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

AbstractTris(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‐CuI3‐acetylide and the dinuclear TL‐CuI2‐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‐CuI3‐acetylide, but dropped about 14‐fold to approximately 55 m−1⋅s−1 for the TL‐CuI2‐acetylide. The results indicated that TL accelerated the reaction by stabilizing the CuI2‐ and CuI3‐acetylide and their azide‐adduct intermediates, but this role is largely weakened by excess alkyne and other competing ligands under catalytic conditions.