Copper-free click chemistry is an alternative approach to click chemistry that 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 the in vivo applications of bioorthogonal chemistry or bioorthogonal 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.3
Scheme 1.Wittig's copper free click chemistry
Scheme 2.Preparation of triazole analogs of phthalate plasticizers by copper-free azide-alkyne click reaction.
Scheme 3. Copper catalyzed azide-alkyne cycloaddition reaction.
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