Mechanistic study of the structure-activity relationship for the free radical scavenging activity of baicalein

Density functional theory calculations were performed to evaluate the antioxidant activity of baicalein. The conformational behaviors of both the isolated and the aqueous-solvated species (simulated with the conductor-like polarizable continuum solvation model) were analyzed at the M052X/6-311 + G(d,p) level. The most stable tautomers of various forms of baicalein displayed three IHBs between O4 and OH5, O5 and OH6, and O6 and OH7. The most stable tautomer of the baicalein radical was obtained by dehydrogenating the hydroxyl at C6, while the most stable anion tautomer was obtained by deprotonating the C7 hydroxyl in gaseous and aqueous phases. The expected antioxidant activity of baicalein was explained by its ionization potentials (IPs) and homolytic O-H bond dissociation enthalpies (BDEs), which were obtained via the UM052X optimization level of the corresponding radical species. Heterolytic O-H bond cleavages (proton dissociation enthalpies, PDEs) were also computed. The calculated IP, BDE, and PDE values suggested that one-step H-atom transfer, rather than sequential proton loss-electron transfer or electron transfer-proton transfer, would be the most favorable mechanism for explaining the antioxidant activity of baicalein in the gas phase and in nonpolar solvents. In aqueous solution, the SPLET mechanism was more important.