The Source of Proton in the Noyori−Ikariya Reaction

The study of the mechanism of the Noyori‒Ikariya asymmetric transfer hydrogenation of ketones spans nearly three decades of investigations. Whereas the early part of the catalytic cycle being the hydride transfer is now well-understood, the late part being the proton transfer is still ambiguous. Specifically, the source of the proton can be the N‒H functionality of the catalyst and/or the O‒H functionality of the reagent/solvent leading to two conceptually different catalytic cycles or even their combination. For three popular reagents/solvents typically used in the method, namely propan-2-ol, 5:2 HCO2H‒NEt3 and water, the source of the proton is presently either unknown, or the evidence is presented partially by only one approach ‒ experimental or computational. This work eliminates this ambiguity by means of various state-of-the-art molecular dynamics simulation methods (ab initio, quantum mechanics/molecular mechanics and path integral to include quantum tunneling effects). Here we show that the source of proton in propan-2-ol is catalyst’s N‒H functionality, whereas in more acidic water, binary 5:2 HCO2H‒NEt3 or neat formic acid the source of proton is reagent/solvent. Thus, depending on the source of reagent/solvent the catalyst’s ligand can be either chemically non-innocent or chemically innocent in the Noyori‒Ikariya reaction, which opens new opportunities for the outer-sphere homogeneous catalysts design.