Abstract
The copper-catalyzed azide–alkyne cycloaddition (CuAAC) is one of the most broadly applicable and easy-to-handle reactions in the arsenal of organic chemistry. However, the mechanistic understanding of this reaction has lagged behind the plethora of its applications for a long time. As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I) alkyne and acetylide complexes. Following an introductory section on common catalyst systems in CuAAC reactions, this review will highlight experimental and computational studies from early proposals to very recent and more sophisticated investigations, which deliver more detailed insights into the CuAAC’s catalytic cycle and the species involved. As diverging mechanistic views are presented in articles, books and online resources, we intend to present the research efforts in this field during the past decade and finally give an up-to-date picture of the currently accepted dinuclear mechanism of CuAAC. Additionally, we hope to inspire research efforts on the development of molecularly defined copper(I) catalysts with defined structural characteristics, whose main advantage in contrast to the regularly used precatalyst reagent mixtures is twofold: on the one hand, the characteristics of molecularly defined, well soluble catalysts can be tuned according to the particular requirements of the experiment; on the other hand, the understanding of the CuAAC reaction mechanism can be further advanced by kinetic studies and the isolation and characterization of key intermediates.
Highlights
In 1893, Michael discovered a reaction between dimethyl but-2ynedioate and phenyl azide at 100 °C in a sealed tube and suggested that regioisomeric triazoles were formed [1].it was only in the 1960s that Huisgen recognized this type of reaction for its generality, scope and mechanism [2,3,4,5], and coined the term 1,3-dipolar cycloaddition
As reagent mixtures of copper salts and additives are commonly used in CuAAC reactions, the structure of the catalytically active species itself has remained subject to speculation, which can be attributed to the multifaceted aggregation chemistry of copper(I) alkyne and acetylide complexes
We hope to inspire research efforts on the development of molecularly defined copper(I) catalysts with defined structural characteristics, whose main advantage in contrast to the regularly used precatalyst reagent mixtures is twofold: on the one hand, the characteristics of molecularly defined, well soluble catalysts can be tuned according to the particular requirements of the experiment; on the other hand, the understanding of the CuAAC reaction mechanism can be further advanced by kinetic studies and the isolation and characterization of key intermediates
Summary
In 1893, Michael discovered a reaction between dimethyl but-2ynedioate and phenyl azide at 100 °C in a sealed tube and suggested that regioisomeric triazoles were formed [1]. The group of Sharpless, on the other hand, presented a coppercatalyzed azide–alkyne cycloaddition under solution-phase conditions (Scheme 2) [12] In their standard procedure, the cost-efficient salt copper(II) sulfate pentahydrate is reduced in situ by ascorbic acid or sodium ascorbate in a solvent mixture of water and alcohol (“Sharpless–Fokin conditions”). In order to protect the copper(I) ions from disproportionation to Cu(0) and Cu(II) and from re-oxidation to Cu(II) by air, to enhance their catalytic activity and to improve the reaction’s applicability with a variety of substrates, the search for suitable ligands started immediately after Sharpless’ and Meldal’s initial reports [8,12] After their seminal communication on the CuAAC reaction, the group of Sharpless reported the observation of an autocatalytic effect in the synthesis of tris(triazolylmethyl)amines, i.e. the tris(triazolylmethyl)amine products act as rate-accelerating ligands [45]. NH NH NH NH NH NCH3 N(CH2)2Me N(CH2)CO2Et N(CH2)CO2t-Bu N(CH2)CO2K N(CH2)3CO2K N(CH2)4CO2K N(CH2)4CO2K N(CH2)4CO2Et N(CH2)4CO2K N(CH2)4CO2K N(CH2)5CO2K N(CH2)5CO2K S
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