pKa estimation of ruthenium(II)-arene PTA complexes and their hydrolysis products via a DFT/continuum electrostatics approach

A combined density functional theory/continuum electrostatics approach has been used to estimate the pK(a) values of a series of metal-based compounds and their hydrolysis products. Specifically, the protonation states and absolute pK(a) values of the complexes [M(eta(6)-arene)(X)(Y)(pta)](n+) (M = Ru or Os; arene = benzene, p-cymene, 1,3,5-trifluorobenzene, benzene-1,3,5-triamine; X, Y = halide, H2O, OH, guanine; pta = 1,3,5-triaza-7-phosphaadamantane) have been investigated by this approach and supplemented with experimental pK(a) determinations using P-31 NMR spectroscopy. Compounds of this type have been recently used as anticancer agents and also to catalyze CO2 reduction. Our calculations show that pta binding to a ruthenium center significantly reduces the basicity of the ligand. The experimentally observed pH-dependent DNA binding is rationalized by the hydroxo/aqua ligand equilibrium in [Ru(eta(6)-benzene)Cl(OH2)(pta)](+). The applied computational scheme predicts that pK(a) tuning can be done most effectively by modifications of the arene ligand.