Click chemistry describes reactions that join molecular building blocks quickly, reliably and cleanly, like the clasp of a seatbelt clicking shut. The idea transformed drug discovery, materials science and biology, and in 2022 it earned the Nobel Prize in Chemistry. This guide explains what makes a reaction “click”, the key reactions and how labs use them.
What makes a reaction “click”?
The concept was set out by K. Barry Sharpless and colleagues around 2001. A click reaction should:
- give high yields with few or harmless by-products;
- work under simple conditions, ideally in water or benign solvents;
- be highly selective, joining only the intended partners;
- need little or no purification;
- use readily available starting materials.
The classic: copper-catalysed azide–alkyne cycloaddition (CuAAC)
The best-known click reaction joins an azide and a terminal alkyne to form a stable five-membered ring called a 1,2,3-triazole. On its own the reaction is slow and gives a mixture of products; with a copper(I) catalyst it becomes fast and selective. The copper-catalysed version was reported independently in 2002 by Morten Meldal’s group in Denmark and Sharpless’s group in the USA.
Bioorthogonal chemistry: click reactions inside living systems
Copper is toxic to cells, which limits CuAAC in living organisms. Carolyn Bertozzi developed strain-promoted azide–alkyne cycloaddition (SPAAC), which uses a strained ring alkyne (a cyclooctyne) that reacts with azides without any metal catalyst. This made it possible to label sugars, proteins and other molecules in living cells without disturbing them. The term bioorthogonal describes reactions like this that proceed inside living systems without interfering with normal biochemistry.
The 2022 Nobel Prize in Chemistry
The prize was awarded jointly to Carolyn R. Bertozzi, Morten Meldal and K. Barry Sharpless “for the development of click chemistry and bioorthogonal chemistry”. It was Sharpless’s second Nobel Prize in Chemistry; he had previously shared the 2001 prize for work on asymmetric catalysis.
Where click chemistry is used
| Field | Example use |
|---|---|
| Drug discovery | Rapidly linking fragments to build compound libraries |
| Chemical biology | Labelling proteins, glycans and DNA with dyes or tags |
| Bioconjugation | Attaching drugs to antibodies; see our NHS ester guide for the amine-based alternative |
| Materials | Making polymers, dendrimers and functional surfaces |
| Diagnostics and imaging | Building probes and imaging agents |
Practical tips for the lab
- Catalyst: copper(I) is often generated in situ from copper(II) sulfate with sodium ascorbate; ligands such as TBTA or THPTA protect the copper and speed up the reaction.
- Azide safety: small organic azides and inorganic azides can be shock-sensitive or explosive, and sodium azide is highly toxic. Follow your institution’s risk assessment, keep scales small and never concentrate low-molecular-weight azides to dryness.
- Buying reagents: click kits, azide and alkyne building blocks, and strained cyclooctynes (DBCO, BCN) are sold by major and specialist suppliers. Order by CAS number where possible.
Frequently asked questions
Who invented click chemistry?
The concept was introduced by K. Barry Sharpless; the copper-catalysed reaction was developed independently by Morten Meldal and Sharpless; Carolyn Bertozzi extended it to living systems.
What is a “click reaction test”?
Usually a quick reaction between a model azide and alkyne to confirm that a catalyst, ligand or labelling kit is working before using precious samples.
What is the German word for click chemistry?
“Click-Chemie”.
