Flavanone-enabled CuAAC Reaction: Noninnocent Reagents Driving a Mononuclear Mechanism Over the Dinuclear Paradigm.

In this work, we report the use of the CuAAC (copper-catalyzed azide-alkyne cycloaddition) reaction to obtain different triazole derivatives bridged to the naringenin skeleton, leading to the combination of a triazole pharmacophoric group with a bioactive flavanone. The generation of Cu(I) active species was done using CuSO salts and sodium ascorbate, resulting in moderate to high yields when the DMSO-water binary system was used as solvents. Mechanistic studies were done using density functional theory calculations and high-resolution mass spectrometry (HRMS). We investigated the reduction process of Cu(II) to Cu(I), and the role of mononuclear and dinuclear copper species in the catalysis of the cycloaddition reaction. Our combined theoretical and experimental results indicate that the mechanism involving a single copper species is taking place, with the cycloaddition step being the rate-determining step. The calculations indicate that the mechanism involving two copper species has the deprotonation of the coordinated terminal alkyne as the rate-determining step.