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 autoxidn. processes in a polar solvent (acetonitrile)​, due to a lower susceptibility to the adverse effects of hydrogen bonding with the solvent. Detn. of O-​H bond dissocn. 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 calcns. of the BDEOH using an explicit methanol mol. 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 arom. ring resulted in a dramatic decrease in the computed BDEOH values suggesting a potentially higher activity than the ref. 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 derivs. in a rational and predictable fashion.