On the Mechanism of Copper(I)-Catalyzed Azide-Alkyne Cycloaddition

Abstract

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction regiospecifically produces 1,4-disubstituted-1,2,3-triazole molecules. This heterocycle formation chemistry has high tolerance to reaction conditions and substrate structures. Therefore, it has been practiced not only within, but also far beyond the area of heterocyclic chemistry. Herein, the mechanistic understanding of CuAAC is summarized, with a particular emphasis on the significance of copper/azide interactions. Our analysis concludes that the formation of the azide/copper(I) acetylide complex in the early stage of the reaction dictates the reaction rate. The subsequent triazole ring-formation step is fast and consequently possibly kinetically invisible. Therefore, structures of substrates and copper catalysts, as well as other reaction variables that are conducive to the formation of the copper/alkyne/azide ternary complex predisposed for cycloaddition would result in highly efficient CuAAC reactions. Specifically, terminal alkynes with relatively low pKa values and an inclination to engage in π-backbonding with copper(I), azides with ancillary copper-binding ligands (aka chelating azides), and copper catalysts that resist aggregation, balance redox activity with Lewis acidity, and allow for dinuclear cooperative catalysis are favored in CuAAC reactions. Brief discussions on the mechanistic aspects of internal alkyne-involved CuAAC reactions are also included, based on the relatively limited data that are available at this point.

Azide–Alkyne Click Conjugation on Quantum Dots by Selective Copper Coordination

“…, cysteine) prevented quenching but also prevented any measurable CuAAC coupling, suggesting charged ligands can prevent Cu + from reaching the nanocrystal surface but may also inhibit interaction with the alkyne. 21, 36–37 Two triazole-based ligands (THPTA and BTTAA) proved most effective at generating Cy5 FRET emission while ameliorating quenching (Table S1), and optimization with THPTA gave us a FRET spectrum most similar to that of the QD-Cy5 conjugate synthesized without Cu (Figure 3b). Previous work has shown that BTTAA is superior to other Cu ligands for promoting CuAAC coupling with hydrophobic substrates, 33, 45–46 while in this case the QD surfaces and Cy5 are both hydrophilic, possibly explaining the differences seen here.…”

Tripodal amine ligands for accelerating Cu-catalyzed azide–alkyne cycloaddition: efficiency and stability against oxidation and dissociation

“…Notably, current mechanistic studies suggest that both oxidation of Cu(I) by O 2 and CuAAC reactions involve a bi-nuclear copper intermediate. 35, 63, 64 …”

“…64–70 The di-Cu(I)-acetylide has been proven as a much more active intermediate in the CuAAC reaction than the mono-Cu(I) species. 63 Recently, results of our kinetic study of CuAAC reaction promoted by tris(triazoylmethl)amine ligands indicated the possibility that the trinuclear acelylide-Cu 3 -ligand complexes might be active intermediates in the reaction.…”

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

“…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].…”

“…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].…”