Solvent polarity effects on thermochemical and NMR parameters of spilanthol pharmacological agent: an experimental and DFT investigation

Abstract

Through experimental and appropriate quantum chemical approaches, we perform a systematic investigation of the solvent effects on thermochemical and nuclear magnetic resonance (NMR) parameters of (2E,6Z,8E)-N-isobutyl-2,6,8-decatrienamide (spilanthol). The NMR parameters linked to the hydrophobic part of spilanthol present insignificant environmental dependence. However, spin-spin coupling constants such as 1JCO, 1JCN, and 1JNH associated with the amine and active carbonyl sites suffer strong solvent effects of ca. 17%. The 17O shielding constants show the highest sensitivity concerning the solvent polarity, ca. 71%, indicating that oxygen is an appropriate probe for structural characterization. However, the results suggest that the structural changes are partly responsible for these effects, and the significant contribution comes from solute polarization. For polar environments, the NMR parameters become invariant regarding the solvent polarity, which suggests that spilanthol stabilizes better in polar surroundings. These results show that the participation of the solvent is fundamental for a series of effects concerning the stability of the compound. For instance, the analysis of the enthalpy, electronic, and Gibbs free energies suggests that spilanthol is more stable when solvated in organic solvents of moderate dielectric constant, which can improve the extraction process of the compound. Moreover, quantum mechanical calculations performed using self-consistent-charge density-functional based on tight-binding methods considering explicit solvent molecules indicated that the energetic yield obtained in ethanol is higher than that in water solution. The used protocol shows that the energetic and structural parameters of spilanthol are strongly disturbed by the environment and allow to predict accurately its behavior.