Rigid versions of PDTA^4- incorporating a 1,3-diaminocyclobutyl spacer for Mn²⁺ complexation: stability, water...

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.