a systematic mechanistic study is reported for the aquation and nucleobase binding process of a series of ru-ii and os-ii arene-based anticancer drug complexes using density functional theory and cosmo implicit solvent model. the structures of ru-ii and os-ii complexes are similar to each other because of lanthanide contraction of osmium. however, the aquation was substantially more facile for ru-ii complexes than os-ii complexes. as to nucleobase substitution, various possible paths were explored based on considering the initial conformation of ethylenediamine (en) and the orientation of guanine (g) and adenine (a). both ru and os complexes exhibited much lower free energy barrier for g than a. this observed predominance toward g mainly originated from larger stabilization energy for the initially formed complex, compared with a, in combination with favored kinetics and thermodynamics. moreover, the calculations indicated that pk(a)s of os-bound water molecules were uniformly much lower than those of ru-bound water molecules. analysis of the natural bond orbital (nbo) charge reveals that os-ii has a higher net positive charge than ru-ii, leading to a stronger electrostatic attractive interaction between os-ii and chloride or water, resulted in higher activation barrier for their departure. these differences between ru-ii and os-ii en complexes discussed in our study may partly explain the inertness of the os-ii complexes in biological system. (c) 2012 elsevier b.v. all rights reserved.