Mechanism of the CuAAC Reaction

In the mechanism of the CuAAC reaction described above, the metal catalyst activates terminal alkyne for reaction with a Cu-coordinated azide. This mode of reactivity operates with other dipolar reagents as well. In fact, the first example of a copper-catalzyed 1,3-dipolar cycloaddition reaction of alkynes was reported for nitriones by Kinugasa in 1972 [124]. An asymmetric version of the Kinugasa reaction was developed by Fu et al. in 2002 [125, 126]. 

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). 

Scheme 1.3 Mechanism of the CuAAC reaction as proposed by Jan H. van Maarseveen [15].

Numerous appUcations of the CuAAC reaction reported during the last several years have been regularly reviewed [7-13], and are continually enriched by investigators in many fields [14]. We focus here on the fundamental aspects of the CuAAC process and on its mechanism, with an emphasis on the qualities of copper that enable this unique mode of reactivity. 

Whatever the details of the interactions of Cu with alkyne during the CuAAC reaction, it is clear that Cu-acetylide species are easily formed and are productive components of the reaction mechanism. Early indications that azide activation was rate-determining came from the CuAAC reaction of diazide 15, shown in Scheme 10.5, which afforded ditriazole 17 as the predominant product, even when 15 was used in excess [113]. The same phenomenon was observed for 1,1-, and 1,2-diazides, but not for 1,4-, 1,5-, and conformationally flexible 1,3-diazide analogues. The dialkyne 18, in contrast to its diazide analogue 15, gave statistical mixtures of mono- and di-triazoles 19 and 20 under similar conditions. Independent kinetics measurements showed that the CuAAC reaction of 16 was slightly slower than that of 15, ruling out the intermediacy of 16 in the efficient production of 17. The Cu-triazolyl precursor 21 is, therefore, likely to be converted to 17 very rapidly. 

The CuAAC click reaction has been widely used for the preparation of interlocked molecules, such as catenanes and rotaxanes [88]. In the case of rotaxanes, the CuAAC reaction has been used mainly for the synthesis of the axle subsequent threading, clipping, or slipping procedures were utilized to produce the mechanically interlocked product. 

Among these reactions, the Cu(l)-catalyzed azide-alkyne cycloaddition (CuAAC) is the most widely used. This reaction has been implemented for the preparation of segmented block copolymers from polymerizable monomers by different mechanisms. For example, Opsteen and van Hest [22] successfully prepared poly(ethylene oxide)-b-poly(methyl methacrylate) (PEO-b-PMMA) and PEO-b-PSt by using azide and alkyne end-functionalized homopolymers as the click reaction components (Scheme 11.2). Here, PEO, PSt, and PMMA homopolymers were obtained via living anionic ring-opening polymerization (AROP), atom transfer radical polymerization (ATRP), and postmodification reactions. Several research groups have demonstrated the combination of different polymerization techniques via CuAAC click chemistry, in the synthesis of poly(e-caprolactone)-b-poly(vinyl alcohol) (PCL-b-PVA)... 

In addition to the immediate synthetic utility of the iodo-CuAAC reactions, examination of the mechanism will provide a better understanding of both the iodo and the parent CuAAC processes. Although both reactions clearly share some common features, the modes of activation of iodo- and terminal alkynes by copper are likely distincdy different. Our current mechanistic proposals are outlined in Scheme 7.17. One possible pathway is similar to that proposed for the CuAAC and... 

Although the detailed mechanism involved in any particular CuAAC reaction may vary, it is now clear that copper(I) catalytic species are mandatory and also that the copper(III) metallacyclic intermediate retains exocyclic copper(I) in some form. The ligands that are attached to the two copper atoms depend on the precise protocol that is used. The results of a number of investigations suggest that, in many reactions two copper(I) atoms are present in the catalytic species while in the presence of multidentate ligands, an equilibrium can exist between ligated copper (I) species that have two copper atoms and species that have only one copper(I) atom. 

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