Understanding and Predicting Post H‑Atom Abstraction Selectivity through Reactive Mode Composition Factor Analysis

The
selective functionalization of C–H bonds is one of the
Grails of synthetic chemistry. In this work, we demonstrate that the
selectivity toward fast hydroxylation or radical diffusion (known
as the OH-rebound and dissociation mechanisms) following H-atom abstraction
(HAA) from a substrate C–H bond by high-valent iron-oxo oxidants
is already encoded in the HAA step when the post-HAA barriers are
much lower than the preceding one. By applying the reactive mode composition
factor (RMCF) analysis, which quantifies the kinetic energy distribution
(KED) at the reactive mode (RM) of transition states, we show that
reactions following the OH-rebound coordinate concentrate the RM kinetic
energy on the motion of the reacting oxygen atom and the nascent substrate
radical, whereas reactions following the dissociation channel localize
most of their kinetic energy in H-atom motion. These motion signatures
serve to predict the post-HAA selectivity, and since KED is affected
by the free energy of reaction and asynchronicity (factor η)
of HAA, we show that bimolecular HAA reactions in solution that are
electron transfer-driven and highly exergonic have the lowest fraction
of KED on the transferred H-atom and the highest chance to follow
rebound hydroxylation. Finally, the RMCF analysis predicts that the
H/D primary kinetic isotope effect can serve as a probe for these
mechanisms, as confirmed in virtually all reported examples in the
literature.