CuAAC

CuAAC, short for copper(I)-catalyzed azide–alkyne cycloaddition, is a chemical reaction that joins an azide and a terminal alkyne to yield a 1,4-disubstituted 1,2,3-triazole under the action of a copper(I) catalyst. Discovered as part of the broader click chemistry concept, CuAAC is celebrated for high yields, robustness, and broad functional-group tolerance, along with predictable regioselectivity.

Mechanistically, copper(I) activates the alkyne by forming a copper acetylide, which reacts with the azide to generate a metallacycle that rearranges to the 1,4-disubstituted triazole after protonation. The reaction is highly regioselective for the 1,4-isomer; in contrast, copper-free versions or less selective conditions can give mixtures or the 1,5-isomer.

Typical conditions use CuSO4 as copper source and a reductant such as sodium ascorbate to generate Cu(I) in situ, in water or water-alcohol mixtures at room temperature or mildly elevated temperatures. Variations employ Cu(I) salts, copper nanoparticles, or ligands (e.g., TBTA, BPhen) to stabilize Cu(I) and improve biocompatibility and rate. The reaction proceeds rapidly and in many cases can be performed in aqueous media, enabling labeling of biomolecules.

CuAAC is widely used for bioconjugation, immobilization, polymer and material synthesis, and surface modification. It enables covalent linkage of biomolecules, fluorescent tags, polymers, and nanoparticles with high efficiency and without interfering functional groups.

While powerful, copper can be cytotoxic, leading to considerations and sometimes preference for strain-promoted azide–alkyne cycloaddition (SPAAC) in living systems, or for optimized ligands to minimize copper toxicity.