5-S-Lipoylhydroxytyrosol, a Multidefense Antioxidant Featuring a Solvent-Tunable Peroxyl Radical-Scavenging 3-Thio-1,2-dihydroxybenzene Motif

5-S-Lipoylhydroxytyrosol (1), the parent member of a novel group of bioinspired multidefense antioxidants, is shown herein to exhibit potent peroxyl radical scavenging properties that are controlled in a solvent-dependent manner by the sulfur center adjacent to the active o-diphenol moiety. With respect to the parent hydroxytyrosol (HTy), 1 proved to be a more potent inhibitor of model autoxidation processes in a polar solvent (acetonitrile), due to a lower susceptibility to the adverse effects of hydrogen bonding with the solvent. Determination of O-H bond dissociation enthalpies (BDE) in t-butanol by EPR radical equilibration technique consistently indicated a ca. 1.5 kcal/mol lower value for 1 relative to HTy. In good agreement, DFT calculations of the BDEOH using an explicit methanol molecule to mimic solvent effects predicted a 1.2 kcal/mol lower value for 1 relative to HTy. Forcing the geometry of the -S-R group to coplanarity with the aromatic ring resulted in a dramatic decrease in the computed BDEOH values suggesting a potentially higher activity than the reference antioxidant α-tocopherol, depending on geometrical constrains in microheterogeneous environments. These results point to sulfur substitution as an expedient tool to tailor the chain-breaking antioxidant properties of catechol derivatives in a rational and predictable fashion.