# 2022 Nobel Prize in Chemistry: Click chemistry: snapping molecules together like a buckle > The 2022 Chemistry prize honours click chemistry: a way to build molecules by snapping two pieces together with a single fast, reliable reaction, the way a seatbelt buckle clicks shut. Morten Meldal and Barry Sharpless found the workhorse version, joining an azide and an alkyne with the help of copper. Carolyn Bertozzi then made the click run safely inside living cells, so scientists can tag a molecule in a living body without disturbing its chemistry. - Laureates: Carolyn Bertozzi (share 1/3, Stanford University, Stanford, CA, USA); Morten Meldal (share 1/3, University of Copenhagen, Copenhagen, Denmark); K. Barry Sharpless (share 1/3, Scripps Research, La Jolla, CA, USA) - Official citation: “for the development of click chemistry and bioorthogonal chemistry” - Course page: https://nobelexplained.com/chemistry/2022-click-chemistry - Last updated: 2026-06-21 ## Explained simply (ELI5) Think of a seatbelt buckle. You bring the two ends together, push, and they snap shut with a click. They only fit each other, they hold tight, and you never have to wonder whether it worked. Click chemistry does the same thing with molecules. Chemists put a small matching clip on each piece they want to join. When the two clips meet, they snap together fast and clean, almost always in the right place, and leave very little mess behind. > **Snap, not glue** Most ways of building molecules are slow and fiddly, like gluing parts and hoping they hold. A click reaction is more like a buckle. It is fast, it is reliable, and it joins only the two pieces you meant to join. Carolyn Bertozzi pushed the trick further. She built a version of the click that works inside a living cell without disturbing anything else in there. Now scientists can attach a tiny glowing tag to a sugar or a protein and watch where it travels while the cell keeps living as normal. ## Explained for undergraduates In 2001 **Barry Sharpless** and his colleagues proposed a new way to think about building molecules. Instead of long, custom syntheses, they argued chemists should rely on a small set of reactions that are fast, give high yields, work in mild conditions, and produce almost no unwanted byproducts. He called this approach **click chemistry**, because joining two pieces should be as simple and dependable as clicking a buckle. The standout example is the reaction between an **azide** and an **alkyne**, two small chemical handles. On their own they react slowly and need heat. In 2002, **Morten Meldal** and **Sharpless** independently found that a copper catalyst transforms this reaction. With copper, the azide and alkyne snap together quickly at room temperature in water, forming a stable ring called a **triazole** and giving a single clean product. > **Copper turns a sluggish reaction into a click** The copper-catalysed azide-alkyne cycloaddition, or CuAAC, became the most-used click reaction. It is selective, high-yielding, and tolerant of the many other groups present in a complex molecule. Today it is used to make pharmaceuticals, map DNA, and build tailored materials. There was one place CuAAC could not go: inside living cells, because copper ions are toxic to them. **Carolyn Bertozzi** solved this. She found older work showing that an alkyne bent into a strained ring, a **cyclooctyne**, reacts with an azide on its own, no copper required. In 2004 she published this copper-free click and used it to track **glycans**, the sugar chains on the surface of cells. - **1960s**: Rolf Huisgen maps out how azides and alkynes add together, a slow reaction that needs heat. - **2001**: Sharpless, Kolb and Finn define click chemistry as a small set of fast, reliable, high-yield reactions. - **2002**: Meldal and Sharpless independently add a copper catalyst, giving the fast, selective CuAAC. - **2003**: Bertozzi coins the term bioorthogonal chemistry for reactions that run inside living systems. - **2004**: Bertozzi publishes the copper-free, strain-promoted click and tracks glycans in living cells. ## Explained for experts Click chemistry is a design philosophy as much as a set of reactions. Sharpless, Kolb and Finn set out the criteria in 2001: a reaction should be wide in scope, give very high yields, generate only harmless byproducts, be stereospecific, and run under simple conditions, ideally in water and with easy product isolation. Reactions that meet this bar behave like modular couplings, letting chemists assemble large libraries of molecules from a few reliable building blocks. > **Copper rewrites the Huisgen cycloaddition** The parent reaction is the Huisgen 1,3-dipolar cycloaddition of an azide and a terminal alkyne, which is slow and yields a mixture of 1,4- and 1,5-triazole regioisomers. Copper(I) changes the path: it forms a copper acetylide, accelerates the cycloaddition by many orders of magnitude, and delivers the 1,4-triazole as the sole product at room temperature and neutral pH. Meldal and Sharpless reported this independently in 2002. Copper(I), though, generates reactive oxygen species and is cytotoxic, so CuAAC cannot run inside living cells. Bertozzi had already framed the goal she called **bioorthogonal chemistry** in 2003: a reaction whose partners are absent from biology and inert toward every functional group a cell contains, so it proceeds without perturbing native processes. Azides and alkynes fit, since neither appears in normal biochemistry. > **The copper-free, strain-promoted click** Bertozzi revived a 1961 observation that an alkyne locked inside a strained eight-membered ring, a cyclooctyne, reacts with an azide without any catalyst. The distortion of the strained triple bond lowers the activation barrier, so the strain-promoted azide-alkyne cycloaddition, SPAAC, fires on its own. Published in 2004, it was an early bioorthogonal click and ran far faster than the Staudinger ligation it replaced. **What bioorthogonal click made possible** - Metabolic labelling: feed cells an azide-tagged sugar, let it incorporate into glycans, then attach a probe with a strain-promoted click to image where those sugars sit. - Imaging in living animals: the copper-free click has been run in cultured cells, live zebrafish, and mice without harming them. - Drug discovery and materials: CuAAC assembles candidate molecules, conjugates antibodies, and stitches together polymers and surfaces. - Cancer research: these reactions are being investigated as ways to diagnose and treat cancer, for example by tagging tumour cells so they can be found and targeted. The breadth of these uses is why the prize was shared three ways. Meldal and Sharpless supplied the reliable copper-catalysed coupling, Sharpless framed the click concept that gave it a purpose, and Bertozzi carried the chemistry across the line into living systems, where it now serves as a standard tool for watching biology at the molecular scale. ## Think first **Q:** Two molecules each carry a small chemical clip, an azide and an alkyne. Left alone they barely react. Add a pinch of copper and they join almost instantly. What is the copper doing? **A:** **It is acting as a catalyst that opens a faster path.** Copper(I) grabs the alkyne to form a copper acetylide, which steers the azide and alkyne together and lets them close into a triazole ring at room temperature. Without it the same two pieces react slowly and give a messy mix of products. With it they snap to a single clean product. This is the copper-catalysed azide-alkyne cycloaddition, the workhorse of click chemistry. **Q:** CuAAC is fast and clean, yet you cannot use it to label molecules inside a living cell. Why not, and how did Bertozzi get around it? **A:** **The copper is the problem.** Copper(I) ions are toxic to cells, so the catalyst that makes CuAAC work would poison the very system you are trying to study. Bertozzi removed the need for copper by bending the alkyne into a strained ring, a cyclooctyne. The built-in strain supplies the push the copper used to provide, so the azide and alkyne click together on their own, gently enough to run inside a living cell. ## A chemical reaction that runs inside a living animal Bertozzi's copper-free click is gentle enough to fire inside a living organism without harming it. Researchers have used it to label sugars on cells in cultured human cells, in live zebrafish, and in mice, watching specific molecules light up while the animal carries on as normal. ## Key terms - **Click chemistry**: An approach to making molecules by joining two pieces with a single fast, selective, high-yield reaction that works in mild conditions and leaves little waste. - **CuAAC**: The copper(I)-catalysed azide-alkyne cycloaddition, the most-used click reaction. Copper turns a slow azide-alkyne reaction into a fast one that gives a single triazole product. - **Triazole**: The stable five-membered ring formed when an azide and an alkyne click together. It is the durable link that holds the two joined pieces in place. - **Bioorthogonal chemistry**: A reaction that can run inside a living system without interfering with native biochemistry. The partners are absent from biology and do not react with the cell's own molecules. - **Cyclooctyne**: An alkyne forced into a strained eight-membered ring. The built-in strain lets it react with an azide on its own, replacing the toxic copper catalyst. - **Glycan**: A chain of sugars, often found coating the surface of cells. Bertozzi used bioorthogonal click reactions to tag and image glycans in living systems. ## Check yourself 1. What does click chemistry aim for in a reaction? - Slow reactions that need high heat - **Fast, selective, high-yield reactions that join two pieces cleanly** (correct) - Reactions that produce many byproducts - Reactions that only work in dry organic solvents - Why: Click chemistry favours reactions that are fast, selective, and high-yielding, joining two building blocks with little waste, much like snapping a buckle shut. 2. What role does copper(I) play in the classic CuAAC click reaction? - It colours the final product - **It catalyses the azide-alkyne reaction, making it fast and giving a single triazole** (correct) - It replaces the azide - It is the glowing tag used for imaging - Why: Copper(I) catalyses the azide-alkyne cycloaddition. It speeds the reaction enormously and steers it to a single 1,4-triazole product at room temperature and neutral pH. 3. Why did Bertozzi develop a copper-free version of the click reaction? - Copper was too expensive - **Copper ions are toxic to living cells** (correct) - Copper made the reaction too slow - Copper changed the colour of cells - Why: Copper(I) is toxic to living cells, so Bertozzi used a strained cyclooctyne instead of a copper catalyst, creating a bioorthogonal click that runs safely inside living systems. ## The laureates ### Carolyn Bertozzi Carolyn R. Bertozzi (born 1966, USA) is a professor at Stanford University. In 2003 she coined the term bioorthogonal chemistry, and in 2004 she published a copper-free click reaction that runs safely inside living cells, which she used to track glycans, the sugar chains that coat cell surfaces. ### Morten Meldal Morten Meldal (born 1954, Denmark) is a professor at the University of Copenhagen. Working at the Carlsberg Laboratory, he reported in 2002, independently of Sharpless, the copper-catalysed reaction that joins an azide and an alkyne into a triazole ring, the workhorse of click chemistry. ### K. Barry Sharpless K. Barry Sharpless (born 1941, USA) works at Scripps Research in La Jolla, California. In 2001 he and his colleagues defined the idea of click chemistry, reactions that join building blocks quickly and cleanly, and in 2002 he reported the copper-catalysed azide-alkyne click independently of Meldal. ## Sources - [The Nobel Prize in Chemistry 2022, popular information (NobelPrize.org)](https://www.nobelprize.org/prizes/chemistry/2022/popular-information/) - [The Nobel Prize in Chemistry 2022, press release (NobelPrize.org)](https://www.nobelprize.org/prizes/chemistry/2022/press-release/) - [Click chemistry (Wikipedia)](https://en.wikipedia.org/wiki/Click_chemistry) - [Bioorthogonal chemistry (Wikipedia)](https://en.wikipedia.org/wiki/Bioorthogonal_chemistry) --- From Nobel Explained (https://nobelexplained.com), a free, independent course on every Nobel Prize since 2020. Not affiliated with the Nobel Foundation. Facts are pinned from the official Nobel Prize API.