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

摘要

Tris(triazolylmethyl)amine ligands (TL) are widely used to accelerate the CuI-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~I_3-acetylide and the dinuclear TL-Cu~I_2-acetylide complexes in aqueous solution. The apparent second-order rate constants of their reaction with an azide were 27 and 783m~(-1)·s~(-1) when the alkyne was tethered to TL. In the catalytic system without the tether, the rate constant increased to >146m~(-1)·s~(-1) for the TL-Cu~I_3-acetylide, but dropped about 14-fold to approximately 55m~(-1)·s~(-1) for the TL-Cu~I_2-acetylide. The results indicated that TL accelerated the reaction by stabilizing the Cu~I_2- and Cu~I_3-acetylide and their azide-adduct intermediates, but this role is largely weakened by excess alkyne and other competing ligands under catalytic conditions.