Cuaac And Beyond: A Review of Click Reaction Advances in Chemistry and Biology

Click chemistry represents a versatile framework for building molecules through reactions that are straightforward, highly selective, and rapid. Within this family, the copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) is regarded as the central reaction, owing to its extensive use in fields such as medicinal chemistry, polymer science, and molecular bioconjugation. A major drawback of CuAAC in biological contexts is the toxicity associated with copper, yet innovations in ligand development and catalyst engineering have enhanced both its safety and efficiency. To address these biological limitations, alternative pathways have been introduced, including copper-free strain-promoted cycloadditions (SPAAC), ruthenium-catalyzed variants (RuAAC), the Staudinger ligation, sulfur–fluoride exchange chemistry (SuFEx), and radical-based thiol–ene reactions. Collectively, these approaches have opened opportunities for applications ranging from visualization of biological systems to the creation of advanced functional materials. This review positions CuAAC as the reference point while also surveying emerging methods that continue to shape the scope of click chemistry in both chemical synthesis and life sciences.