Especially in the case of rhodium-catalyzed process, the latter choice may display a useful complementary profile with respect to CuAAC in that -with the proper choice of the catalytic complex-1,5-disubstituted-1,2,3-triazole products or even trisubstituted ones can be obtained from the reaction of terminal and internal alkynes, respectively. However, these alternatives still suffer from contamination of the product with transition metals and, usually, require more expensive catalyst precursor than CuAAC itself. As far as copper is concerned, some of the shortcomings associated with traditional systems (e.g., CuX salts in the presence of an amine co-catalyst or CuSO\({}_{4}\) with an excess of sodium ascorbate) were eliminated with the introduction of stabilizing ligands for the +I oxidation state of the metal and proper scavenging of reactive by-products [66; 74]. Under these conditions CuAAC proceeds often under air, with catalyst concentration in the \(\upmu\)M range and copper loading that, in some cases, can be reduced down to 0.01 mol % with respect to the substrates. Even so, the use of low-molecular weight soluble catalytic systems leaves unanswered the problem of contamination of the crude product with metal and, possibly, ligand residues. For instance, in the case above a copper content up to 25 ppm might be found in the crude from a CuAAC reaction forming a compound of average molecular weight. This concentration exceeds the metal amount often quoted as acceptable for pharmaceutical applications (15 ppm) [75]. Considering also that the use of 0.01 mol % of copper catalyst represents more the exception than the rule, especially when structurally complex triazoles have to be prepared, one may expect that such a threshold is surpassed by several order of magnitude when this chemistry is employed in scenarios of practical synthetic relevance. In this regard it is worth noting that while the possibility of running CuAAC reactions with catalysts loadings in the low ppm range has been reported with systems comprising self-assembled gel [76], dendrimic ligands [77], and homogeneous catalysts comprising a molecularly-enlarged water-soluble tris-triazole ligand [78], demonstration of the scope of these approaches to molecules more complex of those usually employed for benchmarking new CuAAC protocols are just beginning to appear [78]. Together with the fact that copper removal can be difficult, in particular for highly functionalized or sensitive products [79], these problems tend to collide with the goal of prompt product purification underlying in the concept of click-chemistry. Therefore it is not surprising that many attempts have been described in the course of the years, aimed to separate the CuAAC catalytic system from the reaction mixture in more effective ways. Some of these approaches rely on known homogeneous catalysts employed under alternative conditions like, e.g., recent reports making use of supercritical CO\({}_{2}\)[80], glycerol, poly(ethylene glycol) (PEG), room-temperature ionic liquids, and their combinations thereof, as neoteric reaction media [81; 82; 83; 84; 85]. Similarly, water-soluble catalytic systems can provide an excellent opportunity for separation and recycling [78; 86]. Albeit straightforward, this choice shows occasional limitations in terms of catalytic activity, seamless general implementation and, above all, effectiveness in reducing the residual copper content to an extent that might cope with the said regulatory requirements. In an alternative strategy, catalytic systems specifically designed for easier separation were therefore developed, typically by immobilization of copper species onto insoluble supports or quasi-homogeneous materials, like nanoparticles.