azidealkyn

Azidealkyn, short for azide–alkyne cycloaddition, refers to a family of cycloadditions between azide and alkyne functional groups that form 1,2,3-triazoles. The thermal Huisgen reaction proceeds without metal catalysts at elevated temperature and typically yields a mixture of 1,4- and 1,5-disubstituted triazoles. In the presence of copper(I) catalysts, the reaction becomes copper-catalyzed azide–alkyne cycloaddition (CuAAC), a rapid, highly regiospecific process that predominantly gives 1,4-disubstituted triazoles under mild conditions. Ruthenium catalysts can direct the formation of the 1,5-disubstituted isomer, and copper-free variants exist for sensitive systems, expanding the repertoire of azide–alkyne cycloadditions.

Mechanistically, CuAAC proceeds via formation of a copper-acetylide, coordination of the azide, and a [3+2] cycloaddition that affords a metallacycle, which collapses to the 1,4-triazole after protonolysis and demetallation. The ruthenium-catalyzed pathway and copper-free approaches provide complementary regioselectivity.

The azide–alkyne cycloaddition is a cornerstone of click chemistry. It is widely used for bioconjugation, labeling biomolecules, materials modification, polymer synthesis, and construction of functional nanomaterials. Its robustness, compatibility with aqueous media, and high yields make it a versatile tool in chemical biology and materials science. Limitations include copper-catalyst toxicity in biological contexts, prompting copper-free or ruthenium-mediated variants and alternative strategies in vivo.

Historically, the non-catalytic Huisgen cycloaddition was described in the 1960s, and the copper-catalyzed variant popularized in the early 2000s by Meldal and Sharpless. The broader field of click chemistry was recognized with the 2022 Nobel Prize in Chemistry, awarded to Bertozzi, Meldal, and Sharpless for advances in bioorthogonal and click reactions.