Theoretical Exploration of the NHC-Catalyzed Hydrofluorination of an Enal: Mechanism and Origin of Selectivities

The elucidation of the mechanisms and origins of stereoselectivity, regioselectivity, and chemoselectivity is useful for constructing highly valuable methine chiral centers via asymmetric protonation under redox-neutral conditions. In the present study, density functional theory (DFT) was employed to extensively investigate the reaction mechanism of the <i>N</i>-heterocyclic carbene (NHC)-catalyzed hydrofluorination of enals through an asymmetric β-protonation/α-fluorination cascade. Four possible pathways were examined. The computational results indicate that the most energetically favorable pathway involves six steps: (1) nucleophilic addition of the NHC to the enal, (2) formation of a Breslow intermediate, (3) β-protonation to form an enolate intermediate, (4) α-fluorination, (5) esterification, and (6) regeneration of the NHC catalyst. The stereoselectivity-determining step is identified as α-fluorination with the <i>S</i>-configured isomer being preferentially generated. The origins of stereoselectivity and chemoselectivity are analyzed and reported, providing valuable insights for designing NHC-catalyzed reactions with high selectivity.