title: Regenerable chain-breaking 2,3-dihydrobenzo[b]selenophene-5-ol antioxidants.
abstract: 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, Rinh, increased with increasing methyl substitution (Rinh=46-26 microM/h), but none of the compounds could match alpha-tocopherol (Rinh=22 microM/h). Regenerability as determined by the inhibition time, Tinh, 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, alpha-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 (kinh=3.8x10(5) M-1 s-1) and 5g (kinh=1.5x10(6) 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 alpha-TOC in the two-phase system. Possible mechanisms of regeneration are discussed and evaluated.
authors.affiliation: Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Sangit
authors.initials: S
authors.lastname: Kumar
authors.forename: Henrik
authors.initials: H
authors.lastname: Johansson
authors.forename: Lars
authors.initials: L
authors.lastname: Engman
authors.forename: Luca
authors.initials: L
authors.lastname: Valgimigli
authors.forename: Riccardo
authors.initials: R
authors.lastname: Amorati
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Fumo
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Pedulli
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D000975:Antioxidants / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D015227:Lipid Peroxidation; D015394:Molecular Structure; D010545:Peroxides / Q000737:chemistry; D018036:Selenium Compounds / Q000737:chemistry*
chemical_list: C519435:2,3-dihydrobenzo(b)selenophene-5-ol; D000975:Antioxidants; D010545:Peroxides; D018036:Selenium Compounds; C049375:perhydroxyl radical; D000111:Acetylcysteine