Copper-catalyzed azide–alkyne cycloaddition (CuAAC) and beyond: new reactivity of copper(i) acetylides

Abstract

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is a widely utilized, reliable, and straightforward way for making covalent connections between building blocks containing various functional groups. It has been used in organic synthesis, medicinal chemistry, surface and polymer chemistry, and bioconjugation applications. Despite the apparent simplicity of the reaction, its mechanism involves multiple reversible steps involving coordination complexes of copper(I) acetylides of varying nuclearity. Understanding and controlling these equilibria is of paramount importance for channeling the reaction into the productive catalytic cycle. This tutorial review examines the history of the development of the CuAAC reaction, its key mechanistic aspects, and highlights the features that make it useful to practitioners in different fields of chemical science.

Ligand‐Assisted, Copper(II) Acetate‐Accelerated Azide–Alkyne Cycloaddition

“…On the other hand, based on the kinetic orders of copperA C H T U N G T R E N N U N G (I/II)/TBTA complexes determined by Finn et al and us, we incline to argue that TBTA-assisted CuAAC reactions may take a different pathway than the ligand-free version of the reaction, which has been shown to be second-order in copper. [25,28,29] The kinetic orders of the reaction that involves 1-ethynylcyclohexanol reveal interesting substrate-dependent kinetic behaviors. Compared to phenylacetylene, 1-ethynylcyclohexanol carries a similar kinetic order of 1.5 ( Figure 9).…”

Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications

“…4 The report from Scripps, meanwhile, provides a procedure for the reaction in solution, employing convenient in situ reduction of copper(II) sulfate with ascorbic acid to form the necessary Cu(I) species. 5 This Cu-catalyzed azide alkyne cycloaddition (CuAAC) has since been applied to a great extent, [9][10][11][34][35] not only in chemistry but also in related areas such as biology [36][37][38] and new materials, 39 mainly due to the experimental simplicity of the reaction, as well as its robustness and the high yields obtained. The reaction is tolerant to almost every functional group, can be performed in a wide range of solvents, including water, and has a very favorable atom economy 40 as all ingoing components are, at least in theory, incorporated into the product.…”

“…[4][5] This copper-catalyzed azide alkyne cycloaddition (CuAAC) has since found widespread use even outside the chemistry community. [6][7][8][9][10][11] However, a method to form the corresponding 1,5-disubstituted 1,2,3-triazole isomer was also needed. In 2005 this problem was solved by Fokin and Jia,12 who showed that by exchanging copper for ruthenium, this class of isomers could also be accessed.…”

Utility of tris(4-bromopyridyl) europium complexes as versatile intermediates in the divergent synthesis of emissive chiral probes

“…The triazoleforming copper-catalysed alkyne-azide cycloaddition (CuAAC) reaction is an attractive chemical reaction that allows such synthetic control, due to its wide applicability. 20 The tribromo-complex, [Eu.L 1 ] can be easily transformed into the corresponding triazide, owing to the enhanced electrophilicity of the C-Br bond. Interestingly, only two examples of lanthanide complexes incorporating pyridyl-triazole-aryl acyclic chelating ligands appear in the literature (Fig.…”