Catalytic CuAAC reaction

Scheme 10.6 (A) Early proposed catalytic cycle for the CuAAC reaction based on DFT calculations. (B) Introduction of a second copper(l) atom favorably influences the energetic profile of the reaction (L-H2O in DFT calculations). At the bottom are shown the optimized structures for dinuclear Cu...

Cook TL, Walker JA, Mack J. Scratching the catalytic surface of mechanochemis-try a multi-component CuAAC reaction using a copper reaction vial. Green Chem 2013 15 617-9. 

Second, dinuclear complexes may exhibit enhanced reactivity. However, conclusions about the molecularity of the elementary steps based on the observed rate law are tenuous at best, and are likely wrong. Indeed, to date, we have not seen a CuAAC reaction that exhibits uniform second order in the catalyst as it progresses. It is possible that nuclearity of the catalytic species is maintained throughout the catalytic cycle and, as a consequence, all elementary steps are effectively bimolecular, exhibiting the commonly observed first order in the catalyst, even though the reaction is catalyzed by a dinuclear catalyst. 

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 catalytic perfomiance of this catalyst in CuAAC reaction was investigated for various alkynes and azides. High yields (81-99%) were obtained in the presence of very low amounts of catalyst. 

Despite the enhanced reactivity and regioselectivity of many organic reactions in aqueous media, surprisingly, only a few CuAAC reactions have been performed in this reaction media. This chapter provides an overview of these type of catalytic systems, and, particularly, addressing attention to those using well-defined copper(I) catalysts [16]. 

The use of organic solvents as reaction media dominate in CuAAC reactions. However, several examples have been described that proceed in mixtures of organic solvents and water (i.e., iBuOH/water [9a, 17], MeOH/water [18], dimethyl sulfoxide (DMSO)/water [8c, 19], MeCN/water [20], or tetrahydrofuran (THF)/water [13g,i]). In addition, several catalytic systems. 

On the basis of the wide catalytic applications of NHC transition metal complexes [25], Nolan and coworkers have thoroughly studied the catalytic activity in CuAAC reactions of well-defined copper(I) complexes with general formula [CuX(NHC)]. Organic solvents, mixtures of EtOH/water, and pure water have been used as reaction media. In particular, it has been reported that complexes [CuBr(SIMes)] (1 in Fig. 15.1, SIMes=iVAf-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)) and [CuI(IAd)] (2 in Fig. 15.1, IAd=iVAf-adamantyl imidazol-2-ylidene) show a remarkable activity for the synthesis of a... 

Scheme 9.18 (a) Generic CuAAC reaction, including the most common reaction conditions and (b) the catalytic cycle for the CuAAC... 

In their efforts to develop new organocatalysts, Burke and coworkers have also studied the CuAAC reaction for the synthesis of new 1,2,3-triazole-cinchona catalysts (Scheme 9.22) (P.C. Barrulas, L. Alves, A.J. Burke, unpublished results) [60]. They were screened in a variety of benchmark catalytic reactions such as the ketimine hydrosilylation with HSiClg, Michael addition reactions, and the... 

The results of the kinetic studies provided an impetus to the search for evidence of an intermediate that involved two copper(I) atoms. Despite being entropically disfavoured, those results clearly suggest that two copper centres are involved in the catalytic cycle. Dinuclear and tetranuclear copper(I) complexes are known [95] and could be involved in CuAAC reactions. Computational smdies suggested ways of alleviating the ring strain that is evident in the copper(III) metallacycle shown in Scheme 8. 

The position of copper(I) salts as quite soft Lewis acids has resulted in a significant number of publications where soft phosphorus- and sulfur-containing ligands have been used and shown to enhance the catalytic process in CuAAC reactions. A variety of phosphorus-containing ligands has been used to produce significant rate enhancements or improved efficiency in CuAAC reactions. Examples include the use of triphenylphosphine-copper(I) bromide [137] (e.g., in the synthesis of dendrimers [138]), phosphoramidites [139], and bis(triphenylphosphine)-copper(I) carboxylates [140]. In addition, triethylphosphite-copper(I) iodide complexes have been used in sugar chemistry [141]. 

It is now be generally agreed that the ligation of copper(I) species is required in the catalytic cycles involved in CuAAC reactions, and yet there are many publications where no ligands are purposefully added for example in the sodium... 

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. 

Several Cu(I) complexes with N-heterocyclic carbene ligands have been described as CuAAC catalysts at elevated temperature in organic solvents, under heterogeneous aqueous conditions (when both reactants are not soluble in water), and under neat conditions [75]. These catalyst show high activity under the solvent-free conditions, achieving turnover numbers as high as 20 000. However, their activity in solution-phase reactions is significantly lower than that of other catalytic systems (for example, a stoichiometric reaction of the isolated copper(I) acetylide/NHC complex with benzhydryl azide required 12 h to obtain 65% yield of the product [76], whereas under standard solution conditions even a catalytic reaction would proceed to completion within 1 h). 

Aryl and vinyl azides can also be accessed in one step from the corresponding halides or triflates via a copper-catalyzed reaction with sodium azide in the presence of a catalytic amount of L-proline (Scheme 7.5C) [104]. In this fashion, a range of 1,4-disubstituted 1,2,3-triazoles can be prepared in excellent yields [105-107]. Anilines can also be converted to aryl azides by the reaction with tert-butyl nitrite and azidotrimethylsilane [108]. The resulting azides can be submitted to the CuAAC conditions without isolation, furnishing triazole products in excellent yields. Microwave heating further improves both reactions, significantly reducing reaction time [56, 62]. 

Unfortunately, utilization of copper(i) to control the regioselectivity yields several problems. Although only catalytic amounts are required, copper can induce cytotoxic effects and protein denaturation, ° which can complicate bioconjugation by CuAAC for applications in vitro and in vivo. In addition, copper salts are often rather difficult to remove from the reaction products. Nevertheless, advantages like high selectivity, mild reaction conditions, and almost quantitative product formation have proven CuAAC highly beneficial for the preparation of site-specific peptide- and protein-polymer conjugates. 

When CuAAC was applied using standard conditions (Cu(I)Br/PMDETA, room temperature in THF), a maximum click efficiency of 64% was obtained. By changing the catalytic system, catalytic concentration or temperature, no positive trend was observed. This inefficient CuAAC of the highly branched PiBA star-shaped polymers with the linear polymers is ascribed to the entropic penalty, as also observed by Matyjaszewski (Gao and Matyjaszewski, 2006). In an attempt to improve this click efficiency, the effect of microwave heating on the Cu (I)-mediated click reaction of these bulky star-shaped polymers with other polymer segments... 

The reaction between organo-azides and alkynes, called the Huisgen cycloaddition reaction, was reported many years ago [84]. However, intense attention has been given to this reaction only recently. In 2001, the groups of Fokin and Sharpless [85] and Meldal [86] independently discovered that a catalytic amount of Cu(l) drastically increased the reactivity and regioselectivity of the reaction. This discovery sparked intensive efforts on the integration of CuAAC in interdisciplinary research. 

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