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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ItemImaging the interactions of antimicrobial peptides with model and living cellular membrane systems( 2016)Since the discovery of penicillin over 80 years, the use of antimicrobial compounds has undoubtedly been one of the greatest contributions to modern science and medicine. Due to their use, misuse, and abuse over this time, numerous bacterial species have developed countermeasures to resist the effects of these antimicrobials. This rise in antimicrobial resistance has continued unabated since their first use, and now has the potential for devastating costs to humanity on a global scale; notably, mortality rates well into the millions over the coming decades. In turn, this has sparked interest in new therapeutic options not based on currently existing compounds. Antimicrobial Peptides (AMPs) are one such class of compounds. They can be found in virtually all forms of life, and act as the first-line- of-defence against a broad spectrum of pathogens at very low concentrations with limited resistance capacity. This makes AMPs extremely lucrative for future therapeutic design. Despite extensive investigations into their interactions, detailed mechanistic information about their behaviour with membranes remains elusive. Numerous models have been proposed to account for the observed behaviour of cell death, including pore-formation, detergent action, or some combination of the two. Mechanistic information regarding the progression of these models remains limited, however. In this work, we investigate the mechanistic behaviour of a model AMP with artificial and living bacterial membranes, primarily through the means of time- resolved fluorescence microscopy techniques. The antimicrobial peptide under study is an analogue of melittin; a well-characterised lytic peptide that displays significant activity to both eukaryotic and prokaryotic membranes. The analogue also bears a proline-to-lysine substitute around the centre of the peptide sequence, to which the fluorescent probe Alexa Fluor 430 is grafted. Using known photophysical information of the fluorescent peptide, information regarding the mechanistic progression of its interaction with membranes can be observed and deconvolved. This research progresses from developing a simple mechanistic understanding using model membrane systems, to increasingly complex living systems. In the liposome giant vesicle model, a slow two-step pore-formation mechanism was found to fit to the observed data, with major significance on the roles of aggregates. Leakage studies using the same liposome system found that the same pore-forming mechanism occurred in both unilamellar and multilamellar membranes, but with dramatically reduced pore stability in the latter. Similar experiments on E. coli bacteria revealed a more complex interaction that could not be adequately explained using either model systems. This finding has important ramifications for correlating information gained from model studies to living membranes. Finally, peptide interactions with Pseudomonas aeruginosa L-Forms were investigated in detail for the first time using super-resolution and fluorescence lifetime microscopies. The use of a biologically relevant environment was found to drastically alter the observed outcome of the peptide-membrane interaction, although the importance of peptide aggregates remains. Furthermore, little change in the fluorescence lifetime is observed over time, despite a clear time-resolved killing mechanism. The reasons for this, and the potential importance of the L-Form state, are explored in detail.
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ItemExploring the Petasis reaction through amino acid synthesis( 2015)The Petasis reaction was reviewed and shown to be a versatile and efficient reaction for the synthesis of nitrogen containing compounds and α-amino acids. Many different amines and amine equivalents can be used in the Petasis reaction, in conjunction with a wide variety of aryl and vinyl boronic acids and esters, and a small selection of aldehydes. Chiral reagents can enforce stereochemical control in the reaction. Certain chiral amines and chiral amine equivalents give the highest selectivity. Several limitations remained for the Petasis reaction: yields were low with sterically small amines and the organoborons were largely limited to aryl, heteroaryl and vinyl derivatives. These limitations were addressed to make the Petasis reaction a more well-rounded and useful synthetic method. tert-Butyl sulfinamide was explored as an amine equivalent and the kinetics of the Petasis reaction with this reagent were investigated through the use of in situ FT-IR and 1H NMR spectroscopy analysis. tert-Butyl sulfinamide and glyoxylic acid both had rate orders of one, whereas styrenyl boronic acid had a rate order of two. This accounted for an observed dramatic increase in reaction rate. A mechanism for this reaction system was proposed, in which the boronic acid acts as both a reagent and as a Lewis acid catalyst. Allyl boronic acid pinacol esters were synthesised by palladium catalysed borylation of allyl alcohols, and then reacted with tert-butyl sulfinamide and glyoxylic acid to yield allyl glycine derivatives. Isolated yields of the final amino acids were excellent, but the diastereoselective ratios achieved were low to moderate. The addition of scandium(III) triflate to the allyl-Petasis reaction gave excellent control over the syn/anti configuration of the product, resulting in diastereomeric ratios in the order of >20:1. However, stereochemical control at the α-carbon was still moderate. A mechanism was devised to explain this observation and several supporting reactions were conducted. N-Methyl tert-butyl sulfinamide was synthesised racemically in a single step from the commercially available tert-butyl sulfinyl chloride and methylamine solution. The product was isolated in a pure yield of 98%. Racemic N-methyl tert-butyl sulfinamide was applied to a modified allyl-Petasis reaction, which employed molecular sieves to promote the formation of the initial iminium ion, to yield N-methyl amino acids in a quick and efficient manner. The use of scandium(III) triflate gave excellent control of the syn/anti configurations. Enantiopure N-methyl tert-butyl sulfinamide was also synthesised and applied to the Petasis reaction, resulting in excellent yields and stereochemical control. This work demonstrated the robust and widely applicable nature of the Petasis reaction as a method to synthesise α-amino acids in an efficient manner. The Petasis reaction can therefore be utilised in the chemical total synthesis of more complex natural products containing unusual amino acids residues.
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ItemSynthesis and optical properties of CdSe core and core/shell nanocrystals( 2008)The synthesis of nanocrystals is unique compared to the formation of larger micron-sizesspecies as the final crystal sizes are not much larger than the primary nuclei. As a consequencethe final outcome of a nanocrystal synthesis i.e mean crystal size, concentrationand standard deviation is almost solely determined by the end of the nucleation phase. Directingthe growth of crystals beginning from aggregates of only tens of atoms into maturemonodisperse nanocrystals requires that the governing kinetics are strictly controlled at everymoment of the reaction. To effect this task various different ligands need to be employed,each performing a particular function during both nucleation and growth. (For complete abstract open document)