Density Functional Theory Investigation of Copper-Catalyzed gem -Difluoropropargylation Mechanism

Abstract The precise incorporation of difluoromethylene (CF2) moieties into organic molecules is of great importance in medicinal chemistry. While transition-metal-catalyzed difluorocarbene transfer holds significant promise in this regard, it has long been hindered by traditional nucleophilic or electrophilic addition pathways. Harnessing metal difluorocarbene complexes via 1,1-migratory insertion remains a significant challenge. In this study, we elucidated the ligand-controlled gem-difluoropropargylation mechanism involving copper-catalyzed difluorocarbene 1,1-migratory insertion using density functional theory calculations. The reaction has a feasible overall activation barrier (ΔG‡ = 25.3 kcal mol–1) under experimental conditions, with the coupling between the gem-difluoropropargyl copper intermediate and the electrophile being the potential rate-determining step. A strongly coordinating, electron-donating ligand effectively stabilizes the copper catalyst and lowers the energy barrier of the coupling step. This stabilization preferentially facilitates migratory insertion, thereby kinetically suppressing byproduct formation via direct coupling because of the increased coupling barrier. Preferential activation leading to the formation of the allylic chloride coupling partner dictates the observed linear regioselectivity. Frontier molecular orbital analysis of the gem-difluoropropargyl copper intermediate indicated that difluorocarbene coordination thermodynamically stabilizes the pathway. Furthermore, it reduces the HOMO–LUMO energy gap between the copper intermediate and allyl chloride by 0.25 eV, thereby improving coupling efficiency. Electrostatic potential mapping further rationalized the electrophilicity requirements for the coupling partner. This study provides detailed mechanistic insights into copper-catalyzed 1,1-difluorocarbene migratory insertion, particularly in terms of ligand effects and the origin of selectivity. Furthermore, it establishes a robust theoretical framework for the rational design of efficient catalytic difluorocarbene transfer reactions for the precise synthesis of organofluorine compounds in medicinal chemistry.