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Title: Synthesis and evaluation of novel multidentate N-heterocyclic carbene ligand precursors built on calixarene, DOTA and DTPA scaffolds
Author: Bullough, Emma Karen
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2013
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The synthesis and characterisation of novel multidentate N-heterocyclic carbene (NHC) ligand precursors built on calixarene, DOTA, and DTPA scaffolds is reported in this thesis. Several synthetic procedures to these imidazolium salts were attempted, and it was generally found that the best approach was to react a bromomethylated or chloromethylated reagent with an N-substituted imidazole, forming the imidazolium salt cleanly and in high yields. Neutral tetrakis (methylimidazole) calix[4]arene (2.4) and cationic tetrakis(methylimidazolium) calix[4]arene (2.5) were prepared and their solid state and solution behaviour was examined. It was found that compound 2.4 forms a zwitterion at elevated temperatures, which was seen in both solution and in the solid state. The anion binding properties of compound 2.5 were probed through 1H NMR titration experiments, combined with X-ray crystallography. It was found that compound 2.5 exhibits a large range of hydrogen bonding interactions with anions, interacting via acidic protons on both the upper and lower rim of the calixarene. Propanol-tethered methyl-imidazolium mesityl-calix[4]arene (3.4) and acetate-tethered methyl-imidazolium mesityl calix[4]arene (4.2) were prepared and their structures examined through anion binding experiments and X-ray crystallography. It was found that the propanol tethers of compound 3.4 form the primary interaction with anions, of the type [(O-H)+....X-], over any other acidic protons in the compound. Different routes to form metal-NHC complexes using these imidazolium salts were explored. However, as these compounds contained several acidic protons, traditional routes to form metal-NHC complexes were unsuccessful, resulting in either the formation of a complicated mixture of products, or decomposition of the ligand. It was found that an alternative novel electrochemical method of metal-NHC formation, developed in the Willans group, could be used to prepare metal-NHC complexes from compounds that incorporated several acidic protons. The electrochemical method was used to prepare tetrakis-p-(copper-N-heterocyclic carbene)mesityl calixarene (4.6), which was used as a ligand transfer agent to form tetrakis-p-(palladium-N-heterocyclic carbene) mesityl calix[4]arene (4.7). The activity of the palladium complex was probed in the Suzuki-Miyaura cross-coupling reaction, and was found to be active for the coupling of aryl bromides and phenylboronic acid. An inverse correlation between activity and the concentration of the pre-catalyst (4.7) was observed, suggesting that the calix[4]arene does not offer any protection against aggregation of palladium to form palladium(0)-nanoclusters. NHC-ligand precursor bis[2-imidazolium(3-tert-butylacetate)ethyl]amino benzyl (6.5) was prepared, which was inspired by the structure of DTPA. Using compound 6.5, two bis-imidazolium amine salts were prepared that incorporated different potential donor groups (6.6 and 6.11). The electrochemical procedure was used to prepare a chelating copper(I)-NHC complex (6.16) from compound 6.5. NHC-ligand precursors were also prepared that were appended to a DOTA scaffold (compounds 7.15 and 7.16). The electrochemical approach was explored with compound 7.15, resulting in the formation of a mixed valence copper complex, where a copper(II) ion is coordinated inside the macrocycle, in addition to the formation a of copper(I)-NHC. Compound 7.16 was coordinated to gadolinium (7.17) and the potential of this complex as a contrast agent was examined by measuring the relaxivity. It was found that complex 7.17 has a relaxivity of (r1) = 5.70 mM-1 s-1 (0.5 T, 23.8 ± 0.5 °C), which is larger than the commercially available Gd-DOTA contrast agent Dotarem® (r1 = 3.3 mM-1 s-1 (1.5 T, 37 °C)).
Supervisor: Willans, C. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available