clickchemie

Click chemistry, sometimes referred to as clickchemie in German-language texts, denotes a family of chemical reactions that are rapid, reliable, high-yielding, and modular, designed to join small units into larger structures with few purification steps. The core idea is to select reactions that are highly selective for specific functional groups, tolerant of air and water, and compatible with physiological conditions, enabling easy assembly of complex molecules and materials.

The prototypical reaction is the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC), which joins azides and terminal alkynes to form 1,4-disubstituted 1,2,3-triazoles with high regioselectivity and water-compatible conditions. Variants that avoid copper, such as strain-promoted azide–alkyne cycloaddition (SPAAC), are used for bioconjugation and in living systems where copper toxicity is a concern.

Beyond CuAAC, several other reactions have been embraced as click reactions, including thiol–ene and thiol–yne couplings, the Diels–Alder reaction, and sulfur(VI) fluoride exchange (SuFEx). These reactions typically exhibit fast kinetics, modular compatibility, and product stability. In practice, click chemistry ingredients are designed to be orthogonal to many other functional groups, enabling sequential assembly in complex molecules.

History and impact: The concept emerged in the late 1990s and was popularized by Sharpless, Meldal, and later applied broadly by Bertozzi. In 2022, Carolyn Bertozzi, Morten Meldal, and K. Barry Sharpless were awarded the Nobel Prize in Chemistry for the development of click chemistry and bioorthogonal chemistry.

Applications span pharmaceuticals, materials science, diagnostics, and imaging, where rapid, efficient, and selective ligations enable labeling, tracking, and construction of molecules and surfaces with minimal byproducts. Limitations include copper toxicity in biological contexts and the need to tailor reactions to specific substrates.