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)-MnII(CF3PDP), formation of the active oxidant
species, hydroxylation of the N-heterocycle substrate,
and methylation of the hydroxylated intermediate. The present study
identifies MnIII–OH and MnIII–OOH
as two key intermediates at the catalyst preactivation stage and a
MnIII-peracetate complex and its valence tautomer MnIVO(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).