In this paper, two-layer ONIOM combinations of high-level quantum mechanics (QM) and inexpensive molecular mechanics (MM) are successfully used to investigate the structural characters of metal (M, all the transition metals in the fourth period)-H2O-Lewis base (A(-)) complexes. Global and local descriptors of chemical reactivity and selectivity from conceptual density functional theory are employed to show the properties of the active complexes of M(H2O)(2)A(2) and to study the effect of the Lewis base for the separation of transition metal ions. It is shown that chemical potential, hardness, electrophilicity, as well as the dual and multiphilic descriptors are adequate for characterizing the global and local reactivity trends of the M(H2O)(2)A(2) complex. It is found that the reactivity is well localized at the metallic center in M(H2O)(2)A(2) and the dual descriptor (Delta f(M)(r)) can also be used to characterize the directional attack of the electrophile and nucleophile except for the selectivity of the reaction. On the basis of the values of omega(M) and Delta s(k), and the sign of Delta f(M)(r), the selectivity of the nucleophilic reagent (R-) for M(II) in M(H2O)(2)A(2) (from high to low) follows this order: Cu(II) > Ni(II) > Co(II) > Fe(II) >> Mn(II) > Zn(II) > Cr(II). The Lewis base (A(-)) improves chemical reactivity and selectivity because of changing the reaction path and forming an intermediate, which possesses the higher antibonding character and the larger HOMO/LUMO gap. NBO or AIMALL analysis and Frontier orbital theory results presented here provided more theoretical support for the above reactivity and selectivity studies.