Electrochemically protected copper(I)-catalyzed azide-alkyne cycloaddition

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has found broad application in myriad fields. For the most demanding applications that require high yields at low substrate concentrations, highly active but air-sensitive copper complexes must be used. We describe here the use of an electrochemical potential to maintain catalysts in the active Cu-I oxidation state in the presence of air. This simple procedure efficiently achieves excellent yields of CuAAC products from both small-molecule and protein substrates without the use of potentially damaging chemical reducing agents. A new water-soluble carboxylated version of the popular tris(benzyltriazolylmethyl)amine (TBTA) ligand is also described. Cyclic voltammetry revealed reversible or quasi-reversible electrochemical redox behavior of copper complexes of the TBTA derivative (2; E-1/2 = 60 mV vs. Ag/AgCl), sulfonated bath-ophenanthroline (3; E-1/2 = -60 mV), and sulfonated tris(benzimidazoylmethyl)amine (4; E-1/2 approximate to -70mV), and showed catalytic turnover to be rapid relative to the voltammetry time scale. Under the influence of a -200 mV potential that was established by using a reticulated vitreous carbon working electrode, CuSO4 and 3 formed a superior catalyst Electrochemically protected bioconjugations in air were performed by using bacteriophage Q beta that was derivatized with azide moieties at surface lysine residues. Complete derivatization of more than 600 reactive sites per particle was demonstrated within 12 h of electrolysis with sub-stoichiometric quantities of Cu-3.