This thesis describes the use of Brønsted acid catalysis to promote 6-exo-trig cyclisations in the synthesis of N-heterocyclic compounds. In Chapter one, a general overview of alkaloid structures is given, together with a number of general ways for their synthesis, with a particular focus on the Bischler-Napieralski and Pictet-Spengler methods. Hydroamination as a synthetic method is then briefly reviewed to set into context the present project to develop and optimize an acid-catalysed hydroamination method as an alternative protocol to the Picted-Spengler reaction. Chapter two describes different synthetic routes towards the construction of 2-vinylphenylethylamines and their subsequent cyclisations into tetrahydroisoquinoline alkaloids via the acid-catalysed hydroamination methodology. Key aspects of the diastereochemical outcome of the reaction are discussed, as well as the spectral features and limitations of the researched chemistry. Chapter three describes application of the acid-catalysed hydroamination in the making of more complex, polycyclic structures. Synthesis of polymethoxylated tetrahydroisoquinolines, benzhydryl derivatives and a relay synthesis of racemic salsolidine is described. An attempt to synthesise racemic alkaloid, crispine, is briefly discussed, as well as synthesis of an aporphine and a berberine skeleton. Chapter four covers the attempt to extend the acid-catalysed hydroamination chemistry to unprotected indoles and trans-annular cyclisations. Future work and areas of chemistry in which the acid-catalysed hydroamination underperformed or failed to deliver the desired results altogether are briefly discussed. Chapter five contains the experimental remarks and characterisation data.

In this thesis, studies of the kinetic and mechanism of racemisation of several drug-like molecule have been presented. Chapter 1 provides background information on the general mechanisms of racemisation of drugs in general, and hydantoin derivatives. In particular including reviews of the hydrolysis and the mechanism of base-catalysed racemisation of hydantoin derivatives. The synthesis of different chiral hydantoins, thiohydantoins, thiazolidine-diones, and rhodanines is presented in Chapter 2. Several enantio-enriched 5-substituted 1-acetyl-2-thiohydantoins and two tri-substituted 2-thiohydantoins have been synthesised. Further racemic thiohydantoin derivatives including mono, di, and tri-substituted 2-thiohydantoins have also been prepared. Chapter 3 focuses on the kinetics and mechanism of hydrolysis of 5-substituted 1-acetyl-2-thiohydantoins in physiological-like buffers. The key reaction involves de-acetylation and this is followed by the hydrolysis of the resulting 5-substituted 2-thiohydantoins. Sodium hydroxide and hydrochloric acid have also been used for the hydrolysis of 1-acetyl-5-phenyl-2-thiohydantoin. Similarly, the hydrolysis of several 5-substituted 2-thiohydantoins has been studied. The rate constants for hydrolysis suggest that the 5-substituted 1-acetyl-2-thiohydantoins hydrolyses faster than the subsequent hydrolysis of 5-substituted 2-thiohydantoins. Chapter 4 focuses on the racemisation of 5-substituted 1-acetyl-2-thiohydantoins and shows that substituents at N-1 decelerate racemisation. Racemisation of tri-substituted 2-thiohydantoins is fast in comparison with 5-substituted 1-acetyl-2-thiohydantoins. The substituents at the asymmetric carbon affect the rate of racemisation. The solvent kinetic isotope effect on the racemisation were determined for different substituted 2-thiohydantoins and supported the SE1 mechanism of racemisation. Chapter 5 concerns further confirmation of the mechanism of racemisation by comparing kdeu and krac and this confirms the SE1 mechanism for racemisation of 5-substituted 1-acetyl-2-thiohydantoin as kdeu/krac for all compounds approaches 1. For the racemic 5-substituted 2-thiohydantoins the rate constants of deuteration have been obtained using 1H-NMR spectroscopy and showed fast replacement of hydrogen by deuteron. Assuming kdeu = krac, we can order the rate constants for racemisation form high to low as rhodanine > thiohydantoin > thiazolidine-2,4-dione > hydantoin.

The solvent-free selective epoxidation of dec-1-ene has been achieved under mild conditions and using atmospheric oxygen as the sole oxidant. Furthermore this has been conducted in the absence of radical initiators which is a first for such an oxidation to the best of our knowledge. The selective epoxidation of alkenes typically requires the use of supported active metals such as gold or silver. These have been studied for the epoxidation of dec-1-ene however they were found to be inactive in the absence of radical initiators. Alternatively, this transformation has been achieved using a graphitic oxide catalyst which harbours no active metal species. This is yet another remarkable example of the potential of carbocatalysis for green chemistry. The commonly raised issues when using carbocatalysts such as identification of active species and presence of impurities are addressed. A range of graphitic oxides have been produced using modified Hofmann and Hummers methods with attention given to the effect of amount of oxidant used compared to commonly employed literature standards. We conclude that the popular highly oxidised Hummers materials used in the bulk production of graphene may not be the optimum material for all applications and that specification of graphitic oxides may be required to suit each application. An investigation of activity in the epoxidation of dec-1-ene partnered with a full characterisation of the surface suggests that an optimum level of oxidation is required along with the need for a surface free of potential poisons such as sulphur. We also evaluate the current methods used in the preparation and separation of these materials and suggest that for applications such as epoxidation alternative techniques may be required in order to realise its potential as a carbocatalyst. This work provides the basis for the development of an efficient catalyst for the selective epoxidation of α-alkenes, eradicating the need for expensive stoichiometric reagents or toxic radical initiators.

The industrial Cu/ZnO/Al2O3 heterogeneous catalyst has been in commercialisation for more than 50 years, whilst ambiguity still remains regarding its synthesis procedure. This involves a multi-step process, whereby each of these steps contributes to the resulting microstructural features of the final state catalyst. The initial step involves preparation of a crystalline hydroxycarbonate by aqueous co-precipitation using metal nitrates and sodium carbonate. This is a highly sensitive technique, whereby the retention of residual nitrates and alkali metals is highly influential on the resulting catalyst activity. These impurities are poisons and inhibit the full potential of such catalysts from being exploited. Furthermore, the manufacture of these catalyst materials requires renewed research and investment in order to be more compliant with green chemistry. The widespread utilisation of nitrate salts is primarily attributed to their low cost and significant solubility in aqueous media. However, production of nitrate waste streams places a pronounced burden and strain on our environment and has resulted in government legislation. In many studies, the mineral malachite has been identified as the optimum hydroxycarbonate phase for the role of catalyst precursor. However, whilst fine-tuning of the precipitation route has taken place over the years regarding its optimization, it has in essence remained largely unchanged during this timeframe. Consequently, the work presented in this thesis focuses on identifying, understanding and improving sustainable synthesis routes for the preparation of Cu/ZnO/Al2O3 catalysts that are devoid of nitrate and alkali-metal reagents. Two preparation routes using precipitation techniques for the production of hydroxycarbonates is reported which fulfil these requirements. This involves using supercritical CO2 as an anti-solvent precipitant, as well as utilising a modified co-precipitation methodology based on the current industrial procedure. Moreover, efforts have specifically focused on the preparation of the amorphous hydroxycarbonate termed georgeite. Thus the work neglects the large volume of literature reporting malachite as the optimum catalyst precursor. The ability to readily manufacture what was previously known to be a rare mineralogical phase could potentially open up additional applications. A series of Cu, Zn and Al containing georgeite precursor materials were produced from metal acetate salts using the semi-continuous supercritical CO2 anti-solvent (SAS) process. The addition of water to the system was found to result in a phase transformation of the resulting precipitate from a disordered mixed metal acetate to the georgeite phase. The physicochemical properties of the precipitant are also highly sensitive to the content of water used, whereby a compromise must be struck between enhancing the content of georgeite produced in the resulting precipitate and maintaining an optimum homogeneous system to operate in. Despite georgeite being a meta-stable phase, it is shown to be readily made. It is capable of incorporating both zinc and aluminium into its phase, which enhances the thermal stability of the material. This can be achieved without the production of additional by-phases, which currently implies no limit to the degree of zinc and aluminium incorporation. The choice of aluminium reagent has been investigated, whereby the aluminium acetylacetonate salt and an aluminium boehmite sol have been identified as suitable reagents. Alternatively, georgeite precursors can be readily prepared by co-precipitation using ammonium carbonate reagents. Whilst the simultaneous formation of a copper-ammine complex hinders the precipitation process, these materials can still compete against conventional malachite precursors. This is attributed to the exclusion of sodium carbonate in the preparation which renders the avoidance of catalytic poisons. However, precursors prepared by co-precipitation are still illustrated to be inferior to those prepared using supercritical technology. Georgeite derived catalysts prepared by both SAS and co-precipitation techniques are shown to be capable of competing against established industrial catalysts derived from crystalline precursors. For methanol synthesis, the georgeite catalysts have superior activity for the initial 10 hours but a severe deactivation phenomenon appears to hinder their performance and is a fundamental problem in this chemical process. It is plausible that this deactivation is correlated to the density of intermediate chemical species on the catalyst surface, which facilitates Cu sintering. However in direct contrast, these catalysts display exceptionally superior performance in comparison to the industrial standard for the LTS reaction, both in terms of catalyst activity and stability. This can be achieved without the alumina component which could eventually make it redundant in the construction of these catalysts. It is emphasised that these significant findings will permanently alter the way georgeite is perceived in the field of Cu/ZnO/Al2O3 catalysts regarding how these distinct catalysts operate under testing conditions. Evidently, the ‘structure-activity’ relationship was examined in more detail using state of the art techniques to rationalise these catalyst behaviours. This involved examination of both georgeite and malachite precursors, and their subsequent evolution into final state catalysts. This enabled a direct comparison to be made which could shed new light on their unique properties. It was determined that both precursors have a porous meso-structure, which is found to be a key attribute of an optimum catalyst. However, the formation of intimately mixed, poorly structured phases derived from high temperature carbonate species with negligible sodium loadings are also expressed as essential components of an optimum catalyst, and this is readily achieved from georgeite precursors.

Silver is a clinically important, broad spectrum antibacterial, whose use extends back over several millennia. Its potent antibacterial activity, range of susceptible microorganisms, and lack of developed resistances, elevate silver as an exciting weapon in the fight against hospital acquired infections and so-called ‘superbugs’. The active, ionic form is efficacious at very low concentrations, thus controlling release rates offers potential durable, non-specific, antibacterial medical devices. This thesis examines a number of inorganic systems as potential slow-release, antibacterial silver nanocomposites for incorporation into polyurethane foam wound dressings. A range of silver core-silica shell nanocomposites were synthesised with tuneable dimensions, with porosity introduced into the silica shells, via base-etching or surfactant-templating producing disordered or ordered architectures respectively. An alternative system based on mesoporous SBA-15 silica was also investigated, which was employed as a scaffold for subsequent multilayer titania functionalisation, onto which mixed silver/silver carbonate nanoparticles were subsequently deposited. Detailed characterisation allowed fundamental structural-function relationships for silver dissolution kinetics and their associated impact upon antibacterial activity towards Gram-positive and Gram-negative bacteria including methicillin-resistant Staphylococcus aureus. Silver ion release rates are inversely proportional to silver crystallite size, with further governance via shell thickness and mesoporosity achievable in core shell systems. The intrinsic antibacterial activity of titania coated SBA-15 further enhances performance, independent of silver, whilst support macropore introduction increases silver particle dispersion. Antibacterial prowess of all materials demonstrates a strong activity correlation with dissolution kinetics, evidencing up to seven-fold logarithmic reductions in the bacterial concentrations within four hours. Materials were potent for > 24 hours, with the reverse micelle core-shell formulation showing continuous activity over a 14 day period. Comparative benchmarking indicates mesoporous silver core-silica shell architectures as promising candidates due to antibacterial longevity, manufacturing simplicity and cost, with their hydrophilic nature and small dimensions rendering them amenable to incorporation into compatible polyurethane foams.

This thesis describes the result of synthetic efforts to apply a novel desymmetrisation process to the cladiellin diterpenes, an important group of natural products. The aim is to use the novel Prins-Wagner-Meerwein desymmetrisation of cyclohexa-1,4-dienes to prepare octahydroisobenzofuran structures that are closely related to the cladiellin diterpenes. Chapter 1 presents a short review of the 2,11-cyclised cembranoids including the cladiellin diterpene structures and previous synthetic efforts, followed by a brief discussion of the Prins cyclisation. This is followed by a description of previous work carried out within the Elliott group on the Prins desymmetrisation of cyclohexa-1,4-dienes that sets the stage for the work described in chapters 2 – 5. Chapter 2 describes the alkylation of cyclohexa-1,4-dienes using n-BuLi and TMEDA to give a direct and highly diastereoselective route to the corresponding 4-substituted products in which the alkyl group introduced is trans to the carboxylic acid. Chapter 3 describes the attempted application of Prins cyclisation/rearrangement methodology to the core of the cladiellin diterpenes. This was successful for a model compound containing a 6-membered ring, but when applied to compounds containing 7- and 9-membered rings, macrocyclic dimeric products were obtained. Chapter 4 describes an alternative synthetic strategy from that attempted in Chapter 3, to construct the cladiellin diterpene framework using a 6,5-fused system and cleaving of this to give a 9-membered ring system. Chapter 5 describes the successful synthesis of a model compound containing a fused aromatic ring using the strategy developed in Chapter 4.

This thesis describes the use of organoborate rearrangement reactions to generate quaternary carbon centres, with the ultimate goal of exploring new procedures for the asymmetric synthesis of chiral quaternary carbon centres. Chapter One: this chapter contains a historical review of the use of organoboranes in organic synthesis, focusing mainly on the use of boronic esters in asymmetric organic synthesis. Chapter Two: this chapter focuses on attempts at developing a catalytic method for the generation of quaternary stereocentres using migration reactions of boronic esters with n-butyllithium in the presence of chiral catalysts. This study showed that the reaction is stoichiometric in the absence of the Lewis acid. However, there were strong indications of catalytic turn over in some experiments. Chapters Three and Four: these chapters focus on attempts at designing a chiral version of the DCME reaction using sulfur compounds. Chapter Three focuses on attempts at evaluating a heterocyclic system, specifically a dithiane, as a stereocontrol agent in its reaction with trialkylboranes. The study showed that using 2-methoxy-1,3-dithiane-oxide achieved formation of the double and triple migration product but in poor yield. Chapter Four contains a detailed investigation into the synthesis and evaluation of non-cyclic sulfur compounds such as sulfoxides, sulfoximines, sulfilimines and sulfones for generation of chiral tertiary alcohols. The study of the reaction of dichloromethyl phenyl sulfoxide with trialkylboranes showed a new type of aldol-like reaction. This reaction was utilised to synthesise a series of new compounds. Also, the study of the reaction of dichloromethyl-p-tolyl sulfone with trialkylboranes showed a new type of reaction by replacing the hydrogen with the alkyl group from the trialkylborane. Finally, the study of the reaction of N-methyl-S-(dichloromethyl)-S-phenylsulfoximine with trialkylboranes showed production of the desired triple migration product in moderate to very good yield.

In this thesis, the structure and reactivity of Pd, Au and Au-Pd structures on TiO2(110) single crystals has been investigated with surface science techniques, including X-ray photoelectron spectroscopy (XPS), low energy ion scattering (LEIS), Auger electron spectroscopy (AES) and temperature programmed desorption (TPD). Sputtering a clean titania single crystal resulted in reduction of the surface. The surface was partially re-oxidised by annealing in UHV and further oxidised by annealing in O2. Pd growth on TiO2(110) was found to be Volmer Weber (3D island growth) regardless of the preparation and condition of the titania – whether it was heavily sputtered, sputtered then annealed or annealed in oxygen. On annealing the Pd/TiO2(110) to temperatures above 723K, an SMSI effect was observed between the Pd nanoparticles and the TiO2 support – the Pd is encapsulated by the reduced titania support. This was found to be affected by the oxidation state of the titania – SMSI occurred at a higher temperature for an oxidised surface than for a reduced surface. Au did not show an SMSI effect and is not encapsulated by the titania support, even when annealing to temperatures of 873K. The Au film only sinters and forms nanoparticles. Pd and Au were deposited sequentially on to TiO2(110). They are proposed to form bimetallic Au-Pd core-shell structures on annealing. After continued annealing to higher temperatures an SMSI effect is once again seen. This appears to be diminished with a greater amount of Au present in the bimetallic structure. The reactivity of TiO2(110) towards several small organic molecules was studied with TPD when clean and when deposited with Pd and Au, both separately and combined. Titania showed similar reactivity to that found in the literature – ethanol decomposed primarily to ethene and acetaldehyde, formic acid gave both CO and H2O, and CO2 and H2, and acetic acid gave ketene, CO and CO2. Au was found to be unreactive. Pd was found to reduce the reactivity of the titania. Pd-Au were, in most cases, found to be more reactive than their component metals.

The conformation that polymer-drug conjugates form in solution have a significant effect on properties that are important for designing of drug delivery systems. For N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer conjugates it is known that aggregation number, size and shape affect the rate at which a drug is enzymatically cleaved from the polymer backbone. Investigation of conformational properties could lead to creation of polymeric systems with the ability to keep drug levels at biologically active and safe concentrations for desired period of time. This project is focused on establishing the required modeling methodologies to describe the solution configurations of HPMA based conjugates. Therefore structural properties such as size, shape and density distribution of a range of HPMA copolymers have been investigated. The suitability of atomistic force fields has been assessed against rotational barriers and relative conformational energies obtained from ab initio and DFT data for a monomer and dimer of HPMA. Following this, the AMBER99 parameter set was chosen for all molecular dynamics simulation. Radius of gyration (Rg), radial distribution function (RDF), shape, and density profiles of particular atom types were calculated for a range of HPMA homopolymers sizes from 4 to 200 repeat units (2 to 35 kDa). Results were interpreted in the context of Flory’s mean field approach, and compared with data obtained from small angle neutron scattering (SANS) experiments. Results of this study were used for investigation of HPMA conjugates with drug mimics. A range of linear amines (aminohexane(C6), aminooctane(C8), aminododecane (C12)), hydroxyl and fluoro terminated linear amines as well as aromatic aminoanthracene (ANC), aminocrysene (AC) and aminoanthraquinone (ANQ), bound to the polymeric carrier via a tetrapeptide linker (glycinephenylalanine- leucine-glycine) (GFLG) (Mw ~ 30 kDa) were selected as model objects for study of the effect of drug type and loading on HPMA copolymer conformation. Using obtained results for further investigation we have progressed to more complex systems of mixed polymer conjugates containing drug-mimic parts with similar parameters of hydrophobicity, but different in terms of flexibility for drug-mimic chain. In order to provide corresponding comparison we have selected systems of Adamantane (Ad)/ANC, Ad/ANQ, methyl-Adamantane (AdMe)/C12, hydroxyl-Adamantane (AdOH)/C10OH and Ad/C10 conjugate iii mixtures and investigated the effect of changing ratio of drug-mimic parts for these systems. Analysis of SANS data revealed how conformation can be affected by the drug mimic’s intrinsic volume variation, and allowed us to get closer to finding answers for questions that can increase effective use of polymer-drug therapeutics. SANS experimental scattering curves were compared with theoretical curves, predicted from molecular dynamics (MD) simulations. Parameters such as size and shape fitted to SANS data were compared with relevant simulated structures. Based on results of previous studies as well as additional polymer synthesis and characterization process we were able to develop reliable all-atom (AA) and coarse-gain (CG) computer models for simulation of HPMA polymer. Required tools and software were developed. Various methods were used to increase performance efficiency of Molecular Dynamics calculations. Among them highest practical impact has a domain decomposition parallelization strategy.

This thesis describes the synthesis and characterization (1H, 13C NMR, CHN, and X-ray) of new NHC ligands incorporating a triazine core and their complexation with Ag(I), Pd(II) and Ru(II) metals. Imidazolium salts [2.4H]I – [2.7H]Br and [2.10H] - [2.15H]Br were obtained by reaction of 2,4-diamino-6-chloro-1,3,5-triazine (diamino = morpholine, piperidine, diethylamine, or dimethylamine) with H- imidazole followed by alkylation with a variety of alkyl halides such as propyl, butyl, octyl bromides or isopropyl iodide. While the imidazolium salts [2.3H]Cl, [2.8H]Cl, [2.9H]Cl and [2.13H]Cl were prepared by reaction of N-substituent imidazole (mesityl, phenyl ethyl, and methyl) with 2,4-diamino-6-chloro-1,3,5-triazine (diamino = morpholine or dimethylamine). Silver complexes were prepared from the reaction of Ag2O with an NHC precursor salt using in situ deprotonation techniques giving the desired structures in good yield. X-ray studies with other spectral and analytical studies reveal the formation monodentate complexes of the NHC ligands. The coordination geometry at Ag is slightly distorted from the idealised linear geometry. The Ag(I)-NHC complexes were used as NHC transfer reagents to prepare Ru(ІІ) and Pd(ІІ) complexes. New monodentate Pd (ІІ) complexes were prepared by in situ deprotonation of the NHC ligand by K2CO3 in the presence of PdCl2. The catalytic activity of the complexes in the Suzuki reaction was explored with conversions of up to 100 % being observed. Bis(carbene)Pd(ІІ) complexes were prepared by transmetalation from the silver complexes with Pd(MeCN)Cl2. X-ray crystallography shows a distorted square planar geometry around the palladium metal centre for both complex types. A series of Ru (ІІ) complexes were prepared by transmetalation techniques using the silver complexes as transfer reagents with [Ru(η6-arene)Cl2]2 in dichloromethane. Single crystal studies along with other spectral and analytical studies reveal the coordination of the triazine-NHC ligand in a chelating mode where both the carbene and one of the N-donors of the triazine group ligate the metal. The complexes are active for the transfer hydrogenation of ketones with conversions up to 96%.