Combined Metal–Metal and Metal–Ligand Cooperativity in Dicopper-Catalyzed Azide–Alkyne Cycloaddition Reactions

The mechanism of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been under investigation for over two decades. While catalytically relevant dicopper intermediates have been proposed and a few suspected intermediates have been isolated, the mechanism remains poorly understood. In this work, we describe the synthesis and characterization of neutral dicopper complexes bearing the proton-responsive dinucleating ^{<i><b>iPr</b></i>} <b>PNNP</b> "expanded pincer" ligand, which are demonstrated to be relevant intermediates in the CuAAC reaction. The acetylide complex [Cu₂( ^{<i><b>iPr</b></i>} <b>PNNP*</b>)-(μ-CC-<i>p</i>-F-C₆H₄)] (<b>2</b>) reacts with 1-azido-4-fluorobenzene at ambient temperature to form the dicopper complex [Cu₂( ^{<i><b>iPr</b></i>} <b>PNNP*</b>)-(μ-(1,4-bis-(<i>p</i>-fluorophenyl)-1,2,3-triazolide)] (<b>3</b>), featuring a symmetrically bridging 1,4-substituted 1,2,3-triazolide ligand. Mechanistic studies were performed using both isotopic labeling experiments and density functional theory (DFT) calculations for the subsequent protodemetalation step. These studies show that the release of the triazole product proceeds via a stepwise metal-ligand cooperative (MLC) pathway, which is favored over the direct alkyne-to-triazolide proton transfer as it requires less structural reorganization of the dicopper platform. This demonstrates how cooperativity between the copper centers and metal-ligand cooperativity can offer an alternative mechanistic pathway, bypassing the conventional rate-limiting alkyne-to-triazolide proton transfer in the CuAAC reaction.