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

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-CuI 3 -acetylide and the dinuclear TL-CuI 2 -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-CuI 3 -acetylide, but dropped about 14-fold to approximately 55 m-1 ⋅s-1 for the TL-CuI 2 -acetylide. The results indicated that TL accelerated the reaction by stabilizing the CuI 2 - and CuI 3 -acetylide and their azide-adduct intermediates, but this role is largely weakened by excess alkyne and other competing ligands under catalytic conditions.