Regenerable Chain-Breaking 2,3-Dihydrobenzo[b]selenophene-5-ol Antioxidants

A series of 2,3-dihydrobenzo[b]selenophene-5-ol antioxidants was prepared by subjecting suitably substituted allyl 4-methoxyphenyl selenides to microwave-induced seleno-Claisen rearrangement/intramolecular Markovnikov hydroselenation followed by boron tribromide-induced O-demethylation. The novel antioxidants were assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system containing N-acetylcysteine as a thiol reducing agent in the aqueous phase. Antioxidant efficiency as determined by the inhibited rate of peroxidation, R_inh, increased with increasing methyl substitution (R_inh = 46−26 μM/h), but none of the compounds could match α-tocopherol (R_inh = 22 μM/h). Regenerability as determined by the inhibition time, T_inh, in the presence of the thiol regenerating agent decreased with increasing methyl substitution. Thus, under conditions where the unsubstituted compound 5a inhibited peroxidation for more than 320 min, α-tocopherol worked for 90 min and the trimethylated antioxidant 5g for 60 min only. Sampling of the aqueous phase at intervals during peroxidation using antioxidant 5a showed that N-acetylcysteine was continuously oxidized with time to the corresponding disulfide. In the absence of the regenerating agent, compounds 5 inhibited peroxidation for 50−60 min only. A (RO)B3LYP/LANL2DZdp//B3LYP/LANL2DZ model was used for the calculation of homolytic O−H bond dissociation enthalpies (BDE) and adiabatic ionization potentials (IP) of phenolic antioxidants 5. Both BDE (80.6−76.3 kcal/mol) and IP (163.2−156.0 kcal/mol) decrease with increasing methyl substitution. The phenoxyl radical corresponding to phenol 5g gave an intense ESR signal centered at g = 2.0099. The H−O bond dissociation enthalpy of the phenol was determined by a radical equilibration method using BHA as an equilibration partner. The observed BDE (77.6 ± 0.5 kcal/mol) is in reasonable agreement with calculations (76.3 kcal/mol). As judged by calculated log P values, the lipophilicity of compounds 5 increased slightly when methyl groups were introduced into the phenolic moiety (2.9 > C log P < 4.2). The capacity of compounds 5a (k_inh = 3.8 × 10⁵ M^-1 s^-1) and 5g (k_inh = 1.5 × 10⁶ M^-1 s^-1) to inhibit azo-initiated autoxidation of styrene in the homogeneous phase (chlorobenzene) was also studied. More efficient regeneration at the lipid−aqueous interphase is the most likely explanation why the intrinsically poorest antioxidant 5a can outperform its analogues as well as α-TOC in the two-phase system. Possible mechanisms of regeneration are discussed and evaluated.