Theoretical Insight into the Mechanism and Selectivity in Manganese-Catalyzed Oxidative C(sp³)–H Methylation

Density functional theory calculations were performed to understand the mechanism and selectivity for the manganese-catalyzed oxidative C­(sp³)–H methylation reaction (Nature 2020, 580, 621−627). The calculated results show the detailed mechanisms of several key processes, including preactivation of the catalyst (S,S)-Mn^II(CF₃PDP), formation of the active oxidant species, hydroxylation of the N-heterocycle substrate, and methylation of the hydroxylated intermediate. The present study identifies Mn^III–OH and Mn^III–OOH as two key intermediates at the catalyst preactivation stage and a Mn^III-peracetate complex and its valence tautomer Mn^IVO­(AcO) as the active oxidants, whose formation involves a fascinating two-state reaction mechanism. The substrate hydroxylation consists of two elementary steps: H-atom abstraction with triplet-to-quintet state intersystem crossing and barrierless OH radical rebound on the quintet surface. Methylation of the hydroxylated product is predicted to be a thermodynamically controlled process, which proceeds predominately through a stepwise mechanism: hydroxyl anion abstract followed by methyl migration. The exclusive α-site selectivity is attributed to the electronic effects (C–H position relative to the lone pair on the N atom).