Celebrating click chemistry’s 25th birthday

The 2001 review by Barry Sharpless and his team introducing the concept of ‘clicking’ two molecules together has over 20,000 citations, cementing it as one of the most influential chemistry papers ever written. But why was this concept so revolutionary and how has it changed over the past 25 years?

Click reactions allow chemists to combine molecules efficiently and selectively, with copper-assisted azide–alkyne cycloadditions being the most common. Such reactions have opened up ways to tag biomolecules with radiolabels, form cross-linked polymers and create ‘click-to-release’ drug systems that target specific cells with fewer side effects. Carolyn Bertozzi’s later work on bioorthogonal click reactions – which can be used on cells without affecting the rest of the organism – has also helped scientists probe biological systems.

M G Finn, now at the Georgia Institute of Technology in the US, was among the team that coined the term click chemistry. It ‘was meant to call back that feeling that one gets when you snap together the two halves of a luggage strap – that satisfying click’, Finn recalls. He now shares his thoughts on how the field has changed over the past 25 years and what he thinks the next half a decade may bring.

For starters, Finn thinks that the field ‘is nowhere near mature – if not in its infancy, then perhaps enjoying a highly active childhood’. He hopes that these reactions will continue to democratise chemical synthesis by enabling non-chemists to make bonds simply and consistently. Meanwhile, organic chemists will keep searching for new ways of clicking molecules together. Such click reactions may also become increasingly important in understanding biological evolution – an area that Finn is actively researching.

‘Perhaps the lasting value of click chemistry’s original description lies in its linguistic relativity, comprising a shift of the limits of molecular expectation: making the bonds you want to make, and avoiding making those you do not, is within our capabilities in many different settings,’ says Finn. ’That’s worth thinking about.’