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

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 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 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 I 3 ‐acetylide, but dropped about 14‐fold to approximately 55  m −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.