Attempts have been made to prepare new polymer supported and maleimide functionalised ruthenium catalysts for asymmetric transfer hydrogenation. Synthetic approaches were found to be challenging but did lead to the development of a series of complexes containing the para-Iodobenzenesulfonyl group, which may potentially serve as a handle for future functionalisation. The arene exchange route to tethered complexes as previously published by Wills et al. has been refined in an attempt to improve reliability. The practical challenges of carrying out the reaction and especially purifying the resulting complexes are discussed and the use of molecular sieves as a trap for free hydrogen chloride gas is recommended. Known tethered complexes reported by Wills have been applied to the reduction of electron rich ketones, containing oxygen or nitrogen substituents on their aromatic rings. Such ketones are relatively unreactive and require higher temperatures and extended reaction times, however in most cases the chiral alcohols could still be obtained with good yield and enantioselectivity. The choice of solvent/hydrogen donor is shown to be important and substrate dependant. Finally, reduction of β-chloropropiophenone to the dehalogenated chiral alcohol prompted an investigation into the reductions of enones with tethered catalysts. Selectivity between 1,4- and 1,2- reduction products is shown to be strongly substrate dependant but can also be influenced by the choice of catalyst, with the recently developed methoxy tethered catalyst demonstrating an increased preference for 1,4- reduction in all cases.

Siglecs (Sialic Acid Immunoglobulin-like Lectins) are immune system protein receptors that play important roles in the down-regulation of cellular signals upon Sialic Acid ligand binding. At present, the human Siglec family is composed of 16 members expressed by specific immune system cellular types. Due to their highly restrictive expression patterns and key regulatory function, Siglecs have been pointed out as interesting pharmaceutical targets to treat certain immune diseases where those specific cellular types are involved. This work is focused on Siglec8 which is expressed on the surface of mast cells and eosinophils and has demonstrated to induce their apoptosis upon ligand binding. This effect could be exploited to develop therapeutics that target and reduce the levels of eosinophils in the inflammatory diseases such as asthma where they are the main effectors. The aim of this thesis is to design some Siglec8-ligand mimetic small molecules, test their binding to the receptor and obtain affinity data about the interaction. We managed to express the Siglec8 Ig-like V-type carbohydrate binding domains in Escherichia coli, refold and purify them in solution and perform a biophysical characterization by means of different techniques such as Fluorescence, Absorbance, Mass Spectrometry (MS), Circular Dichroism (CD) and Single-Angle Neutron Scattering (SAXS). We also designed nine small Siglec8-ligand mimetic molecules and tested their binding to the receptor domains using the Octet technology and equilibrium dialysis-1 D H+ NMR measurements. We found the ligand Phospho-Tyrosine to be our best Siglec8 binder and estimated a dissociation constant around 100 μM for the interaction. Thus, the binding information obtained in this work could lead to the development of higher affinity and specific molecules that target Siglec8. This thesis also encompassed an industrial collaboration with the company Mologic Ltd where anti-Siglec8 antibodies where developed with chronic lung disease diagnostic purposes.

In this thesis some fundamental aspects of charge transport and exciton dynamics in organic semiconductors are explored from a theoretical and computational point of view. After a brief review of the field of organic electronics, the theoretical methods most commonly used to describe exciton dynamics and charge transport are summarised, with an emphasis on the specific methods employed in this thesis (chapter 1). A very general kinetic rate of hopping between electronic states in the incoherent regime is then derived (chapter 2). This rate contains the most commonly used rates (Miller-Abrahams, Marcus, Marcus-Levich-Jortner) as special cases. The excitonic couplings between molecules determine the properties of excited states in biological and artificial molecular aggregates. A large number of excitonic couplings in these systems are computed (chapters 3 and 4) including both the Coulombic and the short-range (non-Coulombic) contributions as well as the thermal fluctuation of the coupling (dynamic disorder). The effect of thermal fluctuations in crystalline materials is found to be important when evaluating exciton dynamics (chapter 3). The short-range component of the coupling needs to be included when the interacting molecules are in close contact (chapter 3). The characteristics of charge transport in disordered polymers depend in principle on many parameters. With the aim of accounting for the complicated nature of these materials, a very general charge transport model is presented here (chapter 5). A detailed electronic structure with variable localization of the electronic states is obtained from a simple model Hamiltonian depending on just a few parameters. Using the hopping rate derived in chapter 2, the charge mobility along disordered polymer chains is computed. The proposed model includes features of both variable range hopping (VRH) and mobility edge (ME) models, but it starts from fewer assumptions. Donor-acceptor copolymers have a narrower transport band which in principle should result in lower mobility. Instead, the narrower band is found to enhance mobility if the other parameters are kept constant. By exploring the large parameter space of this model, the temperature dependence of mobility is found to follow a universal Arrhenius behaviour in agreement with experimental data (chapter 6). The activation energy for transport depends only on the effective electronic disorder of the polymer chain. When the 3D structure of the polymer chains and the role of inter-chain hopping are also considered (chapter 7), the mobility is found to be linearly dependent on the persistence length. The activation energy is found to depend only on the electronic disorder and not on chain rigidity.

The challenge of this project was to control the polymerisation of acrylamide monomers, particularly sodium 2-acrylamido-2-methylpropane sulfonate (Lubrizol trademark, AMPS®2405), via reversible addition-fragmentation chain transfer (RAFT) polymerisation in aqueous solution. AMPS® based polymers are employed in a wide range of applications (e.g. medical, paint, oil recovery and water treatment), and are typically obtained via conventional radical polymerisation. Here, the use of the RAFT process to control the polymerisation of AMPS®2405 was reported, and well-defined polymeric architectures were obtained compared to materials obtained via free radical polymerisation (FRP). The chain transfer agent (CTA) of choice for this project was initially DDMAT (CTA-A, Z-group is C12H25), and a water soluble CTA synthesised by the Lubrizol corporation (USA) in tonne-scale. DDMAT is known to form aggregates in water ([CAC]DDMAT =0.005 M) and this is likely to disrupt the RAFT mechanism and consequently diminish the control over the polymerisation. To overcome this problem a chain transfer agent with a shorter alkyl chain (BDMAT, Z-group is C4H9) was used for comparison with DDMAT. The polymerisation of AMPS®2405 monomer was optimised, as discussed in CHAPTER 2, in aqueous solution using either DDMAT or BDMAT as a chain transfer agent. These conditions were found to be universal to other water soluble acrylamide monomers (N,N-dimethylacrylamide, N-hydroxyethyl acrylamide and 4-acryloylmorpholine). More complex architectures were designed, as described in CHAPTER 3, exploiting the high chain end fidelity and chain extensions. A small library of diblock copolymers using various comonomers (N,N-dimethylacrylamide, N-hydroxyethyl acrylamide, 4-acryloylmorpholine, acrylic acid and acrylamide) were first synthesised. The synthesis of star polymers using the arm first approach was further studied, and well-defined multiblock star copolymers were obtained by RAFT polymerisation. These structures synthesised were characterised, as discussed in CHAPTER 4, using diverse techniques (e.g. SAXS, DLS, SEC with triple detection and AFM). While copolymers prepared from AMPS®2405 can be used in numerous applications, the focus of this thesis, as discussed in CHAPTER 5, was to study their benefit as heparin-mimicking polymers.

Graphene is one of a number of layered materials which have tremendous applications in future devices due to their interesting electrical and structural properties. Key to material synthesis is understanding growth mechanisms for thin film formation, and the elimination of defects; consistently creating smooth layers. A number of interesting effects seen in graphene growth highlight the importance of understanding the interaction between the substrate and the growing layer, such as growth on liquid substrates, wrinkling and structural feedback. Chemical vapour deposition (CVD) on a copper substrate has been hailed as a promising scalable route to synthesis, however there are restrictions relating to in situ observation. Recent experimental advances have led to graphene grain production of increasing size and purity, yet the early stages of growth remain relatively unexplored. Current modelling techniques tend to either investigate small systems in a high level of detail, or neglect the substrate detail in a coarser grained model. In this thesis we present results from abstract surface growth modelling which incorporate substrate effects into larger scale simulations. Firstly, we present a lattice Monte Carlo (MC) model of graphene growth on a rough substrate, and show the introduction of a dynamic roughness energy leads to an increase in island size. Secondly, we introduce a dynamic field into the standard random field Ising model, and observe a domain size increase with a dynamic field, but also observe a lower temperature field ordering effect. Thirdly, we construct geometric effective potentials in a Molecular Dynamics model of graphene growth, reproducing experimental island orientation distributions and growth behaviour. Finally, we detail the construction of a cluster moving algorithm for lattice MC simulation, and demonstrate that its implementation leads to an enhancement of island size. Together, these results highlight the importance of substrate roughness and geometry in the early stages of growth.

The oxidative addition to square planar dicyclometallated C^N^C PtII 16 valence electron complexes (C^N^C= 2,6-di(4-fluorophenyl)pyridine and 2-(4-fluorophenyl)-6-tertbutylpyridine) was studied with Cl2 (via PhICl2) and alkyl halides (e.g. MeI, BnBr and allylBr). The two-step nature of the process meant that PtIV 16 valence electron fivecoordinateintermediates could be identified. The product of oxidation was an octahedral 18 valence electron product with the new groups added mutually trans across the metal, with isomerisation seen with time. However, in the case of the chlorine-based oxidant, PhICl2, this was only part of the story, where further reactivity depended on the phosphine coordinated in the fourth coordination site. Oxidation of the PPh3 derivative gave a longlived five-coordinate intermediate (lasting about four hours) before combination with the second chloride. Complexes containing PBu3, PPr3 and P(o-Tol)3 trapped the fivecoordinate complex with agostic interactions, eventually leading to transcyclometallation products. In parallel to these studies, abstraction of X- from the octahedral PtIV oxidation products gave another path to the five-coordinate intermediates, and in most cases, they could be trapped with pyridine. Whilst we did not see any evidence of aryl-Cl coupling, we were able to isolate several three-coordinate monocyclometallated PtII products, which came about through aryl-R reductive elimination via a long-lived five-coordinate complex which were characterised in solution. Addition of a mild base led to the activation of the C(sp2 )-H bond, reforming the five-membered ring. Addition of another equivalent of the alkyl halide, and subsequent addition of AgBF4 showed 100% regioselectivity for reductive coupling of the R group to the ring substituted previously. When C^N^C was 2-(4-fluorophenyl)-6-tertbutylpyridine), the reductive elimination reaction was spontaneous under the reaction conditions for RX addition, showing complete selectivity of C(sp3 )-C(sp2 ) over C(sp3 )-C(sp3 ). Further to these reactions, the PBn3 derivative was also treated with PhICl2, which led to the formation of a PtIV tricyclometallated product. When the halide was removed from the tricyclometallated complex (again with AgBF4), reductive elimination of the coordinated benzyl and aryl group gave a three-coordinate complex with a strained nine-membered ring. Two distinct mechanisms were identified for the inversion of the ring, one of which included the breaking of the C-C bond to reform the five-coordinate intermediate. The fourth coordination site was open enough to allow chloride, CO and H2 to coordinate. Coordination of H2 was not seen directly, instead a product with no cyclometallation and a Pt-H bond was observed.

The work presented in this thesis focuses on the synthesis, analysis and cyclisations of a series of N-halobenzylcycloalkenamides. Chapter 1 provides an introduction to atropisomerism, radical cyclisation and Heck cyclisation, including developments in the reaction conditions for radical and Heck cyclisations. The use of atropisomers in synthesis, and particularly in cyclisation reactions, is also discussed. Chapter 2 reports investigations into the effects of aryl, acyl and alkene substitution on the barrier to rotation about the N-alkenyl bond in a series of enamides. A range of enamides were synthesised and their barriers to rotation were investigated by 1H VT NMR, and where desirable, by racemisation of an enriched atropisomer. The highest barriers to rotation were obtained with tetrasubstituted enamides, although additional bulk adjacent to the double bond (such as in tetralone-based compounds) was found to increase the barrier to rotation to a lesser degree. A precursor analogue to the natural product norchelidonine was also synthesised and was found to have a barrier to rotation between 20 and 24 kcal/mol. Chapter 3 describes the results of Bu3SnH-mediated radical cyclisation of the enamides synthesised in Chapter 2. A range of cyclised products was obtained in most cases, resulting from either the 5-exo pathway or the 6-endo pathway, although the 6-endo pathway was found to predominate in almost all cases. Cyclisations of enamides with higher barriers to rotation proved more difficult, and indeed it was not possible to cyclise some of them, such as the precursor to the natural product norchelidonine. Chiral transfer should be possible with at least one α,α’,α’-substituted enamide, under the conditions used in this chapter. Chapter 4 describes attempts to find a viable alternative method for the cyclisation of the enamides synthesised in Chapter 2, to combat the many disadvantages of the tin method. Samarium diiodide radical cyclisation and palladium Heck cyclisation of the simplest substrate were both successful. Samarium cyclisation generated the same products as tin cyclisation, in a slightly different ratio due to the difference in reaction conditions. Palladium Heck cyclisation gave only 5-exo cyclisation products: the direct product and the isomerised product, in varying ratios depending on the conditions used. The palladium Heck reaction conditions were then optimised for these compounds, and the optimised conditions were used to cyclise a selection of the compounds from Chapter 2.

Linear dichroism (LD) spectroscopy is a technique which uses polarised light to make inferences on the relative orientations of chemical groups within a molecule. A requirement for experiments using this technique is the alignment of molecules in the analyte. This thesis considers the use of fluid flows to align molecules. The use of bead-spring and bead-rod models to simulate the behaviour of polymers and particles in fluid flows has been extensively discussed in the literature. In this work, the FENE-Fraenkel spring force law is implemented in bead-spring chain simulations, to assess the alignment behaviour of molecules in flow. Analytical properties of FENE-Fraenkel springs are derived and used to inform the coding of the simulation programme and to assess its outputs. The results of these simulations were comparable to both analytical results in zero-shear conditions and to data previously published by Hsieh et al. [48] on bead-spring chains in extensional flow, albeit with a reduced signal-to-noise ratio. Simulations of the alignment of FENE-Fraenkel spring dumbbells in shear flows show increased alignment with high shear rates, similar to modelling data published by McLachlan et al. [89]. This work also considers the use of microfluidic devices manufactured from polydimethylsiloxane to perform linear dichroism studies on DNA and vesicles in solution. A wide channel and cross-slot device are developed to provide conditions for pressure-driven and extensional flow to align molecules. Both devices are shown to align DNA molecules to measure an LD signal, with the cross-slot performing better than the wide channel device. With solutions of vesicles containing 1,6-Diphenylhexa-1,3,5-triene, a membrane probe, the wide channel device is shown to provide weak vesicle alignment to measure an LD signal. However, both microfluidic devices are unable to align molecules as well as Couette flow, the method normally used to align molecules for LD experiments.

This thesis describes the synthesis, structural preferences and biological properties of oxetane-containing peptidomimetics in which one of the amide C=O bonds of a peptide backbone is replaced by an oxetane ring. Chapter 1 gives a brief introduction on peptidomimetics, oxetanes in medicinal chemistry and oxetane-containing peptidomimetics. Chapter 2 describes the development of a simple two-step sequence to spirocyclic analogues of 2,5-diketopiperazines. Conjugate addition of α-amino methyl esters to nitroalkenes, generated from oxetan-3-one or N-Boc-azetidin-3-one, followed by reduction of the nitro group with Raney Ni under an atmosphere of hydrogen provides, after spontaneous cyclisation of the primary amine, the spirocycles in good overall yields. These novel spirocycles can be functionalised by selective N-alkylations as well as by carbonyl reduction to the corresponding piperazines. Chapter 3 describes the development of a practical route to oxetane-modified peptides (OMPs) using solid-phase peptide synthesis (SPPS) techniques. Our approach involves the application of oxetane-containing dipeptide building blocks which are easily prepared in three steps in solution. The building blocks are then integrated into peptide chains using conventional Fmoc/ t Bu SPPS. This approach was used to prepare a range of OMPs in high purity including oxetane analogues of Met- and Leu-enkephalin and the nonapeptide bradykinin. Chapter 4 explores the impact of oxetane-modification on the structure and stability of α- helices. Initially, an asymmetric route to a dipeptide building block in which the oxetane- residue is based on alanine is described. Following this, the SPPS methodology described in Chapter 3 was used to prepare oxetane-modified analogues of an alanine-based α- helical peptide in which a single alanine residue is replaced with an oxetane-modified residue. The structural preferences of the oxetane-modified analogues were then studied using circular-dichroism (CD) spectroscopy. These studies revealed that introduction of an oxetane-modification results in a helix-destabilising effect. Chapter 5 gives a summary of the key findings and possible future work. Chapter 6 provides detailed experimental procedures for the work carried out in Chapters 2-4.

The lithium/sulfur battery has been investigated as an attractive candidate for the rechargeable energy storage system, since it can potentially deliver a much higher energy than a typical lithium ion battery of the same weight. In this work, sulfur/acetylene black composite electrodes were prepared by the ball milling method and studied cells with various electrolyte systems. A significant impact of the electrolyte viscosity on the electrochemical performance of the cells was explained in terms of the electrolyte penetration into the sulfur electrode structure, the diffusion rate of lithium salts and the dissolution rate of the solid active materials. Sulfur/acetylene black (AB) composites were also prepared using a direct precipitation method. The smaller particles of sulfur, as well as the well-distributed AB on the surface of sulfur particles resulting from the precipitation method was found to provide a more uniform and conductive S/AB composite with a larger surface area. The resulting electrodes showed less degradation on cycling than those prepared by milling method.<br/><br/>A simple quantitative one-dimensional model of the initial self-discharge has been developed in terms of diffusion of a polysulfide shuttle species. Despite the simplicity of the model, it reproduces very well the decrease in the open circuit potential of the cells under a range of experimental conditions (varying the number of separators between the electrodes, the amount of AB in the sulfur electrode and the pre-saturation of the electrolyte with sulfur). The model provides a detailed understanding of the mechanism of self-discharge, quantifying the two main causes of sulfur loss from the positive electrode: dissolution followed by diffusion down a concentration gradient and direct reaction with polysulfides arriving from the lithium electrode.<br/><br/>Galvanostatic Intermittent Transient Technique (GITT) measurements were conducted to study the diffusion behaviour in Li/S cells. Analysis of the transient voltage change during and after current pulses was performed at different states of discharge/charge. The relaxation time was optimised to avoid errors due to poor equilibration at short times and self-discharge during longer periods.<br/><br/>Finally, the effect of the shuttle reaction on the electrochemical performance of Li/S cells was investigated using a lithium ion conducting glass ceramic (LICGC) separator in an effort to eliminate the self-discharge. This resulted in a higher discharge capacity and more accurate GITT results, showing that better controlled diffusion conditions can be achieved in a Li/S cell containing LICGC separator.<br/>