Relaxometric, Structural, and Dynamic NMR Studies of DOTA-like Ln(III) Complexes (Ln = La, Gd, Ho, Yb) Containing a p-Nitrophenyl Substituent

We report here the synthesis of the ligand 1-((p-nitrophenyl)carboxymethyl)-4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane (3) and its La(III), Gd(III), Ho(III), and Yb(III) complexes. The introduction of the p-nitrophenyl substituent on the methylenic carbon of one acetate group does not alter the overall chelating ability of 3 with respect to the parent DOTA ligand. The [Gd(3)]- complex displays a slightly higher relaxivity than that of [Gd(DOTA)]-, mainly as a consequence of a longer molecular reorientational correlation time (τR), due to the increased molecular dimension of the complex, and of limited changes to the other relaxation parameters. A further increase of relaxivity has been observed upon formation of an inclusion compound with β-cyclodextrin. The solution structure and dynamics were thoroughly investigated by high-resolution NMR spectroscopy. Of the four possible enantiomeric pairs that could be present in the solutions of monosubstituted derivatives of [Ln(DOTA)]- complexes, the proton spectra of Ho and Yb derivatives are consistent with the occurrence of only two isomeric species whose structures have been elucidated through analysis of dipolar shifts and 2D-EXSY data. In both species the bulky aromatic group has replaced the acetate proton pointing outward from the coordination cage. Unlike in the DOTA case, in [Ln(3)]- complexes the isomerization process involves the inversion of the ethylenic groups of the macrocycle rather than the motion of the acetate arms. This behavior is rationalized in terms of steric crowding at the substituent site: minimization of the steric interactions between the aromatic group and the macrocyclic ring protons results in both structural and dynamic selectivity. Interestingly, in the case of the diamagnetic La(III) complex the variable temperature behavior of the 13C NMR spectra is consistent with an exchange process involving one major species and at least one minor isomer of very low concentration, whose relative population increases with temperature. This causes a persistent exchange broadening of the resonances over a wide range of temperatures.