Different transition metal coordination compounds based on py-2,5-dcH2 have been synthesised, i.e. (H2- a-4-mpym)2[Zn(py-2,5-dc)2(H2O)2] (1), (H9-aacr)2[Zn(py-2,5-dc)2(H2O)2].4H2O (2), (H9-aacr)2[Ni(py-2,5- dc)2(H2O)2].2H2O (3), (H9-aacr)2[Cu(py-2,5-dc)2(H2O)].H2O.DMF (4), and (H9-aacr)3[Cr(CN)4(py-2,5- dc)].5H2O (5), starting from two proton-transfer compounds, (H2-a-4-mpym)2(py-2,5-dc) and (H9- aacr)2(py-2,5-dc) [2-a-4-mpym = 2-amino-4-methylpyrimidine, py-2,5-dcH2 = pyridine-2,5-dicarboxyxlic acid, and 9-aacr = 9-aminoacridine]. They were characterized by elemental analyses, IR and 1H-, 13C-NMR spectroscopy, TGA, and single crystal X-ray diffraction analysis. Results revealed that following various experimental conditions such as temperature, solvent, and pH, the py-2,5-dcH2 ligand undertakes different coordination modes to the metal centres determined by their stereoelectronic requirements and affording mononuclear complex anions with the coordination environments (either pseudo-octahedral or square pyramidal geometries) being completed by water molecules (1–4) or CN2 ligands (5). However, in all cases py-2,5-dcH2 acts as a bidentate ligand through the oxygen atom of a carboxylate group and the N atom of the pyridine ring. Complex anions and (H2-a-4-mpym)+/(H9-aacr)+ units together with co-crystallised solvent molecules interact with each other via hydrogen bonds, C–H…p, and/or p…p interactions to afford various interaction synthons that play an important role in building the overall supermolecular crystal lattices. In order to better understand the crystalline network of compounds 1–5, their respective noncovalent interactions have been studied by means of high level DFT-D calculations. These calculations have shown that complexes containing different spatial-directed py-2,5-dcH2 ligands following the stereoelectronic requirements of the central metal ion could have different predictable effects on the structure of pertinent monomers and networks. The method meets the need of contemporary crystal engineering concepts and is useful for practical synthesis and/or design.