Lower denticity leading to higher stability: Structural and solution studies of Ln(III)-OBETA complexes

The heptadentate ligand OBETA (2,2′-oxybis(ethylamine)-N,N,N′,N′-tetraacetic acid) was reported to form complexes with Ln³⁺ ions more stable than those formed by the octadentate and more popular congener EGTA (ethylene glycol O,O′-bis(ethylamine)-N,N,N′,N′-tetraacetic acid). The structural features leading to this puzzling coordination paradox were investigated by X-ray diffraction, solution state NMR, molecular modeling, and relaxometric studies. The stability constant of Gd(OBETA) (log K_GdL = 19.37, 0.1 M KCl) is 2 orders of magnitude higher than that of the higher denticity analogue Gd(EGTA) (log K_GdL = 17.66, 0.1 M KCl). The half-lives (t_1/2) for the dissociation reactions of Gd(OBETA) and Gd(EGTA) ([Cu²⁺]_tot = 0.2 mM, [Cit^3-]_tot = 0.5 mM, [PO₄^3-]_tot = 1.0 mM, and [CO₃^2-]_tot = 25 mM at pH = 7.4 and 25 °C in 0.1 M KCl solution) are 6.8 and 0.63 h, respectively, reflecting the much higher inertness of Gd(OBETA) near physiological conditions. NMR studies and DFT calculations using the B3LYP functional and a large-core ECP indicate that the [Gd(OBETA)(H₂O)₂]^- complex most likely exists in solution as the δ( λ λ)(δδδδ)_A/A(δδ)( λ λ λλ)_A enantiomeric pair, with an activation free energy for the enantiomerization process of ∼40 kJ·mol^-1. The metal ion is nine-coordinate by seven donor atoms of the ligand and two inner-sphere water molecules. The X-ray crystal structure of [C(NH₂)₃]₃[Lu(OBETA)(CO₃)]·2H₂O is in agreement with the predictions of DFT calculations, the two coordinated water molecules being replaced by a bidentate carbonate anion. The ¹H NMRD and ¹⁷O NMR study revealed that the two inner-sphere water molecules in Gd(OBETA) are endowed with a relatively fast water exchange rate (k_ex²⁹⁸ = 13 × 10⁶ s^-1). The higher thermodynamic stability and inertness of Ln(OBETA) complexes, peaking in the center of the 4f series, combined with the presence of two coordinated water molecules suggests that Gd(OBETA) is a promising paramagnetic probe for MRI applications.