Mechanistic aspects of the CuAAC Reaction

Before considering possible mechanistic possibilities for the CuAAC reaction, let us highlight the fundamental reactivity of the reactants organic azides and copper(I) acetylides. With the exception of the thermal and photochemical decomposition, the reactivity of organic azides is dominated by reactions with nucleophiles at the 

While the history of copper(I) acetylides dates back as far as Glaser s discovery in 1869 of the oxidative dimerization of Cu-phenylacetylide, the precise nature of the 

As already mentioned, the nature of the copper counter ion also has a dramatic effect on the rate and efficiency of the reaction. For example, the cuprous iodide-catalyzed reaction takes nearly 40 min to reach the maximum rate and over 100 min to reach full conversion (0.1 M in [azide] = [alkyne] = 0.1 M, [CuI/TTTA] = 0.005 M), whereas the replacement of the iodide with much weaker coordinating tetrafluor-oborate (by treating the reaction solution with 0.005 M of silver tetrafluoroborate salt) propels the reaction to completion within minutes (with v ax t least 10 times higher than for the Cul system). 

the key observations and hypotheses are as follows. First, the formation of higher order polynuclear copper acetylides is detrimental to the rate and the outcome of the reaction. Therefore, solvents that promote ligand exchange (e.g., water and alcohols) are preferred over apolar, organic solvents which promote aggregation of copper species. Ill-defined catalysts perform better in the CuAAC precisely for this reason. 

Second, dinuclear complexes may exhibit enhanced reactivity. However, conclusions about the molecularity of the elementary steps based on the observed rate law are tenuous at best, and are likely wrong. Indeed, to date, we have not seen a CuAAC reaction that exhibits uniform second order in the catalyst as it progresses. It is possible that nuclearity of the catalytic species is maintained throughout the catalytic cycle and, as a consequence, all elementary steps are effectively bimolecular, exhibiting the commonly observed first order in the catalyst, even though the reaction is catalyzed by a dinuclear catalyst. 

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