Copper-catalyzed azide-alkyne cycloaddition mechanisms

Metallic copper efficiently catalyzes azide-alkyne cycloadditions under ultrasound or simultaneous ultrasound/microwave irradiation. Ultrasound favors mechanical depassivation in reactions involving metals and enhances both mass and electron transfer from the metal to the organic acceptor. It has been applied to accelerate the preparation of 1,2,3-triazole phthalimides via a 1,3-dipolar cycloaddition of phthalimidoethyl-azide [67]. 

The mechanism of the CuAAC reaction was rst proposed by Meldal (Tomoe et al., 2002) and Sharpless (Rostovtsev et al., 2002) and later veri ed by computational methods by Sharpless (Himo et al., 2005) in a series of papers. The proposed catalytic cycle based on a concerted mechanism via a Cu-acetylide intermediate is shown in Fig. 12.7. The most effective variant of the catalyzed 1,3-dipolar azide-alkyne cycloaddition system uses terminal alkynes in combination with copper sulfate and sodium ascorbate. The sodium ascorbate reduces copper sulfate to Cu(I), which forms a Cu-acetylide by reaction with the terminal alkyne via an initial r-complex formation. The copper acetyhde formed is considerably more reactive toward the azide so that a rate enhancement of the 1,3-dipolar cycloaddition results (Englert et al., 2005). 

The discovery of copper catalysis in 1,3-dipolar cycloadditions of terminal alkynes to azides (click chemistry) in 2002 <2002AGE2596, 2002JOC3057> has revolutionized the field . It is not only that the catalyzed reactions proceed faster under mild conditions, but full regioselectivity of the products is also achieved. Terminal alkynes generate only 1,4-disubstituted triazoles. A brief outline of the reaction mechanism is given in Scheme 253 . Some aspects of this new methodology are discussed in a review <2007ALD7>. 

---