Mechanistic basis of the Cu(OAc)2 catalyzed azide-ynamine (3 + 2) cycloaddition reaction

Roderick P. Bunschoten, Frederik Peschke, Andrea Taladriz-Sender, Emma Alexander, Matthew J. Andrews, Alan R. Kennedy, Neal J. Fazakerley, Guy C. Lloyd Jones, Allan J. B. Watson*, Glenn A. Burley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser–Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C–H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.
Original languageEnglish
Pages (from-to)13558–13570
JournalJournal of the American Chemical Society
Issue number19
Early online date7 May 2024
Publication statusE-pub ahead of print - 7 May 2024


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