The Copper-Catalyzed Azide–Alkyne Cycloaddition Reaction: Why Two Is Faster than One

The copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction is a foundational transformation in synthetic chemistry, owing to its high efficiency and selectivity. In this work, state-of-the-art quantum chemical methods are applied to elucidate the preference for the dinuclear CuAAC mechanism, involving two copper centers, over the mononuclear analog, involving one copper center. Activation strain and Kohn–Sham molecular orbital analyses reveal that the enhanced reactivity of the dinuclear CuAAC mechanism arises not from alleviation of strain in the copper acetylide upon formation of the six-membered metallacycle, as previously proposed, but rather from reduced steric Pauli repulsion between the copper acetylide and the azide. These results provide mechanistic insight into the origin of dinuclear catalysis in the CuAAC reaction.