Chemistry Nobel 2022 explained: click chemistry?

Click chemistry and bioorthogonal chemistry won this year’s Nobel Prize in Chemistry… but what is it?

The Nobel Prize was awarded to three researchers – Carolyn Bertozzi, Morten Meldal and Barry Sharpless. Between them and their teams, the researchers developed an elegant series of reactions that are used everywhere in chemical preparation and have helped in particular in the production of pharmaceuticals, DNA mapping and the development of cancer treatments.

So what exactly did they do?

Resume of reactions

Assembling new molecules, sometimes atom by atom, is the driving force behind much chemistry. It is at the heart of all pharmaceutical development, and also vital to materials science, recycling and agricultural chemistry – among others.

Over the past century, chemists have developed tens of thousands of different reactions to produce these substances.

At this stage, it’s possible to make almost any molecule you can imagine – but you might need, say, six years, diamond-bearing anvils and some very powerful lasers.

If you’re trying to make a lot, you need to be able to do it cheaply, accurately, and with as few toxic ingredients as possible.

Here comes American chemist Karl Barry Sharpless. During the 1990s and early 2000s, he and his research team refined a list of chemical reactions around a number of requirements, including:

  • They can be applied to a wide range of reactants
  • They work under simple reaction conditions – no ridiculous temperatures or pressures
  • They should require non-offensive solvents and produce inappropriate by-products
  • They should be efficient, with high yields of what you want to make

They summarized these reactions in a 2001 paper as “Click Chemistry.” These reactions have become simple, effective tools in any chemist’s arsenal.

Sharpless, who had already won the Nobel Prize in Chemistry in 2001 for other work, becomes the fifth person to win two Nobel Prizes and the second to win two Chemistry Prizes.

Copper catalyst kills click chemistry

The click reaction that changed chemistry: Azides and alkynes react very efficiently when copper ions are added. This reaction is now used worldwide to link molecules together in a simple way. Credit: ©Johan Jamesstad/The Royal Swedish Academy of Sciences

Among Sharpless et al.’s clicks, there was one reaction that had particularly high potential: a reaction called 1,3-dipolar cycle addition.

This reaction was fast and efficient, but in the advent of click chemistry, it lacked precision and often needed stringent requirements to make it work.

The next leap was made by Sharpless and the Danish chemist Morten Meldal independently.

Both teams of researchers developed a copper catalyst that, like a pair of hands fastening a seat belt, joins the two reactants together neatly and efficiently. It works in a few hours, in a variety of environments, at room temperature.

The possibilities of the copper catalyst were so exciting that manufacturers quickly began sourcing reagents they knew would be useful for it. It has become an extremely common reaction in chemistry.

To become bio-orthogonal

The copper click catalyst is very good at its job, but it doesn’t work in every environment.

Biological applications have been particularly limited because copper ions are very toxic to cells.

But American chemist Carolyn R. Bertozzi, along with her research team, found an alternative to copper. They realized that a class of large carbon-based molecules, called cycloalkynes, could take the place of copper.

This customized reaction could then work in lab-based human cells.

This discovery led to Bertozzi’s development of “bioorthogonal” chemistry, or reactions that occur on the surface of a cell without disrupting the cell’s behavior. The reactions have even been shown to work in live mice.

Bioorthogonal chemistry has now become a valuable tool for the study of cells of all types. It has also been critical to the development of many different cancer drugs that are currently in clinical trials.

Bertozzi is the eighth woman to win the Nobel Prize in Chemistry and among the first openly LGBT Nobel laureates in science.

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