Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide–Alkyne Cycloadditions
By M. Tiscareno, C. Mitchell, C. Murray, Daiana Di Nino, M. Hedman, Jürgen Schmidt, Joseph A. Burns, J. Cuzzi, C. Porco, K. Beurle and 1 more. Science, 2013
696 citations recorded by the source corpus.
How Copper Clicks The copper-catalyzed coupling of azides and alkynes has been termed a “click” reaction on account of its efficiency and versatility, but despite its widespread use, the mechanism remains somewhat unclear. Through a series of kinetic and isotopic labeling studies, Worrell et al. (p. 457, published online 4 April) show that, in the case of terminal alkynes (capped at one end by an H atom), two equivalents of copper participate in activating each molecule's reactivity toward azide. Surprisingly, the reaction also appears to proceed through an intermediate in which the two copper centers become equivalent and functionally exchangeable, despite initially coordinating to distinct sites on the alkyne. The mechanism of a common and highly versatile molecular coupling reaction is elucidated. Copper(I)-catalyzed azide-alkyne cycloaddition has become a commonly employed method for the synthesis of complex molecular architectures under challenging conditions. Despite the widespread use of copper-catalyzed cycloaddition reactions, the mechanism of these processes has remained difficult to establish due to the involvement of multiple equilibria between several reactive intermediates. Real-time monitoring of a representative cycloaddition process via heat-flow reaction calorimetry revealed that monomeric copper acetylide complexes are not reactive toward organic azides unless an exogenous copper catalyst is added. Furthermore, crossover experiments with an isotopically enriched exogenous copper source illustrated the stepwise nature of the carbon–nitrogen bond-forming events and the equivalence of the two copper atoms within the cycloaddition steps.
Subfields: Organic Chemistry
View Paper: https://www.semanticscholar.org/paper/3e7222460e3fd2e82ca8f765df6ba1a9c21b1778
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In Organic Chemistry
Citations in the corpus
- Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation (2014, background): “Copper-catalyzed azide-alkyne cycloaddition (CuAAC, Figure 4) (Rostovtsev et al., 2002; Tornøe et al., 2002; Worrell et al., 2013) has emerged as a highly versatile ligation process for bioconjugation applications of all types, except in living cells and tissues where free copper ions are toxic.”