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 KGdL = 19.37, 0.1 M KCl) is 2 orders of magnitude higher than that of the higher denticity analogue Gd­(EGTA) (log KGdL = 17.66, 0.1 M KCl). The half-lives (t1/2) for the dissociation reactions of Gd­(OBETA) and Gd­(EGTA) ([Cu2+]tot = 0.2 mM, [Cit3–]tot = 0.5 mM, [PO43–]tot = 1.0 mM, and [CO32–]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(λλ)­(δδδδ)A/Λ­(δδ)­(λλλλ)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 (kex298 = 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.