Rigid versions of PDTA4− incorporating a 1,3-diaminocyclobutyl spacer for Mn2+ complexation: stability, water exchange dynamics and relaxivity

Abstract

Rigid derivatives of the acyclic ligand PDTA⁴⁻ (H₄PDTA = propylenediamine-N,N,N′,N′-tetraacetic acid) were prepared by functionalization of a 1,3-diaminocyclobutyl spacer. The new ligands contain either four acetate groups attached to the central scaffold (H₄L1) or incorporate pyridyl (H₂L2) or propylamide (H₂L3) units replacing two of the carboxylate groups. The ligand protonation constants and the stability constants of their Mn²⁺ complexes were determined using potentiometric and spectrophotometric titrations. The stability of the [Mn(L1)]²⁻ complex was found to be significantly higher than that of the flexible [Mn(PDTA)]²⁻ derivative (log K_MnL = 10.78 and 10.01, respectively). A detailed study of the ¹H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and ¹⁷O NMR measurements evidence that the [Mn(L1)]²⁻ and [Mn(L2)] complexes display a hydration equilibrium in solution involving a seven-coordinate species with an inner-sphere water molecule and a six-coordinate species that lacks a coordinated water molecule. As a result the ¹H relaxivities of these complexes are somewhat lower than that of [Mn(EDTA)]²⁻ and related systems. The introduction of propylamide groups in [Mn(L3)] shifts the hydration equilibrium to the seven-coordinate species, which results in a ¹H relaxivity (r_1p = 3.7 mM⁻¹ s⁻¹ at 22 MHz and 25 °C) exceeding that of [Mn(EDTA)]²⁻ (r_1p = 3.3 mM⁻¹ s⁻¹ at 22 MHz and 25 °C). The parameters that control the relaxivities in this family of complexes were determined by simultaneous fitting of the experimental ¹H NMRD and ¹⁷O NMR data (transverse relaxation rates and chemical shifts), with the aid of computational studies performed at the DFT and CASSCF/NEVPT2 levels. These studies provide detailed insight of the parameters that control the efficiency of these relaxation agents at the molecular level.