Résumé
A novel series of α-phenyl-N-tert-butyl nitrone derivatives, bearing a hydrophobic chain on the aromatic ring and three hydroxyl functions on the tert-butyl group, was synthesized through a short and convenient synthetic route based on a one-pot reduction/condensation of tris(hydroxymethyl)nitromethane with a benzaldehyde derivative. Because of the presence of hydroxyl functions on the tert-butyl group, an intramolecular Forrester−Hepburn reaction leading to the formation of an oxazolidine-N-oxyl compound was observed by electron paramagnetic resonance (EPR). The mechanism of cyclization was further studied by computational methods showing that intramolecular hydrogen bonding and high positive charge on the nitronyl carbon could facilitate the nucleophilic addition of a hydroxyl group onto the nitronyl carbon. At high nitrone concentrations, a second paramagnetic species, very likely formed by intermolecular nucleophilic addition of two nitrone molecules, was also observed but to a lesser extent. In addition, theoretical data confirmed that the intramolecular reaction is much more favored than the intermolecular one. These nitrones were also found to efficiently trap carbon-centered radicals, but complex spectra were observed due to the presence of oxazolidine-N-oxyl derivatives. ■ INTRODUCTION Oxidative stress was defined as a disturbance in the prooxidant− antioxidant balance in favor of the former, leading to potential damage, and it has become clear that an overproduction of prooxidant molecules, also termed reactive oxygen and nitrogen species (ROS/RNS), is associated with several pathologies such as neurodegenerative diseases, cancers, and ischemia−reperfu-sion syndromes to name a few. 1 Consequently, any agent that can trap ROS/RNS to form more stable adducts, and as a result can alter the course of diseases progression, may be useful as a novel therapeutic approach. Of particular interest are nitrone spin-traps, which undergo addition reaction with free radicals, making them a popular analytical reagent for the identification of short-lived radicals using electron paramagnetic resonance (EPR) spectroscopy. 2,3