Competitive CuAAC Reaction between Hydrophobic and Hydrophilic Alkynes with Azides in Water

Abstract

The copper‐catalyzed azide alkyne 1,3‐cycloaddition (CuAAC) reaction has received enormous attention as a powerful tool to form 1,4‐disubstituted‐1,2,3‐triazoles easily and conveniently. Particularly, an efficient protocol of the CuAAC reaction for regioselective double ligation through differentiating the reactivity of an azide or alkyne group is interesting for application in chemical biology, material science and pharmaceutical research. Herein, a simple competitive CuAAC reaction in water using miscibility difference of alkynes with water was discovered. Under conventional CuSO4‐NaAsc catalysts, the CuAAC reaction between a water‐insoluble alkyne and an organic azide furnished a wide range of triazole adducts primarily based on a hydrophobic effect in good‐to‐excellent yields even in the presence of a water‐soluble alkyne. This protocol provides environmentally friendly conditions for aqueous medium, easy and convenient access to triazoles without specially designed ligands for the activation and stabilization of the Cu catalyst and thus is applicable to various fields of chemistry.

Glutathione Mediates Control of Dual Differential Bio‐orthogonal Labelling of Biomolecules

“…When the water‐soluble azide 4 b was used, the rate of triazole formation ( 5 e – h ) was slower compared to that observed for the benzyl azide series. The stark reactivity difference of azide 4 b compared to azide 4 a might be attributed to an “on water” effect, which can accelerate cycloaddition reactions when hydrophobic substrates are used [53–55] . In this instance, the kinetics of the otherwise sluggish reaction (Figure S11) between 1 a and 4 b increased by the addition of NaAsc to form 5 b , further suggestive of the influence of the physicochemical properties of the azide on the rate of triazole formation.…”