There has been an astonishing variety of sesqui- and diterpene metabolites isolated—mainly from Laurencia species, or their predators—which possess the enantiopure α,α-dimethylcyclohexyl bromide moiety. The key step in their biogenesis is generally considered to be an enzyme-mediated formation of an asymmetric bromonium ion which initiates a cation-π cyclisation. This diverse array of terpene natural products is explored in the introduction to this thesis and their biogenesis via cation-π cyclisations analysed. Synthetic sources of electrophilic bromine such as NBS, TBCO and BDSB have been shown to initiate brominative polyene cyclisations with excellent control of relative stereochemistry albeit as necessarily racemic products. At the start of this work no asymmetric bromonium ion-induced polyene cyclisations had been demonstrated. Studies on a model system for the key in situ enantiopure bromonium ion generation and intramolecular trapping are described. Sharpless asymmetric dihydroxylation provides access to enantiopure diols of a trisubstituted alkene which can be manipulated to enantiopure bromohydrins. These are activated as 2,3,4,5-tetrafluorobenzoate esters which cyclise cleanly under the action of catalytic triflic acid to give enantiopure bromo-bicycles without racemisation from bromonium ion to alkene transfer. The mechanism of this reaction is investigated, it is practically demonstrated and shorter routes are explored. The synthesis of high purity linear terpene: homogeranyl 4-methoxybenzene is discussed, from which the synthesis of enantiopure bromo-tetrafluorobenzoate esters is carried out. The use of Lewis acid, in this case dimethylaluminium triflate, was found to successfully enact the cyclisation of these alkene containing substrates. Full conversion to cyclic products was achieved and the desired tricyclic product was isolated as a mixture of enantiopure diastereomers. Absolute and relative configuration of both diastereomers were determined by radical dehalogenation and comparison of the sign of the optical rotation of the product to literature values. Finally, the synthesis of homofarnesyl 4-methoxybenzene derived substrates is detailed. The cyclisation of which has the potential to generate tetracyclic compounds. This forms the basis of future work to be carried out.

A new all-atom force field for the simulation of phospholipid bilayers using the AMBER molecular dynamics package has been developed, which is compatible with other AMBER protein, nucleic acid, carbohydrate and small molecule force fields. The force field has been validated by simulating bilayers of six different lipid types, finding favourable comparison to experiment for properties such as area per lipid, volume per lipid, bilayer thickness, NMR order parameters, scattering data, and lipid lateral diffusion. The modular nature of this force field allows numerous combinations of head and tail groups to create different lipid types, enabling the easy insertion of new lipid species. The lipid bilayer model has then been applied to the study of the interaction between radioimaging agents and membranes in an effort to understand the phenomena of non-specific binding, which remains poorly understood yet of serious detrimental consequence to the development of new imaging tracers. The effect of different concentrations of imaging agent on a homogeneous membrane has been examined using unbiased simulations, whilst the permeability coefficient of each imaging agent through a membrane has been calculated using biased simulations. It is found that radiotracers with low non-specific binding must adopt a certain orientation to cross the head group region of a membrane - this requirement may act as a barrier to membrane entry. Furthermore, once partitioned into the membrane, simulations predict that those radiotracers displaying a high degree of non-specific binding act to order lipid tail groups to a greater extent than those with low non-specific binding, reducing the permeability of the membrane and possibly acting to 'trap' radiotracer in the membrane. These simulations also predict that non-specific binding is not related to radiotracer membrane permeability through a homogeneous bilayer.

This thesis is concerned with quantification of non-geminate recombination losses in organic bulk heterojunction solar cells. After description of the context of this work, the theoretical background and the methodology employed are presented. In this thesis, many different polymer:fullerene systems are investigated. In the next chapter, we show that the study of non-geminate losses using charge extraction/transient photovoltage analysis can be applied to many different systems away from P3HT/P3HS blends. We see to what extent ideality factors can give a more precise description of the exact recombination mechanism. Then, the change of optoelectronic properties of a high performance polymer:fullerene blend upon a blend ratio perturbation is investigated. The resulting shifts in energetics and dynamics of the blends are quantified. A quantitative agreement between two methods (charge extraction and electroluminescence) probing the shifts in the energetics at the heterojunction is presented. In the next two chapters, two limits of the common vision of polymer: fullerene systems are explored by combining experiment and 1D drift-diffusion modelling. First, the impact of the variations of the spatial distribution of carriers on the apparent reaction order is experimentally investigated. The study reconciles the apparent contradictions currently in the literature regarding the meaning of high reaction orders. In the following chapter, the often underestimated effects of unintentional doping in polymer blends are addressed experimentally. In particular, its effect on device optimisation, understanding of carrier collection and recombination dynamics are explored. This study suggests that many donor/acceptor blends are not, contrary to common belief, intrinsic semiconductors. Finally, an analysis of the Langevin and non-Langevin behaviour of some efficient systems is presented. The different interpretations of regular observations disproving non-geminate recombination following the Langevin type mechanism are reviewed. We suggest the ratio 'recombination over collision' is often overlooked and question the underlying assumption that it should be unity.

This PhD thesis describes work undertaken to develop efficient silver(I) catalysts for the intramolecular reactions of alkynes with nitrogen and oxygen containing nucleophiles for the synthesis of heterocycles. The introductory chapter provides an overview of recent advances in silver-catalyzed heterofunctionalization reactions of alkynes, with a focus on reactions involving C-N and C-O bond formations. A summary of the catalytic applicat ions of silver(I) NHC catalysts in the literature, which will be explored in Chapter 4, is also provided. Chapter 2 begins with the screening of silver salts as catalysts for the intramolecular hydroamination of alkynes with trichloroacetimidates. A strong counteranion effect on selectivity was observed. The impact of employing silver(I) complexes with variety of P- and N- donor ligands on catalytic activity was also explored, where pyridine-ligated silve r salts showed superior activity and selectivity. Reaction optimization was undertaken, and 1-bromoalkyne substrates were effectively cyclized with catalytic loadings as low as 1 mol%. Chapter 3, the application of the pyridine-ligated silver salts developed in Chapter 2 as catalysts for the cycloisomerization of propargyl amides is described. A broader substrate scope was observed compared to the previously reported AgSbF6 catalyst and a mechanism for the reaction is proposed based on experimental observations. In Chapter 4, the synthesis and characterization of a new class of silver(I) NHC carboxylate complexes are presented. The activity towards the cycloisomerization of propargyl amides was investigated, and they showed complementary reactivities compared to the pyridine-ligated silver catalysts in Chapter 3. In Chapter 5, an overall conclusion and future work are discussed. The last Chapter contains experimental procedures and characterization data of all the compounds synthesized during the course of this project.

Stress response systems are prevalent throughout all organisms with several functioning to maintain the cell envelope. One widely distributed system in bacteria is the Phage Shock Protein (Psp) response which is involved in pathogenicity, biofilm and persister cell formation. Induced under conditions proposed to cause membrane (often Inner-Membrane, IM) stress, the Psp response appears to stabilize the IM and so prevent dissipation of the proton motive force. The central component, PspA, is a peripheral IM protein that acts as both the effector and negative regulator of the Psp response. PspA has a counterpart Vipp1, which functions for chloroplast envelope maintenance and thylakoid biogenesis in plants, algae and photosynthetic bacteria. Mechanistic insight into how PspA and Vipp1 undertake their respective effector functions is limited but thought to be through their direct interactions with cellular membranes. Rigorously controlled, in vitro methodologies with lipid vesicles, purified proteins and peptides were established and used in this study, providing the first biochemical and biophysical characterisation of membrane binding by PspA and Vipp1. Direct membrane association of PspA and Vipp1 was shown to occur through their conserved N-terminal amphipathic helices. Both proteins are found to sense stored curvature elastic (SCE) stress and anionic lipids within the membrane. PspA has enhanced sensitivity for SCE stress while Vipp1 partitioning is most sensitive to membranes with a high net-negative charge. Experimental data points to alleviation of SCE stress by Amphiphatic Helix (AH) insertions as an attractive mechanism for membrane maintenance by PspA and Vipp1. Furthermore, by probing PspA's regulatory role we show that its transcription inhibition, though binding to the transcription activator PspF, can be relieved upon bilayer exposure in a SCE stress specific manner. The identification of a physical, stress related membrane signal suggests a unilateral mechanism that promotes both membrane binding of PspA and a stress triggered induction of the Psp response.

The accurate and reliable prediction of the optical properties of extended systems is a powerful tool for the development of nanostructured optical devices, such as photovoltaic materials. One major challenge faced by excited-state electronic structure methods is the treatment of the two-particle electron-hole interaction which is a key component of optical response properties such as optical absorption and charge transport. In this work we first study the effect of choice of basis set on both ground-state and first-order response properties, extending the molecular studies of Rappoport et al. into periodic and crystalline systems. From the conclusions of this basis set study, we employ a series of polarisation-optimised basis sets to calculate the optical gaps of the alkali halide series AX (where A = Li, Na, K, Rb and X = F, Cl, Br). Secondly, we assess the applicability of a range of methods (HF, LDA, PBE and B3LYP) for excited state calculations of extended systems, and examine the dependence of optical properties on the contribution of Hartree-Fock exchange (cHF ) to the linear-response TD-B3LYP kernel. We find that TD-B3LYP underestimates both the fundamental gap (Eg ) and optical gap (Eo ) in comparison to experimental work, and we show that the optical gap can be reproduced at least quantitatively with cHF ≃ 0.3. The last chapter of this work focusses on the calculation of electronic and optical properties of single-walled carbon nanotubes (SWCNTs). We study the effect of geometry relaxation, curvature, basis set and method on one-electron and linear-response properties, comparing our findings to other theoretical and experimental works. Our study shows that B3LYP is able to accurately and reliably calculate the ground-state electronic properties of a large range of nanotubes ( < 2-46 Å in diameter). Through our geometry optimisations and studies on nanotube diameter, we observe the curvature effect on the qualitative and quantitative properties of the van Hove singularities and Density of States of SWCNTs. We find that TD-B3LYP produces values of Eo that are in good agreement with experimental measurements and GW-BSE calculations, for both metallic and semiconducting nanotubes, however the estimated exciton binding energies for our calculations, Eb (where Eb = Eg - Eo) are in poor agreement with previous theoretical calculations. This is likely due to our comparison of two-particle (Eo ) values and roughly-estimated values of Eg from single-particle eigenvalues.

No description available.

Leishmaniasis is a tropical disease caused by protozoan parasite of the genus Leishmania. The temporins are a class of antimicrobial peptides (AMPs) and have documented antibacterial and antileishmanial activity. Temporins A, B, C, F, L and 1Sa were synthesised. Fluorescein and tetramethylrhodamine, used as biological imaging agents, were attached to temporins A and B and used in biological testing to track the progress of the peptides through infected macrophage cells, and in an in vitro skin model. Temporins A and L were found to be active against both promastigotes and amastigotes, and alanine and lysine scans of these peptides were performed to attempt to identify any residues causing activity. No residues to this effect were identified, however based on this work, the largest library of antimicrobial peptides to date was synthesised and tested gainst Leishmania mexicana promastigotes and axenic amastigotes. Data obtained was subsequently used in the first reported study of computational modelling to predict the sequences of antileishmanials peptides. Based on this work, peptide sequences were predicted that may show activity as antileishmanials agents. The Ciliatamides consist of three lipopeptides named Ciliatamides A-C, of which Ciliatamide B was shown to possess high levels of antileishmanial activity. (S,S), (R,S), (S,R) and (R,R) forms of Ciliatamide B were synthesised and used in biological testing. The activity of both temporins A and B was assayed against L. mexicana promastigote and axenic amastigotes, as well as murine macrophages: Allowing for an as yet undocumented comparison between both stages of the Leishmania spp. lifecyle. Differences were noted in the activity of the promastigotes and amastigotes lifecycle stages of the parasite, with promastigotes being significantly more responsive to AMPs than the amastigotes. As all previous studies had taken place on the promastigotes lifecycle stage, this finding must be taken into consideration in planning future studies.

This thesis describes the work undertaken to study the binding of lipid membranes by the viral matrix proteins hRSV-M and Influenza-A-M1. hRSV-M was recombinantly expressed and purified. It was the subjected to analysis by Langmuir-Blodgett trough experiments, Brewster angle microscopy, Confocal microscopy of giant unilamellar vesicles (GUVs), and binding studies with lipid nanodiscs. These studies showed hRSV-M having a preference for interacting with negatively charged lipids, namely phosphatidylserine, and for having different behaviours in Lo and Ld phases of membranes. During work on hRSV-M to improve its stability, it was discovered calcium stabilised the protein. This relationship was explored by ICPMS, differential scanning fluorimetry (DSF), circular dichroism (CD), mass spectrometry and microscale thermophoresis. This showed the hRSV-M is a calcium binding protein, containing two binding sites. Influenza-A-M1 was cloned into a plasmid vector and subsequently expressed and purified. The stability and structure of the protein was probed by DSF and CD measurements. The lipid interactions of this protein were then also explored by Langmuir-Blodgett trough isotherms and GUV binding under confocal microscopy. These showed that M1 is able to bind to phosphatidylserine containing membranes and causes vesicle budding from those membranes.

The NMR relaxation and chemical shift behaviour of isostructural series of macrocyclic lanthanide(III) complexes has been investigated. The 1H, 31P and 19F longitudinal relaxation rates of multiple series of lanthanide(III) complexes (Tb, Dy, Ho, Er, Tm, Yb) have been measured in solution at five magnetic field strengths in the range 4.7 to 16.5 Tesla. The electronic relaxation time, T1e, is a function of both the lanthanide(III) ion and the local ligand field. Analysis of the field-dependent nuclear relaxation rates, based on Solomon-Bloembergen Morgan theory, describing the paramagnetic enhancement of the nuclear relaxation rates, has allowed reliable estimates of the electronic relaxation times, T1e. It has been shown that in systems of high symmetry, the electronic relaxation times are directly proportional to the ligand field and that in some cases changing the ligand field can have a greater effect on the nuclear relaxation rates than lanthanide selection. The chemical shift data for the series of lanthanide(III) complexes were analysed. The pseudocontact shift of lanthanide(III) complexes is described by Bleaney’s theory of magnetic anisotropy. Most of the assumptions in this theory were shown to be questionable. In particular for systems in low symmetry significant deivations between the experimental chemical shifts and those predicted by theory were found. The low symmetry systems exhibit crystal field splittings of the same order of magnitude as the spin-orbit coupling. The possibility of a mixing of the electronic energy levels of the lanthanide(III) ion has to be considered. The effect of the coordination environment on the magnetic susceptibility was investigated using a variety of methods. Significant deviation (10 – 20%) from the theoretical values was observed in systems of low symmetry. These investigations show that paramagnetic relaxation enhancements and magnetic susceptibility are dependent on the ligand field. Applying this knowledge allows the design of more efficient paramagnetic probes, as needed in PARASHIFT magnetic resonance.