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.
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of Doctor of Philosophy of Loughborough University.