A detailed description of the mechanism of reaction of Grignard reagents with ketones
A detailed description of the reaction of Grignard reagents with ketones is presented based on several studies. The composition of Grignard reagents in Et20 and THF is described based on molecular association and NMR studies. The cause and mechanisms of formation of pinacol and hydrol in the reaction of "CH3MgBr" with benzophenone is also described. Several probes to detect the radical nature of the R group in RMgX and the radical anion nature of the ketyl produced in the reduction of the ketone, were used to study the electron transfer nature of Grignard reagent addition to ketones. The results of thesestudies show clearly that Grignard reagents react with ketones by both a polar and electron transfer pathway. Which of these two pathways involves the lowest energy depends on the nature of the R group of the Grignard, the purity of the magnesium used to prepared the Grignard reaaent. the nature of the ketone and the solvent.Grignard reagents that are difficult to oxidize (e.g. 1° R group), ketones that are difficult to reduce (e.g. acetone), solvents of low polarity (e.g., Et,O) and Grignard reagents made from pure magnesium metal favor a polar pathway, an usually only 1,2-addition product is formed. On the other hand, Grignard reagents that are easily oxidized (e.g. 3° R group), ketones that are easily reduced. (e.g., Ph2C=O) solvents of high polarity (e.g., THF, HMPA) and Grignard reagents made from magnesium containing 1st row transition metals, favor an electron transfer pathway. Usually 1,2and 1,6-addition products are formed as well as some pinacol. INTRODUCTION I am, of course, deeply honored to be invited to present our work carried out at Georgia Tech concerning the mechanism of Grignard compound addition to ketones which began in 1964, and which is still in progress (see note a). To have spent so many years studying the mechanism of a single reaction type, I believe, requires some justification. However, in this particular case, I believe such effort is justified in that the reaction of Grignard reagents with ketones is undoubtedly one of the most fundamental reactions in all of organic chemistry, and therefore should be understood in some depth. In addition, whatever has been learned in this study, hopefully can be applied in a broader way to other reactions involving main group organometallic systems, e.g. organolithium and organoaluminum, since detailed mechanistic studies of reactions in main group metal chemistry are rare indeed. We have also made several discoveries of a practical nature during these mechanistic studies which in themselves could easily justify the time and effort spent in this area. The years spent in this work have not been dull since every time we seemed to be coming closer to the end of our study, another major problem in understanding arose which necessitated more effort. There have been a number of times during the past 14 years that the thought of abandoning our efforts crossed our minds as we met what seemed like insurmountable problems. However, because of the unusual experimental skill and determination of my students, who did this work,I am happy to report that we have finally arrived at what we believe to be the beginning of a much better understanding of the mechanism of Grignard reactions. COMPOSITION OF GRIGNARD REAGENTS IN ETHER SOLVENTS In order to study the mechanism of Grignard reagent addition to any organic substrate, it is necessary first to understand the nature of Grignard reagents in solution. If Grignard reagents consist of a number of species in soltution, it is also important then to determine which of these species is the most reactive toward the organic substrate being studied. A Note a. I would like to dedicate this presentation in honor of a very prominent chemist who has contributed greatly to the field of Grignard chemistry, Professor Henri Normant on the occasion of his 72nd birthday.