Edina Balogh

Pyridine and phosphonate containing ligands for stable lanthanide complexation. An experimental and theoretical study to assess the solution structure

We report an experimental and theoretical study of the stability and solution structure of lanthanide complexes with two novel ligands containing pyridine units and phosphonate pendant arms on either ethane-1,2-diamine (L2) or cyclohexane-1,2-diamine (L3) backbones. Potentiometric studies have been carried out to determine the protonation constants of the ligands and the stability constants of the complexes with Gd(III) and the endogenous metal ions Zn(II) and Cu(II). While the stability constant of the GdL2 complex is too high to be determined by direct pH-potentiometric titrations, the cyclohexyl derivative GdL3 has a lower and assessable stability (log K(GdL3)=17.62). Due to the presence of the phosphonate groups, various protonated species can be detected up to pH approximately 8 for both ligands and all metal ions studied. The molecular clusters [Ln(L)(H2O)](3-).19H2O (Ln=La, Nd, Ho or Lu; L=L2 or L3) were characterized by theoretical calculations at the HF level. Our calculations provide two minimum energy geometries where the ligand adopts different conformations: twist-wrap (tw), in which the ligand wraps around the metal ion by twisting the pyridyl units relative to each other, and twist-fold (tf), where the slight twisting of the pyridyl units is accompanied by an overall folding of the two pyridine units towards one of the phosphonate groups. The relative free energies of the tw and tf conformations of [Ln(L)(H2O)]3- (L=L2, L3) complexes calculated in aqueous solution (C-PCM) by using the B3LYP model indicate that the tw form is the most stable one along the whole lanthanide series for the complexes of L3, while for those of L2 only the Gd(III) complex is more stable in the tf conformation by ca. 0.5 kcal mol-1. 1H NMR studies of the Eu(III) complex of L3 show the initial formation of the tf complex in aqueous solution, which slowly converts to the thermodynamically stable tw form. The structures calculated for the Nd(III) complexes are in reasonably good agreement with the experimental solution structures, as demonstrated by Nd(III)-induced relaxation rate enhancement effects in the 1H NMR spectra.

Monopropionate analogues of DOTA4− and DTPA5−: kinetics of formation and dissociation of their lanthanide(III) complexes

The replacement of an acetate function of the macrocyclic DOTA4-(DO3A-Nprop4-) or the acyclic DTPA5- in terminal position (DTTA-Nprop5-) has been recently shown to result in a significant increase of the water exchange rate on the Gd3+ complexes, which makes these chelates potential contrast agents for MRI applications. Here, two novel and straightforward synthetic routes to H4DO3A-Nprop are described. Protonation constants of DO3A-Nprop4- and stability constants with several alkaline earth and transition metal ions have been determined by potentiometry. For each metal, the thermodynamic stability constant is decreased in comparison to the DOTA chelates. The formation reaction of LnDO3A-Nprop- complexes (Ln=Ce, Gd and Yb) proceeds via the rapid formation of a diprotonated intermediate and its subsequent deprotonation and rearrangement in a slow, OH- catalyzed process. The stability of the LnH2DO3A-Nprop* intermediates is similar to those reported for the corresponding DOTA analogues. The rate constants of the OH- catalyzed deprotonation step increase with decreasing lanthanide ion size, and are slightly higher than for DOTA complexes. The kinetic inertness of GdDTTA-Nprop2- was characterized by the rates of its exchange reactions with Zn2+ and Eu3+. The rate of the reaction between GdDTTA-Nprop2- and Zn2+ increases with Zn2+ concentration, while it is independent of pH, implying that the exchange takes place predominantly via direct attack of the metal ion on the complex. In the Eu3+ exchange, the rate decreases with increasing concentration of the exchanging ion which is accounted for by the transitional formation of a dinuclear GdDTTA-NpropEu+ species. The kinetic inertness of the monopropionate GdDTTA-Nprop2- is decreased in comparison to GdDTPA2-: all rate constants, characterizing the dissociation reaction via either proton- or metal-catalyzed pathways being higher by 1-2 orders of magnitude. Similarly, a study of the acid-catalyzed dissociation of the macrocyclic CeDO3A-Nprop- showed a partial loss of the kinetic inertness with regard to the tetraacetate derivative CeDOTA-.