Click! 2022 Nobel goes to chemistry made simple and reliable

This year's Nobel Prize in Chemistry is a little unusual in that it recognizes three things: a conceptual approach to building complicated molecules, a chemical reaction that exemplifies that concept, and an application of the concept to biological systems. As a result, it's a three-person award, with K. Barry Sharpless winning for the concept (his second Nobel in chemistry), Morten Meldal for the reaction, and Carolyn Bertozzi for the implementation.

The concept is called "click chemistry," and it was a bit of a rebellion against the way chemistry often progresses. Much of the chemistry literature is filled with papers that describe specialized reactions that handle very specific circumstances—adding a methyl group to a complex chemical that already has internal nitrogens and an alcohol group, for example. The focus of click chemistry is on finding a small number of reactions that work consistently and with high efficiency, allowing complex molecules to be built by "clicking" new modules into place.

A few good reactions

The concept is perhaps best illustrated by the organic chemistry textbook I used as an undergrad (Streitwieser and Heathcock, 3rd edition, for the curious). Most chapters focused on specific types of reactions, like linking two hydrocarbons by a nitrogen. Pages were filled with examples, each requiring a distinct combination of catalysts, solvents, and temperatures—and only working in specific circumstances, such as when one of the two hydrocarbons has an oxygen present as an alcohol. An entirely different set of conditions would be needed if the oxygen was present as a ketone. Change the oxygen to a sulfur, and the conditions change yet again.

That sort of compounding complexity is exactly what gives organic chemistry classes their fearsome reputation for convincing erstwhile pre-meds to go major in something else.

But somewhere late in each chapter, my textbook would also note that industrial chemical production often relied on a set of conditions that pretty much always worked no matter what was present in any of the starting materials. Memorize this reaction and you could happily forget the catalog of possible reaction conditions that had preceded it. (To this day, I remember that one reaction worked by heating material in the presence of aluminum oxide, though I've long since forgotten what raw materials or products were involved.)

This kind of radical simplification is what click chemistry is all about. Sure, you can build the exact molecule you want using 14 highly specific reactions, some with low efficiency, others with toxic solvents, and so on. Or, with click chemistry, you can build something similar to what you want through three reactions that pretty much always work. Sharpless helped define the idea and then elaborated on it, describing a set of properties that click chemistry reactions should conform to. Paraphrased from the Nobel materials, these are:

• The reaction should work with a wide range of starting materials.
• The reaction should give high yields and work in conditions that are easy to create, such as room temperature.
• Reactions either don't need solvents or the solvent is something simple, like water.
• Any byproducts of the reaction can be purified away easily.
• The reaction shouldn't produce a mix of molecules that differ only in their geometry.
• The reaction should be energetically favorable, so it wraps up quickly.