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 Gd III complexes, namely the phosphinates H 4 DOTP H , H 4 DOTP hm and H 4 DOTP Et , and the phosphonate monoesters H 4 DOTP OEt and H 4 DOTP OBu , were synthesized with the aim of exploring the influence of the second hydration sphere on the relaxivity of Gd III complexes. The H 4 DOTP H , H 4 DOTP hm and H 4 DOTP OEt ligands and their Ln III complexes were characterized by potentiometry and time-resolved luminescence; the Gd III complexes are thermodynamically much less stable than that of H 4 DOTA, and no water is coordinated in the inner sphere. The crystal structures of the free ligand H 4 DOTP OEt and of the Gd III complexes of H 4 DOTP H and H 4 DOTP OEt were determined by X-ray diffraction. The complexes have the expected octadentate coordination mode with an N 4 O 4 arrangement; no water molecule is bound to the Gd III ion. Information on the structures of the Ln III complexes of all five ligands in aqueous solution were obtained from 1 H and 31 P NMR spectra. The NMR spectra of the [Ln(DOTP hm )]- and [Ln(DOTP Et )]- 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. Ln III -induced 17 O 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 Gd III complexes of all ligands were evaluated by EPR, variable-temperature 17 O NMR spectroscopy and 1 H NMRD re-laxometry. 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.