Design, Synthesis And Characterization Of Ferrous Complexes Displaying Electroneutrality

Magnetism is an intrinsic physical property of matter, the paramagnetic materials can be used for chemical and biological research. The magnetism change of a molecule which can be detected by NMR, MRI or ESR stands for a change of environmental conditions caused by some analytes. Thus it is an alternative readout besides the typical methods based on optical properties and it attracts our great interest for research.The first part introduced the magnetism of matter and MRI as an indispensable tool in modern diagnostics due to their accurate and specific information and moreover the advantages of low toxicity and high spatial resolution. The MRI principle and the influencing factors of relaxation time of water protons were also explained, followed by the elaboration of strategies to design MRI probes then the presentation of advantages of iron(Ⅱ) and TACN which led to the introduction of the previous work in our group. Afterwards the advantages of the low osmolarity and fast clearance of electroneutral MRI CAs reported in the literatures were presented then the PhD project was proposed.The second part introduced two strategies to achieve electroneutrality according to pKa values of pyridylcarboxylic acid and pyrimidinediol, which was followed by design, synthesis and studies on basic properties of the target complexes.The macrocycle TACN was synthesized in large scale which requires much experimental skills, then the monoalkylated TACN was prepared in excellent purity due to the explored methods to form their hydrochlorides.Four groups (COOBn, COOEt, CONH2, CON(Me)(OMe)) for providing carboxyl group on the pyridine ring and three ways (two alkylations and one reductive amination) for its combination with TACN were tried. The ligands bearing the ethyl ester groups were successfully obtained, which were subsequently hydrolyzed under acidic condition for complexation with iron(II) salt, and the obtained complexes were characterized by HRMS and the low-spin one has its 1H NMR and X-Ray Diffraction. Then both of two complexes were used for measurements of their properties such as relaxivities, magnetic moment, UV-vis absorptions, pH titration, cytotoxicity, and cyclic voltammogram. The results showed that they have their own reasonable relaxivities, relatively low cytotoxicity and high stability in physiological media, which implies their potential application in design of MRI probes.The N6 and N5O1 type complexes bearing four methoxyl groups based on pyrimidine were also successfully synthesized and the former showed high-spin state by its XRD analysis. The deprotection of the N6 ligand was successful after many methods were tried, but the condition should be controlled strictly and its complexation in the presence of some base is suggested for improving the solubility of the ligand in MeOH, EtOH and acetonitrile.The third part is the experimental section which described all the conditions and results of the successful reactions, and synthesis of the intermediates of some unsuccessful strategies.In conclusion, the high-spin and low-spin, electroneutral, ferrous and binary complexes based on pyridylcarboxylic acid have been synthesized and characterized. To our knowledge, this is the first instance of an eletroneutral version of a low-spin ferrous complex. Their properties pave a promising way for designing MRI probes based on them. The totally novel N6 type complex bearing four methyl groups based on pyrimidinediol has been synthesized and it is worth studying magnetism of the deprotected form compared to its high-spin property. At present a better method of deprotection and complexation is being explored.