(Aminomethylene)phosphonate Analogues as ZnII Chelators: Synthesis and Characterization

• Published in: European journal of inorganic chemistry 2017-06, Vol.2017 (23), p.2955-2967
• Main Authors: Hevroni, Bosmat Levi, Jantz, Thomas, Gottlieb, Hugo E., Fischer, Bilha
• Format: Article
• Language: English
• Subjects: Affinity; Aminomethylene phosphonate; Bearing; Binding; Chelates; Forming; Heterocycles; Inorganic chemistry; Ligands; NMR spectroscopy; Spectrophotometry; Stability; Stability constants; Stoichiometry; Synthesis; Titration; Zinc
• ISSN: 1434-1948; 1099-0682
• DOI: 10.1002/ejic.201700210

A series of (aminomethylene)phosphonate (AMP) analogues, 8–14, bearing one or two heterocyclic moieties (imidazolyl, pyridyl, and thiazolyl) on the aminomethylene group, were synthesized as potential ZnII chelators. The complexes of analogues 8–14 with ZnII ions were characterized by their stoichiometry, geometry, coordination sites, acid/base equilibria, and stability constants. Analogues 8–14 form stable water‐soluble 2:1 L/ZnII complexes, as established by ZnII titration, monitored by UV/Vis spectrophotometry and by 1H and 31P NMR spectroscopy. Acidity and stability constants were established for each derivative by potentiometric pH titrations. ML2 type ZnII complexes of AMP, bearing either an imidazolyl or pyridyl moiety, 8, 10, and 12, exhibit high log β values (17.68, 16.92, and 16.65, respectively), while for the AMP‐thiazolyl (14) complex with ZnII, log β is 12.53. Generally, ligands 9, 11, and 13, bearing two heterocyclic moieties, present higher log β values (22.25, 21.00, and 18.28, respectively) vs. analogues bearing one heterocyclic moiety. Additionally, based on 1H, 13C, and 31P NMR spectroscopic data, we propose a structure of the AMP‐(Im)2‐ZnII complex in solution, where the ZnII coordination sites involve the phosphonate moiety and both imidazolyl rings of the two binding molecules, forming an octahedral geometry around the ZnII ion. In summary, we propose a new family of water‐soluble high‐affinity ZnII chelators, in particular AMP‐(Im)2, which forms the most stable complex (log β 22). A new family of water‐soluble, high‐affinity ZnII chelators was synthesized, based on an (aminomethylene)phosphonate (AMP) scaffold bearing one/two methylene heterocyclic moieties (imidazolyl/pyridyl/thiazolyl) on the aminomethylene group. The AMP analogue–ZnII complexes were characterized by their stoichiometry, geometry, coordination sites, acid/base equilibria, and stability constants.