Click chemistry was first fully described by K. Barry Sharpless of The Scripps Research Institute in 2001 and describes chemistry tailored to generate substances quickly and reliably by joining small units together. Click chemistry is not a single specific reaction, but was meant to mimic nature, which also generates substances by joining small modular units.
A desirable Click chemistry reaction would:
- be modular
- be wide in scope
- give very high chemical yields
- generate only inoffensive byproducts
- be stereospecific
- be physiologically stable
- exhibit a large thermodynamic driving force (> 84 kJ/mol) to favor a reaction with a single reaction product. A distinct exothermic reaction makes a reactant "spring-loaded".
- have high atom economy.
The process would preferably:
- have simple reaction conditions
- use readily available starting materials and reagents
- use no solvent or use a solvent that is benign or easily removed (preferably water)
- provide simple product isolation by non-chromatographic methods (crystallisation or distillation)
Proteins are made from repeating amino acid units, and sugars are made from repeating monosaccharide units. The connections are carbon - hetero atom bonds C-X-C rather than carbon - carbon bonds. In addition, enzymes ensure that chemical processes can overcome large enthalpy hurdles by a series of reactions each requiring only a small energy step. Mimicking nature in organic synthesis is essential in the discovery of new pharmaceuticals given the large number of possible structures.
In 1996, Guida calculated the size of the pool of drug candidates at 1063, based on the presumption that a candidate consists of fewer than 30 non-hydrogen atoms, weighs less than 500 daltons, is made up of atoms of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine and bromine, is stable at room temperature, and does not react with oxygen and water. Click chemistry in combination with combinatorial chemistry, high-throughput screening and building chemical libraries speeds up new drug discoveries by making each reaction in a multistep synthesis fast, efficient and predictable.
Many of the Click chemistry criteria are subjective, and even if measurable and objective criteria could be agreed upon, it is unlikely that any reaction will be perfect for every situation and application. However, several reactions have been identified that fit the concept better than others:[clarification needed]
- [3+2] cycloadditions, such as the Huisgen 1,3-dipolar cycloaddition, in particular the Cu(I)-catalyzed stepwise variant, are often referred to simply as Click reactions
- thiol-ene click reactions
- Diels-Alder reaction and inverse electron demand Diels-Alder reaction
- [4+1] cycloadditions between isonitriles (isocyanides) and tetrazines
- nucleophilic substitution especially to small strained rings like epoxy and aziridine compounds
- carbonyl-chemistry-like formation of ureas but not reactions of the aldol type due to low thermodynamic driving force.
- addition reactions to carbon-carbon double bonds like dihydroxylation or the alkynes in the thiol-yne reaction.
Azide alkyne Huisgen cycloaddition 
One of the most popular[clarification needed] reactions within the Click chemistry concept is the azide alkyne Huisgen cycloaddition using a Copper (Cu) catalyst at room temperature. It was discovered concurrently and independently by the groups of Valery V. Fokin and K. Barry Sharpless at the Scripps Research Institute in California and Morten Meldal in the Carlsberg Laboratory, Denmark. Although the Cu(I)-catalyzed variant was first reported by Meldal and co-workers for the synthesis of peptidotriazoles on solid support, these authors did not recognize the potential of the reaction and did not make a connection with the click chemistry concept. Fokin and Sharpless independently described it as a reliable catalytic process offering "an unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors which depend on the creation of covalent links between diverse building blocks."
Copper and ruthenium are the commonly used catalysts in the reaction. The use of copper as a catalyst results in the formation of 1,4-regioisomer, whereas ruthenium results in formation of the 1,5- regioisomer. Recently, silver was also used to carry out regioselective synthesis of 1,4 isomer. Silver catalysts had previously shown to be inactive for such transformation. A disadvantage of the Cu-catalysed Click reaction is that it does not work on internal alkynes. A mechanism for this reaction was originally proposed based on theoretical calculations.
Click chemistry has widespread applications. Some of them are:
- Two-dimensional gel electrophoresis separation
- preparative organic synthesis of 1,4-substituted triazoles
- modification of peptide function with triazoles
- modification of natural products and pharmaceuticals
- drug discovery
- macrocyclizations using Cu(I) catalyzed triazole couplings
- modification of DNA and nucleotides by triazole ligation
- supramolecular chemistry: calixarenes, rotaxanes, and catenanes
- dendrimer design
- carbohydrate clusters and carbohydrate conjugation by Cu(1) catalyzed triazole ligation reactions
- material science
- nanotechnology, and
- Bioconjugation, for example, azidocoumarin.
Click chemistry has also been used for selectively labeling biomolecules within biological systems. A Click reaction that is to be performed in a living system must meet an even more rigorous set of criteria than in an in vitro reaction. It must be bioorthogonal, meaning the reagents used may not interact with the biological system in any way, nor may they be toxic. The reaction must also occur at neutral pH and at or around body temperature. Most Click reactions have a high energy content. The reactions are irreversible and involve carbon-hetero atom bonding processes. An example is the Staudinger ligation of azides.
Technology License 
The Scripps Research Institute has a portfolio of click chemistry patents. Licensees include Invitrogen, Allozyne, Aileron, Integrated Diagnostics, and the fine chemical company Baseclick, a BASF spin-off created to sell products made using click chemistry. Fluorescent azides and alkynes also produce such companies as Active Motif Chromeon and Cyandye
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- R. A. Evans (2007). "The Rise of Azide–Alkyne 1,3-Dipolar 'Click' Cycloaddition and its Application to Polymer Science and Surface Modification". Australian Journal of Chemistry 60 (6): 384–395. doi:10.1071/CH06457.
- W.C. Guida et al. Med. Res. Rev. p 3 1996
- Spiteri, Christian and Moses, John E. (2010). "Copper-Catalyzed Azide–Alkyne Cycloaddition: Regioselective Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles". Angewandte Chemie International Edition 49 (1): 31–33. doi:10.1002/anie.200905322.
- Hoyle, Charles E. and Bowman, Christopher N. (2010). "Thiol–Ene Click Chemistry". Angewandte Chemie International Edition 49 (9): 1540–1573. doi:10.1002/anie.200903924.
- Blackman, Melissa L. and Royzen, Maksim and Fox, Joseph M. (2008). "Tetrazine Ligation: Fast Bioconjugation Based on Inverse-Electron-Demand Diels−Alder Reactivity". Journal of the American Chemical Society 130 (41): 13518–13519. doi:10.1021/ja8053805. PMC 2653060. PMID 18798613.Devaraj, Neal K. and Weissleder, Ralph and Hilderbrand, Scott A. (2008). "Tetrazine Based Cycloadditions: Application to Pretargeted Live Cell Labeling". Bioconjugate Chemistry 19 (12): 2297–2299. doi:10.1021/bc8004446. PMC 2677645. PMID 19053305.
- Stöckmann, Henning; Neves, Andre; Stairs, Shaun; Brindle, Kevin; Leeper, Finian (2011). "Exploring isonitrile-based click chemistry for ligation with biomolecules". Organic & Biomolecular Chemistry. doi:10.1039/C1OB06424J.
- Rostovtsev, Vsevolod V.; Green, Luke G; Fokin, Valery V.; Sharpless, K. Barry (2002). "A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective "Ligation" of Azides and Terminal Alkynes". Angewandte Chemie International Edition 41 (14): 2596–2599. doi:10.1002/1521-3773(20020715)41:14<2596::aid-anie2596>3.0.co;2-4.
- Tornoe, C. W.; Christensen, C.; Meldal, M. (2002). "Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides". Journal of Organic Chemistry 67 (9): 3057–3064. doi:10.1021/jo011148j. PMID 11975567.
- Boren, Brant C.; Narayan, Sridhar; Rasmussen, Lars K.; Zhang, Li; Zhao, Haitao; Lin, Zhenyang; Jia, Guochen; Fokin, Valery V. (2008). "Ruthenium-Catalyzed Azide−Alkyne Cycloaddition: Scope and Mechanism". Journal of the American Chemical Society 130 (28): 8923–8930. doi:10.1021/ja0749993. PMID 18570425.
- McNulty,J.; Keskar, K; Vemula, R. (2011). "RThe First Well-Defined Silver(I)-Complex-Catalyzed Cycloaddition of Azides onto Terminal Alkynes at Room Temperature". Chemistry - A European Journal 17 (52): 14727–14730. doi:10.1002/chem.201103244. PMID 22125272.
- F. Himo, T. Lovell, R. Hilgraf, V.V. Rostovtsev, L. Noodleman, K.B. Sharpless, V.V. Fokin (2005). "Copper(I)-Catalyzed Synthesis of Azoles, DFT Study Predicts Unprecedented Reactivity and Intermediates". Journal of the American Chemical Society 127: 210–216. doi:10.1021/ja0471525.
- Ilya A. Osterman, Alexey V. Ustinov, Denis V. Evdokimov, Vladimir A. Korshun, Petr V. Sergiev, Marina V. Serebryakova, Irina A. Demina, Maria A. Galyamina, Vadim M. Govorun, Olga A. Dontsova (January 2013). "A nascent proteome study combining click chemistry with 2DE". PROTEOMICS 13 (1): 17–21. doi:10.1002/pmic.201200393. PMID 23161590.
- John E. Moses and Adam D. Moorhouse (2007). "The growing applications of click chemistry". Chem. Soc. Rev. 36 (36): 1249–1262. doi:10.1039/b613014n. PMID 17619685.
- Click Chemistry: Short Review and Recent Literature
- National Science Foundation: Feature "Going Live with Click Chemistry."
- Chemical and Engineering News: Feature "In-Situ Click Chemistry."
- Chemical and Engineering News: Feature "Copper-free Click Chemistry"
- Metal-free click chemistry review
- Click Chemistry - a Chem Soc Rev themed issue highlighting the latest applications of click chemistry, guest edited by M G Finn and Valery Fokin. Published by the Royal Society of Chemistry