The binding properties of 4,10-bis[(3-hydroxy-4-pyron-2-yl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (L1) and 4,10-bis[(2-hydroxy-5-nitrophenyl)methyl]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (L2) towards Cu(II) and Co(II) transition metal ions in aqueous solution and in the solid state were studied and compared. Each system consists of a cyclen scaffold bearing two different side-arms; the role of the two transition metal ions to involve side-arms in coordination was investigated. Each metal ion is coordinated in a similar way by both ligands although a different side-arm arrangement occurs. The Me2Cyclen base is always involved in the coordination of the transition metal cation with the four amine functions; both side-arms bind Co(II) while only one of them binds Cu(II). As a consequence, Co(II) forms only mononuclear species with both ligands; the main [Co(H−2L)] species exhibits both side-arms on the same part with respect to the macrocyclic plane. In the case of L1, this allows the formation of an electron rich area, formed by the four converging oxygen atoms of the two maltol functions, able to lodge one hard metal ion such as sodium. On the other hand, L1 forms a dinuclear Cu(II)-species using the remaining unbound maltolic function which affords a Cu(II)-tetranuclear species in the solid state. This behavior is attributed to the different coordination requirements of the two metals, thus providing information for the choice of a suitable metal to preorganize side-arms on a polyamine macrocyclic scaffold. Potentiometric and UV-Vis solution studies as well as four crystal structures of metal-complexes support this conclusion.