Thesis (Ph. D.)--University of Wisconsin--Madison, 1966. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains xvi, 498 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 75-82).

It is generally accepted that platinum antitumour drugs bind, preferentially, to Guanine N7 in DNA. Thus the kinetics of formation and the energetics of dissociation of platinum-nitrogen bonding have been investigated, using simple model bases, namely pyridine. pyrimidine. purine and some derivatives. Six complexes of the type cis-PtCl2L2, where L is a N-heterocycle, have been successfully prepared and characterized. The kinetics of the reaction between K2PtCl4 and the N-heterocyclic bases in aqueous solution have beeD studied. This was best achieved by pre-aquating the PtCl4(2-) and measuring the decrease in concentration of platinum or ligand by AA or UV spectroscopy respectively. It was found that the rate of reaction is second order, the rate being dependent on the concentration of both platinum complex and the ligand. The substitution of ligand takes place by direct replacement, involving an associative S.2 mechanism. It was found that the activation entropy and the activation energy for the reactions of platinum complexes in solution are strongly correlated. The energetics of platinum-nitrogen bond dissociation were followed using thermogravimetric analysis. Quantitative data, which enabled calculation of the activation energy for the decomposition process involving the loss of one molecule of ligand was obtained from isothermal studies. No correlation was found between the solid state studies, involving bond breaking, and the syntheses of the complexes, probably because in solution the reaction is complicated by solvent effects. Theoretical studies, which involved Molecular Orbital calculations on the N-heterocyclic bases themselves, were also carried out in an attempt to correlate the kinetic and energetic parameters with the electronic structure of the ligand. Several correlations were attempted but only one was found. This was the relationship between the solid state decomposition energy and the LUMO energy of the quarternized base.

This work details the synthesis, characterisation and fabrication of a range of copolyesters, containing various angular disrupters, especially disubstituted 2,5-diphenyl- -1,3,4-oxadiazoles. These disrupters were incorporated into the polymers, to reduce the temperature at which the polymers may be processed, to enable their fabrication into fibres. The majority of the polymers prepared were found to be liquid crystalline. However, if the angular disrupter content of the polymer was high, it was found that the resultant polymers were non-liquid crystalline. The polymers were prepared by a melt acidolysis process carried out under a nitrogen flow and subsequently under vacuum, as described in Chapter 3. Eighteen of the polymers were characterised in some detail, though a measure of the relative molecular weights was thought to be of little importance in this work, since all polymers were of a different composition. Differential scanning calorimetry and hot-stage microscopy revealed that several of the polymers had rather unusual melting behaviour. The eighteen polymers that were closely characterised were spun into fibres, using a small melt-spinning apparatus that was designed and produced by Bradford University Research Ltd, The resultant fibres were characterised by differential scanning calorimetry, X-ray diffraction end tensile testing. The general conclusion of the work is that although a reduction in the processing temperature of the polymer is achieved by the incorporation of angular disruptors, which is advantageous, the tensile strength and thermal stability of the fibres produced from such polymers are reduced.

The work carried out in this thesis involves the investigation of some reactions of heterocyclic compounds by a wide range of spectroscopic and kinetic techniques. Chapter 1 describes several methods, including stopped-flow spectrophotometry, high pressure kinetics and MNDO calculations, which are used to analyse the mechanism of the reaction of imidazole with diazonium ions. Chapter 2 describes the use of the temperature-jump technique to follow the extremely fast protonation of pyrroles. Diazonium ions are further investigated in Chapter 3 which examines the structure of p-nitrobenzenediazonium tetrafluoroborate by X-ray crystallography. The nature of other benzenediazonium ions and some of their complexes is also investigated by solid state 15N nmr spectroscopy. Chapter 4 switches the emphasis to nmr spectroscopy. The reactive intermediates of reactions of benzil with nitrogen heterocycles are investigated using 13c nmr spectroscopy in a kinetic application. Chapters 5 and 6 continue the use of nmr spectroscopy in the structural assignment of bilirubin and the determination of the nature of bilirubin inclusion complexes. Chapter 6 also examines by spectrophotometry the reaction used in the clinical analysis of bilirubin and the effect on this reaction of binding agents such as albumin and α-cyclodextrin.

The Baylis-Hillman reaction between substituted salicylaldehydes and various acrylate species has been shown to afford complex reaction mixtures, careful chromatography of which has led to the isolation of an extensive range of novel compounds. One- and two-dimensional NMR spectroscopic, mass spectrometric and X-ray crystallographic analysis of these compounds have permitted identification of no less than eight general classes of chromene and coumarin derivatives. The formation of the various product types is attributed to cascades of successive reactions stemming, in each case, from a Baylis-Hillman product as the common intermediate. The mechanistic sequence involved in the formation of the various chromene and coumarin derivatives have been elucidated by examining isolated or specifically prepared compounds as putative reaction intermediates. Conjugate addition and acyl or allylic substitution by various nucleophiles appear to be common processes in the formation of the chromene and coumarin derivatives, and studies focussing on these processes have been undertaken. Reactions of Baylis-Hillman adducts have been carried out, using oxygen, sulfur and nitrogen nucleophiles, in order to explore stereoselectivity and regioselectivity trends. The results show that the reactions proceed with a very high degree of regioselectivity, affording conjugate addition rather than acyl substitution products. The diastereoselectivity observed for the addition products, however was typically low. A kinetic study to explore the regioselectivity of the reaction between various Baylis-Hillman derived halogeno esters and the nucleophile, methyl 3-oxobutanolate enloate, in two different base-solvent systems at high dilution was also undertaken. The reactions were monitored by ¹H NMR spectroscopy, and the results revealed that the reaction kinetics are more complex than originally anticipated. A mechanistic rationalisation is offered which is consistent with both the kinetic data and the observed regioselectivity trends.

This study has focussed on several aspects of chromone chemistry, viz., (i) the influence of remote substituents on the basicity of 2-(N,N-dimethylamino)chromones, (ii) MoritaBaylis-Hillman reactions of substituted chromone-3-carbaldehydes and (iii) an investigation into the application of chromone chemistry in the total synthesis of the marine natural product, Rietone A. Selected 2-(N,N-dimethylamino )chromones were prepared using two different methods; firstly, via cyclisation of salicylate-derived N,N-dimethyl-3;.(2-hydroxyphenyl)-3- oxopropanamide precursors and, secondly, via 2-hydroxyacetophenone boron difluoride complexes. ¹³C NMR analysis of the 6- and 7-methoxy-2-(N,N-dimethylamino)chromones confirmed that protonation occurs at the chromone carbonyl oxygen rather than the amino nitrogen - a conclusion supported by mol~cular orbital calculations. Potentiometric analysis of 2-(N,N-dimethylamino )chromones in ethanol-water afforded pKa (pK [subscript a]) values in the range 2.22 - 2.52. The observed trend has been rationalised in terms of substituent effects with the aid of molecular orbital calculations at the semi-empirical and ab initio levels, while hydrogen-bonding effects have been used to account for the apparently anomalous result obtained for the 6-nitro derivative. A series of seven substituted chromone-3-carbaldehydes, prepared by the application of Vilsmeier-Haack methodology to the corresponding 2-hydroxyacetophenones, have been examined as substrates for Morita-Baylis-Hillman reactions, using DABCO as the catalyst and three different activated alkenes, viz., methyl acrylate, methyl vinyl ketone and acrylonitrile. In all cases, with the exception of 6-nitrochromone-3-carbaldehyde, the reactions have been shown to afford the expected Morita-Baylis-Hillman products. Use of methyl acrylate and methyl vinyl ketone as the activated alkene has been observed to afford additional, unprecedented dimeric products, which have been unambiguously characterised using a combination of single crystal X-ray analysis and spectroscopic (high resolution MS and NMR) techniques. Different dimer-like adducts have been isolated from reactions in which acrylonitrile was used as the activated alkene, and the structures of these novel products have-been determined <spectroscopically. Tentative mechanistic rationalisations for the formation of the "dimeric" products have been presented. Optimisation studies, aimed at improving the yields of the Morita-Baylis-Hillman products, have resulted in significant increases in conversion efficiency (up to 95%). It has also been shown that the Morita-Baylis-Hillman products may be readily converted to the corresponding "dimers". An exploratory study into the synthesis of Rietone A has been initiated. Ring-opening of a chromone derivative was expected to provide access to the aromatic moiety, while retrosynthetic analysis of the aliphatic side chain suggested possible strategies for its construction. These approaches have proved largely unsuccessful, but preliminary studies involving Fries rearrangement of 4-(carbomethoxymethyl)phenyl 3,7-dimethyl-2,6-octadienoate appear to hold some promise for future development.

A range of chromone-2-carboxylic acids has been prepared by condensing suitably substituted 2-hydroxyacetophenones with diethyl oxalate. pK₂ Studies of these acids revealed that 6- or 7-methoxy substituents decreased acidity while the 6-nitro group enhanced acidity; the strongest acid was the 3-chloro derivative, the increase in acidity being attributed to steric inhibition of acid-weakening delocalisation between the carboxyl group and the chromone system. Various chromone-2-carboxamides, derived from acid chloride precursors, were converted to polysubstituted acrylamides by nucleophilic ring-opening with selected amine nucleophiles. The main fragmentation patterns exhibited by these acrylamides were elucidated using a combination of low resolution, high resolution and meta-stable peak analysis, while the effect of substituents on the simultaneous internal rotation involving the carboxamide and enamine moieties were studied using dynamic NMR spectroscopy. Rotational barriers of ca. 67.1 kJmol ̄¹ and ca. 102 kJmol ̄¹ were found for the enamine and amide rotors, respectively. Several synthetic pathways were followed to prepare a series of 2-(N,N-dialkylamino)chromones which were subjected to detailed mass spectral analysis. In addition to substituent-specific fragmentations , the 2-aminochromones appear to fragment via 3 major pathways. The effect of substituents on the internal rotation of the amino moeity was investigated by variable temperature ¹H NMR spectroscopy and the resulting DNMR data was used to calculate the rotational barriers. Examination of the data reveals that the electron-releasing 6- and 7- substituents reduce the C-NMe₂ rotational barrier to ca. 43.5 kJmol ̄¹ , while the nitro analogue has the largest rotational barrier (ca. 46.1 kJmol ̄¹) because of the electron-withdrawing effect of this substituent.

Cross-coupling, which relies on the use of transition metals, is among the most utilized chemical means of establishing carbon-carbon or carbon-heteteroatom bonds between appropriately functionalized sp, sp2, or sp3 centres. However, most cross-coupling reactions rely on the use of palladium to synthesize valuable synthetic targets. This is problematic for the chemical industry as palladium is limited in supply and expensive. Chemists have therefore sought to replace palladium with first-row transition metals (e.g., iron, cobalt and nickel) and recent reports on cobalt and nickel catalyzed cross-coupling reactions indicate that these metals can be used in this capacity. Unfortunately, protocols developed (so far) for these metals are unsuitable for the synthesis of targets with base-sensitive functional groups as they involve strongly basic reaction conditions. Research in this thesis aims to develop both cobalt and nickel pre-formed catalysts that will display high catalytic activity in mildly basic reaction conditions. Current methodologies for cobalt and nickel cross-coupling reactions use either phosphine ligands or NHC ligands of moderate steric bulk (IMes or IPr). Recent advancements in the development of Pd-PEPPSI catalysts have demonstrated that both pre-forming the catalyst and using larger NHC ligands (IPent, IPentCl, or IHept) are required for high catalytic activity in weakly basic conditions. Thus, it was hypothesized that the development of pre-formed cobalt and nickel NHC complexes analogous to their Pd counterparts would improve reactivity in Negishi, Suzuki-Miyaura, and Buchwald-Hartwig amination cross-coupling reactions. Co(IPent)Cl2(Pyr), Co(IPentCl)Cl2(Pyr), and Co2IPr2(OAc)4 were prepared, identified by X-ray crystallography, and evaluated in preliminary Negishi cross-coupling reactions. These complexes were found to be ineffective, but Co2IPr2(OAc)4 was found to be effective for Suzuki-Miyaura cross-coupling. A base screen was performed to enable the use of weak bases, however, the reaction only worked by pre-forming the boronate with n-BuLi, rendering the reaction conditions intolerant of base-sensitive functional groups. [Ni(IPr)]2(µ-Cl)2 , Ni(IPr)Cl(allyl), and Ni(IPent)Cl(allyl) complexes were synthesized and evaluated in Buchwald-Hartwig aminations. Several bases were examined for these reactions but only sodium tert-butoxide was found to be effective. The presence of TEMPO and BHT in these transformations proved deleterious suggesting the involvement of radical intermediates. Finally, stoichiometric reactions were performed to isolate intermediates in the catalytic cycle, supporting the formation of nickel(0).

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