School of Chemistry - Theses
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ItemGas Phase Chemistry of Iranium Ions with Unsaturated Carbon-Carbon Bonds( 2023-10)The study of cyclic iranium ions has developed rapidly over the last few decades as control of stereoselective outcomes during the electrophilic functionalisation of alkenes is mostly determined by the configurational stability of these species. Trace nucleophiles such as solvent, counter-ions, or unreacted alkene may cause decomposition or racemisation of these intermediates as the electrophilicity of both the heteroatom and endocyclic carbons make them susceptible to nucleophilic attack. Mass spectrometry (MS) thus offers an alternative means by which to isolate these charged species and study their bimolecular reactivity in the gas phase. Generation of these ions was achieved by electrospray ionisation of precursors containing a suitably basic group beta to the heteroatom, which upon protonation would fragment either in-source or following collision-induced dissociation of the pseudomolecular ion to give the heterocyclic three-membered ring. The multistage MS capabilities of a modified linear ion trap were utilised to isolate the iranium ion and observe its reactivity with neutral alkenes or alkynes. Changing the chalcogen (Ch) from sulfur to selenium to tellurium had a significant effect on the partitioning between attack at the heteroatom or ring-opening at carbon. Telluriranium ions underwent exclusive pi-ligand exchange with direct transfer of the tellurenium cation to the neutral reagent in a series of identity reactions, whilst all thiiranium ions studied only showed addition products from ring-opening by the neutral species. The reactivity of seleniranium ions towards alkenes partitioned between these two pathways with electron-donating groups on the heteroatom favouring the former, whilst the latter was promoted by electron-withdrawing groups. Computational studies into the pi-ligand exchange reaction revealed a Huckel pseudocoarctate transition state with a disconnection in the orbital array during the bond-breaking and bond-forming step. Extension to the haliranium ions showed kinetics of ion-molecule reactions with both cyclic and linear alkenes proceeding at the collision rate with iodiranium ions reacting dominantly via pi-ligand exchange, but bromiranium ions underwent carbocation-based fragmentation following ring-opening. Conjugation of the double bond to methyl esters suppressed heteroatom attack on iodiranium ions and only gave allylic stabilised oxocarbenium ions. The partitioning between these two reaction channels could be tuned by substituting inductively electron donating methyl groups onto the carbon-carbon double bond or entirely reverted to pi-ligand exchange by disrupting the conjugation with a methylene spacer enabling differentiation between three isomeric unsaturated methyl esters. Stability of the unsaturated irenium ions was examined by natural bond orbital theory to study (anti)aromaticity in these species. This approach revealed the antiaromatic nature of halirenium ions due to repulsion between the lone pairs and filled pi-orbital of the endocyclic double bond, and non-aromatic nature of the chalcogen irenium ions due to introduction of stabilising pi(C=C) - sigma*(Ch-R) hyperconjugative interactions. These species were generated in the gas phase for the first time by ion-molecule reactions of iranium ions with alkynes. The selenirenium ion structure assignment was strongly supported by cross-over experiments showing selenyl transfer to another alkyne, whilst the proposed iodirenium ion showed different reactivity to that of the open beta-iodovinyl cation produced upon reaction with phenylacetylene.
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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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ItemStable isotope labelling and computational data mining approaches in drug metabolism studies( 2017)Many small organic molecules will be chemically modified in some way after entering the body through metabolism. Thus, metabolism plays a significant role in determining the biological properties of a compound including half-life and toxicity profile. Identifying the metabolites of a compound is an important part of drug discovery projects. This thesis describes the development and application of methodologies to detect such metabolites. A guiding principle of this work is the detection of metabolites from a complex sample without prior knowledge of their structure or formation pathways. This ‘non-targeted’ analysis approach allows unknown or unexpected metabolites to be detected, providing a complete picture of the metabolic fate of a xenobiotic. The basis of the non-targeted approach is described in Chapter 2. Here, paracetamol (APAP) and an equal quantity of 13C6-APAP are simultaneously administered to rats. Analysis of blood plasma extracts by liquid chromatography mass spectrometry (LC-MS) resulted in mass spectra that contained pairs of ions that eluted simultaneously with equal intensity and are unique to metabolites. To automate data analysis, software called HiTIME was written enabling the non-targeted but selective detection of metabolites that appear as twin-ions from highly complex samples. In some cases, xenobiotics form electrophilic metabolites that can covalently react with cellular proteins. This is thought to trigger allergic and toxic side-effects. The specific nature of the protein adduct may be a determinant of the biological response. Chapter 3 describes a reactivity survey of the electrophilic APAP metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), towards a panel of amino acids and peptides. In addition to the well-known reactivity toward cysteine, previously undocumented covalent adducts between chemically synthesized NAPQI and tyrosine, tryptophan and methionine were also observed, isolated and characterised. Chapter 4 introduces a non-targeted method to identify the protein targets of reactive metabolites which uses twin-ion and HiTIME analysis to detect tryptic peptides that have been covalently modified by drug metabolites. Software called Xenophile was developed that can identify the site of modification, the mass and the chemical formula of a reactive metabolite directly from shotgun LC-MS data. In Chapter 5, Xenophile was applied to identify the protein targets of APAP and 13C6-APAP metabolites following incubation with liver tissue extracts and global trypsin digest. The Xenophile software correctly identified the reactive metabolite as C8H7NO2 (i.e. NAPQI) and the adduction site as Cysteine residues. Further investigation identified 7 unique proteins that were modified by APAP including those that have been previously identified as adduction targets of NAPQI and other xenobiotic reactive metabolites. HiTIME and Xenophile are then used to assess the small molecule metabolism and protein adduction profile of the environmental contaminants benzene, bromobenzene and toluene in liver extracts. Numerous twin-ions were detected that correspond to glutathione adducts of epoxide and quinone metabolites. No modified proteins were detected following analysis of global protein digests for any sample. To rule out false negatives, targeted approaches were taken to identify protein adducts. As these did not result in the recovery of any missed peptides, we conclude that protein adducts were not formed in these experiments. This finding is rationalized based on the extent of formation of small molecule GSH adducts.
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ItemIon trap studies of single microparticles: optical resonances and mass spectrometry( 2006-12)Microparticle experiments conducted using a newly commissioned quadrupole ion trap (QIT) are reported. Single polystyrene microparticles are confined using three dimensional electrodynamic quadrupole fields and characterised by their fluorescence emission and secular frequency measurements. The advantages of this confinement technique are that single particle properties can be measured free from ensemble averaging effects and unperturbed by solvents and (or) substrates. (For complete abstract open document)
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ItemStudies of the interaction of metal complexes with ligands and biomolecules in the gas phase using mass spectrometry( 2005)Introduction of soft ionization techniques, such as electrospray ionization (ESI), has resulted in extensive use of mass spectrometry based techniques to study biomolecules in the gas phase. Despite thorough studies of the gas-phase chemistry of even-electron biomolecules, the examination of their odd-electron counterparts has to this point been much less extensive due to the inefficiency of ESI in generating such species. Among various methods that could be employed to generate and study odd-electron biomolecules in the gas phase, redox processes involving metal ions and homolytic cleavage of metallated amino acid or peptide derivatives would be attractive from a chemical perspective since, in principle, a wide range of metals and biomolecules or biomolecule derivatives could be explored. An important aspect of these approaches is that they can be carried out on a wide range of tandem mass spectrometers equipped with electrospray ionization and collision induced dissociation capabilities. (For complete abstract open document)