School of Chemistry - Theses
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ItemThe oxidative damage of biological molecules by air pollutants NO2● and NO3●( 2019)Air pollution is perceived as the world’s greatest environmental risk to human health. According to the World Health Organization (WHO), air pollution is responsible for the deaths of about 7 million people each year. In the industrialised urban environment, nitrogen dioxide (NO2•) and ground-level ozone (O3) are the most oxidising air pollutants. Exposure to these gases has been associated with increased respiratory health problems, such as exacerbation of existing asthma and allergies. While the adverse health effects of air pollution are clear, the precise underlying mechanism through which the pollutants affect biological systems is not well understood. It has been speculated that nitrate radicals (NO3•), which are formed from the reaction of NO2• and O3, play an important role in the oxidative damage of biological systems. Therefore, this thesis explores reactions involving NO3• and biomolecules such as proteins through a combination of kinetic, computational and product studies, in order to gain a better understanding of the fundamental chemical pathways that lead to oxidative damage in biological systems upon exposure to air pollution. The first section of this thesis investigates the reaction of NO3• with aliphatic amino acids and peptides. From laser flash photolysis experiments, it was found that NO3• reacts with aliphatic amino acids and peptides at multiple sites through proton-coupled electron transfer (PCET) at the amide nitrogen, and hydrogen atom transfer (HAT) at the α-carbon or the activated C–H moiety (e.g., tertiary carbons) with the rate of about 1 x 10(6) M−1 s−1. Following the above finding, this thesis proceeds to examine the reaction of NO3• with aromatic amino acids and peptides. A faster rate by a factor of 5–6 suggests that the reaction occurs at the aromatic ring through electron transfer (ET). An unprecedented amide neighbouring group effect was discovered, by which the rate of aromatic ring oxidation is increased considerably when the ring is flanked by two amide groups, instead of one amide and one ester group. Due to this effect, phenylalanine can potentially act as a relay amino acid in a long-distance ET even though the aromatic ring in phenylalanine is not readily oxidisable under biochemical conditions. The third section of this thesis explores NO3• reactions involving proline, where its side chain is covalently bound to the α-amino group. This unique structure increases electron density at the nitrogen and significantly accelerates the rate of ET at this nitrogen by a factor of about 600 compared to the other aliphatic substrates. However, when the amide moiety in proline residue is involved in the amide neighbouring group effect, accelerating the rate of aromatic ring oxidation, the rate of ET at this nitrogen was found to decrease significantly. The final part of this thesis studies the reaction of NO2• with various biological molecules, including short peptide and cholesterol derivatives. It was found that contrary to the widely accepted radical pathway, the reaction of NO2• with these molecules involves an ionic pathway through the dissociation of N2O4 into NO+ and NO3−.
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ItemCoinage metal hydrides: reactive intermediates in catalysis and significance to nanoparticle synthesis( 2019)The coinage metal hydrides of copper, silver and gold have applications in catalysis and nanoparticle synthesis. Coinage metal hydrides are key intermediates in the chemical transformations of a range of substrates including fine chemical syntheses and chemical storage of hydrogen. Ranging from mononuclear coinage metal hydrides to clusters and nanoparticles, a fundamental understanding of their atomic and molecular interactions is invaluable in developing innovative solutions to practical problems. The reactive sites can be identified using a range of spectroscopic methods allowing the “tuning” and/or “reshaping” of the reactive site by ligands to control the reactivity. Mass spectrometry provides a means to identify coinage metal hydrides in solution and further allows isolation of discrete coinage metal hydrides that can be: (i) characterised, for example by spectroscopic methods, (ii) reacted with neutral substrates, or (iii) fragmented to generate reactive intermediates in the gas phase. The use of borohydride in nanoparticle synthesis is well-known. Chapter 2 describes a mass spectrometry directed synthesis to afford the first isolable silver hydride borohydride cluster, [Ag3(μ3-H)(μ3-BH4)L3]BF4 (L =bis(diphenylphosphino)methane), structurally characterised by X-ray crystallography. Gas-phase experiments and DFT calculations reveal ligand (L) loss from [Ag3(H)(BH4)L3]+ results in the loss of BH3 and a geometry change of the cluster to yield [Ag3(H)(BH4)Ln]+ (n = 1 or 2). This work reveals links between silver hydride/borohydride and silver hydride nanoclusters adding to our understanding of silver nanoparticle synthesis using borohydride salts. Chapter 3 examines that the reactivity of CO2 with the binuclear silver hydride cation core, [Ag2H]+, can be controlled by design. Reshaping the geometry and reaction environment of [Ag2H]+ using a range of phosphine ligands (bis(diphenylphosphino)methane, 1,2- bis(diphenylphosphino)benzene and bis(diphenylphosphino)ethane) allows “tuning” of the active site’s reactivity toward formic acid to produce H2. Gas-phase ion-molecule reactions, collision-induced dissociation, infrared and ultraviolet action spectroscopy and computational chemistry link structure to reactivity and mechanism. The gas-phase studies were then translated to solution-phase studies using NMR to show that H2 could be produced from solutions comprising well-defined ratios of ligand, AgBF4, NaO2CH and HO2CH at near ambient temperature. Chapter 4 further developed the concept of altering the reactive site by changing the binuclear metal centres of the [LAg2H]+ core to compare all six possible combinations of copper silver and gold i.e. [LAg2H]+, [LCu2H]+, [LAu2H]+, [LCuAgH]+, [LCuAuH]+ and [LAgAuH]+ in the gas phase. DFT calculations, gas-phase ion-molecule reactions and gas-phase energy-resolved collision-induced dissociation showed both metal centres play a role in the reaction with formic acid. One metal site functions as an “anchor” for an oxygen of formic acid or formate while the other facilitates the dehydrogenation step resulting in the formation of H2. It was found that the copper homobinuclear species performed best overall. Attempts to isolate the reactive intermediate [LAg2(O2CH)]+ by using a range of bisphosphine ligands resulted in the isolation of an unusual co-crystal in the case of L = dcpm as described in Chapter 5. Single crystal X-ray diffraction of crystals suitable for crystallographic analysis revealed two discrete tetranuclear silver clusters [(μ2-dcpm)Ag2(μ2-O2CH)(η2-NO3)]2·[(μ2- dcpm)2Ag4(μ2-NO3)4]. The solution-phase studies, tracked by NMR, show that H2 could be produced from solutions comprising well-defined ratios of ligand, AgBF4, NaO2CH and HO2CH at 65⁰C. Gas-phase studies indicate that while the tetranuclear cluster [L2Ag4(O2CH)3]+ undergoes sequential decarboxylation reactions, none of the resultant hydrides react with formic acid. These results highlight important role of the binuclear hydride [LAg2(H)]+ in the catalytic decarboxylation of formic acid. Hydrido cuprate [CuH2]- has been explored for its applications in hydrogen storage. Chapter 6 indicates two chemically induced routes for the liberation of hydrogen when [CuH2]- is reacted with various chemical substrates. One path occurs via homocoupling of both hydride ligands giving the substrate-coordinated copper, the other by protonation with acids.
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ItemTowards the synthesis of the emestrin family of natural products( 2018)A Cope rearrangement of a vinyl pyrrole epoxide (397) was utilised to form the dihydrooxepino[4,3-b]pyrrole core (398) of the emestrin family of natural products which involved the first examples of the dearomatisation of pyrrole in this type of rearrangement. It was found that an electron withdrawing ester substituent on the C2 position of the epoxide was essential for the [3,3]-rearrangement to occur. The vinyl pyrrole epoxides were synthesised in an efficient manner by a vinylogous Darzens reaction. Density functional calculations showed lower transition state energies for Cope rearrangements of epoxides with C2 esters when compared to the unsubstituted substrates which agreed with the observed experimental results. Silyl substituted vinyl bromide esters also participated in the Darzens reactions to give the desired vinyl pyrrole epoxides in good to excellent yields. Only the triethoxysilyl vinyl epoxide 313c underwent Cope rearrangement to provide the fully substituted emestrin core dihydrooxepine. The anion derived from an aryl bromosulfone did not give the Darzens product but underwent a previously unobserved stereoselective trimerization to afford the cyclohexene 343 as a single diastereoisomer. A mechanistic rationale involving SN2’ additions, [3,3]-Cope rearrangements and a stereoselective intramolecular conjugate addition was proposed and this was supported by density functional theory (DFT) calculations. A four-step total synthesis of biaryl ether natural product violaceic acid (11) is described. The steps include an SNAr reaction to afford the biaryl ether 136, tin chloride-mediated chemoselective reduction of the nitro group to amine 135. A Cu-mediated Sandmeyer reaction of 135 gave violaceic acid methyl ester 374 which is hydrolysed to give pure violaceic acid 11. An improved synthesis of the known biaryl iodide 119 is also described via a Sandmeyer reaction of amine 135.
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ItemA journey of synthetic chemistry towards immunogenic glycolipids and non-lipidic antigens( 2018)Microbes, both pathogenic and commensal, produce a wide range of glycolipids that act as unique molecular signatures. The ability of the human immune system to fight infection as well as to modulate commensal organisms are active areas of research. Microbial glycolipids are known to interact with the immune system though discrete protein families including CD1 and Mincle. The main challenge in the study of such systems is the difficulty in, and often impossibility of, obtaining pure, homogeneous material from natural sources. We synthesised four classes of molecules of both natural and unnatural origin to investigate their potential to modulate the human immune system through the CD1 and Mincle axes. Chapter 2 describes the synthesis of a range of cholesteryl α-glucosides that are found in members of the Helicobacter family, including the prominent gut bacterium Helicobacter pylori. As part of this work we investigated the effect of remote protecting groups on the sugar on the stereochemical outcome of glucosylation reactions. In chapter 3 we designed and synthesised a set of purely synthetic glycolipids drawing upon the structures of known Mincle agonists. We investigated these compounds for their ability to signal through Mincle as a prelude to the development of improved vaccine adjuvants that promote cellular and humoral immunity. Chapter 4 discloses the total synthesis of α-glucosyl and α-glucuronosyl diglycerides, found in both pathogenic and commensal organisms relevant to human health. Finally, we prepared a set of analogues of the unique, non-lipidic synthetic CD1d-restricted effector, PPBF, to explore structure activity relationships for T cell activation. In collaboration with immunologists, the synthetic glycolipids and non-lipidic antigens have been studied for their ability to activate CD1d-restricted natural killer T cells or for their ability to stimulate signalling through Mincle.
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ItemNew techniques for elucidating the degradation of modern paints using polyvinyl acetate as a case study( 2017)Conservation of modern art poses many challenges, which include the use and take up of new materials with untested ageing mechanisms. While recent work has established several analytical tools and techniques that can identify and characterise modern materials, further work is required to ascertain fundamental chemical degradation pathways of a range of artists’ materials. Polyvinyl acetate (PVAc) is one such material and is commonly used in the creation and conservation of art. Understanding how PVAc degrades over time is a problem of both fundamental and practical importance. This study explores tools available in polymer chemistry and applies these to conservation research in order to gain further insight into the degradation of PVAc. Computational chemistry techniques using ab initio and Density Functional Theory methods were applied to explore key degradation reactions of PVAc materials. First, benchmarking studies were performed to identify the most appropriate level of theory to use in this investigation. BHandHLYP/cc-pVDZ was identified as being the most suitable as it offered excellent agreement of results calculated with the high-level benchmark method, G3(MP2)- RAD, at a fraction of the computer costs. Second, hydrogen abstraction reactions using dimeric and trimeric units of PVAc with hydroxyl, peroxyl and t-butoxyl radicals were modelled. The results from this study indicated that hydrogen abstraction was very likely to occur at room temperature with energy barriers for abstraction by hydroxyl and t-butoxyl radicals being below 24 kJ mol-1 and 53 kJ mol-1 respectively. Main chain and side chain scission reactions were also modelled, however the energy barriers for these reactions were all in excess of 100 kJ mol-1 indicating that these reactions are unlikely to contribute greatly to the degradation of PVAc at room temperature. Accelerated ageing studies were applied to PVAc films so as to provide insight into the longterm behaviour of PVAc when subjected to heat and light. Profluorescent nitroxide techniques were trailed to monitor the free radical mediated degradation as many commonly employed analytical techniques lack the molecular sensitivity to monitor the onset of degradation within paint films. A perylene based profluorescent nitroxide was identified as most suitable for this application and was synthesized and used to monitor the degradation of solvent borne PVAc resins and two commercial PVAc dispersion products when exposed to four accelerated ageing conditions. While the first nitroxide with the water-based dispersion products presented issues of incompatibility, a novel water-soluble profluorescent nitroxide was synthesized and initial accelerated ageing studies were conducted using one of the commercial dispersion products. To elucidate further information regarding the chemical reactions that occur during degradation, 13C NMR spectroscopy was used to analyse selected PVAc resin and dispersion samples exposed to various accelerated ageing conditions, including samples aged for over five years. The results of this study demonstrate that both the computational chemistry and profluorescent nitroxide techniques are useful tools for degradation studies within conservation research. This study also indicates that PVAc is highly susceptible to free radical induced degradation. This finding provides a secure direction for much needed ongoing research to better help determine practical treatments required to ameliorate the impact of free radical species if important cultural material is to be saved for future generations.
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ItemOxidative and chemical modification of amino acids by nitrogen dioxide, ozone and the reactive paracetamol metabolite NAPQI( 2016)Oxidative damage has been implicated in a wide range of diseases including cardiovascular disease, diabetes, asthma, cancer and atherosclerosis. While this damage is typically caused by ROS or RNS generated in vivo, oxidative damage is also mediated by environmental and secondary oxidants such as NO2•, O3 and reactive drug metabolites. This thesis explores the fundamental reactivity of environmental and secondary oxidants towards model amino acids and peptides. According to the WHO, environmental pollution represents the single greatest environmental risk to human health. Exposure of NO2• and O3, common polluting gases, has been linked to the development of asthma, bronchitis, heart disease, stroke, cancer and COPD. While this link is clear, the precise molecular mechanism through which NO2• and O3 cause these adverse health effects is largely unknown. The first section of this thesis explores the reactivity of NO2•, O3 and NO3• towards model biomolecules. N-Acetyl and C-terminal methyl ester protected amino acids and peptides were treated with NO2•, O3 and NO3•. NO3• was generated in situ from the reaction of NO2• and O3 or from the UV irradiation of CAN. These model biomolecules are irreversibly damaged as a result of exposure. The reaction of NO3• generated from the UV irradiation of CAN yields β-nitrate esters from aromatic amino acids, while NO3• generated in situ generally yields nitration products. In the case of tryptophan, pyrroloindoline and nitrosopyrroloindoline products were obtained. Exposure of NO2• to phenylalanine, glycine, alanine and valine containing peptides was found to lead to an unprecedented modification, rearrangement and ultimate excision of amino acids in a peptide chain. The thesis proceeds to examine the fundamental reactivity of a secondary oxidant, the reactive paracetamol metabolite NAPQI. Paracetamol is one of the most widely used analgesic drugs in the world and overdose represents a significant burden on the health system. NAPQI, generated in high concentrations in the liver by CYP450 enzymes, is known to form protein adducts, which have been linked to the development of liver toxicity. The focus of many studies has been on the role of cysteine – paracetamol adducts, formed from the reaction of NAPQI with cysteine residues. In this work, the reaction of NAPQI with a range of amino acids (Cys, Tyr, Trp, His, Lys, Arg, Met, Gln, Glu, Ser and Val) was examined and it was found that NAPQI forms adducts with Cys, Tyr, Trp and Met. Novel paracetamol – amino acid adducts were isolated and characterised by spectroscopic methods. The final part of this thesis explores the reaction of aromatic amino acids and peptides with CAN under UV irradiation. This method was utilised to form β- substituted amino acids with high diastereoselectivity in a single reaction step. Method development was performed in an effort to improve the yield of the β- nitrate ester products. This included 1H NMR based reaction screening of N- terminal protecting groups, work-up procedure and reaction conditions. From these experiments, it was found that ideal reaction conditions included N-acetyl protection, evaporation in vacuo, an excess of CAN and dilute solution concentrations.