Compounds (1–16) were evaluated against free-living nematodes of the genus Rhabditis sp. In the tested group of rhodanine derivatives, only compound 2 shows very high biological activity (LC50 = 0.93 µg/µL), which is higher than the reference drug albendazole (LC50 = 19.24 µg/µL). Crystal structures of two compounds, active 2 and inactive 4, were determined by the X-ray diffraction method to compare molecular geometry and search for differences responsible for observed biological activity/inactivity. Molecular modelling and selected physicochemical properties prediction were performed to assess the potential mechanism of action and applied in the search for an explanation as to why amongst all similar compounds only one is active. We can conclude that the tested compound 2 can be further investigated as a potential anthelmintic drug.The treatment of parasitic infections requires the application of chemotherapy. In view of increasing resistance to currently in-use drugs, there is a constant need to search for new compounds with anthelmintic activity. A series of 16 cinnamylidene derivatives of rhodanine, including newly synthesized methoxy derivatives ( Multidrug resistance (MDR) has become a factor seriously limiting the treatment of various diseases, including parasitic infections . ParasitIn the group of anthelmintic drugs there are benzimidazoles , salicylanilides , imidazothiazoles (levamizole), thiazolides (nitazoxanide), macrocycliclactones (ivermectin), antitrematodals (praziquantel), quinolines (pyrvinium), cyclic amidines derivatives (pyrantel) ,6. Among2, 3), nitro (12), chloro  and N,N-diethyl  , as well as derivatives containing a methoxy substituent in the para position without carboxyl group (1), followed by compounds containing a carboxyl group with different lengths of the linker (4–7). The newly synthesized compounds were also evaluated against anthelmintic activity using free-living nematodes of the genus Rhabditis sp. According to the available literature, these nematodes can cause inter alia outer ear canal and urinary tract infections. Furthermore, Rhabditis sp. were also found in children + 336, IR (1 mg/400 mg KBr) cm−1: 1715.4C=O, 1697.1 C=O conj., 1641.2 C=C exo., 1574,6 C=CH-CH=CH-Ar, 1464.7 CH3, 1394.3 CH2, 1310.4 C-O-C, 1163.8 C=S, 1H NMR , δ: 13.32 , 7.66 , 7.55 , 7.36 , 6.98 , 4.66 , 3.78 , 13C NMR , δ: 193.3 (S=C-S), 167.9 (HOOC-), 166.2 (N-C=O), 161.7 C4 Ar), 146.9 (C=CH-CH=CH-Ar), 135.7 (C=CH-CH=CH-Ar), 128.8 (C=CH-CH=CH-Ar), 121.8 (C=CH-CH=CH-Ar), 121.8 (C1 Ar), 115.1 (C3 Ar), 56.0 (OCH3), 45.4 (HOOCCH2).m.p. 268–270 °C, MS [M + 1]− 348, IR (1 mg/400 mg KBr) cm−1: 1705.7 C=O, 1684.5 C=O conj., 1641.3 C=C exo., 1574.6 C=CH-CH=CH-Ar, 1463.7 CH3, 1379.8 CH2, 1310.4 C-O-C, 1160.0 C=S, 1H NMR , δ: 12.43 , 7.64 , 7,48 , 7.32 , 6.95 , 6.91 , 4.15 , 3.77 , 2.57 , 13C NMR , δ: 193.3 (S=C-S), 172.3 (HOOC), 166.6 , 146.2 (C=CH-CH=CH-Ar), 134.8 (C=CH-CH=CH-Ar), 130.6 (C2 Ar), 128.8 (C1 Ar), 122.4 (C=CH-CH=CH-Ar), 121.9 (C=CH-CH=CH-Ar), 115.3 (C3 Ar), 55.9 (OCH3), 40.6 (HOOCCH2CH2), 31.4 (HOOCCH2CH2).m.p. 244–246 °C, MS [M − 1]+ 364, IR (1 mg/400 mg KBr) cm−1: 1694.1 C=O, 1684.5 C=O conj., 1642.1 C=C exo., 1574.6 C=CH-CH=CH-Ar, 1453.1 CH3, 1390.4 CH2, 1303.6 C-O-C, 1157.1 C=S, 1H NMR , δ: 12.07 , 7.63 , 7.45 , 7.30 , 6.95 , 6.89 , 3.99 , 3.77 , 2.24 , 1.85–1.80 , 13C NMR , δ: 193.7 (S=C-S), 174.2 (HOOC), 167.0 (N-C=O), 161.6 (C4 Ar), 146.0 (C=CH-CH=CH-Ar), 134.6 (C=CH-CH=CH-Ar), 130.6 (C2 Ar), 128.9 (C1 Ar), 122.6 (C=CH-CH=CH-Ar), 121.9 (C=CH-CH=CH-Ar), 115.1 (C3 Ar), 55.9 (OCH3), 44.1 (HOOCH2CH2CH2), 31.5 (HOOCCH2CH2CH2), 22.6 (HOOCCH2CH2CH2).m.p. 208–211 °C, MS [M + 1]+ 378, IR (1 mg/400 mg KBr) cm−1: 1699.0 C=O, 1684.5 C=O conj., 1641.8 C=C exo., 1573.0 C=CH-CH=CH-Ar, 1460.8 CH3, 1388.5 CH2, 1312.2 C-O-C, 1155.2 C=S, 1H NMR , δ: 11.98 , 7.63 , 7.46 , 7.30 , 6.95 , 6.89 , 3.94 , 3.77 , 2.21 , 1.63–1.57 , 1.49–1.43 , 13C NMR , δ: 193.4 (S=C-S), 174.6 (HOOC), 166.8 (N-C=O), 161.6 (C4 Ar), 146.2 (C=CH-CH=CH-Ar), 134.7 (C=CH-CH=CH-Ar), 130.6 (C2 Ar), 128.9 (C1 Ar), 122.4 (C=CH-CH=CH-Ar), 121.9 (C=CH-CH=CH-Ar), 115.1 (C3 Ar), 55.9 (OCH3), 44.3 (HOOCH2CH2CH2CH2), 33.6 (HOOCCH2CH2CH2CH2), 26.5 (HOOCCH2CH2CH2CH2), 22.6 (HOOCCH2CH2CH2CH2).m.p. 211–213 °C, MS [M + 1]+ 392, IR (1 mg/400 mg KBr) cm−1: 1707.7 C=O, 1685.5 C=O conj., 1640.1 C=C exo., 1578.5 C=CH-CH=CH-Ar, 1464.8 CH3, 1385.5 CH2, 1307.5 C-O-C, 1153.2 C=S, 1H NMR , δ: 11.95 , 7.63 , 7.43 , 7.26 , 6.93 , 6.85 , 3.94 , 3.76 , 2.15 , 1.57 , 1.46 , 1.25 , 13C NMR , δ: 193.4 (S=C-S), 174.9 (HOOC), 166.7 (N-C=O), 161.6 (C4 Ar), 146.1 (C=CH-CH=CH-Ar), 134.7 (C=CH-CH=CH-Ar), 130.6 (C2 Ar), 128.8 (C1 Ar), 122.4 (C=CH-CH=CH-Ar), 121.8 (C=CH-CH=CH-Ar), 115.0 (C3 Ar), 55.9 (OCH3), 44.4 (HOOCCH2CH2CH2CH2CH2-), 33.9 (HOOCCH2CH2CH2CH2CH2-), 26.6 (HOOCCH2CH2CH2CH2CH2-), 26.2 (HOOCCH2CH2CH2CH2CH2-), 24.6 (HOOCCH2CH2CH2CH2CH2-).m.p. 174–176 °C, MS [M + 1]− 460, IR (1 mg/400 mg KBr) cm−1: 1711.5 C=O, 1698.0 C=O conj., 1640.2 C=C exo., 1578.5 C=CH-CH=CH-Ar, 1466.6 CH3, 1385.6 CH2, 1321.0 C-O-C, 1160.9 C=S, 1H NMR , δ: 11.90 , 7.62 , 7.45 , 7.29 , 6.94 , 6.88 , 3.92 , 3.76 , 2.13 , 1.55 , 1.43 , 1,20 , 13C NMR , δ: 193.3 (S=C-S), 175.0 (HOOC), 166.8 (N-C=O), 161.6 (C4 Ar), 146.1 (C=CH-CH=CH-Ar), 134.7 (C=CH-CH=CH-Ar), 128.8 (C=CH-CH=CH-Ar), 122.4 (C=CH-CH=CH-Ar), 121.9 (C1 Ar), 115.1 (C3 Ar), 55.9 (OCH3), 44.6 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 34.2 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 29.3 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 29.3 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 29.3 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 29.1 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 29.0 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 26.8 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 26.7 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-), 25.0 (HOOC-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-).m.p. 153–155 °C, MS [M − 1]− 276, IR (1 mg/400 mg KBr) cm−1: 3149.1 N-H, 1709.6 C=O conj., 1641.1 C=C exo., 1597.3 C=CH-CH=CH-Ar, 1467.6 CH3, 1300.8 C-O-C, 1158.0 C=S, 1H NMR , δ: 13.57 , 7.71 , 7.48 , 7.37–7.33 , 7.04 , 6.97–6.91 , 3.83 , 13C NMR , δ: 195.6 (S=C-S), 169.1 (N-C=O), 158.3 (C-OCH3), 141.4 (C=CH-CH=CH-Ar), 137.4 (C=CH-CH=CH-C), 133.4 (C=CH-CH=CH-Ar), 132.4 (C4 Ar), 128.9 (C5 Ar), 126.9 (C=CH-CH=CH-Ar),124.6 (C=CH-CH=CH-Ar), 121.3 (C4 Ar), 117.0 (C4 Ar), 112.3 (C4 Ar), 56.2 (O-CH3).m.p. 210–211 °C, MS [M − 1]+ 336, IR (1 mg/400 mg KBr) cm−1: 1725.0 C=O, 1700.9 C=O conj., 1641.3 C=C exo., 1581.3 C=CH-CH=CH-Ar, 1466.6 CH3, 1405.8 CH2, 1325.8 C-O-C, 1159.9 C=S, 1H NMR , δ: 13.39 ,7.75 , 7.62–7.57 , 7.38–7.35 , 7.08–7.00 , 6.94 , 4.65 , 3.84 , 13C NMR , δ: 193.2 (S=C-S), 167.9 (HOOC-), 166.1 (N-C=O), 158.1 (C-OCH3), 140.1 (C=CH-CH=CH-Ar), 135.8 (C=CH-CH=CH-Ar), 129.0 (C=CH-CH=CH-Ar), 124.4 (C=CH-CH=CH-Ar), 124.3 (C=CH-CH=CH-Ar), 122.9 (C6 Ar), 121.3 (C5 Ar), 112.3 (C3 Ar), 56.2 (O-CH3), 45.4 (HOOCCH2-).m.p. 289–290 °C, MS [M + 1]− 276, IR (1 mg/400 mg KBr) cm−1: 3160.8 N-H, 1693.2 C=O conj., 1641.1 C=C exo., 1577.5 C=CH-CH=CH-Ar, 1465.6 CH3, 1304.6 C-O-C, 1161.9 C=S, 1H NMR , δ: 13.60 , 7.31–7.24 , 7.23 , 7.19 , 7.00 , 6.92 , 3.76 , 13C NMR , δ: 195.9 (S=C-S), 169.3 (N-C=O), 160.2 (C3 Ar), 145.2 (C=CH-CH=CH-Ar), 137.5 (C1 Ar), 130.5 (C5 Ar), 127.7 (C=CH-CH=CH-Ar), 124.6 (C=CH-CH=CH-Ar), 121.5 (C6 Ar), 116.6 (C4 Ar), 112.9 (C2 Ar), 55.8 (O-CH3).m.p. 253–254 °C, MS [M − 1]+ 336, IR (1 mg/400 mg KBr) cm−1: 1718.3 C=O, 1709.6 C=O conj., 1641.1 C=C exo., 1575.6 C=CH-CH=CH-Ar, 1466.6 CH3, 1398.1 CH2, 1326.8 C-O-C, 1167.7 C=S, 1H NMR , δ: 13.39 , 7.55 , 7.35 , 7.32–7.26 , 7.22 , 7.15–7.09 , 6.94 , 4.66 , 3.77 , 13C NMR , δ: 193.5 (S=C-S), 167.9 (HOOC-), 166.3 (N-C=O), 160.2 (C-OCH3), 146.5 (C=CH-CH=CH-Ar), 137.4 (C=CH-CH=CH-C), 134.9 (C=CH-CH=CH-Ar), 130.5 (C5 Ar), 124.4 (C=CH-CH=CH-Ar),123.7 (C=CH-CH=CH-Ar), 121.8 (C6 Ar), 117.0 (C4 Ar), 113.0 (C2 Ar), 55.8 (O-CH3), 45.4 (HOOC-CH2-N).m.p. 234–235 °C, MS [M + 1]2 and from ethanol for 4.Crystals suitable for an X-ray structure analysis were obtained by slow evaporation of the solvent at ambient conditions from a mixture of dimethyl sulfoxide and acetonitrile for 2 were collected using the Oxford Diffraction SuperNova four circle diffractometer, equipped with the MoKα (0.71073 Å) radiation source and graphite monochromator, while for 4 were collected using the XtaLAB Synergy-S diffractometer, equipped with the CuKα (1.54184 Å) radiation source and graphite monochromator. Positions of all non-hydrogen atoms were determined by direct methods using the SIR-2014  and R1 = 0.0457, wR2 = 0.0852 [all data].4: C17H17NO4S2, Mr = 363.43, crystal size = 0.02 × 0.06 × 0.67 mm3, monoclinic, space group P21/c, a = 17.3826(1) Å, b = 4.7425(1) Å, c = 20.2816(2) Å, β = 94.305(1)°, V = 1667.24(4) Å3, Z = 4, T = 100(2) K, 44217 reflections collected, 3397 unique reflections (Rint = 0.0637), R1 = 0.0267, wR2 = 0.0700 [I > 2σ(I)] and R1 = 0.0281, wR2 = 0.0713 [all data].www.ccdc.cam.ac.uk/data_request/cif (accessed on 24 February 2022).CCDC 2154601-2154602 contain the supplementary crystallographic data. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via Rhabditis sp. were used for the anthelmintic activity experiments. The nematodes were cultured following the procedure developed by A. Bogucka-Kocka and P. Kołodziej at the Department of Biology and Genetics of the Medical University of Lublin [Rhabditis sp. was observed in terms of development, deformity, damage and motility using a stereoscopic and light microscope . To determine the viability of nematodes, they were stained with methylene blue. Live and dead specimens were counted in Bürker  counting chambers.Nematodes of the genus f Lublin . Test dep < 0.05 *, p < 0.01 **, p < 0.001 ***) [Statistical analysis was performed using the GraphPad Prism 5.02 software  using the ANOVA variance analysis and the Tukey test  ,40,41,42A tubulin structure in complex with colchicine (PDB ID 5NM5 ) was selCaenorhabditis elegans—the organism closely related to the one used in the biological activity tests. The sequence alignment was obtained with Clustal Omega [Additional note: the 5NM5 structure is a Bos Taurus tubulin, which shares 88.99% sequence identity with tubulin β-2B from al Omega ,45. Most of the non-identical residues are a long distance from the colchicines binding site. Only four residues are in the proximity of the binding site, however, the character of the mutation does not indicate strong differences in the plausible interactions. The initial 3D geometries of ligands were taken from the crystal structure data. Colchicine randomized 3D structure for the re-docking experiment, as well as the albendazole molecule, wereobtained from SMILES with OpenBabel (version 2.4.1)  and theiDocking procedures were conducted in GOLD . The binhttp://www.vcclab.org; calculations have been performed on 3 February 2022) [The log P and log S values for the investigated compounds were predicted using the ALOGPS 2.1 Java applet of the Virtual Computational Chemistry Laboratory (ry 2022) . All obtRhabditis sp. In the series of 16 compounds, only one shows very high activity, namely 5-(4′-methoxycinnamylidene)-rhodanine-3-etanoic acid (2). Anthelmintic activity of compound 2 is higher than that of the commercial drug—albendazole (2 is through the inhibition of microtubule polymerisation, just as it is postulated for albendazole. The molecular modelling studies have shown good binding of selected compounds to the colchicine highly hydrophobic pocket, which is a known albendazole putative binding site. The lack of anthelmintic activity of other investigated compounds can be connected with their higher lipophilicity in comparison to active compound 2 and albendazole (2, which may explain its lower anthelmintic activity. The mechanism of action of 2 will be verified in the next step of our research. Thus, compound 2 is a good drug candidate with anthelmintic activity.New cinnamaldehyde derivatives of rhodanine were synthesized to search for new compounds with anthelmintic activity against endazole . We set endazole . It is w


Three isomers of Ama+ generated by electron ionization are identified by the vibrational properties of their rather different NH2 groups. The ligands bind preferentially to the acidic NH2 protons, and the strength of the NH…L ionic H‐bonds are probed by the solvation‐induced red‐shifts in the NH stretch modes. The three Ama+ isomers include the most abundant canonical cage isomer (I) produced by vertical ionization, which is separated by appreciable barriers from two bicyclic distonic iminium ions obtained from cage‐opening  and subsequent 1,2 H‐shift , the latter of which is the global minimum on the Ama+ potential energy surface. The effect of solvation on the energetics of the potential energy profile revealed by the calculations is consistent with the observed relative abundance of the three isomers. Comparison to the adamantane cation indicates that substitution of H by the electron‐donating NH2 group substantially lowers the barriers for the isomerization reaction.Radical cations of diamondoids, a fundamental class of very stable cyclic hydrocarbon molecules, play an important role in their functionalization reactions and the chemistry of the interstellar medium. Herein, we characterize the structure, energy, and intermolecular interaction of clusters of the amantadine radical cation (Ama Cage‐opening upon ionization: Three isomers of Ama+ (1‐aminoadamantane) are identified by IR spectroscopy ‐ the cage isomer (I) generated by vertical ionization and separated by substantial barriers from two bicyclic distonic iminium ions generated by cage opening  and subsequent 1,2 H shift . The potential energy profile for this reaction depends strongly on solvation and H→NH2 substitution. Due to their special properties, diamondoids and their derivatives have  applications in a variety of disciplines, ranging from materials and polymer science, molecular electronics, medical sciences, and chemical synthesis to astrochemistry.Amantadine , Gocovri®, Symadine®, and Osmolex ER®.3f, 8 Cs), the H atom of one of the four CH groups of Ada (Td) is replaced by an NH2 group, thus preserving most of the special chemical properties of diamond‐like structures.[+ radical cation, the target of the present work. Low‐resolution electron momentum spectra show that ionization of Ama into the electronic ground state of Ama+ occurs by removal of an electron from the nonbonding lone pair of the NH2 group, with a rough estimate of the vertical ionization energy of 8.6 eV.+ being elimination of C4H9 leading to the formation protonated aniline.In Ama Cs, the H +, considerably more information is available for the Ada+ parent cation, which has been characterized by photoelectron, photoionization, and fragmentation spectroscopy, IR and electronic photodissociation  spectroscopy, and quantum chemical calculations.[+L cluster ions  indicate Jahn‐Teller distortion and C−H bond activation upon ionization into the cation ground state.[+, consistent with low‐resolution EPD spectra of bare Ada+ generated by electron ionization (EI).+.[+ generated by VUV and XUV photoionization as well as EI indicate substantial fragmentation.[+ as local and even global minima on the potential energy surface as reaction intermediates prior to fragmentation, although experimental evidence for such minima has not been presented.[Compared to Amaulations.5b, 19+Ln clusters with L=Ar (n=1‐3), L=N2 (n=1), and L=H2O (n=1) generated in an EI source by means of dispersion‐corrected density functional theory (DFT) calculations at the B3LYP−D3/cc‐pVTZ level. Ama+ was chosen for the study of rearrangement processes of the adamantyl cage (C10H15) upon ionization for the following reasons. Our previous studies on Ada+L and Ama+(H2O)1‐3 using the same experimental and computational approach indicate that, as a result of H→NH2 substitution, one of the C−C bonds of Ama+ is substantially less stable and highly activated compared to Ada+.[+ has a strongly reduced barrier to cage opening which may thus be observable. Indeed, ionization of Ama into its cation ground state occurs by removal of an electron from the nonbonding N lone pair rather than from a bonding C−C σ orbital completely delocalized over the cycloalkane cage in Ada+. Within the ligand series Ar<N2<H2O, we tune the type and strength of the interaction of the solvent molecules with Ama+. While Ar will only weakly interact with Ama+ via dispersion and induction (charge‐induced dipole), the interaction of N2 will be somewhat stronger due to additional electrostatic charge‐quadrupole forces, as has previously been shown for related amine cation clusters (such as aniline+ and 4‐aminobenzonitrile+).2O will form a strong NH…O ionic hydrogen bond (H‐bond) to Ama+ based mostly on electrostatic charge‐dipole interaction.[2 with Ama+ is expected to have only a negligible influence on the structural isomers and the rearrangement process of the Ama+ core ion, while its strong interaction with H2O may substantially perturb the potential energy surface of the Ama+ cage‐opening reaction. In a recent letter,+Ar dimer (n=1), and the main results may be summarized as follows. In addition to the canonical nascent Ama+ isomer with an intact C10H15 cage , we could unambiguously identify two distonic bicyclic iminium isomers in which the adamantyl cage opens upon ionization , whereby III is in fact lower in energy than the canonical cage isomer I  and Ama+L dimers with L=N2 and H2O to determine the effect of solvent molecules with different binding energy on the reaction profile. In fact, we have studied previously the microhydration process of Ama+ by IRPD and DFT of Ama+(H2O)n clusters up to n≤3.+ and the microhydration structure of the cage isomer (I), no evidence of the open‐cage bicyclic isomers was found.+H2O with an improved signal‐to‐noise ratio, which allows us to identify also the open‐cage structures of Ama+H2O (II/III). We also briefly discuss why the cage‐opening process is suppressed for Ada+ and its clusters based on the effect of H→NH2 substitution on the potential energy profile.With the major goal of characterizing the ionization‐induced cage‐opening process of diamondoid cations in the gas phase, we analyze herein IRPD spectra of size‐selected Amah L=Ar n=‐3, L=N2 +Ln clusters are obtained in a quadrupole tandem mass spectrometer coupled to an EI cluster source and an octupole ion trap.+Ln clusters are generated in a pulsed supersonic plasma expansion by electron and/or chemical ionization of a heated Ama sample  seeded in a suitable carrier gas  close to the nozzle orifice and three‐body clustering reactions. For the generation of Ama+H2O clusters, a small amount of distilled water is added to the gas inlet system. The filaments of the EI source are operated at an offset voltage of up to 200 V, which provides the upper limit for the kinetic energy of the electrons hitting the molecular beam. These electrons are (in)elastically scattered by collisions with atoms/molecules in the high‐pressure region of the expansion and produce secondary electrons by ionization events. Ama+ ions are then generated either by EI with primary or secondary electrons or by chemical ionization . As a result of these complex processes in the plasma expansion, the initial excess ionization energy deposited in Ama+ upon ionization is not well characterized. The generated Ama+ and resulting fragment ions are cooled by collisions and form clusters by three‐body aggregation. The upper limit of the internal energy (and thus the effective temperature) of the generated Ama+Ln clusters is then given by the dissociation energy of the ligands, which increases in the order Ar<N2<H2O. After mass selection by the first quadrupole, the desired parent cluster ion is irradiated in the adjacent octupole with a tunable IR laser pulse (νIR) of an optical parametric oscillator  pumped by a nanosecond Q‐switched Nd:YAG laser. The IR laser is characterized by a pulse energy of 2–5 mJ in the 2600–3800 cm−1 range and 0.1–0.5 mJ in the 1200–1800 cm−1 range. The laser frequency is calibrated using a wavemeter. Resonant vibrational excitation of the cluster ions causes the loss of all ligands in the size range investigated. The produced Ama+ fragments are selected by the second quadrupole and monitored by a Daly detector as a function of laser frequency to obtain IRPD spectra of Ama+Ln. The ion source is triggered at twice the laser frequency, which facilitates subtraction of background signal arising from metastable decay. All IRPD spectra are normalized for frequency‐dependent variations in the photon flux. Collision‐induced dissociation experiments (CID) of Ama+Ln clusters mass‐selected by the first quadrupole are performed to confirm their chemical composition . To this end, the octupole is filled with N2 gas (10−5 mbar) leading to collisions with the mass‐selected ions at a collision energy of 10 eV in the laboratory frame.IRPD spectra of Ama+ isomers and their corresponding clusters are calculated using dispersion‐corrected DFT calculations at the unrestricted B3LYP−D3/cc‐pVTZ level.+(H2O)n and Ada+H2O, and is an efficient compromise between computing time and accuracy.[Ee, De) are corrected for harmonic zero‐point vibrational energy to yield E0 and D0. Free energies (G) are obtained at room temperature (T=298.15 K). We will discuss herein only the energies at zero Kelvin, because entropy has only little impact on the reaction profile, but provide G values in the Supporting Information for comparison. Harmonic frequencies of NH/OH stretch modes (νNH/OH) are scaled by a factor of 0.9491 derived from fitting νNH stretch frequencies of neutral Ama to experimental values.νnCH) are scaled by a factor of 0.9618 derived from the experimental data for Ada+He2.2/NH2 bending modes and other vibrations occurring in the fingerprint range below 2000 cm−1 are scaled by 0.9732 derived from fitting the NH2 bending frequency of the related aniline cation to the experimental value of the NH2 bending overtone.−1). In a few cases, anharmonic vibrational calculations are performed to estimate frequencies and IR intensities of overtones and combination bands.Geometries, energies, and harmonic IR spectra of stable Amare T=298.5 K. We wre T=298.5 K. We w+ ion (m/z 151) occur at m/z 136, 108, 94, and 57. These are consistent with the standard EI mass spectrum of Ama and confirm the parent ion as Ama+, with protonated aniline (m/z 94) being the most intense fragment ion.[+ and its fragments with neutral ligands  are generated in the supersonic plasma expansion. CID spectra of size‐selected Ama+Ln cluster ions show merely the loss of neutral ligands, confirming the composition of the clusters and ruling out any isobaric contamination .Typical mass spectra of the EI source are shown in Figure S1. The major observed fragments of the parent Amament ion.18 In ad+Ln clusters recorded in the XH stretch range (2700–3800 cm−1) are compared in Figure +Ar obtained in the fingerprint range (1200–1800 cm−1) is shown in Figure +Ar was reported and partially analyzed before,+H2O spectrum in Figure 2L, 3L, V, 2M, 3M).−1) covers aliphatic CHn stretch modes (νCH/CH2/CH3) of the C10H15 moiety , symmetric (νNHs) and antisymmetric NH stretch (νNHa) modes of the NH2 group of Ama+ , and overtone bands of the NH bend (βNH2) and OH bend (βOH2) fundamentals . In the Ama+H2O spectrum, we also identify bound (νNHb) and free NH stretch (νNHf) modes , as well as symmetric and antisymmetric free OH stretch fundamentals of the H2O ligand  in the higher frequency range . Moreover, the fingerprint range (1200–1800 cm−1) investigated for Ama+Ar covers CHn and NH2 bending (β), rocking (ρ), torsion (τ) and wagging (γ) modes as well as νCN fundamentals . Several observed transitions exhibit systematic shifts as a function of cluster size and ligand type, which provide useful information about the ligand binding site and interaction strength. Clearly, the overall similar appearance of the Ama+Arn and Ama+N2 spectra arise from weak intermolecular interaction of Ama+ with Ar and N2, while the Ama+H2O spectrum differs strongly due to the strong NH…O ionic H‐bonds.The IRPD spectra of all investigated Amange 2700–800 cm−1 nge 2700–800 cm−1 2 clusters reveals six transitions within 3300 and 3500 cm−1, which are readily assigned to νNHs (1‐3J) and νNHa (1‐3K) fundamentals of the NH2 group of three Ama+ isomers (I–III) with rather different N−H bond properties.2 group of I–III. The shifts between the n=1 and n=3 spectra of Ar (≤12 cm−1) are somewhat smaller than those between Ar and N2 for n=1 (≤29 cm−1). Such small shifts are typical for weak van‐der‐Waals or H‐bonds, which do not decouple the two NH stretch normal modes of the NH2 group, justifying their notation as νNHs and νNHa. In contrast, the strong NH…O ionic H‐bonds of all three Ama+H2O isomers decouple the NH stretch normal modes, leading to large red‐shifts for the bound local NH stretch modes , while the free NH stretch modes  occur between νNHs and νNHa of the bare Ama+ isomers.νNHb/f bands of the cage isomer (I) were identified previously , the corresponding weaker bands assigned to the other two bicyclic isomers  are identified herein for the first time  due to the higher signal‐to‐noise ratio achieved.The NH stretch range of the Ar and NN and O bands at 3627 and 3717 cm−1 are solely observed for Ama+H2O and readily assigned to free νOHs/a modes of the H2O ligand.−1 from the corresponding transitions of bare H2O (3657 and 3756 cm−1) are typical for cation‐H2O complexes with charge‐dipole configuration, in which the O atom of H2O is pointing toward the positive charge.[νOHs/a modes of the assigned isomers I–III are not resolved.The +H2O spectrum, the IRPD spectra of all Ama+Ln clusters have very similar appearance in the CH stretch range, with respect to both frequencies (to within 13 cm−1) and relative IR intensities for the νnCH stretch fundamentals of Ama+ (A‐F). The spectra are better resolved for Ama+Ar2/3 because larger clusters are colder. For Ama+H2O, the CH stretch range is strongly affected by the red‐shifted and broadened νNHb transition of the NH…O ionic H‐bond, which carries high IR oscillator strength and thus is involved in NH/CH stretch local mode mixing and anharmonic interactions .[Except for the AmaH near 3150 cm−1 for Ar shifts gradually to the blue for ligands with stronger interaction (3172 and 3187 cm−1 for N2 and H2O), and the same trend is observed for peak I , indicating that these bands are combination or overtone transitions including the bending, scissoring, or wagging motions of the NH2 group. H‐bonding with L generates an additional retarding force for these NH2 modes and thus to higher frequencies for stronger NH…L bonds. The weak and tentative band U (∼3103 cm−1) is only observed in the Ama+N2 spectrum, while the very weak feature G (∼3010 cm−1) is only resolved in the Ama+Ar and Ama+N2 spectra. Moreover, an additional peak V is observed only for H2O at 3213 cm−1, suggesting an assignment to a combination or overtone of the H2O bend (βOH2).Apart from the transitions readily attributed to NH, OH, and CH stretch fundamentals, the IRPD spectra display in the XH stretch range transitions with less obvious assignments. For example, band +Ar, with the main purpose of confirming the number of Ama+ isomers inferred from the NH stretch range.+Ar is dominated by three intense, narrow, and isolated peaks in the NH2 bending range  assigned to βNH2 (scissoring mode) of I–III (Q1‐Q3). There are four other, weaker, and broader peaks R, S, P, and T observed in the range of the βCH2, γCH2, τCH2, ρNH2, and νCN modes, whose detailed assignment has to rely on the DFT calculations. As these bands turn out not to be isomer‐specific (apart from T), we do not consider them in detail further. Significantly, the fingerprint spectrum of Ama+Ar suggests H and I to be overtones of Q1 and Q2, while the corresponding overtone of Q3 is probably hidden in the dense NH stretch range.The fingerprint range is considered only for Ama+Arn suggest only a minor impact of the Ar ligands on the properties of the Ama+ core ion. To this end, the Ama+Ar spectrum has previously been used to identify the three relevant Ama+ isomers I–III,2 group resulting in rather different νNH and βNH2 frequencies. Hence, we briefly summarize the computational results for I–III and compare them to the experimental Ama+Ar spectrum. Subsequently, we will discuss the effects of the ligands on the structural, vibrational, and energetic properties of I–III and finally evaluate the effect of H→NH2 substitution.The very similar IRPD spectra of Ama1A’, Cs) leads to the nascent cage isomer I of the Ama+ radical cation . This ionization process activates one of the C−C bonds, which readily breaks and then leads through cage opening to the formation of the bicyclic distonic isomer II  via transition state TS(I–II) located at a barrier of Vb=54.1 kJ mol−1 for the forward reaction. A subsequent 1,2 H‐shift then forms via TS(II–III) at Vb=81.6 kJ mol−1 the most stable isomer III , which is also a distonic ion and 45.9 kJ mol−1 more stable than the nascent cage isomer I. The structures along with the atomic numbering of neutral Ama and the three Ama+ isomer I–III are compared in Figure A potential energy diagram for the ionization‐induced rearrangement reaction of Ama is shown in Figure 2 group is attached in a pyramidal configuration (sp3 hybridization of N) to the C10H15 cage via a C−N single bond (rCN=1.467 Å). H→NH2 substitution has little impact on the geometry of the C10H15 cage, with a minor but noticeable activation of the C1−C3 bond adjacent to the NH2 group in the Cs symmetry plane . In general, the calculated structure and IR spectrum of Ama agree well with previous computational and experimental data.[2 group  results in the formation of isomer I of Ama+. Due to orbital conjugation and charge delocalization, the partial charge on the NH2 group increases by 0.474 e, the C−N bond order increases from 1 to ∼1.5 (rCN=1.384 Å), the pyramidal NH2 group becomes essentially planar (similar to ionization of NH3), and the NH2 angle increases from 106° to 117° (sp2 hybridization of N). The N−H bonds contract by 3 mÅ, resulting in substantial blue‐shifts in the NH stretch frequencies upon ionization . As a result of the higher positive partial charges on the NH protons (qH=0.405 e), the IR intensities of the νNH fundamentals are enhanced by 2–3 orders of magnitude. This effect is crucial because detection of the νNH bands of Ama+Ln is essential for isomer identification. Significantly, ionization of Ama has also a strong impact on the C−C bonds lying in the Cs symmetry plane due to conjugation with the NH2 lone pair. In particular, the C1−C3 bond adjacent to the NH2 group, already slightly activated by 6 mÅ in neutral Ama by H→NH2 substitution and eventually breaking when the cage opens to form isomer II, is further strongly destabilized and elongated by 153 mÅ upon ionization. The adjacent C3−C9 bond in the Cs plane shortens by merely 16 mÅ due to the increased distance from the N lone pair, while all other C−C bonds of the cage remain almost unchanged. Ionization increases the spread in the C−H bond lengths (ΔrCH=8 vs. 3 mÅ), resulting in a more pronounced splitting of the intense convoluted and mostly unresolved doublet band of the CHn stretch modes of Ama (2890 and 2917 cm−1) into four better resolved single bands at 2840, 2920, 2955, and 3024 cm−1. The NH2 bending mode (βNH2) is slightly red‐shifted by 14 cm−1 to 1595 cm−1, and its IR intensity increases by a factor of 2. As a result, it becomes the most intense fundamental in the fingerprint range, and this aspect is again crucial because, in addition to νNH, also the βNH2 mode provides a sensitive probe of the isomeric structure of Ama+. Due to substantial charge delocalization from NH2 to C10H15, the adamantyl cage carries most of the excess positive charge , whereby the acidic NH protons (qH=0.405 e) still serve as attractive proton donors for H‐bonds with neutral ligands. Finally, the adiabatic ionization energy of IE=7.95 eV predicted for I is consistent with the rough estimation for the vertical value of 8.6 eV obtained from a low‐resolution electron momentum spectrum.In neutral Ama, the NHII is formed from I by breaking the strongly activated C1−C3 bond. At the same time, the cyclohexane ring is converted from the chair into the boat configuration. As a result, the C1…C3 distance of the broken bond increases to 4.650 Å, while the θC1C9C3 angle in the Cs plane opens from 39.2° to 125.1°. This structural rearrangement forms a CH2⋅ radical site and a C=N double bond (rCN=1.295 Å), and is accompanied by a separation of charge and spin. The spin density of this distonic iminium ion is located on the CH2⋅ radical site (sC3=1.005), while the positive charge is mostly localized at the CNH2 charge site (qCNH2=0.754 e). While the C−C bonds to the CH2⋅ and CNH2 groups strongly contract , the other C−C bonds are elongated upon the chair→boat transformation . The largest changes in the C−H bond lengths occur on the CH2⋅ group (+6 mÅ), while all others change less than 3 mÅ. As a result of cage opening, the νnCH modes of II are more spread than for I, with three convoluted bands at 2901, 2926, and 2972 cm−1 and weaker high‐frequency νCH2s/a modes of CH2⋅ at 3021 and 3121 cm−1. The νC9H mode is red‐shifted down to very low frequency (2821 cm−1) and has lost almost all IR activity. Due to the increase in C−N bond order, the CNH2+ group in II is even more planar than in I, and as a result βNH2 couples strongly with the blue‐shifted νCN mode, leading to a very intense and blue‐shifted βNH2 band at 1670 cm−1 and a weak νCN band at lower frequency (1542 cm−1). In line with the minor changes in the N−H bond lengths (≤1 mÅ), νNHs/a exhibit small shifts of +7/−5 cm−1. The slightly larger positive charge on the NH2 protons (Hq=0.421 e) makes this binding site for neutral ligands even more attractive than in I.The bicyclic open‐cage isomer III is formed from II by a 1,2 H‐shift from C9H to the terminal CH2⋅ group. As a result, the primary radical II (CH2⋅) is transformed into a more stable tertiary radical III (CR3⋅), which thus becomes by far the global minimum on the Ama+ potential  with bond angles of 121.2° and 115.8°, while the terminal CH3 group becomes pyramidal (sp3 hybridization of C3) with bond angles of 106.3° and 109.5°. Parallel to the H‐shift, the cyclohexane ring changes back from boat to chair. As a result, the C1…C3 distance contracts again to 3.346 Å and θC1C9C3 decreases slightly to 106.1°. Interestingly, there is substantial orbital overlap between the 2pz orbital of the C9R3⋅ radical center and the 2pπ orbital of the C=N double bond , consistent with the short C1…C9 separation of 2.616 Å and the slightly pyramidal structure of the C9R3⋅ group. The C−C bonds of the CR3⋅ group and the C9−C3 bond to the new CH3 group contract by 51 and 4 mÅ, respectively. Upon boat→chair back transformation, the C−C bonds adjacent to the NH2 group as well as their corresponding parallel C−C bonds are stretched again , while the other C−C bonds contract again . The C−H bonds of the former CH2⋅ radical group are stretched again to a value typical for CH2 bonds (1.091 Å), and most other C−H bonds are also slightly elongated (ΔrCH=2 mÅ). As a result, the νCH and νCH2 fundamentals move again closer together and form two weak bands at 2878 and 2926 cm−1 and one intense band at 2961 cm−1. Of course, the low‐frequency acidic νCH mode of I/II at 2821/2840 cm−1 disappears. Compared to II, the C=N double bond of III is slightly elongated to 1.315 Å, while the N−H bonds contract from 1.012 to 1.009 Å. As a result of the shortest N−H bonds of all three Ama+ isomers, the NH2 stretch modes have the highest frequencies (νNHs/a=3358/3467 cm−1). Similar to II, βNH2 of III couples to νCN, resulting in βNH2 at 1641 cm−1 and νCN at 1500 cm−1. Both modes gain, however, in IR intensity, and this effect is more pronounced for the νCN band (factor ∼20). The βCH2/βCH3 band at 1440 cm−1 also gains in intensity due to the newly formed CH3 group in III. Similar to II, III is also a distonic iminium ion, with spin density located on the CR3⋅ radical site (sC9=0.627) and positive charge localized at the CNH2 site (qCNH2=0.608 e). The similarly high positive partial charge on the NH2 protons (qH=0.411 e) makes this binding site of III also very attractive for neutral ligands.The bicyclic open‐cage isomer +Ar spectrum to the IR spectra computed for the three monomer isomers I–III in Figure + isomers, in particular the observation of six νNH  and three βNH2 bands (1‐3Q). A detailed vibrational and isomer assignment is listed in Table S2. Based on relative intensities and frequencies, the three pairs 1/K1J,2/K2J, and 3/K3J are readily assigned to νNHs/a of I–III, with a maximum, mean, and median deviation of 23, 14, and 16 cm−1 between measured and computed frequencies, respectively. These differences are consistent with the widths of the bands (12±4 cm−1) and possible effects of Ar‐tagging (computed to be ≤10 cm−1). Concerning the βNH2 bands (1‐3Q), a very good match is obtained for isomer I between experiment and prediction (ΔβNH2=4 cm−1 for 1Q). The agreement for the distonic isomers II and III for the corresponding βNH2 modes is somewhat worse (23 and 47 cm−1 for 3Q and 2Q), probably due to the strong coupling between βNH2 and νCN, which may not be accurately described by a single scaling factor for both types of modes (different anharmonicity and bond order for νCN). Nonetheless, the direction and magnitude of these βNH2 band shifts upon this coupling are reproduced reasonably well. Actually, band T at 1551 cm−1 may be assigned to the intense νCN mode of III predicted at 1500 cm−1.Comparison of the experimental Ama1‐3Q, the relative population of the isomers I, II, and III can be roughly estimated as 50, 15, and 35 % (or 10 : 3 : 7), respectively. For this estimate, we assume similar Ar complexation efficiencies for I–III, which is justified by their similar Ar binding energies. Such a population ratio is also consistent with the relative intensities in other spectral ranges, although these are more congested and thus less suitable for a reliable quantitative analysis.By considering the achieved signal‐to‐noise ratio and the calculated and observed IR intensities (peak area) of peaks νNH and βNH2 modes, where a clear‐cut assignment to the individual isomers I–III is feasible due to their rather different NH2 properties, the isomer assignment in the other spectral ranges is less obvious due to similar vibrational frequencies and increased spectral congestion. Nonetheless, the observed IRPD spectrum is consistent with the presence of all three Ama+ isomers. For example, in the CH stretch range, bands B–D  can be attributed to the single and isolated νCH mode and overlapping νCH2 modes predicted at 2840, 2920, and 2955 cm−1 for the predominant I isomer, respectively. Similarly, E (2959 cm−1) and F (2978 cm−1) can be interpreted as νCH2 modes (2961 and 2971 cm−1) of the convoluted peak at 2955 cm−1, while band G (3008 cm−1) is assigned to the isolated single νCH2 mode (3024 cm−1) of the special CH2 group adjacent to the elongated C1−C3 bond of I. Thus, while most CH stretch bands may readily be explained by the most abundant isomer I, there are several indications for the presence of II and III in this spectral range as well. For example, the weak peak A at 2842 cm−1 provides strong evidence for isomer II, because for I and III no such low‐frequency CH stretch band is predicted. In addition, the high relative intensity of band D is not reproduced by the simulation for I and is thus indicative for a significant population of III. While the appearance of bands R, S, and P in the Ama+Ar spectrum is consistent with the predictions of all three isomers, the well isolated transitions H and I at 3151 and 3267 cm−1 are not reproduced by the calculated spectra of any of the isomers. Hence, they are attributed to overtones and combination bands of modes occurring in the fingerprint range, which are not included in the  harmonic calculations. Indeed, strong overtone transitions of the scissoring mode (2βNH2) have been detected in the IR spectra of a variety of amine radical cations, such as (substituted) anilines.[H and I at 3151 and 3267 cm−1 are attributed to 2βNH2 of isomers I and III, with their βNH2 fundamentals being bands Q1 and Q2 (1599 and 1664 cm−1), respectively. The corresponding 2βNH2 overtone of isomer II is estimated near 3400 cm−1 from the fundamental band at 1717 cm−1 (Q3) and thus hidden by the dense and intense NH stretch bands. Anharmonic calculations actually predict significant intensities of such 2βNH2 bands for I–III and thus support this assignment (Tables S2‐S3).In contrast to the range of the rather isolated +Ar spectrum by direct comparison to the spectra computed for the I–III monomers is justified by the minor impact of successive Ar solvation on the appearance of the Ama+Arn spectra. Hence, the IRPD spectra suggest that the weak interaction with Ar causes only a small but noticeable perturbation on both the structure and IR spectra of I–III. This perturbation is most pronounced for the νNH frequencies, which indicates that the NH2 group with its acidic and highly charged NH protons are the most attractive binding sites for Ar . To this end, we have calculated a large variety of Ama+Arn isomers for each core isomer (7–13), and their structures, binding energies, IR spectra, and charge distributions are given in Supporting Information. For all considered I‐Ar, II‐Ar, and III‐Ar isomers, the effect of Ar complexation is less than 9 (I), 5 (II), and 3 cm−1 (III) for the most sensitive νNH and βNH2 modes. Similar small effects are predicted for the clusters with two and three Ar ligands. The Ar ligands are bound via weak dispersion and induction forces to the acidic NH2 group and/or the C10H15 moiety with total binding energies of D0=4.1–8.9 kJ mol−1 (n=1), 11.2–18.2 kJ mol−1 (n=2), and 19.8–27.4 kJ mol−1 (n=3). The energy differences between individual Ama+Arn isomers are small and less than ΔE0=6 kJ mol−1 from the global minimum, so that it is difficult to exclude any of them. Hence, we will discuss here briefly only the global minima of Ama+Arn. The only experimental information about the binding energies of Ama+Arn comes from the observation that single‐photon IRPD is sufficient to evaporate all three Ar ligands of Ama+Ar3 in the XH stretch range (≥2800 cm−1), providing an upper limit for the average Ar binding energy of the order of 1000 cm−1 (or 12 kJ mol−1), which is fully consistent with the computed Ar binding energies.The assignment of the AmaI‐Ar(I), II‐Ar(I), and III‐Ar(I) global minima for each isomer I–III is in all cases the NH2 group  and substantially supported by additional van‐der‐Waals type contacts to the adjacent CH2/CH3 groups (RCH…Ar=2.97–3.17 Å). As a result, the NH…Ar H‐bonds are strongly nonlinear (ϕNHAr=142.9–152.7°), with binding energies of D0=8.4–8.9 kJ mol−1. Upon Ar attachment, the N−H proton donor bonds are slightly elongated (by 1 mÅ) with small red‐shifts in the νNH modes (<9 cm−1), while the involved C−H bonds slightly contract (up to 1 mÅ) resulting in minor blue‐shifts in the corresponding νCH2 modes (<7 cm−1). The charge transfer from Ama+ to Ar is also small (6–7 me) upon complexation, and most other bonds are nearly unaffected. The I‐Ar(II) isomer with a nearly linear NH…Ar bond but no CH…Ar contact is only slightly higher in energy , indicating the subtle competition between the weak NH…Ar H‐bonds and the CH…Ar van‐der‐Waals contacts in these clusters. Nonetheless, also for this stronger NH…Ar H‐bond, the perturbation of the NH2 group is still minor (ΔrNH=1 mÅ). The other less stable Ar binding motifs in I‐Ar(III–VIII), II‐Ar(II–VII), and III‐Ar(II–VII) are mainly weak van‐der‐Waals contacts to the C10H15 moiety further away from the NH2 group, with binding energies of D0=4.1–8.0 kJ mol−1, which have even less impact on the monomer structures than isomers with Ar binding to the NH2 group.The preferred binding site of the first Ar ligand in the most stable p Figure . However2(I)I‐Ar, 2(I)II‐Ar, and 2(I)III‐Ar minima is the mirror image position of the first Ar ligand, thereby restoring Cs symmetry again ‐Ar(I) dimers, due the equivalent binding sites offered by the two NH proton donor sites of the NH2 group. Apparently, nonadditive three‐body contributions to the intermolecular interactions are very minor. Consequently, the properties of the two nonlinear intermolecular NH…Ar bonds and CH…Ar contacts  are similar to those of the (I–III)‐Ar(I) minima with one Ar ligand. The total charge transfer to the ligands (Δq=12‐14 me) increases also linearly with the number of Ar atoms. Overall, the effects on the monomer structures and IR spectra are rather minor also for attaching the second Ar ligand. For all considered Ama+Ar2 isomers, 2(I–VIII)I‐Ar, 2(I–IX)II‐Ar, and 2(I–X)III‐Ar, the total frequency shifts of the νNH2 modes are below 6, 10, and 3 cm−1, respectively.The preferred binding site of the second Ar ligand in the most stable n Figure . The tot3(I)I‐Ar, 3(I)II‐Ar, and 3(I)III‐Ar isomers, the three ligands are arranged around the NH2 group such that the first two Ar atoms form nonlinear NH…Ar H‐bonds with similar binding properties  as in 2(I)(I–III)‐Ar, while the third ligand is attached directly to the N atom at RAr…N=3.36‐3.38 Å . The total binding energies of D0=24.7–27.4 kJ mol−1 are somewhat less than three times those of (I–III)‐Ar(I), because the N site is less attractive than the two NH sites. As a result of the weaker third intermolecular bond, the total charge transfer to the ligands increases only slightly . Also the third Ar ligand has a vanishingly small impact on the monomer structures and their vibrational modes .In the most stable Å Figure . The N a+Ar1‐3 with the calculated IR spectra of the various cluster isomers yields the same assignment (Table S3) as the comparison with the spectra computed for the monomers I–III because of the weak Ama+…Ar interaction. Significantly, the effects of Ar on the νNH modes is much smaller than the splitting observed in the experimental IRPD spectra arising from different isomers, indicating that the bands 1‐3J and 1‐3K do not arise from three distinct Ar binding sites of a single Ama+ isomer but from three different Ama+ isomers. Specifically, all frequencies of the calculated modes of the most stable (I–III)‐Ar(I) isomers differ from those of the I–III monomers by less than 4 cm−1 in the fingerprint range, 9 cm−1 in the νCH range, and 5 cm−1 in the νNH stretch range. Anharmonic calculations confirm the given assignment and show very good correspondence between bands H and I (3151 and 3267 cm−1) with 2βNH2 of I‐Ar(I) and III‐Ar(I) (3150 and 3254 cm−1), respectively. Significantly, band I cannot be assigned to a νNH fundamental which is red‐shifted by Ar‐tagging but must be explained by an 2βNH2 overtone band because of its blue‐shift upon sequential Ar solvation and when going from Ar to N2. In summary, the IRPD spectra of Ama+Ar1‐3 show the clear signature of at least three different monomers in the νNH range and provide a very good approximation of the IR absorption spectrum of bare Ama+. Overall, the largest complexation shifts in the IRPD spectra of Ama+Arn occur for n=1 and 2, and this result is confirmed by the calculations with the two H‐bonded Ar ligands for n=2. As expected, the less strongly N‐bonded third Ar ligand has less impact on both the measured and computed IR spectra.As expected, comparison of the IRPD spectra of Ama2 has a stronger effect on the monomer structures due to its larger proton affinity (PA=494 vs. 369 kJ mol−1) and additional quadrupole moment.2 ligands approach a positive charge in a linear configuration.[2 to form nearly linear NH…N2 H‐bonds to the NH2 group is much more pronounced than for Ar. As a consequence, these H‐bonded isomers are the global minima on the 2(I–III)‐N potentials, with D0=13.4, 15.7, and 13.9 kJ mol−1 for 2(I)(I–III)‐N. These are substantially more stable than those isomers in which N2 simply binds to the C10H15 moiety, with D0=6.6–9.3, 8.4–10.1, and 7.0‐9.8 kJ mol−1 for 2(II–V)I‐N, 2(II–V)II‐N, and 2(II–VII)III‐N, respectively. Thus, the H‐bonded global minima are well separated from the van‐der‐Waals local minima, with energy gaps of ΔE0=4.1, 5.6, and 4.1 kJ mol−1 for I–III, respectively. To this end, we discuss here only the most stable minima 2(I)(I–III)‐N  and larger charge transfer to the ligand . The partial charge on the NH proton donor atoms is increased , leading to a substantial increase of the IR intensities in the νNH modes by a factor of 2–3, an effect typical for H‐bonding. The N−H proton donor bonds are elongated by 3–4 mÅ, resulting in red‐shifts in the νNHs  and νNHa modes . These predicted red‐shifts are somewhat larger than those observed experimentally with respect to the Ama+Ar spectrum  but reproduce the qualitative trend. Part of this discrepancy arises from the neglected experimental shifts upon Ar complexation, while the remaining part may come from an overestimation of the computed harmonic shifts.[I–III, the two bands 2J and 2K assigned to II are difficult to observe due to their larger red‐shift into the shoulders of 1J and 1K. When considering the widths and asymmetric band profiles of these bands and the larger discrepancy between observed and predicted shift, it would be also conceivable that isomer II is not present in the Ama+N2 spectrum at all. However, the very weak band U at 3103 cm−1, which is not observed in the Ama+Arn spectra, agrees well with the νCH2a mode of 2(I)II‐N predicted at 3120 cm−1 and thus may be considered as a marker for the presence of II. Due to the larger retarding force, H‐bonded N2 causes a larger blue‐shift in βNH2 upon complexation than Ar , and this result is nicely reproduced by the measured blue‐shifts of the 2βNH2 overtones of isomers I and III, assigned to bands H (+21 cm−1) and I (+15 cm−1). As the νnCH modes are nearly identical to the corresponding monomer modes, peaks A‐G of the N2 spectrum can be identified analogous to the Ar spectrum.Compared to Ar, N+ and H2O is much stronger than with Ar and N2, because H2O has a much larger proton affinity (PA=691 kJ mol−1)2O prefers binding to the acidic NH2 group rather than to the C10H15 moiety, which has already been reported for the cage isomer I in our previous study of microhydrated Ama+(H2O)1‐3 clusters.2O to isomers II and III is reported here for the first time and compared with new experimental IRPD data (I–III)‐H, are much higher than those with H2O attached to the C10H15 moiety, D0=33.6, 42.0, and 39.1 kJ mol−1 for 2O(II)(I–III)‐H, leading to large energy gaps between NH‐bonded and CH‐bonded isomers . Hence, we discuss only the 2O(I)(I–III)‐H global minima with the strong NH…O ionic H‐bonds further (I–III)‐H global minima, H2O forms a nearly linear and very strong and short NH…O ionic H‐bond to the NH2 group . As a result of the very strong H‐bonds, the νNHs/a normal modes of the NH2 group of the monomers decouple into free and bound NH stretch modes (νNHf/b) upon monohydration. The N−H proton donor bonds of I and II are substantially elongated (ΔrNH=21 and 20 mÅ), leading to massive red‐shifts in the νNHb frequencies down to 3023 and 3033 cm−1, along with drastic enhancements in the IR intensities (factor 6 and 8 compared to νNHs). The N−H bond of III is less stretched than in I and II (ΔNHr=16 mÅ), leading to a smaller red‐shift down to νNHb=3123 cm−1 with an intensity increase of factor 5. The free N−H bonds hardly change, resulting in less intense free νNHf modes at 3378, 3389, and 3420 cm−1 for I–III. Charge transfer to H2O is significantly higher than for N2 and Ar . However, due to the low ionization energy of Ama (IE=8.6 vs. 12.6 eV)[−1 for removing H+ from the NH2 group) as compared to H2O (PA=691 kJ mol−1),10H15NH2 moiety and no proton transfer to H2O occurs upon monohydration. As already noted previously, H2O attachment to I has a significant impact also on the structure of the adamantyl cage.νCH mode is blue‐shifted by 29 cm−1 to 2869 cm−1, while the other νCH/CH2 frequencies do not change much. The impact of H2O on structure II is much smaller. The C=N double bond contracts by 4 mÅ and the C1…C3 distance of the broken bond shortens by 10 mÅ. The νCH mode is only slightly red‐shifted to 2814 cm−1, and the remaining νCH/CH2 frequencies hardly change. H2O attachment to III results in a contraction of the C=N double bond by 8 mÅ and a larger increase in the C1…C3 distance by 51 mÅ, but again the νCH/CH2 frequencies change only slightly.In all +H2O with the spectrum predicted for 2O(I)I‐H demonstrates that all major bands in the experimental spectrum can be explained by this isomer.νNHb mode (3023 cm−1) and free νNHf mode (3378 cm−1) of 2OI‐H(I) are clearly observed at 2990 (1L) and 3368 cm−1 (1M). Band B at 2865 cm−1 is assigned to νCH (2869 cm−1) and band D at 2937 cm−1 to νCH2 modes (2919 and 2957 cm−1). Peaks N and O at 3627 and 3717 cm−1 in the free OH stretch range are readily assigned to νOHs (3597 cm−1) and νOHa (3682 cm−1) of 2OI‐H(I). The bands H and V at 3187 and 3213 cm−1 are probably arising from 2βNH2 and 2βOH2 overtones of 2O(I)I‐H predicted at 3176 and 3238 cm−1. An anharmonic calculation supports this assignment with calculated frequencies of 3187 and 3211 cm−1, respectively.As discussed previously, comparison of the IRPD spectrum of Ama+H2O spectrum two scenarios emerge. In scenario I, all bands are assigned to H2O clusters of isomer I. Then, bands I (3318 cm−1), 2M (3387 cm−1), and 3M (3433 cm−1) may be assigned to the free νNH modes of 2OI‐H isomers with a completely free NH2 group, such as 2OI‐H(II) and 2OI‐H(III) with νNHs=3329 and 3326 cm−1 and νNHa=3445 and 3326 cm−1, respectively . Assuming that only the two most stable isomers 2O(I)I‐H and 2O(II)I‐H are present, one can roughly estimate their population ratio as 10 : 1 from the integrated peak intensities of peaks 1M and I and the calculated IR cross sections, and assuming similar dissociation efficiencies for H2O elimination. Although we cannot exclude scenario I, we consider it unlikely because of the high relative energy gap between 2OI‐H(I) and 2O(II/III)I‐H of 27.8 and 30.9 kJ mol−1, and the clear detection of the open‐cage isomers II and III in the IRPD spectra of Ama+Ar1‐3 and Ama+N2.For the remaining bands in the Ama2L and 2M at 3021 and 3387 cm−1 to νNHb and νNHf of II‐2OH(I) predicted at 3033 and 3389 cm−1. Moreover, the broad and less intense features 3L and 3M at 3147 and 3433 cm−1 are indicative of a small population of 2O(IIII‐H), with computed values of νNHb=3123 cm−1 and νNH2f=3420 cm−1. The population of 2O(I)II‐H and 2O(I)III‐H can then be roughly estimated as ∼30 % and ∼10 % of 2O(I)I‐H by considering the calculated and observed IR intensities of peaks 1‐3M. The overall population ratio for I–III of 10 : 3 : 1 for the H2O‐tagged cations may be compared to that derived for the Ar‐tagged cations (10 : 3 : 7), indicating similar relative abundance for II but a rather reduced population for III, a conclusion rationalized below by considering the potential energy diagram for ring opening and 1,2 H‐shift. In scenario II, the bands B, D, N, and O mostly assigned to 2O(II‐H) will also contain contributions from the corresponding modes of 2O(III/III‐H). Compared to Ar and N2, bands H (3187 cm−1) and I (3318 cm−1) of the H2O spectrum are shifted further to the blue, coherent with their assignment to 2βNH2 of 2O(I)I‐H and 2O(III)I‐H, respectively. Finally, band V (3213 cm−1) can be assigned to 2βOH2 of 2O(I)(I–III)‐H predicted at 3238, 3204 and 3203 cm−1, which explains why this peak V is observed only in the Ama+H2O spectrum.Following our favored scenario II, we attribute bands D0∼60 kJ mol−1 (∼5000 cm−1) for the assigned Ama+H2O isomers substantially exceed the IR photon energy employed for single‐photon IRPD (<4000 cm−1). Consequently, the measured spectrum is produced by internally hot cluster ions that contain an internal energy of at least 1000 cm−1. As a result, the IRPD spectrum of Ama+H2O does not reflect the fundamental transitions (ν) of cold clusters but sequence hot bands of the type ν+νx←νx, where νx are low‐frequency inter‐ and intramolecular modes. This effect causes the widths of the Ama+H2O transitions to be broader than those of Ama+Arn and Ama+N2 for which hν>D0  and three intense bands in the βNH2 range (1‐3Q) clearly indicates the existence of (at least) three different monomer isomers. Moreover, I–III can also be assigned in the Ama+L spectra with L=N2 and H2O. All three isomers differ strongly by the structural and vibrational properties of their NH2 groups, which serve as sensitive probe of their structure. The B3LYP−D3 calculations identify I as the canonical cage radical cation, while II and III are bicyclic distonic iminium ions. The IRPD spectra clearly indicate that the NH2 group is preserved in all three isomers upon ionization and structural rearrangements. This acidic and partially positively charged NH2 group is in all three isomers the preferred binding site for neutral ligands, while the C10H15 moiety is less attractive. The preferred cluster growth is thus solvation of the NH2 group by formation of one or two NH…L ionic H‐bonds. For L=Ar, these H‐bonds are very weak and rather nonlinear because they compete with weak CH…L van‐der‐Waals contacts to the C10H15 moiety. In contrast, the NH…N and NH…O H‐bonds are much stronger because of the additional electrostatic interactions arising from quadrupole and dipole moments of N2 and H2O, respectively. As a result, these H‐bonds are rather linear, with no or little interaction of L with the C10H15 unit. For example, the interaction strength in I–L increases in the order Ar < N2 < H2O as D0=8.4<13.4<61.4 kJ mol−1, in line with the proton affinity of the ligands (PA=369<494<691 kJ mol−1). As a result, the intermolecular NH…L bonds get shorter (2.72>2.14>1.77 Å) and charge transfer from I to L increases (6<14<38 me). Because of the stronger intermolecular bond, the perturbation on the NH2 group gets stronger, with larger N−H bond elongations (ΔrNH=1<4<21 mÅ), and the proton donor NH stretch frequency experiences increasing red‐shifts down to 3322, 3276, and 3023 cm−1. In general, the interaction of II with L is slightly stronger than with I and III for all three ligands , but overall the variation of the ligand binding affinities is small. This is fully consistent with the charge on the acidic NH protons (qH=0.405<0.421>0.411 e) and the NH…L bond lengths. Figure +L clusters and the overall good qualitative and quantitative agreement supports the given vibrational and isomer assignments. When compared to other NH…L ionic H‐bonds, such as those in clusters of small ions (I–III)‐L are significantly weaker and less directional, mainly due to the lower acidity of the NH2 group resulting from the large charge delocalization into the C10H15 moiety and the high PA of the C10H15NH radicals.In addition to the nascent cage isomer + population  will then cool down by collisions in the expansion to form cold ions I. Some part has enough energy to overcome the barriers for cage opening and 1,2 H‐shift and will then cool down to generate cold ions II and III. As a final step, the cold ions will form clusters by three‐body aggregation. Cluster formation may also take place during the isomerization reaction and the cooling process. A further route, which is particularly feasible for H2O, is the formation of larger neutral Ama(H2O)n clusters in the expansion, which are then ionized and cool down via collisions and/or ligand evaporation. For the latter pathway, it is also necessary to consider the potential of the clusters for the ionization‐induced rearrangement reaction. To summarize, experimentally the energetics and kinetics of the processes occurring in the plasma expansion are not well defined.In the following, we discuss the process of ionization, cage‐opening reaction, subsequent 1,2 H‐shift, the corresponding potential energy surface and its dependence on the solvent. Neutral Ama is ionized in the high‐pressure region of the supersonic plasma expansion of the EI source by electron and/or chemical ionization. To this end, electrons hit the expansion gas with a kinetic energy of up to 200 eV, leading to a variety of processes including elastic and inelastic scattering, where the electrons may lose kinetic energy and also produce secondary electrons. At some point, direct EI of Ama (IE<10 eV)I (E0=45.9 kJ mol−1). As a result, the pyramidal NH2 group becomes planar and due to increased delocalization of the N lone pair orbital, the C−N bond order increases from 1 to ∼1.5, and the adjacent C1−C3 bond is slightly activated, which is the first step for opening the cage. The HOMO of I is delocalized over the whole cation , while most charge remains on the CNH2 group (0.528 e). For highly energetic I, it is possible to overcome the barrier for breaking the C1−C3 bond and opening the cage via TS(I–II) , accompanied by a chair→boat conversion of the cyclohexane ring carrying the NH2 group. This process results in a separation of charge and spin, so that the resulting shallow minimum II is a bicyclic distonic iminium ion (E0=87.4 kJ mol−1), with most of the positive charge located on the CNH2 group (0.754 e) and the spin located on the primary CH2⋅ radical center at C3 (sC3=1005). The HOMO of II is mostly the 2pz orbital of the CH2⋅ group with an sp2 C atom . In the final 1,2 H‐shift to the CH2⋅ center, the much more stable tertiary CR3⋅ radical center (sC9=0.627) is formed via a barrier of Vb=81.6 kJ mol−1 (E0=169.0 kJ mol−1), accompanied by a boat→chair back conversion of the cyclohexane ring, resulting in maximum stabilization of the radical in the distonic bicyclic iminium ion III (E0=0), which is by far the global minimum on the Ama+ potential. The HOMO of III is almost completely delocalized again over the entire cation, with some substantial orbital overlap between the 2pz orbital of the C9 radical center and the 2pπ orbital of the C=N double bond . The partial charge of the CNH2 group is reduced to 0.608 e, because some of the charge is transferred to the tertiary C9 atom, but it is still slightly higher than in the initial structure I (0.528 e).The potential for the reaction of the monomer is shown in Figure 2 binding energies are very small (<16 kJ mol−1) compared to the energies involved in the potential energy profile with respect to barriers and relative energies of minima , these ligands are considered to have negligible influence on reaction efficiencies and the final population of the isomers I–III. In particular, they do not change the energetic order of I–III. As the ligand binding energies are similar for each I–III isomer, the potential energy profile for the Ama+Ar dimers are very similar to that of bare Ama+, and we may reliably estimate from the relative isomer population in these clusters directly the isomer abundances of the monomers I–III. The population ratio of 10 : 3 : 7 for I–III derived from the βNH2 intensities of the Ama+Ar spectrum are fully consistent with the potential energy profile predicted for the Ama+ monomer. The high abundance of I is due to its initial preparation by vertical ionization and the high barrier required for isomerization toward II and III of 54.1 and 123.1 kJ mol−1, respectively. Thus, it is likely that a substantial population of Ama+ is trapped in the deep initial well by rapid collisional cooling despite of its high relative energy. The minor population of II is attributed to its shallow potential well (12.6 kJ mol−1), while the higher population of III is rationalized by its highest stability. In addition, tunneling of H through the short barrier between II and III may also enhance the population of III. As illustrated in Figure +H2O differs strongly from that of Ama+ (and Ama+Ar/N2). While the relative energies of the I–III minima and TS(I–II) are similar, TS(II–III) is much higher for Ama+H2O (E0=213 vs. 169 kJ mol−1), which suppresses the formation of III. Indeed, comparison of the population ratio inferred from the Ama+H2O spectrum (10 : 3 : 1 for I–III) compared to that derived from Ama+Ar (10 : 3 : 7) fully confirms this view.As the Ar and N+ with those of Ada+ to extract the impact of H→NH2 substitution on the ionization‐triggered cage‐opening reaction. To this end, we calculated the structures, energies, charge and spin distributions, HOMO orbitals, and IR spectra of the three Ada+ isomers I–III, along with the potential for the rearrangement reaction at the same computational level for direct comparison with Ama+ . Our results for the Ada+ potential are consistent with previous calculations,+. As can be seen, while the energetic order of the isomers I–III is the same for both Ama+ and Ada+, their relative energies and reaction barriers change drastically. Significantly, substitution of H by the NH2 group qualitatively changes the ionization process. While in Ada+, ionization occurs from a bonding CC σ orbital completely delocalized over the whole C10H16 cage,+ occurs from the N lone pair of the NH2 group, which is only partly delocalized into the cage. As a result, the ionization energy of Ama is largely reduced compared to that of Ada .[I of Ada+ (E0=5.4 kJ mol−1) undergoes Jahn‐Teller distortion from Td to C3v symmetry, which leads to an elongation of the three C−C bonds parallel to the C3 axis and a substantial activation of the C−H bond lying on this axis. This very acidic C−H bond with its high positive charge (qH=0.354 e) is an attractive proton donor for H‐bonding with neutral ligands, such as He, Ar, N2, and H2O.[2 group in isomer I of Ama+ strongly activates the C1−C3 bond (rC1C3=1.697 Å), which eventually breaks, no such activation is observed for ionization of Ada+ (rC1C3=1.511 Å). Hence, the barrier for breaking this bond is much higher for Ada+ than for Ama+ (Vb=156.7 vs. 54.1 kJ mol−1), i. e., H→NH2 substitution strongly facilitates cage opening. Similar to Ama+, isomer II of Ada+ is located in a shallow potential well (9 vs. 13 kJ mol−1) and thus much higher in relative energy (153.0 vs. 87.4 kJ mol−1). It is also a distonic ion with a CH2⋅ radical group (s=0.797) separated from the positive charge , mostly located on the opposite CH2‐CH‐CH2 moiety (qCH=0.623 e). The energy barrier for the 1,2 H‐shift at TS(II–III) is much lower compared to Ama+ (Vb=37.8 vs. 81.6 kJ mol−1) even though the relative energy to the global minimum III is higher (E0=190.8 vs. 169.0 kJ mol−1). Similar to III of Ama+, the HOMO of the global minimum III of Ada+ is again delocalized over the entire cation . The charge of the CH2‐‐CH‐‐CH2 group is reduced to 0.337 e, because a large amount of charge is now located at the tertiary radical C‐atom (qC=0.410 e).It is instructive to compare the properties of Ama8.81 eV).16c Isom2 substitution of Ada has a drastic impact on the potential for the cage‐opening reaction and subsequent 1,2 H‐shift. The barrier for this reaction is drastically reduced for Ama+ and thus all three isomers I–III are detected in the IRPD spectra of Ama+L with L=Ar, N2, and H2O. In contrast, the high barrier for this process in Ada+ explains why such a reaction was not detected in previous IRPD spectra of Ada+L with the same ligands.[+L, cage opening was not considered but the comparison of the IR spectra computed for I–III of Ada+ with the IRPD spectrum of Ada+He2 in the CH stretch range  clearly demonstrates that the whole spectrum can be assigned to I, while the population of II and III are clearly below the detection limit, in accordance with the potential shown in Figure In summary, H→NH ligands.20 In pr+ cation and their solvated clusters with Ar, N2, and H2O are probed in a molecular beam by IRPD in the sensitive XH stretch and fingerprint ranges. The analysis of the IRPD spectra by DFT calculations provides direct evidence for the ionization‐induced opening of the adamantyl cage followed by an 1,2 H‐shift, and three distinct minima I–III are identified on the potential energy profile by the unique νNH and βNH2 modes of their rather different NH2 groups. Vertical electron ionization of Ama produces the canonical nascent cage isomer I of Ama+, which then via substantial barriers can react in a unimolecular reaction toward two distonic bicyclic iminium ions II and III. Significantly, isomer III with a tertiary radical center is the global minimum and thus more stable than the canonical cage structure I. In addition to the geometric and vibrational properties of the three isomers, details of the potential energy profile are revealed. The relative abundance of I–III are fully consistent with the shape of this potential energy profile, with respect to both the relative energies of the minima and the barriers for reaction. Although only a local minimum on the potential, the nascent isomer I is most abundant because it is directly produced by vertical ionization of the neutral cage molecule and largely trapped in its deep potential by collisional cooling. Part of the energetic population of I can overcome the high barriers toward II and III, whereby the well of II is quite shallow leading to its smallest population, while the substantial population of III is consistent with its highest stability. Tunneling of H through the short barrier between II and III may also enhance the population of III, a hypothesis which may be tested using partially deuterated samples in the future. Solvation of the ions with Ar and N2 has little impact on the potential energy profile and isomer population, while the production of III is strongly suppressed for solvation with H2O due to a large increase in the barrier for the II→III reaction. Comparison between Ama+ and Ada+ reveals that H→NH2 substitution has a drastic impact on the geometric and electronic structure of the three isomers I–III due to the strong electron‐donating character of the NH2 group. The resulting orbital conjugation drastically reduces the barriers on the potential compared to Ada+, for which the much higher barriers have prevented the detection of the cage‐opening reaction in previous related experiments. To test this hypothesis, experiments with cyano‐adamantane are currently underway to study the effects of an electron‐withdrawing substituent (CN) on the cage‐opening potential energy profile. Significantly, the presented IRPD spectra of Ama+Ln provide the first experimental evidence for the cage‐opening and 1,2 H‐shift reaction for any diamondoid cation and thus yield valuable insight into their chemical reactivity. As the radical cations of diamondoids are frequently invoked in the mechanism for (substitution) reactions in polar solvents, the results of the current study provide valuable insight for developing new routes in organic synthesis in diamondoid chemistry. In addition, the intermediates II and III may also be used in novel routes of iminium ion chemistry in solution, a strategy which has not been exploited so far. The acidic NH2 group serves as the most attractive ligand binding site for all three ions I–III and the ligand‐ and size‐dependent frequency shifts of the νNH and 2βNH2 modes provide a quantitative probe of the type and strength of the Ama+…L interaction and the sequence of the cluster growth. In general, the first two ligands form equivalent NH…L ionic H‐bonds to the two available NH protons before other less stable binding sites are occupied.II is stronger than with I and III which correlates with the acidity of the NH2 group. For Ar ligands, the NH…Ar bonds are very weak and thus rather nonlinear because of competing CH…Ar contacts based on dispersion and induction forces. As a result, the Ama+Ar spectrum provides a very good approximation to the spectrum of bare Ama+. In contrast, stronger NH…N and NH…O ionic H‐bonds are present for clusters with N2 and H2O due to the additional electrostatic forces arising from the nonvanishing quadrupole and dipole moments, respectively. To this end, the choice of solvent has a drastic impact on the reactivity of the isomeric Ama+ ions in organic synthesis.In summary, the structural isomers of the AmaThere are no conflicts of interest to declare.1As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.Supporting InformationClick here for additional data file.


However, their mutual influence during rehabilitation is not well known yet. The aim of this retrospective observational cohort study was to investigate the association between rehabilitation dose and motor and cognitive functions, during UL motor recovery. Inpatients with first unilateral stroke, without time restrictions from onset, and undergoing at least 15 h of rehabilitation were enrolled. Data on dose and modalities of rehabilitation received, together with motor and cognitive outcomes before and after therapy, were collected. Fugl–Meyer values for the Upper Extremity were the primary outcome measure. Logistic regression models were used to detect any associations between UL motor improvement and motor and cognitive-linguistic features at acceptance, regarding dose of rehabilitation received. Thirty-five patients were enrolled and received 80.57 ± 30.1 h of rehabilitation on average. Manual dexterity, level of independence and UL motor function improved after rehabilitation, with no influence of attentive functions on motor recovery. The total amount of rehabilitation delivered was the strongest factor ( Stroke is a cerebrovascular disease representing the second cause of death and a major cause of disability worldwide . The mosAnother major concern is related to CT contents, indeed, even in studies enrolling patients with severe UL impairments after stroke, less than 30% of PTs and OTs rehabilitation sessions are specifically targeted to arm-related activities . In EuroDespite evidence for factors with positive predictive value for UL recovery  being available ,17, to dTherefore, the study aims to (i) explore clinical features and (ii) potential effect of rehabilitation dose that could influence UL recovery, after stroke.The rest of the paper is organized as follow: study materials and methods used for the data collection, management and analyses are described. Then, results are presented, and finally the main findings, limitations and suggestions for future research are discussed.This study was a retrospective observational cohort analysis, from data collected on consecutive stroke subjects hospitalized between July 2019 and November 2020 at IRCCS San Camillo Hospital . Patients enrolled underwent an initial assessment of motor and cognitive-linguistic functions (T0), whereas only motor functions were reassessed after 20 h of rehabilitation (T1). The original cohort included patients according to following criteria: older than 18 years, diagnosis of a first-ever unilateral cortical-subcortical stroke (ischemic or hemorrhagic) without restriction on time from lesion and with at least 4 weeks of rehabilitation completed. Exclusion criteria were cerebellar or bilateral stroke; unstable medical conditions at time of hospitalization; diagnosis of other neurological and/or psychiatric diseases in addition to stroke .The retrospective study design was chosen to analyze data already collected during a standardized screening process at hospital admittance. Therefore, patients hospitalized between July 2019 and November 2020 were contacted by telephone for enrollment and informed on the study purpose, between September and December 2021. Only patients who provided written consent to use their data collected during previous hospitalization were included in the analysis.For a better reporting of the study, the Strengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist has been used . The stuDuring hospitalization lasting 4 weeks at least, patients underwent a motor rehabilitation program consisting at minimum 1 h/day of CT for each day of hospitalization, and one or more hours of other modalities such as UL-specific OT, technology devices  for UL and/or lower limb (LL). The treatment program was delivered according to the individual rehabilitation project agreed with the rehabilitation team  and tailored on patient’s needs. Each session was adapted to individual clinical condition and ability to perform exercises, accomplishing any harm that may occur . All the technology-based modalities reported are included in the hospital clinical pathways and has been developed and validated through the institutional translational research projects funded by the Italian Ministry of Health and the European Commission.Among the therapeutic modalities, technologies for both the upper (UL) and lower (LL) limb were available. Technologies for the UL consisted of Virtual Reality Rehabilitation System , with a computer-based tasks displayed in a virtual scenario. Patients were asked to emulate real arm movements, via a motion tracking system controlling a virtual object . For pat® Balance Manager, Natus Medical Incorporated, Pleasanton, CA, USA), a semi-immersive balance board providing multisensory balance training exercises with augmented visual biofeedback [Regarding technologies for the LL, the VRRS were used also for LL tasks and balance activities . In addifeedback , and thefeedback . Finallyfeedback .Each therapy was delivered by a specialized PT for 1 h/day, 5 dd/w, for 3 weeks, with a one-to-one approach. The number of repetitions and type of exercises was chosen by the PT according to clinical judgment and patient’s needs, tailoring difficulties on patient’s ability.The CT consisted of whole-body exercises selected autonomously by the clinician and performed in a gym or a private room, in a one-to-one setting. Among CT interventions, respiratory therapy was considered. In UL-targeted interventions, patients were asked to perform functional task exercises in each plane including shoulder and elbow flexion-extension, shoulder abduction-adduction, internal-external rotation, circumduction, forearm pronation-supination, both with and without everyday objects. Moreover, exercises were proposed for training coordination, proprioception, and effort resistance capacity in every modality to stimulate patient residual abilities, to reduce compensations and control voluntary muscle activation. If needed, the use of splints or orthosis were considered . Each session lasted at least 1 h/day, 5 days/week, for each week of the hospitalization period.The OT consisted of UL-specific rehabilitation sessions based on the functional use of the limb in ADL , vocational activities , or activities claimed as important by the patient . The OT intervention could be delivered in one-to-one, or group settings.Clinical assessments aimed to quantify residuals motor and cognitive-linguistic functions included collection of anamnestic data from digital record of patient medical history, clinical scales measuring the level of functional and sensorimotor capacity of the upper limb, the degree of stroke severity, and communicative-linguistic rating scales.Demographic and clinical data of each patient were retrieved from digital records of the medical history. Clinical outcomes were retrieved from clinical assessment performed by clinicians . Specifically, data could be tracked back to clinical assessments performed by a PT at the beginning (T0) and end (T1) of a rehabilitation period, and linguistic-cognitive assessments performed by a SLT or neuropsychologist only at T0. The PT and SLT were blinded to rehabilitation intervention, as they were not clinically in charge of the patient. Data on dosage and therapeutic-rehabilitation modalities provided to patients were retrieved from the rehabilitation report filled out by PT.The primary outcome measure was the FMA-UE, a reliable and validated 66-points outcome measure quantifying arm motor function after stroke . Other cFor cognitive and linguistic functions, patients were assessed at baseline with the Oxford Cognitive Screen (OCS), a sensitive screening tool for detection of cognitive deficits after stroke. The scale consists of 10 tasks encompassing five cognitive domains: attention and executive function, language, memory, number processing, and praxis .For each patient, the dose of therapy was quantified both as number of modalities and dose  of intervention received during hospitalization. For the analysis, classes of intervention were defined as follow: total hours of CT (“CT”); total hours of rehabilitation specific for the UL ; total hours of rehabilitation non-specific for the UL ; total amount of rehabilitation . The CT was analyzed only for the primary outcome measure .The sample size of the present study was tailored on the original cohort of stroke patients hospitalized between July 2019 and November 2020 (N = 63) and only those releasing informed consent were finally enrolled and analyzed.To describe the demographic, clinical and cognitive characteristics of the sample, descriptive statistics  were used. Only a portion of the patients performed the cognitive assessments; therefore, it was decided to perform the descriptive analyses of these variables separately.Missing data were found to be present for some of the variables. Where the percentage of missing data was less than 25%, the choice was made to impute data using the multivariate imputations by chain equations (MICE) method.t-test or Wilcoxon signed rank test was performed to study significant difference in motor outcomes before (T0) and after (T1) rehabilitation. For each outcome measure, effect sizes were calculated by Cohen’s d to estimate the standardized effect of rehabilitation [t test for unpaired data or Mann–Whitney test for each clinical variable was performed, depending on distribution properties. Because of differences in data completeness, the variables were divided into three groups for models estimation: Clinical Group , Cognitive Group , and Demographic Group . Within each group, Generalized Linear Regression Models (GLM) were estimated using the responding variables of each clinical scale as dependent variable and results of other variables in the corresponding groups as independent variables.Depending on data distribution, tested through the Shapiro–Wilk test, a paired Student’s litation . Subsequlitation ,32,33,342) [p-value) [Finally, to estimate the overall models of the Responders variable for the primary outcome measure , GLM were estimated, using as independent variables the cognitive, demographic, and motor variables found to be significant in the models estimated within the group. For each model, the odds ratios and their 95% confidence intervals (CI) were calculated. In addition, each regression model fitting was assessed by using the following indices ,36: (i) 2) ; (ii) th2) ; (iii) Cp-value) .2 is close to 1, the more the model is satisfactory; (ii) Brier score for a model can range from 0 (0%) for a perfect model to 1 (100%) for a non-informative model; (iii) an AUC values >0.70 representing a moderately accurate model; (iv) a significant The regression model fitted the original data if the indices met the following criteria: (i) the more pseudo-Rp < 0.05. All the statistical analyses were performed using the free software R Studio 4.0.5 [The statistical significance level was set at io 4.0.5 .Among 63 stroke patients contacted by telephone, 35 of them gave informed consent and were included in the study. Their demographic characteristics (T0) and dose of therapy are described in d < 0.6), as described in The UL motor function was moderately impaired before rehabilitation and significantly improved after treatment. Significant improvements were observed also for level of independence and manual dexterity, with effect sizes ranging from low to moderate (Cohen’s The cognitive outcome measures were collected at T0 in those patients needing a cognitive screening (N = 18) and are described in After treatment, less than half of the patients improved above the MCID or MDC at the FMA-UE, FIM and BBT, thus classified as responders to therapy .p = 0.031, W = 163.5). Actually, the Non-Responders received more hours of rehabilitation than Responders  seem to be weakly associated to a higher probability of clinically relevant motor gains. In relation to the cognitive variables assessed before rehabilitation (T0), results showed no significant evidence that attentive functions and independence in ADL influenced motor recovery, positively .p = 0.005, V = 73), manual dexterity  and level of independence  significantly improved after 80.57 ± 30.1 h of rehabilitation, on average. The overall effect of received intervention was moderate (Cohen’s d 0.45 to 0.60). Conversely, sensation functions did not change importantly . Less than half of the patients responded to therapy, according to FMA-UE and FIM , while almost half of the patients, regarding BBT . However, it must be reported that some patients resulted to be non-responders at FMA-UE as their baseline score, higher than 61/66, was within the ceiling effect-zone of the scale.The present study explored the association between dose of rehabilitation, cognitive and motor characteristics, in a population of chronic stroke patients undergoing a period of rehabilitation. We observed that the UL motor function . Conversely, specific interventions for the UL and total dose of rehabilitation specific for the UL did not emerge as significant factors inducing differences between responders and non-responders, confirming that total dose of rehabilitation is more impacting, than dedicated strategies targeted to specific body districts, as previously demonstrated by McCabe et al. [p = 0.031, W = 163.5), therefore to subjects with more severe impairments, thus with larger ranges of improvement expected. It is worth noticed that mild-moderate impairment of muscle tone, sensation, and executive functions at baseline, make patients fully suitable for any potential rehabilitation intervention targeted to the UL, as well as general cognitive functions. Indeed, 12 patients out of the 18 who performed a cognitive screening, presented good levels of attentive, linguistics and mnemonic functions, whereas 13 patients showed good performance of executive functions and no severe cognitive impairment at baseline. Therefore, because of the presence of good cognitive functions in 72% of patients, it was hard to identify the level of cognitive function relevant for empowering improvement of motor function.An utmost finding was that patients classified as non-responders to FIM after treatment, instead received a significant higher dose of rehabilitation, than responders .Among the responders at FMA-UE, level of independence in ADLs at the beginning of rehabilitation and total dose of intervention accurately predict clinical improvement of UL motor function, as confirmed by the regression model (pseudo-Rp = 0.06).Regarding cognitive variables, the results showed no significant evidence that cognitive-linguistic and attentive functions positively influenced motor recovery, which is not consistent with the present literature . HoweverSome limitations of our study need to be acknowledged; the low number of enrolled patients  may have underpowered results from the regression models and affected estimation precision, thus confounding potential significant inference. Moreover, the retrospective nature of the study design and the absence of a control group did not allow to explore strong cause-and-effect relationships . TherefoThis retrospective cohort study found that total dose is more influential than dose specificity when delivering rehabilitation treatments, for the recovery of motor function, in the chronic phase after stroke. Indeed, higher dose of rehabilitation leads to higher probability of becoming a responder to rehabilitation treatment, for the recovery of the UL motor function. Conversely, the results show that a lower level of independence gain was associated with a higher probability of receiving a larger amount of rehabilitation treatment. Regarding cognitive capability, attentive functions did not seem to be associated with motor recovery, even though their contribution is close to the significance threshold.In conclusion, the total amount of rehabilitation is confirmed to be the strongest factor contributing to a clinically important improvement in the recovery of UL motor function, after stroke.To reach firm and strong insights on the predictive factors for motor recovery, improvement of the model’s statistical fitting and estimation precision is required. Therefore, further research should be conducted with longitudinal cohort studies on a larger sample, considering also the enrolment of control cohorts and adjustments for confounding factors.


The overall stereochemistry of the racemate in each case is defined as aS,R and aR,S. In 1, the hydroxyl group generates inversion dimers via pairwise intermolecular O—H⋯S hydrogen bonds whereas in 2, the O—H⋯S link is intramolecular. Weak C—H⋯π interactions link the molecules into extended arrays in both structures.The closely related title compounds, 1-(dinaphtho[2,1- This undergoes nucleophilic addition to prochiral electrophiles producing separable diastereomeric products with varying degrees of diastereoselectivity -2,2-dimethylpropan-1-ol, 1, and 2--3,3-dimethylbutan-2-ol, 2, confirm the relative stereochemistry of the major isomers.Stereoselective synthetic methodology continues to be a major research focus underpinning many areas of chemical and biological sciences. One design strategy is the utilization of atropisomerism. This exploits the stereoisomerism that results from restricted rotation about single bonds, a particular feature of biaryl compounds ° and the dihedral angle between naphthalene ring mean planes is 65.91 (4)°. Capping the stereogenic auxiliary is a chiral (at atom C2) neopentyl alcohol group .The synthesis of compound 2 Fig. 2 places a 1 Fig. 3: r.m.s. 3.1, inversion dimers form through pairwise classical O2—H2⋯S2 hydrogen bonds . This is supported by a short contact C105—H105⋯S1 of 2.90 Å  forms a screw diad  forms zigzag chains via a glide reflection in the bc plane dinaphthodioxepine -dinaphthodioxepine CAJCEY : dithioacetal 3 in THF was cooled to 173 K under Ar. n-BuLi  was added dropwise and the suspension stirred for 5 min. Pivaldehyde (1.2 equiv.) was similarly added and the reaction stirred for a further 10 min. The mixture was quenched with saturated NH4Cl and extracted with Et2O. The ethereal extract was washed, dried (MgSO4) and concentrated in vacuo then chromatographed (SiO2/CH2Cl2), giving a white solid, a 5:2 mixture of the two possible diastereoisomers of 4 . Further chromatography with a CH2Cl2/hexane solvent allowed separation into major (1) and minor (m4) diastereoisomers. Compounds ps Fig. 8 from ditd:1′,2′-f]dithiepine (5): to a stirred solution of alcohol 4 in CH2Cl2 was added CaCO3 and powdered 4 Å molecular sieves. PCC (3.3 equiv.) was added and the reaction mix stirred . The solvent was concentrated in vacuo and filtered through SiO2 to give the ketone as a white solid, m.p. 445–446 K (88% yield). 1H NMR  δ (ppm): 1.30 , 5.73 , 7.15 , 7.18–7.31 , 7.46–7.56 , 7.64 , 7.83 , 7.95–8.03 . 13C NMR (50 MHz) δ (ppm): 27.2 (Me), 44.3 (CMe3), 64.6 (S–CH—S), 126.3, 126.6, 126.8 (Ar CH), 126.9 (Ar C), 127.5, 127.6 (Ar CH), 127.7 (Ar C), 128.3, 128.4, 129.1, 129.2 (Ar CH), 130.4 (Ar C), 132.2 (Ar CH), 131.5 (Ar C), 133.1 (Ar CH), 134.1, 134.5, 142.8, 143.0 (Ar C), 206.2 (C=O).4-Pivaloyldinaphthodithiepin-4-yl)-2,2-dimethylpropan-1-ol (1): a solution of ketone 5 in THF was cooled to 272 K under Ar. LiAlH4 (2 equiv.) was added in one portion and the suspension stirred for 30 min. The reaction mixture was quenched by addition of H2O and extracted with Et2O. The ethereal extract was washed, dried (MgSO4) and concentrated in vacuo, then chromatographed (SiO2/CH2Cl2) to give 1 as a white solid, m.p. 426 K . Crystals for X-ray diffraction were obtained from slow evaporation of an EtOH/H2O solvent mix. 1H NMR  δ (ppm): 1.01 , 2.70 , 3.29 , 5.16 , 7.10–7.15 , 7.18–7.26 , 7.44–7.51 , 7.80–7.87 , 7.90–7.98 . 13C NMR (75 MHz) δ (ppm): 26.7 (Me), 36.1 (CMe3), 70.1 (COH), 80.2 (S—CH—S), 126.5, 126.7, 127.6, 127.7, 128.3 (Ar CH), 128.8 (Ar C), 129.0, 129.2 (Ar CH), 131.5 (Ar C), 132.2 (Ar CH), 132.3 (Ar C), 133.0 (Ar CH), 133.9, 134.0, 141.7, 142.6 (Ar C).1--3,3-dimethylbutan-2-ol (2): a solution of ketone 5 in THF was cooled to 193 K under Ar. MeLi  was added and the solution stirred 30 min. The reaction mixture was quenched by addition of EtOD then H2O and extracted with Et2O. The ethereal extract was washed, dried (MgSO4) and concentrated in vacuo, then chromatographed on SiO2 (1:1 CH2Cl2/hexane) to give 2 as a white solid, m.p. 448–449 K . Crystals for X-ray diffraction were obtained from slow evaporation of an EtOH/H2O mix. 1H NMR  δ (ppm): 1.10 , 1.16 , 3.09 , 5.18 , 7.08–7.30 , 7.43–7.52 , 7.83 , 7.85 , 7.92–7.99 . 13C NMR (50 MHz) δ (ppm): 20.0 (Me), 26.8 (CMe3), 38.6 (CMe3), 76.1 (COH), 79.4 (S—CH—S), 126.1, 126.2, 126.4, 127.4, 127.9, 128.0, 128.5 (Ar CH), 129.0 (Ar C), 129.1, 131.8 (Ar CH), 131.9, 132.0, 132.1 (Ar C), 132.8 (Ar CH), 133.5, 133.7, 141.8, 142.6 (Ar C).2- = 0.95 Å, Uiso = 1.2Ueq (C) for aromatic H, 1.00 Å, Uiso = 1.2Ueq (C) for CH, 0.98 Å, Uiso = 1.5Ueq (C) for methyl H atoms and d(O—H) = 0.84 Å, Uiso = 1.5Ueq (O) for OH.Crystal data, data collection and structure refinement details are summarized in Table 310.1107/S2056989023000476/hb8049sup1.cifCrystal structure: contains datablock(s) 1, 2, global. DOI: 10.1107/S2056989023000476/hb80491sup2.hklStructure factors: contains datablock(s) 1. DOI: 10.1107/S2056989023000476/hb80492sup3.hklStructure factors: contains datablock(s) 2. DOI: Click here for additional data file.10.1107/S2056989023000476/hb80491sup4.cmlSupporting information file. DOI: Click here for additional data file.10.1107/S2056989023000476/hb80492sup5.cmlSupporting information file. DOI: 2236820, 2236819CCDC references:  crystallographic information; 3D view; checkCIF reportAdditional supporting information: