Luminescent lanthanide complexes are important tools for molecular sensing and cellular staining due to their unique photophysical properties, including their long luminescence lifetimes that permit the use of time-gated measurements. However, a common drawback of such complexes is the non-specific binding associated with their low solubility in biological media. A new class of bright, highly water soluble, and negatively charged sulfonate or carboxylate derivatives of substituted aryl–alkynyl triazacyclononane complexes has been synthesised and their photophysical properties analysed. In addition, new synthetic methodologies have been explored for the introduction of solubilising moieties into the ligand system and for the incorporation of a linkage point for conjugation with biomolecules. Each complex exhibits extremely high quantum yields (up to 38 % in H2O), large extinction coefficients (60,000 M-1 cm-1) and long luminescence lifetimes (1.1 ms). Introduction of the charged solubilising moieties suppresses cellular uptake or adsorption to living cells, making them applicable for labelling and performing assays on membrane receptors. These Eu(III) complexes have been applied to monitor fluorescent ligand binding on cell-surface proteins (G-protein coupled receptors) with time-resolved fluorescence resonance energy transfer (TR-FRET) assays and TR-FRET microscopy. In addition, the introduction of a linkage point for conjugation on the macrocyclic ring provided complete control of the stereochemistry of the final complex. Direct and selective formation of chiral complexes was observed with > 95 % optical purity resulting in an intense circularly polarised luminescence signal.

Structural differences in cross-linked epoxy networks from the use of different isomers (ortho-, meta- and para-) of disubstituted aromatic diglycidyl ethers can have a dramatic effect on the polymer properties. By changing the disubstitution from meta- to para- it has been shown that there is a direct correlation between the diffusion of gasses and the symmetry of related polymers. The aim of this work is to investigate the influence of the chemical structure of aromatic diglycidyl ethers on the ability of the resulting amine-cured epoxy polymer networks to adsorb organic solvents. Pure diglycidyl ethers based on hydroquinone and catechol, have been synthesised in high purity and good yields using a process previously developed at Durham University which utilise elemental fluorine to produce hypofluorous acid. The diglycidyl ether of resorcinol is commercially available and readily purified via vacuum distillation. Using the pure epoxides model networks have been produced by reacting the diglycidyl ethers with the diamine 4,4’-methylenebis(cyclohexylamine) to produce highly cross-linked films. Analytical techniques including DSC, DMTA, TGA, FTIR, solid state NMR, thermodynamic testing, PALs and density measurements have been used to investigate the influence of polymer structure on the network properties. With these materials we are determining the effect of the different epoxide isomers on the chemical resistance of the polymers. The results obtained for the polymers shows consistency with those suggested by the literature which is that the meta- polymer has the best chemical resistance with the other isomers having similar results.

Synthetic, man-made polymers are produced from petroleum, however this activity may well decrease as a function of time because of the non-renewability of the oil. This will result in the decreased production of synthetic polymers with consequent problems to our everyday life because of their ubiquity (food, furniture, containers, electronics…). An alternative could be the use of biopolymers such as cellulose, starch, proteins, amylose and chitin which are extracted from renewable sources. Cellulose is the most abundant biopolymer on earth and is principally found in the cell walls of plants. Cellulose presents interesting properties such as a high thermal stability and high strength, however the principal drawback is its insolubility in both organic and aqueous solvents limiting considerably its use in industry. Chemical modification of the hydroxyl groups of cellulose overcomes some of this problem. In fact, hydroxyethyl cellulose (HEC), where the hydroxyl groups have been modified with ethylene oxide, shows good solubility in aqueous solvents (dimethyl sulfoxide, water) due to the interruption of the cellulose H-bonding networks. Although the chemical modification of cellulose has improved considerably the physical properties of cellulose, the derivatives are usually not competitive against synthetic polymers. Due to its solubility and the presence of the three hydroxyl groups, HEC was chosen as a substrate for chemical modification, with the aim of mimicking the properties of synthetic polymers. The synthetic polymer of reference in our work was poly(N-vinylpyrrolidone) (PVP) because of its solubility in organic and aqueous solvents and sorption properties. The introduction of lactam groups onto HEC could produce a material with properties similar to PVP and this was the goal of our work. Three methods for modifying HEC with lactam groups are reported. The first was the functionalization of HEC with 1-(hydroxymethyl)-2-pyrrolidone (HMP) with degrees of functionalization up to ~0.9 on the primary alcohol functionality of HEC. The functionalized HECs showed markedly different properties to unfunctionalized HEC, such as increased the thermal stability and reduced viscosity. The two others methods led to the preparation of well-defined HEC-g-PVPs using a “grafting from” strategy combined with Atom Transfer Radical Polymerisation (ATRP) and “grafting to” combined with Reversible Addition-Fragmentation Chain-Transfer (RAFT) polymerisation. The ATRP of N-vinylpyrrolidone (NVP) from a prior-synthesised macro-initiator, Br-HEC, did not work efficiently; however, RAFT polymerisation of NVP using an alkyne-terminated xanthate as transfer agent produced an 80% monomer conversion with a 1.4 ƉM. The alkyne-terminated PVP was coupled successfully to partially 15N-labelled N3-HEC and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) was confirmed by 15N NMR spectroscopy. The versatility of the method was demonstrated using poly(N-isopropyl acrylamide) (PNIPAAM) which was synthesised using an alkyne-terminated trithiocarbonate as transfer agent with a 90% monomer conversion and a 1.2 ƉM. Subsequently, this straightforward method was used to prepare anti-microbial graft-copolymers of HEC from an ionic liquid (IL) monomer, 1-(11-acryloyloxyundecyl)-3-methylimidazolium bromide which was polymerised in high monomer conversion (70-80%) with some evidence of control over molecular weight distribution (ƉM =1.5). The influence of the chain length of the grafts on the antibacterial effects was minor with a 20 and 39 µg/mL minimum inhibition concentration (MIC) for E. coli and for S. aureus respectively. The MICs were comparable to those measured for ampicillin, which is known as an antibiotic, indicating the strong effect of our HEC-g-P(IL) on bacteria.

Graphene, a single-layer of graphite, is frequently termed a ‘wonder material’ due to the wide range of extraordinary properties it possesses and the potential it has for uses in a broad variety of different applications. Key to the realisation of graphene’s use in applications is the ability to produce large scale quantities of graphene with consistent quality, which remains a challenge to the field. The aim of this thesis was to investigate the synthesis of graphene via a number of different methodologies in order to develop novel techniques that are suitable to scale and that provide graphene materials that are useful in different applications. To this aim, four studies were carried out; two involving the ‘top-down’ synthesis of graphene from graphite and two involving the ‘bottom-up’ synthesis of graphene from molecular precursors. In the first study a series of intermediate materials between graphene oxide (GO) and reduced GO (rGO) were successfully produced using a well-controlled reduction reaction, and the trend in their properties was explored, while in the second study rGO was successfully produced using a novel method that is simple, scalable and environmentally friendly. In both these studies a novel method of handling GO was used that eliminated the requirement for the final, time consuming purification step of GO synthesis. In the third study bulk graphene platelets were successfully produced using a novel chemical vapour deposition (CVD) method, and in the final study the templated growth of graphene via CVD over metal microcrystals was investigated. The work builds on some relatively new concepts for graphene synthesis; including tailoring the graphene product to the particular application and size/shape control for bulk scale graphene platelets, and also presents an interesting case study on carbon growth on copper which may provide new insights into carbon synthesis in these systems.

Leishmaniasis and Human African trypanosomiasis are tropical diseases caused by kinetoplastid parasites that together affect over 12 million people, with an estimated 400 million at risk worldwide. Both are potentially fatal, yet the current treatments available are expensive and many have toxic side effects. Emerging resistance to many current drugs is also a concern; novel therapeutic agents are therefore urgently required. One novel target for drug discovery previously identified in the group is sphingolipid synthesis. Sphingolipids are ubiquitous biomolecules found in nature and are both structural membrane components and signalling molecules. Inositol phosphorylceramide synthase (IPCS) is an essential enzyme involved in kinetoplastid sphingolipid synthesis that has no mammalian equivalent, making it an attractive drug target. Whilst specific inhibitors of the fungal IPCS are known, they are unsuitable as pharmaceuticals. The overall aim of this project was to identify novel inhibitors of this enzyme that could be further investigated as potential antikinetoplastid drugs. The first stage involved the construction of Saccharomyces cerevisiae strains as expression systems of the kinetoplastid IPCS enzymes. The strain complemented with the Leishmania major enzyme was subsequently used in the development and optimisation of a robust high throughput screening (HTS)-compatible assay. This was used to screen the 1.8 million compound library stored at the GlaxoSmithKline research site in Tres Cantos in what is believed to be the largest screening project undertaken by an academic group to date. 500 compounds were identified as selective inhibitors of the L. major IPCS enzyme, and 216 of these were selected for additional investigation. Further compound triage was achieved by means of a screening process involving multiple in cellulo assays against both Leishmania parasites and mammalian cells. Six compounds demonstrating both high potency and selectivity were identified. Following additional biochemical testing, the two most potent compounds were found to share a common benzazepane chemical structure. Investigation of analogues of these compounds permitted the identification of preliminary structure-activity relationship data, which identified several possible avenues for further investigation.

This thesis explores the synthesis and the reactivity of novel amidine salts resulting from various N-methylformamides and N-methylbenzamides I and II. Treatment of these compounds with triflic anhydride under mild conditions led to extremely facile alkyl transfer from an sp3-hybridised nitrogen centre to very weakly nucleophilic triflate anions. For the reaction pathway of substrates III and VII, in silico studies propose an equilibrium between the more stable tetrahedral triflate intermediate IV and the superelectrophilic amidinium disalt V from which dealkylation takes place. The unprecedented a-aminotriflate IV was characterised by lowtemperature 1H- and 13C-NMR spectra and the rate of alkyl transfer for substrates III and VII determined. Unlike formamides III and VII, in silico and low-temperature NMR studies of the reaction of benzamide IX with triflic anhydride showed amidinium disalt intermediate XI to be more stable than tetrahedral triflate X due to steric factors. Due to the enhanced alkyl transfer activity of amidinium disalt XV derived from benzene-based formamide XIII, low temperature NMR studies did not allow for observation of intermediates XIV or XV. However, the benzamide analogue XVII with phenyl residues on the tertiary amine allowed for isolation and characterisation of amidinium dication XVIII. The reaction protocol was subsequently applied to derivatives of 2-(alkylthio)phenylformamides XIX which underwent alkyl transfer to yield benzothiazolium salt XXII. Interestingly, benzamide analogue XXIII afforded benzthiazolium disalt XXIV upon addition of triflic anhydride, but gradually dephenylated to monocation XXV.

No description available.

The overall objective of this thesis was to elucidate molecular design rules for the preparation of self-assembled aromatic peptide amphiphile based hydrogels. Aromatic peptide amphiphiles can be considered as having three distinct parts: the N-terminal aromatic group, peptide sequence, and the linker between the two. A systematic variation of these three molecular components has in the first instance revealed that contrary to popular belief, the antiparallel or parallel H-bonding supramolecular conformations associated with aromatic peptide amphiphiles cannot be distinguished by FTIR experiments alone. Instead, the 1685 cm-1 peak commonly assigned to an antiparallel arrangement, relates to the methoxycarbonyl linker if present in these systems. The choice of linker is also seen to have implications for assembly in both the aromatic and peptidic domains - as seen by fluorescence emission and FTIR respectively. In addition, the linker influences the supramolecular chirality of the f ibrous nanostructures by CD. The optimal linker for effective self-assembly and gelation is observed to depend primarily on the corresponding aromatic moiety, with fluorenyl and pyrenyl systems exhibiting differential preferences for relatively rigid and relatively flexible linkers, respectively. Besides covalent alterations, aromatic peptide amphiphile materials can also be modified through co-assembly. Here, the co-assembly structure is found to vary depending upon the aromatic and peptide segments associated with co-assembly constituents. Orthogonal co-assembly is observed in systems with different aromatic and peptide parts, as inferred by a preservation of characteristic spectroscopy and material properties associated with the assembly of individual constituents. In contrast, nanoscale phase separation is found to be disfavoured in systems that share either a common aromatic or peptide segment between co-assembly constituents. Consequently, for cooperative and disruptive systems, spectroscopy reveals substantial interactions between constituents, whilst material properties are also found to be affected through co-assembly. Finally, preliminary work demonstrates the functionalisation of bulk electrodes and MEA devices with electrochemically deposited hydrogel coatings possessing an electronic core furnished with a biocompatible coating as derived from the aforementioned co-assembly design rules. Coated electrodes are found to exhibit similar impedances to those of uncoated nodes, but prove inferior to platinised equivalents. Future work will focus on optimising said electrode impedances for potential neuron-device interface applications.

A programme of work towards the total synthesis of the natural product sesquithuriferone has been performed, with significant advances towards the realisation of this overall goal achieved. From this perspective, two main synthetic strategies have been investigated towards the synthesis of a common early-stage intermediate, critical to the construction of the core tricyclic scaffold. In this regard, both of these preparative pathways were explored simultaneously, with the aim of developing a robust and versatile route through to the natural product target. The first of these approaches involved the development of a novel [3+3]-sigmatropic rearrangement, to provide access to range of substituted cyclopentanones. Towards this aim, significant progress has been achieved, with late stage compounds having been prepared. Initial studies concentrated specifically on the synthesis of a novel (Sf(B-lactone key to the synthesis of sesquithuriferone. Additionally, a novel strategy to acce ss a range of substituted systems of structural similarity has been developed and, within the body of this research, a number of preparative pathways designed to access these systems have been explored. As each of the individual routes have been investigated, short optimisation studies have been pursued. The second route towards the synthesis of the common intermediate involved an umpolung conjugate addition strategy. Towards this aim, a robust and versatile set of protocols have been developed to provide access to both the racemic and asymmetric variants of this compound. Towards the construction of the key tricyclic core of sesquithuriferone, a Pauson-Khand approach was pursued. In this regard, a wide range of structural derivatives were synthesised and examined, under a spectrum of standard protocols, to identify an optimal structure to facilitate this key organometallic annulation. Upon completion of this optimisation programme, a range of synthetic strategies were explored towardthe completion of the desired natural target. Significant progress towards this goal has been achieved, with the preparation of several late stage compounds completed. In addition, through the development of this route towards sesquithuriferone, several points of diversity have been identified and investigated with the aim of assessing if the identified synthetic strategy under investigation could be applicable to the synthesis of other members of the same family of natural compounds.

DNA is the fundamental material responsible for storing the genetic coding required for the development of all living organisms. Since its discovery, there has been an intense amount of research into biorecognition events and the detection of DNA sequences coding for specific diseases. The development of the polymerase chain reaction (PCR) involved the amplification of small quantities of DNA allowing for subsequent analysis. However, fluorescence-based methods such as PCR have their limitations, for example the difficulties encountered when detecting multiple targets simultaneously. Therefore, there is a need for novel techniques that overcome these limitations associated with fluorescence-based methods. This research involves the use of SERS for the multiplex detection of target DNA, investigating the possible interactions between fluorescent dyes and DNA and SERS analysis of G-quadruplex formations. A SERS-based detection assay was designed for the simultaneous detection of three bacterial meningitis pathogens; Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae. By using SERS instead of fluorescence-based methods, multiplex detection was readily achieved and by using chemometric analysis it was the first report of pathogen quantification post-assay. To gain an understanding into interactions that can occur between fluorescent dyes (FAM and TAMRA), DNA and spermine, fluorescence and SERS studies were undertaken. Fluorescent studies gave an insight into the interactions that happen off the nanoparticle surface, while the SERS studies demonstrated the competitive interactions that occur between the nanoparticle surface and the two fluorescent dyes. These studies highlighted the consideration needed when selecting fluorescent dyes and target DNA sequences when designing a multiplex SERS assay. SERS was then applied to the detection of G-quadruplex formation. Previous reports used fluorescence-based methods, for example FID assays. Three ligands that selectively bind to and stabilise G-quadruplex DNA, previously used in fluorescence studies, were used and shown to have the ability to aggregate nanoparticles and act as Raman reporters. These ligands allowed for the design of the "on to off" SERS analysis of three G-quadruplex sequences.