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Synthesis of extremely hindered imidazolylphosphine ligands for catalysis and fluorinated dendrimers for ¹⁹F MRI
Grotjahn, Douglas BCole, ThomasSegall, Anca
Dendrimers are highly branched macromolecules which have a well-defined architecture consisting of a central core from which emanate regular repeating units. In recent years, the study and application of MRI as well as of dendrimers have increased tremendously. Because ¹⁹F nuclei are readily detected by NMR at frequencies compatible with existing MRI machines and also because ¹⁹F is not present in biological fluids to any significant extent, the goal of this research is to design and synthesize highly fluorinated dendrimers. Such dendrimers could be employed as imaging agents with the following requirements: (1) a single ¹⁹F signal from multiple fluorine atoms, (2) short (spin-lattice relaxation time) T₁, and (3) good water solubility. In this thesis, the work involves synthesis of the highly fluorinated dendrimers with the three arms arranged in such a way that the fluorine atoms are embedded in the interior of the dendrimer so that the toxicity can be reduced. The synthesis of the fluorinated dendrimers was carried out in a convergent manner to achieve high yield and good purity. Multistep synthesis of novel azide-containing dendrons followed by the triazole-linked dendrimers was successful via copper-catalyzed click reaction. It was found that enantiomerically pure fluorinated amino acid results in a dendrimer showing a single ¹⁹F signal, whereas starting with the racemic amino acid; more than one signal was seen due to stereoisomers present. Our goal is to employ the fluorinated dendrimers as imaging agents for ¹⁹F MRI guided drug therapy. Relevant to the second part of this thesis, bifunctional catalysts for alkyne hydration and alkene isomerisation reported by our group showed improved reactivity and selectivity of the catalyst when heteroarylphosphines were used, leading to rate accelerations of 1000 to 10000 fold. On the heteroarylphosphines, a tert-butyl group near the pendant base nitrogen atom resulted in weakening chelation, thus creating active bifunctional catalysts with control of proton transfer and hydrogen bonding. The work here describes the synthesis of heteroarylphosphine ligands with an extremely bulky group which increases the steric shielding of the pendant base and also changes the rate or proportion of chelate opening. In comparison with the previously reported alkene isomerization catalyst, it shows that the bulky heteroarylphosphine ligand binds to the metal precursor but does not form a chelate because of the extreme steric hindrance near the nitrogen atom, yet the pendant base helps create a catalyst 5000 times faster than a model complex without any pendant base. Clearly, control of the steric environment around the heterocyclic nitrogen can be essential for achieving desired bifunctional reactivity
Master of Science (M.S.) San Diego State University, 2013
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