Click Chemistry: An Ever-growing Toolbox of Efficient Reactions for Versatile and Orthogonal Couplings in Mild Conditions

Organic chemistry and closely related disciplines including polymer and material sciences or, more recently, bio-related domains require straightforward and reliable synthetic methodologies to bind together building blocks including macro- and biomolecules, and thus create more complex chemical entities with potential applications in various domains. Conventional coupling reactions such as those implemented to produce amides or esters generally present inherent drawbacks, especially regarding lack of selectivity, necessitating afall back on time-consuming and expensive protection/deprotection steps prior to and after the coupling itself. As a result, conventional coupling strategies necessitate auxiliary purification steps to isolate the product. In this regard, organic chemists have investigated since the early 2000s the possibility of setting up selective coupling reactions that would additionally present specific undeniable advantages to render them appealing to the broader audience of the scientific community. K. Barry Sharpless, recipient of the 2022 Chemistry Nobel Prize for his contributions to the development of click chemistry, took a step forward in this domain by describing first the concept of click chemistry through his pioneering investigations on the copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) [ 1 ]. This chemical ligation, reported in 1963 by the German chemist Rolf Huisgen [ 2 ], was put up to date and signed the beginning of the click chemistry concept. Since then, the click concept has become a chemical philosophy as numerous organic reactions have joined its powerful synthetic toolbox. To be considered as click, this pool of chemical reactions possesses several remarkable features. Click reactions must be thermodynamically favored, carried out in mild conditions, experimentally simple to perform, wide in scope and should provide the expected product(s) in quantitative yields. Additionally, they ought not to generate byproducts that would be tedious to separate from the targeted compound. This introducing chapter will provide a rather exhaustive description of the wide landscape of different click reactions including the earliest paradigm of copper-catalyzed azide-alkyne cycloaddition, thiol-X addition reactions, the SuFEx reaction or the (hetero-) Diels-Alder cycloaddition. While describing the mechanisms involved in such click reactions, their advantages but also their drawbacks, if existing, will be highlighted.