Acid-Promoted Reaction of the Stilbene Antioxidant Resveratrol with Nitrite Ions:  Mild Phenolic Oxidation at the 4‘-Hydroxystiryl Sector Triggering Nitration, Dimerization, and Aldehyde-Forming Routes

In 0.1 M phosphate buffer, pH 3.0, and at 37 °C, resveratrol ((E)-3,4‘,5-trihydroxystilbene, 1a), an antioxidant and cancer chemopreventive phytoalexin, reacted smoothly at 25 μM or 1 mM concentration with excess nitrite ions (NO2 -) to give a complex pattern of products, including two novel regioisomeric α-nitro (3a) and 3‘-nitro (4) derivatives along with some (E)-3,4‘,5-trihydroxy-2,3‘-dinitrostilbene (5), four oxidative breakdown products, 4-hydroxybenzaldehyde, 4-hydroxy-3-nitrobenzaldehyde, 3,5-dihydroxyphenylnitromethane, and 3,5-dihydroxybenzaldehyde, two dimers, the resveratrol (E)-dehydrodimer 6 and restrytisol B (7), and the partially cleaved dimer 2. The same products were formed in the absence of oxygen. 1H,15N HMBC and LC/MS analysis of the crude mixture obtained by reaction of 1a with Na15NO2 suggested the presence of 3,4‘,5,β-tetrahydroxy-α-nitro-α,β-dihydrostilbene (8) as unstable intermediate which escaped isolation. Under similar conditions, the structurally related catecholic stilbene piceatannol ((E)-3,3‘,4,5‘-tetrahydroxystilbene, 1b) gave, besides (E)-3,3‘,4,5‘-tetrahydroxy-β-nitrostilbene (3b), 3,4-dihydroxybenzaldehyde and small amounts of 3,5-dihydroxybenzaldehyde. Mechanistic experiments were consistent with the initial generation of the phenoxyl radical of 1a at 4‘-OH, which may undergo free radical coupling with NO2 at the α- or 3‘-position, to give eventually nitrated derivatives and/or oxidative double bond fission products, or self-coupling, to give dimers. The oxygen-independent, NO2 - -mediated oxidative fission of the double bond under mild, physiologically relevant conditions is unprecedented in stilbene chemistry and is proposed to involve breakdown of hydroxynitro(so) intermediates of the type 8.