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Click chemistry

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Click chemistry was first fully described by K. Barry Sharpless of The Scripps Research Institute in 2001[1][2] 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)

Explanation

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.[citation needed]

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.[3] 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]

Azide alkyne Huisgen cycloaddition

Main article: 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[8] and Morten Meldal in the Carlsberg Laboratory, Denmark.[9] 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.[10] 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.[11] 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.[12]

Applications

Click chemistry has widespread applications. Some of them are:

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 than 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

On July 15, 2010, it was announced that The Scripps Research Institute signed a license agreement with Allozyne, a privately held, Seattle based biotechnology company. The agreement with The Scripps Research Institute provided Allozyne with a license to apply Click chemistry for exclusive development in key therapeutic fields in addition to a non-exclusive license for diagnostic applications.[citation needed]

References

  1. ^ H. C. Kolb, M. G. Finn and K. B. Sharpless (2001). "Click Chemistry: Diverse Chemical Function from a Few Good Reactions". Angewandte Chemie International Edition. 40 (11): 2004–2021. doi:10.1002/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5. PMID 11433435.
  2. ^ 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.
  3. ^ W.C. Guida et al. Med. Res. Rev. p 3 1996
  4. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ Rostovtsev, Vsevolod V. (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. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ 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.
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