Click Chemistry: Diverse Chemical Function from a Few Good Reactions

TLDR

Nature favors carbon–heteroatom bonds over carbon–carbon bonds, as seen in nucleic acids, proteins, and polysaccharides, where small subunits are linked by such bonds and most building blocks contain few C–C bonds. The authors aim to develop powerful, reliable, selective reactions—click chemistry—for rapid synthesis of new compounds and combinatorial libraries via heteroatom links. Click chemistry is defined by stringent criteria and exemplified by simple, powerful synthetic strategies that produce diverse molecular frameworks through heteroatom linkages.

Abstract

Examination of nature's favorite molecules reveals a striking preference for making carbon–heteroatom bonds over carbon–carbon bonds—surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon–heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C−C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C−X−C), an approach we call “click chemistry”. Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect “spring-loaded” reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.