Proton and sodium cation affinities of harpagide: A computational study

The aim of this work was to estimate the proton and sodium cation affinities of harpagide (Har), an iridoid glycoside responsible for the antiinflammatory properties of the medicinal plant Harpagophytum. Monte Carlo conformational searches were performed at the semiempirical AM1 level to determine the most stable conformers for harpagide and its protonated and Na⁺-cationized forms. The 10 oxygen atoms of the molecule were considered as possible protonation and cationization sites. Geometry optimizations were then refined at the DFT B3LYP/6-31G* level from the geometries of the most stable conformers found. Final energetics were obtained at the B3LYP/6-311+G(2d,2p)//B3LYP/6-31G* level. The proton and sodium ion affinities of harpagide have been estimated at 223.5 and 66.0 kcal/mol, respectively. Since harpagide mainly provides HarNa⁺ ions in electrospray experiments, the Δ_rG₂₉₈ associated with the reaction of proton/sodium exchange between Har and methanol, MeOHNa ⁺ + HarH⁺ → MeOH₂⁺ + HarNa ⁺ (1), has been calculated; it has been estimated to be 1.9 kcal/mol. Complexing a methanol molecule to each reagent and product of reaction 1 makes the reaction become exothermic by 1.7 kcal/mol. These values are in the limit of the accuracy of the method and do not allow us to conclude definitely whether the reaction is endo- or exothermic, but, according to these very small values, the cation exchange reaction is expected to proceed easily in the final stages of the ion desolvation process.