Intermediates Stabilized by Tris(triazolylmethyl)amines in the CuAAC Reaction

Abstract

Tris(triazolylmethyl)amine ligands (TL) are widely used to accelerate the Cu^I -catalyzed azide-alkyne cycloaddition (CuAAC) reaction, but its mechanistic role remains unclear. Using electrospray ionization mass spectrometry, we detected for the first time the trinuclear TL-Cu^I₃ -acetylide and the dinuclear TL-Cu^I₂ -acetylide complexes in aqueous solution. The apparent second-order rate constants of their reaction with an azide were 27 and 783 m^-1 ⋅s^-1 when the alkyne was tethered to TL. In the catalytic system without the tether, the rate constant increased to >146 m^-1 ⋅s^-1 for the TL-Cu^I₃ -acetylide, but dropped about 14-fold to approximately 55 m^-1 ⋅s^-1 for the TL-Cu^I₂ -acetylide. The results indicated that TL accelerated the reaction by stabilizing the Cu^I₂ - and Cu^I₃ -acetylide and their azide-adduct intermediates, but this role is largely weakened by excess alkyne and other competing ligands under catalytic conditions.

Keywords: CuAAC; click chemistry; mass spectrometry; reactive intermediate; tri-copper acetylide.