applications of sulfopropyl derivatives, see: Adamczyk & Rege (1998[@bb1]). For the biological activity of 2-amino­pyridine, see: Salimon *et al.* (2009[@bb7]). For a related structure, see: Koclega *et al.* (2007[@bb6]). For the title compound as a heterogeneous catalyst, see: Jayamurugan *et al.* (2009[@bb5]). For hydrogen-bond motifs, see: Bernstein *et al.* (1995[@bb2]). For the stability of the temperature controller used in the data collection, see: Cosier & Glazer (1986[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~8~H~12~N~2~O~3~S·H~2~O*M* *~r~* = 234.27Monoclinic,*a* = 9.0771 (3) Å*b* = 16.6307 (7) Å*c* = 7.4393 (3) Åβ = 112.794 (1)°*V* = 1035.32 (7) Å^3^*Z* = 4Mo *K*α radiationμ = 0.31 mm^−1^*T* = 100 K0.51 × 0.14 × 0.14 mm ### Data collection {#sec2.1.2} Bruker SMART APEXII CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2009[@bb3]) *T* ~min~ = 0.858, *T* ~max~ = 0.95815075 measured reflections4050 independent reflections3694 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.023 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.028*wR*(*F* ^2^) = 0.082*S* = 1.044050 reflections152 parametersH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.49 e Å^−3^Δρ~min~ = −0.41 e Å^−3^ {#d5e590} Data collection: *APEX2* (Bruker, 2009[@bb3]); cell refinement: *SAINT* (Bruker, 2009[@bb3]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL*; software used to prepare material for publication: *SHELXTL* and *PLATON* (Spek, 2009[@bb9]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811004107/lh5199sup1.cif](http://dx.doi.org/10.1107/S1600536811004107/lh5199sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004107/lh5199Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004107/lh5199Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?lh5199&file=lh5199sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?lh5199sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?lh5199&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [LH5199](http://scripts.iucr.org/cgi-bin/sendsup?lh5199)). The authors would like to thank Universiti Sains Malaysia (USM) for the RU research grant (No. 1001/PKIMIA/814019). CWK would also like to acknowledge an NSF scholarship. HKF and MMR also thank USM for the Research University Grant (No. 1001/PFIZIK/811160). Comment ======= The sulfopropyl group has been widely used as a hydrophilic enhancing agent in dye, nucleocides, proteins and polymers (Adamczyk & Rege, 1998). In addition, derivatives of sulfopropylated compounds are used extensively in both manufacturing and diagnostic industries. For example, sulfopropylated fatty acids have been found to possess antistatic properties while sulfopropylated acridines have been used industrially as chemiluminescent probes (Adamczyk & Rege, 1998). These properties of sultone can be acredited to the CH~2~ group attached to the S atom which allowed attachment to other organic fragments such as the 2-amino pyridine group in the current study. The indisputable application of 2-aminopyridine in the synthesis of pharmaceuticals such as antihistamines and piroxican has been the main reason for its substantial desirability up to now (Salimon *et al.*, 2009). In this study, sultone was reacted with 2-aminopyridine and attachment was achieved through the N atom in the ring. This compound allows the immobilization onto silica to serve as a heterogeneous catalyst in various industrial applications (Jayamurugan *et al.*, 2009). All parameters in the title compound (I), Fig. 1, are within normal ranges and comparable to a related structure (Koclega *et al.*, 2007). The torsion angles S1-C8-C7-C6 and N1-C6-C7-C8 are -178.36 (5) and -179.58 (6)° respectively. In the selected asymmetric unit, the 2-amino-N-3-sulfatepropyl-pyridinium molecule is linked to the water molecule through an N2---H2N2···O1W (Table 1, Fig. 1) intermolecular hydrogen bond. In the crystal structure, intermolecular O1W---H1W1···O2^ii^, O1W---H2W1···O2^iii^, N2---H1N2···O3^i^, C6---H6B···O1^iv^, C1---H1A···O1^iv^, C2---H2A···O1W^v^ and weak C6---H6A···O3^i^ hydrogen bnods (Table 1, Fig. 2) link molecules into a three-dimensional network. The weak C6---H6B···O1^iv^ interactions are involved in R~2~^2^(12) ring motifs while weak C1---H1A···O1^iv^ interactions form R~1~^2^ (6) ring motifs (Bernstein *et al.*, 1995). Experimental {#experimental} ============ 2-amino pyridine (3g, 1.9 mmol) was dissolved in acetonitrile (20 ml). 1,3-propane sultone (2.8 ml, 1.9 mmol) was added to the mixture and was refluxed at 353 K for 1 h. The light yellowish precipitate was filtered and washed with acetonitrile (10 ml) and diethyl ether (10 ml). The product was recrystallized in methanol: water (9:1 ratio) to produce light yellow needle-shaped crystals. Refinement {#refinement} ========== H atoms attached to N and O atoms were located from difference Fourier map and freely refined. The remaining H atoms were positioned geometrically \[C-H = 0.93 and 0.97Å\] and refined using a riding model, with U~iso~(H) = 1.2U~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure, showing 50% probability displacement ellipsoids. Hydrogen atoms are shown as spheres of arbitrary radius. The dashed line indicates a hydrogen bond. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The crystal packing of (I) viewed along the b axis. Dashed lines indicate hydrogen bonds. H atoms not involved in the hydrogen bond interactions have been omitted for clarity. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e159 .table-wrap} -------------------------- --------------------------------------- C~8~H~12~N~2~O~3~S·H~2~O *F*(000) = 496 *M~r~* = 234.27 *D*~x~ = 1.503 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 7571 reflections *a* = 9.0771 (3) Å θ = 3.2--33.6° *b* = 16.6307 (7) Å µ = 0.31 mm^−1^ *c* = 7.4393 (3) Å *T* = 100 K β = 112.794 (1)° Needle, light-yellow *V* = 1035.32 (7) Å^3^ 0.51 × 0.14 × 0.14 mm *Z* = 4 -------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e293 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEXII CCD area-detector diffractometer 4050 independent reflections Radiation source: fine-focus sealed tube 3694 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.023 φ and ω scans θ~max~ = 33.6°, θ~min~ = 3.2° Absorption correction: multi-scan (*SADABS*; Bruker, 2009) *h* = −14→13 *T*~min~ = 0.858, *T*~max~ = 0.958 *k* = −24→25 15075 measured reflections *l* = −11→11 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e410 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.028 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.082 H atoms treated by a mixture of independent and constrained refinement *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0443*P*)^2^ + 0.3224*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4050 reflections (Δ/σ)~max~ \< 0.001 152 parameters Δρ~max~ = 0.49 e Å^−3^ 0 restraints Δρ~min~ = −0.41 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e567 .table-wrap} ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. The crystal was placed in the cold stream of an Oxford Cyrosystems Cobra open-flow nitrogen cryostat (Cosier & Glazer, 1986) operating at 100.0 (1) K. Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ \> 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e618 .table-wrap} ------ -------------- --------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ S1 0.02015 (2) 0.135731 (11) −0.20477 (3) 0.00995 (6) O1 0.04125 (8) 0.05139 (4) −0.23882 (9) 0.01617 (12) O2 −0.13259 (7) 0.16825 (4) −0.34346 (9) 0.01625 (12) O3 0.15490 (7) 0.18591 (4) −0.19553 (9) 0.01467 (12) N1 0.29524 (8) 0.09165 (4) 0.54330 (9) 0.01030 (12) N2 0.40686 (9) 0.22107 (4) 0.57767 (11) 0.01460 (13) C1 0.30927 (10) 0.01161 (5) 0.59030 (12) 0.01312 (14) H1A 0.2253 −0.0229 0.5236 0.016\* C2 0.44337 (10) −0.01854 (5) 0.73247 (12) 0.01495 (14) H2A 0.4531 −0.0733 0.7604 0.018\* C3 0.56716 (10) 0.03537 (5) 0.83638 (12) 0.01397 (14) H3A 0.6577 0.0167 0.9384 0.017\* C4 0.55426 (9) 0.11494 (5) 0.78738 (11) 0.01314 (14) H4A 0.6364 0.1502 0.8558 0.016\* C5 0.41636 (9) 0.14415 (5) 0.63289 (11) 0.01089 (13) C6 0.14495 (9) 0.11861 (5) 0.38687 (11) 0.01081 (13) H6A 0.1216 0.1734 0.4122 0.013\* H6B 0.0575 0.0846 0.3847 0.013\* C7 0.16001 (9) 0.11457 (5) 0.19015 (11) 0.01233 (13) H7A 0.2483 0.1482 0.1932 0.015\* H7B 0.1829 0.0597 0.1649 0.015\* C8 0.00708 (9) 0.14264 (5) 0.02759 (11) 0.01198 (13) H8A −0.0140 0.1980 0.0514 0.014\* H8B −0.0815 0.1100 0.0275 0.014\* O1W 0.71613 (8) 0.30058 (4) 0.75218 (10) 0.01777 (13) H1N2 0.3233 (17) 0.2419 (8) 0.489 (2) 0.020 (3)\* H1W1 0.772 (2) 0.3125 (10) 0.877 (3) 0.034 (4)\* H2N2 0.4915 (18) 0.2508 (9) 0.636 (2) 0.025 (3)\* H2W1 0.765 (2) 0.2638 (11) 0.726 (3) 0.041 (5)\* ------ -------------- --------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1024 .table-wrap} ----- ------------- ------------- ------------- -------------- ------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.01095 (9) 0.01021 (9) 0.00793 (9) −0.00137 (6) 0.00282 (6) −0.00137 (5) O1 0.0228 (3) 0.0105 (3) 0.0159 (3) −0.0020 (2) 0.0082 (2) −0.0038 (2) O2 0.0142 (3) 0.0222 (3) 0.0094 (2) 0.0024 (2) 0.0014 (2) 0.0011 (2) O3 0.0156 (3) 0.0152 (3) 0.0138 (3) −0.0060 (2) 0.0064 (2) −0.0030 (2) N1 0.0103 (3) 0.0104 (3) 0.0087 (3) 0.0005 (2) 0.0021 (2) 0.0004 (2) N2 0.0123 (3) 0.0107 (3) 0.0165 (3) −0.0005 (2) 0.0008 (2) 0.0015 (2) C1 0.0153 (3) 0.0109 (3) 0.0126 (3) −0.0007 (2) 0.0048 (3) 0.0004 (2) C2 0.0169 (3) 0.0123 (3) 0.0147 (3) 0.0022 (3) 0.0051 (3) 0.0029 (3) C3 0.0133 (3) 0.0157 (3) 0.0121 (3) 0.0033 (3) 0.0041 (3) 0.0022 (3) C4 0.0110 (3) 0.0146 (3) 0.0115 (3) 0.0007 (3) 0.0018 (2) 0.0001 (3) C5 0.0103 (3) 0.0112 (3) 0.0102 (3) 0.0003 (2) 0.0029 (2) −0.0005 (2) C6 0.0097 (3) 0.0128 (3) 0.0087 (3) 0.0008 (2) 0.0023 (2) 0.0003 (2) C7 0.0113 (3) 0.0160 (3) 0.0090 (3) 0.0020 (3) 0.0032 (2) 0.0003 (2) C8 0.0108 (3) 0.0156 (3) 0.0085 (3) 0.0015 (2) 0.0027 (2) −0.0001 (2) O1W 0.0167 (3) 0.0174 (3) 0.0147 (3) 0.0013 (2) 0.0010 (2) −0.0018 (2) ----- ------------- ------------- ------------- -------------- ------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1317 .table-wrap} ------------------- ------------- ------------------- ------------- S1---O1 1.4511 (6) C3---C4 1.3655 (12) S1---O3 1.4602 (6) C3---H3A 0.9300 S1---O2 1.4734 (6) C4---C5 1.4174 (11) S1---C8 1.7817 (8) C4---H4A 0.9300 N1---C5 1.3593 (10) C6---C7 1.5231 (11) N1---C1 1.3695 (10) C6---H6A 0.9700 N1---C6 1.4786 (10) C6---H6B 0.9700 N2---C5 1.3361 (10) C7---C8 1.5188 (11) N2---H1N2 0.861 (14) C7---H7A 0.9700 N2---H2N2 0.874 (15) C7---H7B 0.9700 C1---C2 1.3616 (11) C8---H8A 0.9700 C1---H1A 0.9300 C8---H8B 0.9700 C2---C3 1.4110 (12) O1W---H1W1 0.892 (17) C2---H2A 0.9300 O1W---H2W1 0.825 (19) O1---S1---O3 113.32 (4) C5---C4---H4A 119.8 O1---S1---O2 112.62 (4) N2---C5---N1 121.38 (7) O3---S1---O2 111.53 (4) N2---C5---C4 120.60 (7) O1---S1---C8 107.14 (4) N1---C5---C4 118.02 (7) O3---S1---C8 106.67 (4) N1---C6---C7 110.12 (6) O2---S1---C8 104.92 (4) N1---C6---H6A 109.6 C5---N1---C1 121.44 (7) C7---C6---H6A 109.6 C5---N1---C6 121.03 (7) N1---C6---H6B 109.6 C1---N1---C6 117.50 (6) C7---C6---H6B 109.6 C5---N2---H1N2 123.5 (9) H6A---C6---H6B 108.2 C5---N2---H2N2 116.6 (10) C8---C7---C6 110.91 (6) H1N2---N2---H2N2 119.9 (14) C8---C7---H7A 109.5 C2---C1---N1 121.53 (7) C6---C7---H7A 109.5 C2---C1---H1A 119.2 C8---C7---H7B 109.5 N1---C1---H1A 119.2 C6---C7---H7B 109.5 C1---C2---C3 118.30 (8) H7A---C7---H7B 108.0 C1---C2---H2A 120.9 C7---C8---S1 111.64 (6) C3---C2---H2A 120.9 C7---C8---H8A 109.3 C4---C3---C2 120.12 (7) S1---C8---H8A 109.3 C4---C3---H3A 119.9 C7---C8---H8B 109.3 C2---C3---H3A 119.9 S1---C8---H8B 109.3 C3---C4---C5 120.41 (8) H8A---C8---H8B 108.0 C3---C4---H4A 119.8 H1W1---O1W---H2W1 105.9 (16) C5---N1---C1---C2 1.82 (12) C3---C4---C5---N2 −176.43 (8) C6---N1---C1---C2 −179.98 (7) C3---C4---C5---N1 3.44 (12) N1---C1---C2---C3 2.11 (12) C5---N1---C6---C7 87.55 (9) C1---C2---C3---C4 −3.15 (12) C1---N1---C6---C7 −90.66 (8) C2---C3---C4---C5 0.38 (13) N1---C6---C7---C8 −179.58 (6) C1---N1---C5---N2 175.31 (8) C6---C7---C8---S1 −178.36 (5) C6---N1---C5---N2 −2.83 (12) O1---S1---C8---C7 62.61 (7) C1---N1---C5---C4 −4.56 (11) O3---S1---C8---C7 −59.04 (7) C6---N1---C5---C4 177.31 (7) O2---S1---C8---C7 −177.48 (6) ------------------- ------------- ------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1781 .table-wrap} ---------------------- ------------ ------------ ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N2---H1N2···O3^i^ 0.862 (15) 2.009 (14) 2.8553 (10) 167.0 (13) O1W---H1W1···O2^ii^ 0.89 (2) 1.95 (2) 2.8289 (9) 171.5 (19) N2---H2N2···O1W 0.875 (16) 2.055 (16) 2.9139 (11) 166.9 (15) O1W---H2W1···O2^iii^ 0.822 (19) 2.007 (19) 2.8270 (10) 175 (2) C1---H1A···O1^iv^ 0.93 2.57 3.4076 (11) 150 C2---H2A···O1W^v^ 0.93 2.58 3.3595 (11) 142 C6---H6A···O3^i^ 0.97 2.53 3.3160 (11) 138 C6---H6B···O1^iv^ 0.97 2.52 3.2589 (11) 133 ---------------------- ------------ ------------ ------------- --------------- ::: Symmetry codes: (i) *x*, −*y*+1/2, *z*+1/2; (ii) *x*+1, −*y*+1/2, *z*+3/2; (iii) *x*+1, *y*, *z*+1; (iv) −*x*, −*y*, −*z*; (v) −*x*+1, *y*−1/2, −*z*+3/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------------ ------------ ------------ ------------- ------------- N2---H1*N*2⋯O3^i^ 0.862 (15) 2.009 (14) 2.8553 (10) 167.0 (13) O1*W*---H1*W*1⋯O2^ii^ 0.89 (2) 1.95 (2) 2.8289 (9) 171.5 (19) N2---H2*N*2⋯O1*W* 0.875 (16) 2.055 (16) 2.9139 (11) 166.9 (15) O1*W*---H2*W*1⋯O2^iii^ 0.822 (19) 2.007 (19) 2.8270 (10) 175 (2) C1---H1*A*⋯O1^iv^ 0.93 2.57 3.4076 (11) 150 C2---H2*A*⋯O1*W*^v^ 0.93 2.58 3.3595 (11) 142 C6---H6*A*⋯O3^i^ 0.97 2.53 3.3160 (11) 138 C6---H6*B*⋯O1^iv^ 0.97 2.52 3.2589 (11) 133 Symmetry codes: (i) ; (ii) ; (iii) ; (iv) ; (v) . ::: [^1]: ‡ Thomson Reuters ResearcherID: A-3561-2009

PubMed Central

2024-06-05T04:04:17.645344

2011-2-05

PMC3051975

Related literature {#sec1} ================== For the synthesis and structure of the α,α-C~4~S~6~ ligand, see: Krug *et al.* (1977[@bb8]); Beck *et al.* (2006[@bb1]). For related studies on polymeric binary carbon sulfides, see: Galloway *et al.* (1994[@bb5]). For the synthesis and structures of coordination polymers with sulfur-rich ligands, see: Peindy *et al.* (2005[@bb10]); Hameau *et al.* (2006[@bb7]); Ndiaye *et al.* (2007[@bb9]); Guyon *et al.* (2008[@bb6]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Hg~4~I~8~(C~4~S~6~)\]*M* *~r~* = 1028.98Monoclinic,*a* = 8.5502 (6) Å*b* = 11.2156 (8) Å*c* = 13.4634 (9) Åβ = 91.343 (1)°*V* = 1290.73 (16) Å^3^*Z* = 4Mo *K*α radiationμ = 33.76 mm^−1^*T* = 173 K0.30 × 0.10 × 0.10 mm ### Data collection {#sec2.1.2} Bruker APEX CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 1999[@bb2]) *T* ~min~ = 0.035, *T* ~max~ = 0.13324415 measured reflections2543 independent reflections2337 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.086 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.039*wR*(*F* ^2^) = 0.114*S* = 1.032543 reflections100 parametersΔρ~max~ = 3.56 e Å^−3^Δρ~min~ = −3.29 e Å^−3^ {#d5e439} Data collection: *SMART* (Bruker, 2001[@bb3]); cell refinement: *SAINT-Plus* (Bruker, 1999[@bb2]); data reduction: *SAINT-Plus*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb11]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb11]); molecular graphics: *ORTEP-3* (Farrugia, 1997[@bb4]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811006556/fi2103sup1.cif](http://dx.doi.org/10.1107/S1600536811006556/fi2103sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006556/fi2103Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006556/fi2103Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?fi2103&file=fi2103sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?fi2103sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?fi2103&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [FI2103](http://scripts.iucr.org/cgi-bin/sendsup?fi2103)). This work was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. Comment ======= Molecular and polymeric binary carbon sulfides have been the subject of numerous studies (see for example Galloway *et al.*, 1994). In the context of our interest in using sulfur-rich ligands to synthesize coordination polymers (Peindy *et al.*, 2005; Hameau *et al.*, 2006; Ndiaye *et al.* 2007; Guyon *et al.* 2008), carbon sulfides and especially 1,3-dithiol*o*-(4,5-d)-1,3-dithiol-2,5-dithione (α,α-C~4~S~6~) appears attractive due to the presence of two potentially coordinating thiocarbonyl sulfur atoms. The α,α-C~4~S~6~ carbon sulfide compound, first prepared in 1977 (Krug *et al.*, 1977), reacts with HgI~2~ to afford the coordination polymer \[Hg~4~I~8~(C~4~S~6~)\]~n~ (1). As shown in Fig.1, the monomeric unit has a centrosymmetrical tetranuclear structure which is formed by one α,α-C~4~S~6~ ligand linking two Hg~2~I~4~ fragments with an inversion centre located at the mid-point of the central C═C bond. Each mercury(II) centre is arranged in a distorted tetrahedral manner. The Hg1 atom is coordinated by one terminal iodine atom (I1), two bridging iodine atoms (I2 and I4^iii^) and the sulfur of the thiocarbonyl function S2 whereas the coordination sphere of Hg2 involves only bridging iodo ligands (I2, I3, I3^ii^ and I4). Note however that the bridging contribution of I4 is weak since the Hg1^iii^-I4 distance (3.423 (1) Å) is quite long compared to that of Hg2---I4 (2.6497 (8) Å). The C═S bond of α,α-C~4~S~6~ is weakly affected by coordination of the sulfur atom on Hg1 (1.671 (10) Å *versus* 1.645 (2) in the free ligand, Beck *et al.*, 2006). The Hg1---S2 distance of 2.697 (3) Å is somewhat longer than that reported for 4,5-bis(methylthio)-1,3-dithiole-2-thione on HgI~2~ (Hameau *et al.*, 2006). The α,α-C~4~S~6~ ligands connect the inorganic chains built upon the alternance of 8-membered Hg~4~I~4~ and 4-membered Hg~2~I~2~ cycles to form a two-dimensional framework. Note that there are no S---S interactions inferior to the sum of the van der Waals radii of two S atoms in the solid state. Experimental {#experimental} ============ The α,α-C~4~S~6~ ligand was prepared as described previously (Beck *et al.*, 2006). To the α,α-C~4~S~6~ dithione (14 mg, 58 µmol) dissolved in 13.5 ml of a solvent mixture (toluene/acetonitrile/chlorobenzene in 2/1/1 ratio) was added upon stirring a solution of HgI~2~ (53 mg, 116 µmol) in toluene (10 ml). The resulting solution was refluxed for 0.2 h., then allowed to reach room temperature and filtered. Dark red crystals suitable for X-ray analysis were obtained by slow evaporation of the solution (yield 85%). IR (KBr): ν~C═S~ = 1036 cm^-1^. Refinement {#refinement} ========== The largest Fourier peak/hole (3.56 and --3.29 e/Å^3^, respectively) are found 0.95 and 0.68Å from Hg1 (see even extra table). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the title compound along (001). Displacement ellipsoids are drawn at the 50% probability level. Symmetry operations: (i) -x, -y+2, -z+2; (ii) -x, -y+1, -z+2; (iii) -x+1, -y+1, -z+2. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e291 .table-wrap} ------------------------- --------------------------------------- \[Hg~4~I~8~(C~4~S~6~)\] *F*(000) = 1728 *M~r~* = 1028.98 *D*~x~ = 5.295 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 8987 reflections *a* = 8.5502 (6) Å θ = 2.4--26° *b* = 11.2156 (8) Å µ = 33.76 mm^−1^ *c* = 13.4634 (9) Å *T* = 173 K β = 91.343 (1)° Needle, dark red *V* = 1290.73 (16) Å^3^ 0.30 × 0.10 × 0.10 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e422 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker APEX CCD diffractometer 2543 independent reflections Radiation source: fine-focus sealed tube 2337 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.086 ω scans θ~max~ = 26.0°, θ~min~ = 2.4° Absorption correction: multi-scan (*SADABS*; Bruker, 1999) *h* = −10→10 *T*~min~ = 0.035, *T*~max~ = 0.133 *k* = −13→13 24415 measured reflections *l* = −16→16 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e536 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ 0 restraints Least-squares matrix: full Primary atom site location: structure-invariant direct methods *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.039 Secondary atom site location: difference Fourier map *wR*(*F*^2^) = 0.114 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.077*P*)^2^ + 7.1937*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.03 (Δ/σ)~max~ = 0.001 2543 reflections Δρ~max~ = 3.56 e Å^−3^ 100 parameters Δρ~min~ = −3.29 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------ ::: Special details {#specialdetails} =============== ::: {#d1e688 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e787 .table-wrap} ----- ------------- ------------- ------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 0.0263 (12) 0.9542 (9) 1.0288 (7) 0.029 (2) C2 0.2439 (12) 0.9942 (9) 0.9076 (8) 0.033 (2) Hg1 0.51629 (6) 0.77041 (5) 0.83365 (5) 0.05585 (19) Hg2 0.22624 (7) 0.46970 (6) 0.97826 (5) 0.0672 (2) I1 0.82359 (9) 0.77867 (6) 0.83985 (5) 0.0374 (2) I2 0.25603 (8) 0.64475 (6) 0.79810 (5) 0.0372 (2) I3 0.08558 (9) 0.60123 (6) 1.11662 (5) 0.03616 (19) I4 0.45656 (8) 0.32667 (6) 0.92556 (5) 0.03444 (19) S1 0.2076 (3) 0.8973 (2) 1.0033 (2) 0.0374 (6) S2 0.4123 (3) 0.9968 (3) 0.8465 (2) 0.0427 (6) S3 −0.0987 (3) 0.9043 (2) 1.1185 (2) 0.0363 (6) ----- ------------- ------------- ------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e958 .table-wrap} ----- ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.025 (5) 0.035 (5) 0.028 (5) −0.001 (4) 0.003 (4) 0.002 (4) C2 0.031 (5) 0.029 (5) 0.039 (5) −0.002 (4) 0.003 (4) −0.001 (4) Hg1 0.0325 (3) 0.0672 (4) 0.0682 (4) −0.0029 (2) 0.0078 (2) 0.0044 (3) Hg2 0.0477 (4) 0.0668 (4) 0.0881 (5) 0.0157 (3) 0.0243 (3) −0.0110 (3) I1 0.0303 (4) 0.0452 (4) 0.0369 (4) −0.0012 (3) 0.0048 (3) −0.0032 (3) I2 0.0332 (4) 0.0424 (4) 0.0359 (4) −0.0019 (3) 0.0013 (3) 0.0038 (3) I3 0.0351 (4) 0.0365 (4) 0.0369 (4) −0.0014 (3) 0.0029 (3) −0.0047 (3) I4 0.0305 (4) 0.0404 (4) 0.0326 (4) 0.0048 (3) 0.0041 (3) −0.0024 (3) S1 0.0310 (14) 0.0406 (14) 0.0410 (14) 0.0074 (11) 0.0101 (11) 0.0073 (11) S2 0.0350 (15) 0.0365 (13) 0.0576 (17) 0.0020 (11) 0.0205 (13) 0.0038 (12) S3 0.0339 (14) 0.0372 (13) 0.0383 (13) 0.0051 (10) 0.0128 (11) 0.0067 (11) ----- ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1191 .table-wrap} ----------------- ------------ -------------------- ------------- C1---C1^i^ 1.36 (2) Hg1---S2 2.697 (3) C1---S1 1.718 (11) Hg2---I4 2.6496 (9) C1---S3 1.724 (11) Hg2---I3 2.6828 (9) C2---S2 1.675 (11) Hg2---I3^ii^ 3.0353 (10) C2---S3^i^ 1.715 (11) Hg2---I2 3.1357 (10) C2---S1 1.720 (11) I3---Hg2^ii^ 3.0353 (10) Hg1---I1 2.6285 (9) S3---C2^i^ 1.715 (11) Hg1---I2 2.6678 (9) C1^i^---C1---S1 117.1 (11) I4---Hg2---I3^ii^ 112.31 (3) C1^i^---C1---S3 116.3 (11) I3---Hg2---I3^ii^ 91.87 (3) S1---C1---S3 126.6 (6) I4---Hg2---I2 95.60 (3) S2---C2---S3^i^ 121.0 (6) I3---Hg2---I2 103.81 (3) S2---C2---S1 123.4 (6) I3^ii^---Hg2---I2 85.70 (3) S3^i^---C2---S1 115.5 (6) Hg1---I2---Hg2 105.93 (3) I1---Hg1---I2 148.57 (3) Hg2---I3---Hg2^ii^ 88.13 (3) I1---Hg1---S2 107.19 (7) C1---S1---C2 95.4 (5) I2---Hg1---S2 103.53 (7) C2---S2---Hg1 107.7 (4) I4---Hg2---I3 150.11 (4) C2^i^---S3---C1 95.7 (5) ----------------- ------------ -------------------- ------------- ::: Symmetry codes: (i) −*x*, −*y*+2, −*z*+2; (ii) −*x*, −*y*+1, −*z*+2. Table 1 Final difference electron densities {#d1e1427} =========================================== ::: {#d1e1439 .table-wrap} ----- -------------- ---------- ------- Qx nearest atom distance value -Q1 Hg1 0.68 -3.29 Q1 Hg1 0.951 3.56 Q2 Hg2 0.994 1.67 Q3 Hg2 0.770 1.49 Q4 I3 0.797 1.07 Q5 Hg1 1.256 0.92 Q6 I3 0.688 0.92 ----- -------------- ---------- ------- :::

PubMed Central

2024-06-05T04:04:17.650171

2011-2-26

PMC3051976

Related literature {#sec1} ================== For related compounds, see: Oueslati *et al.* (2005*a* [@bb6]); Ben Gharbia *et al.* (2008[@bb1]). For hydrogen-bond networks, see: Oueslati *et al.* (2005*b* [@bb7]); Zaouali *et al.* (2009[@bb9]). For graph-set theory, see: Bernstein *et al.* (1995[@bb2]). For mesomeric effects in related structures, see: Kefi *et al.* (2006[@bb5]); El Glaoui *et al.* (2009[@bb4]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~8~H~12~NO^+^·Cl^−^*M* *~r~* = 173.64Monoclinic,*a* = 11.4234 (11) Å*b* = 8.9384 (9) Å*c* = 8.9490 (9) Åβ = 105.904 (1)°*V* = 878.78 (15) Å^3^*Z* = 4Mo *K*α radiationμ = 0.38 mm^−1^*T* = 100 K0.55 × 0.42 × 0.38 mm ### Data collection {#sec2.1.2} Bruker SMART APEX CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2009[@bb3]) *T* ~min~ = 0.675, *T* ~max~ = 0.7467028 measured reflections2593 independent reflections2411 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.015 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.027*wR*(*F* ^2^) = 0.072*S* = 1.072593 reflections102 parametersH-atom parameters constrainedΔρ~max~ = 0.44 e Å^−3^Δρ~min~ = −0.23 e Å^−3^ {#d5e483} Data collection: *APEX2* (Bruker, 2009[@bb3]); cell refinement: *SAINT* (Bruker, 2009[@bb3]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL*; software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811004363/rz2550sup1.cif](http://dx.doi.org/10.1107/S1600536811004363/rz2550sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004363/rz2550Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004363/rz2550Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?rz2550&file=rz2550sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?rz2550sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?rz2550&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [RZ2550](http://scripts.iucr.org/cgi-bin/sendsup?rz2550)). We would like to acknowledge support by the Secretary of State for Scientific Research and Technology of Tunisia. The diffractometer was funded by the NSF (grant 0087210), the Ohio Board of Regents (grant CAP-491) and YSU. Comment ======= As a part of our ongoing investigations in molecular salts of amine hydrochloride compounds (Oueslati *et al.*, 2005*a*; Ben Gharbia *et al.*, 2008), we report here the crystal structure of one such compound, (4-methoxyphenyl)methanaminium chloride, C~8~H~12~ClNO (Fig. 1). The crystal structure consists of a network of the constituent ammonium and chloride ions connected by N---H···Cl hydrogen bonds (Fig. 2), with a chloride anion acting as a threefold acceptor as similarly observed in related compounds (Oueslati *et al.*, 2005*b*). The N···Cl distances vary between 3.1475 (9) and 3.1680 (8) Å, indicating strong interactions between the ammonium and halogenide ions (Zaouali *et al.*, 2009). Multiple hydrogen bonds connect the different entities of the compound to form inorganic layers, built from the chloride anions and the ammonium groups, parallel to the *bc* plane (Fig. 2). Within the layers, various graph-set motifs (Bernstein *et al.*, 1995) are apparent, including R~2~^4^(8) and R~2~^8^(16) motifs. The organic fragments are located between successive inorganic layers (Fig. 3). No π-π stacking interactions between the phenylene rings or C---H···π interactions towards them are observed. A weak intermolecular C---H···O hydrogen interaction involving an aromatic hydrogen atom is present (Table 1). The organic molecule exhibits a regular spatial configuration with usual distances and angles. The distance C1---O1 \[1.3637 (11) Å\] is slightly shorter than that of C8---O1 \[1.4362 (12) Å\], which can be attributed to the donor mesomeric effect of the methoxy group. All the geometrical features of the title compound agree with those found in related compounds (e.g. Kefi *et al.*, 2006; El Glaoui *et al.*, 2009). Experimental {#experimental} ============ 4-Methoxybenzylamine (2 mmol, 0.274 g) was dissolved in aqueous HCl (10 ml, 1*M*). Colourless crystals suitable for single-crystal X-ray analysis were grown by slow evaporation at room temperature over a period of three weeks (yield 63%). Refinement {#refinement} ========== All H atoms were located in a difference Fourier map, but were repositioned geometrically and refined as riding, with C---H distances of 0.95 (aromatic), 0.99 (methylene) or 0.98 Å (methyl), and N---H distances of 0.91 Å. The torsion angles of the methyl and ammonium H atoms were allowed to refine to best fit the experimental electron density map, and the *U*~iso~(H) values of the these groups were constrained to 1.5 times that of their carrier atom. For the other hydrogen atoms *U*~iso~ was set to 1.2 times *U*~eq~ of the carrier atom. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the title compound, showing 60% probability displacement ellipsoids and arbitrary spheres for the H atoms. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Projection along the a axis of the inorganic layer in the structure of the title compound, showing the N---H···Cl hydrogen bonding interactions (dashed lines). Only the ammonium and chloride sections are shown for clarity. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### Projection of the structure of the title compound along the b axis. Hydrogen bonds are shown as thin black lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e185 .table-wrap} ------------------------- --------------------------------------- C~8~H~12~NO^+^·Cl^−^ *F*(000) = 368 *M~r~* = 173.64 *D*~x~ = 1.312 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 4317 reflections *a* = 11.4234 (11) Å θ = 2.3--30.9° *b* = 8.9384 (9) Å µ = 0.38 mm^−1^ *c* = 8.9490 (9) Å *T* = 100 K β = 105.904 (1)° Block, colourless *V* = 878.78 (15) Å^3^ 0.55 × 0.42 × 0.38 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e316 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEX CCD diffractometer 2593 independent reflections Radiation source: fine-focus sealed tube 2411 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.015 ω scans θ~max~ = 31.0°, θ~min~ = 1.9° Absorption correction: multi-scan (*SADABS*; Bruker, 2009) *h* = −15→16 *T*~min~ = 0.675, *T*~max~ = 0.746 *k* = −12→12 7028 measured reflections *l* = −12→12 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e430 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.027 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.072 H-atom parameters constrained *S* = 1.07 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0349*P*)^2^ + 0.3154*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2593 reflections (Δ/σ)~max~ = 0.001 102 parameters Δρ~max~ = 0.44 e Å^−3^ 0 restraints Δρ~min~ = −0.23 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e587 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e686 .table-wrap} ----- --------------- -------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl1 0.874270 (19) 0.40670 (2) 0.15865 (3) 0.01574 (7) O1 0.54020 (6) 1.00932 (8) 0.27742 (9) 0.01962 (15) N1 0.97373 (7) 0.71225 (9) 0.06200 (9) 0.01532 (15) H1A 1.0144 0.7700 0.1435 0.023\* H1B 1.0261 0.6811 0.0080 0.023\* H1C 0.9417 0.6312 0.0982 0.023\* C2 0.71566 (8) 1.04328 (10) 0.19393 (11) 0.01744 (18) H2 0.7270 1.1373 0.2454 0.021\* C5 0.68479 (8) 0.76756 (10) 0.04614 (11) 0.01565 (17) H5 0.6743 0.6728 −0.0039 0.019\* C1 0.61611 (8) 0.95355 (10) 0.19710 (11) 0.01482 (17) C6 0.60029 (8) 0.81501 (10) 0.12293 (11) 0.01576 (17) H6 0.5328 0.7536 0.1246 0.019\* C3 0.79770 (8) 0.99464 (10) 0.11556 (11) 0.01656 (18) H3 0.8644 1.0568 0.1124 0.020\* C7 0.87306 (9) 0.80189 (11) −0.04294 (11) 0.01650 (17) H7A 0.9082 0.8891 −0.0835 0.020\* H7B 0.8300 0.7394 −0.1325 0.020\* C4 0.78390 (8) 0.85561 (10) 0.04109 (10) 0.01412 (16) C8 0.43276 (9) 0.92405 (12) 0.27309 (13) 0.0218 (2) H8A 0.3835 0.9135 0.1652 0.033\* H8B 0.3852 0.9757 0.3334 0.033\* H8C 0.4562 0.8247 0.3177 0.033\* ----- --------------- -------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1008 .table-wrap} ----- -------------- -------------- -------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.01692 (12) 0.01417 (11) 0.01804 (12) 0.00094 (7) 0.00799 (8) 0.00074 (7) O1 0.0163 (3) 0.0169 (3) 0.0289 (4) 0.0001 (2) 0.0116 (3) −0.0034 (3) N1 0.0178 (4) 0.0137 (3) 0.0164 (3) 0.0002 (3) 0.0080 (3) −0.0007 (3) C2 0.0162 (4) 0.0132 (4) 0.0233 (5) −0.0005 (3) 0.0062 (3) −0.0019 (3) C5 0.0175 (4) 0.0148 (4) 0.0148 (4) −0.0011 (3) 0.0048 (3) −0.0012 (3) C1 0.0138 (4) 0.0143 (4) 0.0169 (4) 0.0020 (3) 0.0051 (3) 0.0008 (3) C6 0.0149 (4) 0.0151 (4) 0.0177 (4) −0.0019 (3) 0.0051 (3) −0.0003 (3) C3 0.0144 (4) 0.0149 (4) 0.0208 (4) −0.0013 (3) 0.0055 (3) 0.0010 (3) C7 0.0182 (4) 0.0191 (4) 0.0135 (4) 0.0010 (3) 0.0065 (3) 0.0014 (3) C4 0.0144 (4) 0.0155 (4) 0.0127 (4) 0.0010 (3) 0.0042 (3) 0.0017 (3) C8 0.0145 (4) 0.0227 (4) 0.0304 (5) −0.0001 (3) 0.0096 (4) −0.0008 (4) ----- -------------- -------------- -------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1241 .table-wrap} ------------------- ------------- ------------------- ------------- O1---C1 1.3634 (11) C5---H5 0.9500 O1---C8 1.4362 (12) C1---C6 1.3932 (13) N1---C7 1.5015 (12) C6---H6 0.9500 N1---H1A 0.9100 C3---C4 1.3984 (13) N1---H1B 0.9100 C3---H3 0.9500 N1---H1C 0.9100 C7---C4 1.5011 (13) C2---C3 1.3854 (13) C7---H7A 0.9900 C2---C1 1.3982 (13) C7---H7B 0.9900 C2---H2 0.9500 C8---H8A 0.9800 C5---C4 1.3897 (13) C8---H8B 0.9800 C5---C6 1.3954 (13) C8---H8C 0.9800 C1---O1---C8 117.00 (8) C2---C3---C4 121.10 (8) C7---N1---H1A 109.5 C2---C3---H3 119.4 C7---N1---H1B 109.5 C4---C3---H3 119.4 H1A---N1---H1B 109.5 C4---C7---N1 111.46 (7) C7---N1---H1C 109.5 C4---C7---H7A 109.3 H1A---N1---H1C 109.5 N1---C7---H7A 109.3 H1B---N1---H1C 109.5 C4---C7---H7B 109.3 C3---C2---C1 119.80 (8) N1---C7---H7B 109.3 C3---C2---H2 120.1 H7A---C7---H7B 108.0 C1---C2---H2 120.1 C5---C4---C3 118.31 (8) C4---C5---C6 121.57 (8) C5---C4---C7 120.38 (8) C4---C5---H5 119.2 C3---C4---C7 121.31 (8) C6---C5---H5 119.2 O1---C8---H8A 109.5 O1---C1---C6 123.91 (8) O1---C8---H8B 109.5 O1---C1---C2 116.06 (8) H8A---C8---H8B 109.5 C6---C1---C2 120.02 (8) O1---C8---H8C 109.5 C1---C6---C5 119.20 (8) H8A---C8---H8C 109.5 C1---C6---H6 120.4 H8B---C8---H8C 109.5 C5---C6---H6 120.4 C8---O1---C1---C6 −5.30 (13) C1---C2---C3---C4 −1.01 (14) C8---O1---C1---C2 175.73 (8) C6---C5---C4---C3 0.05 (14) C3---C2---C1---O1 179.65 (8) C6---C5---C4---C7 −179.76 (8) C3---C2---C1---C6 0.64 (14) C2---C3---C4---C5 0.66 (14) O1---C1---C6---C5 −178.88 (9) C2---C3---C4---C7 −179.53 (9) C2---C1---C6---C5 0.05 (14) N1---C7---C4---C5 −88.82 (10) C4---C5---C6---C1 −0.40 (14) N1---C7---C4---C3 91.37 (10) ------------------- ------------- ------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1615 .table-wrap} -------------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1A···Cl1^i^ 0.91 2.24 3.1475 (9) 176 N1---H1B···Cl1^ii^ 0.91 2.25 3.1502 (8) 170 N1---H1C···Cl1 0.91 2.27 3.1680 (8) 170 C6---H6···O1^iii^ 0.95 2.58 3.4090 (11) 147 -------------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) −*x*+2, *y*+1/2, −*z*+1/2; (ii) −*x*+2, −*y*+1, −*z*; (iii) −*x*+1, *y*−1/2, −*z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- --------- ------- ------------- ------------- N1---H1*A*⋯Cl1^i^ 0.91 2.24 3.1475 (9) 176 N1---H1*B*⋯Cl1^ii^ 0.91 2.25 3.1502 (8) 170 N1---H1*C*⋯Cl1 0.91 2.27 3.1680 (8) 170 C6---H6⋯O1^iii^ 0.95 2.58 3.4090 (11) 147 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.652426

2011-2-16

PMC3051977

Related literature {#sec1} ================== For related ternary compounds, see: Brec *et al.* (1983*a* [@bb3],*b* [@bb4]). For related quaternary compounds, see: Goh *et al.* (2002[@bb12]); Do & Yun (1996[@bb5]); Kim & Yun (2002[@bb15]); Kwak *et al.* (2007[@bb16]); Bang *et al.* (2008[@bb2]); Do & Yun (2009[@bb6]). For related penta­nary compounds, see: Kwak & Yun (2008[@bb17]); Dong *et al.* (2005*a* [@bb8],*b* [@bb7]); Park & Yun (2010[@bb18]). For typical Nb^4+^---Nb^4+^ bond lengths, see: Angenault *et al.* (2000[@bb1]) Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} KNb~1.75~V~0.25~PS~10~*M* *~r~* = 2264.39Orthorhombic,*a* = 12.9696 (3) Å*b* = 7.5229 (2) Å*c* = 13.3248 (4) Å*V* = 1300.09 (6) Å^3^*Z* = 1Mo *K*α radiationμ = 3.73 mm^−1^*T* = 290 K0.36 × 0.06 × 0.06 mm ### Data collection {#sec2.1.2} Rigaku R-AXIS RAPID diffractometerAbsorption correction: multi-scan (*ABSCOR*; Higashi, 1995[@bb13]) *T* ~min~ = 0.649, *T* ~max~ = 1.00011855 measured reflections2970 independent reflections2859 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.028 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.019*wR*(*F* ^2^) = 0.042*S* = 1.072970 reflections130 parameters1 restraintΔρ~max~ = 0.49 e Å^−3^Δρ~min~ = −0.28 e Å^−3^Absolute structure: Flack (1983[@bb10]), 1417 Friedel pairsFlack parameter: 0.47 (4) {#d5e483} Data collection: *RAPID-AUTO* (Rigaku, 2006[@bb19]); cell refinement: *RAPID-AUTO*; data reduction: *RAPID-AUTO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb20]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb20]); molecular graphics: locally modified version of *ORTEP* (Johnson, 1965[@bb14]); software used to prepare material for publication: *STRUCTURE* *TIDY* (Gelato & Parthé, 1987[@bb11]) and *WinGX* (Farrugia, 1999[@bb9]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811004430/fj2392sup1.cif](http://dx.doi.org/10.1107/S1600536811004430/fj2392sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004430/fj2392Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004430/fj2392Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?fj2392&file=fj2392sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?fj2392sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?fj2392&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [FJ2392](http://scripts.iucr.org/cgi-bin/sendsup?fj2392)). This work was supported by the Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2010--0029617). Use was made of the X-ray facilities supported by Ajou University. Comment ======= Ternary group 5 metal thiophosphates have been reported to have mostly low-dimensional structures. Especially the Nb~2~PS~10~ phase has a two-dimensional layered structure (Brec *et al.*, 1983*a*) and V~2~PS~10~ adopts a one-dimensional chain structure (Brec *et al.*, 1983*b*). Due to empty spaces and the orbitals which can accommodate electrons, they have been of potential importance as cathode materials for secondary batteries and a number of quaternary alkali metal Nb thiophosphates, ANb~2~PS~10~ (A=monovalent metals) have been investigated. Among them are NaNb~2~PS~10~ (Goh *et al.*, 2002), KNb~2~PS~10~ (Do & Yun, 1996), RbNb~2~PS~10~ (Kim & Yun, 2002), CsNb~2~PS~10~ (Kwak *et al.*, 2007), TlNb~2~PS~10~ (Bang *et al.*, 2008), Ag~0.88~Nb~2~PS~10~ (Do & Yun, 2009), K~0.34~Cu~0.5~Nb~2~PS~10~ (Kwak & Yun, 2008), K~0.5~Ag~0.5~Nb~2~PS~10~ (Dong *et al.*, 2005*a*), Rb~0.38~Ag~0.5~Nb~2~PS~10~ (Dong *et al.*, 2005*b*), and Cs~0.5~Ag~0.5~Nb~2~PS~10~ (Park & Yun, 2010). It is interesting that no V analogue of these phases has been discovered yet. As a result of efforts to find new phases in this family, we report the synthesis and characterization of a new mixed-metal quintenary thiophosphate, KNb~2\ -~*~x~*V*~x~*PS~10~ (*x*=0.25). The structure of KNb~2\ -~*~x~*V*~x~*PS~10~ is isostructural with the quaternary KNb~2~PS~10~ and detailed description of the structure is given previously (Do & Yun, 1996). The title compound is made up of the bicapped trigonal biprismatic \[*M*~2~S~12~\] unit (*M*=Nb/V) and the tetrahedral \[PS~4~\] group. The *M* sites are occupied by the statistically disordered Nb(\~87.5%) and V(\~12.5%) atoms. The bicapped biprismatic \[*M*~2~S~12~\] units and its neighboring tetrahedral \[PS~4~\] groups are given in Figure 1. These \[*M*~2~S~12~\] units are linked together to form the one-dimensional chains by sharing the S~2~^2-^ prism edge. The one-dimensional chain composed of *M*, P, and S extends along \[100\] and can be described as ∞^1^\[*M*~2~PS~10~^-1^\]. The *M* atoms associate in pairs with M---*M* interactions alternating in the sequence of one short (2.8851 (3) Å) and one long (3.7590 (3) Å) distances. The short distance is typical of Nb^4+^---Nb^4+^ bonding interactions (Angenault *et al.*, 2000). There are no interchain bonding interactions except the van der Waals forces and the K^+^ ions in this van der Waals gap stabilize the structure through the electrostatic interactions (Figure 2). Finally, the classical charge balance of this phase can be represented by \[K^+^\]\[*M*^4+^\]~2~\[PS~4~^3-^\]\[S~2~^2-^\]~3~ and this is consistent with the highly resistive and diamagnetic nature of the compound. Experimental {#experimental} ============ The compound KNb~2\ -~*~x~*V*~x~*PS~10~ was prepared by the reaction of the elemental Nb, V, P, and S with the use of the reactive alkali metal halides. A combination of the pure elements, Nb powder (CERAC 99.9%), V powder (CERAC 99.5%), P powder(CERAC99.95%), and S powder (Aldrich 99.999%) were mixed in a fused silica tube in a molar ratio of Nb: V: P: S = 1:1:1:5 with the eutectic mixture of KCl/LiCl. The mass ratio of the reactants and the halides flux was 2:1. The tube was evacuated to 0.133 Pa, sealed and heated gradually (50 K/h) to 650 K, where it was kept for 72 h. The tube was cooled to 423 K at 3 K/h and then was quenched to room temperature. The excess halides were removed with distilled water and black needle shaped crystals were obtained. The crystals are stable in air and water. A microprobe analysis of the crystals was made with an EDAX equipped scanning electron microscope (Jeol JSM-6700 F). Analysis of these crystals showed only the presence of K, Nb, V, P, and S. A quantitative analysis performed with standards gave the ratio of Nb: V = 87: 13, which corresponds to KNb~1.74~V~0.26~PS~10~. Refinement {#refinement} ========== The refinement of the model with occupational disorder on the *M* site caused significant decrease of the *R*-factor (wR2 = 0.042) in comparison if the full occupation by either metal had been considered (wR2 \> 0.05). Also the displacement parameters in the disordered model became plausible. The disordered atoms were supposed to have the same displacement parameters. The nonstoichiometry of the K site was checked by refining the occupancy of K while those of the other atoms were fixed. With the nonstoichiometric model, the parameter remained the same. The large anisotropic displacement parameters for alkali metals are also found in the related compounds such as KNb~2~PS~10~ (Do & Yun, 1996). The highest residual electron density is 0.86 Å from the M2 site and the deepest hole is 0.85 Å from the M1 site. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the bicapped trigonal biprismatic \[M2S12\] unit (M=V/Nb) and its neighboring tetrahedral \[PS4\] groups. Open circles are S atoms, filled circle are Nb atoms, dark and pale gray circles are P and K atoms, respectively. Displacement ellipsoids are drawn at the 50% probability level. \[Symmetry code: (i) 1 - x, -y, -1/2 + z; (ii) 0.5 - x, -y, -1/2 + z; (ii) -1/2 + x, -y, z\] :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### View of the KNb2 -xVxPS10 down the b axis showing the one-dimensional nature of the compound. Atoms are as marked in Fig. 1. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e481 .table-wrap} ------------------------- ---------------------------------------- KNb~1.75~V~0.25~PS~10~ *F*(000) = 1086 *M~r~* = 2264.39 *D*~x~ = 2.892 Mg m^−3^ Orthorhombic, *Pca*2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2c -2ac Cell parameters from 11171 reflections *a* = 12.9696 (3) Å θ = 3.1--27.5° *b* = 7.5229 (2) Å µ = 3.73 mm^−1^ *c* = 13.3248 (4) Å *T* = 290 K *V* = 1300.09 (6) Å^3^ Needle, black *Z* = 1 0.36 × 0.06 × 0.06 mm ------------------------- ---------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e603 .table-wrap} ------------------------------------------------------------- -------------------------------------- Rigaku R-AXIS RAPID diffractometer 2859 reflections with *I* \> 2σ(*I*) ω scans *R*~int~ = 0.028 Absorption correction: multi-scan (*ABSCOR*; Higashi, 1995) θ~max~ = 27.5°, θ~min~ = 3.1° *T*~min~ = 0.649, *T*~max~ = 1.000 *h* = −16→16 11855 measured reflections *k* = −9→9 2970 independent reflections *l* = −17→17 ------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e712 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ 1 restraint Least-squares matrix: full *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0125*P*)^2^ + 1.1461*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.019 (Δ/σ)~max~ = 0.002 *wR*(*F*^2^) = 0.042 Δρ~max~ = 0.49 e Å^−3^ *S* = 1.07 Δρ~min~ = −0.28 e Å^−3^ 2970 reflections Absolute structure: Flack (1983), 1417 Friedel pairs 130 parameters Flack parameter: 0.47 (4) ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e866 .table-wrap} ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e886 .table-wrap} ----- --------------- -------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) K1 0.38307 (10) 0.50472 (16) 0.30096 (10) 0.0642 (3) Nb1 0.023833 (17) 0.05293 (3) 0.03457 (3) 0.01512 (9) 0.861 (4) V1 0.023833 (17) 0.05293 (3) 0.03457 (3) 0.01512 (9) 0.139 (4) Nb2 0.313453 (17) 0.07166 (3) 0.03513 (3) 0.01521 (10) 0.889 (4) V2 0.313453 (17) 0.07166 (3) 0.03513 (3) 0.01521 (10) 0.111 (4) P1 0.15973 (6) 0.40030 (12) 0.11232 (7) 0.02169 (18) S1 0.03047 (5) 0.39473 (11) 0.02326 (8) 0.0258 (2) S2 0.05595 (7) 0.15141 (14) 0.40819 (7) 0.0255 (2) S3 0.15066 (9) 0.58306 (14) 0.21803 (9) 0.0408 (3) S4 0.16690 (6) 0.13978 (11) 0.16577 (6) 0.01913 (18) S5 0.29187 (5) 0.41184 (10) 0.02883 (11) 0.03005 (19) S6 0.33126 (6) 0.05595 (12) 0.40601 (7) 0.02107 (19) S7 0.44830 (7) 0.13335 (13) 0.16897 (6) 0.02327 (19) S8 0.60124 (7) 0.10543 (14) 0.39868 (7) 0.0257 (2) S9 0.60983 (7) 0.11862 (12) 0.66562 (6) 0.02271 (19) S10 0.67360 (6) 0.15938 (11) 0.00015 (6) 0.02081 (17) ----- --------------- -------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1120 .table-wrap} ----- -------------- -------------- -------------- -------------- --------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ K1 0.0831 (8) 0.0470 (6) 0.0625 (8) 0.0035 (6) −0.0317 (7) 0.0031 (5) Nb1 0.01049 (12) 0.01887 (15) 0.01601 (14) −0.00123 (9) −0.00013 (16) 0.00103 (15) V1 0.01049 (12) 0.01887 (15) 0.01601 (14) −0.00123 (9) −0.00013 (16) 0.00103 (15) Nb2 0.01068 (13) 0.01820 (15) 0.01675 (14) 0.00116 (9) 0.00020 (16) −0.00022 (15) V2 0.01068 (13) 0.01820 (15) 0.01675 (14) 0.00116 (9) 0.00020 (16) −0.00022 (15) P1 0.0173 (4) 0.0182 (4) 0.0296 (5) 0.0017 (3) −0.0002 (3) −0.0028 (4) S1 0.0170 (3) 0.0225 (4) 0.0380 (5) 0.0025 (3) −0.0034 (4) 0.0057 (4) S2 0.0177 (4) 0.0362 (5) 0.0225 (4) −0.0038 (4) −0.0021 (4) 0.0077 (4) S3 0.0463 (6) 0.0299 (5) 0.0462 (6) 0.0077 (5) −0.0039 (5) −0.0184 (5) S4 0.0164 (4) 0.0221 (4) 0.0188 (4) 0.0005 (3) 0.0004 (3) −0.0008 (4) S5 0.0178 (3) 0.0214 (4) 0.0510 (5) −0.0009 (3) 0.0070 (5) 0.0067 (5) S6 0.0153 (4) 0.0292 (5) 0.0187 (4) −0.0010 (3) 0.0004 (3) 0.0031 (3) S7 0.0203 (4) 0.0279 (5) 0.0216 (4) 0.0006 (4) −0.0003 (4) −0.0050 (4) S8 0.0178 (4) 0.0374 (5) 0.0219 (4) 0.0055 (4) 0.0024 (3) 0.0087 (4) S9 0.0200 (4) 0.0274 (5) 0.0208 (4) 0.0013 (4) −0.0012 (3) −0.0034 (4) S10 0.0187 (4) 0.0185 (4) 0.0252 (4) 0.0001 (3) −0.0012 (3) 0.0014 (3) ----- -------------- -------------- -------------- -------------- --------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1450 .table-wrap} ------------------------- -------------- ------------------------ -------------- Nb1---S8^i^ 2.4631 (10) Nb2---S6^i^ 2.5490 (9) Nb1---S7^ii^ 2.4760 (9) Nb2---S10^ii^ 2.5551 (8) Nb1---S2^iii^ 2.5039 (10) Nb2---S5 2.5758 (8) Nb1---S9^i^ 2.5098 (9) Nb2---S4 2.6279 (8) Nb1---S6^i^ 2.5431 (9) Nb2---V1^v^ 2.8851 (3) Nb1---S10^ii^ 2.5562 (8) Nb2---Nb1^v^ 2.8851 (3) Nb1---S1 2.5772 (9) P1---S3 1.9718 (13) Nb1---S4 2.6319 (8) P1---S5 2.0451 (13) Nb1---Nb2^ii^ 2.8851 (3) P1---S1 2.0544 (13) Nb1---V2^ii^ 2.8851 (3) P1---S4 2.0874 (13) Nb2---S9^iv^ 2.4622 (9) S2---S8^ii^ 2.0235 (15) Nb2---S2^i^ 2.4678 (9) S6---S10^vi^ 2.0498 (12) Nb2---S8^iv^ 2.5110 (10) S7---S9^iv^ 2.0405 (14) Nb2---S7 2.5406 (9) S8^i^---Nb1---S7^ii^ 111.22 (3) S9^iv^---Nb2---S7 48.11 (3) S8^i^---Nb1---S2^iii^ 48.07 (4) S2^i^---Nb2---S7 87.95 (3) S7^ii^---Nb1---S2^iii^ 88.59 (3) S8^iv^---Nb2---S7 107.57 (3) S8^i^---Nb1---S9^i^ 91.43 (3) S9^iv^---Nb2---S6^i^ 138.35 (3) S7^ii^---Nb1---S9^i^ 48.31 (3) S2^i^---Nb2---S6^i^ 93.10 (3) S2^iii^---Nb1---S9^i^ 107.66 (3) S8^iv^---Nb2---S6^i^ 79.11 (3) S8^i^---Nb1---S6^i^ 89.43 (3) S7---Nb2---S6^i^ 171.57 (3) S7^ii^---Nb1---S6^i^ 141.69 (3) S9^iv^---Nb2---S10^ii^ 91.16 (3) S2^iii^---Nb1---S6^i^ 81.83 (3) S2^i^---Nb2---S10^ii^ 121.84 (3) S9^i^---Nb1---S6^i^ 167.80 (3) S8^iv^---Nb2---S10^ii^ 79.62 (3) S8^i^---Nb1---S10^ii^ 117.95 (3) S7---Nb2---S10^ii^ 137.82 (3) S7^ii^---Nb1---S10^ii^ 94.40 (3) S6^i^---Nb2---S10^ii^ 47.36 (3) S2^iii^---Nb1---S10^ii^ 79.03 (3) S9^iv^---Nb2---S5 130.13 (4) S9^i^---Nb1---S10^ii^ 140.60 (3) S2^i^---Nb2---S5 79.09 (3) S6^i^---Nb1---S10^ii^ 47.40 (3) S8^iv^---Nb2---S5 123.47 (4) S8^i^---Nb1---S1 79.57 (3) S7---Nb2---S5 85.19 (3) S7^ii^---Nb1---S1 128.33 (3) S6^i^---Nb2---S5 86.79 (3) S2^iii^---Nb1---S1 125.94 (3) S10^ii^---Nb2---S5 126.35 (3) S9^i^---Nb1---S1 82.37 (3) S9^iv^---Nb2---S4 86.44 (3) S6^i^---Nb1---S1 85.81 (3) S2^i^---Nb2---S4 154.57 (3) S10^ii^---Nb1---S1 125.98 (3) S8^iv^---Nb2---S4 154.40 (3) S8^i^---Nb1---S4 155.91 (3) S7---Nb2---S4 89.85 (3) S7^ii^---Nb1---S4 86.50 (3) S6^i^---Nb2---S4 85.62 (3) S2^iii^---Nb1---S4 152.94 (3) S10^ii^---Nb2---S4 74.93 (3) S9^i^---Nb1---S4 88.62 (3) S5---Nb2---S4 75.48 (3) S6^i^---Nb1---S4 85.65 (3) S9^iv^---Nb2---V1^v^ 55.30 (2) S10^ii^---Nb1---S4 74.84 (3) S2^i^---Nb2---V1^v^ 55.11 (2) S1---Nb1---S4 76.56 (3) S8^iv^---Nb2---V1^v^ 53.78 (2) S8^i^---Nb1---Nb2^ii^ 55.33 (2) S7---Nb2---V1^v^ 53.85 (2) S7^ii^---Nb1---Nb2^ii^ 55.95 (2) S6^i^---Nb2---V1^v^ 132.81 (2) S2^iii^---Nb1---Nb2^ii^ 53.95 (2) S10^ii^---Nb2---V1^v^ 116.74 (2) S9^i^---Nb1---Nb2^ii^ 53.76 (2) S5---Nb2---V1^v^ 115.182 (19) S6^i^---Nb1---Nb2^ii^ 134.72 (2) S4---Nb2---V1^v^ 138.52 (2) S10^ii^---Nb1---Nb2^ii^ 121.07 (2) S9^iv^---Nb2---Nb1^v^ 55.30 (2) S1---Nb1---Nb2^ii^ 110.848 (18) S2^i^---Nb2---Nb1^v^ 55.11 (2) S4---Nb1---Nb2^ii^ 138.22 (2) S8^iv^---Nb2---Nb1^v^ 53.78 (2) S8^i^---Nb1---V2^ii^ 55.33 (2) S7---Nb2---Nb1^v^ 53.85 (2) S7^ii^---Nb1---V2^ii^ 55.95 (2) S6^i^---Nb2---Nb1^v^ 132.81 (2) S2^iii^---Nb1---V2^ii^ 53.95 (2) S10^ii^---Nb2---Nb1^v^ 116.74 (2) S9^i^---Nb1---V2^ii^ 53.76 (2) S5---Nb2---Nb1^v^ 115.182 (19) S6^i^---Nb1---V2^ii^ 134.72 (2) S4---Nb2---Nb1^v^ 138.52 (2) S10^ii^---Nb1---V2^ii^ 121.07 (2) V1^v^---Nb2---Nb1^v^ 0.000 (17) S1---Nb1---V2^ii^ 110.848 (18) S3---P1---S5 114.14 (6) S4---Nb1---V2^ii^ 138.22 (2) S3---P1---S1 112.22 (6) Nb2^ii^---Nb1---V2^ii^ 0.000 (18) S5---P1---S1 111.74 (7) S9^iv^---Nb2---S2^i^ 110.37 (3) S3---P1---S4 114.43 (6) S9^iv^---Nb2---S8^iv^ 91.42 (3) S5---P1---S4 100.84 (5) S2^i^---Nb2---S8^iv^ 47.95 (4) S1---P1---S4 102.37 (5) ------------------------- -------------- ------------------------ -------------- ::: Symmetry codes: (i) −*x*+1/2, *y*, *z*−1/2; (ii) *x*−1/2, −*y*, *z*; (iii) −*x*, −*y*, *z*−1/2; (iv) −*x*+1, −*y*, *z*−1/2; (v) *x*+1/2, −*y*, *z*; (vi) −*x*+1, −*y*, *z*+1/2.

PubMed Central

2024-06-05T04:04:17.655763

2011-2-12

PMC3051978

Related literature {#sec1} ================== For similar structures, see: Kartal *et al.* (2006[@bb5]); Petek *et al.* (2004[@bb8]); Dinçer *et al.* (2004[@bb3]). For other related structures, see: Şahin, *et al.* (2007[@bb9]); Wu *et al.* (2010[@bb12]); Yazıcı *et al.* (2004[@bb13]). For general background to phthalocyanines and metallophthalocyanines, see: Lenznoff & Lever (1989--1996[@bb6]); McKeown (1998[@bb7]); Wöhrle (2001[@bb11]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~36~H~44~N~2~O~2~*M* *~r~* = 536.76Triclinic,*a* = 10.9468 (3) Å*b* = 11.0416 (4) Å*c* = 15.3133 (5) Åα = 99.719 (1)°β = 102.996 (1)°γ = 110.963 (1)°*V* = 1619.71 (9) Å^3^*Z* = 2Mo *K*α radiationμ = 0.07 mm^−1^*T* = 175 K0.21 × 0.19 × 0.14 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2008[@bb2]) *T* ~min~ = 0.986, *T* ~max~ = 0.99031007 measured reflections7785 independent reflections5255 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.031 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.052*wR*(*F* ^2^) = 0.148*S* = 1.037785 reflections399 parameters3 restraintsH-atom parameters constrainedΔρ~max~ = 0.29 e Å^−3^Δρ~min~ = −0.30 e Å^−3^ {#d5e496} Data collection: *APEX2* (Bruker, 2008[@bb2]); cell refinement: *SAINT-Plus* (Bruker, 2008[@bb2]); data reduction: *SAINT-Plus* and *XPREP* (Bruker, 2008[@bb2]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb10]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb10]); molecular graphics: *DIAMOND* (Brandenberg & Putz, 2005[@bb1]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb4]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811006118/lr2003sup1.cif](http://dx.doi.org/10.1107/S1600536811006118/lr2003sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006118/lr2003Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006118/lr2003Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?lr2003&file=lr2003sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?lr2003sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?lr2003&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [LR2003](http://scripts.iucr.org/cgi-bin/sendsup?lr2003)). The University of the Free State and Sasol are gratefully acknowledged for financial support. Special thanks are due to Professor Andreas Roodt. Comment ======= Substituted phthalonitriles have been used as starting materials for synthesizing peripherally substituted phtalocyanines and subphthalocyanines (McKeown, 1998). Phthalocyanines and metallophthalocyanines have been invesitigated for many years because of their wide range of applications, including use in chemical sensors, liquid crystals, Langmiur-Blodgett films, non-linear optics, batteries, and as carrier generation materials in the near-infrared (Lennoff & Lever, 1989--1996). Some phthalocyanines have been used in the petroleum industry as catalysts for the oxidation of sulfur compounds in the gasoline fraction. Applications such as photoconducters in the xerographic double layers of laser printers and coping machines, and as as active materials in writable data-storage disks, are also known. The production of phthalocyanines for use in dyes and pigments is around 80 000 tonnes per year (Wöhrle, 2001). The crystal structure of the title compound is presented here. It containes three aromatic rings. Ring A (C3---C8, r.m.s = 0.0047), ring B (C11---C16, r.m.s = 0.0051) and ring C (C25---C30, r.m.s = 0.0038) are essentialy planar. C1, C2 and N1 is coplanar to ring A but N2 is -0.1252 (41) Å out of the plane formed by ring A. The C1≡N1 and the C2≡N2 triple bond distances are 1.145 (2) Å and 1.143 (2) Å respectively and are consistent with values found in similar compounds (Kartal *et al.* 2006, Petek *et al.* 2004 and Dinçer *et al.* 2004). The N1---C1---C3 and N2---C2---C4 bond angles are 179.26 (18) ° and 178.4 (3) ° respectively, this is consistent with values found for simular compounds (Şahin, *et al.* 2007, Wu, *et al.* 2010 and Yazıcı, *et al.* 2004). The dihedral angles between rings A and B and between rings A and C are 68.134 (8) ° and 70.637 (11) ° respectively. The angle between rings B and C is 48.12 (6) °. The crystal packing is stabilized by C---H···O intermolecular hydrogen interactions. Experimental {#experimental} ============ Ground K~2~CO~3~ (4.91 g; 35.5 mmol; 7 eq.) was added to a solution of 4,5-dichlorophthalonitrile (1.00 g; 5.08 mmol) and 2,4-di-*tert*-butylphenol (2.20 g; 10.7 mmol; 2.1 eq.) in dry DMF (75 ml) before stirring overnight at 80 °C. The reaction mixture was cooled to room temperature before being transferred to 3*M* HCl (80 ml conc. HCl in 200 ml H~2~O). The precipitate was filtered off, washed with H~2~O and allowed to dry in air. The crude product was recrystallized from hot ethyl acetate and ethanol (1:1) to yield the title compound (77.9%). *R~f~* 0.8 (Hexane:Acetone; 8:2); Mp 269.0 °C; ^1^H NMR (600 MHz, CDCl~3~) δ 7.52 (2*H*, d, *J* = 2.3 Hz, H-3\', 3\"), 7.31 (2*H*, dd, *J* = 8.4, 2.3 Hz, H-5\', 5\"), 7.21 (2*H*, s, H-3,6), 6.86 (2*H*, d, *J* = 8.4 Hz, H-6\', 6\" H-2,6), 1.39 (36*H*, s, --C(CH~3~)~3~). ^13^C NMR (151 MHz, CDCl~3~) δ 152.51, 150.60, 148.46, 140.82, 125.13 (C-3\',3\"), 124.74 (C-5\',5\"), 121.66 (C-3,6), 120.36 (C-6\',6\"), 115.42 (--CN), 109.64 (C-1,2), 35.03 (--C(CH~3~)~3~), 34.82 (--C(CH~3~)~3~), 31.57 (--C(CH~3~)~3~), 30.40 (--C(CH~3~)~3~). Refinement {#refinement} ========== The aromatic H atoms were placed in geometrically idealized positions and constrained to ride on its parent atoms with *U*~iso~ (H) = 1.2*U*~eq~(C) and at a distance of 0.93 Å. The methyl H atoms were placed in geometrically idealized positions and constrained to ride on its parent atoms with *U*~iso~(H) = 1.5*U*~eq~(C) and at a distance of 0.96 Å. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Diamond representation of the title compound, showing the numbering scheme and displacement ellipsoids (50% probability). Some H atoms and the disorder was left out for clarity. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e234 .table-wrap} ------------------------ --------------------------------------- C~36~H~44~N~2~O~2~ *Z* = 2 *M~r~* = 536.76 *F*(000) = 580 Triclinic, *P*1 *D*~x~ = 1.1 Mg m^−3^ *a* = 10.9468 (3) Å Mo *K*α radiation, λ = 0.71073 Å *b* = 11.0416 (4) Å Cell parameters from 7569 reflections *c* = 15.3133 (5) Å θ = 2.8--28.6° α = 99.719 (1)° µ = 0.07 mm^−1^ β = 102.996 (1)° *T* = 175 K γ = 110.963 (1)° Cuboid, colourless *V* = 1619.71 (9) Å^3^ 0.21 × 0.19 × 0.14 mm ------------------------ --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e365 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker APEXII CCD diffractometer 5255 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.031 φ and ω scans θ~max~ = 28°, θ~min~ = 3.3° Absorption correction: multi-scan (*SADABS*; Bruker, 2008) *h* = −14→14 *T*~min~ = 0.986, *T*~max~ = 0.990 *k* = −14→14 31007 measured reflections *l* = −20→20 7785 independent reflections ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e481 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.052 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.148 H-atom parameters constrained *S* = 1.03 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0592*P*)^2^ + 0.5205*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 7785 reflections (Δ/σ)~max~ = 0.017 399 parameters Δρ~max~ = 0.29 e Å^−3^ 3 restraints Δρ~min~ = −0.30 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e638 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Experimental. The intensity data was collected on a Bruker X8 ApexII 4 K Kappa CCD diffractometer using an exposure time of 40 s/frame. A total of 2019 frames were collected with a frame width of 0.5° covering up to θ = 28.57° with 99.4% completeness accomplished. Geometry. All s.u.\'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.\'s are taken into account individually in the estimation of s.u.\'s in distances, angles and torsion angles; correlations between s.u.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.\'s is used for estimating s.u.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> 2σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e746 .table-wrap} ------ --------------- --------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) C1 0.32485 (17) −0.09576 (17) 0.99913 (12) 0.0399 (4) C2 0.2111 (2) 0.0801 (2) 1.06591 (15) 0.0601 (6) C3 0.27916 (16) −0.02106 (15) 0.94090 (12) 0.0350 (3) C4 0.22520 (18) 0.06741 (17) 0.97435 (12) 0.0399 (4) C5 0.18274 (18) 0.14119 (17) 0.91845 (12) 0.0428 (4) H5 0.1479 0.201 0.9412 0.051\* C6 0.19232 (16) 0.12561 (15) 0.82952 (11) 0.0344 (3) C7 0.24483 (15) 0.03433 (15) 0.79532 (11) 0.0325 (3) C8 0.28764 (16) −0.03739 (15) 0.85123 (12) 0.0356 (4) H8 0.3225 −0.0972 0.8286 0.043\* C11 0.32695 (16) −0.03783 (15) 0.67397 (11) 0.0341 (3) C12 0.46705 (18) 0.02362 (17) 0.71765 (12) 0.0422 (4) H12 0.5042 0.099 0.7687 0.051\* C13 0.55247 (17) −0.02689 (18) 0.68553 (12) 0.0421 (4) H13 0.6467 0.0138 0.716 0.05\* C14 0.49885 (16) −0.13740 (16) 0.60855 (11) 0.0342 (3) C15 0.35667 (16) −0.19584 (16) 0.56661 (11) 0.0335 (3) H15 0.32 −0.2701 0.5148 0.04\* C16 0.26543 (16) −0.15055 (15) 0.59701 (11) 0.0317 (3) C17 0.10949 (16) −0.22154 (16) 0.54796 (12) 0.0364 (4) C18 0.07343 (19) −0.33885 (19) 0.46378 (13) 0.0503 (5) H18A 0.1151 −0.3052 0.419 0.075\* H18B −0.0247 −0.3829 0.4359 0.075\* H18C 0.1071 −0.4021 0.4836 0.075\* C19 0.03676 (18) −0.27803 (18) 0.61657 (13) 0.0458 (4) H19A −0.0601 −0.327 0.585 0.069\* H19B 0.0516 −0.205 0.6675 0.069\* H19C 0.0734 −0.3373 0.64 0.069\* C20 0.05301 (19) −0.1242 (2) 0.51307 (14) 0.0495 (5) H20A 0.0705 −0.0513 0.5649 0.074\* H20B −0.0443 −0.1713 0.4826 0.074\* H20C 0.0974 −0.0891 0.4698 0.074\* C21 0.58891 (17) −0.19560 (18) 0.56883 (12) 0.0414 (4) C25 0.09512 (16) 0.28072 (16) 0.79279 (11) 0.0334 (3) C26 −0.03540 (17) 0.22322 (16) 0.80045 (12) 0.0406 (4) H26 −0.0763 0.1312 0.7942 0.049\* C27 −0.10495 (16) 0.30261 (16) 0.81741 (12) 0.0385 (4) H27 −0.1921 0.2638 0.8236 0.046\* C28 −0.04634 (15) 0.43969 (15) 0.82533 (11) 0.0310 (3) C29 0.08501 (15) 0.49289 (15) 0.81665 (10) 0.0300 (3) H29 0.1251 0.5846 0.8218 0.036\* C30 0.16077 (15) 0.41736 (15) 0.80073 (10) 0.0294 (3) C31 −0.12629 (16) 0.52644 (17) 0.84061 (12) 0.0371 (4) C32 −0.1880 (2) 0.5004 (2) 0.91925 (15) 0.0562 (5) H32A −0.2375 0.5556 0.9278 0.084\* H32B −0.1156 0.5223 0.9759 0.084\* H32C −0.2498 0.4071 0.9035 0.084\* C33 −0.0344 (2) 0.6768 (2) 0.8677 (2) 0.0792 (8) H33A 0.0028 0.698 0.8184 0.119\* H33B 0.0394 0.6995 0.9237 0.119\* H33C −0.0876 0.7274 0.8781 0.119\* C34 −0.2414 (3) 0.4900 (3) 0.75103 (16) 0.0823 (8) H34A −0.203 0.5063 0.7014 0.124\* H34B −0.2919 0.5442 0.7592 0.124\* H34C −0.3022 0.3964 0.7358 0.124\* C35 0.30789 (15) 0.48317 (16) 0.79499 (11) 0.0352 (4) C36 0.40825 (18) 0.4698 (2) 0.87618 (14) 0.0540 (5) H36A 0.5008 0.517 0.876 0.081\* H36B 0.389 0.3762 0.8696 0.081\* H36C 0.398 0.5077 0.9339 0.081\* C37 0.31886 (19) 0.4175 (2) 0.70201 (13) 0.0485 (4) H37A 0.2603 0.4318 0.6517 0.073\* H37B 0.2908 0.3224 0.6945 0.073\* H37C 0.4124 0.4571 0.7017 0.073\* C38 0.35244 (18) 0.63396 (18) 0.80263 (15) 0.0504 (5) H38A 0.29 0.6458 0.7532 0.076\* H38B 0.4437 0.6712 0.7979 0.076\* H38C 0.3515 0.6793 0.8616 0.076\* N1 0.36199 (18) −0.15552 (17) 1.04487 (12) 0.0546 (4) N2 0.1971 (3) 0.0875 (3) 1.13809 (15) 0.0937 (8) O1 0.24505 (12) 0.02227 (11) 0.70557 (8) 0.0384 (3) O2 0.15855 (12) 0.19450 (11) 0.76953 (8) 0.0400 (3) C22A 0.7447 (3) −0.1104 (4) 0.6219 (2) 0.0569 (8) 0.814 (6) H22A 0.7633 −0.1136 0.6856 0.085\* 0.814 (6) H22B 0.7686 −0.0186 0.6198 0.085\* 0.814 (6) H22C 0.7982 −0.1465 0.593 0.085\* 0.814 (6) C23A 0.5683 (3) −0.1892 (5) 0.46811 (18) 0.0696 (12) 0.814 (6) H23A 0.6292 −0.2192 0.4438 0.104\* 0.814 (6) H23B 0.5879 −0.0981 0.4658 0.104\* 0.814 (6) H23C 0.4748 −0.2464 0.4314 0.104\* 0.814 (6) C24A 0.5532 (5) −0.3364 (4) 0.5778 (5) 0.0921 (16) 0.814 (6) H24A 0.6091 −0.3733 0.5526 0.138\* 0.814 (6) H24B 0.4579 −0.3913 0.5441 0.138\* 0.814 (6) H24C 0.5696 −0.3348 0.6423 0.138\* 0.814 (6) C22B 0.5042 (14) −0.2940 (15) 0.4618 (7) 0.050 (3) 0.186 (6) H22D 0.5663 −0.3179 0.4347 0.075\* 0.186 (6) H22E 0.4646 −0.2471 0.425 0.075\* 0.186 (6) H22F 0.4323 −0.3743 0.4633 0.075\* 0.186 (6) C23B 0.6083 (13) −0.2968 (14) 0.6183 (9) 0.0414 (4) 0.186 (6) H23D 0.664 −0.3346 0.5936 0.062\* 0.186 (6) H23E 0.5203 −0.3674 0.6093 0.062\* 0.186 (6) H23F 0.653 −0.2532 0.6837 0.062\* 0.186 (6) C24B 0.7055 (16) −0.0922 (14) 0.5672 (16) 0.075 (5) 0.186 (6) H24D 0.7568 −0.0353 0.6294 0.112\* 0.186 (6) H24E 0.6791 −0.04 0.5286 0.112\* 0.186 (6) H24F 0.7615 −0.1295 0.5424 0.112\* 0.186 (6) ------ --------------- --------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e2103 .table-wrap} ------ ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0435 (9) 0.0387 (9) 0.0422 (10) 0.0193 (8) 0.0179 (8) 0.0111 (8) C2 0.0913 (16) 0.0783 (14) 0.0484 (12) 0.0639 (13) 0.0374 (11) 0.0255 (11) C3 0.0367 (8) 0.0329 (8) 0.0402 (9) 0.0163 (7) 0.0168 (7) 0.0114 (7) C4 0.0487 (9) 0.0455 (9) 0.0374 (10) 0.0275 (8) 0.0209 (8) 0.0120 (8) C5 0.0564 (10) 0.0455 (10) 0.0435 (10) 0.0343 (9) 0.0254 (8) 0.0112 (8) C6 0.0411 (8) 0.0319 (8) 0.0388 (9) 0.0208 (7) 0.0184 (7) 0.0099 (7) C7 0.0371 (8) 0.0290 (7) 0.0362 (9) 0.0164 (6) 0.0180 (7) 0.0059 (6) C8 0.0411 (8) 0.0318 (8) 0.0425 (10) 0.0208 (7) 0.0202 (7) 0.0091 (7) C11 0.0445 (9) 0.0340 (8) 0.0359 (9) 0.0234 (7) 0.0224 (7) 0.0100 (7) C12 0.0461 (9) 0.0396 (9) 0.0378 (10) 0.0166 (8) 0.0173 (8) −0.0005 (7) C13 0.0366 (8) 0.0496 (10) 0.0378 (10) 0.0167 (8) 0.0149 (7) 0.0042 (8) C14 0.0397 (8) 0.0394 (9) 0.0332 (9) 0.0209 (7) 0.0200 (7) 0.0116 (7) C15 0.0418 (8) 0.0324 (8) 0.0318 (8) 0.0191 (7) 0.0166 (7) 0.0069 (7) C16 0.0383 (8) 0.0310 (8) 0.0348 (9) 0.0189 (6) 0.0176 (7) 0.0126 (7) C17 0.0384 (8) 0.0378 (8) 0.0398 (9) 0.0203 (7) 0.0157 (7) 0.0125 (7) C18 0.0424 (10) 0.0524 (11) 0.0477 (11) 0.0187 (8) 0.0093 (8) 0.0010 (9) C19 0.0422 (9) 0.0455 (10) 0.0548 (12) 0.0171 (8) 0.0226 (8) 0.0187 (9) C20 0.0474 (10) 0.0566 (11) 0.0579 (12) 0.0305 (9) 0.0182 (9) 0.0262 (10) C21 0.0431 (9) 0.0505 (10) 0.0425 (10) 0.0268 (8) 0.0239 (8) 0.0111 (8) C25 0.0409 (8) 0.0361 (8) 0.0316 (8) 0.0247 (7) 0.0142 (7) 0.0061 (7) C26 0.0433 (9) 0.0299 (8) 0.0481 (11) 0.0149 (7) 0.0171 (8) 0.0061 (7) C27 0.0319 (8) 0.0369 (9) 0.0446 (10) 0.0131 (7) 0.0140 (7) 0.0056 (7) C28 0.0316 (7) 0.0362 (8) 0.0296 (8) 0.0189 (6) 0.0108 (6) 0.0069 (6) C29 0.0320 (7) 0.0314 (8) 0.0306 (8) 0.0167 (6) 0.0113 (6) 0.0078 (6) C30 0.0322 (7) 0.0365 (8) 0.0242 (8) 0.0192 (6) 0.0097 (6) 0.0071 (6) C31 0.0359 (8) 0.0433 (9) 0.0433 (10) 0.0252 (7) 0.0173 (7) 0.0132 (8) C32 0.0628 (12) 0.0676 (13) 0.0641 (14) 0.0428 (11) 0.0377 (11) 0.0227 (11) C33 0.0718 (14) 0.0479 (12) 0.150 (3) 0.0396 (11) 0.0676 (16) 0.0295 (14) C34 0.0867 (17) 0.133 (2) 0.0566 (15) 0.0862 (18) 0.0123 (12) 0.0214 (15) C35 0.0315 (7) 0.0435 (9) 0.0369 (9) 0.0209 (7) 0.0142 (7) 0.0097 (7) C36 0.0365 (9) 0.0752 (14) 0.0522 (12) 0.0262 (9) 0.0092 (8) 0.0212 (10) C37 0.0474 (10) 0.0597 (12) 0.0464 (11) 0.0251 (9) 0.0264 (9) 0.0115 (9) C38 0.0397 (9) 0.0461 (10) 0.0706 (14) 0.0170 (8) 0.0276 (9) 0.0161 (10) N1 0.0664 (11) 0.0530 (10) 0.0526 (10) 0.0305 (8) 0.0185 (8) 0.0214 (8) N2 0.160 (2) 0.137 (2) 0.0594 (13) 0.1165 (19) 0.0640 (14) 0.0490 (13) O1 0.0530 (7) 0.0419 (6) 0.0368 (7) 0.0314 (6) 0.0243 (5) 0.0116 (5) O2 0.0580 (7) 0.0415 (6) 0.0394 (7) 0.0352 (6) 0.0242 (6) 0.0129 (5) C22A 0.0425 (14) 0.089 (2) 0.0473 (17) 0.0339 (14) 0.0231 (13) 0.0108 (15) C23A 0.0579 (18) 0.117 (3) 0.0391 (15) 0.046 (2) 0.0224 (13) 0.0008 (17) C24A 0.075 (2) 0.054 (2) 0.178 (5) 0.0412 (18) 0.072 (3) 0.033 (3) C22B 0.066 (8) 0.061 (8) 0.037 (6) 0.044 (7) 0.023 (5) 0.000 (5) C23B 0.0431 (9) 0.0505 (10) 0.0425 (10) 0.0268 (8) 0.0239 (8) 0.0111 (8) C24B 0.059 (9) 0.071 (8) 0.105 (15) 0.029 (7) 0.055 (10) 0.007 (9) ------ ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2798 .table-wrap} ------------------- ------------- -------------------- ------------- C1---N1 1.145 (2) C27---C28 1.388 (2) C1---C3 1.438 (2) C27---H27 0.93 C2---N2 1.143 (3) C28---C29 1.392 (2) C2---C4 1.434 (3) C28---C31 1.534 (2) C3---C8 1.383 (2) C29---C30 1.3999 (19) C3---C4 1.395 (2) C29---H29 0.93 C4---C5 1.393 (2) C30---C35 1.542 (2) C5---C6 1.376 (2) C31---C34 1.518 (3) C5---H5 0.93 C31---C33 1.525 (3) C6---O2 1.3578 (19) C31---C32 1.528 (2) C6---C7 1.412 (2) C32---H32A 0.96 C7---O1 1.3588 (19) C32---H32B 0.96 C7---C8 1.376 (2) C32---H32C 0.96 C8---H8 0.93 C33---H33A 0.96 C11---C12 1.379 (2) C33---H33B 0.96 C11---C16 1.393 (2) C33---H33C 0.96 C11---O1 1.4110 (17) C34---H34A 0.96 C12---C13 1.384 (2) C34---H34B 0.96 C12---H12 0.93 C34---H34C 0.96 C13---C14 1.383 (2) C35---C36 1.529 (2) C13---H13 0.93 C35---C38 1.533 (2) C14---C15 1.394 (2) C35---C37 1.536 (2) C14---C21 1.532 (2) C36---H36A 0.96 C15---C16 1.397 (2) C36---H36B 0.96 C15---H15 0.93 C36---H36C 0.96 C16---C17 1.536 (2) C37---H37A 0.96 C17---C18 1.529 (2) C37---H37B 0.96 C17---C20 1.531 (2) C37---H37C 0.96 C17---C19 1.539 (2) C38---H38A 0.96 C18---H18A 0.96 C38---H38B 0.96 C18---H18B 0.96 C38---H38C 0.96 C18---H18C 0.96 C22A---H22A 0.96 C19---H19A 0.96 C22A---H22B 0.96 C19---H19B 0.96 C22A---H22C 0.96 C19---H19C 0.96 C23A---H23A 0.96 C20---H20A 0.96 C23A---H23B 0.96 C20---H20B 0.96 C23A---H23C 0.96 C20---H20C 0.96 C24A---H24A 0.96 C21---C24B 1.384 (13) C24A---H24B 0.96 C21---C24A 1.500 (4) C24A---H24C 0.96 C21---C23B 1.501 (12) C22B---H22D 0.96 C21---C23A 1.525 (3) C22B---H22E 0.96 C21---C22A 1.557 (3) C22B---H22F 0.96 C21---C22B 1.650 (11) C23B---H23D 0.96 C25---C26 1.382 (2) C23B---H23E 0.96 C25---C30 1.390 (2) C23B---H23F 0.96 C25---O2 1.4089 (17) C24B---H24D 0.96 C26---C27 1.380 (2) C24B---H24E 0.96 C26---H26 0.93 C24B---H24F 0.96 N1---C1---C3 179.26 (18) C26---C27---C28 120.78 (15) N2---C2---C4 178.4 (3) C26---C27---H27 119.6 C8---C3---C4 119.70 (15) C28---C27---H27 119.6 C8---C3---C1 120.12 (14) C27---C28---C29 117.23 (13) C4---C3---C1 120.18 (15) C27---C28---C31 120.53 (13) C5---C4---C3 120.20 (15) C29---C28---C31 122.23 (14) C5---C4---C2 120.12 (15) C28---C29---C30 124.32 (14) C3---C4---C2 119.67 (15) C28---C29---H29 117.8 C6---C5---C4 119.99 (14) C30---C29---H29 117.8 C6---C5---H5 120 C25---C30---C29 115.24 (13) C4---C5---H5 120 C25---C30---C35 122.92 (13) O2---C6---C5 125.57 (13) C29---C30---C35 121.83 (14) O2---C6---C7 114.72 (14) C34---C31---C33 109.46 (19) C5---C6---C7 119.68 (14) C34---C31---C32 109.21 (17) O1---C7---C8 124.80 (13) C33---C31---C32 106.95 (16) O1---C7---C6 115.18 (13) C34---C31---C28 108.44 (14) C8---C7---C6 120.00 (14) C33---C31---C28 112.04 (14) C7---C8---C3 120.42 (14) C32---C31---C28 110.70 (13) C7---C8---H8 119.8 C31---C32---H32A 109.5 C3---C8---H8 119.8 C31---C32---H32B 109.5 C12---C11---C16 122.65 (13) H32A---C32---H32B 109.5 C12---C11---O1 117.89 (14) C31---C32---H32C 109.5 C16---C11---O1 119.32 (14) H32A---C32---H32C 109.5 C11---C12---C13 120.01 (16) H32B---C32---H32C 109.5 C11---C12---H12 120 C31---C33---H33A 109.5 C13---C12---H12 120 C31---C33---H33B 109.5 C14---C13---C12 120.56 (16) H33A---C33---H33B 109.5 C14---C13---H13 119.7 C31---C33---H33C 109.5 C12---C13---H13 119.7 H33A---C33---H33C 109.5 C13---C14---C15 117.32 (14) H33B---C33---H33C 109.5 C13---C14---C21 122.73 (15) C31---C34---H34A 109.5 C15---C14---C21 119.95 (14) C31---C34---H34B 109.5 C14---C15---C16 124.54 (15) H34A---C34---H34B 109.5 C14---C15---H15 117.7 C31---C34---H34C 109.5 C16---C15---H15 117.7 H34A---C34---H34C 109.5 C11---C16---C15 114.91 (14) H34B---C34---H34C 109.5 C11---C16---C17 123.53 (13) C36---C35---C38 107.50 (15) C15---C16---C17 121.56 (14) C36---C35---C37 110.04 (14) C18---C17---C20 107.50 (15) C38---C35---C37 107.12 (14) C18---C17---C16 111.47 (13) C36---C35---C30 109.04 (14) C20---C17---C16 111.28 (14) C38---C35---C30 111.76 (12) C18---C17---C19 108.14 (15) C37---C35---C30 111.30 (14) C20---C17---C19 109.01 (14) C35---C36---H36A 109.5 C16---C17---C19 109.35 (14) C35---C36---H36B 109.5 C17---C18---H18A 109.5 H36A---C36---H36B 109.5 C17---C18---H18B 109.5 C35---C36---H36C 109.5 H18A---C18---H18B 109.5 H36A---C36---H36C 109.5 C17---C18---H18C 109.5 H36B---C36---H36C 109.5 H18A---C18---H18C 109.5 C35---C37---H37A 109.5 H18B---C18---H18C 109.5 C35---C37---H37B 109.5 C17---C19---H19A 109.5 H37A---C37---H37B 109.5 C17---C19---H19B 109.5 C35---C37---H37C 109.5 H19A---C19---H19B 109.5 H37A---C37---H37C 109.5 C17---C19---H19C 109.5 H37B---C37---H37C 109.5 H19A---C19---H19C 109.5 C35---C38---H38A 109.5 H19B---C19---H19C 109.5 C35---C38---H38B 109.5 C17---C20---H20A 109.5 H38A---C38---H38B 109.5 C17---C20---H20B 109.5 C35---C38---H38C 109.5 H20A---C20---H20B 109.5 H38A---C38---H38C 109.5 C17---C20---H20C 109.5 H38B---C38---H38C 109.5 H20A---C20---H20C 109.5 C7---O1---C11 118.38 (12) H20B---C20---H20C 109.5 C6---O2---C25 120.00 (12) C24B---C21---C24A 135.6 (7) C21---C22A---H22A 109.5 C24B---C21---C23B 117.8 (9) C21---C22A---H22B 109.5 C24A---C21---C23B 27.0 (4) C21---C22A---H22C 109.5 C24B---C21---C23A 72.6 (9) C21---C23A---H23A 109.5 C24A---C21---C23A 112.7 (3) C21---C23A---H23B 109.5 C23B---C21---C23A 133.6 (5) C21---C23A---H23C 109.5 C24B---C21---C14 110.0 (5) C21---C24A---H24A 109.5 C24A---C21---C14 109.31 (17) C21---C24A---H24B 109.5 C23B---C21---C14 108.7 (5) C21---C24A---H24C 109.5 C23A---C21---C14 108.60 (16) C21---C22B---H22D 109.5 C24B---C21---C22A 36.7 (9) C21---C22B---H22E 109.5 C24A---C21---C22A 108.2 (2) H22D---C22B---H22E 109.5 C23B---C21---C22A 84.1 (5) C21---C22B---H22F 109.5 C23A---C21---C22A 106.40 (19) H22D---C22B---H22F 109.5 C14---C21---C22A 111.68 (16) H22E---C22B---H22F 109.5 C24B---C21---C22B 108.7 (8) C21---C23B---H23D 109.5 C24A---C21---C22B 75.0 (5) C21---C23B---H23E 109.5 C23B---C21---C22B 100.4 (6) H23D---C23B---H23E 109.5 C23A---C21---C22B 40.0 (5) C21---C23B---H23F 109.5 C14---C21---C22B 110.8 (4) H23D---C23B---H23F 109.5 C22A---C21---C22B 133.0 (4) H23E---C23B---H23F 109.5 C26---C25---C30 122.53 (13) C21---C24B---H24D 109.5 C26---C25---O2 117.88 (14) C21---C24B---H24E 109.5 C30---C25---O2 119.43 (13) H24D---C24B---H24E 109.5 C27---C26---C25 119.90 (15) C21---C24B---H24F 109.5 C27---C26---H26 120 H24D---C24B---H24F 109.5 C25---C26---H26 120 H24E---C24B---H24F 109.5 ------------------- ------------- -------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e4073 .table-wrap} --------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C19---H19B···O1 0.96 2.5 3.117 (2) 122 C20---H20A···O1 0.96 2.32 2.982 (3) 125 C36---H36B···O2 0.96 2.52 3.122 (3) 121 C37---H37B···O2 0.96 2.29 2.966 (2) 127 C22A---H22A···N2^i^ 0.96 2.59 3.535 (4) 170 --------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*, −*z*+2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ----------------------- --------- ------- ----------- ------------- C19---H19*B*⋯O1 0.96 2.5 3.117 (2) 122 C20---H20*A*⋯O1 0.96 2.32 2.982 (3) 125 C36---H36*B*⋯O2 0.96 2.52 3.122 (3) 121 C37---H37*B*⋯O2 0.96 2.29 2.966 (2) 127 C22*A*---H22*A*⋯N2^i^ 0.96 2.59 3.535 (4) 170 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.658761

2011-2-26

PMC3051979

Related literature {#sec1} ================== For the crystal structure of a Pb(II) complex with pyridazine-4-carboxyl­ate and water ligands, see: Starosta & Leciejewicz, (2009[@bb7]). The structure of pyridazine-4-carb­oxy­lic acid hydro­chloride was determined earlier (Starosta & Leciejewicz, 2008[@bb6]). The structure of a Mg^II^ complex with pyridazine-3-carboxyl­ate and water ligands has been also reported by Gryz *et al.* (2006[@bb1]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Mg(C~5~H~3~N~2~O~2~)~2~(H~2~O)~4~\]·2H~2~O*M* *~r~* = 378.59Monoclinic,*a* = 7.2571 (15) Å*b* = 11.688 (2) Å*c* = 10.550 (2) Åβ = 108.36 (3)°*V* = 849.3 (3) Å^3^*Z* = 2Mo *K*α radiationμ = 0.16 mm^−1^*T* = 293 K0.24 × 0.22 × 0.08 mm ### Data collection {#sec2.1.2} Kuma KM-4 four-circle diffractometerAbsorption correction: analytical (*CrysAlis RED*; Oxford Diffraction, 2008)[@bb4] *T* ~min~ = 0.968, *T* ~max~ = 0.9872007 measured reflections1873 independent reflections1136 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.0233 standard reflections every 200 reflections intensity decay: 1.3% ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.036*wR*(*F* ^2^) = 0.122*S* = 1.041873 reflections139 parameters6 restraintsH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.28 e Å^−3^Δρ~min~ = −0.21 e Å^−3^ {#d5e536} Data collection: *KM-4 Software* (Kuma, 1996[@bb2]); cell refinement: *KM-4 Software*; data reduction: *DATAPROC* (Kuma, 2001[@bb3]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb5]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb5]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb5]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004168/kp2307sup1.cif](http://dx.doi.org/10.1107/S1600536811004168/kp2307sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004168/kp2307Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004168/kp2307Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?kp2307&file=kp2307sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?kp2307sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?kp2307&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [KP2307](http://scripts.iucr.org/cgi-bin/sendsup?kp2307)). Comment ======= The structure of the title compound (I) is built of monomeric molecules in which the Mg^+2^ located in an inversion centre is chelated by two carboxylate atoms each donated by one of symmetry ralated ligand molecules and by two pairs of aqua O atoms resulting in a slightly distorted octahedral geometry. The carboxylate O1, O1^(i)^ and aqua O3, O3^(i)^ atoms form an equatorial plane, aqua O4 and O4^(i)^ atoms are at the axial positions. The observed Mg---O bond lengths and bond angles are almost the same as reported for the complex with pyridazine-3-carboxylate and water ligands (Gryz *et al.*, 2006). The pyridazine ring is planar with r.m.s. of 0.0046 (1) Å. The observed bond distances and angles are close to those reported for the parent acid (Starosta & Leciejewicz, 2008). The carboxylate group is rotated from the mean plane by 8.1 (1)°. Hydrogen bonds link the monomers to form molecular sheets. They operate between coordinated water O atoms as donors and uncoordinated carboxylate O atoms and pyridazine-N atoms in adjacent monomers as acceptors. The sheets are held together by hydrogen bonds in which crystal water molecules act as donors and acceptors resulting in a three-dimensional network. The coordination mode reported in the structure of a Mg^II^ complex with pyridazine-3-carboxylate and water ligands is also octahedral but the Mg^II^ ion is coordinated by a pair of symmetry related N,*O*-chelating groups of the ligands and a pair of water O atoms (Gryz *et al.*, 2006). The Pb(II) complex with the title ligand shows entirely different coordination mode. Two symmetry related metal ions form a dimer in which they are bridged by hetero-ring N atoms of two symmetry related ligands amd two aqua-O atoms. Each Pb(II) ion is also coordinated by both carboxylate O atoms of another ligand whose hetero-ring N atoms do not coordinate to Pb(II). (Starosta & Leciejewicz, 2009). Experimental {#experimental} ============ The title compound was obtained by mixing boiling aqueous solutions, one containig 2 mmols of pyridazine-4-carboxylic acid (Aldrich), the other 1 mmol of magnesium diacetate tetrahydrate (Aldrich). The mixture was boiled under reflux for two h, then cooled to room temperature and left to crystallise. A few days latter, colourless crystalline plates were found after evaporation to dryness. They were recrystallised from water several times until well formed single crystals were obtained. Crystals were washed with cold ethanol and dried in the air. Refinement {#refinement} ========== Water hydrogen atoms were located in a difference map and were allowed to ride on the parent atom with *U*~iso~(H)=1.5*U*~eq~(O). H atoms attached to pyridazine-ring C atoms were positioned at calculated positions and were treated as riding on the parent atoms, with C---H=0.93 Å and *U*~iso~(H)=1.5*U*~eq~(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A structural unit of (I) with atom labelling scheme and the 50% probability displacement ellipsoids. Symmetry code: (i) -x + 1,-y + 1,-z + 1. (ii) x, y, z + 1. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Crystal packing of I. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e163 .table-wrap} ------------------------------------------ ------------------------------------- \[Mg(C~5~H~3~N~2~O~2~)~2~(H2O)~4~\]·2H2O *F*(000) = 396 *M~r~* = 378.59 *D*~x~ = 1.480 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å *a* = 7.2571 (15) Å Cell parameters from 25 reflections *b* = 11.688 (2) Å θ = 6--15° *c* = 10.550 (2) Å µ = 0.16 mm^−1^ β = 108.36 (3)° *T* = 293 K *V* = 849.3 (3) Å^3^ Plate, colourless *Z* = 2 0.24 × 0.22 × 0.08 mm ------------------------------------------ ------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e297 .table-wrap} ------------------------------------------------------------------------------ ---------------------------------------------- Kuma KM-4 four-circle diffractometer 1136 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.023 graphite θ~max~ = 27.7°, θ~min~ = 2.7° profile data from ω/2θ scans *h* = −9→0 Absorption correction: analytical (*CrysAlis RED*; Oxford Diffraction, 2008) *k* = 0→15 *T*~min~ = 0.968, *T*~max~ = 0.987 *l* = −13→12 2007 measured reflections 3 standard reflections every 200 reflections 1873 independent reflections intensity decay: 1.3% ------------------------------------------------------------------------------ ---------------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e417 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.036 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.122 H atoms treated by a mixture of independent and constrained refinement *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0628*P*)^2^ + 0.293*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 1873 reflections (Δ/σ)~max~ \< 0.001 139 parameters Δρ~max~ = 0.28 e Å^−3^ 6 restraints Δρ~min~ = −0.21 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------ ::: Special details {#specialdetails} =============== ::: {#d1e574 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e673 .table-wrap} ----- ------------ -------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Mg1 0.5000 0.5000 0.5000 0.0236 (3) O1 0.3810 (2) 0.54000 (14) 0.29844 (14) 0.0318 (4) O2 0.2156 (3) 0.38329 (15) 0.20927 (16) 0.0453 (5) N1 0.2554 (3) 0.58217 (18) −0.19230 (18) 0.0339 (5) C7 0.2921 (3) 0.47760 (19) 0.2019 (2) 0.0284 (5) N2 0.1945 (3) 0.47789 (17) −0.16963 (18) 0.0336 (5) C5 0.3386 (3) 0.62622 (19) 0.0395 (2) 0.0311 (5) H5 0.3895 0.6782 0.1084 0.037\* C4 0.2765 (3) 0.52021 (19) 0.0639 (2) 0.0260 (5) C3 0.2036 (3) 0.4491 (2) −0.0472 (2) 0.0312 (5) H3 0.1587 0.3770 −0.0338 0.037\* C6 0.3231 (4) 0.6534 (2) −0.0916 (2) 0.0344 (5) H6 0.3626 0.7257 −0.1092 0.041\* O4 0.2870 (2) 0.59132 (16) 0.54856 (16) 0.0347 (4) O5 0.9316 (3) 0.67116 (16) 0.38743 (16) 0.0358 (4) O3 0.6662 (3) 0.64863 (14) 0.52618 (17) 0.0338 (4) H31 0.751 (4) 0.642 (3) 0.489 (3) 0.056 (10)\* H42 0.267 (5) 0.586 (3) 0.620 (2) 0.058 (10)\* H51 0.896 (4) 0.628 (2) 0.323 (2) 0.041 (8)\* H32 0.711 (5) 0.656 (3) 0.6052 (19) 0.062 (10)\* H52 0.905 (5) 0.7357 (18) 0.360 (3) 0.065 (11)\* H41 0.187 (3) 0.614 (2) 0.498 (3) 0.048 (9)\* ----- ------------ -------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e987 .table-wrap} ----- ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Mg1 0.0276 (5) 0.0249 (5) 0.0176 (5) −0.0002 (4) 0.0061 (4) 0.0006 (4) O1 0.0389 (9) 0.0329 (8) 0.0207 (7) −0.0020 (7) 0.0052 (6) −0.0005 (6) O2 0.0681 (13) 0.0384 (10) 0.0276 (8) −0.0184 (9) 0.0126 (8) −0.0026 (7) N1 0.0380 (11) 0.0409 (11) 0.0239 (9) 0.0057 (9) 0.0111 (8) 0.0042 (8) C7 0.0290 (11) 0.0335 (12) 0.0221 (10) 0.0032 (9) 0.0073 (9) −0.0013 (8) N2 0.0374 (11) 0.0386 (11) 0.0221 (9) 0.0020 (8) 0.0056 (8) −0.0031 (7) C5 0.0363 (12) 0.0314 (12) 0.0242 (10) 0.0000 (9) 0.0077 (9) −0.0046 (9) C4 0.0223 (10) 0.0325 (12) 0.0221 (10) 0.0044 (8) 0.0052 (8) −0.0014 (8) C3 0.0353 (12) 0.0309 (12) 0.0252 (11) 0.0003 (10) 0.0063 (9) −0.0028 (9) C6 0.0408 (13) 0.0328 (12) 0.0305 (11) 0.0024 (10) 0.0125 (10) 0.0013 (10) O4 0.0337 (9) 0.0476 (10) 0.0230 (8) 0.0114 (8) 0.0091 (7) 0.0051 (7) O5 0.0403 (10) 0.0352 (10) 0.0269 (8) 0.0016 (8) 0.0035 (7) −0.0006 (7) O3 0.0407 (10) 0.0342 (9) 0.0276 (9) −0.0055 (7) 0.0123 (8) 0.0010 (7) ----- ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1252 .table-wrap} --------------------- ------------- ---------------- ------------- Mg1---O4^i^ 2.0714 (17) C5---C4 1.370 (3) Mg1---O4 2.0714 (17) C5---C6 1.389 (3) Mg1---O1^i^ 2.0807 (16) C5---H5 0.9300 Mg1---O1 2.0807 (16) C4---C3 1.398 (3) Mg1---O3 2.0829 (17) C3---H3 0.9300 Mg1---O3^i^ 2.0829 (17) C6---H6 0.9300 Mg1---H32 2.42 (3) O4---H42 0.809 (18) O1---C7 1.254 (3) O4---H41 0.798 (18) O2---C7 1.248 (3) O5---H51 0.819 (17) N1---C6 1.317 (3) O5---H52 0.809 (18) N1---N2 1.343 (3) O3---H31 0.828 (18) C7---C4 1.509 (3) O3---H32 0.799 (18) N2---C3 1.316 (3) O4^i^---Mg1---O4 180.00 (6) O2---C7---O1 126.0 (2) O4^i^---Mg1---O1^i^ 92.02 (7) O2---C7---C4 116.88 (19) O4---Mg1---O1^i^ 87.99 (7) O1---C7---C4 117.1 (2) O4^i^---Mg1---O1 87.98 (7) C3---N2---N1 119.28 (19) O4---Mg1---O1 92.02 (7) C4---C5---C6 117.8 (2) O1^i^---Mg1---O1 180.0 C4---C5---H5 121.1 O4^i^---Mg1---O3 90.95 (7) C6---C5---H5 121.1 O4---Mg1---O3 89.05 (7) C5---C4---C3 116.1 (2) O1^i^---Mg1---O3 90.88 (7) C5---C4---C7 123.40 (19) O1---Mg1---O3 89.12 (7) C3---C4---C7 120.4 (2) O4^i^---Mg1---O3^i^ 89.05 (7) N2---C3---C4 124.0 (2) O4---Mg1---O3^i^ 90.95 (7) N2---C3---H3 118.0 O1^i^---Mg1---O3^i^ 89.12 (7) C4---C3---H3 118.0 O1---Mg1---O3^i^ 90.88 (7) N1---C6---C5 123.5 (2) O3---Mg1---O3^i^ 180.000 (1) N1---C6---H6 118.3 O4^i^---Mg1---H32 95.0 (8) C5---C6---H6 118.3 O4---Mg1---H32 85.0 (8) Mg1---O4---H42 123 (2) O1^i^---Mg1---H32 72.6 (6) Mg1---O4---H41 127 (2) O1---Mg1---H32 107.4 (6) H42---O4---H41 105 (3) O3---Mg1---H32 18.6 (6) H51---O5---H52 108 (3) O3^i^---Mg1---H32 161.4 (6) Mg1---O3---H31 110 (2) C7---O1---Mg1 129.89 (15) Mg1---O3---H32 105 (2) C6---N1---N2 119.35 (19) H31---O3---H32 112 (3) --------------------- ------------- ---------------- ------------- ::: Symmetry codes: (i) −*x*+1, −*y*+1, −*z*+1. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1664 .table-wrap} -------------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O3---H31···O5 0.83 (2) 1.97 (2) 2.775 (3) 164 (3) O4---H42···N1^ii^ 0.81 (2) 2.01 (2) 2.817 (2) 172 (3) O5---H51···N2^iii^ 0.82 (2) 1.98 (2) 2.798 (3) 179 (3) O3---H32···O2^i^ 0.80 (2) 1.92 (2) 2.675 (2) 159 (3) O5---H52···O2^iv^ 0.81 (2) 1.97 (2) 2.765 (3) 168 (3) O4---H41···O5^v^ 0.80 (2) 1.97 (2) 2.766 (3) 175 (3) -------------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (ii) *x*, *y*, *z*+1; (iii) −*x*+1, −*y*+1, −*z*; (i) −*x*+1, −*y*+1, −*z*+1; (iv) −*x*+1, *y*+1/2, −*z*+1/2; (v) *x*−1, *y*, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------ ---------- ---------- ----------- ------------- O3---H31⋯O5 0.83 (2) 1.97 (2) 2.775 (3) 164 (3) O4---H42⋯N1^i^ 0.81 (2) 2.01 (2) 2.817 (2) 172 (3) O5---H51⋯N2^ii^ 0.82 (2) 1.98 (2) 2.798 (3) 179 (3) O3---H32⋯O2^iii^ 0.80 (2) 1.92 (2) 2.675 (2) 159 (3) O5---H52⋯O2^iv^ 0.81 (2) 1.97 (2) 2.765 (3) 168 (3) O4---H41⋯O5^v^ 0.80 (2) 1.97 (2) 2.766 (3) 175 (3) Symmetry codes: (i) ; (ii) ; (iii) ; (iv) ; (v) . :::

PubMed Central

2024-06-05T04:04:17.668690

2011-2-09

PMC3051980

Related literature {#sec1} ================== For a related structure, see: Xiao & Charpentier (2010[@bb9]). For the design and applications of the title compound, see: Moad *et al.* (2005[@bb4], 2008[@bb5]); Stenzel *et al.* (2003[@bb8]); Coote & Radom (2004[@bb3]); Coote *et al.* (2006[@bb2]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~4~H~6~O~3~S~2~*M* *~r~* = 166.21Monoclinic,*a* = 7.1009 (3) Å*b* = 10.6485 (5) Å*c* = 9.2022 (4) Åβ = 93.370 (1)°*V* = 694.61 (5) Å^3^*Z* = 4Mo *K*α radiationμ = 0.70 mm^−1^*T* = 150 K0.10 × 0.07 × 0.06 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb6]) *T* ~min~ = 0.931, *T* ~max~ = 0.96333976 measured reflections1723 independent reflections1517 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.038 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.021*wR*(*F* ^2^) = 0.056*S* = 1.051723 reflections84 parametersH-atom parameters constrainedΔρ~max~ = 0.29 e Å^−3^Δρ~min~ = −0.20 e Å^−3^ {#d5e394} Data collection: *APEX2* (Bruker, 2009[@bb1]); cell refinement: *SAINT* (Bruker, 2009[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb7]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811003941/ng5085sup1.cif](http://dx.doi.org/10.1107/S1600536811003941/ng5085sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003941/ng5085Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003941/ng5085Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?ng5085&file=ng5085sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?ng5085sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?ng5085&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [NG5085](http://scripts.iucr.org/cgi-bin/sendsup?ng5085)). This work was supported by the Canadian Natural Sciences and Engineering Research Council (NSERC) Idea to Innovation (I2I) Program. The authors are grateful to Dr Guerman Popov of the Department of Chemistry, the University of Western Ontario, for the XRD data acquisition and inter­pretation. Comment ======= Carbonothioylthio (S=C---S) compounds are used as chain transfer agents (CTA) in addition-fragmentation chain-transfer (RAFT) polymerization. In the addition-fragmentation equilibria, addition of the propagating radicals to the S=C group followed by fragmentation of the intermediate radical at the C---S bond generates a new radical and a polymeric carbonothioylthio compound (Moad *et al.*, 2005, 2008). *O*-alkyl xanthates show low reactivity in RAFT equilibria due to the conjugation of the *O* lone pair electrons and the C=S bond which is favorable to the zwitterionic canonical forms of xanthates (Moad *et al.*, 2005; Coote *et al.*, 2006). However, xanthates can promote fragmentation of unstable radicals, such as vinyl acetate radicals that undergo fast addition and slow fragmentation (Coote *et al.*, 2006). Though studies have been done on RAFT polymerization of vinyl acetate with methyl 2-(methoxycarbonothioylthio)acetate (Stenzel *et al.*, 2003; Coote & Radom, 2004), 2-(methoxycarbonothioylthio)acetic acid has not been used in RAFT polymerization. Therefore, efforts were made to use 2-(methoxycarbonothioylthio)acetic acid as the CTA in RAFT polymerization, and poly(vinyl acetate)s containing carboxylic acid end groups were successfully prepared. A similar compound, 2-(isopropoxycarbonothioylthio)acetic acid, has been reported for the same application (Xiao & Charpentier, 2010). Experimental {#experimental} ============ Potassium hydroxide 5.6 g (50 mmol) was dissolved in methanol 30 ml at room temperature. The solution was cooled with an ice bath when carbon disulfide 20 ml was charged into the flask dropwise. After 1 day reaction at room temperature, a solution of 2-bromoacetic acid 6.9 g (50 mmol) / methanol 20 ml was added into the flask dropwise in an ice bath. The precipitates were removed by filtration after 2 days reaction at room temperature, and the solvent was evaporated with a rotary evaporator. The crude product was run through a silica gel column with a mixture of ethyl ether / hexanes (5:1). Colorless crystals were obtained from crystalization in hexanes/ cyclohexane (4:1). m.p.: 112.6 °C (DSC). MS: 165.9764. Refinement {#refinement} ========== The structure was solved and refined using the Bruker *SHELXTL* Software Package, using the space group P 1 21/c 1, with *Z* = 4 for the formula unit, C~4~H~6~O~3~S~2~. All of the non-hydrogen atoms were refined with anisotropic thermal parameters. The hydrogen atom positions were calculated geometrically and were included as riding on their respective carbon/oxygen atoms. The final anisotropic full-matrix least-squares refinement on F^2^ with 84 variables converged at R1 = 2.13%, for the observed data and wR2 = 5.55% for all data. The goodness-of-fit was 1.047. The largest peak in the final difference electron density synthesis was 0.288 e^-^/Å^3^ and the largest hole was -0.195 e^-^/Å^3^ with an RMS deviation of 0.040 e^-^/Å^3^. On the basis of the final model, the calculated density was 1.589 g/cm^3^ and F(000), 344 e^-^. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### View of the title compound (50% probability displacement ellipsoids). :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Packing diagram of the structure with H-bonds. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e164 .table-wrap} ------------------------- --------------------------------------- C~4~H~6~O~3~S~2~ *F*(000) = 344 *M~r~* = 166.21 *D*~x~ = 1.589 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 9941 reflections *a* = 7.1009 (3) Å θ = 2.9--30.2° *b* = 10.6485 (5) Å µ = 0.70 mm^−1^ *c* = 9.2022 (4) Å *T* = 150 K β = 93.370 (1)° Block, colourless *V* = 694.61 (5) Å^3^ 0.10 × 0.07 × 0.06 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e294 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker APEXII CCD diffractometer 1723 independent reflections Radiation source: fine-focus sealed tube 1517 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.038 φ and ω scans θ~max~ = 28.3°, θ~min~ = 2.9° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −9→9 *T*~min~ = 0.931, *T*~max~ = 0.963 *k* = −14→13 33976 measured reflections *l* = −12→12 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e411 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.021 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.056 H-atom parameters constrained *S* = 1.05 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0234*P*)^2^ + 0.2541*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 1723 reflections (Δ/σ)~max~ = 0.001 84 parameters Δρ~max~ = 0.29 e Å^−3^ 0 restraints Δρ~min~ = −0.20 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e568 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e667 .table-wrap} ----- --------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ S1 0.15918 (5) 0.31498 (3) 0.78725 (4) 0.02980 (9) S2 −0.11784 (5) 0.12843 (3) 0.90015 (4) 0.03122 (9) O1 −0.10815 (13) 0.37609 (8) 0.93394 (10) 0.0311 (2) O2 0.41851 (14) −0.01297 (9) 0.81022 (10) 0.0319 (2) H2 0.4754 −0.0511 0.8797 0.048\* O3 0.38409 (12) 0.13435 (8) 0.98001 (9) 0.02570 (19) C1 −0.2814 (2) 0.36782 (14) 1.00825 (15) 0.0354 (3) H1A −0.3839 0.3404 0.9395 0.053\* H1B −0.3120 0.4504 1.0476 0.053\* H1C −0.2659 0.3070 1.0880 0.053\* C2 −0.03785 (16) 0.27021 (11) 0.88181 (13) 0.0233 (2) C3 0.25018 (18) 0.16615 (12) 0.73538 (13) 0.0279 (3) H3A 0.1438 0.1134 0.6969 0.034\* H3B 0.3354 0.1794 0.6554 0.034\* C4 0.35645 (16) 0.09552 (11) 0.85644 (13) 0.0224 (2) ----- --------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e902 .table-wrap} ---- -------------- -------------- -------------- --------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.03072 (17) 0.02100 (15) 0.03800 (18) 0.00050 (12) 0.00457 (13) 0.00871 (12) S2 0.03306 (17) 0.02151 (16) 0.03927 (19) −0.00432 (12) 0.00377 (13) 0.00243 (12) O1 0.0293 (5) 0.0230 (4) 0.0407 (5) 0.0011 (3) 0.0005 (4) −0.0062 (4) O2 0.0404 (5) 0.0291 (5) 0.0252 (4) 0.0120 (4) −0.0050 (4) −0.0049 (4) O3 0.0264 (4) 0.0255 (4) 0.0248 (4) 0.0046 (3) −0.0011 (3) −0.0034 (3) C1 0.0337 (7) 0.0385 (7) 0.0339 (7) 0.0061 (6) 0.0026 (6) −0.0058 (6) C2 0.0245 (6) 0.0223 (6) 0.0224 (5) 0.0007 (4) −0.0060 (4) 0.0009 (4) C3 0.0317 (6) 0.0281 (6) 0.0242 (6) 0.0041 (5) 0.0040 (5) 0.0041 (5) C4 0.0195 (5) 0.0226 (5) 0.0254 (6) −0.0001 (4) 0.0040 (4) 0.0005 (4) ---- -------------- -------------- -------------- --------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1100 .table-wrap} ---------------- ------------- ---------------- ------------- S1---C2 1.7564 (13) O3---C4 1.2150 (14) S1---C3 1.7870 (13) C1---H1A 0.9800 S2---C2 1.6253 (12) C1---H1B 0.9800 O1---C2 1.3336 (15) C1---H1C 0.9800 O1---C1 1.4451 (17) C3---C4 1.5091 (16) O2---C4 1.3159 (14) C3---H3A 0.9900 O2---H2 0.8400 C3---H3B 0.9900 C2---S1---C3 101.69 (6) S2---C2---S1 126.65 (7) C2---O1---C1 117.76 (10) C4---C3---S1 114.70 (9) C4---O2---H2 109.5 C4---C3---H3A 108.6 O1---C1---H1A 109.5 S1---C3---H3A 108.6 O1---C1---H1B 109.5 C4---C3---H3B 108.6 H1A---C1---H1B 109.5 S1---C3---H3B 108.6 O1---C1---H1C 109.5 H3A---C3---H3B 107.6 H1A---C1---H1C 109.5 O3---C4---O2 124.23 (11) H1B---C1---H1C 109.5 O3---C4---C3 124.58 (11) O1---C2---S2 127.40 (10) O2---C4---C3 111.18 (10) O1---C2---S1 105.94 (8) ---------------- ------------- ---------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1282 .table-wrap} ----------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O2---H2···O3^i^ 0.84 1.82 2.6540 (12) 175 ----------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*, −*z*+2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------- --------- ------- ------------- ------------- O2---H2⋯O3^i^ 0.84 1.82 2.6540 (12) 175 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.672201

2011-2-05

PMC3051981

Related literature {#sec1} ================== For general background to the chemistry of phosphine-imine ligands and palladium complexes, see: Batsanov *et al.* (2002[@bb1]); Chen *et al.* (2003[@bb3]); Doherty *et al.* (2007[@bb4]); Flapper *et al.* (2009*a* [@bb5],*b* [@bb6]); Guan & Marshall (2002[@bb7]); Kermagoret & Braunstein (2008[@bb8]); Speiser *et al.* (2004[@bb10]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Pd(CH~3~)(C~26~H~14~F~18~NOP)(C~2~H~3~N)\]\[SbF~6~\]·0.5CH~2~Cl~2~*M* *~r~* = 1170.05Triclinic,*a* = 8.8635 (8) Å*b* = 12.1336 (12) Å*c* = 19.107 (2) Åα = 79.166 (8)°β = 80.147 (8)°γ = 78.266 (8)°*V* = 1957.2 (3) Å^3^*Z* = 2Cu *K*α radiationμ = 11.56 mm^−1^*T* = 100 K0.15 × 0.10 × 0.05 mm ### Data collection {#sec2.1.2} Bruker APEXII CCD diffractometerAbsorption correction: numerical (*SADABS*; Bruker, 2007[@bb2]) *T* ~min~ = 0.276, *T* ~max~ = 0.59612653 measured reflections6232 independent reflections4802 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.052 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.066*wR*(*F* ^2^) = 0.191*S* = 1.026232 reflections590 parameters63 restraintsH-atom parameters constrainedΔρ~max~ = 2.34 e Å^−3^Δρ~min~ = −0.95 e Å^−3^ {#d5e564} Data collection: *APEX2* (Bruker, 2007[@bb2]); cell refinement: *SAINT* (Bruker, 2007[@bb2]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb9]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb9]); molecular graphics: *SHELXTL* (Sheldrick, 2008[@bb9]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811005277/cv5026sup1.cif](http://dx.doi.org/10.1107/S1600536811005277/cv5026sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005277/cv5026Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005277/cv5026Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?cv5026&file=cv5026sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?cv5026sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?cv5026&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [CV5026](http://scripts.iucr.org/cgi-bin/sendsup?cv5026)). We thank Professor Maurice S. Brookhart for helpful discussions. Comment ======= The oligomerization of ethylene is one of the most important industrial processes to obtain linear alpha-olefins (Chen *et al.*, 2003; Guan *et al.*,2002). Bidentate phosphine-imine ligands (P\^N ligands) have attracted considerable concerns in the field of transition metal catalysis. Palladium and nickel complexes with P\^N ligands have been widely applied in the oligomerization and polymerization of ethylene(Doherty *et al.*, 2007; Flapper *et al.*, 2009*a*,*b*; Kermagoret *et al.*, 2008; Speiser *et al.*, 2004). Herein, we report the synthesis and characterization of cationic palladium complex, with electron-poor bulky ligand bearing tris(trifluoromethyl) phenyl phosphine, which can be synthesized according to the literature (Batsanov *et al.*, 2002; Speiser *et al.*, 2004), \[(CH~3~N)(CH~3~)*L*Pd\]^+^ \[SbF~6~\]^-^ 0.5(CH~2~Cl~2~), where *L* = \[2-ethyl-(1\'-methyl-1\'-oxy(bis(2,4,6-tris(trifluoromethyl) phenyl)phosphino)\]pyridine. In the title compound, each Pd center has a distorted square-planar environment being coordinated by acetonitrile \[Pd---N 2.078 (8) Å\], methyl \[Pd---C 2.052 (9) Å\] and bidentate ligand *L*. In *L*, one CF~3~ group is rotationally disordered between two orientations in a ratio 1:1. The solvent molecule has been treated as disordered between two positions related by inversion center with occupancies fixed to 0.5 each. The crystal packing exhibits weak intermolecular C---H···F contacts (Table 1). Experimental {#experimental} ============ All manipulations of air- and/or moisture-sensitive compounds were conducted using standard Schlenk techniques. Argon was purified by passage through columns of BASF R3--11 catalyst (Chemalog) and 4Å molecular sieves. All solvents were deoxygenated, dried and distilled using common techniques. 2-Pyridin-2-ylpropan-2-ol and di\[tris(trifluoromethyl)phenyl\]phosphine chloride were prepared according to the literature procedures(Batsanov *et al.*, 2002; Speiser *et al.*, 2004). A flame-dried Schlenk flask was charged with 2-pyridin-2-ylpropan-2-ol (280 mg, 1.30 mmol) and dried THF (5 ml). The solution was cooled to -78°C, and 2.5 mol/l n-BuLi in hexane (0.52 ml, 1.30 mmol) was added slowly. After stirring of 2.0 hrs at -78°C, 800 mg in THF(2 ml) was added slowly. Stirring for 1 day, 30 ml degassed saturated NaCl solution was charged for hydrolysis. After separation, dry and column purification, the ligand of 2-ethyl-\[1\'-methyl-1\'-oxy(di(2, 4, 6-tris(trifluoromethyl) phenyl)phosphino)\] pyridine was obtained. The cationic complex was prepared by reaction of the above ligand (1.0 equiv.), (COD)PdMeCl (1.0 equiv.), and AgSbF~6~ (1.0 equiv.) at RT, and the single-crystal was cultivated by recrystallization of CH~2~Cl~2~ and pentane. Calcd for C29H20F24N2OPPdSb: C, 30.89; H, 1.79; N, 2.48. Found: C, 30.89; H, 1.59; N, 2.21. Refinement {#refinement} ========== All H atoms were geometrically positioned (C---H 0.95-0.99 Å) and refined as riding, with Uiso(H) = 1.2-1.5 Ueq(C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of (I) showing the atom-numbering scheme and 50% probabilty displacement ellipsoids. Only one part of the disordered CF3 group is shown. The H atoms and solvent molecules were omitted for clarity. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e177 .table-wrap} ---------------------------------------------------------------------- --------------------------------------- \[Pd(CH~3~)(C~26~H~14~F~18~NOP)(C~2~H~3~N)\]\[SbF~6~\]·0.5CH~2~Cl~2~ *Z* = 2 *M~r~* = 1170.05 *F*(000) = 1130 Triclinic, *P*1 *D*~x~ = 1.985 Mg m^−3^ Hall symbol: -P 1 Cu *K*α radiation, λ = 1.54178 Å *a* = 8.8635 (8) Å Cell parameters from 3085 reflections *b* = 12.1336 (12) Å θ = 2.4--66.3° *c* = 19.107 (2) Å µ = 11.56 mm^−1^ α = 79.166 (8)° *T* = 100 K β = 80.147 (8)° Prism, colourless γ = 78.266 (8)° 0.15 × 0.10 × 0.05 mm *V* = 1957.2 (3) Å^3^ ---------------------------------------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e329 .table-wrap} ----------------------------------------------------------- -------------------------------------- Bruker APEXII CCD diffractometer 6232 independent reflections Radiation source: fine-focus sealed tube 4802 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.052 φ and ω scans θ~max~ = 67.3°, θ~min~ = 2.4° Absorption correction: numerical (*SADABS*; Bruker, 2007) *h* = −10→10 *T*~min~ = 0.276, *T*~max~ = 0.596 *k* = −14→13 12653 measured reflections *l* = −22→22 ----------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e446 .table-wrap} ------------------------------------- -------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.066 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.191 H-atom parameters constrained *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.1096*P*)^2^ + 11.4198*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 6232 reflections (Δ/σ)~max~ \< 0.001 590 parameters Δρ~max~ = 2.34 e Å^−3^ 63 restraints Δρ~min~ = −0.95 e Å^−3^ ------------------------------------- -------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e603 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e702 .table-wrap} ------ -------------- -------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) Pd1 0.39331 (7) 0.28306 (5) 0.20297 (4) 0.0287 (2) P1 0.2317 (2) 0.17257 (18) 0.26378 (12) 0.0271 (5) C1 0.3238 (12) 0.3978 (8) 0.2736 (5) 0.038 (2) H1A 0.4154 0.4136 0.2896 0.058\* H1B 0.2561 0.3658 0.3153 0.058\* H1C 0.2668 0.4687 0.2496 0.058\* C3 0.5856 (11) 0.4644 (8) 0.1041 (6) 0.035 (2) C4 0.6566 (13) 0.5542 (9) 0.0576 (6) 0.044 (2) H4A 0.5830 0.6265 0.0569 0.066\* H4B 0.6842 0.5357 0.0087 0.066\* H4C 0.7507 0.5612 0.0757 0.066\* N5 0.5278 (9) 0.3961 (7) 0.1395 (4) 0.0329 (17) O6 0.1387 (7) 0.1455 (5) 0.2067 (3) 0.0279 (13) C7 0.2062 (10) 0.1351 (8) 0.1295 (5) 0.0293 (19) C8 0.3807 (10) 0.0855 (8) 0.1224 (5) 0.0290 (19) N9 0.4740 (9) 0.1537 (7) 0.1327 (4) 0.0301 (16) C10 0.1082 (11) 0.0593 (9) 0.1097 (5) 0.035 (2) H10A −0.0023 0.0895 0.1227 0.052\* H10B 0.1336 −0.0182 0.1358 0.052\* H10C 0.1302 0.0578 0.0578 0.052\* C11 0.1809 (11) 0.2512 (8) 0.0820 (5) 0.034 (2) H11A 0.2297 0.2440 0.0326 0.052\* H11B 0.2277 0.3047 0.1003 0.052\* H11C 0.0691 0.2796 0.0825 0.052\* C12 0.6264 (10) 0.1235 (8) 0.1163 (5) 0.0307 (19) H12 0.6913 0.1744 0.1209 0.037\* C13 0.6963 (11) 0.0210 (9) 0.0926 (5) 0.037 (2) H13 0.8062 0.0018 0.0815 0.045\* C14 0.6010 (12) −0.0513 (9) 0.0857 (5) 0.038 (2) H14 0.6443 −0.1237 0.0719 0.046\* C15 0.4404 (12) −0.0178 (8) 0.0991 (5) 0.036 (2) H15 0.3727 −0.0652 0.0923 0.044\* C16 0.0614 (11) 0.2221 (7) 0.3317 (5) 0.032 (2) C17 0.0542 (11) 0.1885 (8) 0.4067 (5) 0.032 (2) C18 −0.0813 (12) 0.2128 (8) 0.4534 (6) 0.038 (2) H18 −0.0823 0.1875 0.5037 0.045\* C19 −0.2166 (12) 0.2743 (9) 0.4271 (6) 0.040 (2) C20 −0.2084 (11) 0.3147 (8) 0.3550 (6) 0.036 (2) H20 −0.2984 0.3604 0.3372 0.043\* C21 −0.0762 (11) 0.2923 (8) 0.3076 (6) 0.034 (2) C22 0.1891 (12) 0.1192 (9) 0.4428 (6) 0.039 (2) C23 −0.3671 (13) 0.2958 (11) 0.4782 (6) 0.049 (3) C24 −0.0904 (11) 0.3491 (8) 0.2309 (6) 0.037 (2) F25 0.1962 (7) 0.0064 (5) 0.4459 (3) 0.0479 (15) F26 0.3246 (6) 0.1442 (5) 0.4090 (3) 0.0425 (13) F27 0.1776 (8) 0.1381 (6) 0.5101 (3) 0.0548 (17) F28 −0.346 (2) 0.323 (2) 0.5373 (11) 0.081 (5) 0.50 F29 −0.4321 (18) 0.1986 (15) 0.4936 (10) 0.068 (4) 0.50 F30 −0.4754 (19) 0.3697 (17) 0.4483 (9) 0.070 (4) 0.50 F28A −0.354 (2) 0.2539 (18) 0.5459 (9) 0.072 (5) 0.50 F29A −0.476 (3) 0.263 (3) 0.4619 (14) 0.103 (7) 0.50 F30A −0.411 (2) 0.4029 (17) 0.4800 (12) 0.091 (6) 0.50 F31 −0.1953 (7) 0.4478 (5) 0.2306 (3) 0.0470 (15) F32 −0.1387 (7) 0.2859 (5) 0.1925 (3) 0.0404 (13) F33 0.0422 (6) 0.3815 (5) 0.1958 (3) 0.0382 (12) C34 0.3269 (10) 0.0207 (8) 0.2948 (5) 0.0274 (18) C35 0.4889 (11) −0.0100 (8) 0.2957 (5) 0.033 (2) C36 0.5675 (12) −0.1170 (9) 0.2856 (5) 0.041 (2) H36 0.6771 −0.1342 0.2851 0.049\* C37 0.4903 (13) −0.1995 (8) 0.2763 (6) 0.043 (3) C38 0.3305 (13) −0.1775 (9) 0.2834 (6) 0.041 (2) H38 0.2757 −0.2360 0.2811 0.049\* C39 0.2482 (12) −0.0697 (8) 0.2941 (5) 0.035 (2) C40 0.5991 (11) 0.0602 (9) 0.3100 (6) 0.039 (2) C41 0.5765 (16) −0.3156 (10) 0.2601 (8) 0.060 (4) C42 0.0767 (12) −0.0694 (8) 0.3098 (5) 0.037 (2) F43 0.5466 (7) 0.1693 (5) 0.3180 (3) 0.0430 (13) F44 0.7231 (7) 0.0620 (6) 0.2587 (3) 0.0486 (15) F45 0.6537 (7) 0.0103 (6) 0.3723 (3) 0.0490 (15) F46 0.7237 (11) −0.3168 (7) 0.2408 (8) 0.121 (5) F47 0.5548 (11) −0.3967 (6) 0.3154 (5) 0.080 (3) F48 0.5253 (16) −0.3471 (8) 0.2071 (6) 0.114 (4) F49 0.0470 (7) −0.1512 (5) 0.3669 (3) 0.0488 (15) F50 0.0170 (7) −0.0935 (5) 0.2562 (3) 0.0456 (14) F51 −0.0107 (6) 0.0275 (5) 0.3278 (3) 0.0381 (13) Sb1 0.13293 (7) 0.70526 (5) 0.07820 (4) 0.0384 (2) F1 0.2407 (9) 0.5556 (5) 0.0969 (4) 0.0581 (18) F2 −0.0566 (8) 0.6539 (8) 0.0901 (4) 0.068 (2) F3 0.0296 (10) 0.8560 (6) 0.0551 (5) 0.078 (3) F4 0.3226 (8) 0.7596 (7) 0.0633 (5) 0.071 (2) F5 0.1630 (7) 0.6941 (6) −0.0202 (3) 0.0465 (14) F6 0.1099 (11) 0.7165 (9) 0.1756 (4) 0.085 (3) C52 0.026 (3) 0.411 (3) 0.6363 (14) 0.077 (8) 0.50 H52A 0.0107 0.3478 0.6766 0.093\* 0.50 H52B 0.0313 0.4793 0.6562 0.093\* 0.50 Cl1 −0.1188 (19) 0.4375 (15) 0.5867 (9) 0.169 (6) 0.50 Cl2 0.190 (2) 0.374 (3) 0.5796 (15) 0.273 (13) 0.50 ------ -------------- -------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1881 .table-wrap} ------ ------------- ------------- ------------- ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Pd1 0.0282 (3) 0.0193 (3) 0.0379 (4) −0.0050 (3) −0.0009 (3) −0.0052 (3) P1 0.0243 (10) 0.0179 (10) 0.0382 (12) −0.0025 (9) −0.0017 (9) −0.0058 (9) C1 0.048 (6) 0.025 (5) 0.043 (5) −0.006 (4) −0.002 (4) −0.014 (4) C3 0.031 (5) 0.023 (5) 0.050 (6) 0.001 (4) −0.001 (4) −0.014 (4) C4 0.050 (6) 0.025 (5) 0.054 (6) −0.013 (5) 0.008 (5) −0.006 (4) N5 0.029 (4) 0.023 (4) 0.046 (4) −0.008 (4) −0.003 (3) −0.002 (3) O6 0.023 (3) 0.023 (3) 0.038 (3) −0.002 (2) −0.001 (2) −0.008 (2) C7 0.030 (4) 0.033 (5) 0.027 (4) −0.007 (4) −0.004 (3) −0.007 (4) C8 0.029 (4) 0.028 (5) 0.030 (4) −0.004 (4) 0.000 (3) −0.008 (4) N9 0.032 (4) 0.029 (4) 0.027 (4) −0.001 (3) 0.000 (3) −0.009 (3) C10 0.028 (4) 0.038 (5) 0.043 (5) −0.006 (4) −0.001 (4) −0.020 (4) C11 0.031 (5) 0.034 (5) 0.037 (5) −0.002 (4) −0.007 (4) −0.005 (4) C12 0.022 (4) 0.025 (5) 0.044 (5) −0.008 (4) 0.000 (4) −0.004 (4) C13 0.033 (5) 0.035 (5) 0.039 (5) −0.001 (4) 0.002 (4) −0.004 (4) C14 0.043 (5) 0.028 (5) 0.042 (5) −0.002 (4) 0.003 (4) −0.015 (4) C15 0.041 (5) 0.027 (5) 0.040 (5) −0.009 (4) 0.000 (4) −0.005 (4) C16 0.034 (5) 0.016 (4) 0.048 (5) −0.006 (4) −0.004 (4) −0.009 (4) C17 0.033 (5) 0.024 (4) 0.038 (5) −0.004 (4) 0.002 (4) −0.010 (4) C18 0.041 (5) 0.029 (5) 0.042 (5) −0.005 (4) −0.005 (4) −0.007 (4) C19 0.034 (5) 0.036 (6) 0.052 (6) −0.003 (4) 0.002 (4) −0.019 (5) C20 0.027 (5) 0.021 (5) 0.056 (6) 0.009 (4) −0.006 (4) −0.013 (4) C21 0.030 (5) 0.023 (5) 0.049 (6) 0.001 (4) −0.002 (4) −0.013 (4) C22 0.036 (5) 0.033 (5) 0.044 (6) 0.002 (4) −0.005 (4) −0.007 (4) C23 0.038 (5) 0.059 (6) 0.047 (5) 0.002 (5) 0.001 (4) −0.019 (5) C24 0.030 (5) 0.026 (5) 0.050 (6) 0.007 (4) −0.002 (4) −0.010 (4) F25 0.051 (3) 0.035 (3) 0.049 (3) 0.001 (3) −0.003 (3) 0.003 (3) F26 0.034 (3) 0.047 (4) 0.048 (3) −0.005 (3) −0.009 (2) −0.010 (3) F27 0.054 (4) 0.067 (5) 0.039 (3) 0.008 (3) −0.010 (3) −0.014 (3) F28 0.078 (9) 0.093 (9) 0.070 (8) −0.011 (8) 0.012 (7) −0.037 (8) F29 0.048 (7) 0.059 (7) 0.083 (8) −0.010 (6) 0.021 (6) −0.008 (6) F30 0.048 (7) 0.074 (8) 0.067 (7) 0.014 (6) 0.008 (6) −0.001 (6) F28A 0.062 (7) 0.075 (8) 0.055 (7) 0.009 (7) 0.017 (6) 0.004 (7) F29A 0.088 (10) 0.125 (11) 0.106 (10) −0.030 (9) −0.002 (8) −0.041 (9) F30A 0.075 (8) 0.074 (9) 0.097 (9) 0.018 (7) 0.031 (7) −0.021 (7) F31 0.044 (3) 0.033 (3) 0.053 (4) 0.012 (3) −0.004 (3) −0.004 (3) F32 0.039 (3) 0.038 (3) 0.045 (3) −0.003 (3) −0.009 (2) −0.010 (3) F33 0.038 (3) 0.028 (3) 0.044 (3) −0.001 (2) −0.004 (2) 0.000 (2) C34 0.029 (4) 0.023 (4) 0.029 (4) −0.006 (4) 0.003 (3) −0.005 (3) C35 0.034 (5) 0.030 (5) 0.033 (5) −0.006 (4) −0.005 (4) 0.003 (4) C36 0.033 (5) 0.034 (6) 0.042 (5) 0.009 (4) 0.006 (4) 0.002 (4) C37 0.050 (6) 0.021 (5) 0.046 (6) 0.004 (5) 0.012 (5) −0.004 (4) C38 0.050 (6) 0.026 (5) 0.043 (6) −0.011 (5) 0.004 (4) −0.005 (4) C39 0.046 (6) 0.023 (5) 0.034 (5) −0.007 (4) 0.004 (4) −0.003 (4) C40 0.027 (5) 0.038 (6) 0.045 (5) 0.004 (4) −0.005 (4) 0.000 (4) C41 0.063 (8) 0.025 (6) 0.074 (9) 0.006 (6) 0.020 (6) −0.003 (5) C42 0.044 (5) 0.025 (5) 0.041 (5) −0.003 (4) −0.001 (4) −0.008 (4) F43 0.041 (3) 0.036 (3) 0.054 (3) −0.011 (3) −0.009 (3) −0.004 (3) F44 0.032 (3) 0.058 (4) 0.054 (4) −0.011 (3) −0.002 (3) −0.006 (3) F45 0.046 (3) 0.048 (4) 0.050 (4) −0.006 (3) −0.014 (3) 0.003 (3) F46 0.061 (5) 0.036 (4) 0.237 (14) −0.002 (4) 0.065 (7) −0.033 (6) F47 0.093 (6) 0.024 (3) 0.096 (6) 0.009 (4) 0.023 (5) 0.003 (3) F48 0.167 (11) 0.063 (6) 0.106 (7) 0.033 (7) −0.023 (7) −0.052 (6) F49 0.046 (3) 0.039 (3) 0.054 (4) −0.011 (3) 0.009 (3) 0.002 (3) F50 0.045 (3) 0.043 (3) 0.054 (4) −0.018 (3) 0.002 (3) −0.019 (3) F51 0.025 (3) 0.028 (3) 0.061 (4) −0.005 (2) 0.002 (2) −0.013 (3) Sb1 0.0345 (4) 0.0292 (4) 0.0533 (4) 0.0007 (3) −0.0098 (3) −0.0143 (3) F1 0.076 (5) 0.024 (3) 0.068 (4) 0.013 (3) −0.024 (4) −0.003 (3) F2 0.040 (3) 0.106 (7) 0.063 (4) −0.035 (4) −0.001 (3) −0.008 (4) F3 0.079 (5) 0.037 (4) 0.123 (7) 0.027 (4) −0.048 (5) −0.033 (4) F4 0.048 (4) 0.055 (4) 0.120 (7) −0.021 (4) −0.034 (4) −0.002 (4) F5 0.044 (3) 0.049 (4) 0.044 (3) −0.006 (3) −0.004 (3) −0.004 (3) F6 0.088 (6) 0.124 (8) 0.046 (4) 0.011 (5) −0.014 (4) −0.045 (5) C52 0.082 (12) 0.069 (11) 0.090 (12) −0.023 (9) −0.008 (9) −0.030 (9) Cl1 0.186 (10) 0.154 (9) 0.173 (9) −0.001 (8) −0.025 (8) −0.071 (8) Cl2 0.272 (15) 0.281 (16) 0.277 (15) −0.060 (10) −0.038 (10) −0.059 (10) ------ ------------- ------------- ------------- ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e3182 .table-wrap} ------------------------- ------------- ------------------------- ------------- Pd1---C1 2.052 (9) C22---F27 1.332 (12) Pd1---N5 2.078 (8) C22---F25 1.348 (12) Pd1---N9 2.187 (7) C23---F29A 1.23 (3) Pd1---P1 2.197 (2) C23---F30A 1.28 (2) P1---O6 1.591 (6) C23---F28 1.29 (2) P1---C16 1.891 (9) C23---F30 1.30 (2) P1---C34 1.894 (9) C23---F28A 1.31 (2) C1---H1A 0.9800 C23---F29 1.38 (2) C1---H1B 0.9800 C24---F32 1.328 (12) C1---H1C 0.9800 C24---F33 1.343 (11) C3---N5 1.118 (13) C24---F31 1.358 (11) C3---C4 1.448 (14) F28---F28A 0.84 (2) C4---H4A 0.9800 F28---F30A 1.43 (3) C4---H4B 0.9800 F29---F29A 0.95 (3) C4---H4C 0.9800 F29---F28A 1.61 (3) O6---C7 1.513 (10) F30---F30A 1.08 (3) C7---C10 1.519 (12) F30---F29A 1.28 (3) C7---C11 1.523 (13) C34---C35 1.410 (13) C7---C8 1.533 (12) C34---C39 1.418 (14) C8---N9 1.343 (12) C35---C36 1.374 (14) C8---C15 1.381 (13) C35---C40 1.507 (15) N9---C12 1.324 (12) C36---C37 1.375 (16) C10---H10A 0.9800 C36---H36 0.9500 C10---H10B 0.9800 C37---C38 1.375 (16) C10---H10C 0.9800 C37---C41 1.520 (14) C11---H11A 0.9800 C38---C39 1.394 (14) C11---H11B 0.9800 C38---H38 0.9500 C11---H11C 0.9800 C39---C42 1.498 (14) C12---C13 1.392 (14) C40---F43 1.340 (12) C12---H12 0.9500 C40---F44 1.342 (12) C13---C14 1.373 (15) C40---F45 1.351 (12) C13---H13 0.9500 C41---F46 1.292 (16) C14---C15 1.392 (14) C41---F47 1.318 (14) C14---H14 0.9500 C41---F48 1.322 (19) C15---H15 0.9500 C42---F50 1.332 (12) C16---C17 1.409 (14) C42---F51 1.338 (11) C16---C21 1.430 (14) C42---F49 1.359 (12) C17---C18 1.384 (14) Sb1---F6 1.865 (7) C17---C22 1.507 (14) Sb1---F2 1.872 (7) C18---C19 1.396 (15) Sb1---F1 1.873 (6) C18---H18 0.9500 Sb1---F3 1.880 (7) C19---C20 1.367 (16) Sb1---F5 1.880 (6) C19---C23 1.519 (14) Sb1---F4 1.887 (7) C20---C21 1.367 (14) C52---Cl1 1.666 (18) C20---H20 0.9500 C52---Cl2 1.692 (18) C21---C24 1.512 (15) C52---H52A 0.9900 C22---F26 1.327 (12) C52---H52B 0.9900 C1---Pd1---N5 88.1 (4) F28---C23---F28A 37.6 (12) C1---Pd1---N9 176.6 (4) F30---C23---F28A 131.5 (13) N5---Pd1---N9 93.3 (3) F29A---C23---F29 42.4 (15) C1---Pd1---P1 91.8 (3) F30A---C23---F29 138.1 (15) N5---Pd1---P1 174.1 (2) F28---C23---F29 109.0 (16) N9---Pd1---P1 87.0 (2) F30---C23---F29 101.6 (15) O6---P1---C16 99.1 (4) F28A---C23---F29 73.5 (15) O6---P1---C34 97.4 (4) F29A---C23---C19 114.1 (14) C16---P1---C34 111.1 (4) F30A---C23---C19 110.6 (13) O6---P1---Pd1 106.3 (3) F28---C23---C19 112.6 (13) C16---P1---Pd1 123.4 (3) F30---C23---C19 112.9 (12) C34---P1---Pd1 114.5 (3) F28A---C23---C19 114.2 (12) Pd1---C1---H1A 109.5 F29---C23---C19 108.7 (11) Pd1---C1---H1B 109.5 F32---C24---F33 109.1 (8) H1A---C1---H1B 109.5 F32---C24---F31 106.8 (8) Pd1---C1---H1C 109.5 F33---C24---F31 104.3 (8) H1A---C1---H1C 109.5 F32---C24---C21 113.5 (9) H1B---C1---H1C 109.5 F33---C24---C21 112.8 (8) N5---C3---C4 178.6 (11) F31---C24---C21 109.8 (8) C3---C4---H4A 109.5 F28A---F28---C23 73 (2) C3---C4---H4B 109.5 F28A---F28---F30A 124 (3) H4A---C4---H4B 109.5 C23---F28---F30A 55.9 (14) C3---C4---H4C 109.5 F29A---F29---C23 60.4 (19) H4A---C4---H4C 109.5 F29A---F29---F28A 104 (2) H4B---C4---H4C 109.5 C23---F29---F28A 51.4 (10) C3---N5---Pd1 172.5 (8) F30A---F30---F29A 117 (2) C7---O6---P1 124.2 (5) F30A---F30---C23 64.4 (15) O6---C7---C10 102.8 (7) F29A---F30---C23 56.8 (14) O6---C7---C11 110.2 (7) F28---F28A---C23 70 (2) C10---C7---C11 109.1 (8) F28---F28A---F29 122 (3) O6---C7---C8 111.6 (7) C23---F28A---F29 55.1 (12) C10---C7---C8 113.7 (8) F29---F29A---C23 77 (2) C11---C7---C8 109.2 (8) F29---F29A---F30 137 (3) N9---C8---C15 121.5 (9) C23---F29A---F30 62.7 (16) N9---C8---C7 116.1 (8) F30---F30A---C23 66.3 (17) C15---C8---C7 122.1 (9) F30---F30A---F28 116 (2) C12---N9---C8 118.8 (8) C23---F30A---F28 56.2 (12) C12---N9---Pd1 117.0 (6) C35---C34---C39 115.7 (9) C8---N9---Pd1 121.8 (6) C35---C34---P1 121.8 (7) C7---C10---H10A 109.5 C39---C34---P1 119.1 (7) C7---C10---H10B 109.5 C36---C35---C34 121.6 (10) H10A---C10---H10B 109.5 C36---C35---C40 110.1 (9) C7---C10---H10C 109.5 C34---C35---C40 128.3 (9) H10A---C10---H10C 109.5 C35---C36---C37 121.1 (10) H10B---C10---H10C 109.5 C35---C36---H36 119.4 C7---C11---H11A 109.5 C37---C36---H36 119.4 C7---C11---H11B 109.5 C38---C37---C36 119.2 (9) H11A---C11---H11B 109.5 C38---C37---C41 119.0 (11) C7---C11---H11C 109.5 C36---C37---C41 121.8 (11) H11A---C11---H11C 109.5 C37---C38---C39 120.4 (10) H11B---C11---H11C 109.5 C37---C38---H38 119.8 N9---C12---C13 123.4 (9) C39---C38---H38 119.8 N9---C12---H12 118.3 C38---C39---C34 121.1 (10) C13---C12---H12 118.3 C38---C39---C42 111.1 (9) C14---C13---C12 117.7 (9) C34---C39---C42 127.6 (8) C14---C13---H13 121.2 F43---C40---F44 105.3 (9) C12---C13---H13 121.2 F43---C40---F45 104.7 (8) C13---C14---C15 119.4 (9) F44---C40---F45 106.7 (7) C13---C14---H14 120.3 F43---C40---C35 119.5 (8) C15---C14---H14 120.3 F44---C40---C35 111.8 (9) C8---C15---C14 119.1 (10) F45---C40---C35 108.0 (8) C8---C15---H15 120.5 F46---C41---F47 109.7 (12) C14---C15---H15 120.5 F46---C41---F48 106.4 (12) C17---C16---C21 115.5 (9) F47---C41---F48 104.6 (13) C17---C16---P1 124.5 (7) F46---C41---C37 112.0 (12) C21---C16---P1 119.9 (7) F47---C41---C37 111.6 (10) C18---C17---C16 122.2 (9) F48---C41---C37 112.2 (12) C18---C17---C22 114.2 (9) F50---C42---F51 106.5 (8) C16---C17---C22 123.5 (8) F50---C42---F49 105.6 (8) C17---C18---C19 120.3 (10) F51---C42---F49 105.2 (8) C17---C18---H18 119.9 F50---C42---C39 113.9 (8) C19---C18---H18 119.9 F51---C42---C39 115.3 (8) C20---C19---C18 118.1 (9) F49---C42---C39 109.4 (8) C20---C19---C23 121.7 (10) F6---Sb1---F2 91.6 (4) C18---C19---C23 120.1 (10) F6---Sb1---F1 90.2 (4) C21---C20---C19 122.8 (9) F2---Sb1---F1 91.3 (4) C21---C20---H20 118.6 F6---Sb1---F3 92.2 (4) C19---C20---H20 118.6 F2---Sb1---F3 89.8 (4) C20---C21---C16 120.7 (10) F1---Sb1---F3 177.4 (4) C20---C21---C24 114.2 (9) F6---Sb1---F5 178.2 (3) C16---C21---C24 125.1 (9) F2---Sb1---F5 90.2 (3) F26---C22---F27 106.9 (8) F1---Sb1---F5 89.2 (3) F26---C22---F25 107.4 (8) F3---Sb1---F5 88.4 (3) F27---C22---F25 107.1 (8) F6---Sb1---F4 89.9 (4) F26---C22---C17 112.2 (8) F2---Sb1---F4 178.2 (4) F27---C22---C17 111.1 (8) F1---Sb1---F4 89.8 (3) F25---C22---C17 111.9 (9) F3---Sb1---F4 89.0 (4) F29A---C23---F30A 106 (2) F5---Sb1---F4 88.3 (3) F29A---C23---F28 131.4 (17) Cl1---C52---Cl2 105.5 (14) F30A---C23---F28 67.9 (16) Cl1---C52---H52A 110.6 F29A---C23---F30 60.5 (16) Cl2---C52---H52A 110.6 F30A---C23---F30 49.3 (13) Cl1---C52---H52B 110.6 F28---C23---F30 111.3 (16) Cl2---C52---H52B 110.6 F29A---C23---F28A 108.2 (19) H52A---C52---H52B 108.8 F30A---C23---F28A 102.4 (16) C1---Pd1---P1---O6 130.4 (4) F29A---C23---F29---F28A −144 (2) N5---Pd1---P1---O6 41 (2) F30A---C23---F29---F28A −90 (3) N9---Pd1---P1---O6 −52.8 (3) F28---C23---F29---F28A −12.6 (14) C1---Pd1---P1---C16 17.5 (5) F30---C23---F29---F28A −130.1 (14) N5---Pd1---P1---C16 −72 (2) C19---C23---F29---F28A 110.5 (13) N9---Pd1---P1---C16 −165.7 (4) F29A---C23---F30---F30A 156 (2) C1---Pd1---P1---C34 −123.3 (4) F28---C23---F30---F30A 29.8 (19) N5---Pd1---P1---C34 147 (2) F28A---C23---F30---F30A 67 (3) N9---Pd1---P1---C34 53.5 (4) F29---C23---F30---F30A 145.7 (17) C4---C3---N5---Pd1 −12 (50) C19---C23---F30---F30A −98.0 (17) C1---Pd1---N5---C3 −68 (6) F30A---C23---F30---F29A −156 (2) N9---Pd1---N5---C3 115 (6) F28---C23---F30---F29A −126 (2) P1---Pd1---N5---C3 22 (8) F28A---C23---F30---F29A −89 (3) C16---P1---O6---C7 161.2 (6) F29---C23---F30---F29A −10.6 (16) C34---P1---O6---C7 −85.9 (7) C19---C23---F30---F29A 105.7 (17) Pd1---P1---O6---C7 32.4 (7) F30A---F28---F28A---C23 25 (2) P1---O6---C7---C10 155.1 (6) C23---F28---F28A---F29 −19 (2) P1---O6---C7---C11 −88.7 (8) F30A---F28---F28A---F29 6(4) P1---O6---C7---C8 32.9 (10) F29A---C23---F28A---F28 −136 (3) O6---C7---C8---N9 −70.3 (10) F30A---C23---F28A---F28 −23 (2) C10---C7---C8---N9 174.0 (8) F30---C23---F28A---F28 −69 (3) C11---C7---C8---N9 51.8 (10) F29---C23---F28A---F28 −160 (2) O6---C7---C8---C15 116.6 (9) C19---C23---F28A---F28 96 (2) C10---C7---C8---C15 0.9 (13) F29A---C23---F28A---F29 24.7 (16) C11---C7---C8---C15 −121.2 (10) F30A---C23---F28A---F29 136.9 (16) C15---C8---N9---C12 3.8 (13) F28---C23---F28A---F29 160 (2) C7---C8---N9---C12 −169.4 (8) F30---C23---F28A---F29 91 (2) C15---C8---N9---Pd1 −158.1 (7) C19---C23---F28A---F29 −103.5 (13) C7---C8---N9---Pd1 28.7 (10) F29A---F29---F28A---F28 −10 (3) C1---Pd1---N9---C12 −64 (6) C23---F29---F28A---F28 22 (2) N5---Pd1---N9---C12 52.0 (7) F29A---F29---F28A---C23 −31.9 (19) P1---Pd1---N9---C12 −133.9 (7) F28A---F29---F29A---C23 28.3 (15) C1---Pd1---N9---C8 98 (6) C23---F29---F29A---F30 −20 (3) N5---Pd1---N9---C8 −145.8 (7) F28A---F29---F29A---F30 8(4) P1---Pd1---N9---C8 28.3 (7) F30A---C23---F29A---F29 −146.0 (19) C8---N9---C12---C13 −3.9 (14) F28---C23---F29A---F29 −71 (3) Pd1---N9---C12---C13 158.9 (8) F30---C23---F29A---F29 −165 (2) N9---C12---C13---C14 0.4 (15) F28A---C23---F29A---F29 −37 (2) C12---C13---C14---C15 3.0 (15) C19---C23---F29A---F29 92 (2) N9---C8---C15---C14 −0.4 (14) F30A---C23---F29A---F30 18.6 (17) C7---C8---C15---C14 172.3 (9) F28---C23---F29A---F30 93 (3) C13---C14---C15---C8 −3.1 (15) F28A---C23---F29A---F30 128.0 (16) O6---P1---C16---C17 135.4 (8) F29---C23---F29A---F30 165 (2) C34---P1---C16---C17 33.8 (9) C19---C23---F29A---F30 −103.7 (15) Pd1---P1---C16---C17 −108.1 (8) F30A---F30---F29A---F29 −2(5) O6---P1---C16---C21 −40.0 (8) C23---F30---F29A---F29 23 (3) C34---P1---C16---C21 −141.6 (7) F30A---F30---F29A---C23 −24 (2) Pd1---P1---C16---C21 76.5 (8) F29A---F30---F30A---C23 22.2 (19) C21---C16---C17---C18 5.7 (14) F29A---F30---F30A---F28 −5(3) P1---C16---C17---C18 −169.9 (8) C23---F30---F30A---F28 −27.4 (15) C21---C16---C17---C22 −177.1 (9) F29A---C23---F30A---F30 −21 (2) P1---C16---C17---C22 7.3 (14) F28---C23---F30A---F30 −150.0 (19) C16---C17---C18---C19 −1.2 (16) F28A---C23---F30A---F30 −134.9 (17) C22---C17---C18---C19 −178.5 (9) F29---C23---F30A---F30 −56 (3) C17---C18---C19---C20 −3.7 (15) C19---C23---F30A---F30 103.0 (16) C17---C18---C19---C23 177.1 (10) F29A---C23---F30A---F28 128.6 (19) C18---C19---C20---C21 3.7 (16) F30---C23---F30A---F28 150.0 (19) C23---C19---C20---C21 −177.1 (10) F28A---C23---F30A---F28 15.1 (16) C19---C20---C21---C16 1.2 (16) F29---C23---F30A---F28 94 (3) C19---C20---C21---C24 −177.7 (10) C19---C23---F30A---F28 −106.9 (15) C17---C16---C21---C20 −5.7 (14) F28A---F28---F30A---F30 2(4) P1---C16---C21---C20 170.1 (8) C23---F28---F30A---F30 30.5 (17) C17---C16---C21---C24 173.0 (9) F28A---F28---F30A---C23 −29 (3) P1---C16---C21---C24 −11.2 (13) O6---P1---C34---C35 127.6 (8) C18---C17---C22---F26 −148.1 (9) C16---P1---C34---C35 −129.6 (8) C16---C17---C22---F26 34.6 (13) Pd1---P1---C34---C35 15.9 (8) C18---C17---C22---F27 −28.5 (13) O6---P1---C34---C39 −30.7 (7) C16---C17---C22---F27 154.2 (9) C16---P1---C34---C39 72.0 (8) C18---C17---C22---F25 91.1 (10) Pd1---P1---C34---C39 −142.4 (6) C16---C17---C22---F25 −86.2 (11) C39---C34---C35---C36 9.2 (13) C20---C19---C23---F29A 57 (2) P1---C34---C35---C36 −149.8 (8) C18---C19---C23---F29A −124 (2) C39---C34---C35---C40 −167.8 (9) C20---C19---C23---F30A −63.4 (19) P1---C34---C35---C40 33.1 (13) C18---C19---C23---F30A 115.8 (17) C34---C35---C36---C37 −1.8 (15) C20---C19---C23---F28 −137.2 (16) C40---C35---C36---C37 175.7 (9) C18---C19---C23---F28 42 (2) C35---C36---C37---C38 −5.7 (16) C20---C19---C23---F30 −10 (2) C35---C36---C37---C41 175.7 (10) C18---C19---C23---F30 169.1 (15) C36---C37---C38---C39 5.2 (16) C20---C19---C23---F28A −178.3 (15) C41---C37---C38---C39 −176.2 (10) C18---C19---C23---F28A 1(2) C37---C38---C39---C34 2.7 (15) C20---C19---C23---F29 101.9 (15) C37---C38---C39---C42 −172.7 (9) C18---C19---C23---F29 −78.9 (15) C35---C34---C39---C38 −9.6 (13) C20---C21---C24---F32 −90.2 (10) P1---C34---C39---C38 150.0 (8) C16---C21---C24---F32 91.0 (11) C35---C34---C39---C42 164.9 (9) C20---C21---C24---F33 145.1 (9) P1---C34---C39---C42 −35.4 (13) C16---C21---C24---F33 −33.7 (13) C36---C35---C40---F43 177.0 (9) C20---C21---C24---F31 29.2 (12) C34---C35---C40---F43 −5.7 (15) C16---C21---C24---F31 −149.6 (9) C36---C35---C40---F44 53.4 (11) F29A---C23---F28---F28A 62 (3) C34---C35---C40---F44 −129.3 (10) F30A---C23---F28---F28A 155 (3) C36---C35---C40---F45 −63.7 (10) F30---C23---F28---F28A 131 (2) C34---C35---C40---F45 113.6 (10) F29---C23---F28---F28A 20 (2) C38---C37---C41---F46 167.1 (13) C19---C23---F28---F28A −101 (2) C36---C37---C41---F46 −14.3 (18) F29A---C23---F28---F30A −93 (3) C38---C37---C41---F47 −69.5 (17) F30---C23---F28---F30A −24.0 (16) C36---C37---C41---F47 109.1 (14) F28A---C23---F28---F30A −155 (3) C38---C37---C41---F48 47.5 (15) F29---C23---F28---F30A −135.3 (16) C36---C37---C41---F48 −133.9 (13) C19---C23---F28---F30A 104.0 (16) C38---C39---C42---F50 −62.7 (11) F30A---C23---F29---F29A 54 (3) C34---C39---C42---F50 122.4 (10) F28---C23---F29---F29A 131 (2) C38---C39---C42---F51 173.7 (9) F30---C23---F29---F29A 14 (2) C34---C39---C42---F51 −1.3 (15) F28A---C23---F29---F29A 144 (2) C38---C39---C42---F49 55.3 (11) C19---C23---F29---F29A −106 (2) C34---C39---C42---F49 −119.7 (10) ------------------------- ------------- ------------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e5635 .table-wrap} ---------------------- --------- --------- ------------ --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C4---H4B···F1^i^ 0.98 2.40 3.365 (13) 166 C12---H12···F5^i^ 0.95 2.60 3.276 (11) 129 C4---H4A···F4 0.98 2.53 3.464 (13) 158 C4---H4C···F2^ii^ 0.98 2.30 3.225 (13) 155 C11---H11C···F5^iii^ 0.98 2.49 3.352 (11) 146 ---------------------- --------- --------- ------------ --------------- ::: Symmetry codes: (i) −*x*+1, −*y*+1, −*z*; (ii) *x*+1, *y*, *z*; (iii) −*x*, −*y*+1, −*z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ---------------------- --------- ------- ------------ ------------- C4---H4*B*⋯F1^i^ 0.98 2.40 3.365 (13) 166 C12---H12⋯F5^i^ 0.95 2.60 3.276 (11) 129 C4---H4*A*⋯F4 0.98 2.53 3.464 (13) 158 C4---H4*C*⋯F2^ii^ 0.98 2.30 3.225 (13) 155 C11---H11*C*⋯F5^iii^ 0.98 2.49 3.352 (11) 146 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.674484

2011-2-23

PMC3051982

Related literature {#sec1} ================== The starting compound, Fe(NO)~2~(CO)~2~, was prepared using a published method described by Eisch & King (1965[@bb4]). For the structures of some related dinitrosyl complexes, see: Li *et al.* (2003[@bb5]); Atkinson *et al.* (1996[@bb2]); Li Kam Wah *et al.* (1989[@bb6]); Albano *et al.* (1974[@bb1]). For general information on metal nitrosyl chemistry, see: Richter-Addo & Legzdins (1992[@bb7]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Fe(NO)~2~(C~18~H~12~F~3~P)~2~\]·CHCl~3~*M* *~r~* = 867.73Monoclinic,*a* = 13.994 (5) Å*b* = 15.746 (6) Å*c* = 16.716 (6) Åβ = 97.651 (8)°*V* = 3651 (2) Å^3^*Z* = 4Mo *K*α radiationμ = 0.79 mm^−1^*T* = 100 K0.44 × 0.22 × 0.04 mm ### Data collection {#sec2.1.2} Bruker APEX CCD diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 2001[@bb8]) *T* ~min~ = 0.721, *T* ~max~ = 0.97222634 measured reflections6325 independent reflections5006 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.056 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.042*wR*(*F* ^2^) = 0.115*S* = 1.026325 reflections478 parametersH-atom parameters constrainedΔρ~max~ = 1.24 e Å^−3^Δρ~min~ = −0.46 e Å^−3^ {#d5e403} Data collection: *SMART* (Bruker, 2007[@bb3]); cell refinement: *SAINT* (Bruker, 2007[@bb3]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb9]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL*; software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004673/fk2035sup1.cif](http://dx.doi.org/10.1107/S1600536811004673/fk2035sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004673/fk2035Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004673/fk2035Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?fk2035&file=fk2035sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?fk2035sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?fk2035&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [FK2035](http://scripts.iucr.org/cgi-bin/sendsup?fk2035)). We are grateful to the US Department of Education (GAANN Fellowship to MWJ; P200A030196), and the National Science Foundation (CHE-0076640 and CHE-0911537) for funding this work. The authors thank the National Science Foundation (CHE-0130835) and the University of Oklahoma for funds to acquire the diffractometer and computers used in this work. Comment ======= The molecular structure of the title compound is shown in Fig. 1. The structure includes one metal complex molecule and one chloroform solvent molecule. The metal complex molecule possesses a distorted tetrahedral geometry around the iron center. The iron is bound to two nitrosyl groups *via* the nitrogen atoms and to two phosphine ligands *via* the phorphorus atoms. The Fe(NO)~2~ moiety exhibits an *attracto* conformation where the bond angle O···Fe···O \< N---Fe---N (Richter-Addo & Legzdins, 1992). The N---Fe---N bond angle is 127.02 (11)° and the interphosphine bond angle, P---Fe---P, is 108.27 (4)°. The Fe---N---O bond angles are 178.1 (2)° and 177.0 (2)°. Experimental {#experimental} ============ A light yellow toluene solution (5 ml) of P(C~6~H~4~-*p*-F)~3~ (127 mg, 0.40 mmol) was charged with Fe(NO)~2~(CO)~2~ (21 µ*L*, 0.19 mmol) (Eisch & King, 1965). The light red/orange solution was heated and stirred under nitrogen for 3.25 h after which time the infrared spectrum was consistent with the presence of the product and no trace of Fe(NO)~2~(CO)~2~ (ν~CO~ = 2090 cm^-1^ and 2040 cm^-1^) was observed. The reaction mixture was filtered through celite under N~2~ and the solvent was subsequently removed under vacuum. Isolated yield of the Fe(NO)~2~*L*~2~ compound: 23%. IR (toluene, cm^-1^): ν~NO~ = 1720 s and 1682 s; ^31^P{^1^H} NMR (CDCl~3~): δ 59.3 (*s*) referenced to 85% H~3~PO~4~. Suitable crystals for X-ray diffraction studies were grown by slow evaporation of a chloroform solution of the complex under nitrogen at ambient temperature. Refinement {#refinement} ========== H atoms were placed using known geometry with C---H (phenyl = 0.95 Å, methylene = 1.00 Å). Displacement parameters of phenyl H atoms were set to 1.2 times the isotropic equivalent for the bonded C. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound. Hydrogen atoms were omitted for clarity. The displacement ellipsoids were drawn at the 50% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e181 .table-wrap} ------------------------------------------- --------------------------------------- \[Fe(NO)~2~(C~18~H~12~F~3~P)~2~\]·CHCl~3~ *F*(000) = 1752 *M~r~* = 867.73 *D*~x~ = 1.579 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 5630 reflections *a* = 13.994 (5) Å θ = 2.4--25.7° *b* = 15.746 (6) Å µ = 0.79 mm^−1^ *c* = 16.716 (6) Å *T* = 100 K β = 97.651 (8)° Prism, red *V* = 3651 (2) Å^3^ 0.44 × 0.22 × 0.04 mm *Z* = 4 ------------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e318 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker APEX CCD diffractometer 6325 independent reflections Radiation source: fine-focus sealed tube 5006 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.056 ω scans θ~max~ = 25.0°, θ~min~ = 2.0° Absorption correction: multi-scan (*SADABS*; Sheldrick, 2001) *h* = −16→16 *T*~min~ = 0.721, *T*~max~ = 0.972 *k* = −18→18 22634 measured reflections *l* = −19→19 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e432 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.042 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.115 H-atom parameters constrained *S* = 1.02 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.074*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 6325 reflections (Δ/σ)~max~ = 0.001 478 parameters Δρ~max~ = 1.24 e Å^−3^ 0 restraints Δρ~min~ = −0.46 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e588 .table-wrap} ------ --------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Fe1 0.37827 (3) 0.78849 (2) 0.33064 (2) 0.01773 (13) P1 0.47836 (5) 0.73871 (4) 0.24750 (4) 0.01786 (18) P2 0.22602 (5) 0.76296 (4) 0.27435 (4) 0.01742 (18) F1 0.64936 (13) 0.98173 (11) 0.03475 (10) 0.0316 (4) F2 0.83075 (13) 0.62487 (11) 0.45867 (11) 0.0377 (5) F3 0.34188 (16) 0.44281 (11) 0.04389 (11) 0.0474 (6) F4 0.08751 (14) 0.94290 (11) −0.03130 (9) 0.0358 (5) F5 0.11645 (14) 0.40322 (10) 0.20664 (11) 0.0380 (5) F6 −0.03371 (12) 0.88266 (11) 0.50522 (10) 0.0325 (4) O1 0.39333 (16) 0.96864 (13) 0.34007 (12) 0.0307 (5) O2 0.41657 (17) 0.67401 (13) 0.46305 (13) 0.0366 (6) N1 0.38753 (17) 0.89340 (15) 0.33402 (13) 0.0213 (5) N2 0.39889 (17) 0.72178 (14) 0.40736 (14) 0.0228 (5) C1 0.5291 (2) 0.81458 (17) 0.18170 (16) 0.0185 (6) C2 0.4853 (2) 0.89178 (16) 0.16116 (16) 0.0194 (6) H2 0.4273 0.9063 0.1818 0.023\* C3 0.5248 (2) 0.94872 (17) 0.11063 (17) 0.0223 (6) H3 0.4943 1.0014 0.0961 0.027\* C4 0.6085 (2) 0.92645 (18) 0.08276 (16) 0.0227 (6) C5 0.6549 (2) 0.85066 (18) 0.10161 (17) 0.0246 (7) H5 0.7132 0.8373 0.0811 0.030\* C6 0.6146 (2) 0.79450 (18) 0.15110 (17) 0.0236 (7) H6 0.6453 0.7416 0.1645 0.028\* C7 0.5880 (2) 0.69932 (17) 0.30903 (16) 0.0195 (6) C8 0.6333 (2) 0.75458 (18) 0.36730 (17) 0.0244 (7) H8 0.6068 0.8094 0.3733 0.029\* C9 0.7164 (2) 0.73055 (19) 0.41664 (18) 0.0273 (7) H9 0.7489 0.7689 0.4549 0.033\* C10 0.7504 (2) 0.64994 (19) 0.40848 (17) 0.0258 (7) C11 0.7081 (2) 0.59301 (18) 0.35257 (18) 0.0250 (7) H11 0.7341 0.5377 0.3486 0.030\* C12 0.6262 (2) 0.61843 (18) 0.30184 (17) 0.0227 (6) H12 0.5962 0.5804 0.2621 0.027\* C13 0.4398 (2) 0.64918 (17) 0.18126 (16) 0.0200 (6) C14 0.4392 (2) 0.65064 (19) 0.09849 (17) 0.0295 (7) H14 0.4615 0.6996 0.0735 0.035\* C15 0.4061 (3) 0.5809 (2) 0.05134 (19) 0.0380 (8) H15 0.4056 0.5816 −0.0055 0.046\* C16 0.3742 (2) 0.51132 (18) 0.08944 (19) 0.0317 (8) C17 0.3733 (2) 0.50733 (17) 0.17158 (17) 0.0233 (6) H17 0.3514 0.4579 0.1962 0.028\* C18 0.4053 (2) 0.57763 (17) 0.21709 (17) 0.0218 (6) H18 0.4037 0.5771 0.2737 0.026\* C19 0.1808 (2) 0.82030 (16) 0.18227 (16) 0.0197 (6) C20 0.0885 (2) 0.85538 (18) 0.16838 (17) 0.0243 (7) H20 0.0467 0.8507 0.2085 0.029\* C21 0.0571 (2) 0.89696 (19) 0.09674 (18) 0.0291 (7) H21 −0.0056 0.9212 0.0874 0.035\* C22 0.1186 (2) 0.90232 (18) 0.03967 (16) 0.0251 (7) C23 0.2093 (2) 0.86878 (18) 0.04979 (17) 0.0267 (7) H23 0.2501 0.8738 0.0089 0.032\* C24 0.2401 (2) 0.82711 (18) 0.12187 (17) 0.0233 (6) H24 0.3028 0.8028 0.1302 0.028\* C25 0.19084 (19) 0.65336 (17) 0.25032 (16) 0.0191 (6) C26 0.1510 (2) 0.62711 (17) 0.17335 (16) 0.0208 (6) H26 0.1403 0.6675 0.1309 0.025\* C27 0.1267 (2) 0.54248 (18) 0.15809 (17) 0.0253 (7) H27 0.1007 0.5243 0.1055 0.030\* C28 0.1411 (2) 0.48607 (18) 0.22068 (18) 0.0265 (7) C29 0.1803 (2) 0.50879 (18) 0.29794 (18) 0.0249 (7) H29 0.1890 0.4680 0.3402 0.030\* C30 0.2062 (2) 0.59248 (17) 0.31186 (17) 0.0206 (6) H30 0.2350 0.6092 0.3642 0.025\* C31 0.1431 (2) 0.79517 (17) 0.34546 (16) 0.0188 (6) C32 0.0698 (2) 0.74415 (18) 0.36738 (17) 0.0226 (6) H32 0.0600 0.6890 0.3447 0.027\* C33 0.0109 (2) 0.77292 (18) 0.42185 (17) 0.0234 (6) H33 −0.0388 0.7380 0.4374 0.028\* C34 0.0260 (2) 0.85280 (19) 0.45277 (17) 0.0240 (7) C35 0.0971 (2) 0.90590 (18) 0.43289 (17) 0.0253 (7) H35 0.1051 0.9613 0.4553 0.030\* C36 0.1564 (2) 0.87624 (18) 0.37938 (17) 0.0237 (6) H36 0.2069 0.9113 0.3654 0.028\* Cl1S 0.22226 (6) 0.10408 (5) 0.38685 (5) 0.0335 (2) Cl2S 0.13359 (6) 0.23683 (5) 0.28321 (6) 0.0417 (2) Cl3S 0.08805 (6) 0.06170 (5) 0.24465 (5) 0.0344 (2) C1S 0.1178 (2) 0.13555 (19) 0.32295 (19) 0.0297 (7) H1S 0.0631 0.1383 0.3557 0.036\* ------ --------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1577 .table-wrap} ------ ------------- ------------- ------------- -------------- --------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Fe1 0.0201 (2) 0.0199 (2) 0.0119 (2) 0.00032 (16) −0.00246 (16) −0.00012 (15) P1 0.0197 (4) 0.0194 (4) 0.0134 (4) 0.0006 (3) −0.0022 (3) −0.0002 (3) P2 0.0198 (4) 0.0196 (4) 0.0118 (4) 0.0009 (3) −0.0019 (3) 0.0005 (3) F1 0.0371 (11) 0.0325 (9) 0.0249 (10) −0.0067 (8) 0.0033 (8) 0.0082 (8) F2 0.0271 (10) 0.0443 (11) 0.0363 (11) 0.0028 (8) −0.0156 (8) 0.0083 (9) F3 0.0810 (16) 0.0270 (10) 0.0271 (10) −0.0122 (9) −0.0192 (10) −0.0062 (8) F4 0.0521 (12) 0.0392 (10) 0.0137 (9) 0.0141 (9) −0.0048 (8) 0.0082 (7) F5 0.0498 (12) 0.0205 (9) 0.0384 (11) −0.0079 (8) −0.0137 (9) 0.0008 (8) F6 0.0336 (11) 0.0411 (11) 0.0245 (10) 0.0029 (8) 0.0098 (8) −0.0061 (8) O1 0.0412 (14) 0.0221 (11) 0.0293 (12) −0.0027 (10) 0.0064 (10) −0.0002 (9) O2 0.0474 (15) 0.0364 (12) 0.0228 (12) −0.0005 (11) −0.0065 (10) 0.0143 (10) N1 0.0237 (14) 0.0232 (14) 0.0162 (13) 0.0005 (10) −0.0005 (10) −0.0008 (10) N2 0.0244 (14) 0.0237 (12) 0.0196 (14) −0.0033 (10) 0.0006 (11) −0.0007 (10) C1 0.0223 (16) 0.0218 (14) 0.0102 (14) −0.0025 (12) −0.0025 (11) −0.0029 (11) C2 0.0203 (15) 0.0229 (14) 0.0136 (14) 0.0015 (12) −0.0024 (11) −0.0035 (11) C3 0.0267 (17) 0.0217 (14) 0.0161 (15) 0.0004 (12) −0.0054 (12) 0.0010 (12) C4 0.0286 (17) 0.0266 (15) 0.0115 (14) −0.0069 (13) −0.0021 (12) −0.0006 (12) C5 0.0241 (17) 0.0294 (16) 0.0201 (16) −0.0001 (13) 0.0020 (13) −0.0010 (13) C6 0.0272 (17) 0.0216 (15) 0.0205 (16) 0.0044 (12) −0.0013 (13) 0.0030 (12) C7 0.0187 (15) 0.0233 (14) 0.0153 (15) 0.0000 (12) −0.0018 (11) 0.0023 (11) C8 0.0259 (17) 0.0263 (15) 0.0195 (16) 0.0019 (13) −0.0022 (13) −0.0006 (12) C9 0.0263 (17) 0.0336 (17) 0.0194 (16) −0.0043 (13) −0.0070 (13) −0.0016 (13) C10 0.0181 (16) 0.0358 (17) 0.0211 (16) 0.0007 (13) −0.0054 (12) 0.0097 (13) C11 0.0237 (17) 0.0229 (15) 0.0281 (17) 0.0049 (13) 0.0020 (13) 0.0051 (13) C12 0.0217 (16) 0.0264 (15) 0.0193 (16) −0.0016 (12) 0.0000 (12) −0.0011 (12) C13 0.0199 (15) 0.0212 (14) 0.0174 (15) 0.0032 (12) −0.0026 (12) −0.0019 (11) C14 0.043 (2) 0.0256 (16) 0.0171 (16) −0.0029 (14) −0.0052 (14) 0.0025 (12) C15 0.064 (2) 0.0313 (17) 0.0140 (16) −0.0036 (16) −0.0114 (15) −0.0002 (13) C16 0.045 (2) 0.0210 (15) 0.0239 (17) −0.0020 (14) −0.0135 (14) −0.0052 (13) C17 0.0229 (16) 0.0211 (14) 0.0239 (17) 0.0002 (12) −0.0042 (12) 0.0035 (12) C18 0.0208 (16) 0.0256 (15) 0.0175 (15) 0.0041 (12) −0.0026 (12) −0.0013 (12) C19 0.0263 (16) 0.0170 (13) 0.0137 (14) −0.0022 (12) −0.0048 (12) 0.0010 (11) C20 0.0246 (17) 0.0269 (15) 0.0210 (16) 0.0032 (13) 0.0009 (12) −0.0006 (12) C21 0.0310 (18) 0.0339 (17) 0.0205 (16) 0.0123 (14) −0.0042 (13) 0.0015 (13) C22 0.0393 (19) 0.0224 (15) 0.0114 (15) 0.0043 (13) −0.0043 (13) 0.0016 (11) C23 0.0354 (19) 0.0306 (16) 0.0135 (15) −0.0016 (14) 0.0007 (13) 0.0020 (12) C24 0.0221 (16) 0.0278 (15) 0.0185 (15) 0.0018 (12) −0.0023 (12) 0.0016 (12) C25 0.0153 (15) 0.0231 (14) 0.0183 (15) 0.0001 (11) −0.0004 (11) −0.0007 (12) C26 0.0215 (16) 0.0230 (14) 0.0165 (15) 0.0020 (12) −0.0023 (12) 0.0019 (11) C27 0.0274 (17) 0.0265 (16) 0.0193 (16) 0.0000 (13) −0.0067 (13) −0.0031 (12) C28 0.0259 (17) 0.0232 (15) 0.0285 (17) −0.0020 (13) −0.0032 (13) −0.0017 (13) C29 0.0239 (17) 0.0271 (15) 0.0227 (16) 0.0003 (13) −0.0003 (13) 0.0076 (12) C30 0.0205 (16) 0.0244 (14) 0.0153 (15) 0.0004 (12) −0.0036 (12) −0.0004 (11) C31 0.0207 (16) 0.0233 (14) 0.0111 (14) 0.0035 (12) −0.0032 (11) 0.0008 (11) C32 0.0224 (16) 0.0245 (15) 0.0189 (16) 0.0007 (12) −0.0047 (12) 0.0003 (12) C33 0.0210 (16) 0.0282 (16) 0.0199 (16) −0.0009 (12) −0.0010 (12) 0.0015 (12) C34 0.0246 (16) 0.0336 (17) 0.0136 (15) 0.0066 (13) 0.0016 (12) −0.0002 (12) C35 0.0294 (17) 0.0239 (15) 0.0222 (16) 0.0014 (13) 0.0017 (13) −0.0039 (12) C36 0.0263 (17) 0.0253 (15) 0.0193 (15) −0.0022 (13) 0.0019 (13) −0.0016 (12) Cl1S 0.0312 (5) 0.0322 (4) 0.0338 (5) −0.0014 (3) −0.0086 (3) 0.0084 (3) Cl2S 0.0412 (5) 0.0307 (4) 0.0479 (6) −0.0011 (4) −0.0140 (4) 0.0073 (4) Cl3S 0.0350 (5) 0.0372 (4) 0.0297 (4) −0.0069 (3) −0.0005 (3) −0.0039 (3) C1S 0.0296 (18) 0.0324 (17) 0.0253 (17) 0.0019 (14) −0.0027 (13) 0.0001 (14) ------ ------------- ------------- ------------- -------------- --------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2600 .table-wrap} ----------------------- -------------- ----------------------- ------------- Fe1---N2 1.653 (2) C14---H14 0.9500 Fe1---N1 1.657 (2) C15---C16 1.371 (4) Fe1---P1 2.2420 (10) C15---H15 0.9500 Fe1---P2 2.2478 (11) C16---C17 1.376 (4) P1---C13 1.829 (3) C17---C18 1.383 (4) P1---C1 1.830 (3) C17---H17 0.9500 P1---C7 1.837 (3) C18---H18 0.9500 P2---C19 1.824 (3) C19---C24 1.394 (4) P2---C25 1.825 (3) C19---C20 1.396 (4) P2---C31 1.840 (3) C20---C21 1.384 (4) F1---C4 1.361 (3) C20---H20 0.9500 F2---C10 1.369 (3) C21---C22 1.370 (4) F3---C16 1.363 (3) C21---H21 0.9500 F4---C22 1.367 (3) C22---C23 1.365 (4) F5---C28 1.362 (3) C23---C24 1.389 (4) F6---C34 1.372 (3) C23---H23 0.9500 O1---N1 1.191 (3) C24---H24 0.9500 O2---N2 1.197 (3) C25---C26 1.395 (4) C1---C2 1.384 (4) C25---C30 1.402 (4) C1---C6 1.399 (4) C26---C27 1.390 (4) C2---C3 1.396 (4) C26---H26 0.9500 C2---H2 0.9500 C27---C28 1.367 (4) C3---C4 1.362 (4) C27---H27 0.9500 C3---H3 0.9500 C28---C29 1.381 (4) C4---C5 1.375 (4) C29---C30 1.378 (4) C5---C6 1.381 (4) C29---H29 0.9500 C5---H5 0.9500 C30---H30 0.9500 C6---H6 0.9500 C31---C32 1.390 (4) C7---C12 1.393 (4) C31---C36 1.399 (4) C7---C8 1.394 (4) C32---C33 1.383 (4) C8---C9 1.387 (4) C32---H32 0.9500 C8---H8 0.9500 C33---C34 1.366 (4) C9---C10 1.369 (4) C33---H33 0.9500 C9---H9 0.9500 C34---C35 1.374 (4) C10---C11 1.371 (4) C35---C36 1.380 (4) C11---C12 1.391 (4) C35---H35 0.9500 C11---H11 0.9500 C36---H36 0.9500 C12---H12 0.9500 Cl1S---C1S 1.763 (3) C13---C14 1.383 (4) Cl2S---C1S 1.753 (3) C13---C18 1.392 (4) Cl3S---C1S 1.759 (3) C14---C15 1.395 (4) C1S---H1S 1.0000 N2---Fe1---N1 127.02 (11) C15---C16---C17 123.1 (3) N2---Fe1---P1 101.53 (9) C16---C17---C18 117.8 (3) N1---Fe1---P1 108.49 (8) C16---C17---H17 121.1 N2---Fe1---P2 105.60 (9) C18---C17---H17 121.1 N1---Fe1---P2 104.96 (9) C17---C18---C13 121.1 (3) P1---Fe1---P2 108.27 (4) C17---C18---H18 119.5 C13---P1---C1 104.24 (13) C13---C18---H18 119.5 C13---P1---C7 103.62 (13) C24---C19---C20 118.5 (3) C1---P1---C7 101.25 (13) C24---C19---P2 118.4 (2) C13---P1---Fe1 119.13 (10) C20---C19---P2 123.1 (2) C1---P1---Fe1 117.95 (9) C21---C20---C19 120.7 (3) C7---P1---Fe1 108.36 (9) C21---C20---H20 119.6 C19---P2---C25 103.27 (12) C19---C20---H20 119.6 C19---P2---C31 103.37 (13) C22---C21---C20 118.4 (3) C25---P2---C31 103.19 (12) C22---C21---H21 120.8 C19---P2---Fe1 117.89 (10) C20---C21---H21 120.8 C25---P2---Fe1 118.31 (9) C23---C22---F4 118.2 (3) C31---P2---Fe1 108.92 (9) C23---C22---C21 123.4 (3) O1---N1---Fe1 177.0 (2) F4---C22---C21 118.4 (3) O2---N2---Fe1 178.1 (2) C22---C23---C24 117.8 (3) C2---C1---C6 118.7 (3) C22---C23---H23 121.1 C2---C1---P1 121.9 (2) C24---C23---H23 121.1 C6---C1---P1 119.4 (2) C23---C24---C19 121.2 (3) C1---C2---C3 121.1 (3) C23---C24---H24 119.4 C1---C2---H2 119.5 C19---C24---H24 119.4 C3---C2---H2 119.5 C26---C25---C30 118.5 (3) C4---C3---C2 118.0 (3) C26---C25---P2 123.1 (2) C4---C3---H3 121.0 C30---C25---P2 118.4 (2) C2---C3---H3 121.0 C27---C26---C25 120.7 (3) F1---C4---C3 119.0 (3) C27---C26---H26 119.6 F1---C4---C5 117.9 (3) C25---C26---H26 119.6 C3---C4---C5 123.1 (3) C28---C27---C26 118.3 (3) C4---C5---C6 118.3 (3) C28---C27---H27 120.8 C4---C5---H5 120.8 C26---C27---H27 120.8 C6---C5---H5 120.8 F5---C28---C27 118.8 (3) C5---C6---C1 120.8 (3) F5---C28---C29 118.0 (3) C5---C6---H6 119.6 C27---C28---C29 123.2 (3) C1---C6---H6 119.6 C30---C29---C28 117.9 (3) C12---C7---C8 119.1 (3) C30---C29---H29 121.0 C12---C7---P1 124.2 (2) C28---C29---H29 121.0 C8---C7---P1 116.6 (2) C29---C30---C25 121.3 (3) C9---C8---C7 120.9 (3) C29---C30---H30 119.4 C9---C8---H8 119.6 C25---C30---H30 119.4 C7---C8---H8 119.6 C32---C31---C36 118.9 (3) C10---C9---C8 118.0 (3) C32---C31---P2 124.2 (2) C10---C9---H9 121.0 C36---C31---P2 116.9 (2) C8---C9---H9 121.0 C33---C32---C31 120.6 (3) F2---C10---C9 118.3 (3) C33---C32---H32 119.7 F2---C10---C11 118.3 (3) C31---C32---H32 119.7 C9---C10---C11 123.4 (3) C34---C33---C32 118.4 (3) C10---C11---C12 118.2 (3) C34---C33---H33 120.8 C10---C11---H11 120.9 C32---C33---H33 120.8 C12---C11---H11 120.9 C33---C34---F6 118.7 (3) C11---C12---C7 120.4 (3) C33---C34---C35 123.3 (3) C11---C12---H12 119.8 F6---C34---C35 117.9 (3) C7---C12---H12 119.8 C34---C35---C36 117.9 (3) C14---C13---C18 119.2 (3) C34---C35---H35 121.0 C14---C13---P1 123.7 (2) C36---C35---H35 121.0 C18---C13---P1 117.0 (2) C35---C36---C31 120.8 (3) C13---C14---C15 120.6 (3) C35---C36---H36 119.6 C13---C14---H14 119.7 C31---C36---H36 119.6 C15---C14---H14 119.7 Cl2S---C1S---Cl3S 110.41 (17) C16---C15---C14 118.1 (3) Cl2S---C1S---Cl1S 110.44 (17) C16---C15---H15 121.0 Cl3S---C1S---Cl1S 111.10 (17) C14---C15---H15 121.0 Cl2S---C1S---H1S 108.3 F3---C16---C15 118.5 (3) Cl3S---C1S---H1S 108.3 F3---C16---C17 118.3 (3) Cl1S---C1S---H1S 108.3 N2---Fe1---P1---C13 82.58 (13) P1---C13---C14---C15 −178.0 (3) N1---Fe1---P1---C13 −141.68 (13) C13---C14---C15---C16 0.1 (5) P2---Fe1---P1---C13 −28.29 (11) C14---C15---C16---F3 −179.9 (3) N2---Fe1---P1---C1 −149.51 (13) C14---C15---C16---C17 0.2 (5) N1---Fe1---P1---C1 −13.77 (13) F3---C16---C17---C18 −179.3 (3) P2---Fe1---P1---C1 99.61 (10) C15---C16---C17---C18 0.7 (5) N2---Fe1---P1---C7 −35.38 (12) C16---C17---C18---C13 −1.7 (4) N1---Fe1---P1---C7 100.36 (13) C14---C13---C18---C17 2.0 (4) P2---Fe1---P1---C7 −146.25 (10) P1---C13---C18---C17 179.1 (2) N2---Fe1---P2---C19 −175.56 (13) C25---P2---C19---C24 −88.2 (2) N1---Fe1---P2---C19 48.24 (13) C31---P2---C19---C24 164.5 (2) P1---Fe1---P2---C19 −67.47 (11) Fe1---P2---C19---C24 44.3 (2) N2---Fe1---P2---C25 −50.12 (13) C25---P2---C19---C20 89.7 (2) N1---Fe1---P2---C25 173.69 (13) C31---P2---C19---C20 −17.6 (3) P1---Fe1---P2---C25 57.98 (11) Fe1---P2---C19---C20 −137.8 (2) N2---Fe1---P2---C31 67.18 (13) C24---C19---C20---C21 −0.9 (4) N1---Fe1---P2---C31 −69.01 (12) P2---C19---C20---C21 −178.8 (2) P1---Fe1---P2---C31 175.28 (9) C19---C20---C21---C22 0.4 (4) C13---P1---C1---C2 112.3 (2) C20---C21---C22---C23 0.0 (5) C7---P1---C1---C2 −140.4 (2) C20---C21---C22---F4 179.6 (3) Fe1---P1---C1---C2 −22.4 (3) F4---C22---C23---C24 −179.5 (2) C13---P1---C1---C6 −67.8 (2) C21---C22---C23---C24 0.1 (5) C7---P1---C1---C6 39.5 (2) C22---C23---C24---C19 −0.5 (4) Fe1---P1---C1---C6 157.51 (19) C20---C19---C24---C23 0.9 (4) C6---C1---C2---C3 0.3 (4) P2---C19---C24---C23 179.0 (2) P1---C1---C2---C3 −179.7 (2) C19---P2---C25---C26 7.5 (3) C1---C2---C3---C4 −0.7 (4) C31---P2---C25---C26 114.9 (2) C2---C3---C4---F1 −178.7 (2) Fe1---P2---C25---C26 −124.8 (2) C2---C3---C4---C5 0.5 (4) C19---P2---C25---C30 −173.6 (2) F1---C4---C5---C6 179.2 (2) C31---P2---C25---C30 −66.2 (2) C3---C4---C5---C6 0.1 (4) Fe1---P2---C25---C30 54.1 (2) C4---C5---C6---C1 −0.4 (4) C30---C25---C26---C27 0.2 (4) C2---C1---C6---C5 0.2 (4) P2---C25---C26---C27 179.1 (2) P1---C1---C6---C5 −179.7 (2) C25---C26---C27---C28 1.2 (4) C13---P1---C7---C12 −0.2 (3) C26---C27---C28---F5 179.2 (3) C1---P1---C7---C12 −108.0 (3) C26---C27---C28---C29 −1.2 (5) Fe1---P1---C7---C12 127.2 (2) F5---C28---C29---C30 179.3 (3) C13---P1---C7---C8 −178.8 (2) C27---C28---C29---C30 −0.3 (5) C1---P1---C7---C8 73.3 (2) C28---C29---C30---C25 1.8 (4) Fe1---P1---C7---C8 −51.4 (2) C26---C25---C30---C29 −1.8 (4) C12---C7---C8---C9 1.3 (4) P2---C25---C30---C29 179.3 (2) P1---C7---C8---C9 −180.0 (2) C19---P2---C31---C32 103.9 (2) C7---C8---C9---C10 −2.5 (4) C25---P2---C31---C32 −3.4 (3) C8---C9---C10---F2 −178.0 (3) Fe1---P2---C31---C32 −130.0 (2) C8---C9---C10---C11 2.1 (5) C19---P2---C31---C36 −76.6 (2) F2---C10---C11---C12 179.7 (2) C25---P2---C31---C36 176.1 (2) C9---C10---C11---C12 −0.4 (5) Fe1---P2---C31---C36 49.6 (2) C10---C11---C12---C7 −0.9 (4) C36---C31---C32---C33 0.0 (4) C8---C7---C12---C11 0.4 (4) P2---C31---C32---C33 179.5 (2) P1---C7---C12---C11 −178.2 (2) C31---C32---C33---C34 0.7 (4) C1---P1---C13---C14 −8.4 (3) C32---C33---C34---F6 178.3 (2) C7---P1---C13---C14 −114.0 (3) C32---C33---C34---C35 −0.4 (4) Fe1---P1---C13---C14 125.6 (2) C33---C34---C35---C36 −0.5 (4) C1---P1---C13---C18 174.7 (2) F6---C34---C35---C36 −179.3 (2) C7---P1---C13---C18 69.1 (2) C34---C35---C36---C31 1.2 (4) Fe1---P1---C13---C18 −51.3 (2) C32---C31---C36---C35 −0.9 (4) C18---C13---C14---C15 −1.2 (5) P2---C31---C36---C35 179.5 (2) ----------------------- -------------- ----------------------- ------------- :::

PubMed Central

2024-06-05T04:04:17.686083

2011-2-12

PMC3051983

Related literature {#sec1} ================== For the sulfanilamide moiety in sulfonamide drugs, see; Maren (1976[@bb6]). For its ability to form hydrogen bonds in the solid state, see; Yang & Guillory (1972[@bb11]). For hydrogen-bonding preferences of sulfonamides, see; Adsmond & Grant (2001[@bb1]). For the effect of substituents on the crystal structures of sulfono­amides, see: Gowda *et al.* (2008**a*[@bb4],b* [@bb5], 2010[@bb3]) Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~9~H~10~ClNO~3~S*M* *~r~* = 247.69Triclinic,*a* = 7.4439 (8) Å*b* = 7.5195 (8) Å*c* = 10.519 (1) Åα = 93.64 (1)°β = 109.72 (1)°γ = 102.52 (1)°*V* = 535.07 (10) Å^3^*Z* = 2Cu *K*α radiationμ = 4.90 mm^−1^*T* = 299 K0.50 × 0.40 × 0.18 mm ### Data collection {#sec2.1.2} Enraf--Nonius CAD-4 diffractometerAbsorption correction: ψ scan (North *et al.*, 1968[@bb7]) *T* ~min~ = 0.193, *T* ~max~ = 0.4733727 measured reflections1891 independent reflections1771 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.0513 standard reflections every 120 min intensity decay: 0.5% ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.050*wR*(*F* ^2^) = 0.137*S* = 1.081891 reflections141 parameters1 restraintH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.52 e Å^−3^Δρ~min~ = −0.57 e Å^−3^ {#d5e436} Data collection: *CAD-4-PC* (Enraf--Nonius, 1996[@bb2]); cell refinement: *CAD-4-PC*; data reduction: *REDU4* (Stoe & Cie, 1987[@bb10]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb8]); molecular graphics: *PLATON* (Spek, 2009[@bb9]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811003655/ds2090sup1.cif](http://dx.doi.org/10.1107/S1600536811003655/ds2090sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811003655/ds2090Isup2.hkl](http://dx.doi.org/10.1107/S1600536811003655/ds2090Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?ds2090&file=ds2090sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?ds2090sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?ds2090&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [DS2090](http://scripts.iucr.org/cgi-bin/sendsup?ds2090)). KS thanks the University Grants Commission, Government of India, New Delhi, for the award of a research fellowship under its faculty improvement program. Comment ======= The molecular structures of sulfonamide drugs contain the sulfanilamide moiety (Maren, 1976). The propensity for hydrogen bonding in the solid state, due to the presence of various hydrogen bond donors and acceptors can give rise to polymorphism (Yang & Guillory, 1972). The hydrogen bonding preferences of sulfonamides has also been investigated (Adsmond & Grant, 2001). The nature and position of substituents play a significant role on the crystal structures of *N*-(aryl)sulfonoamides (Gowda *et al.*, 2008**a*,b*, 2010). As a part of studying the substituent effects on the structures of this class of compounds, the structure of 2-chloro-*N*-(2-methylphenylsulfonyl)- acetamide (I) has been determined. The conformations of the N---H and C=O bonds of the SO~2~---NH---CO---C segment in the structure are anti to each other (Fig. 1), similar to that observed in *N*-(phenylsulfonyl)acetamide (II)(Gowda *et al.*, 2010), *N*-(phenylsulfonyl)- 2,2-dichloroacetamide (III) (Gowda *et al.*, 2008*b*) and *N*-(4-methylphenylsulfonyl)-2,2-dichloroacetamide (IV) (Gowda *et al.*, 2008*a*). The molecule in (I) is bent at the *S*-atom with a C1---S1---N1---C7 torsion angle of -67.0 (3)°, compared to the values of -58.8 (4)° in (II), -66.3 (3)° in (III) and -71.1 (2)° in (IV). Further, the dihedral angle between the benzene ring and the SO2---NH---CO---C group in (I) is 78.9 (1)°, compared to the values of 89.0 (2)° in (II), 79.8 (1)° in (III) and 81.0 (1)° in (IV), The structure exhibits both the intramolecular N---H···Cl and the intermolecular N---H···O(S) hydrogen bonds. In the crystal structure, the pairs of intermolecular N--H···O hydrogen bonds (Table 1) link the molecules through inversion-related dimers into zigzag chains running in the *bc*-plane. Part of the crystal structure is shown in Fig. 2. Experimental {#experimental} ============ The title compound was prepared by refluxing 2-methylbenzenesulfonamide (0.10 mole) with an excess of chloroacetyl chloride (0.20 mole) for about an hour on a water bath. The reaction mixture was cooled and poured into ice cold water. The resulting solid was separated, washed thoroughly with water and dissolved in warm dilute sodium hydrogen carbonate solution. The title compound was reprecipitated by acidifying the filtered solution with glacial acetic acid. It was filtered, dried and recrystallized from ethanol. The purity of the compound was checked by determining its melting point. It was further characterized by recording its infrared spectra. Prism like colorless single crystals of the title compound used in X-ray diffraction studies were obtained from a slow evaporation of an ethanolic solution of the compound. Refinement {#refinement} ========== The H atom of the NH group was located in a difference map and later restrained to the distance N---H = 0.86 (3) Å. The other H atoms were positioned with idealized geometry using a riding model with C---H = 0.93--0.97 Å. All H atoms were refined with isotropic displacement parameters (set to 1.2 times of the *U*~eq~ of the parent atom). The U^ij^ components of C3, C4 and C5 were restrained to approximate isotropic behavoir. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Molecular structure of the title compound, showing the atom- labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Molecular packing in the title compound. Hydrogen bonds are shown as dashed lines. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e162 .table-wrap} ------------------------ ------------------------------------- C~9~H~10~ClNO~3~S *Z* = 2 *M~r~* = 247.69 *F*(000) = 256 Triclinic, *P*1 *D*~x~ = 1.537 Mg m^−3^ Hall symbol: -P 1 Cu *K*α radiation, λ = 1.54180 Å *a* = 7.4439 (8) Å Cell parameters from 25 reflections *b* = 7.5195 (8) Å θ = 7.0--23.1° *c* = 10.519 (1) Å µ = 4.90 mm^−1^ α = 93.64 (1)° *T* = 299 K β = 109.72 (1)° Prism, colourless γ = 102.52 (1)° 0.50 × 0.40 × 0.18 mm *V* = 535.07 (10) Å^3^ ------------------------ ------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e296 .table-wrap} ------------------------------------------------------ -------------------------------------- Enraf--Nonius CAD-4 diffractometer 1771 reflections with *I* \> 2σ(*I*) Radiation source: fine-focus sealed tube *R*~int~ = 0.051 graphite θ~max~ = 66.9°, θ~min~ = 4.5° ω/2θ scans *h* = −8→8 Absorption correction: ψ scan (North *et al.*, 1968) *k* = −8→8 *T*~min~ = 0.193, *T*~max~ = 0.473 *l* = −12→12 3727 measured reflections 3 standard reflections every 120 min 1891 independent reflections intensity decay: 0.5% ------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e421 .table-wrap} ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.050 H atoms treated by a mixture of independent and constrained refinement *wR*(*F*^2^) = 0.137 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0853*P*)^2^ + 0.2427*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.08 (Δ/σ)~max~ \< 0.001 1891 reflections Δρ~max~ = 0.52 e Å^−3^ 141 parameters Δρ~min~ = −0.57 e Å^−3^ 1 restraint Extinction correction: *SHELXL97* (Sheldrick, 2008), Fc^\*^=kFc\[1+0.001xFc^2^λ^3^/sin(2θ)\]^-1/4^ Primary atom site location: structure-invariant direct methods Extinction coefficient: 0.028 (3) ---------------------------------------------------------------- ---------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e602 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e701 .table-wrap} ----- -------------- ------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 0.4813 (4) 0.6426 (3) 0.3198 (2) 0.0356 (6) C2 0.6844 (5) 0.7012 (3) 0.3580 (3) 0.0465 (7) C3 0.7891 (6) 0.7927 (4) 0.4905 (3) 0.0674 (10) H3 0.9259 0.8321 0.5206 0.081\* C4 0.6944 (8) 0.8259 (5) 0.5778 (3) 0.0764 (13) H4 0.7682 0.8892 0.6653 0.092\* C5 0.4938 (8) 0.7680 (5) 0.5388 (3) 0.0754 (12) H5 0.4320 0.7916 0.5992 0.090\* C6 0.3832 (6) 0.6737 (4) 0.4081 (3) 0.0531 (8) H6 0.2468 0.6321 0.3800 0.064\* C7 0.2227 (4) 0.8123 (3) 0.0563 (2) 0.0336 (5) C8 0.1973 (4) 0.9327 (3) −0.0539 (3) 0.0397 (6) H8A 0.2593 1.0596 −0.0110 0.048\* H8B 0.0574 0.9224 −0.0984 0.048\* C9 0.7974 (5) 0.6716 (5) 0.2685 (4) 0.0622 (8) H9A 0.7241 0.6847 0.1766 0.075\* H9B 0.8181 0.5500 0.2704 0.075\* H9C 0.9226 0.7610 0.3010 0.075\* N1 0.3146 (3) 0.6745 (3) 0.05184 (19) 0.0327 (5) H1N 0.366 (4) 0.660 (4) −0.001 (3) 0.039\* O1 0.4251 (3) 0.3986 (2) 0.11017 (18) 0.0450 (5) O2 0.1386 (3) 0.4445 (3) 0.1603 (2) 0.0516 (5) O3 0.1615 (3) 0.8425 (3) 0.14615 (19) 0.0504 (5) Cl1 0.29367 (12) 0.88507 (9) −0.18091 (7) 0.0525 (3) S1 0.32891 (8) 0.51904 (7) 0.15752 (5) 0.0320 (3) ----- -------------- ------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1049 .table-wrap} ----- ------------- ------------- ------------- ------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0487 (16) 0.0278 (10) 0.0267 (11) 0.0120 (10) 0.0075 (10) 0.0051 (8) C2 0.0512 (18) 0.0318 (12) 0.0458 (14) 0.0066 (11) 0.0055 (12) 0.0113 (10) C3 0.076 (3) 0.0459 (16) 0.0511 (18) 0.0051 (15) −0.0078 (16) 0.0068 (13) C4 0.112 (4) 0.0511 (18) 0.0400 (17) 0.017 (2) −0.0020 (19) −0.0004 (13) C5 0.137 (4) 0.070 (2) 0.0381 (16) 0.051 (2) 0.039 (2) 0.0132 (14) C6 0.076 (2) 0.0538 (16) 0.0392 (14) 0.0305 (15) 0.0231 (14) 0.0143 (11) C7 0.0357 (13) 0.0325 (11) 0.0310 (11) 0.0118 (9) 0.0084 (9) 0.0030 (8) C8 0.0451 (16) 0.0363 (12) 0.0417 (13) 0.0181 (11) 0.0150 (11) 0.0101 (10) C9 0.0466 (19) 0.0606 (18) 0.076 (2) 0.0087 (14) 0.0209 (15) 0.0130 (15) N1 0.0407 (12) 0.0335 (10) 0.0287 (9) 0.0161 (8) 0.0141 (8) 0.0063 (8) O1 0.0661 (14) 0.0323 (9) 0.0412 (9) 0.0231 (9) 0.0185 (9) 0.0057 (7) O2 0.0432 (12) 0.0498 (11) 0.0537 (11) −0.0001 (9) 0.0134 (9) 0.0151 (8) O3 0.0648 (14) 0.0597 (12) 0.0438 (10) 0.0355 (10) 0.0277 (10) 0.0130 (8) Cl1 0.0744 (6) 0.0547 (5) 0.0462 (4) 0.0325 (4) 0.0314 (4) 0.0216 (3) S1 0.0384 (4) 0.0259 (4) 0.0298 (4) 0.0087 (3) 0.0093 (3) 0.0049 (2) ----- ------------- ------------- ------------- ------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1328 .table-wrap} -------------------- ------------ -------------------- -------------- C1---C2 1.386 (4) C7---N1 1.367 (3) C1---C6 1.398 (4) C7---C8 1.502 (3) C1---S1 1.760 (2) C8---Cl1 1.768 (3) C2---C3 1.392 (4) C8---H8A 0.9700 C2---C9 1.494 (5) C8---H8B 0.9700 C3---C4 1.374 (7) C9---H9A 0.9600 C3---H3 0.9300 C9---H9B 0.9600 C4---C5 1.367 (6) C9---H9C 0.9600 C4---H4 0.9300 N1---S1 1.6590 (19) C5---C6 1.389 (5) N1---H1N 0.79 (2) C5---H5 0.9300 O1---S1 1.4303 (18) C6---H6 0.9300 O2---S1 1.417 (2) C7---O3 1.208 (3) C2---C1---C6 122.5 (2) C7---C8---Cl1 116.35 (17) C2---C1---S1 122.3 (2) C7---C8---H8A 108.2 C6---C1---S1 115.3 (2) Cl1---C8---H8A 108.2 C1---C2---C3 116.8 (3) C7---C8---H8B 108.2 C1---C2---C9 124.9 (2) Cl1---C8---H8B 108.2 C3---C2---C9 118.3 (3) H8A---C8---H8B 107.4 C4---C3---C2 121.3 (4) C2---C9---H9A 109.5 C4---C3---H3 119.4 C2---C9---H9B 109.5 C2---C3---H3 119.4 H9A---C9---H9B 109.5 C5---C4---C3 121.4 (3) C2---C9---H9C 109.5 C5---C4---H4 119.3 H9A---C9---H9C 109.5 C3---C4---H4 119.3 H9B---C9---H9C 109.5 C4---C5---C6 119.4 (3) C7---N1---S1 123.27 (17) C4---C5---H5 120.3 C7---N1---H1N 124 (2) C6---C5---H5 120.3 S1---N1---H1N 113 (2) C5---C6---C1 118.7 (4) O2---S1---O1 118.71 (12) C5---C6---H6 120.7 O2---S1---N1 108.92 (11) C1---C6---H6 120.7 O1---S1---N1 103.64 (10) O3---C7---N1 122.6 (2) O2---S1---C1 108.50 (12) O3---C7---C8 118.3 (2) O1---S1---C1 110.83 (12) N1---C7---C8 119.1 (2) N1---S1---C1 105.34 (10) C6---C1---C2---C3 0.5 (4) N1---C7---C8---Cl1 −0.7 (3) S1---C1---C2---C3 −178.1 (2) O3---C7---N1---S1 7.4 (4) C6---C1---C2---C9 179.8 (3) C8---C7---N1---S1 −172.97 (18) S1---C1---C2---C9 1.2 (4) C7---N1---S1---O2 49.3 (2) C1---C2---C3---C4 −1.2 (4) C7---N1---S1---O1 176.60 (19) C9---C2---C3---C4 179.4 (3) C7---N1---S1---C1 −66.9 (2) C2---C3---C4---C5 1.0 (5) C2---C1---S1---O2 167.1 (2) C3---C4---C5---C6 0.0 (5) C6---C1---S1---O2 −11.5 (2) C4---C5---C6---C1 −0.7 (5) C2---C1---S1---O1 35.1 (2) C2---C1---C6---C5 0.4 (4) C6---C1---S1---O1 −143.56 (19) S1---C1---C6---C5 179.1 (2) C2---C1---S1---N1 −76.3 (2) O3---C7---C8---Cl1 178.8 (2) C6---C1---S1---N1 105.0 (2) -------------------- ------------ -------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1788 .table-wrap} ------------------ ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1N···O1^i^ 0.79 (2) 2.32 (2) 3.087 (3) 166 (3) N1---H1N···Cl1 0.79 (2) 2.62 (3) 2.978 (2) 110 (2) ------------------ ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*+1, −*z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------ ---------- ---------- ----------- ------------- N1---H1*N*⋯O1^i^ 0.79 (2) 2.32 (2) 3.087 (3) 166 (3) N1---H1*N*⋯Cl1 0.79 (2) 2.62 (3) 2.978 (2) 110 (2) Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.696564

2011-2-02

PMC3051984

Related literature {#sec1} ================== For preparation of the title compound, see: Shetty *et al.* (2009[@bb9]). For general background to benzothio­phenes, see: Katritzky *et al.* (1996[@bb6]); Shishoo & Jain (1992[@bb10]). For related structures, see: Akkurt *et al.* (2008[@bb1]); Harrison *et al.* (2006[@bb5]); Vasu *et al.* (2004[@bb11]). For graph-set notation, see: Bernstein *et al.* (1995[@bb2]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~10~H~12~N~2~S*M* *~r~* = 192.29Monoclinic,*a* = 9.0415 (2) Å*b* = 8.3294 (2) Å*c* = 13.1283 (3) Åβ = 90.169 (2)°*V* = 988.69 (4) Å^3^*Z* = 4Mo *K*α radiationμ = 0.28 mm^−1^*T* = 123 K0.16 × 0.16 × 0.14 mm ### Data collection {#sec2.1.2} Bruker SMART APEX CCD detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 1998[@bb3]) *T* ~min~ = 0.957, *T* ~max~ = 0.96211284 measured reflections2441 independent reflections1878 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.039 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.040*wR*(*F* ^2^) = 0.107*S* = 1.072441 reflections127 parametersH-atom parameters constrainedΔρ~max~ = 0.39 e Å^−3^Δρ~min~ = −0.30 e Å^−3^ {#d5e458} Data collection: *SMART* (Bruker, 1998[@bb3]); cell refinement: *SAINT-Plus* (Bruker, 1998[@bb3]); data reduction: *SAINT-Plus*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb8]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb8]); molecular graphics: *CAMERON* (Watkin *et al.*, 1996[@bb12]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb4]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811006076/pv2384sup1.cif](http://dx.doi.org/10.1107/S1600536811006076/pv2384sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006076/pv2384Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006076/pv2384Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?pv2384&file=pv2384sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?pv2384sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?pv2384&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [PV2384](http://scripts.iucr.org/cgi-bin/sendsup?pv2384)). NSB is thankful to the University Grants Commission (UGC), India, for financial assistance and the Department of Science and Technology, (DST), India, for the data collection facility under the IRHPA--DST program. Comment ======= Benzothiophenes are important heterocycles either as biological active molecules or as luminescent components used in organic materials (Shishoo & Jain, 1992; Katritzky *et al.*, 1996). In this paper, we report the crystal structure of a benzothiophene derivative. In the title compound (Fig. 1), the fused benzothiophene ring system is substituted with amino, methyl and carbonitrile groups. The carbon atoms C9 and C10 are disordered over two sites (C9A/C9B and C10A/C10B) with site occupancy factors 0.650 (3) and 0.350 (3) resulting in a major and a minor conformers. The cyclohexene ring in both conformers is in a half-chair conformation with C9A and C9B 0.547 (4) and 0.506 (6) Å, respectively, displaced on the opposite sides from the plane formed by the rest of the ring C-atoms (max. deviation being 0.063 (2) Å for C6). The thiophene ring is essentially planar. In several benzothiophene derivatives the cyclohexyl ring adopts half-chair conformation (Akkurt *et al.*, 2008; Harrison *et al.*, 2006; Vasu *et al.*, 2004). The crystal structure is stabilized by two types of N---H···N intermolecular interactions (Table 1); N2---H2A···N1 hydrogen bond forms centrosymmetric, head-to-head dimers about inversion centers corresponding to graph set *R*^2^~2~(12) motif(Bernstein *et al.*, 1995) while N2---H2B···N1 hydrogen bonds generate chains of molecules in a zigzag pattern along the *a* axis (Fig. 2). Experimental {#experimental} ============ The title compound was synthesized by following the procedure reported earlier (Shetty *et al.*, 2009). Refinement {#refinement} ========== The H atoms were placed at calculated positions in the riding model approximation with N---H = 0.88 Å and C---H = 0.98, 0.99 and 1.00 Å for methylene, methyl and methyne type H-atoms, respectively; *U*~iso~(H) = 1.2*U*~eq~(N/non-methyl C) and 1.5*U*~eq~(methyl C). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### ORTEP (Farrugia, 1999) view of the title compound, showing 50% probability ellipsoids and the atom numbering scheme; C-atoms C9b and C10b represent the minor conformer. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### A unit cell packing of the title compound showing intermolecular interactions with dotted lines. H-atoms not involved in hydrogen bonding have been excluded. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e144 .table-wrap} ------------------------- --------------------------------------- C~10~H~12~N~2~S *F*(000) = 408 *M~r~* = 192.29 *D*~x~ = 1.292 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 2441 reflections *a* = 9.0415 (2) Å θ = 2.9--29.2° *b* = 8.3294 (2) Å µ = 0.28 mm^−1^ *c* = 13.1283 (3) Å *T* = 123 K β = 90.169 (2)° Block, yellow *V* = 988.69 (4) Å^3^ 0.16 × 0.16 × 0.14 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e272 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEX CCD detector diffractometer 2441 independent reflections Radiation source: Enhance (Mo) X-ray Source 1878 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.039 ω scans θ~max~ = 29.2°, θ~min~ = 2.9° Absorption correction: multi-scan (*SADABS*; Bruker, 1998) *h* = −11→12 *T*~min~ = 0.957, *T*~max~ = 0.962 *k* = −11→10 11284 measured reflections *l* = −17→16 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e386 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.040 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.107 H-atom parameters constrained *S* = 1.07 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0536*P*)^2^ + 0.2028*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 2441 reflections (Δ/σ)~max~ = 0.001 127 parameters Δρ~max~ = 0.39 e Å^−3^ 0 restraints Δρ~min~ = −0.30 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e543 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Experimental. The compound was synthesized by following the procedure given in NitinKumar *et al.*, (2009) Geometry. All s.u.\'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.\'s are taken into account individually in the estimation of s.u.\'s in distances, angles and torsion angles; correlations between s.u.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.\'s is used for estimating s.u.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> 2σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e651 .table-wrap} ------ -------------- --------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) S1 0.68698 (5) 0.02703 (5) 0.34885 (3) 0.02519 (15) N1 0.5603 (2) −0.40456 (18) 0.60740 (11) 0.0378 (4) N2 0.54766 (17) −0.25706 (17) 0.33230 (10) 0.0292 (4) H2A 0.5129 −0.3480 0.3565 0.035\* H2B 0.5362 −0.2336 0.2674 0.035\* C1 0.5991 (2) −0.3000 (2) 0.55684 (12) 0.0263 (4) C2 0.64719 (19) −0.16794 (19) 0.49726 (12) 0.0224 (4) C3 0.61829 (18) −0.15372 (19) 0.39455 (12) 0.0217 (3) C4 0.75534 (19) 0.0810 (2) 0.46849 (12) 0.0251 (4) C5 0.72696 (19) −0.0328 (2) 0.53858 (12) 0.0236 (4) C6 0.7762 (2) −0.0180 (2) 0.64700 (13) 0.0303 (4) H6A 0.8312 −0.1158 0.6670 0.036\* H6B 0.6885 −0.0088 0.6916 0.036\* C7 0.8734 (3) 0.1266 (3) 0.66129 (16) 0.0514 (6) H7A 0.8688 0.1572 0.7341 0.062\* 0.650 (3) H7B 0.9764 0.0931 0.6474 0.062\* 0.650 (3) C8 0.8387 (2) 0.2343 (2) 0.48637 (13) 0.0328 (4) H8A 0.7892 0.3236 0.4500 0.039\* 0.650 (3) H8B 0.9405 0.2241 0.4596 0.039\* 0.650 (3) C9A 0.8440 (3) 0.2705 (3) 0.6012 (2) 0.0296 (5) 0.650 (3) H9AA 0.7434 0.3094 0.6209 0.036\* 0.650 (3) C10A 0.9518 (5) 0.4053 (5) 0.6248 (3) 0.0429 (10) 0.650 (3) H10A 0.9544 0.4241 0.6985 0.064\* 0.650 (3) H10B 0.9199 0.5034 0.5900 0.064\* 0.650 (3) H10C 1.0508 0.3753 0.6013 0.064\* 0.650 (3) H7C 0.8128 0.2072 0.6977 0.062\* 0.350 (3) H7D 0.9527 0.0937 0.7091 0.062\* 0.350 (3) H8C 0.7690 0.3238 0.4988 0.039\* 0.350 (3) H8D 0.8997 0.2611 0.4262 0.039\* 0.350 (3) C9B 0.9414 (6) 0.2065 (6) 0.5837 (4) 0.0296 (5) 0.350 (3) H9BA 1.0221 0.1334 0.5601 0.036\* 0.350 (3) C10B 1.0183 (9) 0.3644 (11) 0.6111 (7) 0.0429 (10) 0.350 (3) H10D 0.9449 0.4508 0.6140 0.064\* 0.350 (3) H10E 1.0924 0.3897 0.5592 0.064\* 0.350 (3) H10F 1.0669 0.3537 0.6775 0.064\* 0.350 (3) ------ -------------- --------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1153 .table-wrap} ------ ------------- ------------- ------------- --------------- --------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ S1 0.0327 (3) 0.0257 (2) 0.0171 (2) −0.00706 (18) −0.00294 (16) 0.00388 (16) N1 0.0684 (12) 0.0241 (8) 0.0207 (8) −0.0089 (8) −0.0066 (7) 0.0026 (6) N2 0.0453 (9) 0.0247 (8) 0.0175 (7) −0.0093 (7) −0.0035 (6) 0.0003 (6) C1 0.0395 (10) 0.0207 (8) 0.0187 (8) −0.0005 (7) −0.0035 (7) −0.0027 (7) C2 0.0287 (9) 0.0203 (8) 0.0183 (8) 0.0000 (7) −0.0001 (6) 0.0010 (6) C3 0.0241 (8) 0.0207 (8) 0.0203 (8) −0.0003 (6) 0.0011 (6) 0.0004 (6) C4 0.0296 (9) 0.0270 (9) 0.0185 (8) −0.0053 (7) −0.0033 (7) 0.0010 (7) C5 0.0263 (9) 0.0243 (8) 0.0202 (8) −0.0017 (7) −0.0011 (7) 0.0004 (7) C6 0.0427 (11) 0.0294 (9) 0.0189 (9) −0.0041 (8) −0.0057 (7) 0.0030 (7) C7 0.0744 (17) 0.0471 (13) 0.0327 (11) −0.0244 (12) −0.0248 (11) 0.0067 (9) C8 0.0418 (11) 0.0330 (10) 0.0237 (9) −0.0159 (8) −0.0040 (8) 0.0028 (7) C9A 0.0321 (14) 0.0302 (13) 0.0265 (12) −0.0074 (10) −0.0027 (11) −0.0028 (10) C10A 0.047 (3) 0.052 (2) 0.0294 (16) −0.029 (2) −0.0007 (19) −0.0052 (15) C7A 0.0744 (17) 0.0471 (13) 0.0327 (11) −0.0244 (12) −0.0248 (11) 0.0067 (9) C8A 0.0418 (11) 0.0330 (10) 0.0237 (9) −0.0159 (8) −0.0040 (8) 0.0028 (7) C9B 0.0321 (14) 0.0302 (13) 0.0265 (12) −0.0074 (10) −0.0027 (11) −0.0028 (10) C10B 0.047 (3) 0.052 (2) 0.0294 (16) −0.029 (2) −0.0007 (19) −0.0052 (15) ------ ------------- ------------- ------------- --------------- --------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1528 .table-wrap} ------------------- -------------- ---------------------- -------------- S1---C3 1.7363 (16) C7---H7A 0.9900 S1---C4 1.7451 (17) C7---H7B 0.9900 N1---C1 1.150 (2) C8---C9A 1.538 (3) N2---C3 1.347 (2) C8---H8A 0.9900 N2---H2A 0.8800 C8---H8B 0.9900 N2---H2B 0.8800 C9A---C10A 1.519 (5) C1---C2 1.419 (2) C9A---H9AA 1.0000 C2---C3 1.378 (2) C10A---H10A 0.9800 C2---C5 1.442 (2) C10A---H10B 0.9800 C4---C5 1.346 (2) C10A---H10C 0.9800 C4---C8 1.501 (2) C9B---C10B 1.530 (10) C5---C6 1.495 (2) C9B---H9BA 1.0000 C6---C7 1.502 (3) C10B---H10D 0.9800 C6---H6A 0.9900 C10B---H10E 0.9800 C6---H6B 0.9900 C10B---H10F 0.9800 C7---C9A 1.459 (3) C3---S1---C4 92.20 (8) C9A---C7---H7A 107.6 C3---N2---H2A 120.0 C6---C7---H7A 107.6 C3---N2---H2B 120.0 C9A---C7---H7B 107.6 H2A---N2---H2B 120.0 C6---C7---H7B 107.6 N1---C1---C2 178.19 (17) H7A---C7---H7B 107.0 C3---C2---C1 123.28 (15) C4---C8---C9A 109.52 (16) C3---C2---C5 113.22 (14) C4---C8---H8A 109.8 C1---C2---C5 123.47 (14) C9A---C8---H8A 109.8 N2---C3---C2 128.84 (15) C4---C8---H8B 109.8 N2---C3---S1 120.93 (12) C9A---C8---H8B 109.8 C2---C3---S1 110.22 (12) H8A---C8---H8B 108.2 C5---C4---C8 126.07 (15) C7---C9A---C10A 112.4 (3) C5---C4---S1 111.48 (13) C7---C9A---C8 112.0 (2) C8---C4---S1 122.42 (12) C10A---C9A---C8 111.3 (2) C4---C5---C2 112.86 (15) C7---C9A---H9AA 106.9 C4---C5---C6 122.40 (15) C10A---C9A---H9AA 106.9 C2---C5---C6 124.73 (15) C8---C9A---H9AA 106.9 C5---C6---C7 110.93 (15) C10B---C9B---H9BA 105.4 C5---C6---H6A 109.5 C9B---C10B---H10D 109.5 C7---C6---H6A 109.5 C9B---C10B---H10E 109.5 C5---C6---H6B 109.5 H10D---C10B---H10E 109.5 C7---C6---H6B 109.5 C9B---C10B---H10F 109.5 H6A---C6---H6B 108.0 H10D---C10B---H10F 109.5 C9A---C7---C6 119.06 (19) H10E---C10B---H10F 109.5 C1---C2---C3---N2 −2.3 (3) C1---C2---C5---C4 −177.32 (17) C5---C2---C3---N2 179.55 (17) C3---C2---C5---C6 −178.44 (17) C1---C2---C3---S1 177.36 (14) C1---C2---C5---C6 3.4 (3) C5---C2---C3---S1 −0.78 (19) C4---C5---C6---C7 −6.7 (3) C4---S1---C3---N2 −179.86 (15) C2---C5---C6---C7 172.46 (19) C4---S1---C3---C2 0.45 (13) C5---C6---C7---C9A 34.4 (3) C3---S1---C4---C5 0.01 (14) C5---C4---C8---C9A −18.3 (3) C3---S1---C4---C8 178.33 (16) S1---C4---C8---C9A 163.68 (16) C8---C4---C5---C2 −178.70 (17) C6---C7---C9A---C10A 179.9 (3) S1---C4---C5---C2 −0.5 (2) C6---C7---C9A---C8 −53.9 (3) C8---C4---C5---C6 0.6 (3) C4---C8---C9A---C7 42.0 (3) S1---C4---C5---C6 178.83 (14) C4---C8---C9A---C10A 168.8 (3) C3---C2---C5---C4 0.8 (2) ------------------- -------------- ---------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2052 .table-wrap} ------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N2---H2A···N1^i^ 0.88 2.22 3.087 (2) 170 N2---H2B···N1^ii^ 0.88 2.41 3.247 (2) 160 ------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*−1, −*z*+1; (ii) *x*, −*y*−1/2, *z*−1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------- --------- ------- ----------- ------------- N2---H2*A*⋯N1^i^ 0.88 2.22 3.087 (2) 170 N2---H2*B*⋯N1^ii^ 0.88 2.41 3.247 (2) 160 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.701398

2011-2-23

PMC3051985

Related literature {#sec1} ================== For the biological properties of indole derivatives, see: Chai *et al.* (2006[@bb2]); Nieto *et al.* (2005[@bb5]). For the structures of closely related compounds, see: Chakkaravarthi *et al.* (2007[@bb4], 2008[@bb3]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~15~H~12~INO~2~S*M* *~r~* = 397.22Monoclinic,*a* = 10.7068 (3) Å*b* = 16.2670 (4) Å*c* = 8.5147 (2) Åβ = 104.540 (1)°*V* = 1435.49 (6) Å^3^*Z* = 4Mo *K*α radiationμ = 2.38 mm^−1^*T* = 295 K0.30 × 0.24 × 0.20 mm ### Data collection {#sec2.1.2} Bruker Kappa APEXII diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb6]) *T* ~min~ = 0.536, *T* ~max~ = 0.64821249 measured reflections5276 independent reflections3696 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.023 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.043*wR*(*F* ^2^) = 0.144*S* = 1.065276 reflections182 parameters1 restraintH-atom parameters constrainedΔρ~max~ = 0.94 e Å^−3^Δρ~min~ = −1.56 e Å^−3^ {#d5e457} Data collection: *APEX2* (Bruker, 2004[@bb1]); cell refinement: *SAINT* (Bruker, 2004[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *PLATON* (Spek, 2009[@bb8]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004685/gk2346sup1.cif](http://dx.doi.org/10.1107/S1600536811004685/gk2346sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004685/gk2346Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004685/gk2346Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?gk2346&file=gk2346sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?gk2346sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?gk2346&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [GK2346](http://scripts.iucr.org/cgi-bin/sendsup?gk2346)). CR wishes to acknowledge AMET University management, India, for their kind support. Comment ======= Indole derivatives exhibit antihepatitis B virus (Chai *et al.*, 2006) and antibacterial (Nieto *et al.*, 2005) activities. The geometric parameters of the title molecule (Fig. 1) agree well with the reported similar structures (Chakkaravarthi *et al.* 2007, 2008). The phenyl ring makes the dihedral angle of 82.84 (9)° with the indole ring system. The sum of the bond angles around N1 \[359.4 (2)°\] indicates that N1 atom is *sp*^2^ hybridized. The molecular structure is stabilized by weak intramolecular C---H···O hydrogen bond. The crystal structure exhibits weak intermolecular C---H···π (Table 1) and π--π interactions \[*Cg*1···*Cg*3 (1 - *x*,-*y*,1 - *z*) 3.7617 (18) Å; *Cg*1 and *Cg*3 are the centroids of the rings N1/C7/C8/C9/C14 and C9---C14, respectively\]. Experimental {#experimental} ============ 3-Iodo-2-methylindole (5 g,0.02 mmole) was dissolved in distilled benzene (100 ml).To this, benzenesulfonyl chloride(3.23 ml,0.025 mmol) and 60% aqueous NaOH solution (40 g in 67.0 ml) were added along with tetrabutyl ammonium hydrogensulfate (1.0 g). This two phase system was stirred at room temperature for 2 h. It was then diluted with water (200 ml) and the organic layer was separated. The aqueous layer was extracted with benzene (2x20 ml). The combined organic layer was dried(Na~2~SO~4~).The benzene was then removed completely and the crude product was recrystallized from methanol (m.p. 395--397 K). Refinement {#refinement} ========== H atoms were positioned geometrically and refined using riding model with C---H = 0.93 Å and *U*~iso~(H) = 1.2Ueq(C) for aromatic C---H and C---H = 0.96 Å and *U*~iso~(H) = 1.5Ueq(C) for CH~3~. The components of the anisotropic displacement parameters in direction of the bond of I1 and C8 were restrained to be equal within an effective standard deviation of 0.001 using the DELU command in *SHELXL* (Sheldrick, 2008). Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound with 30% probability displacement ellipsoids for non-H atoms. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Crystal packing viewed along the b axis. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e167 .table-wrap} ------------------------- --------------------------------------- C~15~H~12~INO~2~S *F*(000) = 776 *M~r~* = 397.22 *D*~x~ = 1.838 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 8510 reflections *a* = 10.7068 (3) Å θ = 2.5--30.4° *b* = 16.2670 (4) Å µ = 2.38 mm^−1^ *c* = 8.5147 (2) Å *T* = 295 K β = 104.540 (1)° Block, colourless *V* = 1435.49 (6) Å^3^ 0.30 × 0.24 × 0.20 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e295 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker Kappa APEXII diffractometer 5276 independent reflections Radiation source: fine-focus sealed tube 3696 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.023 ω and φ scans θ~max~ = 32.8°, θ~min~ = 2.5° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −15→16 *T*~min~ = 0.536, *T*~max~ = 0.648 *k* = −23→24 21249 measured reflections *l* = −12→11 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e412 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.043 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.144 H-atom parameters constrained *S* = 1.06 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0743*P*)^2^ + 0.987*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 5276 reflections (Δ/σ)~max~ \< 0.001 182 parameters Δρ~max~ = 0.94 e Å^−3^ 1 restraint Δρ~min~ = −1.56 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e571 .table-wrap} ------ ------------- ---------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ C1 0.8489 (3) 0.14775 (16) 0.8788 (3) 0.0350 (5) C2 0.8848 (4) 0.0951 (2) 1.0097 (4) 0.0495 (7) H2 0.8265 0.0574 1.0324 0.059\* C3 1.0098 (4) 0.0998 (3) 1.1063 (5) 0.0638 (10) H3 1.0365 0.0646 1.1944 0.077\* C4 1.0940 (4) 0.1562 (3) 1.0722 (5) 0.0643 (11) H4 1.1778 0.1587 1.1375 0.077\* C5 1.0569 (3) 0.2092 (3) 0.9431 (5) 0.0556 (9) H5 1.1149 0.2478 0.9227 0.067\* C6 0.9331 (3) 0.20492 (19) 0.8436 (4) 0.0433 (6) H6 0.9073 0.2398 0.7549 0.052\* C7 0.7397 (3) 0.04833 (16) 0.5161 (3) 0.0329 (5) C8 0.7262 (3) −0.03190 (16) 0.4724 (3) 0.0336 (5) C9 0.6619 (2) −0.07527 (14) 0.5739 (3) 0.0297 (4) C10 0.6230 (3) −0.15718 (17) 0.5777 (4) 0.0387 (6) H10 0.6379 −0.1950 0.5025 0.046\* C11 0.5626 (3) −0.1805 (2) 0.6940 (4) 0.0478 (7) H11 0.5362 −0.2348 0.6978 0.057\* C12 0.5402 (3) −0.1249 (2) 0.8061 (4) 0.0486 (7) H12 0.5005 −0.1429 0.8852 0.058\* C13 0.5753 (3) −0.0428 (2) 0.8043 (4) 0.0435 (6) H13 0.5585 −0.0055 0.8792 0.052\* C14 0.6367 (2) −0.01869 (15) 0.6857 (3) 0.0309 (5) C15 0.7993 (4) 0.1168 (2) 0.4432 (5) 0.0509 (7) H15A 0.8230 0.0972 0.3483 0.076\* H15B 0.8748 0.1362 0.5208 0.076\* H15C 0.7383 0.1609 0.4137 0.076\* N1 0.6822 (2) 0.05838 (13) 0.6481 (3) 0.0335 (4) O1 0.6046 (2) 0.13114 (15) 0.8577 (4) 0.0552 (6) O2 0.6719 (2) 0.21172 (13) 0.6496 (3) 0.0533 (6) S1 0.68958 (6) 0.14402 (4) 0.75748 (10) 0.03797 (16) I1 0.78752 (3) −0.084909 (16) 0.28650 (3) 0.06383 (12) ------ ------------- ---------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1017 .table-wrap} ----- ------------- -------------- -------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0355 (12) 0.0307 (11) 0.0379 (13) 0.0043 (9) 0.0078 (10) −0.0078 (10) C2 0.0583 (19) 0.0487 (17) 0.0391 (15) 0.0014 (14) 0.0076 (14) 0.0020 (12) C3 0.071 (3) 0.070 (2) 0.0421 (18) 0.020 (2) −0.0008 (17) 0.0018 (17) C4 0.0421 (17) 0.087 (3) 0.056 (2) 0.0121 (17) −0.0013 (15) −0.025 (2) C5 0.0409 (16) 0.065 (2) 0.061 (2) −0.0088 (14) 0.0131 (14) −0.0205 (18) C6 0.0436 (15) 0.0406 (14) 0.0458 (15) −0.0039 (11) 0.0117 (12) −0.0062 (12) C7 0.0368 (12) 0.0290 (11) 0.0337 (12) −0.0026 (9) 0.0107 (9) 0.0026 (9) C8 0.0411 (13) 0.0293 (11) 0.0303 (11) −0.0013 (9) 0.0088 (9) 0.0012 (8) C9 0.0297 (11) 0.0280 (11) 0.0287 (11) −0.0016 (8) 0.0025 (8) 0.0014 (8) C10 0.0444 (14) 0.0295 (12) 0.0376 (13) −0.0067 (10) 0.0021 (11) −0.0005 (10) C11 0.0440 (15) 0.0395 (15) 0.0552 (17) −0.0157 (12) 0.0036 (13) 0.0100 (13) C12 0.0407 (15) 0.0578 (19) 0.0489 (17) −0.0109 (13) 0.0143 (12) 0.0130 (15) C13 0.0415 (14) 0.0501 (16) 0.0427 (15) −0.0046 (12) 0.0178 (12) 0.0006 (12) C14 0.0272 (10) 0.0321 (11) 0.0326 (11) −0.0008 (8) 0.0058 (9) 0.0005 (9) C15 0.064 (2) 0.0396 (15) 0.0548 (18) −0.0110 (14) 0.0261 (15) 0.0073 (14) N1 0.0389 (11) 0.0255 (9) 0.0373 (11) −0.0027 (8) 0.0120 (9) −0.0033 (8) O1 0.0433 (11) 0.0543 (13) 0.0750 (17) 0.0013 (10) 0.0278 (11) −0.0227 (12) O2 0.0528 (13) 0.0308 (10) 0.0659 (15) 0.0113 (9) −0.0047 (11) 0.0013 (10) S1 0.0335 (3) 0.0299 (3) 0.0491 (4) 0.0048 (2) 0.0078 (3) −0.0079 (3) I1 0.0954 (2) 0.05448 (17) 0.05233 (17) 0.00090 (11) 0.03859 (15) −0.00527 (9) ----- ------------- -------------- -------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1410 .table-wrap} ----------------------- ------------- --------------------- -------------- C1---C6 1.380 (4) C9---C14 1.399 (4) C1---C2 1.381 (4) C9---C10 1.399 (3) C1---S1 1.759 (3) C10---C11 1.365 (5) C2---C3 1.386 (6) C10---H10 0.9300 C2---H2 0.9300 C11---C12 1.379 (5) C3---C4 1.367 (7) C11---H11 0.9300 C3---H3 0.9300 C12---C13 1.387 (5) C4---C5 1.375 (6) C12---H12 0.9300 C4---H4 0.9300 C13---C14 1.392 (4) C5---C6 1.384 (5) C13---H13 0.9300 C5---H5 0.9300 C14---N1 1.411 (3) C6---H6 0.9300 C15---H15A 0.9600 C7---C8 1.355 (4) C15---H15B 0.9600 C7---N1 1.420 (3) C15---H15C 0.9600 C7---C15 1.493 (4) N1---S1 1.667 (2) C8---C9 1.421 (4) O1---S1 1.411 (3) C8---I1 2.050 (3) O2---S1 1.416 (3) C6---C1---C2 121.9 (3) C9---C10---H10 120.7 C6---C1---S1 119.1 (2) C10---C11---C12 121.0 (3) C2---C1---S1 119.0 (2) C10---C11---H11 119.5 C1---C2---C3 118.5 (4) C12---C11---H11 119.5 C1---C2---H2 120.8 C11---C12---C13 122.0 (3) C3---C2---H2 120.8 C11---C12---H12 119.0 C4---C3---C2 120.0 (4) C13---C12---H12 119.0 C4---C3---H3 120.0 C12---C13---C14 117.2 (3) C2---C3---H3 120.0 C12---C13---H13 121.4 C3---C4---C5 121.1 (3) C14---C13---H13 121.4 C3---C4---H4 119.4 C13---C14---C9 121.0 (2) C5---C4---H4 119.4 C13---C14---N1 132.0 (3) C4---C5---C6 119.9 (4) C9---C14---N1 107.0 (2) C4---C5---H5 120.0 C7---C15---H15A 109.5 C6---C5---H5 120.0 C7---C15---H15B 109.5 C1---C6---C5 118.6 (3) H15A---C15---H15B 109.5 C1---C6---H6 120.7 C7---C15---H15C 109.5 C5---C6---H6 120.7 H15A---C15---H15C 109.5 C8---C7---N1 106.9 (2) H15B---C15---H15C 109.5 C8---C7---C15 129.1 (3) C14---N1---C7 108.7 (2) N1---C7---C15 123.9 (3) C14---N1---S1 125.89 (19) C7---C8---C9 110.2 (2) C7---N1---S1 124.72 (18) C7---C8---I1 125.8 (2) O1---S1---O2 120.43 (16) C9---C8---I1 124.00 (18) O1---S1---N1 105.47 (13) C14---C9---C10 120.1 (2) O2---S1---N1 107.93 (14) C14---C9---C8 107.1 (2) O1---S1---C1 109.09 (15) C10---C9---C8 132.8 (3) O2---S1---C1 107.83 (14) C11---C10---C9 118.7 (3) N1---S1---C1 105.06 (12) C11---C10---H10 120.7 C6---C1---C2---C3 −0.7 (5) C8---C9---C14---C13 −179.2 (3) S1---C1---C2---C3 −178.7 (3) C10---C9---C14---N1 −177.8 (2) C1---C2---C3---C4 0.7 (6) C8---C9---C14---N1 1.6 (3) C2---C3---C4---C5 0.3 (6) C13---C14---N1---C7 179.0 (3) C3---C4---C5---C6 −1.1 (6) C9---C14---N1---C7 −2.0 (3) C2---C1---C6---C5 −0.1 (5) C13---C14---N1---S1 8.1 (4) S1---C1---C6---C5 177.9 (2) C9---C14---N1---S1 −172.91 (19) C4---C5---C6---C1 1.0 (5) C8---C7---N1---C14 1.6 (3) N1---C7---C8---C9 −0.5 (3) C15---C7---N1---C14 −179.7 (3) C15---C7---C8---C9 −179.2 (3) C8---C7---N1---S1 172.6 (2) N1---C7---C8---I1 179.13 (18) C15---C7---N1---S1 −8.7 (4) C15---C7---C8---I1 0.5 (5) C14---N1---S1---O1 −19.0 (3) C7---C8---C9---C14 −0.7 (3) C7---N1---S1---O1 171.5 (2) I1---C8---C9---C14 179.62 (18) C14---N1---S1---O2 −149.0 (2) C7---C8---C9---C10 178.6 (3) C7---N1---S1---O2 41.5 (3) I1---C8---C9---C10 −1.1 (4) C14---N1---S1---C1 96.2 (2) C14---C9---C10---C11 −1.3 (4) C7---N1---S1---C1 −73.3 (2) C8---C9---C10---C11 179.5 (3) C6---C1---S1---O1 −139.6 (2) C9---C10---C11---C12 0.0 (5) C2---C1---S1---O1 38.4 (3) C10---C11---C12---C13 1.3 (5) C6---C1---S1---O2 −7.2 (3) C11---C12---C13---C14 −1.1 (5) C2---C1---S1---O2 170.8 (3) C12---C13---C14---C9 −0.2 (4) C6---C1---S1---N1 107.7 (2) C12---C13---C14---N1 178.7 (3) C2---C1---S1---N1 −74.2 (3) C10---C9---C14---C13 1.4 (4) ----------------------- ------------- --------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2115 .table-wrap} ------------------------------------------ Cg3 is the centroid of the C9--C14 ring. ------------------------------------------ ::: ::: {#d1e2119 .table-wrap} ------------------ --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C13---H13···O1 0.93 2.29 2.871 (4) 120 C4---H4···Cg3^i^ 0.93 2.65 3.517 (5) 156 ------------------ --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+2, −*y*, −*z*+2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) *Cg*3 is the centroid of the C9--C14 ring. ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ------------------ --------- ------- ----------- ------------- C13---H13⋯O1 0.93 2.29 2.871 (4) 120 C4---H4⋯*Cg*3^i^ 0.93 2.65 3.517 (5) 156 Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.705882

2011-2-12

PMC3051986

Related literature {#sec1} ================== For a related structure, see: Jang *et al.* (2005[@bb3]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~25~H~31~NO~4~*M* *~r~* = 409.51Monoclinic,*a* = 9.7037 (2) Å*b* = 16.5123 (3) Å*c* = 13.8847 (3) Åβ = 102.132 (3)°*V* = 2175.06 (8) Å^3^*Z* = 4Mo *K*α radiationμ = 0.08 mm^−1^*T* = 100 K0.25 × 0.20 × 0.15 mm ### Data collection {#sec2.1.2} Agilent SuperNova Dual diffractometer with an Atlas detectorAbsorption correction: multi-scan (*CrysAlis PRO*; Agilent, 2010[@bb1]) *T* ~min~ = 0.979, *T* ~max~ = 0.98819082 measured reflections4915 independent reflections3770 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.042 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.048*wR*(*F* ^2^) = 0.123*S* = 1.034915 reflections279 parameters2 restraintsH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 0.27 e Å^−3^Δρ~min~ = −0.26 e Å^−3^ {#d5e426} Data collection: *CrysAlis PRO* (Agilent, 2010[@bb1]); cell refinement: *CrysAlis PRO*; data reduction: *CrysAlis PRO*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb4]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb4]); molecular graphics: *X-SEED* (Barbour, 2001[@bb2]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb5]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811006969/im2270sup1.cif](http://dx.doi.org/10.1107/S1600536811006969/im2270sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006969/im2270Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006969/im2270Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?im2270&file=im2270sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?im2270sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?im2270&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [IM2270](http://scripts.iucr.org/cgi-bin/sendsup?im2270)). We thank Manchester Metropolitan University, Baku State University and the University of Malaya for supporting this study. Comment ======= Substituted benzaldehydes react with dimedone along with a primary amine to yield *N*-substituted 1,2,3,4,5,6,7,8,9,10-decahydro-acridine-1,8-diones. The title compound has a hydroxy group in 2-position of the aromatic ring. This permits intramolecular hydrogen bonding, a feature also noted in the related 9-(2,6-dihydroxyphenyl)-3,3,6,6-tetramethyl-*N*-(4-methylphenyl)-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridine (Jang *et al.*, 2005). The second hydroxy unit in this case engages in intermolecular hydrogen bonding to afford a centrosymmetric dimer. The title compound (Scheme I, Fig. 1) has another hydroxy unit in the N bonded hydroxyethyl substituent. This groups engages in intermolecular hydrogen bond furnishing a linear chain that runs along the *c*-axis of the monoclinic unit cell. Experimental {#experimental} ============ Dimedone (20 mmol), salicylic aldehyde (10 mmol) and 2-amino-ethanol (10 mmol) were heated in ethanol (100 ml) for 5 h. After cooling the solution the product was collected by filtration and crystallized from ethanol; m.p. 462 K. Refinement {#refinement} ========== Carbon-bound H-atoms were placed in calculated positions \[C---H 0.95 to 0.98 Å, *U*~iso~(H) 1.2 to 1.5*U*~eq~(C)\] and were included in the refinement in the riding model approximation. The hydroxy H-atoms were located in a difference Fourier map, and were refined with a distance restraint of O--H 0.84±0.01 Å; their temperature factors were refined. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Thermal ellipsoid plot (Barbour, 2001) of C25H31NO4 at the 70% probability level; hydrogen atoms are drawn as spheres of arbitrary radius. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e121 .table-wrap} ------------------------- --------------------------------------- C~25~H~31~NO~4~ *F*(000) = 880 *M~r~* = 409.51 *D*~x~ = 1.251 Mg m^−3^ Monoclinic, *P*2~1~/*n* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2yn Cell parameters from 6079 reflections *a* = 9.7037 (2) Å θ = 2.3--29.4° *b* = 16.5123 (3) Å µ = 0.08 mm^−1^ *c* = 13.8847 (3) Å *T* = 100 K β = 102.132 (3)° Irregular block, light yellow *V* = 2175.06 (8) Å^3^ 0.25 × 0.20 × 0.15 mm *Z* = 4 ------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e248 .table-wrap} ------------------------------------------------------------------- -------------------------------------- Agilent SuperNova Dual diffractometer with an Atlas detector 4915 independent reflections Radiation source: SuperNova (Mo) X-ray Source 3770 reflections with *I* \> 2σ(*I*) Mirror *R*~int~ = 0.042 Detector resolution: 10.4041 pixels mm^-1^ θ~max~ = 27.5°, θ~min~ = 2.4° ω scans *h* = −12→12 Absorption correction: multi-scan (*CrysAlis PRO*; Agilent, 2010) *k* = −21→21 *T*~min~ = 0.979, *T*~max~ = 0.988 *l* = −18→18 19082 measured reflections ------------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e368 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.048 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.123 H atoms treated by a mixture of independent and constrained refinement *S* = 1.03 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0517*P*)^2^ + 0.8053*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 4915 reflections (Δ/σ)~max~ = 0.001 279 parameters Δρ~max~ = 0.27 e Å^−3^ 2 restraints Δρ~min~ = −0.26 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e527 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ O1 0.48778 (12) 0.25598 (7) 0.49186 (8) 0.0245 (3) O2 0.71758 (12) 0.26499 (7) 0.63474 (8) 0.0239 (3) O3 0.32877 (12) 0.07916 (7) 0.64843 (8) 0.0252 (3) O4 0.36042 (14) 0.44954 (8) 0.90598 (10) 0.0357 (3) N1 0.45983 (13) 0.28498 (7) 0.88782 (9) 0.0174 (3) C1 0.37807 (16) 0.29121 (9) 0.52419 (11) 0.0198 (3) C2 0.28360 (17) 0.33708 (10) 0.45699 (12) 0.0242 (4) H2 0.2980 0.3443 0.3919 0.029\* C3 0.16843 (17) 0.37236 (10) 0.48466 (12) 0.0245 (4) H3 0.1030 0.4030 0.4382 0.029\* C4 0.14843 (17) 0.36311 (9) 0.57997 (12) 0.0232 (4) H4A 0.0701 0.3878 0.5993 0.028\* C5 0.24353 (16) 0.31759 (9) 0.64673 (11) 0.0201 (3) H5 0.2297 0.3118 0.7121 0.024\* C6 0.35895 (16) 0.28008 (9) 0.62057 (11) 0.0181 (3) C7 0.46282 (16) 0.22884 (9) 0.69374 (11) 0.0173 (3) H7 0.5066 0.1884 0.6557 0.021\* C8 0.57885 (16) 0.27978 (9) 0.75365 (11) 0.0182 (3) C9 0.70525 (17) 0.29325 (9) 0.71557 (11) 0.0195 (3) C10 0.82323 (16) 0.34044 (9) 0.77743 (12) 0.0212 (3) H10A 0.8826 0.3637 0.7344 0.025\* H10B 0.8828 0.3034 0.8247 0.025\* C11 0.76993 (17) 0.40884 (9) 0.83440 (12) 0.0216 (3) C12 0.67029 (16) 0.37278 (9) 0.89612 (11) 0.0204 (3) H12A 0.7278 0.3468 0.9554 0.024\* H12B 0.6167 0.4175 0.9186 0.024\* C13 0.56744 (16) 0.31146 (9) 0.84253 (11) 0.0173 (3) C14 0.69201 (19) 0.47206 (10) 0.76251 (13) 0.0298 (4) H14A 0.7563 0.4945 0.7236 0.045\* H14B 0.6581 0.5156 0.7995 0.045\* H14C 0.6117 0.4465 0.7184 0.045\* C15 0.89404 (18) 0.44878 (10) 0.90356 (13) 0.0273 (4) H15A 0.9575 0.4726 0.8649 0.041\* H15B 0.9452 0.4081 0.9487 0.041\* H15C 0.8592 0.4913 0.9415 0.041\* C16 0.43798 (17) 0.32332 (9) 0.97968 (11) 0.0204 (3) H16A 0.5266 0.3500 1.0131 0.025\* H16B 0.4154 0.2808 1.0243 0.025\* C17 0.32055 (19) 0.38537 (10) 0.96141 (12) 0.0266 (4) H17A 0.2323 0.3602 0.9249 0.032\* H17B 0.3039 0.4060 1.0249 0.032\* C18 0.38348 (16) 0.21533 (9) 0.85240 (11) 0.0169 (3) C19 0.29342 (16) 0.17702 (9) 0.91636 (11) 0.0195 (3) H19A 0.2381 0.2200 0.9405 0.023\* H19B 0.3559 0.1523 0.9745 0.023\* C20 0.19150 (17) 0.11202 (9) 0.86392 (11) 0.0203 (3) C21 0.27110 (18) 0.05689 (9) 0.80557 (12) 0.0236 (4) H21A 0.3488 0.0292 0.8514 0.028\* H21B 0.2063 0.0150 0.7708 0.028\* C22 0.33022 (16) 0.10522 (9) 0.73201 (11) 0.0193 (3) C23 0.39203 (16) 0.18370 (9) 0.76380 (11) 0.0179 (3) C24 0.13741 (18) 0.06237 (10) 0.94152 (13) 0.0259 (4) H24A 0.0883 0.0981 0.9795 0.039\* H24B 0.2172 0.0365 0.9859 0.039\* H24C 0.0722 0.0207 0.9088 0.039\* C25 0.06713 (17) 0.15154 (10) 0.79316 (12) 0.0238 (4) H25A 0.1023 0.1835 0.7439 0.036\* H25B 0.0162 0.1870 0.8303 0.036\* H25C 0.0033 0.1094 0.7600 0.036\* H1 0.5572 (17) 0.2508 (14) 0.5393 (12) 0.051 (7)\* H4 0.2939 (18) 0.4842 (11) 0.8949 (16) 0.053 (7)\* ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1300 .table-wrap} ----- ------------- ------------ ------------ ------------- ------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ O1 0.0232 (6) 0.0345 (7) 0.0163 (6) −0.0009 (5) 0.0056 (5) −0.0008 (5) O2 0.0219 (6) 0.0323 (6) 0.0188 (6) −0.0007 (5) 0.0074 (5) −0.0029 (5) O3 0.0310 (7) 0.0246 (6) 0.0225 (6) −0.0054 (5) 0.0110 (5) −0.0070 (5) O4 0.0373 (8) 0.0282 (7) 0.0454 (8) 0.0109 (6) 0.0175 (6) 0.0102 (6) N1 0.0183 (7) 0.0202 (6) 0.0141 (6) 0.0011 (5) 0.0040 (5) −0.0022 (5) C1 0.0210 (8) 0.0203 (8) 0.0181 (7) −0.0056 (6) 0.0041 (6) −0.0021 (6) C2 0.0262 (9) 0.0266 (8) 0.0181 (8) −0.0098 (7) 0.0009 (7) 0.0014 (7) C3 0.0218 (8) 0.0229 (8) 0.0244 (8) −0.0047 (7) −0.0049 (7) 0.0027 (7) C4 0.0208 (8) 0.0212 (8) 0.0261 (8) −0.0010 (7) 0.0013 (7) −0.0031 (7) C5 0.0213 (8) 0.0196 (8) 0.0190 (8) −0.0039 (6) 0.0034 (6) −0.0027 (6) C6 0.0191 (8) 0.0170 (7) 0.0170 (7) −0.0059 (6) 0.0007 (6) −0.0024 (6) C7 0.0186 (8) 0.0193 (7) 0.0151 (7) −0.0003 (6) 0.0057 (6) −0.0021 (6) C8 0.0184 (8) 0.0186 (7) 0.0174 (7) 0.0020 (6) 0.0036 (6) 0.0015 (6) C9 0.0201 (8) 0.0203 (8) 0.0182 (8) 0.0035 (6) 0.0039 (6) 0.0024 (6) C10 0.0187 (8) 0.0245 (8) 0.0204 (8) −0.0006 (7) 0.0044 (6) 0.0013 (7) C11 0.0209 (8) 0.0203 (8) 0.0230 (8) −0.0012 (6) 0.0029 (7) −0.0004 (7) C12 0.0193 (8) 0.0219 (8) 0.0191 (8) 0.0024 (6) 0.0020 (6) −0.0032 (6) C13 0.0167 (8) 0.0174 (7) 0.0172 (7) 0.0039 (6) 0.0024 (6) 0.0012 (6) C14 0.0313 (10) 0.0240 (8) 0.0322 (9) 0.0013 (7) 0.0021 (8) 0.0045 (7) C15 0.0231 (9) 0.0280 (9) 0.0305 (9) −0.0042 (7) 0.0048 (7) −0.0041 (7) C16 0.0243 (8) 0.0234 (8) 0.0144 (7) 0.0007 (7) 0.0058 (6) −0.0040 (6) C17 0.0338 (10) 0.0248 (8) 0.0244 (8) 0.0055 (7) 0.0132 (7) −0.0010 (7) C18 0.0154 (7) 0.0170 (7) 0.0179 (7) 0.0033 (6) 0.0026 (6) 0.0010 (6) C19 0.0218 (8) 0.0223 (8) 0.0152 (7) 0.0017 (6) 0.0059 (6) −0.0003 (6) C20 0.0220 (8) 0.0204 (8) 0.0201 (8) −0.0011 (6) 0.0080 (7) 0.0008 (6) C21 0.0286 (9) 0.0186 (8) 0.0257 (8) 0.0004 (7) 0.0105 (7) −0.0003 (7) C22 0.0188 (8) 0.0201 (7) 0.0196 (7) 0.0026 (6) 0.0057 (6) −0.0005 (6) C23 0.0179 (8) 0.0185 (7) 0.0176 (7) 0.0025 (6) 0.0047 (6) 0.0004 (6) C24 0.0299 (9) 0.0240 (8) 0.0268 (8) −0.0012 (7) 0.0127 (7) 0.0031 (7) C25 0.0208 (8) 0.0281 (8) 0.0230 (8) −0.0031 (7) 0.0058 (7) 0.0000 (7) ----- ------------- ------------ ------------ ------------- ------------- ------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1864 .table-wrap} ------------------- ------------- ------------------- ------------- O1---C1 1.3690 (19) C12---C13 1.504 (2) O1---H1 0.841 (10) C12---H12A 0.9900 O2---C9 1.2442 (18) C12---H12B 0.9900 O3---C22 1.2349 (18) C14---H14A 0.9800 O4---C17 1.411 (2) C14---H14B 0.9800 O4---H4 0.852 (9) C14---H14C 0.9800 N1---C13 1.3975 (19) C15---H15A 0.9800 N1---C18 1.400 (2) C15---H15B 0.9800 N1---C16 1.4785 (18) C15---H15C 0.9800 C1---C2 1.388 (2) C16---C17 1.514 (2) C1---C6 1.401 (2) C16---H16A 0.9900 C2---C3 1.384 (2) C16---H16B 0.9900 C2---H2 0.9500 C17---H17A 0.9900 C3---C4 1.386 (2) C17---H17B 0.9900 C3---H3 0.9500 C18---C23 1.355 (2) C4---C5 1.384 (2) C18---C19 1.510 (2) C4---H4A 0.9500 C19---C20 1.535 (2) C5---C6 1.393 (2) C19---H19A 0.9900 C5---H5 0.9500 C19---H19B 0.9900 C6---C7 1.528 (2) C20---C24 1.532 (2) C7---C23 1.502 (2) C20---C21 1.531 (2) C7---C8 1.508 (2) C20---C25 1.533 (2) C7---H7 1.0000 C21---C22 1.502 (2) C8---C13 1.366 (2) C21---H21A 0.9900 C8---C9 1.451 (2) C21---H21B 0.9900 C9---C10 1.497 (2) C22---C23 1.457 (2) C10---C11 1.530 (2) C24---H24A 0.9800 C10---H10A 0.9900 C24---H24B 0.9800 C10---H10B 0.9900 C24---H24C 0.9800 C11---C15 1.524 (2) C25---H25A 0.9800 C11---C14 1.530 (2) C25---H25B 0.9800 C11---C12 1.540 (2) C25---H25C 0.9800 C1---O1---H1 109.6 (16) H14A---C14---H14C 109.5 C17---O4---H4 108.6 (15) H14B---C14---H14C 109.5 C13---N1---C18 119.28 (12) C11---C15---H15A 109.5 C13---N1---C16 120.69 (12) C11---C15---H15B 109.5 C18---N1---C16 119.57 (12) H15A---C15---H15B 109.5 O1---C1---C2 117.44 (14) C11---C15---H15C 109.5 O1---C1---C6 121.71 (14) H15A---C15---H15C 109.5 C2---C1---C6 120.83 (15) H15B---C15---H15C 109.5 C3---C2---C1 120.06 (15) N1---C16---C17 112.62 (13) C3---C2---H2 120.0 N1---C16---H16A 109.1 C1---C2---H2 120.0 C17---C16---H16A 109.1 C2---C3---C4 120.13 (16) N1---C16---H16B 109.1 C2---C3---H3 119.9 C17---C16---H16B 109.1 C4---C3---H3 119.9 H16A---C16---H16B 107.8 C5---C4---C3 119.46 (15) O4---C17---C16 108.47 (13) C5---C4---H4A 120.3 O4---C17---H17A 110.0 C3---C4---H4A 120.3 C16---C17---H17A 110.0 C4---C5---C6 121.74 (15) O4---C17---H17B 110.0 C4---C5---H5 119.1 C16---C17---H17B 110.0 C6---C5---H5 119.1 H17A---C17---H17B 108.4 C5---C6---C1 117.76 (14) C23---C18---N1 120.45 (13) C5---C6---C7 121.80 (13) C23---C18---C19 121.74 (14) C1---C6---C7 120.43 (14) N1---C18---C19 117.81 (12) C23---C7---C8 108.04 (12) C18---C19---C20 114.13 (12) C23---C7---C6 112.22 (12) C18---C19---H19A 108.7 C8---C7---C6 111.70 (12) C20---C19---H19A 108.7 C23---C7---H7 108.2 C18---C19---H19B 108.7 C8---C7---H7 108.3 C20---C19---H19B 108.7 C6---C7---H7 108.2 H19A---C19---H19B 107.6 C13---C8---C9 120.37 (14) C24---C20---C21 109.84 (13) C13---C8---C7 121.27 (13) C24---C20---C25 109.79 (13) C9---C8---C7 118.35 (13) C21---C20---C25 109.31 (13) O2---C9---C8 121.33 (14) C24---C20---C19 108.81 (13) O2---C9---C10 120.38 (14) C21---C20---C19 108.68 (13) C8---C9---C10 118.27 (13) C25---C20---C19 110.39 (13) C9---C10---C11 112.33 (13) C22---C21---C20 110.56 (13) C9---C10---H10A 109.1 C22---C21---H21A 109.5 C11---C10---H10A 109.1 C20---C21---H21A 109.5 C9---C10---H10B 109.1 C22---C21---H21B 109.5 C11---C10---H10B 109.1 C20---C21---H21B 109.5 H10A---C10---H10B 107.9 H21A---C21---H21B 108.1 C15---C11---C14 109.44 (14) O3---C22---C23 121.15 (14) C15---C11---C10 109.70 (13) O3---C22---C21 121.56 (14) C14---C11---C10 109.92 (13) C23---C22---C21 117.28 (13) C15---C11---C12 108.79 (13) C18---C23---C22 121.21 (13) C14---C11---C12 110.17 (13) C18---C23---C7 121.36 (14) C10---C11---C12 108.80 (12) C22---C23---C7 117.42 (13) C13---C12---C11 114.45 (12) C20---C24---H24A 109.5 C13---C12---H12A 108.6 C20---C24---H24B 109.5 C11---C12---H12A 108.6 H24A---C24---H24B 109.5 C13---C12---H12B 108.6 C20---C24---H24C 109.5 C11---C12---H12B 108.6 H24A---C24---H24C 109.5 H12A---C12---H12B 107.6 H24B---C24---H24C 109.5 C8---C13---N1 119.79 (14) C20---C25---H25A 109.5 C8---C13---C12 122.23 (13) C20---C25---H25B 109.5 N1---C13---C12 117.95 (13) H25A---C25---H25B 109.5 C11---C14---H14A 109.5 C20---C25---H25C 109.5 C11---C14---H14B 109.5 H25A---C25---H25C 109.5 H14A---C14---H14B 109.5 H25B---C25---H25C 109.5 C11---C14---H14C 109.5 ------------------- ------------- ------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2720 .table-wrap} ----------------- ---------- ---------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O1---H1···O2 0.84 (1) 1.84 (1) 2.659 (2) 166 (2) O4---H4···O3^i^ 0.85 (1) 1.98 (1) 2.818 (2) 166 (2) ----------------- ---------- ---------- ----------- --------------- ::: Symmetry codes: (i) −*x*+1/2, *y*+1/2, −*z*+3/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------- ---------- ---------- ----------- ------------- O1---H1⋯O2 0.84 (1) 1.84 (1) 2.659 (2) 166 (2) O4---H4⋯O3^i^ 0.85 (1) 1.98 (1) 2.818 (2) 166 (2) Symmetry code: (i) . :::

PubMed Central

2024-06-05T04:04:17.710640

2011-2-26

PMC3051987

Related literature {#sec1} ================== For the structures of related binuclear copper(II) complexes, see: Shahid *et al.* (2008[@bb5], 2009[@bb6]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Cu(SO~4~)(C~6~H~7~N)~4~\]·4.393H~2~O*M* *~r~* = 611.27Triclinic,*a* = 10.4688 (12) Å*b* = 11.6327 (14) Å*c* = 12.8300 (15) Åα = 78.672 (3)°β = 87.609 (3)°γ = 67.571 (3)°*V* = 1415.2 (3) Å^3^*Z* = 2Mo *K*α radiationμ = 0.90 mm^−1^*T* = 100 K0.60 × 0.45 × 0.40 mm ### Data collection {#sec2.1.2} Bruker SMART APEX CCD diffractometerAbsorption correction: multi-scan (*TWINABS*; Bruker, 2008[@bb2]) *T* ~min~ = 0.607, *T* ~max~ = 0.74616814 measured reflections6963 independent reflections6170 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.033 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.046*wR*(*F* ^2^) = 0.118*S* = 1.066963 reflections361 parametersH-atom parameters constrainedΔρ~max~ = 0.68 e Å^−3^Δρ~min~ = −0.61 e Å^−3^ {#d5e760} Data collection: *SMART* (Bruker, 2002[@bb1]); cell refinement: *SAINT* (Bruker, 2009[@bb3]); data reduction: *CELL NOW* (Bruker, 2009[@bb3]) and *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL* and *Mercury* (Macrae *et al.*, 2008[@bb4]); software used to prepare material for publication: *SHELXTL*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811006325/wm2458sup1.cif](http://dx.doi.org/10.1107/S1600536811006325/wm2458sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006325/wm2458Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006325/wm2458Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?wm2458&file=wm2458sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?wm2458sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?wm2458&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [WM2458](http://scripts.iucr.org/cgi-bin/sendsup?wm2458)). We are thankful to the Higher Education Commission of Pakistan for funding. The X-ray diffractometer was funded by NSF grant 0087210, Ohio Board of Regents grant CAP-491 and Youngstown State University. Comment ======= In relation to our previous work on the structural chemistry of copper complexes (Shahid *et al.*, 2008; 2009) the title compound was prepared as the unintended product of the reaction of CuSO~4~^.^5H~2~O with pyrolidine in acetone and 4-methylpyridine. In the title structure (Fig. 1), two crystallographically independent Cu^2+^ ions are each located on an inversion center. Their coordination environments are distorted octahedral, with a CuN~4~O~2~ set of ligating atoms, composed of four N atoms from four 4-methylpyridine groups and two O atoms of two sulfate anions. The equatorial plane is made up of four N atoms of the 4-methylpyridine ligands, N1, N1^i^, N2 and N2^i^ for Cu1 and N3, N3^ii^, N4 and N4^ii^ for Cu2 (symmetry operators (i) -*x* + 1, -*y* + 2, -*z* + 1; (ii) -*x* + 1, -*y* + 2, -*z*.), with distances ranging between 2.041 (2) and 2.046 (2) Å. The O atoms O1, O1^i^, O2 and O2^ii^ of the sulfate anion are bonded at the axial positions of Cu1 and Cu2, respectively, resulting in considerably longer Cu---O bonds of 2.393 (2) Å for Cu1---O1 and 2.443 (2) Å for Cu2---O2. The bridging sulfate ions connect the Cu(4-methylpyridine)~4~ units to form infinite \[Cu{H~3~C(C~5~H~4~N)}~4~SO~4~\]~n~ zigzag chains along the \[001\] direction of the crystal (Fig. 2). The shape of the zigzag chain follows the coordination geometry of the copper and sulfate ions: Cu---O---S angles are close to 180° (169.62 (13) for S1---O1---Cu1 and 172.99 (1) for S1---O2---Cu2), the O---Cu---O angles are exactly 180° (due to the location of the copper ions on inversion centers). The angles of the zigzag chain, represented by the Cu---S---Cu angles, thus follow closely the tetrahedral sulfate O---S---O angles and are 111.73 ° (the O---S---O angles range between 108.76 (12) and 110.04 (13)°). Parallel zigzag chains interdigitate as shown in Fig. 3, but interstitial space is left between neighboring molecules. Along the *a*-axis neighboring sulfate ions are connected through O---H···O hydrogen bonds mediated by the water molecules O5 and O7 to form infinite {O···H~2~O···H~2~O···O···H~2~O···H~2~O···}~n~ chains. Parallel pairs of these chains are connected with each other through additional O---H···O hydrogen bonds mediated by the water molecules of O6 and O8. Due to hydrogen bonding between symmetry equivalent water molecules across inversion centers, the H atoms of O6 and O8 are partially disordered over mutually exclusive positions (see refinement section for details). The connection of the sulfate ions with these water molecules creates flat strands made up of slightly wobbly single molecule layers of tightly hydrogen-bonded water and sulfate molecules about seven to eight Å wide that stretch infinitely parallel to the *a*-axis (Figs. 3 and 4). The last of the five crystallographically independent water solvate molecules (O9) is not part of these strands but is located about three Å away and is only weakly hydrogen bonded with the other water molecules (Fig. 4). It is only partially occupied with a refined occupancy factor of 0.396 (4). For details and numerical values of the hydrogen bonding geometries, including symmetry operators, see: Table 1. Experimental {#experimental} ============ CuSO~4~^.^5H~2~O (0.30 g, 1.21 mmol) was added directly to a stirred solution of pyrolidine (0.5 g, 2.43 mmole) in 20 ml acetone. The contents were stirred until complete dissolution of the salt to which about 30 ml of 4-methylpyridine was added and stirring was continued for another hour. Insoluble matter was removed by filtration and slow evaporation of the reaction mixture at room temperature gave the title compound as blue crystals after three weeks. Yield 60% (0.44 g), m.p. 373 K. Elemental analysis: calculated (found): C 47.15(47.66), H 6.06(5.92), N 9.20(8.95)%. Refinement {#refinement} ========== The crystal under investigation was found to be non-merohedrally twinned by a 180° rotation around the reciprocal *b*-axis. The orientation matrices for the two components were identified using the program *CELL NOW* (Bruker, 2008), and the two components were integrated using *SAINT*, resulting in a total of 23387 reflections. 6633 reflections (4611 unique ones) involved component 1 only (mean I/σ = 12.2), 6573 reflections (3653 unique ones) involved component 2 only (mean I/σ = 5.8), and 10181 reflections (5801 unique ones) involved both components (mean I/σ = 9.4). The exact twin matrix identified by the integration program was found to be -1.00018 0.00039 0.00025, -0.83074 0.99991 - 0.32879, 0.00016 - 0.00153 - 0.99973. The structure was solved using direct methods with only the non-overlapping reflections of component 1. The structure was refined using the HKLF5 routine with all reflections of component 1 (including the overlapping ones) below a *d*-spacing threshold of 0.75 Å, resulting in a BASF value of 0.211 (1). The *R*~int~ value given is for all reflections before the cutoff at d = 0.75 Å and is based on agreement between observed single and composite intensities and those calculated from refined unique intensities and twin fractions (*TWINABS*; Bruker, 2008). Hydrogen atoms of the water molecules are partially disordered over mutually exclusive positions due to hydrogen bonding between symmetry equivalent water molecules across inversion centers. The H atoms in question are H6A and H8C, which are each located close to a crystallographic inversion center between pairs of symmetry equivalent atoms of O6 and O8. Both H atoms were thus refined as 50% occupied. For both water molecules O6 and O8 a second half occupied hydrogen atom is located in a position in which it hydrogen-bonds with the a neighboring water molecule of O8 and O6, respectively, thus again creating a pair of close by half occupied H atoms (H6C and H8B) in mutually exclusive positions. The water solvate molecule of O9 is only partially occupied with a refined occupancy factor of 0.396 (4). Water hydrogen atoms were located in difference density Fourier maps, assigned occupancies as described above and their positions were refined with an O---H distance of 0.84 (1) Å and H···H distances of 1.30 (1) Å. In the final refinement cycles the water H atoms were set to ride on their carrying oxygen atoms. All other hydrogen atoms were immediately placed in calculated positions and all H atoms were refined with an isotropic displacement parameter *U*~iso~ of 1.5 (methyl, hydroxyl) or 1.2 times (aromatic) that of *U*~eq~ of the adjacent carbon or oxygen atom. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### View of the molecular structure of the title compound with displacement ellipsoids drawn at the 50% probability level with atom labeling. Symmetry transformations used to generate equivalent atoms: (i) -x + 1,-y + 2,-z + 1; (ii) -x + 1,-y + 2,-z. For the water molecules all disordered H atoms are shown. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### View of the polymeric zigzag chains along the \[001\] direction. Symmetry transformations used to generate equivalent atoms: (i) -x + 1, -y + 2,-z + 1; (ii) -x + 1,-y + 2,-z. :::  ::: ::: {#Fap3 .fig} Fig. 3. ::: {.caption} ###### Interdigitation between parallel zigzag chains and hydrogen bonding. View is down the c axis along the direction of the polymeric chains shown in Fig. 2. Note the interdigitation of tolyl groups of parallel chains along the a axis and the water filled areas between chains along the b axis. Hydrogen bonds are indicated by dashed light blue lines. Bands of H--bonded water molecules stretch infinitely parallel to the a axis. :::  ::: ::: {#Fap4 .fig} Fig. 4. ::: {.caption} ###### Packing and hydrogen bonding in the structure of the title compound. View is down the a axis. Hydrogen bonds are indicated by dashed light blue lines (H atoms omitted for clarity). Layers of H bonded water molecules stretch infinitely parallel to the a-axis. The single water molecule O9 that is not part of the water cluster is clearly visible in this view. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e323 .table-wrap} ---------------------------------------- --------------------------------------- \[Cu(SO~4~)(C~6~H~7~N)~4~\]·4.393H~2~O *Z* = 2 *M~r~* = 611.27 *F*(000) = 642 Triclinic, *P*1 *D*~x~ = 1.434 Mg m^−3^ Hall symbol: -P 1 Melting point: 373 K *a* = 10.4688 (12) Å Mo *K*α radiation, λ = 0.71073 Å *b* = 11.6327 (14) Å Cell parameters from 4676 reflections *c* = 12.8300 (15) Å θ = 2.3--30.4° α = 78.672 (3)° µ = 0.90 mm^−1^ β = 87.609 (3)° *T* = 100 K γ = 67.571 (3)° Block, blue *V* = 1415.2 (3) Å^3^ 0.60 × 0.45 × 0.40 mm ---------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e464 .table-wrap} ------------------------------------------------------------- -------------------------------------- Bruker SMART APEX CCD diffractometer 6963 independent reflections Radiation source: fine-focus sealed tube 6170 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.033 ω scans θ~max~ = 28.3°, θ~min~ = 1.6° Absorption correction: multi-scan (*TWINABS*; Bruker, 2008) *h* = −13→13 *T*~min~ = 0.607, *T*~max~ = 0.746 *k* = −15→15 16814 measured reflections *l* = 0→17 ------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e575 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.046 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.118 H-atom parameters constrained *S* = 1.06 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0573*P*)^2^ + 1.4896*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 6963 reflections (Δ/σ)~max~ \< 0.001 361 parameters Δρ~max~ = 0.68 e Å^−3^ 0 restraints Δρ~min~ = −0.61 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e732 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e831 .table-wrap} ------ ------------- -------------- -------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) C1 0.7599 (3) 1.0000 (3) 0.5809 (2) 0.0204 (5) H1 0.7594 0.9263 0.6281 0.024\* C2 0.8641 (3) 1.0426 (3) 0.5935 (2) 0.0231 (5) H2 0.9329 0.9984 0.6488 0.028\* C3 0.8680 (3) 1.1497 (3) 0.5255 (2) 0.0230 (5) C4 0.7680 (3) 1.2070 (3) 0.4436 (2) 0.0254 (6) H4 0.7692 1.2784 0.3932 0.030\* C5 0.6665 (3) 1.1597 (3) 0.4355 (2) 0.0242 (6) H5 0.5990 1.1999 0.3789 0.029\* C6 0.9755 (3) 1.2030 (3) 0.5399 (3) 0.0313 (6) H6F 0.9338 1.2775 0.5729 0.047\* H6E 1.0100 1.2278 0.4704 0.047\* H6D 1.0523 1.1385 0.5856 0.047\* C7 0.6771 (3) 0.7248 (3) 0.5052 (2) 0.0259 (6) H7 0.6453 0.7125 0.5754 0.031\* C8 0.7656 (4) 0.6209 (3) 0.4678 (2) 0.0318 (7) H8 0.7943 0.5392 0.5123 0.038\* C9 0.8136 (3) 0.6346 (3) 0.3647 (2) 0.0272 (6) C10 0.9073 (4) 0.5230 (3) 0.3195 (3) 0.0451 (9) H10A 0.8548 0.4736 0.3050 0.068\* H10B 0.9834 0.4695 0.3709 0.068\* H10C 0.9449 0.5532 0.2533 0.068\* C11 0.7700 (3) 0.7568 (3) 0.3053 (2) 0.0224 (5) H11 0.8015 0.7715 0.2353 0.027\* C12 0.6808 (3) 0.8575 (3) 0.3476 (2) 0.0212 (5) H12 0.6517 0.9402 0.3048 0.025\* C13 0.4334 (3) 0.8651 (3) 0.2020 (2) 0.0216 (5) H13 0.3870 0.9490 0.2138 0.026\* C14 0.4296 (3) 0.7646 (3) 0.2792 (2) 0.0208 (5) H14 0.3811 0.7806 0.3424 0.025\* C15 0.4963 (3) 0.6413 (3) 0.2645 (2) 0.0253 (6) C16 0.5674 (4) 0.6247 (3) 0.1714 (2) 0.0341 (7) H16 0.6166 0.5416 0.1585 0.041\* C17 0.5667 (3) 0.7287 (3) 0.0975 (2) 0.0310 (6) H17 0.6156 0.7150 0.0342 0.037\* C18 0.4934 (4) 0.5303 (3) 0.3466 (2) 0.0371 (8) H18A 0.5735 0.5000 0.3960 0.056\* H18B 0.4967 0.4620 0.3112 0.056\* H18C 0.4082 0.5569 0.3860 0.056\* C19 0.7394 (3) 1.0233 (3) 0.0928 (2) 0.0228 (5) H19 0.6692 1.0967 0.1105 0.027\* C20 0.8748 (3) 0.9916 (3) 0.1272 (2) 0.0258 (6) H20 0.8958 1.0428 0.1676 0.031\* C21 0.9792 (3) 0.8852 (3) 0.1023 (2) 0.0256 (6) C22 0.9428 (3) 0.8158 (3) 0.0406 (2) 0.0291 (6) H22 1.0113 0.7430 0.0207 0.035\* C23 0.8054 (3) 0.8539 (3) 0.0084 (2) 0.0272 (6) H23 0.7822 0.8067 −0.0349 0.033\* C24 1.1264 (3) 0.8448 (3) 0.1420 (2) 0.0328 (7) H24A 1.1478 0.9201 0.1405 0.049\* H24B 1.1893 0.7918 0.0962 0.049\* H24C 1.1378 0.7964 0.2150 0.049\* Cu1 0.5000 1.0000 0.5000 0.01857 (11) Cu2 0.5000 1.0000 0.0000 0.02031 (11) N1 0.6596 (2) 1.0589 (2) 0.50462 (17) 0.0197 (4) N2 0.6332 (2) 0.8438 (2) 0.44667 (17) 0.0196 (4) N3 0.5002 (2) 0.8479 (2) 0.11114 (17) 0.0204 (4) N4 0.7039 (2) 0.9544 (2) 0.03565 (17) 0.0208 (4) O1 0.4432 (2) 1.11465 (19) 0.32076 (14) 0.0241 (4) O2 0.4297 (2) 1.1372 (2) 0.13099 (15) 0.0257 (4) O3 0.2438 (2) 1.2743 (2) 0.21897 (18) 0.0387 (6) O4 0.4641 (3) 1.2969 (2) 0.20710 (19) 0.0389 (6) O5 0.7247 (3) 0.3043 (2) 0.1438 (2) 0.0501 (7) H5A 0.7007 0.3519 0.0826 0.075\* H5B 0.6529 0.2956 0.1714 0.075\* O6 0.3674 (3) 0.5172 (3) 0.0548 (2) 0.0568 (7) H6A 0.4103 0.5011 −0.0008 0.085\* 0.50 H6B 0.4034 0.4467 0.0972 0.085\* H6C 0.2905 0.5147 0.0399 0.085\* 0.50 O7 0.9960 (3) 0.2146 (3) 0.2479 (2) 0.0567 (8) H7A 0.9293 0.2632 0.2054 0.085\* H7B 1.0552 0.2449 0.2228 0.085\* O8 0.1306 (4) 0.4630 (4) 0.0397 (4) 0.0971 (15) H8A 0.1109 0.4722 0.1027 0.146\* H8B 0.1842 0.5027 0.0261 0.146\* 0.50 H8C 0.0507 0.4844 0.0125 0.146\* 0.50 O9 0.2000 (7) 0.5327 (6) 0.2704 (5) 0.045 (2) 0.393 (8) H9A 0.2311 0.5640 0.2151 0.067\* 0.393 (8) H9B 0.2166 0.4593 0.2590 0.067\* 0.393 (8) S3 0.39467 (7) 1.20521 (6) 0.21937 (5) 0.01904 (13) ------ ------------- -------------- -------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1846 .table-wrap} ----- ------------- ------------- ------------- --------------- --------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ C1 0.0229 (13) 0.0205 (12) 0.0186 (12) −0.0087 (11) −0.0004 (9) −0.0046 (10) C2 0.0201 (12) 0.0294 (14) 0.0220 (13) −0.0095 (11) −0.0012 (10) −0.0099 (11) C3 0.0187 (12) 0.0275 (14) 0.0274 (14) −0.0106 (11) 0.0047 (10) −0.0131 (11) C4 0.0276 (14) 0.0269 (14) 0.0247 (14) −0.0145 (12) 0.0019 (11) −0.0035 (11) C5 0.0278 (14) 0.0285 (14) 0.0198 (13) −0.0162 (12) −0.0028 (10) −0.0002 (10) C6 0.0259 (14) 0.0341 (16) 0.0411 (17) −0.0166 (13) 0.0008 (12) −0.0126 (13) C7 0.0371 (16) 0.0245 (14) 0.0176 (12) −0.0145 (12) −0.0017 (11) −0.0015 (10) C8 0.0478 (19) 0.0231 (14) 0.0235 (14) −0.0138 (14) −0.0010 (13) −0.0013 (11) C9 0.0316 (15) 0.0267 (15) 0.0241 (14) −0.0111 (12) −0.0026 (11) −0.0056 (11) C10 0.062 (2) 0.0287 (17) 0.0363 (19) −0.0067 (17) 0.0047 (17) −0.0091 (14) C11 0.0238 (13) 0.0278 (14) 0.0184 (12) −0.0128 (11) 0.0005 (10) −0.0046 (10) C12 0.0202 (12) 0.0258 (13) 0.0190 (12) −0.0118 (11) −0.0009 (10) −0.0014 (10) C13 0.0212 (13) 0.0235 (13) 0.0222 (13) −0.0106 (11) −0.0007 (10) −0.0044 (10) C14 0.0221 (12) 0.0275 (14) 0.0178 (12) −0.0145 (11) 0.0002 (10) −0.0051 (10) C15 0.0333 (15) 0.0262 (14) 0.0187 (13) −0.0148 (12) −0.0032 (11) −0.0017 (10) C16 0.053 (2) 0.0220 (14) 0.0234 (14) −0.0103 (14) 0.0054 (13) −0.0057 (11) C17 0.0429 (18) 0.0297 (15) 0.0183 (13) −0.0117 (14) 0.0062 (12) −0.0053 (11) C18 0.062 (2) 0.0293 (16) 0.0227 (15) −0.0231 (16) 0.0065 (14) −0.0013 (12) C19 0.0259 (13) 0.0262 (14) 0.0201 (12) −0.0157 (11) −0.0012 (10) −0.0010 (10) C20 0.0290 (14) 0.0341 (15) 0.0208 (13) −0.0211 (13) −0.0035 (10) −0.0006 (11) C21 0.0212 (13) 0.0377 (16) 0.0175 (12) −0.0147 (12) −0.0016 (10) 0.0032 (11) C22 0.0232 (14) 0.0358 (16) 0.0252 (14) −0.0078 (12) −0.0004 (11) −0.0059 (12) C23 0.0280 (14) 0.0338 (15) 0.0223 (13) −0.0134 (13) −0.0044 (11) −0.0065 (12) C24 0.0235 (14) 0.0469 (18) 0.0278 (15) −0.0162 (14) −0.0024 (11) −0.0009 (13) Cu1 0.0212 (2) 0.0220 (2) 0.0169 (2) −0.01266 (19) −0.00015 (16) −0.00454 (18) Cu2 0.0198 (2) 0.0240 (2) 0.0176 (2) −0.0110 (2) −0.00355 (16) 0.00135 (18) N1 0.0229 (11) 0.0248 (11) 0.0158 (10) −0.0127 (9) 0.0005 (8) −0.0060 (8) N2 0.0237 (11) 0.0233 (11) 0.0163 (10) −0.0141 (9) −0.0028 (8) −0.0025 (8) N3 0.0213 (11) 0.0236 (11) 0.0178 (10) −0.0103 (9) −0.0041 (8) −0.0027 (9) N4 0.0221 (11) 0.0242 (11) 0.0172 (10) −0.0119 (9) −0.0015 (8) 0.0003 (8) O1 0.0311 (10) 0.0295 (10) 0.0130 (8) −0.0145 (9) −0.0030 (7) −0.0002 (7) O2 0.0331 (11) 0.0319 (11) 0.0149 (9) −0.0143 (9) 0.0015 (8) −0.0069 (8) O3 0.0250 (11) 0.0461 (14) 0.0315 (12) −0.0004 (10) 0.0011 (9) −0.0046 (10) O4 0.0571 (15) 0.0289 (11) 0.0373 (13) −0.0282 (11) −0.0223 (11) 0.0077 (9) O5 0.0516 (16) 0.0386 (14) 0.0540 (16) −0.0131 (12) −0.0121 (13) −0.0011 (12) O6 0.077 (2) 0.0500 (17) 0.0409 (15) −0.0260 (16) −0.0023 (14) 0.0007 (13) O7 0.0577 (17) 0.0562 (17) 0.0492 (16) −0.0260 (15) −0.0123 (13) 0.0174 (14) O8 0.066 (2) 0.089 (3) 0.123 (3) −0.044 (2) −0.044 (2) 0.050 (2) O9 0.049 (4) 0.044 (4) 0.045 (4) −0.017 (3) 0.001 (3) −0.017 (3) S3 0.0231 (3) 0.0207 (3) 0.0147 (3) −0.0099 (2) −0.0032 (2) −0.0026 (2) ----- ------------- ------------- ------------- --------------- --------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2694 .table-wrap} ----------------------- ------------ ------------------------- -------------- C1---N1 1.343 (3) C19---N4 1.342 (3) C1---C2 1.386 (4) C19---C20 1.388 (4) C1---H1 0.9500 C19---H19 0.9500 C2---C3 1.387 (4) C20---C21 1.386 (4) C2---H2 0.9500 C20---H20 0.9500 C3---C4 1.389 (4) C21---C22 1.391 (4) C3---C6 1.509 (4) C21---C24 1.508 (4) C4---C5 1.386 (4) C22---C23 1.388 (4) C4---H4 0.9500 C22---H22 0.9500 C5---N1 1.348 (4) C23---N4 1.341 (4) C5---H5 0.9500 C23---H23 0.9500 C6---H6F 0.9800 C24---H24A 0.9800 C6---H6E 0.9800 C24---H24B 0.9800 C6---H6D 0.9800 C24---H24C 0.9800 C7---N2 1.352 (4) Cu1---N1^i^ 2.041 (2) C7---C8 1.373 (4) Cu1---N1 2.041 (2) C7---H7 0.9500 Cu1---N2 2.046 (2) C8---C9 1.397 (4) Cu1---N2^i^ 2.046 (2) C8---H8 0.9500 Cu1---O1 2.3926 (18) C9---C11 1.385 (4) Cu1---O1^i^ 2.3926 (18) C9---C10 1.503 (4) Cu2---N4^ii^ 2.042 (2) C10---H10A 0.9800 Cu2---N4 2.042 (2) C10---H10B 0.9800 Cu2---N3 2.042 (2) C10---H10C 0.9800 Cu2---N3^ii^ 2.042 (2) C11---C12 1.382 (4) Cu2---O2^ii^ 2.443 (2) C11---H11 0.9500 Cu2---O2 2.443 (2) C12---N2 1.348 (3) O1---S3 1.4726 (19) C12---H12 0.9500 O2---S3 1.464 (2) C13---N3 1.344 (3) O3---S3 1.473 (2) C13---C14 1.387 (4) O4---S3 1.485 (2) C13---H13 0.9500 O5---H5A 0.8515 C14---C15 1.382 (4) O5---H5B 0.8498 C14---H14 0.9500 O6---H6A 0.8408 C15---C16 1.388 (4) O6---H6B 0.8470 C15---C18 1.507 (4) O6---H6C 0.8472 C16---C17 1.381 (4) O7---H7A 0.8445 C16---H16 0.9500 O7---H7B 0.8477 C17---N3 1.336 (4) O8---H8A 0.8431 C17---H17 0.9500 O8---H8B 0.8459 C18---H18A 0.9800 O8---H8C 0.8456 C18---H18B 0.9800 O9---H9A 0.8436 C18---H18C 0.9800 O9---H9B 0.8448 N1---C1---C2 122.6 (3) C22---C21---C24 121.1 (3) N1---C1---H1 118.7 C23---C22---C21 119.3 (3) C2---C1---H1 118.7 C23---C22---H22 120.3 C1---C2---C3 120.0 (3) C21---C22---H22 120.3 C1---C2---H2 120.0 N4---C23---C22 123.0 (3) C3---C2---H2 120.0 N4---C23---H23 118.5 C2---C3---C4 117.3 (2) C22---C23---H23 118.5 C2---C3---C6 121.7 (3) C21---C24---H24A 109.5 C4---C3---C6 121.0 (3) C21---C24---H24B 109.5 C5---C4---C3 119.7 (3) H24A---C24---H24B 109.5 C5---C4---H4 120.1 C21---C24---H24C 109.5 C3---C4---H4 120.1 H24A---C24---H24C 109.5 N1---C5---C4 122.7 (3) H24B---C24---H24C 109.5 N1---C5---H5 118.7 N1^i^---Cu1---N1 180.00 (11) C4---C5---H5 118.7 N1^i^---Cu1---N2 91.28 (9) C3---C6---H6F 109.5 N1---Cu1---N2 88.72 (9) C3---C6---H6E 109.5 N1^i^---Cu1---N2^i^ 88.72 (9) H6F---C6---H6E 109.5 N1---Cu1---N2^i^ 91.28 (9) C3---C6---H6D 109.5 N2---Cu1---N2^i^ 179.999 (1) H6F---C6---H6D 109.5 N1^i^---Cu1---O1 90.27 (8) H6E---C6---H6D 109.5 N1---Cu1---O1 89.73 (8) N2---C7---C8 122.9 (3) N2---Cu1---O1 90.38 (8) N2---C7---H7 118.5 N2^i^---Cu1---O1 89.62 (8) C8---C7---H7 118.5 N1^i^---Cu1---O1^i^ 89.73 (8) C7---C8---C9 120.4 (3) N1---Cu1---O1^i^ 90.27 (8) C7---C8---H8 119.8 N2---Cu1---O1^i^ 89.62 (8) C9---C8---H8 119.8 N2^i^---Cu1---O1^i^ 90.38 (8) C11---C9---C8 116.6 (3) O1---Cu1---O1^i^ 180.0 C11---C9---C10 121.3 (3) N4^ii^---Cu2---N4 180.0 C8---C9---C10 122.1 (3) N4^ii^---Cu2---N3 89.63 (9) C9---C10---H10A 109.5 N4---Cu2---N3 90.37 (9) C9---C10---H10B 109.5 N4^ii^---Cu2---N3^ii^ 90.37 (9) H10A---C10---H10B 109.5 N4---Cu2---N3^ii^ 89.63 (9) C9---C10---H10C 109.5 N3---Cu2---N3^ii^ 179.999 (1) H10A---C10---H10C 109.5 N4---Cu2---O2^ii^ 88.90 (8) H10B---C10---H10C 109.5 N4^ii^---Cu2---O2^ii^ 91.11 (8) C12---C11---C9 120.2 (3) N3---Cu2---O2^ii^ 88.72 (8) C12---C11---H11 119.9 N3^ii^---Cu2---O2^ii^ 91.28 (8) C9---C11---H11 119.9 N4---Cu2---O2 91.11 (8) N2---C12---C11 123.1 (3) N4^ii^---Cu2---O2 88.90 (8) N2---C12---H12 118.5 N3---Cu2---O2 91.28 (8) C11---C12---H12 118.5 N3^ii^---Cu2---O2 88.72 (8) N3---C13---C14 122.4 (3) O2^ii^---Cu2---O2 180.000 (1) N3---C13---H13 118.8 C1---N1---C5 117.5 (2) C14---C13---H13 118.8 C1---N1---Cu1 120.11 (18) C15---C14---C13 120.2 (3) C5---N1---Cu1 122.30 (18) C15---C14---H14 119.9 C12---N2---C7 116.8 (2) C13---C14---H14 119.9 C12---N2---Cu1 119.50 (19) C14---C15---C16 116.9 (3) C7---N2---Cu1 123.72 (19) C14---C15---C18 121.5 (3) C17---N3---C13 117.5 (2) C16---C15---C18 121.7 (3) C17---N3---Cu2 122.05 (19) C17---C16---C15 120.1 (3) C13---N3---Cu2 120.41 (19) C17---C16---H16 120.0 C23---N4---C19 117.7 (2) C15---C16---H16 120.0 C23---N4---Cu2 122.75 (19) N3---C17---C16 122.9 (3) C19---N4---Cu2 119.52 (19) N3---C17---H17 118.5 S3---O1---Cu1 169.60 (13) C16---C17---H17 118.5 H5A---O5---H5B 107.6 C15---C18---H18A 109.5 H6A---O6---H6B 101.2 C15---C18---H18B 109.5 H6A---O6---H6C 101.0 H18A---C18---H18B 109.5 H6B---O6---H6C 100.4 C15---C18---H18C 109.5 H7A---O7---H7B 97.7 H18A---C18---H18C 109.5 H8A---O8---H8B 100.6 H18B---C18---H18C 109.5 H8A---O8---H8C 100.5 N4---C19---C20 122.5 (3) H8B---O8---H8C 126.9 N4---C19---H19 118.7 H9A---O9---H9B 100.6 C20---C19---H19 118.7 O2---S3---O1 109.72 (12) C21---C20---C19 119.9 (3) O2---S3---O3 109.57 (13) C21---C20---H20 120.0 O1---S3---O3 110.06 (13) C19---C20---H20 120.0 O2---S3---O4 109.34 (14) C20---C21---C22 117.5 (3) O1---S3---O4 108.76 (12) C20---C21---C24 121.4 (3) O3---S3---O4 109.37 (15) N1---C1---C2---C3 −0.3 (4) C11---C12---N2---C7 0.1 (4) C1---C2---C3---C4 −2.6 (4) C11---C12---N2---Cu1 −179.4 (2) C1---C2---C3---C6 176.9 (3) C8---C7---N2---C12 −0.1 (4) C2---C3---C4---C5 2.7 (4) C8---C7---N2---Cu1 179.4 (2) C6---C3---C4---C5 −176.8 (3) N1^i^---Cu1---N2---C12 109.81 (19) C3---C4---C5---N1 0.1 (5) N1---Cu1---N2---C12 −70.19 (19) N2---C7---C8---C9 −0.7 (5) O1---Cu1---N2---C12 19.53 (19) C7---C8---C9---C11 1.5 (4) O1^i^---Cu1---N2---C12 −160.47 (19) C7---C8---C9---C10 −178.2 (3) N1^i^---Cu1---N2---C7 −69.7 (2) C8---C9---C11---C12 −1.5 (4) N1---Cu1---N2---C7 110.3 (2) C10---C9---C11---C12 178.3 (3) O1---Cu1---N2---C7 −160.0 (2) C9---C11---C12---N2 0.7 (4) O1^i^---Cu1---N2---C7 20.0 (2) N3---C13---C14---C15 0.1 (4) C16---C17---N3---C13 1.0 (5) C13---C14---C15---C16 1.2 (4) C16---C17---N3---Cu2 −179.6 (3) C13---C14---C15---C18 −179.7 (3) C14---C13---N3---C17 −1.2 (4) C14---C15---C16---C17 −1.4 (5) C14---C13---N3---Cu2 179.34 (19) C18---C15---C16---C17 179.4 (3) N4^ii^---Cu2---N3---C17 109.5 (2) C15---C16---C17---N3 0.4 (5) N4---Cu2---N3---C17 −70.5 (2) N4---C19---C20---C21 0.1 (4) N4^ii^---Cu2---N3---C13 −71.1 (2) C19---C20---C21---C22 1.6 (4) N4---Cu2---N3---C13 108.9 (2) C19---C20---C21---C24 −177.5 (3) C22---C23---N4---C19 2.9 (4) C20---C21---C22---C23 −1.1 (4) C22---C23---N4---Cu2 −174.0 (2) C24---C21---C22---C23 178.1 (3) C20---C19---N4---C23 −2.3 (4) C21---C22---C23---N4 −1.2 (5) C20---C19---N4---Cu2 174.7 (2) C2---C1---N1---C5 3.2 (4) N3---Cu2---N4---C23 71.8 (2) C2---C1---N1---Cu1 −174.3 (2) N3^ii^---Cu2---N4---C23 −108.2 (2) C4---C5---N1---C1 −3.1 (4) N3---Cu2---N4---C19 −105.1 (2) C4---C5---N1---Cu1 174.3 (2) N3^ii^---Cu2---N4---C19 74.9 (2) N2---Cu1---N1---C1 −73.2 (2) N1^i^---Cu1---O1---S3 97.0 (7) N2^i^---Cu1---N1---C1 106.8 (2) N1---Cu1---O1---S3 −83.0 (7) O1---Cu1---N1---C1 −163.6 (2) N2---Cu1---O1---S3 −171.7 (7) O1^i^---Cu1---N1---C1 16.4 (2) N2^i^---Cu1---O1---S3 8.3 (7) N2---Cu1---N1---C5 109.4 (2) Cu1---O1---S3---O2 −173.0 (7) N2^i^---Cu1---N1---C5 −70.6 (2) Cu1---O1---S3---O3 −52.3 (7) O1---Cu1---N1---C5 19.1 (2) Cu1---O1---S3---O4 67.4 (7) O1^i^---Cu1---N1---C5 −160.9 (2) ----------------------- ------------ ------------------------- -------------- ::: Symmetry codes: (i) −*x*+1, −*y*+2, −*z*+1; (ii) −*x*+1, −*y*+2, −*z*. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e4294 .table-wrap} -------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O5---H5A···O6^iii^ 0.85 2.04 2.887 (4) 173 O5---H5B···O4^iv^ 0.85 2.01 2.843 (4) 168 O6---H6A···O6^iii^ 0.84 2.34 2.983 (6) 133 O6---H6B···O4^iv^ 0.85 1.92 2.762 (4) 172 O6---H6C···O8 0.85 1.98 2.804 (5) 163 O7---H7A···O5 0.84 2.16 2.906 (4) 148 O7---H7B···O3^v^ 0.85 2.13 2.923 (4) 157 O8---H8A···O3^iv^ 0.84 2.42 2.788 (4) 107 O8---H8B···O6 0.85 2.04 2.804 (5) 149 O8---H8C···O8^vi^ 0.85 1.87 2.710 (7) 176 O9---H9A···O6 0.84 2.48 3.210 (7) 145 O9---H9B···O3^iv^ 0.84 2.22 3.063 (7) 175 O9---H9B···O4^iv^ 0.84 2.71 3.275 (7) 126 -------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (iii) −*x*+1, −*y*+1, −*z*; (iv) *x*, *y*−1, *z*; (v) *x*+1, *y*−1, *z*; (vi) −*x*, −*y*+1, −*z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- --------- ------- ----------- ------------- O5---H5*A*⋯O6^i^ 0.85 2.04 2.887 (4) 173 O5---H5*B*⋯O4^ii^ 0.85 2.01 2.843 (4) 168 O6---H6*A*⋯O6^i^ 0.84 2.34 2.983 (6) 133 O6---H6*B*⋯O4^ii^ 0.85 1.92 2.762 (4) 172 O6---H6*C*⋯O8 0.85 1.98 2.804 (5) 163 O7---H7*A*⋯O5 0.84 2.16 2.906 (4) 148 O7---H7*B*⋯O3^iii^ 0.85 2.13 2.923 (4) 157 O8---H8*A*⋯O3^ii^ 0.84 2.42 2.788 (4) 107 O8---H8*B*⋯O6 0.85 2.04 2.804 (5) 149 O8---H8*C*⋯O8^iv^ 0.85 1.87 2.710 (7) 176 O9---H9*A*⋯O6 0.84 2.48 3.210 (7) 145 O9---H9*B*⋯O3^ii^ 0.84 2.22 3.063 (7) 175 O9---H9*B*⋯O4^ii^ 0.84 2.71 3.275 (7) 126 Symmetry codes: (i) ; (ii) ; (iii) ; (iv) . :::

PubMed Central

2024-06-05T04:04:17.717484

2011-2-26

PMC3051988

Related literature {#sec1} ================== For background to ketamine, see: Holtman (2006[@bb3]); Holtman *et al.* (2006[@bb4]); Heshmati *et al.* (2003[@bb2]); Kohrs & Durieux (1998[@bb6]). For the synthesis, see: Hong & Davisson (1982[@bb5]); Parcell & Sanchez (1981[@bb9]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~12~H~15~ClNO^+^·C~4~H~5~O~6~ ^−^*M* *~r~* = 373.78Orthorhombic,*a* = 7.1411 (2) Å*b* = 9.9878 (4) Å*c* = 23.7530 (11) Å*V* = 1694.16 (11) Å^3^*Z* = 4Mo *K*α radiationμ = 0.27 mm^−1^*T* = 90 K0.20 × 0.20 × 0.03 mm ### Data collection {#sec2.1.2} Nonius KappaCCD diffractometerAbsorption correction: multi-scan (*SCALEPACK*; Otwinowski & Minor, 1997[@bb8]) *T* ~min~ = 0.949, *T* ~max~ = 0.99213735 measured reflections2986 independent reflections1519 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.110 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.060*wR*(*F* ^2^) = 0.139*S* = 0.962986 reflections230 parametersH-atom parameters constrainedΔρ~max~ = 0.28 e Å^−3^Δρ~min~ = −0.27 e Å^−3^Absolute structure: Flack (1983[@bb1]), 1241 Friedel pairsFlack parameter: 0.10 (10) {#d5e594} Data collection: *COLLECT* (Nonius, 1998[@bb7]); cell refinement: *SCALEPACK* (Otwinowski & Minor, 1997[@bb8]); data reduction: *DENZO-SMN* (Otwinowski & Minor, 1997[@bb8]); program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb10]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb10]); molecular graphics: *XP* in *SHELXTL* (Sheldrick, 2008[@bb10]); software used to prepare material for publication: *SHELXL97* and local procedures. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811006131/hg2766sup1.cif](http://dx.doi.org/10.1107/S1600536811006131/hg2766sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006131/hg2766Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006131/hg2766Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?hg2766&file=hg2766sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?hg2766sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?hg2766&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [HG2766](http://scripts.iucr.org/cgi-bin/sendsup?hg2766)). The research was funded by the US Army Medical Research Material Command, Combat Casualty Care Research, Fort Detrick, MD contract W81XWH-06--1-0275 (MB) and by Yaupon Therapeutics, Inc. (MH, GZ, MS, SP and PAC). Comment ======= Ketalar^TM^, the racemic mixture of *R-* and *S*-Ketamines is becoming the sedative and anesthetic of choice for emergency sedation in children and victims with unknown medical history, *e.g.* from traffic accidents to battlefield conditions, because it causes minimal respiratory depression in comparison to other anesthetics (Heshmati *et al.*, 2003). *S*-Ketamine was found 3--4 times more potent as an anesthetic than its *R*-enantiomer, and twice as potent as Ketalar^TM^ with fewer side effects such as psychedelic, disorientation and anxiety (Kohrs & Durieux, 1998). *S*-Norketamine, the major metabolite of *S*-Ketamine in humans and animals, is emerging as a novel drug for treatment of neuropathic pain (Holtman *et al.*, 2006) and for analgesia (Holtman, 2006). To confirm the absolute configuration of (+)-norketamine, herein we report on the X-ray crystallographic characterization of crystalline *S*-norketamine D-tartrate salt. Experimental {#experimental} ============ *S*-Norketamine was obtained as a D-tartrate salt form *via* chiral resolution of racemic norketamine by fractional crystallization of the D-tartrate salt (Hong & Davisson, 1982). Racemic norketamine was produced in large quantity according to literature report (Parcell & Sanchez, 1981). The chiral purity of the product was determined by chiral HPLC on a Chiralcel OJ---H column, and afforded ee% \> 99%. The specific rotation of the tartrate salt is \[*a*\]~D~ + 55.7° (c = 2, H~2~O), and the specific rotations for the corresponding corresponding free base and HCl salt are \[*a*\]~D~ + 3.6° (c = 2, EtOH) and \[*a*\]~D~ + 75.9° (c = 1, H~2~O), respectively. Refinement {#refinement} ========== H atoms were found in difference Fourier maps and subsequently placed in idealized positions with constrained distances of 0.95 Å (C~Ar~H), 1.00 Å (*R*~3~CH), 0.99 Å (*R*~2~CH~2~), 0.84 Å (O---H), 0.91 Å (NH~3~), and with *U*~iso~(H) values set to either 1.2*U*~eq~ or 1.5*U*~eq~ (NH~3~, OH) of the attached atom. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### A view of the molecules with the atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e195 .table-wrap} ----------------------------------- --------------------------------------- C~12~H~15~ClNO^+^·C~4~H~5~O~6~^−^ *F*(000) = 784 *M~r~* = 373.78 *D*~x~ = 1.465 Mg m^−3^ Orthorhombic, *P*2~1~2~1~2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2ac 2ab Cell parameters from 2155 reflections *a* = 7.1411 (2) Å θ = 1.0--27.5° *b* = 9.9878 (4) Å µ = 0.27 mm^−1^ *c* = 23.7530 (11) Å *T* = 90 K *V* = 1694.16 (11) Å^3^ Plate, colourless *Z* = 4 0.20 × 0.20 × 0.03 mm ----------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e332 .table-wrap} --------------------------------------------------------------------------- -------------------------------------- Nonius KappaCCD diffractometer 2986 independent reflections Radiation source: fine-focus sealed tube 1519 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.110 Detector resolution: 9.1 pixels mm^-1^ θ~max~ = 25.0°, θ~min~ = 1.7° ω scans at fixed χ = 55° *h* = −8→8 Absorption correction: multi-scan (*SCALEPACK*; Otwinowski & Minor, 1997) *k* = −11→11 *T*~min~ = 0.949, *T*~max~ = 0.992 *l* = −27→28 13735 measured reflections --------------------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e455 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.060 H-atom parameters constrained *wR*(*F*^2^) = 0.139 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0568*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 0.96 (Δ/σ)~max~ \< 0.001 2986 reflections Δρ~max~ = 0.28 e Å^−3^ 230 parameters Δρ~min~ = −0.27 e Å^−3^ 0 restraints Absolute structure: Flack (1983), 1241 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: 0.10 (10) ---------------------------------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e614 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> 2σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e713 .table-wrap} ------ ------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl1 0.3664 (2) 0.71723 (16) 0.91603 (9) 0.0776 (7) O1 0.4054 (5) 0.4009 (4) 0.92986 (16) 0.0391 (11) N1 0.5914 (5) 0.4734 (4) 0.83868 (16) 0.0254 (12) H1A 0.6786 0.4352 0.8158 0.038\* H1B 0.5453 0.5485 0.8220 0.038\* H1C 0.4964 0.4144 0.8448 0.038\* C1 0.5939 (7) 0.7596 (6) 0.8988 (2) 0.0418 (17) C2 0.6335 (10) 0.8933 (6) 0.8922 (3) 0.057 (2) H2 0.5381 0.9585 0.8973 0.069\* C3 0.8128 (10) 0.9322 (6) 0.8779 (2) 0.0449 (18) H3 0.8403 1.0242 0.8720 0.054\* C4 0.9520 (9) 0.8374 (6) 0.8723 (2) 0.0339 (15) H4 1.0764 0.8643 0.8638 0.041\* C5 0.9097 (7) 0.7021 (5) 0.8790 (2) 0.0282 (15) H5 1.0058 0.6375 0.8740 0.034\* C6 0.7292 (7) 0.6595 (5) 0.8931 (2) 0.0246 (14) C7 0.6805 (7) 0.5100 (5) 0.8940 (2) 0.0226 (13) C8 0.8535 (7) 0.4174 (5) 0.9031 (2) 0.0291 (14) H8A 0.8155 0.3229 0.8978 0.035\* H8B 0.9501 0.4387 0.8746 0.035\* C9 0.9367 (8) 0.4348 (6) 0.9620 (2) 0.0399 (16) H9A 1.0470 0.3756 0.9662 0.048\* H9B 0.9791 0.5285 0.9669 0.048\* C10 0.7954 (9) 0.4015 (6) 1.0067 (2) 0.0489 (18) H10A 0.8503 0.4184 1.0443 0.059\* H10B 0.7626 0.3054 1.0043 0.059\* C11 0.6186 (9) 0.4861 (7) 0.9995 (2) 0.0505 (19) H11A 0.5231 0.4588 1.0274 0.061\* H11B 0.6481 0.5819 1.0055 0.061\* C12 0.5447 (9) 0.4655 (5) 0.9409 (2) 0.0321 (14) C13 0.5503 (8) 0.6596 (5) 0.6984 (3) 0.0266 (14) C14 0.7637 (7) 0.6537 (5) 0.6976 (2) 0.0242 (14) H14 0.8039 0.5662 0.7141 0.029\* C15 0.8443 (7) 0.7649 (5) 0.7331 (2) 0.0218 (13) H15 0.7942 0.7538 0.7721 0.026\* C16 1.0558 (8) 0.7639 (6) 0.7370 (2) 0.0255 (14) O2 0.8330 (5) 0.6619 (4) 0.64159 (14) 0.0297 (10) H2A 0.7541 0.7012 0.6212 0.045\* O3 0.4634 (5) 0.6867 (3) 0.65555 (16) 0.0291 (10) O4 0.4745 (5) 0.6434 (3) 0.74860 (16) 0.0334 (10) O5 0.7747 (5) 0.8881 (3) 0.71191 (15) 0.0287 (10) H5A 0.8366 0.9517 0.7257 0.043\* O6 1.1301 (5) 0.6502 (3) 0.74840 (16) 0.0304 (9) H6 1.2464 0.6547 0.7436 0.046\* O7 1.1404 (5) 0.8705 (3) 0.72982 (14) 0.0269 (9) ------ ------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1293 .table-wrap} ----- ------------- ------------ ----------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.0331 (10) 0.0394 (9) 0.160 (2) 0.0090 (9) 0.0157 (11) −0.0109 (12) O1 0.029 (3) 0.038 (2) 0.050 (3) −0.0149 (19) 0.003 (2) −0.008 (2) N1 0.025 (3) 0.019 (2) 0.032 (3) 0.001 (2) 0.000 (2) −0.002 (2) C1 0.031 (4) 0.027 (4) 0.068 (5) 0.004 (3) −0.004 (3) −0.005 (3) C2 0.045 (4) 0.030 (4) 0.096 (6) 0.009 (4) −0.009 (4) −0.008 (4) C3 0.066 (5) 0.026 (4) 0.042 (4) −0.011 (4) −0.025 (4) −0.004 (3) C4 0.041 (4) 0.033 (4) 0.028 (3) −0.009 (3) 0.003 (3) 0.003 (3) C5 0.030 (4) 0.029 (4) 0.026 (3) −0.006 (3) −0.002 (3) 0.001 (3) C6 0.031 (3) 0.026 (3) 0.017 (3) −0.001 (3) −0.001 (3) 0.000 (3) C7 0.024 (3) 0.021 (3) 0.023 (3) −0.005 (3) −0.005 (3) −0.001 (3) C8 0.030 (3) 0.021 (3) 0.036 (4) 0.001 (3) −0.005 (3) 0.005 (3) C9 0.043 (4) 0.037 (4) 0.040 (4) 0.000 (3) −0.004 (4) 0.010 (3) C10 0.053 (5) 0.055 (5) 0.039 (4) −0.008 (4) −0.010 (4) 0.010 (4) C11 0.056 (5) 0.068 (5) 0.027 (4) −0.013 (4) 0.016 (4) −0.004 (4) C12 0.035 (4) 0.028 (4) 0.033 (4) 0.009 (3) 0.005 (3) −0.001 (3) C13 0.023 (3) 0.014 (3) 0.043 (4) −0.003 (3) −0.007 (3) 0.005 (3) C14 0.023 (3) 0.022 (3) 0.028 (4) −0.002 (3) 0.002 (3) 0.010 (3) C15 0.018 (3) 0.023 (3) 0.025 (3) 0.003 (3) 0.001 (3) 0.003 (3) C16 0.031 (4) 0.030 (4) 0.016 (3) 0.006 (3) 0.007 (3) 0.001 (3) O2 0.030 (2) 0.031 (2) 0.028 (2) 0.004 (2) −0.0047 (19) −0.0057 (18) O3 0.025 (2) 0.022 (2) 0.040 (2) 0.0016 (18) −0.012 (2) 0.0039 (19) O4 0.027 (2) 0.035 (2) 0.039 (2) −0.0003 (19) −0.005 (2) 0.010 (2) O5 0.028 (2) 0.014 (2) 0.044 (2) 0.0049 (17) −0.0106 (19) −0.0062 (19) O6 0.013 (2) 0.027 (2) 0.052 (3) 0.0024 (19) 0.002 (2) 0.010 (2) O7 0.027 (2) 0.023 (2) 0.031 (2) −0.0046 (19) 0.0049 (19) 0.0026 (18) ----- ------------- ------------ ----------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1789 .table-wrap} --------------------- ------------ ----------------------- ------------ Cl1---C1 1.728 (6) C9---H9A 0.9900 O1---C12 1.214 (6) C9---H9B 0.9900 N1---C7 1.505 (6) C10---C11 1.529 (8) N1---H1A 0.9100 C10---H10A 0.9900 N1---H1B 0.9100 C10---H10B 0.9900 N1---H1C 0.9100 C11---C12 1.503 (8) C1---C2 1.374 (8) C11---H11A 0.9900 C1---C6 1.397 (7) C11---H11B 0.9900 C2---C3 1.380 (8) C13---O3 1.223 (6) C2---H2 0.9500 C13---O4 1.320 (6) C3---C4 1.379 (7) C13---C14 1.525 (7) C3---H3 0.9500 C14---O2 1.423 (5) C4---C5 1.393 (7) C14---C15 1.508 (6) C4---H4 0.9500 C14---H14 1.0000 C5---C6 1.398 (7) C15---O5 1.419 (5) C5---H5 0.9500 C15---C16 1.513 (6) C6---C7 1.533 (7) C15---H15 1.0000 C7---C12 1.542 (7) C16---O7 1.237 (6) C7---C8 1.558 (7) C16---O6 1.282 (6) C8---C9 1.531 (7) O2---H2A 0.8400 C8---H8A 0.9900 O5---H5A 0.8400 C8---H8B 0.9900 O6---H6 0.8400 C9---C10 1.501 (7) C7---N1---H1A 109.5 C10---C9---H9B 109.4 C7---N1---H1B 109.5 C8---C9---H9B 109.4 H1A---N1---H1B 109.5 H9A---C9---H9B 108.0 C7---N1---H1C 109.5 C9---C10---C11 110.7 (5) H1A---N1---H1C 109.5 C9---C10---H10A 109.5 H1B---N1---H1C 109.5 C11---C10---H10A 109.5 C2---C1---C6 122.9 (6) C9---C10---H10B 109.5 C2---C1---Cl1 117.3 (5) C11---C10---H10B 109.5 C6---C1---Cl1 119.8 (4) H10A---C10---H10B 108.1 C1---C2---C3 119.5 (6) C12---C11---C10 108.5 (5) C1---C2---H2 120.2 C12---C11---H11A 110.0 C3---C2---H2 120.2 C10---C11---H11A 110.0 C4---C3---C2 119.9 (6) C12---C11---H11B 110.0 C4---C3---H3 120.0 C10---C11---H11B 110.0 C2---C3---H3 120.0 H11A---C11---H11B 108.4 C3---C4---C5 119.9 (6) O1---C12---C11 124.0 (6) C3---C4---H4 120.1 O1---C12---C7 120.9 (5) C5---C4---H4 120.1 C11---C12---C7 114.1 (5) C4---C5---C6 121.5 (5) O3---C13---O4 124.8 (5) C4---C5---H5 119.2 O3---C13---C14 120.4 (5) C6---C5---H5 119.2 O4---C13---C14 114.6 (5) C1---C6---C5 116.3 (5) O2---C14---C15 110.3 (4) C1---C6---C7 122.6 (5) O2---C14---C13 110.9 (4) C5---C6---C7 120.6 (5) C15---C14---C13 110.3 (5) N1---C7---C6 108.6 (4) O2---C14---H14 108.4 N1---C7---C12 107.1 (4) C15---C14---H14 108.4 C6---C7---C12 115.7 (4) C13---C14---H14 108.4 N1---C7---C8 108.2 (4) O5---C15---C14 107.9 (4) C6---C7---C8 113.6 (4) O5---C15---C16 112.2 (4) C12---C7---C8 103.2 (4) C14---C15---C16 114.3 (4) C9---C8---C7 111.5 (4) O5---C15---H15 107.4 C9---C8---H8A 109.3 C14---C15---H15 107.4 C7---C8---H8A 109.3 C16---C15---H15 107.4 C9---C8---H8B 109.3 O7---C16---O6 126.1 (5) C7---C8---H8B 109.3 O7---C16---C15 118.3 (5) H8A---C8---H8B 108.0 O6---C16---C15 115.6 (5) C10---C9---C8 111.1 (5) C14---O2---H2A 109.5 C10---C9---H9A 109.4 C15---O5---H5A 109.5 C8---C9---H9A 109.4 C16---O6---H6 109.5 C6---C1---C2---C3 1.5 (10) C9---C10---C11---C12 55.6 (7) Cl1---C1---C2---C3 −179.4 (5) C10---C11---C12---O1 107.0 (6) C1---C2---C3---C4 −2.1 (10) C10---C11---C12---C7 −61.8 (6) C2---C3---C4---C5 2.2 (9) N1---C7---C12---O1 6.8 (6) C3---C4---C5---C6 −1.8 (8) C6---C7---C12---O1 128.1 (5) C2---C1---C6---C5 −1.0 (8) C8---C7---C12---O1 −107.2 (5) Cl1---C1---C6---C5 179.9 (4) N1---C7---C12---C11 175.9 (5) C2---C1---C6---C7 −173.0 (5) C6---C7---C12---C11 −62.8 (6) Cl1---C1---C6---C7 7.9 (7) C8---C7---C12---C11 61.9 (6) C4---C5---C6---C1 1.2 (8) O3---C13---C14---O2 −9.2 (7) C4---C5---C6---C7 173.3 (5) O4---C13---C14---O2 175.6 (4) C1---C6---C7---N1 75.1 (6) O3---C13---C14---C15 113.3 (5) C5---C6---C7---N1 −96.5 (5) O4---C13---C14---C15 −61.9 (6) C1---C6---C7---C12 −45.3 (7) O2---C14---C15---O5 65.8 (5) C5---C6---C7---C12 143.0 (5) C13---C14---C15---O5 −57.0 (6) C1---C6---C7---C8 −164.5 (5) O2---C14---C15---C16 −59.7 (6) C5---C6---C7---C8 23.9 (6) C13---C14---C15---C16 177.5 (5) N1---C7---C8---C9 −172.2 (4) O5---C15---C16---O7 9.9 (7) C6---C7---C8---C9 67.1 (6) C14---C15---C16---O7 133.1 (5) C12---C7---C8---C9 −59.0 (5) O5---C15---C16---O6 −170.8 (4) C7---C8---C9---C10 59.8 (6) C14---C15---C16---O6 −47.6 (6) C8---C9---C10---C11 −56.0 (7) --------------------- ------------ ----------------------- ------------ ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2614 .table-wrap} -------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N1---H1A···O7^i^ 0.91 1.81 2.715 (5) 176 N1---H1B···O4 0.91 2.05 2.856 (5) 147 N1---H1C···O1 0.91 2.13 2.642 (5) 115 N1---H1C···O3^ii^ 0.91 2.29 2.893 (5) 123 N1---H1C···O5^ii^ 0.91 2.37 3.001 (5) 126 O2---H2A···O3 0.84 2.24 2.672 (5) 112 O2---H2A···O1^iii^ 0.84 2.60 3.388 (5) 157 O5---H5A···O6^iv^ 0.84 2.09 2.864 (5) 153 O6---H6···O4^v^ 0.84 1.64 2.460 (5) 166 O6---H6···O3^v^ 0.84 2.62 3.265 (5) 134 -------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+2, *y*−1/2, −*z*+3/2; (ii) −*x*+1, *y*−1/2, −*z*+3/2; (iii) −*x*+1, *y*+1/2, −*z*+3/2; (iv) −*x*+2, *y*+1/2, −*z*+3/2; (v) *x*+1, *y*, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* -------------------- --------- ------- ----------- ------------- N1---H1*A*⋯O7^i^ 0.91 1.81 2.715 (5) 176 N1---H1*B*⋯O4 0.91 2.05 2.856 (5) 147 N1---H1*C*⋯O3^ii^ 0.91 2.29 2.893 (5) 123 N1---H1*C*⋯O5^ii^ 0.91 2.37 3.001 (5) 126 O2---H2*A*⋯O1^iii^ 0.84 2.60 3.388 (5) 157 O5---H5*A*⋯O6^iv^ 0.84 2.09 2.864 (5) 153 O6---H6⋯O4^v^ 0.84 1.64 2.460 (5) 166 O6---H6⋯O3^v^ 0.84 2.62 3.265 (5) 134 Symmetry codes: (i) ; (ii) ; (iii) ; (iv) ; (v) . :::

PubMed Central

2024-06-05T04:04:17.727454

2011-2-26

PMC3051989

Related literature {#sec1} ================== The title compound is a derivative of 4-amino-2(5*H*)-furan­one. For the biological activity of 4-amino-2(5*H*)-furan­ones, see: Lattmann *et al.* (2005[@bb4]); Prasad & Gandi (2010[@bb5]); Steenackers *et al.* (2010[@bb9]). For asymmetric Michael addition reactions of 2(5*H*)-furan­one and for the synthesis of the title compound, see: Song *et al.* (2009[@bb8]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~20~H~32~ClNO~3~*M* *~r~* = 369.92Orthorhombic,*a* = 9.187 (5) Å*b* = 9.248 (5) Å*c* = 24.987 (12) Å*V* = 2122.9 (19) Å^3^*Z* = 4Mo *K*α radiationμ = 0.20 mm^−1^*T* = 298 K0.32 × 0.30 × 0.28 mm ### Data collection {#sec2.1.2} Bruker APEXII area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Sheldrick, 1996[@bb6]) *T* ~min~ = 0.940, *T* ~max~ = 0.94712264 measured reflections4505 independent reflections2620 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.038 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.043*wR*(*F* ^2^) = 0.112*S* = 1.014505 reflections231 parameters24 restraintsH-atom parameters constrainedΔρ~max~ = 0.13 e Å^−3^Δρ~min~ = −0.16 e Å^−3^Absolute structure: Flack (1983[@bb3]), 1921 Friedel pairsFlack parameter: 0.10 (8) {#d5e455} Data collection: *APEX2* (Bruker, 2008[@bb1]); cell refinement: *SAINT* (Bruker, 2008[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *ORTEP-3 for Windows* (Farrugia, 1997[@bb2]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811005216/go2003sup1.cif](http://dx.doi.org/10.1107/S1600536811005216/go2003sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005216/go2003Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005216/go2003Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?go2003&file=go2003sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?go2003sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?go2003&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [GO2003](http://scripts.iucr.org/cgi-bin/sendsup?go2003)). The work was supported by the National Natural Science Foundation of China (grant No. 20772035) and the Natural Science Foundation of Guangdong Province, China (grant No. 5300082). Comment ======= 2(5H)-furanones are heterocyclic carbonyl compounds, which are widespread in natural and in synthetic products (Prasad & Gandi, 2010; Steenackers *et al.*, 2010). 5-menthyloxy-3,4-dihalo-2(5H)-furanones, being a kind of chiral synthons, are widely used in asymmetric Michael addition-elimination tandem reactions (Song *et al.*, 2009). 4-amino-2(5H)-furanones show an antibiotic activity against Staphylococcus aureus (Lattmann *et al.*, 2005). We are interested in the tandem Michael addition-elimination reaction of the chiral synthon 3,4-dichloro-5-(*S*)-(*l*-menthyloxy)-2(5H)-furanone and 4-methylpiperidine in the presence of potassium fluoride. The structure of the title compound (I) is illustrated in Fig. 1. The crystal structure of the title compound, which has four chiral centers (C4(*S*), C5(*R*), C6(*S*), C9(*R*)) contains a five-membered furanone ring and a six-membered cyclohexane ring connected each other *via* C4---O3---C5 ether bond. The furanone ring of C4---O1---C1---C2---C3 is approximately planar, whereas a six-membered cyclohexane ring displays a chair conformation. At the same time, the furanone ring is connected to piperidine heterocycle *via* C3---N1 bond. Experimental {#experimental} ============ The precursor 3,4-dichloro-5-(*S*)-(*l*-menthyloxy)-2(5H)-furanone was prepared according to the literature procedure (Song *et al.*, 2009). After the mixture of 3,4-dichloro-5-(*S*)-(*l*-menthyloxy)-2(5H)-furanone (2.0 mmol) and potassium fluoride (6.0 mmol) was dissolved in absolute tetrahydrofuran (2.0 mL) under nitrogen atmosphere, tetrahydrofuran solution of 4-methylpiperidine (2.0 mmol) was added. The reaction was carried out by stirring at room temperature for 24 h. Once the reaction was complete, the solvents were removed under reduced pressure. The residual solid was dissolved in dichloromethane. Then the combined organic layers from extraction were concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography with the gradient mixture of petroleum ether and ethyl acetate to give the product yielding (I) 0.5685 g (76.8%). Refinement {#refinement} ========== H atoms were positioned in calculated positions with C---H = 0.93-0.98 Å and were refined using a riding model, with U~iso~(H) = 1.5U~eq~(C) for methyl and 1.2U~eq~(C) for the others. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The molecular structure of the title compound showing the atom-labelling scheme. Ellipsoids are drawn at the 50% probability level. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Perspective view of the crystal packing. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e155 .table-wrap} ------------------------------- --------------------------------------- C~20~H~32~ClNO~3~ *F*(000) = 800 *M~r~* = 369.92 *D*~x~ = 1.157 Mg m^−3^ Orthorhombic, *P*2~1~2~1~2~1~ Mo *K*α radiation, λ = 0.71073 Å Hall symbol: P 2ac 2ab Cell parameters from 2408 reflections *a* = 9.187 (5) Å θ = 2.7--19.8° *b* = 9.248 (5) Å µ = 0.20 mm^−1^ *c* = 24.987 (12) Å *T* = 298 K *V* = 2122.9 (19) Å^3^ Block, colourless *Z* = 4 0.32 × 0.30 × 0.28 mm ------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e279 .table-wrap} --------------------------------------------------------------- -------------------------------------- Bruker APEXII area-detector diffractometer 4505 independent reflections Radiation source: fine-focus sealed tube 2620 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.038 φ and ω scans θ~max~ = 26.8°, θ~min~ = 2.4° Absorption correction: multi-scan (*SADABS*; Sheldrick, 1996) *h* = −10→11 *T*~min~ = 0.940, *T*~max~ = 0.947 *k* = −11→10 12264 measured reflections *l* = −31→31 --------------------------------------------------------------- -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e396 .table-wrap} ---------------------------------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ Secondary atom site location: difference Fourier map Least-squares matrix: full Hydrogen site location: inferred from neighbouring sites *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.043 H-atom parameters constrained *wR*(*F*^2^) = 0.112 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0492*P*)^2^ + 0.001*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 *S* = 1.01 (Δ/σ)~max~ \< 0.001 4505 reflections Δρ~max~ = 0.13 e Å^−3^ 231 parameters Δρ~min~ = −0.16 e Å^−3^ 24 restraints Absolute structure: Flack (1983), 1921 Friedel pairs Primary atom site location: structure-invariant direct methods Flack parameter: 0.10 (8) ---------------------------------------------------------------- ------------------------------------------------------------------------------------------------ ::: Special details {#specialdetails} =============== ::: {#d1e558 .table-wrap} -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. Data for (I): \[α\]^20°^~D~ = 96.2° (c 0.600, CH~3~CH~2~OH); ^1^H NMR (400 MHz, CDCl~3~, TMS): 0.769 (3H, *d*, *J* = 6.8 Hz, CH~3~), 0.831-0.934 (7H, *m*, CH, 2CH~3~), 0.981-1.166 (5H, *m*, CH~2~, CH~3~), 1.212-1.756 (9H, *m*, 3CH, 3CH~2~), 2.160-2.271 (2H, *m*, CH~2~), 2.974-3.090 (2H, *m*, CH~2~), 3.529-3.581 (1H, *m*, CH), 4.079-4.335 (2H, *m*, CH~2~), 5.762 (1H, *s*, CH), ESI-MS, *m*/*z* (%): Calcd for C~20~H~32~ClNO~3~^+^(\[M+H\]^+^): 370.21(100.0), 372.20(32.0), Found: 370.29 (45.0), 372.33(15.0). Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ \> 2sigma(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e708 .table-wrap} ------ -------------- -------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cl1 0.60861 (9) −0.13528 (9) 0.17373 (3) 0.0923 (3) C3 0.7320 (3) 0.0841 (3) 0.23600 (8) 0.0557 (6) C4 0.8425 (3) 0.0853 (3) 0.28119 (8) 0.0578 (6) H4 0.9252 0.1479 0.2725 0.069\* C2 0.7123 (3) −0.0578 (3) 0.22267 (9) 0.0621 (7) C1 0.8084 (3) −0.1478 (4) 0.25291 (10) 0.0681 (7) C5 0.8604 (3) 0.1414 (3) 0.37500 (8) 0.0621 (6) H5 0.9630 0.1522 0.3650 0.074\* C6 0.8125 (3) 0.2733 (3) 0.40633 (9) 0.0702 (8) H6 0.7085 0.2604 0.4136 0.084\* C7 0.8883 (4) 0.2751 (4) 0.46068 (10) 0.0956 (9) H7A 0.9919 0.2897 0.4554 0.115\* H7B 0.8517 0.3558 0.4815 0.115\* C10 0.8414 (4) 0.0021 (4) 0.40651 (11) 0.0960 (11) H10A 0.8791 −0.0780 0.3856 0.115\* H10B 0.7385 −0.0149 0.4124 0.115\* C11 0.8269 (4) 0.4160 (4) 0.37596 (11) 0.0878 (10) H11 0.7799 0.4016 0.3412 0.105\* C9 0.9194 (5) 0.0065 (4) 0.46042 (11) 0.1115 (13) H9 1.0238 0.0194 0.4538 0.134\* C8 0.8648 (6) 0.1363 (5) 0.49177 (11) 0.1279 (14) H8A 0.7619 0.1245 0.4993 0.153\* H8B 0.9160 0.1419 0.5257 0.153\* C13 0.7463 (5) 0.5387 (4) 0.40314 (16) 0.1393 (16) H13A 0.7508 0.6236 0.3811 0.209\* H13B 0.7906 0.5586 0.4371 0.209\* H13C 0.6465 0.5117 0.4084 0.209\* C14 0.9795 (6) 0.4590 (5) 0.36473 (16) 0.1399 (16) H14A 1.0262 0.4871 0.3975 0.210\* H14B 0.9802 0.5388 0.3402 0.210\* H14C 1.0308 0.3788 0.3493 0.210\* C18 0.7583 (3) 0.4266 (3) 0.17613 (10) 0.0709 (7) H18A 0.8318 0.3755 0.1557 0.085\* H18B 0.7946 0.5232 0.1833 0.085\* C19 0.7345 (3) 0.3499 (3) 0.22804 (9) 0.0711 (7) H19A 0.8266 0.3401 0.2467 0.085\* H19B 0.6696 0.4065 0.2504 0.085\* C16 0.5572 (3) 0.2862 (3) 0.13592 (10) 0.0750 (8) H16A 0.4646 0.2930 0.1174 0.090\* H16B 0.6226 0.2290 0.1140 0.090\* C15 0.5354 (3) 0.2122 (3) 0.18891 (9) 0.0691 (7) H15A 0.4628 0.2643 0.2095 0.083\* H15B 0.4996 0.1149 0.1830 0.083\* C17 0.6204 (3) 0.4374 (3) 0.14313 (10) 0.0755 (8) H17 0.5498 0.4957 0.1631 0.091\* C20 0.6467 (4) 0.5099 (4) 0.08935 (13) 0.1153 (13) H20A 0.5553 0.5251 0.0716 0.173\* H20B 0.7073 0.4490 0.0676 0.173\* H20C 0.6941 0.6012 0.0948 0.173\* N1 0.6712 (2) 0.2061 (3) 0.21914 (8) 0.0635 (6) O3 0.77190 (15) 0.13329 (19) 0.32666 (5) 0.0606 (4) O1 0.88796 (18) −0.0624 (2) 0.28665 (6) 0.0692 (5) O2 0.8292 (2) −0.2765 (3) 0.25154 (9) 0.0958 (7) C12 0.8980 (9) −0.1363 (5) 0.49012 (16) 0.193 (2) H12A 0.7961 −0.1514 0.4966 0.290\* H12B 0.9489 −0.1329 0.5237 0.290\* H12C 0.9355 −0.2142 0.4688 0.290\* ------ -------------- -------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1455 .table-wrap} ----- ------------- ------------- ------------- -------------- -------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cl1 0.0966 (5) 0.0925 (6) 0.0878 (5) −0.0040 (5) −0.0238 (4) −0.0303 (4) C3 0.0532 (14) 0.0716 (19) 0.0423 (11) −0.0039 (13) 0.0037 (10) −0.0047 (12) C4 0.0566 (14) 0.0663 (19) 0.0507 (13) −0.0053 (12) −0.0014 (11) −0.0038 (12) C2 0.0612 (16) 0.072 (2) 0.0534 (13) −0.0043 (14) −0.0029 (12) −0.0094 (13) C1 0.0596 (15) 0.077 (2) 0.0677 (16) 0.0055 (16) 0.0053 (13) −0.0158 (17) C5 0.0649 (16) 0.0735 (17) 0.0478 (12) −0.0011 (14) −0.0084 (11) −0.0026 (13) C6 0.0673 (16) 0.092 (2) 0.0511 (13) 0.0086 (15) −0.0004 (12) −0.0171 (15) C7 0.132 (3) 0.100 (2) 0.0542 (15) −0.003 (2) −0.0164 (17) −0.0124 (17) C10 0.132 (3) 0.092 (2) 0.0633 (16) −0.020 (2) −0.0195 (18) 0.0117 (17) C11 0.126 (3) 0.078 (2) 0.0596 (16) 0.022 (2) −0.0152 (17) −0.0160 (16) C9 0.173 (3) 0.094 (3) 0.0678 (18) −0.024 (3) −0.037 (2) 0.0227 (19) C8 0.183 (4) 0.150 (3) 0.0514 (16) −0.022 (3) −0.016 (2) 0.002 (2) C13 0.161 (4) 0.120 (3) 0.137 (3) 0.055 (3) −0.042 (3) −0.052 (3) C14 0.165 (4) 0.103 (3) 0.152 (3) 0.002 (3) 0.053 (3) 0.013 (3) C18 0.0791 (18) 0.0660 (18) 0.0678 (15) −0.0153 (14) −0.0104 (14) 0.0016 (14) C19 0.0835 (19) 0.0686 (19) 0.0610 (15) −0.0105 (16) −0.0154 (14) −0.0090 (14) C16 0.0752 (18) 0.084 (2) 0.0663 (16) −0.0017 (16) −0.0243 (13) −0.0002 (16) C15 0.0592 (15) 0.0720 (18) 0.0760 (17) −0.0043 (13) −0.0121 (13) −0.0002 (15) C17 0.087 (2) 0.0695 (19) 0.0700 (15) −0.0068 (17) −0.0108 (15) 0.0073 (15) C20 0.144 (3) 0.112 (3) 0.091 (2) −0.029 (2) −0.022 (2) 0.040 (2) N1 0.0670 (13) 0.0634 (14) 0.0601 (11) −0.0079 (12) −0.0147 (10) 0.0039 (11) O3 0.0557 (9) 0.0823 (12) 0.0436 (8) 0.0034 (9) −0.0045 (7) −0.0074 (9) O1 0.0577 (10) 0.0779 (13) 0.0719 (10) 0.0108 (10) −0.0093 (9) −0.0086 (10) O2 0.0908 (14) 0.0731 (15) 0.1237 (17) 0.0195 (12) −0.0096 (12) −0.0176 (14) C12 0.339 (7) 0.136 (4) 0.105 (3) −0.040 (5) −0.072 (4) 0.049 (3) ----- ------------- ------------- ------------- -------------- -------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1987 .table-wrap} ------------------- ------------- ------------------- ------------- Cl1---C2 1.708 (2) C8---H8B 0.9700 C3---N1 1.327 (3) C13---H13A 0.9600 C3---C2 1.366 (4) C13---H13B 0.9600 C3---C4 1.519 (3) C13---H13C 0.9600 C4---O3 1.381 (3) C14---H14A 0.9600 C4---O1 1.435 (3) C14---H14B 0.9600 C4---H4 0.9800 C14---H14C 0.9600 C2---C1 1.429 (4) C18---C19 1.495 (4) C1---O2 1.206 (4) C18---C17 1.514 (4) C1---O1 1.367 (3) C18---H18A 0.9700 C5---O3 1.458 (3) C18---H18B 0.9700 C5---C6 1.514 (4) C19---N1 1.468 (3) C5---C10 1.520 (4) C19---H19A 0.9700 C5---H5 0.9800 C19---H19B 0.9700 C6---C7 1.526 (4) C16---C15 1.504 (3) C6---C11 1.529 (4) C16---C17 1.525 (4) C6---H6 0.9800 C16---H16A 0.9700 C7---C8 1.516 (4) C16---H16B 0.9700 C7---H7A 0.9700 C15---N1 1.460 (3) C7---H7B 0.9700 C15---H15A 0.9700 C10---C9 1.526 (4) C15---H15B 0.9700 C10---H10A 0.9700 C17---C20 1.521 (4) C10---H10B 0.9700 C17---H17 0.9800 C11---C14 1.484 (5) C20---H20A 0.9600 C11---C13 1.516 (5) C20---H20B 0.9600 C11---H11 0.9800 C20---H20C 0.9600 C9---C8 1.519 (5) C12---H12A 0.9600 C9---C12 1.527 (5) C12---H12B 0.9600 C9---H9 0.9800 C12---H12C 0.9600 C8---H8A 0.9700 N1---C3---C2 133.1 (2) C11---C13---H13B 109.5 N1---C3---C4 120.7 (2) H13A---C13---H13B 109.5 C2---C3---C4 106.1 (2) C11---C13---H13C 109.5 O3---C4---O1 111.37 (19) H13A---C13---H13C 109.5 O3---C4---C3 107.47 (18) H13B---C13---H13C 109.5 O1---C4---C3 105.0 (2) C11---C14---H14A 109.5 O3---C4---H4 110.9 C11---C14---H14B 109.5 O1---C4---H4 110.9 H14A---C14---H14B 109.5 C3---C4---H4 110.9 C11---C14---H14C 109.5 C3---C2---C1 110.4 (2) H14A---C14---H14C 109.5 C3---C2---Cl1 130.7 (2) H14B---C14---H14C 109.5 C1---C2---Cl1 118.6 (2) C19---C18---C17 112.4 (2) O2---C1---O1 120.2 (3) C19---C18---H18A 109.1 O2---C1---C2 131.1 (3) C17---C18---H18A 109.1 O1---C1---C2 108.7 (3) C19---C18---H18B 109.1 O3---C5---C6 107.9 (2) C17---C18---H18B 109.1 O3---C5---C10 108.7 (2) H18A---C18---H18B 107.9 C6---C5---C10 112.4 (2) N1---C19---C18 110.9 (2) O3---C5---H5 109.2 N1---C19---H19A 109.5 C6---C5---H5 109.2 C18---C19---H19A 109.5 C10---C5---H5 109.2 N1---C19---H19B 109.5 C5---C6---C7 109.6 (2) C18---C19---H19B 109.5 C5---C6---C11 114.4 (2) H19A---C19---H19B 108.0 C7---C6---C11 113.1 (2) C15---C16---C17 111.3 (2) C5---C6---H6 106.3 C15---C16---H16A 109.4 C7---C6---H6 106.3 C17---C16---H16A 109.4 C11---C6---H6 106.3 C15---C16---H16B 109.4 C8---C7---C6 112.4 (3) C17---C16---H16B 109.4 C8---C7---H7A 109.1 H16A---C16---H16B 108.0 C6---C7---H7A 109.1 N1---C15---C16 111.1 (2) C8---C7---H7B 109.1 N1---C15---H15A 109.4 C6---C7---H7B 109.1 C16---C15---H15A 109.4 H7A---C7---H7B 107.8 N1---C15---H15B 109.4 C5---C10---C9 112.4 (3) C16---C15---H15B 109.4 C5---C10---H10A 109.1 H15A---C15---H15B 108.0 C9---C10---H10A 109.1 C18---C17---C20 112.2 (3) C5---C10---H10B 109.1 C18---C17---C16 108.8 (2) C9---C10---H10B 109.1 C20---C17---C16 111.1 (2) H10A---C10---H10B 107.9 C18---C17---H17 108.2 C14---C11---C13 110.2 (4) C20---C17---H17 108.2 C14---C11---C6 114.0 (3) C16---C17---H17 108.2 C13---C11---C6 112.4 (3) C17---C20---H20A 109.5 C14---C11---H11 106.5 C17---C20---H20B 109.5 C13---C11---H11 106.5 H20A---C20---H20B 109.5 C6---C11---H11 106.5 C17---C20---H20C 109.5 C8---C9---C10 108.7 (3) H20A---C20---H20C 109.5 C8---C9---C12 112.9 (4) H20B---C20---H20C 109.5 C10---C9---C12 110.2 (3) C3---N1---C15 123.8 (2) C8---C9---H9 108.3 C3---N1---C19 123.74 (19) C10---C9---H9 108.3 C15---N1---C19 112.4 (2) C12---C9---H9 108.3 C4---O3---C5 115.85 (16) C7---C8---C9 111.0 (3) C1---O1---C4 109.6 (2) C7---C8---H8A 109.4 C9---C12---H12A 109.5 C9---C8---H8A 109.4 C9---C12---H12B 109.5 C7---C8---H8B 109.4 H12A---C12---H12B 109.5 C9---C8---H8B 109.4 C9---C12---H12C 109.5 H8A---C8---H8B 108.0 H12A---C12---H12C 109.5 C11---C13---H13A 109.5 H12B---C12---H12C 109.5 ------------------- ------------- ------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e2806 .table-wrap} --------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C4---H4···O2^i^ 0.98 2.44 3.376 (3) 160 C18---H18B···O2^ii^ 0.97 2.54 3.393 (4) 147 --------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) −*x*+2, *y*+1/2, −*z*+1/2; (ii) *x*, *y*+1, *z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ----------- ------------- C4---H4⋯O2^i^ 0.98 2.44 3.376 (3) 160 C18---H18*B*⋯O2^ii^ 0.97 2.54 3.393 (4) 147 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.734164

2011-2-19

PMC3051990

Related literature {#sec1} ================== For the preparation of biheterocyclic complexes, see: Juanes *et al.* (1985[@bb11]); Arrieta *et al.* (1998[@bb1]); El Ghayati *et al.* (2010[@bb8]); Cohen-Fernandez *et al.* (1979[@bb6]); Tarrago *et al.* (1980[@bb15]). For applications of transition metal complexes with biheterocyclic ligands, see: Bekhit & Abdel-Aziem (2004[@bb3]); Benabdallah *et al.* (2007[@bb4]); Das & Mittra (1978[@bb7]); Sendai *et al.* (2000[@bb12]); Attayibat *et al.* (2006[@bb2]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[CuCl~2~(C~9~H~12~N~4~)\]*M* *~r~* = 310.67Triclinic,*a* = 8.5475 (2) Å*b* = 9.3475 (3) Å*c* = 9.3512 (3) Åα = 66.379 (2)°β = 62.876 (1)°γ = 78.065 (2)°*V* = 608.99 (3) Å^3^*Z* = 2Mo *K*α radiationμ = 2.21 mm^−1^*T* = 296 K0.26 × 0.16 × 0.08 mm ### Data collection {#sec2.1.2} Bruker X8 APEXII area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2005[@bb5]) *T* ~min~ = 0.661, *T* ~max~ = 0.83819588 measured reflections5535 independent reflections4468 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.020 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.030*wR*(*F* ^2^) = 0.096*S* = 1.045535 reflections145 parametersH-atom parameters constrainedΔρ~max~ = 0.78 e Å^−3^Δρ~min~ = −0.53 e Å^−3^ {#d5e514} Data collection: *APEX2* (Bruker, 2005[@bb5]); cell refinement: *SAINT* (Bruker, 2005[@bb5]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb13]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb13]); molecular graphics: *ORTEP-3 for Windows* (Farrugia,1997[@bb9]) and *PLATON* (Spek, 2009[@bb14]); software used to prepare material for publication: *WinGX* (Farrugia, 1999[@bb10]). Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811004375/fj2386sup1.cif](http://dx.doi.org/10.1107/S1600536811004375/fj2386sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811004375/fj2386Isup2.hkl](http://dx.doi.org/10.1107/S1600536811004375/fj2386Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?fj2386&file=fj2386sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?fj2386sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?fj2386&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [FJ2386](http://scripts.iucr.org/cgi-bin/sendsup?fj2386)). The authors thank the Unit of Support for Technical and Scientific Research (UATRS, CNRST) for the X-ray measurements. Comment ======= The 1,1\'-bipyrazoles and 3,4\'-bipyrazoles have been the subject of several studies (Juanes *et al.* (1985); Arrieta *et al.* (1998); El Ghayati *et al.* (2010). A particular interest has been brought to 1,3\'-bipyrazoles which present, contrary to those cited above, a carbon-- nitrogen bond between the two pyrazoles (Cohen-Fernandez *et al.* (1979); Tarrago *et al.* 1980). The ability of biheterocycles to form biochemically interesting complexes, with transition metals has prompted several researchers to test them in some areas: medicine (Bekhit & Abdel-Aziem, (2004); Sendai *et al.* 2000), agriculture (Das & Mittra, 1978) corrosion (Benabdallah *et al.* 2007) and as extractors of metals such as Cu^2+^, Cd^2+^ and Pb^2+^ (Attayibat *et al.* 2006). To better understand the interactions between the bipyrazoles and transition metals we have chosen to study some copper complex of bipyrazole possessing a Carbone-nitrogen bond between the two pyrazolics cycles. The title molecule is built up from two interconnected five-membered rings as schown in Fig.1. Each of the two heterocyclic rings and the linked carbon are almost planar with a maximum deviations of -0.0101 (15) Å and -0.0107 (15) Å from N1 and N3 respectively. The dihedral angle between them is about 3.80 (9)°. The Cu^II^ ion is surrounded by two nitrogen atoms belonging to the organic molecule and two chlorides which form a very distorted square planar.The values of adjacent angles around the Cu^II^ ions are in the range 78.14 (5)--98.297 (16)° and 151.99 (4)--161.72 (4)° (Table 1), which confirms the distorted square-planar geometry. The chelate ring (N1---N2---C4---N3) and the copper atom are almost planar with a maximum deviations of 0.0181 (17) Å from C4 and build dihedral angle of 30.75 (6)° with the plane through the three ions: Cu^II+^ and two Cl^-^. In the crystal, each pair of molecules linked by N4---H4···Cl1 hydrogen bonds form a dimer as schown in Fig.2 and table 2. The structure is held together by weak slipped π-π stacking between symmetry related molecules (N3---N4---C4---C5---C6 rings) with interplanar distance of 3.439 (19) Å and centroid to centroid vector of 3.581 (19) Å (Fig. 2). The crystal structure is also stabilized by an intermolecular C7---H7B···N1 and C9---H9B···Cl1 hydrogen bonds as schown in Fig.2 and Table 2. Experimental {#experimental} ============ The title compound was synthesized by mixing a solution of bipyrazole in methanol and an aqueous solution of cupric chloride with ligand/metal ratio of 2. Heating was maintaind for few minutes.Then a pinch of NaCl was added and heating was continued until the solution became clear. After a long time, green crystals were collected and dried over P2O5. Refinement {#refinement} ========== The C-bound H atoms were positioned geometrically \[C---H = 0.93--0.96 Å\] and refined using a riding model with *U*~iso~(H) = 1.2 and 1.5 for methylene and methyl. Reflections 2--43 110, 250, 3--21, 114 and 1--31 were omitted because of the large difference between their calculated and observed intensities. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of the title compound, with the atom-labeling scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are represented as small spheres of arbitrary radii. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Packing diagram showing hydrogen-bonded (dashed lines) complex molecules and distance between centroids. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e158 .table-wrap} ---------------------------- --------------------------------------- \[CuCl~2~(C~9~H~12~N~4~)\] *Z* = 2 *M~r~* = 310.67 *F*(000) = 314 Triclinic, *P*1 *D*~x~ = 1.694 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 8.5475 (2) Å Cell parameters from 5535 reflections *b* = 9.3475 (3) Å θ = 2.9--35.5° *c* = 9.3512 (3) Å µ = 2.21 mm^−1^ α = 66.379 (2)° *T* = 296 K β = 62.876 (1)° Prism, clear green γ = 78.065 (2)° 0.26 × 0.16 × 0.08 mm *V* = 608.99 (3) Å^3^ ---------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e295 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker X8 APEXII area-detector diffractometer 5535 independent reflections Radiation source: fine-focus sealed tube 4468 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.020 φ and ω scans θ~max~ = 35.5°, θ~min~ = 2.9° Absorption correction: multi-scan (*SADABS*; Bruker, 2005) *h* = −13→13 *T*~min~ = 0.661, *T*~max~ = 0.838 *k* = −15→15 19588 measured reflections *l* = −15→15 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e412 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------ Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.030 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.096 H-atom parameters constrained *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.053*P*)^2^ + 0.1288*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 5535 reflections (Δ/σ)~max~ = 0.001 145 parameters Δρ~max~ = 0.78 e Å^−3^ 0 restraints Δρ~min~ = −0.53 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------ ::: Special details {#specialdetails} =============== ::: {#d1e569 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Geometry. All s.u.\'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.\'s are taken into account individually in the estimation of s.u.\'s in distances, angles and torsion angles; correlations between s.u.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.\'s is used for estimating s.u.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> 2σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e668 .table-wrap} ----- --------------- --------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ Cu1 0.15845 (2) 0.378309 (18) 0.126139 (19) 0.03371 (6) Cl1 0.32602 (6) 0.27845 (5) −0.07595 (5) 0.04576 (10) Cl2 0.17371 (7) 0.63132 (4) −0.04198 (5) 0.05123 (11) N1 0.19189 (18) 0.19578 (13) 0.32890 (15) 0.0350 (2) N2 0.06621 (18) 0.19922 (13) 0.48517 (14) 0.0338 (2) N3 −0.03865 (17) 0.41525 (14) 0.32360 (14) 0.0341 (2) N4 −0.16369 (17) 0.52865 (15) 0.34407 (15) 0.0357 (2) H4 −0.1782 0.6055 0.2609 0.043\* C1 0.2969 (2) 0.07094 (17) 0.3644 (2) 0.0415 (3) C2 0.2341 (3) −0.00505 (18) 0.5432 (2) 0.0471 (4) H2 0.2824 −0.0952 0.6008 0.056\* C3 0.0881 (3) 0.07866 (16) 0.61715 (19) 0.0406 (3) C4 −0.05733 (19) 0.32244 (15) 0.48068 (15) 0.0304 (2) C5 −0.1967 (2) 0.37413 (18) 0.60475 (17) 0.0368 (3) H5 −0.2360 0.3297 0.7234 0.044\* C6 −0.26295 (19) 0.50668 (17) 0.51088 (18) 0.0344 (2) C7 −0.4133 (2) 0.6144 (2) 0.5670 (2) 0.0456 (3) H7A −0.4235 0.6954 0.4680 0.068\* H7B −0.3936 0.6602 0.6326 0.068\* H7C −0.5199 0.5571 0.6366 0.068\* C8 −0.0262 (4) 0.0550 (2) 0.8008 (2) 0.0576 (5) H8A −0.1176 0.1347 0.8090 0.086\* H8B 0.0429 0.0607 0.8553 0.086\* H8C −0.0779 −0.0457 0.8567 0.086\* C9 0.4575 (3) 0.0306 (3) 0.2294 (3) 0.0605 (6) H9A 0.4677 0.1029 0.1184 0.091\* H9B 0.4495 −0.0735 0.2372 0.091\* H9C 0.5591 0.0362 0.2453 0.091\* ----- --------------- --------------- --------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1082 .table-wrap} ----- -------------- -------------- -------------- --------------- --------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Cu1 0.04382 (11) 0.02877 (8) 0.02047 (8) 0.00351 (6) −0.00980 (7) −0.00738 (5) Cl1 0.0559 (2) 0.04221 (17) 0.02692 (14) 0.01764 (15) −0.01377 (14) −0.01382 (13) Cl2 0.0665 (3) 0.03027 (15) 0.03254 (17) −0.00083 (15) −0.00632 (17) −0.00494 (12) N1 0.0460 (7) 0.0321 (5) 0.0255 (5) 0.0042 (4) −0.0167 (5) −0.0094 (4) N2 0.0466 (7) 0.0307 (5) 0.0221 (4) −0.0015 (4) −0.0159 (4) −0.0052 (4) N3 0.0410 (6) 0.0351 (5) 0.0211 (4) 0.0044 (4) −0.0124 (4) −0.0083 (4) N4 0.0386 (6) 0.0383 (5) 0.0261 (5) 0.0048 (4) −0.0128 (4) −0.0112 (4) C1 0.0589 (10) 0.0325 (6) 0.0408 (7) 0.0091 (6) −0.0303 (7) −0.0141 (5) C2 0.0759 (12) 0.0306 (6) 0.0423 (8) 0.0058 (6) −0.0376 (8) −0.0085 (5) C3 0.0649 (10) 0.0296 (5) 0.0295 (6) −0.0066 (6) −0.0262 (7) −0.0023 (5) C4 0.0375 (6) 0.0313 (5) 0.0207 (5) −0.0060 (4) −0.0111 (4) −0.0062 (4) C5 0.0420 (7) 0.0409 (6) 0.0217 (5) −0.0071 (5) −0.0074 (5) −0.0096 (5) C6 0.0332 (6) 0.0398 (6) 0.0288 (6) −0.0058 (5) −0.0075 (5) −0.0147 (5) C7 0.0378 (8) 0.0488 (8) 0.0470 (9) −0.0006 (6) −0.0081 (6) −0.0253 (7) C8 0.0937 (16) 0.0430 (8) 0.0262 (6) −0.0065 (9) −0.0249 (8) −0.0007 (6) C9 0.0735 (14) 0.0597 (11) 0.0552 (11) 0.0337 (10) −0.0389 (11) −0.0298 (9) ----- -------------- -------------- -------------- --------------- --------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e1448 .table-wrap} ----------------- ------------- ---------------- ------------- Cu1---N3 1.9496 (12) C2---H2 0.9300 Cu1---N1 2.0707 (11) C3---C8 1.485 (2) Cu1---Cl1 2.2106 (4) C4---C5 1.396 (2) Cu1---Cl2 2.2456 (4) C5---C6 1.385 (2) N1---C1 1.3436 (18) C5---H5 0.9300 N1---N2 1.3720 (17) C6---C7 1.488 (2) N2---C3 1.3552 (17) C7---H7A 0.9600 N2---C4 1.3935 (18) C7---H7B 0.9600 N3---C4 1.3260 (16) C7---H7C 0.9600 N3---N4 1.3453 (17) C8---H8A 0.9600 N4---C6 1.3431 (18) C8---H8B 0.9600 N4---H4 0.8600 C8---H8C 0.9600 C1---C2 1.406 (2) C9---H9A 0.9600 C1---C9 1.486 (3) C9---H9B 0.9600 C2---C3 1.375 (3) C9---H9C 0.9600 N3---Cu1---N1 78.14 (5) N3---C4---C5 111.28 (12) N3---Cu1---Cl1 161.72 (4) N3---C4---N2 114.03 (12) N1---Cu1---Cl1 97.11 (3) C5---C4---N2 134.67 (12) N3---Cu1---Cl2 93.55 (4) C6---C5---C4 104.26 (12) N1---Cu1---Cl2 151.99 (4) C6---C5---H5 127.9 Cl1---Cu1---Cl2 98.297 (16) C4---C5---H5 127.9 C1---N1---N2 105.58 (12) N4---C6---C5 107.30 (13) C1---N1---Cu1 142.15 (11) N4---C6---C7 121.67 (14) N2---N1---Cu1 112.27 (8) C5---C6---C7 131.03 (14) C3---N2---N1 111.92 (13) C6---C7---H7A 109.5 C3---N2---C4 132.08 (13) C6---C7---H7B 109.5 N1---N2---C4 116.00 (10) H7A---C7---H7B 109.5 C4---N3---N4 105.72 (11) C6---C7---H7C 109.5 C4---N3---Cu1 119.46 (10) H7A---C7---H7C 109.5 N4---N3---Cu1 134.50 (9) H7B---C7---H7C 109.5 C6---N4---N3 111.41 (12) C3---C8---H8A 109.5 C6---N4---H4 124.3 C3---C8---H8B 109.5 N3---N4---H4 124.3 H8A---C8---H8B 109.5 N1---C1---C2 109.39 (15) C3---C8---H8C 109.5 N1---C1---C9 122.85 (15) H8A---C8---H8C 109.5 C2---C1---C9 127.70 (14) H8B---C8---H8C 109.5 C3---C2---C1 107.25 (13) C1---C9---H9A 109.5 C3---C2---H2 126.4 C1---C9---H9B 109.5 C1---C2---H2 126.4 H9A---C9---H9B 109.5 N2---C3---C2 105.86 (14) C1---C9---H9C 109.5 N2---C3---C8 123.69 (16) H9A---C9---H9C 109.5 C2---C3---C8 130.41 (15) H9B---C9---H9C 109.5 ----------------- ------------- ---------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e1850 .table-wrap} --------------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* N4---H4···Cl1^i^ 0.86 2.38 3.1587 (12) 150 C7---H7B···N1^ii^ 0.96 2.61 3.483 (2) 151 C9---H9B···Cl1^iii^ 0.96 2.79 3.5377 (19) 135 --------------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) −*x*, −*y*+1, −*z*; (ii) −*x*, −*y*+1, −*z*+1; (iii) −*x*+1, −*y*, −*z*. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ------------- ------------- N4---H4⋯Cl1^i^ 0.86 2.38 3.1587 (12) 150 C7---H7*B*⋯N1^ii^ 0.96 2.61 3.483 (2) 151 C9---H9*B*⋯Cl1^iii^ 0.96 2.79 3.5377 (19) 135 Symmetry codes: (i) ; (ii) ; (iii) . :::

PubMed Central

2024-06-05T04:04:17.740112

2011-2-12

PMC3051991

Related literature {#sec1} ================== For applications of *N*-heterocyclic carbenes (NHCs), see: Winkelmann & Navarro (2010[@bb11]); Papini *et al.* (2008[@bb6]); Marion *et al.* (2007[@bb5]); Burstein & Glorius (2004[@bb2]); Sohn *et al.* (2004[@bb9]); Grasa *et al.* (2002[@bb4]); Singh & Nolan (2005[@bb8]). For the stability of the temperature controller used in the data collection, see: Cosier & Glazer (1986[@bb3]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} C~31~H~34~N~4~ ^2+^·2Br^−^*M* *~r~* = 622.44Monoclinic,*a* = 8.9851 (2) Å*b* = 12.8044 (2) Å*c* = 25.6419 (5) Åβ = 102.611 (1)°*V* = 2878.90 (10) Å^3^*Z* = 4Mo *K*α radiationμ = 2.84 mm^−1^*T* = 100 K0.49 × 0.43 × 0.21 mm ### Data collection {#sec2.1.2} Bruker SMART APEXII CCD area-detector diffractometerAbsorption correction: multi-scan (*SADABS*; Bruker, 2009[@bb1]) *T* ~min~ = 0.337, *T* ~max~ = 0.58532884 measured reflections8490 independent reflections6550 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.036 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.040*wR*(*F* ^2^) = 0.101*S* = 1.048490 reflections337 parametersH-atom parameters constrainedΔρ~max~ = 1.28 e Å^−3^Δρ~min~ = −0.40 e Å^−3^ {#d5e551} Data collection: *APEX2* (Bruker, 2009[@bb1]); cell refinement: *SAINT* (Bruker, 2009[@bb1]); data reduction: *SAINT*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXTL*; molecular graphics: *SHELXTL*; software used to prepare material for publication: *SHELXTL* and *PLATON* (Spek, 2009[@bb10]). Supplementary Material ====================== Crystal structure: contains datablocks global, I. DOI: [10.1107/S1600536811005204/wn2422sup1.cif](http://dx.doi.org/10.1107/S1600536811005204/wn2422sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811005204/wn2422Isup2.hkl](http://dx.doi.org/10.1107/S1600536811005204/wn2422Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?wn2422&file=wn2422sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?wn2422sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?wn2422&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [WN2422](http://scripts.iucr.org/cgi-bin/sendsup?wn2422)). RAH thanks Universiti Sains Malaysia (USM) for the FRGS fund (203/PKIMIA/671115), short term grant (304/PKIMIA/639001) and RU grants (1001/PKIMIA/813023 and 1001/PKIMIA/811157). AWS thanks USM for the RU grant (1001/PKIMIA/843090). HKF and MH thank the Malaysian Government and USM for the Research University grant No. 1001/PFIZIK/811160. MH also thanks Universiti Sains Malaysia for a post-doctoral research fellowship. Comment ======= *N*-Heterocyclic carbenes (NHCs) have found widespread applications as ligands in organometallic chemistry during recent years (Winkelmann & Navarro, 2010). They typically have strong σ-donor properties but poor π-acceptor character and have been widely employed as alternatives to phosphine ligands to stabilise transition metal complexes. NHCs are relatively inexpensive, non-toxic and easily prepared from azolium salts (Papini *et al.*, 2008). Notably, NHCs also exhibit excellent catalytic activity in metal-free organocatalysis (Marion *et al.*, 2007) including umpolung and condensation of carbonyl compounds (Burstein & Glorius, 2004; Sohn *et al.*, 2004) and transesterification reactions (Grasa *et al.*, 2002; Singh & Nolan, 2005). The asymmetric unit of the title compound, (Fig. 1), consists of one 1,3-bis(3-benzylimidazolium-1-ylmethyl)mesitylene cation and two bromide anions. The central benzene ring (C12--C17) makes dihedral angles of 80.47 (12)° and 82.78 (12)° with the adjacent imidazole rings (N1/N2/C8--C10) and (N3/N4/C19--C21). The dihedral angle between the two terminal phenyl rings (C1--C6) and (C23--C28) is 79.16 (13)°. In the crystal structure (Fig. 2), the cations and anions are linked together *via* intermolecular C---H···Br (Table 1) hydrogen bonds, forming one-dimensional supramolecular chains along the *c*-axis. Experimental {#experimental} ============ A mixture of imidazole (1.0 g, 14.0 mmol) and sodium hydroxide (0.6 g, 15.0 mmol) in DMSO (20 ml) was heated to 363 K for 2 h. The mixture was cooled at room temperature then 1,3-bis(bromomethyl)mesitylene (2.0 g, 6.5 mmol) in 10 ml of DMSO was added, heated to 413 K for 1 h and poured into water (200 ml), then cooled in an ice bath. The resulting precipitate was collected by filtration, washed with water (3x10 ml), and recrystallised from methanol/water to give 1,3-bis(*N*-imidazole-1-ylmethyl)mesitylene as an off-white solid (1.45 g, 79 %). Further, a mixture of 1,3-bis(*N*-imidazole-1-ylmethyl)mesitylene (0.7 g, 2.5 mmol) and benzyl bromide (1.0 g, 5.8 mmol) in 30 ml of acetonitrile, was refluxed for 24 h, then cooled to room temperature and left standing overnight, giving the title compound as light brown crystals which were isolated by decantation and washed with diethyl ether (2x5 ml) and placed in a desiccator. The yield was (1.15 g, 74%). The resulting crystals were suitable for X-ray diffraction. Refinement {#refinement} ========== All H atoms were positioned geometrically \[C--H = 0.93--0.97 Å\] and were refined using a riding model, with *U*~iso~(H) = x*U*~eq~(C), where x = 1.5 for methyl H and 1.2 for all other H atoms. The highest peak in the final difference map was found at a distance of 0.77 Å from Br1. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### The asymmetric unit of the title compound, showing 30% probability displacement ellipsoids. H atoms have been omitted for clarity. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### The crystal packing of the title compound, showing hydrogen-bonded (dashed lines) one-dimensional supramolecular chains along the c-axis. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e145 .table-wrap} --------------------------- --------------------------------------- C~31~H~34~N~4~^2+^·2Br^−^ *F*(000) = 1272 *M~r~* = 622.44 *D*~x~ = 1.436 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71073 Å Hall symbol: -P 2ybc Cell parameters from 9955 reflections *a* = 8.9851 (2) Å θ = 2.3--29.9° *b* = 12.8044 (2) Å µ = 2.84 mm^−1^ *c* = 25.6419 (5) Å *T* = 100 K β = 102.611 (1)° Plate, colourless *V* = 2878.90 (10) Å^3^ 0.49 × 0.43 × 0.21 mm *Z* = 4 --------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e278 .table-wrap} ------------------------------------------------------------ -------------------------------------- Bruker SMART APEXII CCD area-detector diffractometer 8490 independent reflections Radiation source: fine-focus sealed tube 6550 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.036 φ and ω scans θ~max~ = 30.2°, θ~min~ = 2.3° Absorption correction: multi-scan (*SADABS*; Bruker, 2009) *h* = −12→12 *T*~min~ = 0.337, *T*~max~ = 0.585 *k* = −17→18 32884 measured reflections *l* = −30→36 ------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e395 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.040 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.101 H-atom parameters constrained *S* = 1.04 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0549*P*)^2^ + 0.6972*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 8490 reflections (Δ/σ)~max~ = 0.003 337 parameters Δρ~max~ = 1.28 e Å^−3^ 0 restraints Δρ~min~ = −0.40 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e552 .table-wrap} ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ Experimental. The crystal was placed in the cold stream of an Oxford Cryosystems Cobra open-flow nitrogen cryostat (Cosier & Glazer, 1986) operating at 100.0 (1) K. Geometry. All s.u.\'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.\'s are taken into account individually in the estimation of s.u.\'s in distances, angles and torsion angles; correlations between s.u.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.\'s is used for estimating s.u.\'s involving l.s. planes. Refinement. Refinement of F^2^ against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F^2^, conventional R-factors R are based on F, with F set to zero for negative F^2^. The threshold expression of F^2^ \> 2σ(F^2^) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F^2^ are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger. ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e606 .table-wrap} ------ ------------- --------------- -------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ N1 0.6565 (2) 0.78480 (15) 0.80723 (7) 0.0240 (4) N2 0.4998 (2) 0.82215 (14) 0.85747 (8) 0.0235 (4) N3 0.9596 (2) 0.88648 (15) 1.09775 (8) 0.0244 (4) N4 1.1823 (2) 0.82656 (14) 1.09554 (8) 0.0242 (4) C1 0.9744 (3) 0.8645 (3) 0.74204 (12) 0.0452 (7) H1A 1.0412 0.8088 0.7517 0.054\* C2 1.0150 (4) 0.9467 (3) 0.71276 (14) 0.0591 (9) H2A 1.1091 0.9461 0.7033 0.071\* C3 0.9160 (4) 1.0297 (3) 0.69757 (12) 0.0504 (8) H3A 0.9425 1.0845 0.6776 0.060\* C4 0.7775 (3) 1.0297 (2) 0.71252 (11) 0.0395 (6) H4A 0.7102 1.0850 0.7024 0.047\* C5 0.7372 (3) 0.94820 (19) 0.74249 (10) 0.0309 (5) H5A 0.6441 0.9499 0.7527 0.037\* C6 0.8349 (3) 0.86441 (19) 0.75719 (9) 0.0274 (5) C7 0.7989 (3) 0.77211 (19) 0.78865 (9) 0.0268 (5) H7A 0.7912 0.7101 0.7665 0.032\* H7B 0.8822 0.7616 0.8193 0.032\* C8 0.5118 (3) 0.76704 (19) 0.77738 (10) 0.0292 (5) H8A 0.4861 0.7428 0.7424 0.035\* C9 0.4139 (3) 0.79170 (19) 0.80890 (10) 0.0298 (5) H9A 0.3080 0.7886 0.7993 0.036\* C10 0.6473 (2) 0.81899 (16) 0.85554 (9) 0.0216 (4) H10A 0.7289 0.8374 0.8830 0.026\* C11 0.4391 (2) 0.85726 (18) 0.90348 (9) 0.0248 (4) H11A 0.3343 0.8340 0.8989 0.030\* H11B 0.4393 0.9330 0.9046 0.030\* C12 0.5310 (2) 0.81582 (16) 0.95579 (9) 0.0226 (4) C13 0.6366 (2) 0.87950 (16) 0.98984 (9) 0.0225 (4) C14 0.7047 (2) 0.84395 (17) 1.04123 (9) 0.0236 (4) C15 0.6774 (3) 0.74111 (18) 1.05665 (9) 0.0261 (5) C16 0.5809 (3) 0.67784 (17) 1.02034 (10) 0.0272 (5) H16A 0.5668 0.6090 1.0298 0.033\* C17 0.5045 (2) 0.71272 (17) 0.97056 (9) 0.0249 (5) C18 0.7980 (3) 0.91657 (17) 1.08167 (10) 0.0269 (5) H18A 0.7914 0.9865 1.0668 0.032\* H18B 0.7547 0.9183 1.1132 0.032\* C19 1.0401 (2) 0.83681 (17) 1.06739 (9) 0.0236 (4) H19A 1.0032 0.8134 1.0326 0.028\* C20 1.0534 (3) 0.90914 (19) 1.14621 (10) 0.0322 (5) H20A 1.0258 0.9440 1.1745 0.039\* C21 1.1933 (3) 0.87145 (19) 1.14526 (10) 0.0315 (5) H21A 1.2800 0.8750 1.1727 0.038\* C22 1.3042 (3) 0.76808 (17) 1.07770 (10) 0.0268 (5) H22A 1.4030 0.7916 1.0976 0.032\* H22B 1.2985 0.7816 1.0401 0.032\* C23 1.2878 (2) 0.65205 (18) 1.08634 (9) 0.0236 (4) C24 1.1996 (3) 0.59206 (19) 1.04611 (10) 0.0307 (5) H24A 1.1554 0.6224 1.0134 0.037\* C25 1.1774 (3) 0.4869 (2) 1.05463 (12) 0.0395 (6) H25A 1.1199 0.4464 1.0274 0.047\* C26 1.2404 (3) 0.44214 (19) 1.10336 (12) 0.0385 (6) H26A 1.2218 0.3723 1.1095 0.046\* C27 1.3312 (3) 0.5008 (2) 1.14307 (11) 0.0360 (6) H27A 1.3760 0.4701 1.1756 0.043\* C28 1.3553 (3) 0.6056 (2) 1.13442 (10) 0.0304 (5) H28A 1.4171 0.6450 1.1611 0.036\* C29 0.6784 (3) 0.98590 (17) 0.97157 (10) 0.0263 (5) H29A 0.7857 0.9975 0.9843 0.039\* H29B 0.6224 1.0388 0.9856 0.039\* H29C 0.6535 0.9888 0.9332 0.039\* C30 0.3955 (3) 0.64136 (19) 0.93407 (11) 0.0315 (5) H30A 0.3917 0.5752 0.9513 0.047\* H30B 0.4297 0.6314 0.9015 0.047\* H30C 0.2956 0.6721 0.9262 0.047\* C31 0.7495 (3) 0.69928 (19) 1.11128 (10) 0.0336 (5) H31A 0.7026 0.6341 1.1168 0.050\* H31B 0.7352 0.7485 1.1380 0.050\* H31C 0.8566 0.6887 1.1138 0.050\* Br1 0.03325 (2) 0.815324 (18) 0.928724 (9) 0.02679 (7) Br2 0.59309 (3) 0.572410 (19) 0.692096 (9) 0.03010 (7) ------ ------------- --------------- -------------- -------------------- -- ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1500 .table-wrap} ----- -------------- -------------- -------------- -------------- ------------- -------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ N1 0.0227 (9) 0.0246 (9) 0.0250 (9) 0.0029 (7) 0.0060 (7) −0.0007 (7) N2 0.0216 (9) 0.0207 (9) 0.0288 (10) 0.0030 (7) 0.0070 (7) 0.0024 (7) N3 0.0271 (9) 0.0217 (9) 0.0264 (10) 0.0038 (7) 0.0100 (7) 0.0010 (8) N4 0.0245 (9) 0.0191 (9) 0.0306 (10) 0.0010 (7) 0.0095 (7) 0.0012 (7) C1 0.0230 (12) 0.066 (2) 0.0476 (16) −0.0013 (13) 0.0093 (11) 0.0009 (15) C2 0.0332 (15) 0.089 (3) 0.060 (2) −0.0205 (16) 0.0208 (14) 0.0009 (19) C3 0.0549 (19) 0.0547 (19) 0.0431 (17) −0.0281 (16) 0.0142 (14) −0.0028 (14) C4 0.0529 (17) 0.0309 (14) 0.0354 (14) −0.0077 (12) 0.0111 (12) −0.0017 (11) C5 0.0350 (13) 0.0304 (13) 0.0296 (12) −0.0032 (10) 0.0118 (10) −0.0056 (10) C6 0.0244 (11) 0.0336 (13) 0.0242 (11) −0.0037 (9) 0.0050 (9) −0.0073 (9) C7 0.0245 (11) 0.0302 (12) 0.0265 (11) 0.0061 (9) 0.0071 (9) −0.0041 (9) C8 0.0279 (11) 0.0306 (13) 0.0274 (12) −0.0010 (9) 0.0025 (9) −0.0031 (10) C9 0.0224 (11) 0.0298 (12) 0.0361 (13) −0.0006 (9) 0.0038 (9) −0.0004 (10) C10 0.0224 (10) 0.0192 (10) 0.0234 (10) 0.0019 (8) 0.0055 (8) 0.0009 (8) C11 0.0228 (10) 0.0236 (11) 0.0307 (12) 0.0053 (8) 0.0119 (9) 0.0026 (9) C12 0.0235 (10) 0.0201 (10) 0.0281 (11) 0.0066 (8) 0.0140 (8) 0.0039 (9) C13 0.0243 (10) 0.0171 (10) 0.0311 (12) 0.0048 (8) 0.0167 (9) 0.0025 (8) C14 0.0226 (10) 0.0220 (11) 0.0304 (12) 0.0052 (8) 0.0149 (9) 0.0035 (9) C15 0.0272 (11) 0.0234 (11) 0.0316 (12) 0.0078 (9) 0.0152 (9) 0.0069 (9) C16 0.0326 (12) 0.0173 (11) 0.0361 (13) 0.0053 (9) 0.0171 (10) 0.0052 (9) C17 0.0248 (10) 0.0186 (10) 0.0356 (12) 0.0029 (8) 0.0160 (9) 0.0003 (9) C18 0.0278 (11) 0.0222 (11) 0.0339 (12) 0.0064 (9) 0.0136 (9) 0.0017 (9) C19 0.0256 (11) 0.0205 (11) 0.0267 (11) 0.0010 (8) 0.0102 (9) 0.0015 (8) C20 0.0388 (13) 0.0311 (13) 0.0274 (12) 0.0054 (10) 0.0089 (10) −0.0037 (10) C21 0.0336 (13) 0.0279 (13) 0.0314 (13) 0.0051 (10) 0.0032 (10) −0.0044 (10) C22 0.0230 (10) 0.0221 (11) 0.0386 (13) 0.0011 (8) 0.0138 (9) 0.0012 (9) C23 0.0212 (10) 0.0224 (11) 0.0296 (11) 0.0034 (8) 0.0106 (8) 0.0024 (9) C24 0.0291 (12) 0.0268 (12) 0.0345 (13) 0.0019 (9) 0.0031 (10) 0.0031 (10) C25 0.0333 (13) 0.0279 (13) 0.0540 (17) −0.0006 (10) 0.0022 (12) −0.0048 (12) C26 0.0368 (14) 0.0186 (12) 0.0631 (19) 0.0061 (10) 0.0175 (13) 0.0087 (11) C27 0.0382 (14) 0.0359 (14) 0.0366 (14) 0.0139 (11) 0.0142 (11) 0.0137 (11) C28 0.0283 (12) 0.0329 (13) 0.0304 (12) 0.0089 (10) 0.0074 (9) −0.0010 (10) C29 0.0306 (11) 0.0195 (11) 0.0322 (12) 0.0034 (9) 0.0143 (9) 0.0045 (9) C30 0.0342 (13) 0.0211 (11) 0.0415 (14) 0.0000 (10) 0.0135 (11) −0.0001 (10) C31 0.0408 (14) 0.0254 (12) 0.0356 (14) 0.0047 (10) 0.0100 (11) 0.0089 (10) Br1 0.02077 (11) 0.03140 (13) 0.02841 (12) 0.00005 (9) 0.00584 (8) 0.00150 (9) Br2 0.03523 (13) 0.02893 (13) 0.02839 (13) −0.00436 (9) 0.01185 (9) −0.00585 (9) ----- -------------- -------------- -------------- -------------- ------------- -------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2151 .table-wrap} ----------------------- -------------- ----------------------- -------------- N1---C10 1.333 (3) C14---C15 1.412 (3) N1---C8 1.376 (3) C14---C18 1.504 (3) N1---C7 1.468 (3) C15---C16 1.387 (4) N2---C10 1.337 (3) C15---C31 1.507 (3) N2---C9 1.371 (3) C16---C17 1.385 (3) N2---C11 1.474 (3) C16---H16A 0.9300 N3---C19 1.334 (3) C17---C30 1.506 (3) N3---C20 1.371 (3) C18---H18A 0.9700 N3---C18 1.472 (3) C18---H18B 0.9700 N4---C19 1.330 (3) C19---H19A 0.9300 N4---C21 1.382 (3) C20---C21 1.352 (3) N4---C22 1.479 (3) C20---H20A 0.9300 C1---C2 1.387 (4) C21---H21A 0.9300 C1---C6 1.391 (3) C22---C23 1.514 (3) C1---H1A 0.9300 C22---H22A 0.9700 C2---C3 1.386 (5) C22---H22B 0.9700 C2---H2A 0.9300 C23---C28 1.384 (3) C3---C4 1.380 (4) C23---C24 1.388 (3) C3---H3A 0.9300 C24---C25 1.385 (3) C4---C5 1.390 (4) C24---H24A 0.9300 C4---H4A 0.9300 C25---C26 1.379 (4) C5---C6 1.385 (3) C25---H25A 0.9300 C5---H5A 0.9300 C26---C27 1.380 (4) C6---C7 1.505 (3) C26---H26A 0.9300 C7---H7A 0.9700 C27---C28 1.384 (4) C7---H7B 0.9700 C27---H27A 0.9300 C8---C9 1.355 (3) C28---H28A 0.9300 C8---H8A 0.9300 C29---H29A 0.9600 C9---H9A 0.9300 C29---H29B 0.9600 C10---H10A 0.9300 C29---H29C 0.9600 C11---C12 1.510 (3) C30---H30A 0.9600 C11---H11A 0.9700 C30---H30B 0.9600 C11---H11B 0.9700 C30---H30C 0.9600 C12---C13 1.402 (3) C31---H31A 0.9600 C12---C17 1.408 (3) C31---H31B 0.9600 C13---C14 1.402 (3) C31---H31C 0.9600 C13---C29 1.515 (3) C10---N1---C8 109.14 (18) C17---C16---C15 122.8 (2) C10---N1---C7 124.97 (19) C17---C16---H16A 118.6 C8---N1---C7 125.85 (19) C15---C16---H16A 118.6 C10---N2---C9 108.90 (18) C16---C17---C12 118.1 (2) C10---N2---C11 125.60 (19) C16---C17---C30 120.1 (2) C9---N2---C11 125.44 (19) C12---C17---C30 121.8 (2) C19---N3---C20 109.00 (19) N3---C18---C14 113.49 (18) C19---N3---C18 126.1 (2) N3---C18---H18A 108.9 C20---N3---C18 124.88 (19) C14---C18---H18A 108.9 C19---N4---C21 109.05 (19) N3---C18---H18B 108.9 C19---N4---C22 124.8 (2) C14---C18---H18B 108.9 C21---N4---C22 125.9 (2) H18A---C18---H18B 107.7 C2---C1---C6 120.8 (3) N4---C19---N3 108.0 (2) C2---C1---H1A 119.6 N4---C19---H19A 126.0 C6---C1---H1A 119.6 N3---C19---H19A 126.0 C3---C2---C1 120.4 (3) C21---C20---N3 107.3 (2) C3---C2---H2A 119.8 C21---C20---H20A 126.3 C1---C2---H2A 119.8 N3---C20---H20A 126.3 C4---C3---C2 119.0 (3) C20---C21---N4 106.6 (2) C4---C3---H3A 120.5 C20---C21---H21A 126.7 C2---C3---H3A 120.5 N4---C21---H21A 126.7 C3---C4---C5 120.9 (3) N4---C22---C23 110.43 (17) C3---C4---H4A 119.6 N4---C22---H22A 109.6 C5---C4---H4A 119.6 C23---C22---H22A 109.6 C6---C5---C4 120.4 (2) N4---C22---H22B 109.6 C6---C5---H5A 119.8 C23---C22---H22B 109.6 C4---C5---H5A 119.8 H22A---C22---H22B 108.1 C5---C6---C1 118.7 (2) C28---C23---C24 119.5 (2) C5---C6---C7 123.8 (2) C28---C23---C22 121.0 (2) C1---C6---C7 117.5 (2) C24---C23---C22 119.5 (2) N1---C7---C6 113.04 (19) C25---C24---C23 119.9 (2) N1---C7---H7A 109.0 C25---C24---H24A 120.0 C6---C7---H7A 109.0 C23---C24---H24A 120.0 N1---C7---H7B 109.0 C26---C25---C24 120.2 (3) C6---C7---H7B 109.0 C26---C25---H25A 119.9 H7A---C7---H7B 107.8 C24---C25---H25A 119.9 C9---C8---N1 106.7 (2) C25---C26---C27 120.1 (2) C9---C8---H8A 126.6 C25---C26---H26A 119.9 N1---C8---H8A 126.6 C27---C26---H26A 119.9 C8---C9---N2 107.3 (2) C26---C27---C28 119.8 (2) C8---C9---H9A 126.3 C26---C27---H27A 120.1 N2---C9---H9A 126.3 C28---C27---H27A 120.1 N1---C10---N2 107.92 (19) C23---C28---C27 120.4 (2) N1---C10---H10A 126.0 C23---C28---H28A 119.8 N2---C10---H10A 126.0 C27---C28---H28A 119.8 N2---C11---C12 112.17 (17) C13---C29---H29A 109.5 N2---C11---H11A 109.2 C13---C29---H29B 109.5 C12---C11---H11A 109.2 H29A---C29---H29B 109.5 N2---C11---H11B 109.2 C13---C29---H29C 109.5 C12---C11---H11B 109.2 H29A---C29---H29C 109.5 H11A---C11---H11B 107.9 H29B---C29---H29C 109.5 C13---C12---C17 120.6 (2) C17---C30---H30A 109.5 C13---C12---C11 120.90 (19) C17---C30---H30B 109.5 C17---C12---C11 118.5 (2) H30A---C30---H30B 109.5 C12---C13---C14 119.6 (2) C17---C30---H30C 109.5 C12---C13---C29 120.7 (2) H30A---C30---H30C 109.5 C14---C13---C29 119.7 (2) H30B---C30---H30C 109.5 C13---C14---C15 119.9 (2) C15---C31---H31A 109.5 C13---C14---C18 120.7 (2) C15---C31---H31B 109.5 C15---C14---C18 119.2 (2) H31A---C31---H31B 109.5 C16---C15---C14 118.6 (2) C15---C31---H31C 109.5 C16---C15---C31 119.7 (2) H31A---C31---H31C 109.5 C14---C15---C31 121.7 (2) H31B---C31---H31C 109.5 C6---C1---C2---C3 −0.7 (5) C13---C14---C15---C31 179.4 (2) C1---C2---C3---C4 0.7 (5) C18---C14---C15---C31 −5.0 (3) C2---C3---C4---C5 0.2 (4) C14---C15---C16---C17 −3.1 (3) C3---C4---C5---C6 −1.0 (4) C31---C15---C16---C17 176.5 (2) C4---C5---C6---C1 0.9 (4) C15---C16---C17---C12 2.4 (3) C4---C5---C6---C7 −178.8 (2) C15---C16---C17---C30 −177.1 (2) C2---C1---C6---C5 −0.1 (4) C13---C12---C17---C16 2.5 (3) C2---C1---C6---C7 179.7 (3) C11---C12---C17---C16 −175.25 (18) C10---N1---C7---C6 −96.1 (3) C13---C12---C17---C30 −178.02 (19) C8---N1---C7---C6 81.5 (3) C11---C12---C17---C30 4.2 (3) C5---C6---C7---N1 −6.2 (3) C19---N3---C18---C14 30.3 (3) C1---C6---C7---N1 174.1 (2) C20---N3---C18---C14 −152.4 (2) C10---N1---C8---C9 0.2 (3) C13---C14---C18---N3 −116.1 (2) C7---N1---C8---C9 −177.8 (2) C15---C14---C18---N3 68.3 (3) N1---C8---C9---N2 −1.0 (3) C21---N4---C19---N3 −0.3 (3) C10---N2---C9---C8 1.6 (3) C22---N4---C19---N3 174.75 (19) C11---N2---C9---C8 179.0 (2) C20---N3---C19---N4 0.5 (3) C8---N1---C10---N2 0.8 (2) C18---N3---C19---N4 178.19 (19) C7---N1---C10---N2 178.76 (19) C19---N3---C20---C21 −0.6 (3) C9---N2---C10---N1 −1.5 (2) C18---N3---C20---C21 −178.2 (2) C11---N2---C10---N1 −178.90 (19) N3---C20---C21---N4 0.4 (3) C10---N2---C11---C12 −42.9 (3) C19---N4---C21---C20 0.0 (3) C9---N2---C11---C12 140.1 (2) C22---N4---C21---C20 −175.0 (2) N2---C11---C12---C13 101.9 (2) C19---N4---C22---C23 −79.9 (3) N2---C11---C12---C17 −80.3 (2) C21---N4---C22---C23 94.4 (3) C17---C12---C13---C14 −6.5 (3) N4---C22---C23---C28 −88.0 (3) C11---C12---C13---C14 171.21 (18) N4---C22---C23---C24 89.8 (3) C17---C12---C13---C29 173.11 (18) C28---C23---C24---C25 1.2 (3) C11---C12---C13---C29 −9.2 (3) C22---C23---C24---C25 −176.7 (2) C12---C13---C14---C15 5.7 (3) C23---C24---C25---C26 1.2 (4) C29---C13---C14---C15 −173.94 (18) C24---C25---C26---C27 −2.7 (4) C12---C13---C14---C18 −169.92 (18) C25---C26---C27---C28 1.8 (4) C29---C13---C14---C18 10.4 (3) C24---C23---C28---C27 −2.1 (3) C13---C14---C15---C16 −1.0 (3) C22---C23---C28---C27 175.7 (2) C18---C14---C15---C16 174.71 (19) C26---C27---C28---C23 0.6 (4) ----------------------- -------------- ----------------------- -------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3468 .table-wrap} ----------------------- --------- --------- ----------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* C7---H7A···Br2 0.97 2.90 3.754 (2) 147 C7---H7B···Br1^i^ 0.97 2.92 3.787 (2) 149 C8---H8A···Br2 0.93 2.81 3.496 (3) 132 C10---H10A···Br1^i^ 0.93 2.74 3.565 (2) 148 C18---H18B···Br2^ii^ 0.97 2.74 3.702 (2) 172 C19---H19A···Br1^i^ 0.93 2.74 3.553 (2) 147 C21---H21A···Br2^iii^ 0.93 2.83 3.603 (3) 141 ----------------------- --------- --------- ----------- --------------- ::: Symmetry codes: (i) *x*+1, *y*, *z*; (ii) *x*, −*y*+3/2, *z*+1/2; (iii) *x*+1, −*y*+3/2, *z*+1/2. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ----------------------- --------- ------- ----------- ------------- C7---H7*A*⋯Br2 0.97 2.90 3.754 (2) 147 C7---H7*B*⋯Br1^i^ 0.97 2.92 3.787 (2) 149 C8---H8*A*⋯Br2 0.93 2.81 3.496 (3) 132 C10---H10*A*⋯Br1^i^ 0.93 2.74 3.565 (2) 148 C18---H18*B*⋯Br2^ii^ 0.97 2.74 3.702 (2) 172 C19---H19*A*⋯Br1^i^ 0.93 2.74 3.553 (2) 147 C21---H21*A*⋯Br2^iii^ 0.93 2.83 3.603 (3) 141 Symmetry codes: (i) ; (ii) ; (iii) . ::: [^1]: ‡ Thomson Reuters ResearcherID: A-3561-2009.

PubMed Central

2024-06-05T04:04:17.744352

2011-2-16

PMC3051992

Related literature {#sec1} ================== For the coordination chemistry of β-diketone derivatives and their structural analogues, see Skopenko *et al.* (2004[@bb10]). For details of the pharmacological and biological properties of sulfonyl­amide derivatives, see: Kishino & Saito (1979[@bb4]); Xu & Angell (2000[@bb12]). For structural discussion, see: Cremer & Pople (1975[@bb2]); Zefirov *et al.* (1990[@bb13]). For related structures, see: Moroz *et al.* (2009[@bb5]); Shatrava *et al.* (2010[@bb8]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[Co(C~8~H~11~NO~5~PS)~2~(H~2~O)~2~\]*M* *~r~* = 623.38Triclinic,*a* = 9.875 (1) Å*b* = 10.207 (1) Å*c* = 13.345 (2) Åα = 91.60 (1)°β = 110.59 (1)°γ = 92.84 (1)°*V* = 1256.2 (3) Å^3^*Z* = 2Mo *K*α radiationμ = 1.04 mm^−1^*T* = 294 K0.40 × 0.20 × 0.10 mm ### Data collection {#sec2.1.2} Oxford Diffraction Xcalibur3 diffractometerAbsorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009[@bb7]) *T* ~min~ = 0.681, *T* ~max~ = 0.9039231 measured reflections5612 independent reflections4025 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.019 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.029*wR*(*F* ^2^) = 0.066*S* = 0.905612 reflections354 parameters4 restraintsH-atom parameters constrainedΔρ~max~ = 0.34 e Å^−3^Δρ~min~ = −0.22 e Å^−3^ {#d5e519} Data collection: *CrysAlis CCD* (Oxford Diffraction, 2006[@bb6]); cell refinement: *CrysAlis RED* (Oxford Diffraction, 2006[@bb6]); data reduction: *CrysAlis RED*; program(s) used to solve structure: *SHELXTL* (Sheldrick, 2008[@bb9]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb9]); molecular graphics: *ORTEPIII* (Burnett & Johnson, 1996[@bb1]), *ORTEP-3 for Windows* (Farrugia, 1997[@bb3]) and *PLATON* (Spek, 2009[@bb11]); software used to prepare material for publication: *SHELXL97*. Supplementary Material ====================== Crystal structure: contains datablocks I, global. DOI: [10.1107/S1600536811006027/dn2630sup1.cif](http://dx.doi.org/10.1107/S1600536811006027/dn2630sup1.cif) Structure factors: contains datablocks I. DOI: [10.1107/S1600536811006027/dn2630Isup2.hkl](http://dx.doi.org/10.1107/S1600536811006027/dn2630Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?dn2630&file=dn2630sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?dn2630sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?dn2630&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [DN2630](http://scripts.iucr.org/cgi-bin/sendsup?dn2630)). The authors gratefully acknowledge the Ukrainian State Fund for Fundamental Researchers (SFFR) for financial support of the Research Program (Chemistry). Comment ======= Many efforts are devoted to the coordination chemistry of β- diketones derivatives and their structural analogues (Skopenko *et al.*, 2004). The phosphorylated sulfonylamides, RSO~2~NHP(O)(*R*\')~2~ (SAPh), present such type of heterosubstituted structural analogues with different substituents at sulfur and phosphorus atoms. In the past few decades SAPh have been intensively used as bactericidal agents in medicine and toxicology (Xu & Angell, 2000). Some of them are effective pesticides (Kishino & Saito, 1979). So a variety of new s-, d-, and f- metals based coordination compounds containing this type of phosphoramides have been synthesized. Structural investigation of compounds with phosphorylated sulfonylamide ligands have already been reported (Moroz *et al.*, 2009, Shatrava *et al.*, 2010). Herein we report the structure of the title compound containing one of the simplest representative of this class of ligands: the dimethyl(phenylsulfonyl)amidophosphate. The crystal structure of CoL~2~2H~2~O (I) is built up from non-centrosymmetric molecular species with the two water molecules in *cis-* position to each other. The CoO~6~ fragment is formed by two oxygen atoms of water molecules and four oxygen atoms of phosphoryl and sulfonyl groups from two ligands which are coordinated in bidentate chelating mode (Fig. 1). The coordination environment of cobalt can be described as a distorted octahedron. The six-membered chelate rings have a twist--boat conformation (the puckering parameters (Cremer & Pople,1975) are θ=81.19,ψ=25.33, S=0.60 for CoO~2~SNPO~3~ fragment and θ=67.91, ψ=17.44, S=0.57 for the CoO~7~S~2~N~2~P~2~O~8~ (Zefirov *et al.*, 1990). The O4 and O5 atoms of methoxy groups are disordered over two positions due to the rotation around P1---O4 and P1---O5 bonds with populations 40:60%. O---H···O intermolecular hydrogen bonds between the water and non-coordinated sulfonyl oxygen atoms and coordinated phosphoryl groups of neighboring SAPh molecules (Table 1) build up chains parallel to the \[0 1 0\] direction (Fig.2). Experimental {#experimental} ============ The sodium salt (NaL) was prepared by the reaction between equimolar amounts of sodium isopropylate (0,023 g, 1 mmol of Na was solved in 2-propanol) and HL (0,2652 g, 1 mmol) in an 2-propanol medium and was used for preparation of complexes without isolation from the reaction mixture. The solution of NaL (1 mmol) was added to the solution of CoCl~2~6H~2~O (0,124 2 g, 0,5 mmol) in 2-propanol (10 ml). The resulting mixture was filtrated off and mother liquor was left on air at room temperature for several days. Precipitated from the solution purple crystals were filtered and washed with cool 2-propanol. Single crystals of \[Co(*L*)~2~2H~2~O\] were prepared by slow recrystallization in 2-propanol-chloroform (3:1) mixture (yield - 80--90%). This complex as prepared is less soluble in non-polar aprotic solvents and H~2~O. Analysis found: IR (KBr pellet, cm^-1^): 1220, 1060 (s, SO~2~) and 1190 (s, PO). Refinement {#refinement} ========== All H atoms attached to C atoms were fixed geometrically and treated as riding with C---H = 0.96 Å (methyl) or 0.93 Å (aromatic) with U~iso~(H) = 1.2U~eq~(Caromatic) or U~iso~(H) = 1.5U~eq~(Cmethyl). H atoms of water molecule were located in difference Fourier maps and included in the subsequent refinement using restraints (O-H= 0.85 (1)Å and H···H= 1.39 (2)Å) with U~iso~(H) = 1.5U~eq~(O). In the last cycles of refinement, they were treated as riding on their parent oxygen atoms. Two methoxy groups attached to one phosphorus are disordered over two positions. Two sets of positions were then defined for the atoms of these groups and the site occupation factors of each conformation were refined while restraining their sum to unity. The site occupation factor of the major conformation refined to 0.585 (5). Then the occupancy factors were fixed to 0.6 and 0.4 respectively for the two components. The O-C distances were restrained to have chemically reasonable bond values of 1.45(0.02)Å. Figures ======= ::: {#Fap1 .fig} Fig. 1. ::: {.caption} ###### Molecular view of (I) with the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. H atoms have been omitted for clarity. Only the major component of the disorder is shown in the figure. :::  ::: ::: {#Fap2 .fig} Fig. 2. ::: {.caption} ###### Partial packing view of compound ( I ), showing the formation of chains along \[010\] built from hydrogen bonds. H atoms not involved in hydrogen bonding have been omitted for clarity. :::  ::: Crystal data {#tablewrapcrystaldatalong} ============ ::: {#d1e221 .table-wrap} --------------------------------------- --------------------------------------- \[Co(C~8~H~11~NO~5~PS)~2~(H~2~O)~2~\] *Z* = 2 *M~r~* = 623.38 *F*(000) = 642 Triclinic, *P*1 *D*~x~ = 1.648 Mg m^−3^ Hall symbol: -P 1 Mo *K*α radiation, λ = 0.71073 Å *a* = 9.875 (1) Å Cell parameters from 4537 reflections *b* = 10.207 (1) Å θ = 3.0--34.8° *c* = 13.345 (2) Å µ = 1.04 mm^−1^ α = 91.60 (1)° *T* = 294 K β = 110.59 (1)° Plate, purple γ = 92.84 (1)° 0.40 × 0.20 × 0.10 mm *V* = 1256.2 (3) Å^3^ --------------------------------------- --------------------------------------- ::: Data collection {#tablewrapdatacollectionlong} =============== ::: {#d1e365 .table-wrap} ------------------------------------------------------------------------------ -------------------------------------- Oxford Diffraction Xcalibur3 diffractometer 5612 independent reflections Radiation source: Enhance (Mo) X-ray Source 4025 reflections with *I* \> 2σ(*I*) graphite *R*~int~ = 0.019 Detector resolution: 16.1827 pixels mm^-1^ θ~max~ = 27.5°, θ~min~ = 3.0° ω scans *h* = −12→12 Absorption correction: multi-scan (*CrysAlis PRO*; Oxford Diffraction, 2009) *k* = −13→12 *T*~min~ = 0.681, *T*~max~ = 0.903 *l* = −17→17 9231 measured reflections ------------------------------------------------------------------------------ -------------------------------------- ::: Refinement {#tablewraprefinementdatalong} ========== ::: {#d1e485 .table-wrap} ------------------------------------- ------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.029 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.066 H-atom parameters constrained *S* = 0.90 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0363*P*)^2^\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 5612 reflections (Δ/σ)~max~ = 0.001 354 parameters Δρ~max~ = 0.34 e Å^−3^ 4 restraints Δρ~min~ = −0.22 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------- ::: Special details {#specialdetails} =============== ::: {#d1e639 .table-wrap} ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Experimental. Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. CrysAlisPRO (Oxford Diffraction, 2009) Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- ::: Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ::: {#d1e744 .table-wrap} ------ -------------- -------------- --------------- -------------------- ------------ *x* *y* *z* *U*~iso~\*/*U*~eq~ Occ. (\<1) Co1 0.53757 (3) 0.25048 (2) 0.49629 (2) 0.02561 (8) S1 0.52838 (5) 0.13796 (5) 0.26446 (4) 0.02895 (11) S2 0.76726 (5) 0.37652 (5) 0.72245 (4) 0.02815 (11) O3 0.64121 (18) 0.39270 (13) 0.43552 (12) 0.0433 (4) P1 0.68038 (7) 0.38043 (6) 0.33995 (5) 0.04364 (16) O4 0.5573 (4) 0.4744 (3) 0.2591 (3) 0.0543 (9) 0.60 C7 0.5608 (12) 0.5119 (16) 0.1582 (8) 0.076 (3) 0.60 H7A 0.6552 0.5506 0.1673 0.115\* 0.60 H7B 0.4895 0.5747 0.1292 0.115\* 0.60 H7C 0.5399 0.4359 0.1100 0.115\* 0.60 O5 0.8157 (3) 0.4492 (2) 0.3338 (2) 0.0464 (7) 0.60 C8 0.9520 (11) 0.3888 (12) 0.3764 (11) 0.071 (3) 0.60 H8A 0.9525 0.3375 0.4358 0.106\* 0.60 H8B 1.0298 0.4557 0.4001 0.106\* 0.60 H8C 0.9643 0.3328 0.3216 0.106\* 0.60 O4A 0.6779 (5) 0.4913 (4) 0.2748 (3) 0.0520 (11) 0.40 C7A 0.5421 (13) 0.4968 (18) 0.1864 (11) 0.074 (5) 0.40 H7A1 0.5463 0.5724 0.1462 0.112\* 0.40 H7A2 0.4646 0.5029 0.2137 0.112\* 0.40 H7A3 0.5253 0.4188 0.1408 0.112\* 0.40 O5A 0.8642 (5) 0.3924 (4) 0.4153 (3) 0.0464 (10) 0.40 C8A 0.9676 (14) 0.3964 (12) 0.3623 (13) 0.049 (4) 0.40 H8A1 1.0639 0.4028 0.4147 0.073\* 0.40 H8A2 0.9540 0.4714 0.3187 0.073\* 0.40 H8A3 0.9543 0.3178 0.3178 0.073\* 0.40 P2 0.86187 (6) 0.16991 (5) 0.62440 (4) 0.02887 (12) O1 0.57367 (17) 0.00623 (13) 0.26086 (12) 0.0414 (4) O2 0.45315 (15) 0.15860 (13) 0.33970 (10) 0.0321 (3) O6 0.79818 (17) 0.51694 (13) 0.72756 (12) 0.0384 (3) O7 0.61859 (15) 0.33380 (13) 0.65460 (11) 0.0341 (3) O8 0.71640 (15) 0.13434 (12) 0.54199 (11) 0.0334 (3) O9 0.91160 (17) 0.06168 (14) 0.70876 (12) 0.0436 (4) O10 0.97392 (16) 0.17385 (15) 0.56604 (12) 0.0413 (4) O11 0.36115 (15) 0.36550 (13) 0.46253 (11) 0.0370 (3) H11A 0.3755 0.4409 0.4997 0.055\* H11B 0.3157 0.3944 0.3963 0.055\* O12 0.41962 (15) 0.11126 (12) 0.54596 (11) 0.0331 (3) H12A 0.4369 0.0941 0.6169 0.050\* H12B 0.3853 0.0377 0.5082 0.050\* N1 0.65693 (18) 0.23960 (16) 0.28018 (13) 0.0342 (4) N2 0.88326 (18) 0.30347 (16) 0.69393 (13) 0.0335 (4) C1 0.3978 (2) 0.16127 (18) 0.13660 (16) 0.0307 (4) C2 0.2605 (3) 0.1922 (3) 0.1249 (2) 0.0519 (6) H2 0.2330 0.2019 0.1844 0.062\* C3 0.1620 (3) 0.2089 (3) 0.0225 (2) 0.0660 (8) H3 0.0683 0.2307 0.0137 0.079\* C4 0.2014 (3) 0.1938 (3) −0.0644 (2) 0.0599 (7) H4 0.1341 0.2036 −0.1325 0.072\* C5 0.3395 (3) 0.1643 (3) −0.05244 (19) 0.0561 (7) H5 0.3667 0.1556 −0.1122 0.067\* C6 0.4385 (3) 0.1473 (2) 0.04848 (17) 0.0458 (6) H6 0.5324 0.1265 0.0569 0.055\* C10 0.7510 (3) 0.2074 (2) 0.87303 (19) 0.0443 (6) H10 0.7241 0.1425 0.8181 0.053\* C11 0.7603 (3) 0.1775 (3) 0.9745 (2) 0.0555 (7) H11 0.7395 0.0915 0.9884 0.067\* C12 0.7996 (3) 0.2720 (3) 1.0556 (2) 0.0576 (7) H12 0.8043 0.2503 1.1240 0.069\* C13 0.8322 (3) 0.3988 (3) 1.0366 (2) 0.0566 (7) H13 0.8603 0.4629 1.0922 0.068\* C14 0.8232 (3) 0.4313 (2) 0.93455 (18) 0.0430 (5) H14 0.8449 0.5173 0.9211 0.052\* C15 0.7821 (2) 0.33569 (19) 0.85348 (16) 0.0306 (4) C16 1.1267 (3) 0.2070 (3) 0.6236 (2) 0.0603 (7) H16A 1.1755 0.2187 0.5734 0.090\* H16B 1.1679 0.1373 0.6694 0.090\* H16C 1.1380 0.2869 0.6663 0.090\* C17 0.9315 (3) −0.0702 (2) 0.6758 (2) 0.0691 (9) H17A 0.9856 −0.1161 0.7377 0.104\* H17B 0.9836 −0.0660 0.6272 0.104\* H17C 0.8386 −0.1159 0.6408 0.104\* ------ -------------- -------------- --------------- -------------------- ------------ ::: Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ::: {#d1e1675 .table-wrap} ----- -------------- -------------- -------------- -------------- -------------- --------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ Co1 0.02756 (15) 0.02457 (13) 0.02328 (14) 0.00186 (11) 0.00724 (11) 0.00077 (10) S1 0.0328 (3) 0.0307 (2) 0.0227 (3) 0.0018 (2) 0.0091 (2) 0.00059 (19) S2 0.0289 (3) 0.0294 (2) 0.0243 (3) 0.0013 (2) 0.0073 (2) −0.00163 (19) O3 0.0625 (11) 0.0311 (7) 0.0414 (9) −0.0096 (7) 0.0267 (8) −0.0037 (7) P1 0.0558 (4) 0.0341 (3) 0.0529 (4) −0.0083 (3) 0.0358 (3) −0.0035 (3) O4 0.060 (2) 0.056 (2) 0.064 (2) 0.0239 (17) 0.037 (2) 0.0253 (17) C7 0.068 (6) 0.091 (7) 0.079 (4) 0.022 (4) 0.031 (4) 0.053 (4) O5 0.0392 (16) 0.0383 (14) 0.065 (2) −0.0020 (12) 0.0234 (15) 0.0073 (14) C8 0.039 (5) 0.106 (7) 0.070 (5) 0.006 (4) 0.021 (4) 0.021 (5) O4A 0.055 (3) 0.049 (2) 0.054 (3) −0.001 (2) 0.020 (2) 0.023 (2) C7A 0.053 (6) 0.050 (6) 0.128 (15) 0.026 (5) 0.036 (9) 0.041 (10) O5A 0.035 (2) 0.060 (3) 0.039 (2) −0.011 (2) 0.010 (2) −0.001 (2) C8A 0.038 (6) 0.037 (5) 0.068 (8) 0.004 (4) 0.015 (5) −0.008 (5) P2 0.0269 (3) 0.0333 (3) 0.0255 (3) 0.0058 (2) 0.0078 (2) 0.0002 (2) O1 0.0565 (10) 0.0318 (7) 0.0353 (9) 0.0095 (7) 0.0145 (8) 0.0011 (6) O2 0.0348 (8) 0.0376 (7) 0.0238 (7) −0.0052 (6) 0.0114 (6) −0.0013 (6) O6 0.0481 (9) 0.0289 (7) 0.0368 (8) 0.0012 (7) 0.0133 (7) 0.0019 (6) O7 0.0268 (7) 0.0443 (8) 0.0274 (8) 0.0051 (6) 0.0053 (6) −0.0071 (6) O8 0.0301 (8) 0.0314 (7) 0.0341 (8) 0.0049 (6) 0.0054 (6) −0.0053 (6) O9 0.0526 (10) 0.0425 (8) 0.0331 (9) 0.0143 (8) 0.0102 (7) 0.0074 (7) O10 0.0357 (9) 0.0571 (9) 0.0342 (8) 0.0069 (7) 0.0160 (7) −0.0029 (7) O11 0.0401 (8) 0.0308 (7) 0.0352 (8) 0.0111 (6) 0.0060 (7) 0.0028 (6) O12 0.0417 (8) 0.0279 (7) 0.0293 (8) −0.0029 (6) 0.0129 (7) 0.0008 (6) N1 0.0315 (10) 0.0422 (9) 0.0309 (10) −0.0012 (8) 0.0142 (8) −0.0016 (8) N2 0.0262 (9) 0.0410 (9) 0.0329 (10) 0.0008 (8) 0.0107 (8) −0.0070 (8) C1 0.0349 (12) 0.0289 (10) 0.0255 (10) −0.0011 (9) 0.0077 (9) −0.0002 (8) C2 0.0427 (14) 0.0752 (17) 0.0370 (14) 0.0124 (13) 0.0124 (11) −0.0053 (12) C3 0.0429 (15) 0.093 (2) 0.0497 (16) 0.0200 (15) 0.0000 (13) −0.0050 (15) C4 0.070 (2) 0.0619 (16) 0.0316 (14) 0.0069 (15) −0.0022 (13) 0.0015 (12) C5 0.0713 (19) 0.0683 (16) 0.0274 (13) −0.0002 (15) 0.0165 (13) 0.0006 (12) C6 0.0444 (14) 0.0629 (14) 0.0303 (12) 0.0001 (12) 0.0140 (11) −0.0003 (11) C10 0.0556 (15) 0.0395 (12) 0.0403 (14) −0.0070 (11) 0.0218 (12) −0.0029 (10) C11 0.0700 (18) 0.0553 (15) 0.0483 (16) −0.0082 (14) 0.0309 (14) 0.0101 (13) C12 0.0610 (18) 0.0813 (19) 0.0353 (14) −0.0014 (15) 0.0235 (13) 0.0094 (14) C13 0.0611 (17) 0.0721 (17) 0.0324 (13) −0.0076 (14) 0.0142 (12) −0.0139 (12) C14 0.0498 (14) 0.0428 (12) 0.0333 (12) −0.0065 (11) 0.0126 (11) −0.0065 (10) C15 0.0260 (10) 0.0380 (11) 0.0267 (11) 0.0014 (9) 0.0081 (9) 0.0000 (9) C16 0.0355 (14) 0.087 (2) 0.0619 (18) 0.0025 (14) 0.0220 (13) −0.0037 (15) C17 0.085 (2) 0.0417 (14) 0.075 (2) 0.0230 (14) 0.0182 (17) 0.0126 (14) ----- -------------- -------------- -------------- -------------- -------------- --------------- ::: Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== ::: {#d1e2378 .table-wrap} ------------------- ------------- ------------------- ------------- Co1---O12 2.0608 (13) P2---O10 1.5607 (16) Co1---O11 2.0729 (13) P2---O9 1.5695 (15) Co1---O3 2.0771 (14) P2---N2 1.5897 (17) Co1---O8 2.0942 (13) O9---C17 1.448 (3) Co1---O7 2.1143 (14) O10---C16 1.450 (3) Co1---O2 2.1282 (14) O11---H11A 0.8808 S1---O1 1.4427 (14) O11---H11B 0.9049 S1---O2 1.4604 (14) O12---H12A 0.9239 S1---N1 1.5497 (18) O12---H12B 0.8753 S1---C1 1.771 (2) C1---C2 1.363 (3) S2---O6 1.4452 (14) C1---C6 1.376 (3) S2---O7 1.4646 (14) C2---C3 1.392 (3) S2---N2 1.5454 (17) C2---H2 0.9300 S2---C15 1.766 (2) C3---C4 1.353 (4) O3---P1 1.4610 (16) C3---H3 0.9300 P1---O4A 1.442 (4) C4---C5 1.367 (4) P1---O5 1.508 (3) C4---H4 0.9300 P1---N1 1.5903 (18) C5---C6 1.380 (3) P1---O4 1.677 (4) C5---H5 0.9300 P1---O5A 1.735 (4) C6---H6 0.9300 O4---C7 1.422 (7) C10---C11 1.369 (3) C7---H7A 0.9600 C10---C15 1.383 (3) C7---H7B 0.9600 C10---H10 0.9300 C7---H7C 0.9600 C11---C12 1.365 (4) O5---C8 1.442 (8) C11---H11 0.9300 C8---H8A 0.9600 C12---C13 1.370 (4) C8---H8B 0.9600 C12---H12 0.9300 C8---H8C 0.9600 C13---C14 1.384 (3) O4A---C7A 1.446 (9) C13---H13 0.9300 C7A---H7A1 0.9600 C14---C15 1.371 (3) C7A---H7A2 0.9600 C14---H14 0.9300 C7A---H7A3 0.9600 C16---H16A 0.9600 O5A---C8A 1.432 (10) C16---H16B 0.9600 C8A---H8A1 0.9600 C16---H16C 0.9600 C8A---H8A2 0.9600 C17---H17A 0.9600 C8A---H8A3 0.9600 C17---H17B 0.9600 P2---O8 1.4899 (14) C17---H17C 0.9600 O12---Co1---O11 87.46 (6) H8A1---C8A---H8A3 109.5 O12---Co1---O3 175.32 (6) H8A2---C8A---H8A3 109.5 O11---Co1---O3 89.17 (6) O8---P2---O10 107.45 (8) O12---Co1---O8 90.37 (5) O8---P2---O9 112.00 (9) O11---Co1---O8 175.81 (6) O10---P2---O9 105.32 (8) O3---Co1---O8 93.20 (6) O8---P2---N2 118.12 (8) O12---Co1---O7 88.52 (6) O10---P2---N2 108.42 (9) O11---Co1---O7 89.44 (5) O9---P2---N2 104.80 (9) O3---Co1---O7 94.69 (6) S1---O2---Co1 128.04 (8) O8---Co1---O7 86.92 (5) S2---O7---Co1 129.91 (9) O12---Co1---O2 88.98 (5) P2---O8---Co1 126.80 (8) O11---Co1---O2 91.24 (6) C17---O9---P2 120.67 (16) O3---Co1---O2 87.86 (6) C16---O10---P2 121.54 (14) O8---Co1---O2 92.30 (5) Co1---O11---H11A 116.3 O7---Co1---O2 177.37 (5) Co1---O11---H11B 122.1 O1---S1---O2 113.80 (9) H11A---O11---H11B 98.9 O1---S1---N1 110.36 (10) Co1---O12---H12A 124.1 O2---S1---N1 113.78 (9) Co1---O12---H12B 121.0 O1---S1---C1 106.44 (9) H12A---O12---H12B 107.1 O2---S1---C1 105.01 (9) S1---N1---P1 125.91 (11) N1---S1---C1 106.78 (9) S2---N2---P2 127.90 (11) O6---S2---O7 113.82 (9) C2---C1---C6 120.5 (2) O6---S2---N2 110.57 (9) C2---C1---S1 121.42 (17) O7---S2---N2 113.34 (9) C6---C1---S1 118.12 (17) O6---S2---C15 105.87 (9) C1---C2---C3 119.0 (2) O7---S2---C15 105.32 (9) C1---C2---H2 120.5 N2---S2---C15 107.28 (9) C3---C2---H2 120.5 P1---O3---Co1 127.44 (9) C4---C3---C2 120.6 (3) O4A---P1---O3 120.9 (2) C4---C3---H3 119.7 O4A---P1---O5 56.9 (2) C2---C3---H3 119.7 O3---P1---O5 121.88 (14) C3---C4---C5 120.3 (2) O4A---P1---N1 115.9 (2) C3---C4---H4 119.8 O3---P1---N1 117.82 (9) C5---C4---H4 119.8 O5---P1---N1 108.73 (12) C4---C5---C6 119.8 (2) O4A---P1---O4 41.9 (2) C4---C5---H5 120.1 O3---P1---O4 99.20 (13) C6---C5---H5 120.1 O5---P1---O4 98.84 (17) C1---C6---C5 119.7 (2) N1---P1---O4 106.62 (15) C1---C6---H6 120.1 O4A---P1---O5A 98.0 (2) C5---C6---H6 120.1 O3---P1---O5A 92.25 (16) C11---C10---C15 118.9 (2) O5---P1---O5A 42.78 (16) C11---C10---H10 120.5 N1---P1---O5A 103.27 (16) C15---C10---H10 120.5 O4---P1---O5A 137.9 (2) C12---C11---C10 121.0 (2) C7---O4---P1 122.6 (6) C12---C11---H11 119.5 O4---C7---H7A 109.5 C10---C11---H11 119.5 O4---C7---H7B 109.5 C11---C12---C13 120.1 (2) H7A---C7---H7B 109.5 C11---C12---H12 119.9 O4---C7---H7C 109.5 C13---C12---H12 119.9 H7A---C7---H7C 109.5 C12---C13---C14 119.9 (2) H7B---C7---H7C 109.5 C12---C13---H13 120.1 C8---O5---P1 119.5 (5) C14---C13---H13 120.1 O5---C8---H8A 109.5 C15---C14---C13 119.4 (2) O5---C8---H8B 109.5 C15---C14---H14 120.3 H8A---C8---H8B 109.5 C13---C14---H14 120.3 O5---C8---H8C 109.5 C14---C15---C10 120.66 (19) H8A---C8---H8C 109.5 C14---C15---S2 119.84 (16) H8B---C8---H8C 109.5 C10---C15---S2 119.49 (16) P1---O4A---C7A 113.0 (7) O10---C16---H16A 109.5 O4A---C7A---H7A1 109.5 O10---C16---H16B 109.5 O4A---C7A---H7A2 109.5 H16A---C16---H16B 109.5 H7A1---C7A---H7A2 109.5 O10---C16---H16C 109.5 O4A---C7A---H7A3 109.5 H16A---C16---H16C 109.5 H7A1---C7A---H7A3 109.5 H16B---C16---H16C 109.5 H7A2---C7A---H7A3 109.5 O9---C17---H17A 109.5 C8A---O5A---P1 119.7 (7) O9---C17---H17B 109.5 O5A---C8A---H8A1 109.5 H17A---C17---H17B 109.5 O5A---C8A---H8A2 109.5 O9---C17---H17C 109.5 H8A1---C8A---H8A2 109.5 H17A---C17---H17C 109.5 O5A---C8A---H8A3 109.5 H17B---C17---H17C 109.5 ------------------- ------------- ------------------- ------------- ::: Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ::: {#d1e3362 .table-wrap} --------------------- --------- --------- ------------- --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O11---H11A···O3^i^ 0.88 1.93 2.7898 (19) 167 O11---H11B···O6^i^ 0.90 1.92 2.811 (2) 167 O12---H12A···O1^ii^ 0.92 1.98 2.855 (2) 157 O12---H12B···O8^ii^ 0.88 1.96 2.8035 (18) 163 --------------------- --------- --------- ------------- --------------- ::: Symmetry codes: (i) −*x*+1, −*y*+1, −*z*+1; (ii) −*x*+1, −*y*, −*z*+1. ::: {#table1 .table-wrap} Table 1 ::: {.caption} ###### Hydrogen-bond geometry (Å, °) ::: *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* --------------------- --------- ------- ------------- ------------- O11---H11*A*⋯O3^i^ 0.88 1.93 2.7898 (19) 167 O11---H11*B*⋯O6^i^ 0.90 1.92 2.811 (2) 167 O12---H12*A*⋯O1^ii^ 0.92 1.98 2.855 (2) 157 O12---H12*B*⋯O8^ii^ 0.88 1.96 2.8035 (18) 163 Symmetry codes: (i) ; (ii) . :::

PubMed Central

2024-06-05T04:04:17.752530

2011-2-23