Chain‐Breaking Phenolic 2,3‐Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies

• Published in: Chemistry : a European journal 2017-10, Vol.23 (60), p.15080-15088
• Main Authors: Singh, Vijay P., Yan, Jiajie, Poon, Jia‐Fei, Gates, Paul J., Butcher, Ray J., Engman, Lars
• Format: Article
• Language: English
• Subjects: Acetylcysteine; Antioxidants; Ascorbic acid; Binary systems; chain-breaking antioxidants; Chemistry; Chemistry with specialization in Organic Chemistry; Claisen rearrangement; co-antioxidants; Crystallography; dihydrobenzoselenophenes; Dithiothreitol; Glutathione; Hydrogen bonds; Kemi med inriktning mot organisk kemi; Linoleic acid; Lipid peroxidation; Peroxidation; Peroxyl radicals; pH effects; Phenolic compounds; Phenols; Phosphine; Quenching; Regeneration; Selenium; Tocopherol; X-ray crystallography
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.201702350

Phenolic 2,3‐dihydrobenzo[b]selenophene antioxidants bearing an OH‐group ortho (9), meta (10, 11) and para (8) to the Se were prepared by seleno‐Claisen rearrangement/intramolecular hydroselenation. meta‐Isomer (11) was studied by X‐ray crystallography. The radical‐trapping activity and regenerability of compounds 8–11 were evaluated using a two‐phase system in which linoleic acid was undergoing peroxidation in the lipid phase while regeneration of the antioxidant by co‐antioxidants (N‐acetylcysteine, glutathione, dithiothreitol, ascorbic acid, tris(carboxyethyl)phosphine hydrochloride) was ongoing in the aqueous layer. Compound 9 quenched peroxyl radicals more efficiently than α‐tocopherol. It also provided the most long‐lasting antioxidant protection. With thiol co‐antioxidants it could inhibit peroxidation for more than five‐fold longer than the natural product. Regeneration was more efficient when the aqueous phase pH was slightly acidic. Since calculated O−H bond dissociation energies for 8–11 were substantially larger than for α‐tocopherol, an antioxidant mechanism involving O‐atom transfer from peroxyl to selenium was proposed. The resulting phenolic selenoxide/alkoxyl radical would then exchange a hydrogen atom in a solvent cage before antioxidant regeneration at the aqueous lipid interphase. A phenolic dihydrobenzoselenophene antioxidant, bearing the OH‐group ortho to the Se atom quenches lipid peroxyl radicals more efficiently than α‐tocopherol and is readily regenerable by aqueous‐phase co‐antioxidants such as N‐acetylcysteine, glutathione, dithiothreitol, ascorbic acid, and tris(carboxyethyl)phosphine hydrochloride.