The Source of Proton in the Noyori–Ikariya Catalytic Cycle

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 later 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, either the source of the proton
is presently unknown or the evidence is presented partially by only
one approachexperimental or computational. The present work
eliminates this ambiguity by means of various molecular dynamics simulation
methods such as ab initio, quantum mechanics/molecular mechanics,
and path integral to include quantum tunneling effects. Here, we show
that for the archetypal (S)-RuH[(R,R)-Tsdpen](mesitylene) catalyst complex, the source
of the proton in propan-2-ol is the catalyst’s N–H functionality,
whereas in more acidic water, binary 5:2 HCO2H–NEt3, or neat formic acid, the source of the proton is the reagent/solvent.
Thus, depending on the nature of the reagent/solvent, the catalyst’s
ligand can be either chemically non-innocent or chemically innocent
in the Noyori–Ikariya reaction, which opens opportunities for
outer-sphere homogeneous catalyst design.