Mechanistic Insights Into Synephrine Isomerization Under Acidic and Neutral Conditions: A Combined Kinetic, Thermodynamic, and Quantum Chemical Approach

Abstract

Synephrine is a chiral compound that exists as two enantiomers, the (R)- and (S)-forms. The present study investigated the effects of pH and heating conditions on the isomerization of synephrine. Each enantiomer was quantified after FMOC derivatization using chiral liquid chromatography with UV detection (chiral-LC/UV). When (R)-synephrine was incubated under acidic or neutral conditions at elevated temperatures, isomerization was promoted in a temperature-dependent manner under both conditions. The isomerization rate under the acidic condition was approximately 10- to 40-fold higher than that under the neutral condition, and the time-dependent progression followed pseudo-first-order kinetics under both conditions. Analysis of physicochemical parameters, including the activation entropy (ΔS^‡), suggested that the reaction mechanisms differ between the acidic and neutral conditions. To elucidate the detailed isomerization mechanisms, quantum chemical calculations based on density functional theory (DFT) were performed. Under acidic conditions, DFT geometry optimization demonstrated that the amino group is preferentially protonated (NH₂⁺), consistent with its higher thermodynamic basicity, followed by departure of the β-hydroxyl group to generate a benzylic carbocation intermediate. LUMO localization at the β-carbon of the benzylic carbocation and its planar sp² geometry support nucleophilic water attack from either face, leading to racemization. Under neutral conditions, a retro-Mannich-type fragmentation mechanism was proposed, in which the C–C bond between the α- and β-carbons undergoes heterolytic cleavage—driven primarily by electron donation from the β-hydroxyl oxygen lone pair and assisted by vinylogous conjugation from the phenolic oxygen via the aromatic ring—to generate an aldehyde and an imine as intermediates. Subsequent recombination of these fragments was proposed to yield a racemic mixture. These findings confirmed that synephrine undergoes isomerization upon heating under both acidic and neutral conditions.