Ambident Reactivity of Phenolate Anions Revisited: A Quantitative Approach to Phenolate Reactivities

Prompted by the observation that the regioselectivities of phenolate reactions (C versus O attack) are opposite to the predictions by the principle of hard and soft acids and bases, we performed a comprehensive experimental and computational investigation of phenolate reactivities. Rate and equilibrium constants for the reactions of various phenolate ions with benzhydrylium ions (Aryl₂CH⁺) and structurally related quinone methides have been determined photometrically in polar aprotic solvents. Quantum chemical calculations at the SMD(MeCN)/M06-2X/6-31+G(d,p) level confirmed that O attack is generally favored under kinetically controlled conditions, whereas C attack is favored under thermodynamically controlled conditions. Exceptions are diffusion-limited reactions with strong electrophiles, which give mixtures of products arising from O and C attack, as well as reactions with metal alkoxides in nonpolar solvents, where oxygen attack is blocked by strong ion pairing. The Lewis basicity (LB) and nucleophilicity (N, s_N) parameters of phenolates determined in this work can be used to predict whether their reactions with electrophiles are kinetically or thermodynamically controlled and whether the rates are activation- or diffusion-limited. Comparison of the measured rate constants for the reactions of phenolates with carbocations with the Gibbs energies for single-electron transfer manifests that these reactions proceed via polar mechanisms.