Chemistry can be a messy, sluggish business, frequently involving cocktails of chemicals in round-bottomed flasks that must later be painstakingly separated. But in 2001, K. Barry Sharpless and his colleagues outlined an idea they called click chemistry that broke the mould. The snappy name, which was Sharpless’s wife Janet Dueser’s idea, summed it up well: a new set of reactions that worked quickly, cleanly and consistently.
If it seems like a simple idea, it is – and therein lies its brilliance. Sharpless and his colleagues Hartmuth C. Kolb and M. G. Finn described their new reactions as “spring-loaded”. The idea was that you could apply them to a plethora of different starting chemicals, snapping them together almost like Lego bricks, and so quickly build a huge range of new and useful molecules – it was medicines that Sharpless mostly had in mind.
The unifying thought behind these reactions was that they shied away from forming carbon-carbon bonds, as was the orthodoxy among chemists at the time, and instead formed bonds between carbon and what chemists call “heteroatoms”, principally oxygen and nitrogen. The best-known click reaction snaps together two reactants to form a triazole, a ring of carbon and nitrogen atoms. This chemical motif tends to be good at sticking to large biological molecules like proteins, making it useful in creating drug molecules. Sharpless unveiled this particular reaction independently, but at the same time as chemist Morten Meldal at the University of Copenhagen, and it has since been used to make, among other things, the anticonvulsant drug rufinamide.
This reaction, says chemist Tom Brown at the University of Oxford, was easy, highly specific and worked in almost any solvent. “I think you can say this was just a great idea,” he says.
A few years later, chemist Carolyn Bertozzi at Stanford University in California developed a click-style reaction that works without any toxic catalysts, meaning it could be used inside cells without disrupting them.
For chemist Alison Hulme at the University of Edinburgh, UK, it was this work that elevated click chemistry from a good idea to a truly great one. It enabled biologists to peg together proteins and other bits of biological machinery at will, and to label them with fluorescent tags to investigate what happened. “It’s just so simple and straightforward,” says Hulme. “It brought small molecule chemistry to biologists in a way that doesn’t require a chemistry degree.”
Bertozzi, Meldal and Sharpless shared the 2022 Nobel prize in chemistry for their work – to the surprise of no one.
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