Copper-free click chemistry is an alternative approach toclick chemistrythat proceeds at a lower activation barrier and is free of cytotoxic transition metal catalysts.1 The absence of exogenous metal catalysts makes these reactions suitable for thein vivoapplications ofbioorthogonal chemistry orbioorthogonal click chemistry. Copper-free click chemistry is based on an old reaction, published in 1961 by Wittig et al.It involved the reaction between cyclooctyne and phenyl azide, which proceeded like an explosion to give a single product, 1-phenyl-4,5,6,7,8,9-hexahydro-1H-cycloocta[d][1,2,3]triazole.2 The reaction is ultrafast due to the large amount of ring-strain (18 kcal/mol of ring strain) in the cyclooctyne molecule. Release of the ring-strain in the molecule drives the fast reaction. Cyclooctynes are reported to react selectively with azides to form regioisomeric mixtures of triazoles at ambient temperatures and pressures without the need for metal catalysis and no apparent cytotoxicity.3What is Copper-Free Click Chemistry?
Wittig’s Copper-Free Click Reaction
Scheme 1.Wittig's copper free click chemistry
Copper-Free Click Chemistry Products
Loading
Copper-Free Click Chemistry Applications
Scheme 2.Preparation of triazole analogs of phthalate plasticizers by copper-free azide-alkyne click reaction.
Scheme 3. Copper catalyzed azide-alkyne cycloaddition reaction.
References
1.
Rostovtsev, VV, Green, LG, Fokin, VV, Sharpless, KB. 2002. Angew. Chem.. 114, 2596.
2.
Akeroyd N. 2010. Click chemistry for the preparation of advanced macromolecular architectures Stellenbosch University.
3.
Lahann J. 2009. Click Chemistry for Biotechnology and Materials Science. https://doi.org/10.1002/9780470748862
4.
Himo F, Lovell T, Hilgraf R, Rostovtsev VV, Noodleman L, Sharpless KB, Fokin VV. 2005. Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates. J. Am. Chem. Soc.. 127(1):210-216. https://doi.org/10.1021/ja0471525
5.
Chang PV, Prescher JA, Sletten EM, Baskin JM, Miller IA, Agard NJ, Lo A, Bertozzi CR. 2010. Copper-free click chemistry in living animals. Proc Natl Acad Sci USA. 107(5):1821-1826. https://doi.org/10.1073/pnas.0911116107
6.
Jewett JC, Sletten EM, Bertozzi CR. 2010. Rapid Cu-Free Click Chemistry with Readily Synthesized Biarylazacyclooctynones. J. Am. Chem. Soc.. 132(11):3688-3690. https://doi.org/10.1021/ja100014q
7.
Johnson JA, Baskin JM, Bertozzi CR, Koberstein JT, Turro NJ. 2008. Copper-free click chemistry for the in situ crosslinking of photodegradable star polymers. Chem. Commun..(26):3064. https://doi.org/10.1039/b803043j
8.
Pathak RK, McNitt CD, Popik VV, Dhar S. 2014. Copper-Free Click-Chemistry Platform to Functionalize Cisplatin Prodrugs. Chem. Eur. J.. 20(23):6861-6865. https://doi.org/10.1002/chem.201402573
9.
Nieves DJ, Azmi NS, Xu R, Lévy R, Yates EA, Fernig DG. Monovalent maleimide functionalization of gold nanoparticles via copper-free click chemistry. Chem. Commun.. 50(86):13157-13160. https://doi.org/10.1039/c4cc05909c
10.
Fan M, Ma Y, Mao J, Zhang Z, Tan H. 2015. Cytocompatible in situ forming chitosan/hyaluronan hydrogels via a metal-free click chemistry for soft tissue engineering. Acta Biomaterialia. 2060-68. https://doi.org/10.1016/j.actbio.2015.03.033
11.
Earla A, Braslau R. 2014. Covalently Linked Plasticizers: Triazole Analogues of Phthalate Plasticizers Prepared by Mild Copper-Free ?Click? Reactions with Azide-Functionalized PVC. Macromol. Rapid Commun.. 35(6):666-671. https://doi.org/10.1002/marc.201300865
12.
Codelli JA, Baskin JM, Agard NJ, Bertozzi CR. 2008. Second-Generation Difluorinated Cyclooctynes for Copper-Free Click Chemistry. J. Am. Chem. Soc.. 130(34):11486-11493. https://doi.org/10.1021/ja803086r
13.
Satpati D, Bauer N, Hausner SH, Sutcliffe JL. 2014. Synthesis of [64Cu]DOTA-ADIBON3-Ala-PEG28-A20FMDV2 via copper-free click chemistry for PET imaging of integrin ?v?6. J Radioanal Nucl Chem. 302(2):765-771. https://doi.org/10.1007/s10967-014-3197-8
14.
Jeon J, Kang JA, Shim HE, Nam YR, Yoon S, Kim HR, Lee DE, Park SH. 2015. Efficient method for iodine radioisotope labeling of cyclooctyne-containing molecules using strain-promoted copper-free click reaction. Bioorganic & Medicinal Chemistry. 23(13):3303-3308. https://doi.org/10.1016/j.bmc.2015.04.045
15.
Zhang G, Zheng S, Liu H, Chen PR. Illuminating biological processes through site-specific protein labeling. Chem. Soc. Rev.. 44(11):3405-3417. https://doi.org/10.1039/c4cs00393d