Recent Advances in Recoverable Systems for the Copper-Catalyzed Azide-Alkyne Cycloaddition Reaction (CuAAC)  
[PERSON]  
1 Dipartimento di Chimica e Chimica Industriale Universita di Pisa, Via [PERSON] 13, Pisa 56124, Italy; 1 [EMAIL_ADDRESS]; Tel. : +39-050-221-92801  
In addition of being an effective way for linking together different molecules, the appreciation that the triazole structural motif may have pharmacologic relevance, e.g., as a more stable replacement for peptide bonds and in virtue of its dipole moment, hydrogen-bonding, and \(\pi\)-\(\pi\) stacking capabilities [42], improved further the interest towards CuAAC in the medicinal chemistry field. Even if less represented than the isomeric 1,2,4-triazole motif, contained in various approved drugs [62; 63], examples of bio-active compounds that embed the 1,2,3-triazole nucleus keep appearing continuously in the literature or have already an established clinical use (Figure 2) [40; 42]. Figure 1: Main publication areas of CuAAC-related papers and selected examples of recent trends. Figure 2: Selected examples of drugs and other bioactive compounds containing the 1,2,3-triazole nucleus. Despite the many successes of CuAAC, the underlying chemistry suffers from three main drawbacks that pose limits to its usefulness, not only in a medicinal chemistry perspective but often also in the case of materials for special applications: (i) use of organic azides, which are not easy to purify and handle at scale because of their potential instability; (ii) contamination of the click product with catalyst components, copper above all; and (iii) instability of the Cu(I) oxidation state, which imposes inert-atmosphere handling techniques or the addition of an excess of a reducing agent like sodium ascorbate [64]. In the specific context of the modification of bio-molecules like, e.g., polysaccharides and polypeptides, further problems may arise then from the generation of highly reactive species (H\({}_{2}\)O\({}_{2}\), hydroxyl radicals, and dehydroosaccharide acid), which cause chain cleavage or denaturation [65; 66; 67]. In addition to the use of flow-chemistry [32], a potentially general solution for the former problem is represented by in situ generation of the organic azide under multi-component reaction conditions [68]. In principle, with this approach it is possible to realize the consumption of the organic azide in the CuAAC step, as soon as it forms, and then avoid any build-up in the reaction mixture. Depending on the nature of the azide intermediate (e.g., aliphatic or aromatic) and of the starting material selected for the purpose, different possibilities exists in this respect. As summarized in Scheme 2, those met more frequently, and discussed in detail in the following sections, involve the use of:  
* Alkyl halides (Scheme 2a), often of the \"activated\" type (benzyl, allyl, \(\alpha\)-halocarbonyls) with respect to the nucleophilic substitution reaction;
* Epoxides (Scheme 2b), which can lead to the formation of differently substituted triazoles (**3** and **4**) in dependence of the regioselectivity of attack of azide ions on the oxirane ring;
* Aromatic diazonium salts (Scheme 2c), either commercially available (e.g., tetrafluoroborate salts) or produced in situ by diazotisation of the corresponding aromatic amine;
* Aromatic boronic acids (Scheme 2d), which may undergo azido-deboronation under the action of the same copper catalyst involved in the CuAAC process [69]. On the contrary, the problems associated with the use of the copper catalyst have been tackled by adopting widely different strategies, including the use of strained alkynes or highly reactive azides,that do not require metal catalysis at all [65; 70; 71; 72], and reactants with chelating capability, which allow to reduce the catalyst loading [73]. Besides, many efforts were committed to the development of more effective catalytic systems based on copper or other metals [30].