In this work, the hybrid density functional theory/effective fragment potential (DFT/EFP) approach was applied to investigate the ligand exchange reactions [Ru(NH3)(4)(Cl)(L)](2+)(aq) + H2O -> [Ru(NH3)(4)(H2O)-(L)](3+)(aq) + Cl-(aq) in solution, with L= NH3 and pyridine (Py). A procedure to generate the EFP water clusters is described. The reaction. proceeds through an interchange mechanism with dissociative character, I-d, and displays a high sensitivity to the basicity of the ligand trans to the chloride. Changing the nature of the nitrogenated ligand has a drastic impact on the activation and reaction energy. When ammonia is used, the activation energy, computed at the B3LYP/cc-pVDZ/EFP level of theory is 22.7 kcal/mol, which is similar to 40% higher than the value of 13.4 kcal/mol computed when for L = Py. In addition, the spontaneity of the reaction changes upon changing the nature of the nitrogenatecl ligand. Changing the level of theory used in the QM part of the calculation from B3LYP/cc-PVDZ to MP2/cc-pVTZ does not change the results appreciably, and inclusion of long-range effects by means of the polarizable continuum model has a negligible effect on the energetic of the reaction. The activation enthalpy computed at the B3LYP/cc-pVDZ/EFP is in very good agreement with the experimental findings, attesting to the validity of the QM/EFP approach used in this work.