Science of Synthesis

Paterson, A. J.; Beke-Somfai, T.; Kann, N., Science of Synthesis: Click Chemistry, (2021) 1, 289.

General Introduction

Heterocyclic triazoles are useful in many areas of chemistry, such as in the synthesis of bioactive compounds, in materials science, or as components of electronic devices.[‌1‌–‌3‌] Disubstituted 1,2,3-triazoles are of particular interest, because they can be accessed in a single step simply by heating an azide and an alkyne, whereby all atoms of the starting materials are incorporated into the final product.[‌4‌] Under such thermal conditions, the disubstituted triazole is formed as a mixture of two isomers (‌Scheme 1‌, path a).[‌5‌] Control over the regioselectivity is therefore necessary to find practical use for this azide–alkyne cycloaddition reaction. This problem was in part solved by the groups of Meldal[‌6‌] and Sharpless,[‌7‌] who in 2002 both reported that by adding catalytic amounts of copper(I) to the reaction, the 1,4-disubstituted 1,2,3-triazole isomer could be produced selectively (‌Scheme 1‌, path b). This copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction (see Section 2) has since then found a plethora of applications,[‌8‌–‌11‌] including ligation methods for “clicking” a chemical entity onto a biomolecule[‌12‌] or a surface.[‌13‌] Only a few years later, Fokin, Jia, and co-workers showed that by changing copper for ruthenium, the 1,5-disubstituted 1,2,3-triazole isomer could instead be accessed in a selective manner via a ruthenium-catalyzed azide–alkyne cycloaddition (RuAAC) reaction (‌Scheme 1‌, path c).[‌14‌]

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References