Kinetic studies of the asymmetric transfer hydrogenation of imines with HCOOH using Rh-chiral diamine catalysts reveal anomalous concentration dependences attributed to the participation of both reactant and product in the formation of formate salts. The resting state of the catalyst is suggested to be the Rh hydride species 5. The role of bases such as Et 3 N in metering HCOOH into the catalytic cycle is discussed. A practical reaction protocol for achieving high productivity based on slow addition of HCOOH is presented. These studies highlight the value of in situ reaction monitoring techniques in developing a detailed mechanistic picture of a complex reaction system. IntroductionAsymmetric hydrogenation of CdO and CdN groups via transfer of hydrogen from an organic molecule has come under recent attention as an attractive alternative to reduction using gaseous hydrogen. Ru, Rh and Ir precursor complexes together with chiral diamine ligands have been shown to effect these reactions in high enantioselectivity and high efficiency. 1 Noyori and co-workers 2 have studied the mechanism of the reaction for ketones with both simple alcohols and formic acid as the source of hydrogen, and they were the first to propose that the reaction proceeds outside the coordination sphere of the metal. Such a concerted mechanism involving the transfer of both a metal hydride and a ligand proton has been supported by theoretical studies. 3 In addition, DFT (density functional theory) calculations 4 and deuterium-labeling studies 5 for ketone substrates suggested a similar mechanism for transfer hydrogenation and dehy-
Quality assurance and process understanding are assuming increasing importance in the production of Active Pharmaceutical Ingredients (APIs). NMR has the potential to report on physical processes, quantities, structures, and speciation as chemical reactions progress. Following the progression of chemical reactions by placing the sample in an NMR tube, one can perform a large number of useful studies that provide chemical and mechanistic insight. But this simple approach can have limitations, and we have therefore constructed an apparatus comprising a laboratory reactor coupled with an NMR flow cell. The reactor duplicates the exact reaction conditions that will apply with large-scale production. This reaction mixture is sampled and pumped to a high-resolution NMR flow cell where the spectrum is recorded through the course of the reaction. We demonstrate the utility of reaction monitoring using NMR both for simple cases where tubes can be used, and describe the design of the on-flow apparatus and highlight its utility with an example.
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