Physicochemical Properties of 4-(4-Hydroxyphenyl)-butan-2-one (‘Raspberry Ketone’) Evaluated Using a Computational Chemistry Approach

Raspberry ketone (RK) is a product of the phenylpropanoid pathway in a variety of plants and is the second mostexpensive natural flavouring in the world. It is also widely used as a nutritional supplement due to its reported ability to promotelipolysis and fat oxidation in vivo. We have evaluated the thermodynamics of RK using the correlation consistent ccCA-CBS-2approach which afforded calculation of (inter alia) the enthalpy of formation. To obtain pKa, log D, electrode potential, solubility,and reactivity indices, we used TPSS/def2-TZVP geometries followed by single-point energies obtained at the M06-2X/def2-TZVPP level of theory. We obtained ΔfHo = −299.4 ± 0.17 kJ·mol−1; the pKa and logD were found to be 9.95 and 1.84, respectively,consistent with chemometric predictions. Using the enthalpy of fusion obtained from theory, we evaluated the aqueous solubility ofRK to be in the region of 2.5 mg·mL−1 which is in agreement with limited literature reports. In terms of reactivity, we obtained aformal electrode potential of 1.29 V (vs SHE) at pH 7.4 and 298.15 K. The HOMO−LUMO energy separation in an aqueousenvironment was found to be ca. 7.8 eV, suggesting moderate chemical reactivity. Analysis of the frontier molecular orbitals usingconceptual density functional theory supported this and revealed a reactivity pattern consistent with the metabolite profile obtainedin mammals, namely, a propensity for nucleophilic attack at the carbonyl carbon and electrophilic addition of the benzene ring.