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A Lesson From Nature: What Click Chemistry Is, and Why It Won a Nobel Prize

This year's Nobel prize in Chemistry was awarded for the development of 'Click Chemistry', which works kind of like molecular Legos.

“This year’s [Nobel] Prize in Chemistry deals with not overcomplicating matters” says Johan Åqvist, Chair of the Nobel Committee for Chemistry. It has a simple and catchy name: Click Chemistry.

There is a certain chemical reaction that is often referred to as the click reaction. But that’s a bit of a misnomer. Click chemistry is a framework or methodology for doing chemistry. Specifically, making complex organic molecules, mainly pharmaceutical ones.

A very short aside: the meaning of “organic” in organic chemistry is very different than its meaning in “organic food”. A food being labelled organic means it adheres to a set of guidelines that differ in each country, but generally are hypothetically better for the environment (but the same nutrition wise) and avoid using certain fertilizers and pesticides. Organic chemistry, meanwhile, just means that the molecules involved are made up almost entirely of carbon to carbon and carbon to hydrogen bonds, with some oxygen and nitrogen atoms thrown in for good measure.

With that out of the way, let’s take a look at the click chemistry sensation that has been sweeping the nations!

Just prior to the 21st century, K. Barry Sharpless got to thinking about the way we research new potential drug molecules. The most complex chemical structures weren’t made by chemists, they were made by nature. Far more often than not, researchers were inspired by an effect observed in nature. Chemists would then spend months or years trying to synthesize the same, compound that the plant, animal, or microorganism made nearly effortlessly.

For researchers, effortless it was not. To build a complicated chemical structure could take dozens and dozens of steps, each of which needed to be optimized, and which generated waste and by-products. It was time consuming, money consuming and energy consuming—both in the literal sense, as lab equipment can use a lot of electricity, and for the researchers. Purifying the desired product at each step was a pain, and a properly disposing of toxic waste generated during each step posed an environmental concern. Barry Sharpless wondered if there wasn’t a better way of approaching this challenge.

It was in 2001 when he realized that nature was the key, but not in the way we’d previously thought. Where other chemists tried to imitate nature, using scores of different highly specialized chemical reactions to perfectly mimic natural compounds, Sharpless took a different viewpoint. He observed that nature builds all of the molecules it needs out of around 35 carbon-based building blocks, none of which are really that complex. Nearly infinite compounds can be created from just a few relatively small molecules, just by linking them together with a nitrogen or oxygen atom. It’s how DNA is made, as well as sugars and proteins.

Sharpless argued for a minimalist, streamlined approach to synthesizing complex molecules, wherein only a handful of really good (i.e. high-yielding and widely applicable) reactions would be used. He envisioned using a small range of organic “building blocks” derived from petrochemicals joined together by these really good reactions, to synthesize large chemical structures that could function as drugs or have other purposes.

The Nobel committee likens it to the IKEA flatpack approach. Having built an apartment’s worth of IKEA furniture in the last week, I love this analogy. Basically, builders (chemists) are provided with all of the necessary furniture parts (the building blocks), along with simple to use hardware like Allen keys (the very good reactions), and instructions that are easy enough for anyone to follow to put it all together.

Barry Sharpless defined criteria for being considered one of these excellent reactions—which he named “click reactions”—since they worked so well that they essentially just clicked molecules together like Lego. To be considered part of click chemistry, a reaction needs a few characteristics:

  • Modular (they can be used with many different building blocks)
  • High yielding (they don’t make many, if any, by-products, and make large amounts of the desired product)
  • Simple to purify (if they did make by-products, they should be non-toxic and easy to remove)
  • Simple reactions conditions (No fancy equipment or working under vacuum)
  • Use readily available starting materials (No super weird and expensive compounds)
  • Use either no solvent, or something benign like water that is easily removed
  • Happen quickly (No days or weeks long reactions)

diagram of click chemistry reaction

Image Source:

As I wrote above, there is one reaction that has become synonymous with click chemistry, to the point that it’s often referred to as simply “the click reaction”: the copper catalyzed azide-alkyne cycloaddition, or CuAAC (Cu is the periodic table shortform for copper). Barry Sharpless discovered it, but across the world in Denmark, at almost exactly the same time, so did Morten Meldal. Although Sharpless described its potential as enormous, neither researcher really knew that they were ushering in a new age of organic chemistry.

CuAAC quickly became the epitome of click chemistry. Before long it was it was the go-to for attaching nearly any two organic molecules together. Among many reasons it was so heavily embraced include how well it works, and the triazole linkage that it creates. Triazoles are quite stable, and are part of several important drugs, like fluconazole, a widely used antifungal medication. The CuAAC reaction sped up drug development tremendously and enabled all kinds of research that would have previously been very impractical, if not impossible.

However, there was one problem with the CuAAC reaction: its copper catalyst. Unfortunately, copper is highly toxic to living things. Some attempts were made to develop and include other compounds that could sequester the copper and prevent it from harming cells, but the next breakthrough came in 2004. This is where the third winner of the 2022 Nobel Prize in Chemistry comes in- Carolynn R. Bertozzi.

Wanting to study the complex sugars that sit on the surface of certain cells, Bertozzi was inspired by click chemistry’s simple and efficient nature. But, wanting to apply click chemistry to living cells meant finding a copper-free way of catalyzing the reaction. Looking back to the literature of 1961, she was inspired to use a ring-shaped molecule that was very unhappy being a ring.

Much like if you bend a pool noodle into a circle, molecules can often be bent into rings. But just like the pool noodle, they are clearly strained. The moment they’re given a chance, the molecule will spring open, just like the pool noodle when you let go. Bertozzi was able to harness that energy and create an incredibly powerful tool for studying molecular biology: the strain-promoted alkyne-azide cycloaddition, or SPAAC. With the toxic copper catalyst eliminated, researchers were off to the races! The applications for labelling and creating compounds that can be used in living cells or animals are numerous. I should know—it was absolutely integral to my M.Sc. thesis research!

We haven’t yet seen the full research impact of click chemistry, and we’ve already seen a lot. I have no doubt that Sharpless, Meldal and Bertozzi’s innovations will go down as defining moments in scientific history. Their impact on scientific research can’t be overstated, and therefore their potential to improve the lives of many. As the The Royal Swedish Academy of Sciences wrote, “In addition to being elegant, clever, novel and useful, it also brings the greatest benefit to humankind.”


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