title: Mn2+ complexes with 12-membered pyridine based macrocycles bearing carboxylate or phosphonate pendant arm: crystallographic, thermodynamic, kinetic, redox, and 1H/17O relaxation studies.
abstract: Mn(2+) complexes represent an alternative to Gd(3+) chelates which are widely used contrast agents in magnetic resonance imaging. In this perspective, we investigated the Mn(2+) complexes of two 12-membered, pyridine-containing macrocyclic ligands bearing one pendant arm with a carboxylic acid (HL(1), 6-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene) or a phosphonic acid function (H(2)L(2), 6-dihydroxyphosphorylmethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene). Both ligands were synthesized using nosyl or tosyl amino-protecting groups (starting from diethylenetriamine or tosylaziridine). The X-ray crystal structures confirmed a coordination number of 6 for Mn(2+) in their complexes. In aqueous solution, these pentadentate ligands allow one free coordination site for a water molecule. Potentiometric titration data indicated a higher basicity for H(2)L(2) than that for HL(1), related to the electron-donating effect of the negatively charged phosphonate group. According to the protonation sequence determined by (1)H and (31)P pH-NMR titrations, the first two protons are attached to macrocyclic amino groups whereas the subsequent protonation steps occur on the pendant arm. Both ligands form thermodynamically stable complexes with Mn(2+), with full complexation at physiological pH and 1:1 metal to ligand ratio. The kinetic inertness was studied via reaction with excess of Zn(2+) under various pHs. The dissociation of MnL(2) is instantaneous (at pH 6). For MnL(1), the dissociation is very fast (k(obs) = 1-12 × 10(3) s(-1)), much faster than that for MnDOTA, MnNOTA, or the Mn(2+) complex of the 15-membered analogue. It proceeds exclusively via the dissociation of the monoprotonated complex, without any influence of Zn(2+). In aqueous solution, both complexes are air-sensitive leading to Mn(3+) species, as evidenced by UV-vis and (1)H NMRD measurements and X-ray crystallography. Cyclic voltammetry gave low oxidation peak potentials (E(ox) = 0.73 V for MnL(1) and E(ox) = 0.68 V for MnL(2)), in accordance with air-oxidation. The parameters governing the relaxivity of the Mn(2+) complexes were determined from variable-temperature (17)O NMR and (1)H NMRD data. The water exchange is extremely fast, k(ex) = 3.03 and 1.77 × 10(9) s(-1) for MnL(1) and MnL(2), respectively. Variable-pressure (17)O NMR measurements have been performed to assess the water exchange mechanism on MnL(1) and MnL(2) as well as on other Mn(2+) complexes. The negative activation volumes for both MnL(1) and MnL(2) complexes confirmed an associative mechanism of the water exchange as expected for a hexacoordinated Mn(2+) ion. The hydration number of q = 1 was confirmed for both complexes by (17)O chemical shifts. A relaxometric titration with phosphate, carbonate or citrate excluded the replacement of the coordinated water molecule by these small endogenous anions.
authors.affiliation: Department of Inorganic Chemistry, Faculty of Science, Universita Karlova (Charles University), Hlavova 2030, 128 43 Prague 2, Czech Republic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Drahoš
authors.forename: Jan
authors.initials: J
authors.lastname: Kotek
authors.forename: Ivana
authors.initials: I
authors.lastname: Císařová
authors.forename: Petr
authors.initials: P
authors.lastname: Hermann
authors.forename: Lothar
authors.initials: L
authors.lastname: Helm
authors.forename: Ivan
authors.initials: I
authors.lastname: Lukeš
authors.forename: Éva
authors.initials: É
authors.lastname: Tóth
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry*; D002614:Chelating Agents / Q000138:chemical synthesis; D003287:Contrast Media / Q000138:chemical synthesis*; D056831:Coordination Complexes / Q000138:chemical synthesis*; D018360:Crystallography, X-Ray; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000379:methods; D009682:Magnetic Resonance Spectroscopy; D008345:Manganese / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry*; D010084:Oxidation-Reduction; D011199:Potentiometry; D011725:Pyridines / Q000737:chemistry; D013696:Temperature; D013816:Thermodynamics
chemical_list: D002264:Carboxylic Acids; D002614:Chelating Agents; D003287:Contrast Media; D056831:Coordination Complexes; D006574:Heterocyclic Compounds, 2-Ring; D063065:Organophosphonates; D011725:Pyridines; D008345:Manganese