The Role of the Leaving Group in the Photo-Favorskii Rearrangement of p-Hydroxyphenacyl

Abstract

The p-hydroxyphenacyl group has several features that make it an attractive photoremovable protecting group. Literature examples support this statement and the benzoate, formate, and sulfonate derivatives are not exceptions. The synthesis of these targets is straight forward involving few synthetic steps that produce the desired product in good to excellent yield. The purification of these targets is simplified by the fact that these derivatives are all solids. Their solubility and stability in polar organic solvents and in water at low concentrations, the formate solubility in water is the exception, make them ideal for use in organic synthesis and in biological applications. The bulk of the photochemical reactions on these derivatives were performed using a low intensity commercially available Southern New England Photoreactor fitted with RPR 3000 Å lamps in order to excite the chromophore in the region where reasonable absorptivity is displayed, at or above 300 nm. Departure of the substrate or leaving group from the p-hydroxyphenacyl chromophore occurs by the heterolytic rupture of the covalent bond connecting the two and is a primary photochemical process. The reaction results in the formation of two major photoproducts, the released substrate and a product resulting from the rearrangement of chromophore. Their lack of photochemical or chemical reactivity with other reagents, solvent, or other products established the stability of these two products. Finally, the photochemical release is fast (108 s-1) and efficient (Φdis = 0.20 - 1.00). p-Hydroxyphenacyl (pHP) caged compounds release substrates through a novel photo-Favorskii rearrangement. In an effort to systematically explore the effects of the leaving group on the efficacy of photorelease, a series of pHP substituted phenol, benzoate, formate, phosphate, and sulfonate esters have been examined. The quantum yields (Φ), Stern-Volmer quenching rates (kq), and release rates (kr) were determined. When this data was combined with the data from laser flash photolysis data, a correlation between the release rate and the pKa of the leaving group was observed. The βLG for this correlation was calculated to be roughly -0.24 showing that photorelease of the substrate is less sensitive to the structure and pKa of the leaving group than is the reference deprotonation reaction of water. The modest value of βLG suggests a small amount of bond cleavage to leaving group in the transition state. The mechanism of photorelease in aqueous or mixed aqueous solvents follows an ionic pathway with the substrate and a proton release occurring from the triplet ester forming a triplet biradical. This biradical then decays forming a spirodienedione intermediate which can either react with water as part of a Favorskii-like rearrangement yielding p-hydroxyphenylacetic acid, or it can undergo decarbonylation to form p-quinone methide. Subsequent reaction of p-quinone methide with water results in the formation of p-hydroxybenzyl alcohol. This mechanism is supported by the results of the quenching of the reaction of the benzoates by a triplet quencher (piperylene), the formation of only photoproducts when pHP formate, mesylate, and tosylate were photolyzed in the presence of a triplet sensitizer (acetone), the absorption bands for the triplet biradical and p-quinone methide that were observed using laser flash photolysis, and the appearance and decay of singlet and triplet species in the time resolved spectra of pHP benzoate and tosylate. A Brønsted correlation relating the rate constant for photorelease to the pKa of the substrate leaving group for several pHP derivatives, including the benzoate, formate, and sulfonate esters, which indicated there is a moderate degree of bond cleavage in the transition state for the adiabatic triplet fragmentation step. These results have added further insight into the mechanism for the photo-Favorskii rearrangements of p-hydroxyphenacyl derivatives.