Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions

Abstract

The copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) has become a commonly employed method for the synthesis of complex molecular architectures under challenging conditions. Despite the widespread use of copper-catalyzed cycloaddition reactions, the mechanism of these processes has remained difficult to establish due to the involvement of multiple equilibria between several reactive intermediates. Real-time monitoring of a representative cycloaddition process via heat flow reaction calorimetry revealed that monomeric copper acetylide complexes are not reactive toward organic azides unless an exogenous copper catalyst is added. Furthermore, crossover experiments with an isotopically enriched exogenous copper source illustrated the stepwise nature of the C–N bond-forming events and the equivalence of the two copper atoms within the cycloaddition steps.

Metal-catalyzed azide-alkyne “click” reactions: Mechanistic overview and recent trends

“…Following the seminal work by Nolan's group [33], the Cu(I) complexes of NHC ligands were continuously very efficient catalysts for the click cycloaddition reaction between azides and alkynes [38,113]. Lal et al compared the catalytic activity of NHC and phosphine complexes M a n u s c r i p t 26 for the CuAAC formation of 5-iodo-1,2,3-triazoles (Fig.…”

“…Since the early reports, a variety of transition-metal catalysts have been used for the reactions between mono-or disubstituted alkynes and azides (vide infra). For the Cu(I) catalyzed reaction, a variety of mechanisms involving Cu(I)-aryl intermediates have been proposed in which the key-step species contains either mononuclear [35] or binuclear copper species [30][31][32][33][34][35][36][37][38]. Theoretical studies of the RuAAC reaction have also been reported [28,[39][40][41].…”

“…The most recent experimental mechanistic study by Fokin's group unambiguously demonstrated the participation of a dinuclear copper intermediate in the case of a CuAAC reaction in which a mixture of Cu(I)(aryl) complex and [Cu(I)(MeCN) 4 ] + were used ( Figure 2). Their study revealed that monomeric copper acetylide complexes were not reactive toward organic azides, except in the presence of exogenous copper catalyst [38]. Furthermore, direct injection by time-of-flight mass spectrometry (TOF-MS) for crossover experiments with an isotopically enriched exogenous copper source showed that two copper centers were involved within the cycloaddition process yielding the 1,4-substituted 1,2,3-triazoles.…”

Binuclear Copper(I) Borohydride Complex Containing Bridging Bis(diphenylphosphino) Methane Ligands: Polymorphic Structures of [(µ2-dppm)2Cu2(η2-BH4)2] Dichloromethane Solvate

“…Many examples The Cu(I)-dppm complexes are emerging class of polynuclear complexes, that are drawing considerable attention because of their photophysical properties [19][20][21][22] and prospective use as a catalyst [23][24][25] and a sensor for various organic bases [26] and anions [27]. Binuclear Cu(I) species possess an enhanced reactivity toward organic azides in copper-catalysed azide-alkyne cycloaddition compared to monomeric copper complexes [28][29][30][31][32][33][34][35]. Copper(I) tetrahydroborates with phosphine ligands featuring relative stability to air oxygen and moisture are used as selective reducing agents [36][37][38][39][40], catalysts of photosensitized isomerization of dienes [41][42][43] and hydrolytic dehydrogenation of ammonia borane [44].…”

“…Binuclear Cu(I) species possess an enhanced reactivity toward organic azides in copper-catalysed azide-alkyne cycloaddition compared to monomeric copper complexes [28][29][30][31][32][33][34][35]. Copper(I) tetrahydroborates with phosphine ligands featuring relative stability to air oxygen and moisture are used as selective reducing agents [36][37][38][39][40], catalysts of photosensitized isomerization of dienes [41][42][43] and hydrolytic dehydrogenation of ammonia borane [44].…”