Picolinate-Containing Macrocyclic Mn²⁺ Complexes as Potential MRI Contrast Agents

We report the synthesis of the ligand Hnompa (6-((1,4,7-triaza­cyclononan-1-yl)­methyl)­picolinic acid) and a detailed characterization of the Mn2+ complexes formed by this ligand and the related ligands Hdompa (6-((1,4,7,10-tetra­azacyclo­dodecan-1-yl)­methyl)­picolinic acid) and Htempa (6-((1,4,8,11-tetra­azacyclo­tetradecan-1-yl)­methyl)­picolinic acid). These ligands form thermodynamically stable complexes in aqueous solution with stability constants of logKMnL = 10.28(1) (nompa), 14.48(1) (dompa), and 12.53(1) (tempa). A detailed study of the dissociation kinetics of these Mn2+ complexes indicates that the decomplexation reaction at about neutral pH occurs mainly following a spontaneous dissociation mechanism. The X-ray structure of [Mn2(nompa)2(H2O)2]­(ClO4)2 shows that the Mn2+ ion is seven-coordinate in the solid state, being directly bound to five donor atoms of the ligand, the oxygen atom of a coordinated water molecule and an oxygen atom of a neighboring nompa– ligand acting as a bridging bidentate carboxylate group (μ–η1-carboxylate). Nuclear magnetic relaxation dispersion (1H NMRD) profiles and 17O NMR chemical shifts and transverse relaxation rates of aqueous solutions of [Mn­(nompa)]+ indicate that the Mn2+ ion is six-coordinate in solution by the pentadentate ligand and one inner-sphere water molecule. The analysis of the 1H NMRD and 17O NMR data provides a very high water exchange rate of the inner-sphere water molecule (kex298 = 2.8 × 109 s–1) and an unusually high value of the 17O hyperfine coupling constant of the coordinated water molecule (AO/ℏ = 73.3 ± 0.6 rad s–1). DFT calculations performed on the [Mn­(nompa)­(H2O)]+·2H2O system (TPSSh model) provide a AO/ℏ value in excellent agreement with the one obtained experimentally.