Lanthanide(III) Complexes of Phosphorus Acid Analogues of H4DOTA as Model Compounds for the Evaluation of the Second-Sphere Hydration



Five DOTA-like ligands lacking a water molecule in the first coordination sphere of their GdIII complexes, namely the phosphinates H4DOTPH, H4DOTPhm and H4DOTPEt, and the phosphonate monoesters H4DOTPOEt and H4DOTPOBu, were synthesized with the aim of exploring the influence of the second hydration sphere on the relaxivity of GdIII complexes. The H4DOTPH, H4DOTPhm and H4DOTPOEt ligands and their LnIII complexes were characterized by potentiometry and time-resolved luminescence; the GdIII complexes are thermodynamically much less stable than that of H4DOTA, and no water is coordinated in the inner sphere. The crystal structures of the free ligand H4DOTPOEt and of the GdIII complexes of H4DOTPH and H4DOTPOEt were determined by X-ray diffraction. The complexes have the expected octadentate coordination mode with an N4O4 arrangement; no water molecule is bound to the GdIII ion. Information on the structures of the LnIII complexes of all five ligands in aqueous solution were obtained from 1H and 31P NMR spectra. The NMR spectra of the [Ln(DOTPhm)] and [Ln(DOTPEt)] complexes show that these compounds have a clear preference for a specific arrangement of phosphorus atoms which gives rise to the symmetrical RRRR (or SSSS) isomer. However, many diastereoisomers were observed for all other complexes. LnIII-induced 17O NMR shift data reveal that the spatial location of the second-sphere water molecules for the two groups of complexes differs. The parameters governing the effect of the second hydration sphere on the relaxivity of the GdIII complexes of all ligands were evaluated by EPR, variable-temperature 17O NMR spectroscopy and 1H NMRD relaxometry. The presence of second-sphere water molecules is clearly confirmed, depending on the character of the pendant arms. As the relaxivity does not depend significantly on the nature of the phosphorus substituents and/or on the isomerism present in solution, the second-sphere water molecules should be located close to the phosphorus–oxygen atoms.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)