Abstract: The copper-catalyzed azide-alkyne cycloaddition (CuAAC) is the flagship transformation of click chemistry and one of the most versatile reactions in modern synthesis. Remarkably, CuAAC can be initiated from an exceptionally broad range of catalyst precursors—spanning Cu(0), Cu(I), and Cu(II) salts and complexes, clusters, nanoparticles, heterogeneous materials, and electrochemically or biologically generated species—yet consistently delivers high efficiency and selectivity. In this article, we analyze this universality from the perspective of catalyst precursors and propose that the robustness of the reaction may arise from a cocktail-type ensemble of dynamically interconverting copper species formed in situ. By bringing together mechanistic observations from homogeneous, heterogeneous, and biological systems, we outline a unifying view of CuAAC as a dynamic catalytic network, analogous to well-established Pd- and Ni-based cocktail systems. Although current data do not yet allow a definitive description of the active species manifold, recognizing the dynamic nature of CuAAC provides a coherent mechanistic rationale for its broad applicability and points toward new directions in catalyst optimization. This framework highlights the importance of further mechanistic speciation in click chemistry and offers insight for the discovery of next-generation copper catalysts.

Cite: Karlinskii B.Y. , Ananikov V.P.
Origins of universality of copper-catalyzed azide-alkyne cycloaddition
Chem. 2026. V.12. N9. 103209 . DOI: 10.1016/j.chempr.2026.103209 WOS Scopus OpenAlex

Dates:

Published online:

Sep 10, 2026

Identifiers:

≡ Web of science:	WOS:001875610800001
≡ Scopus:	2-s2.0-105049190578
≡ OpenAlex:	W7207830685

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