On the Effect of Iodide and Acids in the Metolachlor Process

Iridium-catalyzed asymmetric imine hydrogenation is the
key step
in the industrial syntheses of dextromethorphan and metolachlor. Nevertheless,
the mechanism of this reaction relying on ferrocenyldiphosphine ligands
remains unclear. Through computational studies, we propose a mechanism
that is in line with all experimental observations including the enantioselectivity.
The calculated mechanism reveals the interplay of potentially three
rate-determining transition states, namely, the migratory insertion,
amido-ligand protonation, and heterolytic H2-activation.
Most salient, the mechanism rationalizes the “magic iodide
effect” in combination with proton co-catalysis, which improve
the reaction rate as well as enantioselectivity. Acid additives accelerate
both the protonation- and H2-splitting steps. Iodide further
facilitates the protonation and potentially the H2-activation.
Thus, these additives prevent that other elementary steps within the
catalytic cycle compromise the enantioselectivity control exerted
by the migratory insertion step.