Mechanistic Elucidation of Catalyst Synergy and Stereochemical Origins in Ni/NHC Cooperative Umpolung Propargylic Substitution of Enals

Abstract

A comprehensive density functional theory (DFT) study was conducted to elucidate the detailed reaction mechanism and stereochemical origins of the nickel/N-heterocyclic carbene (NHC) cooperative catalytic umpolung propargylic substitution of enals. Comparative mechanistic analyses performed in the absence of either NHC or nickel clearly demonstrate that the reaction relies on two mechanistically independent yet complementary catalytic cycles, thereby excluding a ligand-only role for the NHC and establishing its function as an independent organocatalyst. The NHC functions as an organocatalyst enabling umpolung activation of enals, while the nickel catalyst selectively activates the propargylic electrophile via heterolytic C–O bond cleavage. Quantitative analysis of the rate-determining hydrogen-transfer step reveals that NHC structure modulates reactivity primarily through electrostatic stabilization of the transition state, as evidenced by ESP analysis, whereas variations in phosphine ligands on nickel affect catalytic efficiency mainly by altering the distortion energy of the Ni–phosphine fragment, as demonstrated by distortion–interaction analysis. Furthermore, analysis of the stereodetermining transition states reveals that the experimentally observed enantio- and diastereoselectivity originates from favorable geometric preorganization and the cooperative accumulation of multiple weak noncovalent interactions, as visualized by IGMH analysis.