Click Reactions Meet Flow Chemistry: An Overview of the Applications of Click Chemistry under Continuous Flow Conditions

Click reactions are versatile tools in the hands of synthetic chemists and materials scientists around the world. Coupling click chemistry with the advantages and convenience of continuous flow reaction techniques opens even further possibilities that allow researchers to overcome particular challenges such as catalyst handling, toxicity of the reactants, and the dangers of pyrophoric or explosive materials. These advantages open up horizons for greener and more sustainable solutions that improve yields and contamination profiles and facilitate the application of green chemistry techniques. A prime example is the copper-catalyzed Huisgen cycloaddition between alkynes and azides, which has the highest number of literature precedents where flow chemical reactors are involved. Other click reaction types such as the thiol-ene click reaction, the sulfur-fluoride exchange ("SuFEx") and the keto-imine click reaction are much less represented in the publications, whereas there are a number of click reaction types that have never been performed under continuous flow conditions. In this Account, the authors intend to provide a comprehensive overview of click reactions performed under continuous flow conditions.