The evolution of click chemistry: from classical reactions to next-generation platforms

Abstract

Click chemistry has transformed modern synthetic chemistry by providing efficient, selective, and modular strategies for constructing complex molecular structures. Since its introduction, the field has expanded from classical synthetic reactions to bioorthogonal and next-generation click platforms, broadening its applications across organic synthesis, polymer science, materials engineering, chemical biology, medicinal chemistry, and biomedicine. This review summarizes the evolution of click chemistry across three major generations. The first generation includes classical reactions such as copper-catalyzed azide–alkyne cycloaddition (CuAAC), thiol–ene, thiol–yne, thiol–ene Michael addition (TEMA), Diels–Alder (DA) cycloadditions, and nucleophilic ring-opening reactions. The second generation focuses on bioorthogonal transformations, including Strain-Promoted Alkyne–Azide Cycloaddition (SPAAC), Strain-Promoted Alkyne–Nitrone Cycloaddition (SPANC), and inverse electron-demand Diels–Alder (IEDDA) reactions, which enable selective chemical modification in living systems. The third generation encompasses emerging platforms such as sulfur(vi) fluoride exchange (SuFEx) and phosphorus(v) fluoride exchange (PFEx), which provide enhanced structural tunability, external control, and broader application potential. For each reaction class, the review discusses fundamental mechanisms, key advantages, limitations, and representative applications, highlighting how click chemistry has evolved from efficient bond formation toward increasingly precise chemical control in biological and materials environments.