Mechanism of CuAAC reaction: In acetic acid and aprotic conditions

Protonation of copper-triazolide is a distinctive and final part in CuAAC reaction which has kinetic importance such that it can even affect the product distribution. In the context of this study, the protonation mechanism of copper-triazolide was investigated with quantum mechanical calculations to have a deeper understanding of the mechanism. In aprotic conditions where the alkyne is considered as proton donor, the key finding of DFT calculations performed in this study is that the activation energy barrier for the protonation step is greater than the cycloaddition step. In the absence of a strong proton donor the final protonation step is coupled with the alkyne deprotonation step in the catalytic cycle, which slows down the reaction. A conceivable pathway for acetic acid promoted CuAAC reaction on the basis of experimental and computational studies was also sought. With acetate as ligand, cycloaddition is a facile reaction and the energetics shows that it speeds up the cycloaddition step. Acetic acid in CuAAC reaction provides proton for the final protonation step in the catalytic cycle, decouples the protonation/deprotonation step by acting as a strong proton donor in the last step and facilitates protonation. The energetics presented herein are in accordance with the experimental proposals on rate-determining step in aprotic conditions and decreased reaction times obtained in the experiments in the presence of acetic acid.