clickchemistry

Click chemistry refers to a class of chemical reactions that are rapid, high-yielding, and reliable, enabling the modular assembly of complex molecules from simple building blocks with simple purification. Coined by K. Barry Sharpless and colleagues, the concept emphasizes reactions that are selective, tolerant of diverse functional groups, proceed under mild conditions, and produce few byproducts. The idea is to provide tools that work reliably in a variety of environments, including biological contexts.

The best-known example is the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC), which forms 1,4-disubstituted 1,2,3-triazoles with high efficiency under aqueous, ambient conditions. A copper-free variant, the strain-promoted azide-alkyne cycloaddition (SPAAC), uses ring-strained alkynes to achieve similar coupling without copper, improving compatibility with living systems. Other reactions commonly associated with click chemistry include thiol-ene click reactions, oxime and hydrazone ligations, and certain robust Diels–Alder processes. While not all of these are universally applicable, they share characteristics such as operational simplicity, broad scope, and high yields, making them useful for rapid assembly and labeling tasks.

Applications span bioconjugation, molecular labeling for imaging, polymer and materials science, surface modification, and drug discovery. Click reactions enable the construction of complex probes, therapeutic conjugates, and functional materials with modular, reproducible chemistry. Limitations can include copper-catalyst toxicity in biological settings, the need to carefully control reaction conditions for sensitive substrates, and safety considerations regarding reactive azides or strained intermediates.