A mechanistic investigation of the synthesis of thyroxine
thesisposted on 15.01.2014 by Natalie V. Bell
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Chapter One reviews the literature concerning oxidative phenolic coupling and summarises the biological aspects of thyroxine and early syntheses of the compound. The aims of the research are also discussed. Chapter two discusses the ortho-ortho coupling of diiodinated phenols comparing a radical mechanism versus a polar mechanism. The conditions under which this coupling occurs are carefully examined. The evidence towards the reaction going through a polar mechanism gives rise to methods of blocking this ortho-ortho coupling during the reaction to form thyroxine. Chapter three discusses the results obtained from an electrochemical study of the oxidation potentials of various phenols, with particular interest in the effects of various substituents on the ortho and para positions on the oxidation potential of the phenols and phenoxide ions. The implications of these results to the conditions necessary for thyroxine synthesis and their relevance to the oxygen-para coupling mechanism in the formation of thyroxine derivatives are discussed. Chapter four summarises the literature precedent for the oxidation of the tyrosine amino acid side chain prior to coupling in the formation of thyroxine, and other similar oxidations. The experiments carried out using a variety of known oxidants and oxidative conditions and their failure to perform the desired oxidation are discussed. The results from the coupling of ethyl N-acetyl 3,5-diiodotyrosinate with various oxidised derivatives provides further evidence for the lack of oxidation of the amino acid prior to coupling. Chapter five investigates the various requirements of the industrial synthesis of thyroxine, and their function. A mechanism is proposed for the coupling to form thyroxine, and is discussed with reference to the products formed as a result of exposing other diiodinated phenols to the 'thyroxine coupling' conditions.