Aquation of the Ruthenium-Based Anticancer Drug NAMI-A: A Density Functional Study

We carried out density functional theory (DFT) calculations to investigate the thermodynamics and the kinetics
of the double aquation reaction of the anticancer drug NAMI-A. Three explicit water molecules were included
in the calculations to improve the PB solvation energies. Our calculations show that the chloride substitution
reactions on the considered Ru(III) octahedral complex follow a dissociative interchange mechanism, Id, passing
through a loose heptacoordinate transition state. We calculated an activation enthalpy and free energy for the
first aquation step of 101.5 and 103.7 kJ mol-1, respectively, values that are in good agreement with the
available experimental results. The activation enthalpy and free energy for the second aquation step were
found significantly higher, 118.7 and 125.0 kJ mol-1, again in agreement with the experimental evidence
indicating a slower rate for the second aquation.