And then suddenly there was a “click” in the test tube

Dhe nature is the great role model for many chemists and an inexhaustible source of ideas. After all, it has produced a large number of extremely complex molecules and a variety of structures over millions of years. For every task, no matter how complicated, there is a corresponding protein. Meanwhile, chemists have become better and better at rebuilding biomolecules or mimicking their functionalities, often with the aim of creating more potent drugs. The fact that syntheses are now much faster, more efficient, and cheaper is not least thanks to Barry Sharpless, Morten Meldal, and Carolyn Bertozzi, who were awarded this year’s Nobel Prize in Chemistry—“for the development of click and bioorthogonal chemistry,” as they say the Swedish Academy of Sciences said on Wednesday morning.

Barry Sharpless got the ball rolling at the Scripps Research Center in La Jolla in 2001, the same year he received his first Nobel Prize in Chemistry—for the development of symmetric syntheses. Sharpless had long been dissatisfied with the way chemists tried to mimic the way natural biomolecules work when developing new medicines. These methods often resulted in difficult to control and expensive molecular constructions. When a potential drug was identified, often only small quantities could be produced for testing and clinical trials. Industrial production was usually out of the question.

Sharpless pursued a new and minimalist approach to chemistry, which he called “click chemistry” and presented in the journal “Angewandte Chemie”. To be worthy of the name, such a click reaction should proceed in the presence of oxygen, nitrogen, and water as solvents. With his process, he had already succeeded in producing the antibiotic meropenem on a large scale based on smaller building blocks. However, this took him six years to develop.

A major stumbling block in the synthesis of biomolecules are the bonds between carbon atoms, which play a central role in the chemistry of life. These bonds are strong and therefore difficult to break, but even more difficult to make, for example if you want to make new connections. Sharpless experimented with smaller molecules whose carbon atoms he could easily link together with oxygen and nitrogen atoms. As a result, he received meropenem, among other things.

The way to perfect click reaction

Little did Sharpless know that at almost the same time in Denmark, Mordan Meldal had discovered a reaction mechanism that would become synonymous with click chemistry. During his search for active ingredients, the Danish chemist accidentally discovered that, in the presence of copper as a catalyst, a molecule of triply unsaturated alkynes combined with a halogen-containing hydrocarbon. However, not in the way one should expect. The alkyne had reacted with what was thought to be the “wrong” end of the halide, forming a cyclic hydrocarbon compound, a triazole. Undesirable by-products were virtually non-existent. Sharpless showed that Meldal’s approach also works in water.

Meldal’s click reaction is used today to connect organic molecules together in a simple and efficient way, for example to synthesize active pharmaceutical ingredients, to incorporate plasticizers or other components with special properties into plastics, so to speak with a “click”.

Finally, Carolyn Bertozzi from Stanford University in California succeeded in modifying the click reaction so that it proceeds without the copper catalyst. This enabled her, among other things, to equip sugar molecules that are, for example, on the surface of a living cell with dye molecules. The cell can thus be made visible under a microscope using fluorescent light. Bertozzi’s so-called bioorthogonal reaction is used today to study cancer cells and the effects of drugs.