School of Chemistry - Theses
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ItemStudies towards the biomimetic total synthesis of dihydrooxepin-containing epipolythiodiketopiperazine natural products( 2009)SCH-64874 (5) is a fungal metabolite that inhibits the epidermal growth factor receptor (EGFR), a high-profile oncology target, with an IC50 of 1.0µg/mL. It is of particular interest because it is unlikely to inhibit the protein’s intramolecular kinase domain (as typical chemical EGFR inhibitors do), and may act instead by obstructing the receptor’s ligand binding and/or dimerisation processes. In this work, the epipolythiodiketopiperazine family of natural products is reviewed, leading to a discussion of the probable biosynthetic pathways by which these complex molecules are produced in nature. A laboratory synthesis based on this proposed biosynthesis was subsequently proposed and undertaken. The oxidation of aromatic systems was investigated, which led to the synthesis, for the first time, of complex functionalised arene oxides such as 178. The regioselective epoxidation of 178 was accessed by derivatisation as the Diels-Alder adduct 180. Subsequent epoxidation and manipulation led to the amino alcohol 195b, possessing the exo-epoxide endo-alcohol stereochemistry shown. This stereochemical assignment was based on detailed NMR analysis of the product, and also on AM1 semi-empirical molecular modelling and Ab initio molecular orbital calculations, which were used to evaluate the relative stabilities of the cyclisation products.
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ItemPreparation and characterisation of biocompatible semiconductor nanocrystals( 2009)Semiconductor nanocrystals exhibit unique optical and physical properties that make them an attractive alternative to organic dyes for fluorescent bioapplications. Although significant advances have been made since their first reported use in biology a decade ago, it still remains a challenge to prepare high quality, biocompatible semiconductor nanocrystals. In this thesis, studies are described with the aim to prepare robust, biocompatible semiconductor nanocrystals that exhibit each of the properties necessary for their implementation in biological applications. Two different approaches were investigated: ligand exchange and polymer encapsulation, and advances in each are presented. A heterobifunctional ligand suitable for bioconjugation, carboxyl terminated dihydrolipoic acid poly(ethylene glycol) (DHLA-PEG-COOH), was synthesised and characterised to prepare water-soluble, biocompatible semiconductor nanocrystals via ligand exchange. It was found that nanocrystals transferred into water using DHLA-PEG-COOH exhibit the same optical properties and colloidal stability as those prepared using DHLA-PEG. It was demonstrated that the surface charge of the nanocrystals may be controlled by altering the ratio of DHLA-PEG:DHLA-PEG- COOH ligands. In a different approach, colloidally stable, biocompatible nanocrystals were prepared via polymer encapsulation. It was found that by employing a low molecular weight polymer, biocompatible nanocrystals that exhibit a small hydrodynamic diameter could be realised. Experimental results are presented on the conjugation of biocompatible nanocrystals to protein targets. It was found that while standard coupling chemistries yield protein-dye conjugates, these chemistries did not result in protein-nanocrystal conjugates. In order to overcome the drawbacks of standard coupling chemistries, which are susceptible to hydrolysis, a novel conjugation scheme utilising copper-free click chemistry is proposed. Finally, the success of nanocrystals in bioapplications depends on the ability to characterise nanocrystal-protein conjugates. By means of analytical ultracentrifugation, data on the sedimentation properties of nanocrystals and nanocrystal-protein conjugates was obtained. Analysis of these data provided information on fundamental physical properties of biocompatible nanocrystals and nanocrystal-protein conjugates, in particular the core crystal size, hydrodynamic size, number of surface ligands and nanocrystal:protein stoichiometry. Such a precise, comprehensive characterisation of nanocrystals in general, and nanocrystal-protein conjugates in particular, will greatly facilitate their use in bioapplications.
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ItemThiyl radical reactions with alkynes in the absence and presence of oxygen( 2009)This thesis is concerned with the reactions of sulfur-centred radicals and alkynes. The first objective of this work was to extend the scope of “self-terminating radical cyclisations” to sulfur-centred radicals, such as thiyl radicals. Preliminary experiments revealed that the reaction of thiyl radicals with alkynes was sensitive to residual oxygen. In the absence of oxygen, the reactions of photochemically generated phenylthiyl radicals with cyclodecyne (1) resulted in three isomeric sulfides, which were identified through a combination of techniques. (1S,6S)-2-phenylthiobicyclo[4.4.0]decane (trans-49a, unknown stereochemistry at C2) was identified by synthesis of an authentic sample, while the structure of (1S,2R,6S)-2-phenylthiobicyclo[4.4.0]decane (cis-49a1) was determined by X-ray analysis of the corresponding crystalline sulfone, cis-69. The third sulfide, (1S,2S,6S)-2-phenylthio-bicyclo[4.4.0]decane (cis-49a2), was assigned based on computational studies. In addition, the reactions of benzylthiyl, tert-butylthiyl and allylthiyl radicals with cyclodecyne (1) were investigated. Various sources of thiyl radical generation were utilized, such as the photolysis of disulfides and thiols, hydrogen atom abstraction of thiols using radical initiators, as well as thiol autoxidation in the presence of oxygen. The radical cascade initiated by the addition of thiyl radicals to alkyne 1 was typically terminated by either reduction or disproportionation, whereas “self-termination” was only observed in one particular instance where the tert-butylthiyl radical was generated by autoxidation. However, this was only a minor pathway. The second objective of this work was to investigate the reactions of thiyl radicals with alkynes in the presence of oxygen. For this purpose, phenylthiyl radicals were generated in the presence of diphenylacetylene (89) and molecular oxygen. Benzil (91), an α-diketone, and 1,2-diphenyl-2-(phenylthio)ethanone (93), an α-ketosulfide, were formed. The novel thiyl radical-mediated oxidation of diphenylacetylene to benzil mediated proceeds under mild and metal-free conditions, using various methods of thiyl radical generation. The product ratio of diketone to ketosulfide varied with the reaction conditions. Under photochemical conditions, benzil was formed but its photodegradation was also observed. Using autoxidation, moderate to good yields of both diketone 91 and ketosulfide 93 were obtained, although the product ratios varied with solvent and reaction conditions. Diketone 91 was the major product when the thiyl radical was generated electrochemically. Following investigation of the reaction mechanism using experimental and computational studies, the phenylthiyl peroxyl radical was identified as the key reactive intermediate. This represents the first synthetic application of thiyl peroxyl radicals. Using autoxidation conditions, the oxidation was explored using substituted aromatic thiyl radicals, e.g. 2,6-dimethylbenzene, 2,4,6-tri-tert-butylbenzene, 4-methoxybenzene and 4-nitrobenzene thiyl radicals. Except for the case of 4-methoxybenzene thiyl radicals, where generation of the thiyl radicals was inefficient, diketone 91 was formed as the dominant product. This oxidation of alkynes to ketones, via thiyl radical-mediated activation of oxygen, was then applied to cyclodecyne (1). Bicyclic ketones 7/8 were found as the major products under photochemical conditions, while sulfides 152/trans-49a were the dominant products under autoxidation conditions. Bicyclic ketones 7/8 were formed due to the intramolecular radical processes directed by the transannular strain of the ten-membered carbon framework. Only trace amounts of the cyclic α-diketone 151 were detected under autoxidation conditions.
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ItemSonochemistry and advanced oxidation processes: synthesis of nanoparticles and degradation of organic pollutants( 2009)This century has seen a phenomenal growth in energy demands and environmental pollution, which has given rise to a worldwide awareness for the need to address these issues immediately. This thesis focuses on the fabrication of high performance electrocatalysts applied in fuel cells and developing appropriate advanced oxidation processes for environmental remediation. It has been shown that ultrasonic irradiation is a promising method of synthesizing nanometre sized metal colloids with specific properties. Sonophotocatalysis has proved to be an effective process for the degradation of organic pollutants The synthesis of platinum monometallic and platinum-ruthenium bimetallic nanoparticles was successfully achieved by using sonochemical irradiation. A chemical method and a hybrid method were used to reveal and understand the process of Ru(III) reduction by sonochemistry. TEM images of the Pt and PtRu monometallic/bimetallic particles indicate typical diameters of less than 10 nm. An effort was made to investigate the influence of two different methods, namely simultaneous and sequential sonochemical reduction, on the structure and formation of PtRu bimetallic nanoparticles. It has been shown that the sequential reduction method produces a relatively higher yield of core-shell nanoparticles than the simultaneous reduction method. It has been concluded that Pt nanoparticles, which are formed first, play an important role in catalysing the formation of Ru nanoparticles. A number of methods including chemical, sonochemical and radiolytic synthesis were used to fabricate platinum and platinum-ruthenium monometallic/bimetallic nanoparticles. Furthermore, the evaluation of the electrocatalytic performance of these particles was performed by using cyclic voltammetry. Simultaneous and sequential methods for the synthesis of PtRu were adopted to investigate their influence on the electrocatalytic performance of these bimetallic nanoparticles. thas been shown that simultaneous reduction is an effective means of fabricating high performance electrocatalytic PtRu catalysts. A number of experiments with different ratios of platinum to ruthenium ions in precursor solution were carried out to study the effect of the ruthenium composition in platinum-ruthenium electrodes. It has been found that the methanol oxidation ability of platinum-ruthenium bimetallic nanoparticles can change with the alternation of ratio of Pt(II) to Ru(III) in the precursor solution. Simultaneous radiolytic reduction has the potential to fabricate higher performance electrocatalytic bimetallic nanoparticles. Although both photo-oxidation and sono-oxidation techniques are fascinating solutions to the environmental problems at hand, the critical limit of these individual processes is their low efficiency of environmental remediation. In my project, sonolysis and photocatalysis (sonophotocatalysis) have been simultaneously employed to degrade selective organic pollutants in aqueous environments, such as methyl orange, p-chlorobenzoic acid, p-aminobenzoic acid and p-hydroxybenzoic acid. Experiments have been carried out in order to improve the efficiency of sonophotocatalytic reactions to ensure that a substantial amount of the electrical energy is utilized in degrading the organic pollutants. Methyl orange, an azo dye, was selected as the degradation target for sonophotocatalysis. An orthogonal array analysis method was employed to clarify the correlation between the efficiencies of sonolysis, photocatalysis and sonophotocatalysis and the various operation conditions studied. Emphasis was placed on investigating the influence of pH and the ultrasound parameters on these three advanced oxidation processes. It was of interest to find that the degradation of methyl orange originates from hydroxylation and demethylation processes preceding aromatic ring-opening. Sonophotocatalysis was also applied in the degradation of three aromatic carboxylic acids, p-chlorobenzoic acid, p-hydroxybenzoic acid and p-aminobenzoic acid. Experiments were carried out in order to get a thorough understanding of the synergy effects produced by combining the two oxidation techniques. A number of advanced analytical techniques, such as HPLC and Q-TOF MS/LC, were employed to comprehensively monitor and analyse the sonophotocatalytic degradation process. It has been found that synergistic effects of the combined system have been identified with respect to the parent organic pollutant as well as its degradation products. Additionally, products were quantitatively analysed by a kinetic simulation method in order to understand the reaction mechanism. This method also allowed us to quantify the synergy effects. It was observed that the solution pH played a key role in determining the degradation rate and controlling the direction of the degradation reaction. Based on the analytical data gathered, the sonophotocatalytic degradation pathway of the aromatic carboxylic acids was established. The experimental results suggest that the sonophotocatalytic technique is likely to lead to a complete mineralization of organic pollutants in aqueous solutions.