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 iPrPNNP “expanded pincer” ligand, which are demonstrated to
be relevant intermediates in the CuAAC reaction. The acetylide complex
[Cu2(iPrPNNP*)(μ-CC-p-F-C6H4)] (2) reacts with 1-azido-4-fluorobenzene
at ambient temperature to form the dicopper complex [Cu2(iPrPNNP*)(μ-(1,4-bis(p-fluorophenyl)-1,2,3-triazolide)] (3), 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.