Mechanistic insights into copper-mediated benzylic C(sp³)-H bond trifluoromethylation

The mechanisms underlying copper-mediated trifluoromethylation of benzylic C(sp³)-H bonds were investigated using density functional theory (DFT) calculations. Two distinct pathways were identified: radical recombination/reductive elimination and single-electron transfer (SET). In the radical recombination/reductive elimination pathway, the Cu^II species recombines with benzyl radicals to generate a Cu^III intermediate, which subsequently undergoes reductive elimination. Conversely, the SET pathway involves single-electron transfer from benzyl radicals to Cu^II species, forming a cationic benzylic intermediate and Cu^I species, followed by coupling with a CF₃ group coordinated to Cu. DFT calculations revealed that the radical recombination/reductive elimination pathway is favoured for trifluoromethylation of primary and secondary benzylic C(sp³)-H bonds, with the reductive elimination step being rate-determining. In contrast, the SET pathway exhibits preference for trifluoromethylation of tertiary benzylic C(sp³)-H bonds. These mechanistic insights have significant implications for enhancing the selectivity of copper-mediated trifluoromethylation reactions.