Time-resolved keto–enol tautomerization of the medicinal pigment curcumin

Abstract

Curcumin is a medicinal agent that exhibits anti-cancer and anti-Alzheimer's disease properties. It has a keto–enol moiety that gives rise to many of its chemical properties including metal complexation and acid–base equilibria. A previous study has shown that keto–enol tautomerization at this moiety is implicated in the anti-Alzheimer's disease effect of curcumin, highlighting the importance of this process. In this study, tautomerization of curcumin in methanol, acetone and acetonitrile was investigated using time-resolved ¹H nuclear magnetic resonance spectroscopy. Curcumin undergoes hydrogen–deuterium exchange with the solvents and the proton resonance peak corresponding to the hydrogen at the α-carbon position (C_α) decays as a function of time, signifying deuteration at this position. Because tautomerization is the rate limiting step in the deuteration of curcumin at the C_α position, the rate of tautomerization is inferred from the rate of deuteration. The rate constant of tautomerization of curcumin shows a temperature dependence and analysis using the Arrhenius equation revealed activation energies (E_a) of tautomerization of (80.1 ± 5.9), (64.1 ± 1.0) and (68.3 ± 5.5) kJ mol⁻¹ in methanol, D₂O/acetone and D₂O/acetonitrile, respectively. Insight into the role of water in tautomerization of curcumin was further offered by density functional theory studies. The transition state of tautomerization was optimized in the presence of water molecules. The results show a hydrogen-bonded solvent bridge between the diketo moiety and C_α of curcumin. The E_a of tautomerization of curcumin shows a strong dependence on the number of water molecules in the solvent bridge, indicating the critical role played by the solvent bridge in catalyzing tautomerization of curcumin.