How Does an Earth-Abundant Copper-Based Catalyst Achieve Anti-Markovnikov Hydrobromination of Alkynes? A DFT Mechanistic Study

The first catalytic hydrohalogenation of alkynes was recently achieved using a copper(I) N-heterocyclic carbene (NHC) complex, and the reaction was found to be syn and anti-Markovnikov selective. The present work is a density functional theory (DFT) computational study (B3LYP and M06) on the detailed mechanism of this remarkable catalytic reaction. The reaction begins with a phenoxide additive turning over the precatalyst (NHC)CuCl into (NHC)Cu(OAr), which subsequently transmetalates with the hydride source Ph₂SiH₂ to deliver the copper(I) hydride complex (NHC)CuH. (NHC)CuH undertakes hydrocupration of the substrate RC≡CH via alkyne coordination and subsequent migratory insertion into the Cu-H bond, forming (E)-(NHC)Cu(CH=CHR). The migratory insertion step determines the syn selectivity because it occurs by a concerted pathway, and it also determines the anti-Markovnikov regioselectivity that arises from the charge distributions across the Cu-H and C≡C bonds. The brominating agent (BrCl₂C)₂ uses the bromonium end to attack the Cu-bound vinylic carbon atom of (E)-(NHC)Cu(CH=CHR), leading to the final (E)-alkenyl bromide product (E)-RHC=CHBr, as well as the copper(I) alkyl complex (NHC)Cu(CCl₂CBrCl₂), which undergoes β-bromide elimination to give the catalyst precursor (NHC)CuBr for the next cycle. (NHC)CuBr reacts with the phenoxide to regenerate the active catalyst (NHC)Cu(OAr). The computational results rationalize the experimental observations, reveal new insights into the mechanism of the Cu(I)-catalyzed hydrobromination of alkynes, and have implications for other catalytic functionalization reactions of alkynes involving active [Cu]-H intermediates.