Stability constants of Cu(II)/indomethacin mononuclear complexes in solution

The stability constants of the non-steroidal anti-inflammatory drug indomethacin mononuclear copper complexes, Cu(Indo)(+) and Cu(Indo)(2), were calculated by thermodynamic cycles in the frame of density functional theory. The BH&HLYP functional with LANL2DZ and Def2SVP basis set for copper ion and lighter atoms, respectively, were used to perform the search of minimums, and to consider thermal corrections in gas phase. For the minimums found, electronic energies were evaluated by performing single point calculations, using the basis set LANL2TZ+f for copper ion and the 6-311++ G(2d, 2p) for the rest. To include the continuum contribution to the solvation energy, the solvation model based on density was applied. Cluster/continuum model yields acceptable results in predicting solvation energies of Cu(II) ion and proton with deviations of 4.2 and 4.7 kcal/mol at the worked level of theory. Cluster/continuum calculations of Cu(Indo)(+) and Cu(Indo)(2) complexes stability constants, reported as log beta, predict 1.65 and -3.17 in water and 15.9 and 26.7 in ethanol. We also apply the ion-exchange thermodynamic cycle, which aims error cancelation through structural similarity between species in both sides of chemical reactions. Encouraging results are obtained for Cu(Indo)(2) stability constant in ethanol, log beta = 16.37, differing just 2.32 units from the experimental value. Structural features and charge distribution, of the species involved in the complexation reaction, are discussed to rationalize the performing of thermodynamic cycles in predicting complexation stability constants.