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Mechanistic Basis of the Cu(OAc)2Catalyzed Azide-Ynamine (3 + 2) Cycloaddition Reaction
- Source :
- Journal of the American Chemical Society; May 2024, Vol. 146 Issue: 19 p13558-13570, 13p
- Publication Year :
- 2024
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 00027863 and 15205126
- Volume :
- 146
- Issue :
- 19
- Database :
- Supplemental Index
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Periodical
- Accession number :
- ejs66269497
- Full Text :
- https://doi.org/10.1021/jacs.4c03348