Mechanism and Site Selectivity in Visible-Light Photocatalyzed C–H Functionalization: Insights from DFT Calculations

Visible-light
photocatalyzed (VLPC) late-stage C–H functionalization
is a powerful addition to the chemical synthesis toolkit. VLPC has
a demonstrated potential for discovery of elusive and valuable transformations,
particularly in functionalization of bioactive heterocycles. In order
to fully harvest the potential of VLPC in the context of complex molecule
synthesis, a thorough understanding of the elementary processes involved
is crucial. This would enable more rational design of suitable reagents
and catalysts, as well as prediction of activated C–H sites
for functionalization. Such knowledge is essential when VLPC is to
be employed in retrosynthetic analysis of complex molecules. Herein,
we present a density functional theory (DFT) study of mechanistic
details in the C–H functionalization of bioactive heterocycles
exemplified by the methylation of the antifungal agent voriconazole.
Moreover, we show that readily computed atomic charges can predict
major site-selectivity in good agreement with experimental studies
and thus be informative tools for the identification of active C–H
functionalization sites in synthetic planning.