In this Thesis, computational models for carbonaceous dust grains were examined and compared to known experimental data. Different formation routes of molecules, important to the astrochemical evolution of the universe, have been investigated and their relative energies were analysed with respect to the harsh conditions in interstellar dark clouds of extremely low pressure (10‐17 bar) and temperature (10 – 20 K). Dust grains are present in the universe, and evidence shows they are siliceous or carbonaceous, possible with an icy mantle surrounding the core. In this research, only carbonaceous surfaces were examined. Two models were used to represent polycyclic, aromatic carbonaceous surfaces: coronene, C24H12, representing a relatively small hydrocarbon, and graphene – a single graphite sheet – which represents an extended carbonaceous surface. The main aims of this Thesis were to examine the validity of computationally modelled astrochemical reactions and to investigate the catalytic effect of dust grain surfaces on these reactions. Several formation reactions were examined, including water, methanol and carbonyl sulfide formation. The abundance of these molecules in dark molecular clouds cannot be explained by solely considering gas phase type reactions, and the influence that the carbonaceous surfaces have on these reactions was investigated in order to examine any catalytic effect that they may have.

The present thesis is concerned with a novel approach towards the design of artificial aldolase mimics. The introductory chapter provides an overview of previous strategies and approaches that have been employed in the design and synthesis of artificial enzyme systems. Following on from a brief introduction to previous work within our own group, Chapter 2 presents and discusses the preparation and reactivity of a number of novel polymeric systems which are capable of catalysing the aldol reaction. The strategy adopted consisted of the preparation of regiochemically defined alternating co-polymers wherein each of the two monomers, an N-alkylated maleimide and a para carboxamide styrene possessed either a carboxylic acid or an amino group and were hence capable of functioning as Class I aldolase mimetics. A complementary strategy has also been undertaken wherein both functional groups involved in catalysis are attached to a single monomer, and subsequently subjected to ring opening metathesis polymerisation. This approach guaranteed attachment of these two groups in a fixed 1:1 ratio and had the added advantage of acting as organocatalysts in their own right. For this purpose, systems based on 7- azabicyclo[2.2.1]hept-2-ene, tropane alkaloid like derivatives and a functionalised norbornene were studied. Preliminary work towards functionalised bispidinone derivatives were also considered within this framework. Chapter 3 provides a formal description of the detailed experimental results and procedures used.

The high-temperature (HT) Water Gas Shift (WGS) reaction has considerable technological relevance for lowering CO content during the conversion of natural gas or liquid hydrocarbons to hydrogen. Conventional HT-WGS catalysts based on oxides of iron and chromium are well established industrially. However, it is crucial to remove any impurities present such as Cr6+, S or N during the catalytic process. In particular, Cr6+ is regarded as a Class I carcinogen and its presence is restricted by EU legislation. Even though Cr6+ is reduced during the catalytic process, caution must still be taken to eliminate any further impurities. Hence, it is desirable to identify alternative promoters and develop a Cr-free HT-WGS catalyst. This thesis presents results obtained using atomistic simulation techniques to investigate the effect of Cr3+ and possible alternative dopants in three important iron oxide materials, Hematite (α-Fe2O3), Maghemite (γ-Fe2O3) and Magnetite (Fe3O4). The starting point is to develop an understanding of the structural properties and distribution of Cr3+ on the bulk and surface material of hematite. The critical stage of understanding the role of Cr3+ provides the basis from which criteria for novel dopants can be assessed. Al3+ and Mn3+ are proposed as the promising candidates on the basis of this study. The research has been extended to other complex iron oxides, such as maghemite and magnetite. In summary, the role of chromium in the HT-WGS reaction has been investigated to establish criteria for effective, alternative promoter dopants. This investigation has provided a detailed insight into the atomic level behaviour of Cr3+, Mn3+, Al3+ impurities in three major iron oxide phases. The alternative dopants predicted in this study have been the subject of parallel experimental studies conducted by Johnson Matthey. The results of this study are already benefiting the design of more efficient iron-oxide catalysts for the HT-WGS reaction.

The total chemical synthesis of a protein provides atomic-level control over its covalent structure, however polypeptides prepared by solid phase peptide synthesis are limited to approximately fifty amino acid residues. This limitation has been overcome by 'Native Chemical Ligation‘, which involves amide bond formation between two unprotected polypeptides: a peptide with a C-terminal thioester and an N-terminal cysteinyl peptide. Synthesis of the required peptide thioester is difficult, particularly by Fmoc-chemistry. During our studies towards the semisynthesis of erythropoietin, we discovered reaction conditions that reversed Native Chemical Ligation and generated peptide and protein thioesters through an N→S acyl transfer. A peptide with both a Gly-Cys and an Ala-Cys-Pro-glycolate ester sequence was selectively thioesterified between the Gly-Cys sequence upon microwave-heating at 80 °C with 30 % v/v 3-mercaptopropionic acid (MPA), to afford the peptide-Gly-MPA thioester (84 % yield). Recombinant erythropoietin containing 4(Xaa-Cys) sites was also selectively thioesterified between His-Cys and Gly-Cys sequences upon treatment with 20 % MPA at 60 °C to give the peptide-MPA thioesters. His-/Gly-/Cys-Cys sequences were found to be particularly prone to thioesterification but thioester hydrolysis and disulfide bond formation also occurred with MPA, and therefore optimisation studies were conducted using 13C NMR spectroscopy. Sodium 2-mercaptoethanesulfonate (MESNa) was found to be a better thiol because it resulted in 100 % conversion into the peptide thioester and no thioester hydrolysis. The first biological application of this new method was then completed with the total synthesis of 45-amino acid Ser22His human β-defensin 3 (HBD3) for which a more complex 22-amino acid peptide thioester (22 % yield) was synthesised. Folded Ser22His HBD3 was assessed to have bioactivity equivalent to that reported: MBCs against P. aeruginosa = 0.9 μM, S. aureus = 1.8 μM; and optimal chemoattraction concentration = 0.2 nM. Posttranslationally modified native N-linked glycopeptide thioesters were also synthesised using the new thioesterification method, containing protected (20 % yield) or deprotected monosaccharides (64 % yield).

Approximately half of all pharmaceutical drugs are marketed as salts. This thesis pioneers the application of computational crystal structure prediction to organic salts containing the commonly used chloride or carboxylate counterions, and assesses the extent to which the theoretical calculations can be used to aid experimental efforts targeting organic salts. A screen for multi-component solid forms of pyridine and 4- dimethylaminopyridine (DMAP) using a range of dicarboxylic acids led to one novel cocrystal of pyridine and six novel salts of DMAP. All novel crystal structures were solved using single crystal X-ray diffraction. At a simplistic level, salts differ from cocrystals in the position of the acidic proton within the crystal. For a selected set of structures, periodic ab initio calculations were shown to be useful in suggesting the observed N+-H (salt) or O-H (cocrystal) covalent bond as the preferred atomic connectivity. Modelling the same crystal structures by lattice energy minimisation using a distributed multipole based electrostatic model proved successful if the correct proton connectivity was used. The observed structures of a model salt, cocrystal and disordered salt-cocrystal system were found to be the most stable or almost equienergetic with the most stable structure in the predicted crystal energy landscapes. When the predictions were repeated using molecular structures with the wrong proton connectivity, the energetic ranking of the structure got worse. The computational model of crystal structure prediction was successfully used to rationalise the different polymorphic and hydration behaviour of the pharmacologically active amantadine hydrochloride and memantine hydrochloride salts. Finally, a similar methodology was applied to 1,8-naphthyridinium fumarate and the calculations performed as part of the fifth international blind test of crystal structure prediction. Overall, the success in modelling the crystal structures of carboxylate and chloride salts illustrates the promise of crystal structure prediction in aiding experimental efforts of organic salt selection.

The present thesis is concerned with the concept of an enolate directed carbometallation reaction. The first chapter provides a review of the area of heteroatom directed carbometallation of isolated alkynes and allenes as a powerful method for the formation of double bonds and attempts to rationalise the regio and stereochemistry of such additions. The second chapter begins with the results of a small study on the copper(I) mediated carbometallation reactions of homoallenols. The research into the aforementioned enolate directed carbometallation reaction is then presented and discussed, and especially the efforts made towards efficient formation of a novel “bis-carbanionic” intermediate, possessing both an enolate and a vinyl organometallic reagent. Following on from a preliminary result within the group research was carried out into the carbometallation reactions of enolates derived from carboxylic acids, amides, esters. Whilst amide enolates proved to be problematic, carboxylic acid dianions were found to be suitable substrates for carbometallation and dialkylation of the “bis-carbanion” was successful. After considerable experimentation involving a variety of organometallic reagents and protocols for enolate anion generation, ester enolates were found to be most successful, giving rise to high yields of products and allowing selective reactions of both the vinyl organometallic reagent and the enolate. Finally, very encouraging preliminary results were obtained with an adventurous strategy involving the enolate intermediate obtained from a conjugate addition to an enone. Experiments to probe the reactivity of these novel intermediates, with the aim of selective reaction of only one of the carbanions, are discussed throughout. These results are then summarised and logical conclusions as well as perspectives for future research are drawn. The thesis concludes with a detailed description of the experimental procedures used and characterisation of the compounds prepared.

There are three areas of research in this thesis. The first is concerned with the silica polymorph, tridymite, with simulations carried out using three computational methods: free energy minimisation, molecular dynamics and Density Functional Theory. A number of tridymite structures with different atomic configurations have been found in nature. The simulations explore various properties of these different forms of tridymite and investigate whether it is possible to distinguish between them using the three computational techniques. It was found that the interatomic potential and simulation technique used, rather than the simulation temperature, were the main factors affecting the resulting structure. There are a number of possible explanations for this result: The techniques may not be sensitive enough to deal with an energy landscape as at as in the case of tridymite. Another reason is that the potentials have been parameterised to distinguish between structures which have reconstructive transitions (where bonds are broken and formed) and may not be able to deal with displacive transitions (where only angles between atoms change) as with tridymite. The final possible explanation is that a number of the known structures may be meta-stable and/or poorly characterised. For the second research area molecular dynamics simulations using a rigid ion two body potential were carried out in order to investigate the properties of silica melts and glasses. A number of different silica crystals were melted to see whether the melts are all similar or whether their properties can be differentiated according to the original crystal structure. At sufficiently high temperatures the starting structure did not affect the properties of the melt. Several properties of silica melts and glasses were investigated: mean square displacement, autocorrelation functions, pair distribution functions, the extent to which silicon and oxygen atoms move together, Arrhenius plots, coordination number, bond lengths and angles. Investigations were also carried out as to whether it is possible to use a shell model to simulate a silica melt. Various properties were calculated and it was found that agreement with experiment was not as accurate as when using the rigid ion model. The third research area is an exploration of the properties of amorphous silica at elevated pressures and a range of temperatures, using molecular dynamics with a rigid ion two body potential. Calculations show that, at low temperatures, the distortion of the tetrahedra is not recovered upon decompression whereas experimental results find complete recovery of the tetrahedra. There is little available experimental data on the behaviour of silica at both high pressures and temperatures. Calculations show that at high temperatures all properties of the initial structure before compression are recovered.

The application of chemical methods to biological systems has led to great advances in all life sciences and the discovery of novel approaches for therapy and diagnosis. Pivotal amongst these methods is the ability to chemically modify proteins to enhance their biophysical properties or add new functionality. Despite the success, the chemical toolbox of efficient and widely applicable protocols is relatively limited. In the work presented in this thesis the idea of protein modification via the targeting of solvent accessible disulfide bonds is explored. These are fairly common in secreted proteins and their reduction affords two cysteine residues, which are highly reactive nucleophiles. However, to preserve their native function – stabilisation and maintenance of the protein structure – ideally bis-reactive compounds are used that react simultaneously with both thiols and keep the covalent connection of the disulfide bond intact. To this end a selection of maleimides substituted with good leaving groups in the 3 and 4 positions as well as their N-functionalised versions were synthesised and tested for their reactivity. The findings were transferred to the small peptide hormone somatostatin, which served as a model system to explore kinetics and feasibility of the proposed “functionalisation by bridging”. Changing the leaving groups from halides to thiols enabled the development of in situ protocols where the bridging reagent could be employed in tandem with the reducing agent, greatly decreasing the reaction time and unwanted side reactions such as dimerisation or unfolding. The developed methods were then utilised to bridge the cystines of insulin as well as a selection of full length antibodies and antibody fragments. PEGylated, biotinylated, fluorescent or spin labelled analogues of these proteins were also synthesised. The biological activity, stability and functionality of the conjugates were assessed in biochemical and biophysical assays. Overall the functionalisation of disulfide bonds with maleimides was found to be site-specific, fast, high yielding and the inserted bridge was stable under various conditions. The modification was well tolerated and all prepared analogues exhibited the desired functionality. The scope and potential of present and future applications of the method are discussed.

The synthesis and characterization of a variety of novel biobased epoxy thermosets comprising plant oil-derived epoxy prepolymers and dicarboxylic acids (DCAs) and/or glutaric anhydride, in the presence of amine curing agents, in order to develop new insights on structure-property relationships, are reported. The effect of: i. different epoxy prepolymers: epoxidized linseed oil (ELO); epoxidized soybean oil (ESBO), and; their corresponding epoxidized methyl esters EML and EMS; ii. systematically increasing carbon-carbon chain length of a series of α,ω-dicarboxylic acids (DCAs); iii. different curing conditions based on type and concentration of accelerant: N,N-4-dimethylaminopyridine (DMAP); 1-methylimidazole (1-MI); 2-methylimidazole (2-MI); vinylimidazole (VI), and; trimethylamine (TEA), cure temperature and time. iv. mixtures glutaric anhydride-adipic acid, and; v. inclusion of native and modified starch to ELO-adipic acid resins, on thermal and mechanical properties are discussed in detail. Resins derived from DCAs gave soft and flexible materials. ELO-derived samples possessed higher Tg and better mechanical properties due to their higher oxirane content and functionality. Systematically increasing the carbon-carbon chain length improves thermal stability but reduces Tg, tensile strength, Young’s modulus, elongation at break and toughness. Among the various accelerants trialed, DMAP gave samples with best properties while TEA gave samples with poorest properties. Increasing DMAP concentration resulted in improved Tg, tensile strength and Young’s modulus but reduced thermal stability. Resins derived from glutaric anhydride gave hard and rigid materials. By changing the ratio of glutaric anhydride to adipic acid, resins with various properties ranging from soft flexible to hard tough materials were attained. Biobased thermoset composites comprising ELO-adipic acid and starch (native and modified) accelerated by DMAP, showed increased Young’s modulus while decreased tensile strength and elongation at break.

Studies towards the total synthesis of pyxidatol C I, isolated from the medicinal mushroom Clavicorona pyxidata, are described herein. Pyxidatol C I is a member of the africanane family of sesquiterpenes, which share a decahydro-1H-cyclopropa[e]azulene core structure. Chapter 1 provides an introduction while Chapter 2 outlines work on a desmethyl model system. A Cope rearrangement was used to prepare synthetic cycloheptadiene IX. Unfortunately, the analogous rearrangement using the gem-dimethyl substituted divinylcyclopropane X was unsuccessful. As such, the reactivity of a range of substituted divinylcyclopropanes towards the thermal Cope rearrangement was investigated (Chapter 3). The effects of gemdimethyl substitution on the cyclopropane, the alkene geometry, the relative stereochemistry of the cyclopropane and the steric and electronic effects of a range of functional groups were all examined, and the methods developed were used to synthesise a range of functionalised 1,4-cycloheptadienes in high yields. Chapters 4 and 5 describe studies towards the total synthesis of pyxidatol C. Advanced intermediates were prepared including ester XII and lactone XIII containing the requisite gem-dimethyl substituted 7-membered ring, the cyclopropane moiety and the methyl ketone side chain in place.