Equilibrium and NMR studies on GdIII, YIII, CuII and ZnII complexes of various DTPA–N,N″-bis(amide) ligands. Kinetic stabilities of the gadolinium(iii) complexes

Abstract

Three DTPA-derivative ligands, the non-substituted DTPA–bis(amide) (L⁰), the mono-substituted DTPA–bis(n-butylamide) (L¹) and the di-substituted DTPA–bis[bis(n-butylamide)] (L²) were synthesized. The stability constants of their Gd³⁺ complexes (GdL) have been determined by pH-potentiometry with the use of EDTA or DTPA as competing ligands. The endogenous Cu²⁺ and Zn²⁺ ions form ML, MHL and M₂L species. For the complexes CuL⁰ and CuL¹ the dissociation of the amide hydrogens (CuLH₋₁) has also been detected. The stability constants of complexes formed with Gd³⁺, Cu²⁺ and Zn²⁺ increase with an increase in the number of butyl substituents in the order ML⁰ < ML¹ < ML². NMR studies of the diamagnetic YL⁰ show the presence of four diastereomers formed by changing the chirality of the terminal nitrogens of their enantiomers. At 323 K, the enantiomerization process, involving the racemization of central nitrogen, falls into the fast exchange range. By the assignment and interpretation of ¹H and ¹³C NMR spectra, the fractions of the diastereomers were found to be equal at pH = 5.8 for YL⁰. The kinetic stabilities of GdL⁰, GdL¹ and GdL² have been characterized by the rates of the exchange reactions occurring between the complexes and Eu³⁺, Cu²⁺ or Zn²⁺. The rates of reaction with Eu³⁺ are independent of the [Eu³⁺] and increase with increasing [H⁺], indicating the rate determining role of the proton assisted dissociation of complexes. The rates of reaction with Cu²⁺ and Zn²⁺ increase with rising metal ion concentration, which shows that the exchange can take place with direct attack of Cu²⁺ or Zn²⁺ on the complex, via the formation of a dinuclear intermediate. The rates of the proton, Cu²⁺ and Zn²⁺ assisted dissociation of Gd³⁺ complexes decrease with increasing number of the n-butyl substituents, which is presumably the result of steric hindrance hampering the formation or dissociation of the intermediates. The kinetic stabilities of GdL⁰ and GdL¹ at pH = 7.4, [Cu²⁺] = 1 × 10⁻⁶ M and [Zn²⁺] = 1 × 10⁻⁵ M are similar to that of Gd(DTPA)²⁻, while the complex GdL² possesses a much higher kinetic stability.