Oxidation with a Stopover - Stable Zwitterions as Intermediates in the Oxidation of α-Tocopherol (Vitamin E) Model Compounds to their Corresponding ortho-Quinone Methides

As a prominent member of the vitamin E group, alpha-tocopherol is an important lipophilic antioxidant. It has a special oxidation chemistry that involves phenoxyl radicals, quinones and quinone methides. During the oxidation to the ortho-quinone methide, an intermediary zwitterion is formed. This aromatic intermediate turns into the quinone methide by simply rotating the initially oxidized, exocyclic methyl group into the molecule's plane. This initial zwitterionic intermediate and the quinone methide are not resonance structures but individual species, whose distinct electronic structures are separated by a mere 90 degrees bond rotation. In this work, we hindered this crucial rotation, by substituting the affected methyl group with alkyl or phenyl groups. The alkyl groups slowed down the conversion to the quinone methide by 18-times, while the phenyl substituents, which additionally stabilize the zwitterion electronically, completely halted the conversion to the quinone methide at -78 degrees C, allowing for the first time the direct observation of a tocopherol-derived zwitterion. Employing a C-13-labeled model, the individual steps of the oxidation sequence could be observed directly by NMR, and the activation energy for the rotation could be estimated to be approximately 2.8 kcal/mol. Reaction rates were solvent dependent, with polar solvents exerting a stabilizing effect on the zwitterion. The observed effects confirmed the central relevance of the rotation step in the change from the aromatic to the quinoid state and allowed a more detailed examination of the oxidation behavior of tocopherol. The concept that a simple bond rotation can be used to switch between an aromatic and an anti-aromatic structure could find its use in molecular switches or molecular engines, driven by the specific absorption of external energy.

Automated summary

This study investigates the oxidation process of alpha-tocopherol, revealing the mechanism of formation for the intermediate zwitterion and quinone methide, and demonstrating that substituting the affected methyl group can slow down the conversion rate. The results confirm the central relevance of the rotation step in the transition from an aromatic to a quinoid state.