The two MeCN ligands in [Ru(2-C6H4-2'-Py-kappa C,N)(Phen, trans-C) (MeCN)(2)]PF6 (1), both trans to a sp(2) hybridized N atom, cannot be substituted by any other ligand. In contrast, the isomerized derivative [Ru(2-C6H4-2'-Py-kappa C,N)(Phen, cis-C)(MeCN)(2)]PF6 (2), in which one MeCN ligand is now trans to the C atom of the phenyl ring orthometalated to Ru, leads to fast and quantitative substitution reactions with several monodentate ligands. With PPh3, 2 affords [Ru(2-C6H4-2'-Py-kappa C,N)(Phen, cisC)(PPh3)(MeCN)]PF6 (3), in which PP(h)3 is trans to the C o- bound to Ru. Compound 3 is not kinetically stable, because, under thermodynamic control, it leads to 4, in which the PPh3 is trans to a N atom of the Phen ligand. Dimethylsulfoxide (DMSO) can also substitute a MeCN ligand in 2, leading to 5, in which DMSO is coordinated to Ru via its S atom trans to the N atom of the Phen ligand, the isomer under thermodynamic control being the only compound observed. We also found evidence for the fast to very fast substitution of MeCN in 2 by water or a chloride anion by studying the electronic spectra of 2 in the presence of water or NBu4Cl, respectively. An isomerization related to that observed between 3 and 4 is also found for the known monophosphine derivative [Ru(2-C(6)H(4-)2'-Py-kappa C,N)(PPh3, trans-C)(MeCN)(3)]PF6 (10), in which the PPh3 is located trans to the C of the cyclometalated 2-phenylpyridine, since, upon treatment by refluxing MeCN, it leads to its isomer 11, [Ru(2-C6H4-2'-Py-kappa C,N)(PPh3, cis-C)(MeCN)(3)]PF6. Further substitutions are also observed on 11, whereby NAN chelates ((NN)-N-boolean AND = 2,2'-bipyridine and phenanthroline) substitute two MeCN ligands, affording [Ru(2-C6H4-2'-Py-kappa C,N) (PPh3, cis-C) (NAN)(MeCN)]PF6 (12a and 12b). Altogether, the behavior of the obtained complexes by ligand substitution reactions can be rationalized by an antisymbiotic effect on the Ru center, trans to the C atom of the cydometalated unit, leading to compounds having the least nudeophilic ligand trans to C whenever an isomerization, involving either a monodentate or a bidentate ligand, is possible.