Mechanism of Oxygenation of 2,6-Di-tert-butylphenol Derivative (2006)

The base-catalyzed oxygenation of phenol or naphthol derivatives has been of interest in both biological and synthetic system. In general, when phenoxide anions 1 are exposed to triplet molecular oxygen, the corresponding epoxy alcohols 7 are formed in nearly quantitative yield. Possible reaction pathway for the oxidation process is proposed as shown in Scheme 1. Reaction of the phenoxide anions 1 and molecular oxygen results in the peroxides 4, which then undergo intramolecular conjugate addition to form the dioxetane enolate anions 5. Finally, dioxetane ring opening by nucleophilic displacement yields the epoxy alcohols 6. However, the reaction pathway of molecular oxygen and phenoxide anions 1 to form the peroxides 4 might be unfavorable because the singlet phenolate anions 1 cannot react in a single step with triplet molecular oxygen to yield the singlet products. To overcome the spin-forbidden rule, two possible mechanisms of base-catalyzed oxygenation of phenol derivatives have been proposed. One is a charge transfer mechanism (pathway 1), where the phenolate anion 1 interacts with πorbital of molecular oxygen to afford a triplet charge transfer complex 2. The complex then experiences intersystem crossing i.e., one of unpaired electrons undergoes the spin inversion from the triplet charge transfer complex to the singlet complex, giving a singlet oxygen. Alternative pathway is an electron transfer mechanism (pathway 2). The phenoxide anions 1 react with molecular oxygen to give the phenoxyl radicals 3 and superoxide by one-electron transfer. The phenoxyl radicals 3 then trap superoxide to yield the peroxy anions 4. Here we report theoretical and experimental investigations of the possible intermediate involved in the base-catalyzed oxygenation of phenol derivative. Previously, we synthesized the cyclopropyl derivative 8 of 2,6-di-tert-butylphenol to distinguish phenoxide anion 11 from the phenoxy radical 12 in the course of autoxidation because rearrangement of the cyclopropyl radical to homoallylcarbinyl radical was thought to be effective in the shortlived radical trap. When a solution of potassium phenolate 9 in tetrahydrofuran was stirred under an atmosphere of oxygen at room temperature, the corresponding epoxy alcohol 10 was formed and no ring-opened product 14 was detected in the reaction mixtures. Therefore, we suggested a charge transfer mechanism describing the action of basecatalyzed oxygenation of phenols. Although it has been suggested that α-cyclopropylbenzyl radicals undergo fairly rapid rearrangement, little is known about the stabilities of cyclopropylcarbinyl radical 12 with the radical-stabilizing group and homoallylcarbinyl radical 13. Interestingly, in this study, our semi-empirical calculation using AM1 indicated that the Gibbs free energies of radical 12 and radical 13 are −4266.39 kcal/mol and −4265.70 kcal/ mol, respectively, showing that the free energy change of rearrangement is endothermic by 0.69 kcal/mol. This result suggests that ring-opening of 12 can not be only reversible but that equilibrium may favor the ring closed form, and the radical probe 8 might give an unclear guide to charge transfer mechanism in the previous work. To examine whether singlet oxygen was really produced via energy transfer, we then carried out the oxygenation reaction of potassium phenolate 9 in the presence of 1,4-diazbicyclo[2,2,2]octane(Dabco), which has been known to inhibit singlet oxygen reactions but has little effect on free radical reactions. However, addition of Dabco did not have any influence, indicating that singlet oxygen was not a primary oxidizing species in the base-catalyzed autoxidation. Regarding electron transfer from the phenoxide anion to molecular oxygen (pathway 2), it has been proposed that superoxide ion does not couple with 2,6-di-tert-butylphenoxy radicals but reduces radicals to give the corresponding phenoxide anions, and mechanism involving for the base-