This thesis describes investigation into catalytic formation of pyridinium ylides from diazo compounds and their subsequent reactivity. In particular, cycloaddition reactions with electrophilic alkenes are performed to generate tetrahydroindolizines that can be transformed into indolzidines by reduction. Pyridinium ylides have been shown to be very reactive intermediates that are able to generate complex molecules with excellent yield and diastereoselectivity. The introduction section provides a background on the chemistry of pyridinium ylides. This section also reports on development in the field of 1,3-dipolar cycloaddition chemistry of pyridinium ylides. A background to the generation of the pyridinium ylides by in situ decomposition of diazo compounds with transition metal catalysts was described. The results and discussion section is divided into three sections. Section one describes metal-catalysed decomposition of diazo compounds to produce pyridinium ylides in situ. Performing this reaction in the presence of dipolarophiles gives tetrahydroindolizine cycloadducts in good yield with excellent diastereoselectivity. Subsequent reduction of the 1,2-dihydropyridine moiety component of the resulting cycloadducts is also demonstrated. Crystal structures of some of the resulting indolizidine products were valuable for assigning relative stereochemistry. Section two describes attempts towards an asymmetric (3+2) dipolar cycloaddition, using pyridinium ylides produced by the in-situ decomposition of diazo compounds with either chiral transition metal catalysts or achiral catalysts in the presence of chiral Brønsted acids. We started our investigation by exploring how acids with various pKa’s e.g. camphorsulfonic acid, benzoic acid and p-nitro benzoic acid influenced the reaction between pyridine and diazo compounds. Finally, section three describes attempts to develop new multicomponent catalytic reactions with mono and di-substituted diazo compounds to access structurally complex pyridinium salts via in situ C-alkylation of catalytically generated pyridinium ylides.

The work presented in this thesis aims to highlight the differences in heating methods, which are conventional, microwave electric, and microwave magnetic heating, for the ring opening polymerisation of ɛ-caprolactone, as well as the development of an alternative catalyst that is specifically used in microwave magnetic heating to replace the current benchmark catalyst. Chapter 1 introduces the background of this thesis. There is also an overview of various types of biodegradable polymers, polymerisation techniques, and catalysts used in the polymerisation. An introduction into the basics of microwave and microwave electric and magnetic heating is also provided in this chapter. Chapter 2 goes on to explain the analytical techniques that are used to characterise the polymer and the dielectric properties. Procedures in locating the reaction vessel at the microwave electric and magnetic dominant positions in the microwave reactor are described. Experimental procedures that are used throughout this thesis are also explained. Chapter 3 investigates the dielectric properties of various types of metal complexes in both solid powder form and when dissolved in a solvent, to study the factors that affect the interaction between these complexes and the microwave electromagnetic field. Then further investigation into a series of heating experiments of solutions containing these complexes is carried out, to see if the empirical observations follow the same trend as predicted from the dielectric property results. Chapter 4 explores the first application of microwave magnetic heating to the ring opening polymerisation of ɛ-caprolactone catalysed by metal halides, and compares this to the conventional and microwave electric heating, and investigates the effects of different heating methods have on the overall polymerisation. This chapter also investigates various metal halides that experienced different response to the microwave electric and magnetic heating to see how this affects the polymerisation process. Chapter 5 describes the development of novel organometllic catalysts that can be used in the ring opening polymerisation of ɛ-caprolactone with the application of microwave magnetic heating, and possibly replace the existing benchmark catalyst Sn(Oct)2. The use of various heating methods is also investigated to see what effects they have on the overall process.

The Rh(III)-catalysed oxidative C–H allylation and homoallylation of N-acetylbenzamides with 1,3-dienes is described. The presence of allylic hydrogens cis to the less substituted alkene of the 1,3-diene is important for the success of these reactions, though not essential. With the assistance of reactions using deuterated 1,3-dienes, a proposed mechanism is provided. The key step is postulated to be the first reported examples of allyl-to-allyl 1,4-Rh(III) migration. Importantly, migration to primary or secondary allylic position results in allylation products, whereas migration to a tertiary position leads to homoallylation. Using 1,4-dienes as the coupling partner, N-tosylbenzamides are homoallylated. Preliminary results indicate a mixture of isomer products, with major isomer resulting from an allyl-to-allyl 1,4-Rh(III) migration.

Naphthalene diimides have been explored in a wide variety of ways; They are a promising candidate for organic electronics, boasting the ability to form n-type semiconductor materials, the stability of their anions further aiding in this regard. Their electron poor aromatic core can be used in host guest chemistry to generate interlocked species. The ability to tune their electronic properties and how this could be manipulated to create photovoltaic devices is primarily focus of this thesis. A series of naphthalene diimides substituted at the core with morpholine moieties have been synthesized and their optical and electronic properties have been probed. Interestingly these species were found to not follow the typical trends for core substituted naphthalene diimides. Through further investigation it was revealed that this unexpected behavior was due to the conformation of core substituents, typically considered unimpactful. In addition to these species, more complex naphthalene diimide systems, core substituted with phenothiazine and phenoxazine, have been synthesized. By combination of the electron deficient naphthalene diimide with the electron rich phenothiazine and phenoxazine electron donor-acceptor species have been created. These species can be excited by visible light and upon excitation have the potential to generate a charge separated state, which could be used to generate current in a photovoltaic device. Finally a naphthalene diimide furnished with two BODIPY units was synthesized in an attempt to utilize it as the central rod of a rotaxane. The electronic properties of this rod species were also attempted to be modulated via thionation of the naphthalene diimide core. These species would be used to assess the viability of utilizing BODIPY as a light harvesting antenna for naphthalene diimide systems.

The biosynthesis of the superfamily of pyrones such as (+)-tridachione, (-)-crispatone or tridachiahydropyrone have drawn much attention. However, the isolated natural products are enantiomerically pure whereas the syntheses of these natural products were completed in racemic form. This raises the question of where, in nature, the chirality is derived from. It has been hypothesized that the all (E)-polyene tridachiahydropyrone precursor is present in the membrane of the producing mollusc, and during the reaction the membrane provides a favourable chiral environment for obtaining only the tridachiahydropyrone enantiomer. The project aims to use different systems that mimic the cell membrane of the sacoglossan to show that a chiral environment induce chirality for electrocyclisations such as beta-cyclodextrin and chiral liquid crystals. Also, our efforts were towards the development of novel asymmetric 6Pi electrocyclic reactions that exploit catalyst-induced enantioselectivity with a secondary amine such as proline or (S)-alpha,alpha-diphenylprolinol, (S)-alpha,alpha-diphenylprolinol silylether, and MacMillan’s catalyst second generation. Unfortunately, all these electrocyclic reactions gave a racemic mixture.

The work presented in this thesis is focused on the development of a multifaceted approach to the catalytic activation of nitriles. To develop a versatile method for catalytic nitrile activation two probes were utilised; i) the development of a direct synthesis of allylic amides from the corresponding allylic alcohol and nitrile using a commercial platinum salt, together with a detailed mechanistic investigation into the process, ii) the direct synthesis of 2-bezoxazole from the corresponding 2-aminophenol and nitrile with the aid of a commercial platinum salt as well as the use of alcoholic solvents. In addition to nitrile activation a preliminary study on the application and further functionisation of 2-trichlorobenzoxazoles was undertaken. i) A novel multifaceted approach to the direct synthesis of allylic amides via the catalytic activation of di- and trichloroacetonitrile will be discussed. This one-pot methodology relies on the same platinum catalyst to activate a nitrile towards nucleophilic attack of allylic alcohol as well as activate the newly formed allylic imidate towards a [3,3]-sigmatropic rearrangement, which produced a number of allylic amides. In addition to the development of the one-pot allylic amide methodology a number of mechanistic studies including 1H, 13C{1H} and gas chromatography were under taken to better understand the process. ii) The second probe used to identify the versatility of this multifaceted catalyst approach to nitrile activation was the direct synthesis of 2-benzoxazoles. Within this study it was discovered that protic solvents were able to activate di- and trichloroacetonitrile efficiently towards nucleophilic attack of the nitrogen nucleophile. From this discovery a mild and effective synthesis of a variety of di- and trichlorobenzoxazoles was developed in which the solvent was acting as the activating agent towards nucleophilic attack. iii) Preliminary results will also be reported on the novel manipulation of the trichloromethyl moiety of benzoxazoles. Within this study two efficient methodologies for the selective synthesis of 2-(pyrrolidin-1-yl)benzo[d]oxazole and benzo[d]oxazol-2-yl(pyrrolidin-1-yl)methanone were developed from a single starting material. These results show a positive direction for the study into diversity oriented synthesis to form a number of different small molecules from a single starting material by altering the conditions of the reaction.

This thesis describes the conjugate addition of nitrogen nucelophiles to alpha,beta-unsaturated enones using cinchona derived amines. Two separate projects are outlined within, intermolecular and intramolecular N-conjugate addition reactions. The first project involves the investigation of a range of nitrogen nucleophiles in their intermolecular additions to alpha,beta-unsaturated ketones. The reactions were performed using either 9-deoxy-9-epi-aminoquinine or 9-deoxy-9-epi-aminoquinidine as the catalyst with phenylacetic acid as a co-catalyst. These catalysts were found to promote conjugate addition of a range of nitrogen heterocycles to acyclic alpha,beta-unsaturated ketones. In particular, the addition of pyrazoles was found to proceed in high yield and enantioselectivity. In contrast, addition of these nucleophiles to cyclic ketones gave low enantioselectivity. The second project involves the investigation of intramolecular N-conjugate addition processes. In this case, the reactions were performed using 9-deoxy-9-epi-aminoquinine and trifluoroacetic acid as the catalyst system. Several different groups on nitrogen were investigated and the reaction conditions optimised for each group. The ring size and substitution around the ring system formed were also investigated with high yields and enantioselectivites obtained.

Tolerated by normal tissues, implementation of anti-cancer therapies based on titanium compounds is limited by low efficacy/selectivity, lack of understanding of their mode(s) of action and access to the most active chiral variants. This thesis reports the synthesis, characterization and biological evaluation of a novel class of chiral substituted titanocenes from novel chiral cyclopentadienyl ligands, themselves accessible from substituted pentafulvenes. After an introductory chapter, the second chapter describes the synthesis and biological evaluation of substituted (rac/meso)-mixtures of TiCl2{η- C5H4CHEt(phenyl)}2 (abbreviated CpR2TiCl2). Addition of a substituted pentafulvene to alkyl/branched-alkyl/phenyl Grignard solutions with catalytic copper catalyst resulted in the formation of novel racemic/tautomeric cyclopentadienyl ligands in yields of up to 92%. The deprotonation of the racemic substituted cyclopentadienyl ligands with n-butyllithium and subsequent transmetallation with titanium(IV) tetrachloride resulted in the formation of novel substituted titanocene complexes in yields up to 81%. The antiproliferative activities of the (rac/meso)- mixtures of titanocenes in comparison to the simple benzyl-substituted titanocene analogue, titanocene dichloride and cisplatin were then evaluated in vitro against HCT-116, MiaPaCa-2 and MDA-MB-468 carcinoma cell lines, which represented intractable cancers from three different organ sites. All chiral substituted titanocenes were micromolar active against all the studied cancer cell lines. Finally, cyclic voltammetry studies using chiral substituted titanocenes were carried which confirmed a close to optimal fit of the chiral substituted ethyl titanocene. The third chapter reports the synthesis and biological evaluation of single enantiomers of TiCl2{η-C5H4CHEt(2-MeOPh)}2 (abbreviated CpR2TiCl2), attained through unprecedented asymmetric copper-catalysed addition of ZnEt2 to the C=C bond of substituted pentafulvenes C5H4(=CHAr) (Ar = 2-MeOPh and related species). Such enantioselective reaction resulted in enantiomerically enriched (up to 93:7 e.r.) cyclopentadienyl ligands. Copper catalyst promotion with both chiral phosphoramidite ligands and a phosphate additive was vital in realizing both acceptable enantioselectivies and reaction rates. Chloride hydrolysis of the enantiopure titanocene to [CpR2Ti(OH]+ can be detected by NMR, GCMS and LCMS in vitro under near therapeutic conditions. The anti-cancer potency of (S,S)- CpR2TiCl2 was twice that of other stereoisomers, selective for cancer cells, and the kinetics of formation of the soluble hydroxy species correlate with the latter being the biologically active species. Extensive cytoplasmic vacuolization, endoplasmic reticulum (ER) swelling and activation of MAPKinase signal transduction were consistent with ligand-induced paraptosis (type III cell death), which is morphologically distinct from, and independent of, caspase-mediated apoptosis in MDA-MB-468 and HCT-116 cells.

Acrylic based monomers are used to create a wide range of organic polymers with applications from false nails to lighting panels and from lightweight, scratch-proof laptop screens to viewing windows in aquariums and submarines. Petrochemicals have been the predominant feedstock for these monomers since their introduction, but moves to make the industry “cleaner” and “greener” have led to a growing interest in renewable resources. Exploiting such resources for bulk plastic manufacture is the focus of this project. This thesis describes the hydrothermal conversion of di- and tricarboxylic acids into acrylic acid and methacrylic acid. In order to produce these chemicals via sustainable routes, the di- and tri-carboxylic acid precursors used in this work are all available from biomass or from known biological processes that convert biomass into useful precursors. Previous work in this area has focussed on the production of methacrylic acid from itaconic acid and its isomers or from citramalic acid. However, the first section of this thesis investigates the production of acrylic acid from malic acid. Malic acid is readily available from biomass sources and can produce acrylic acid after decarboxylation and dehydration akin to the previously reported route from citramalic acid to methacrylic acid. However, significant levels of by-products and unselective extractions meant we were unable to present an industrially viable route that could compete with current processes. The focus of the project then returned to the production of methacrylic acid. Fermentation of sugar molasses using Aspergillus terreus yields itaconic acid. This acid can then be used in the continuous production of methacrylic acid in high temperature water (>200 °C), at elevated pressure (>2000 psi) in the presence of sodium hydroxide. Our research looks at the stability of methacrylic acid under these reaction conditions, showing the hydration to 2-hydroxyisobutyric acid and decomposition to acetone. By investigating the effect of temperature and residence time on the stability of methacrylic acid and 2 hydroxyisobutyric acid, it is suggested that reactions do not exceed 260°C and have a residence time shorter than 360 s. Finally, this thesis describes a proposed new process for methacrylic acid production to include the recycling of a sodium hydroxide catalyst. Subsequent acidification of reaction exit solutions releases free methacrylic acid that can be extracted with a suitable organic solvent. Previous work in this area demonstrated this process with the use of sulfuric acid to release free methacrylic acid and yield the free acid as well as aqueous sodium sulfate waste. However, by using an acidic precursor, such as itaconic acid, to acidify the exit solution, methacrylic acid can be extracted and the remaining aqueous solution can be cycled through the continuous flow equipment, recycling the base catalyst as sodium itaconate. This process is demonstrated up to 20 cycles, and collected methacrylic acid has been esterified and polymerised to yield a sample of poly(methyl methacrylate), demonstrating proof of the concept behind our new process as a route to bulk plastic manufacture from renewable resources.

Gene delivery vectors that are safe, efficient and affordable could significantly enhance the prospects for genetic-based therapies. Here we describe an approach to such vectors, using new variants of polyphosphazene materials and describe the synthesis of a series of degradable polyphosphazenes with both cationic and anionic side-chains, and report their use as mixed polyelectrolyte complexes for DNA and RNA delivery to glioblastoma cells in vitro and in vivo. Precursor poly(allylamino-phosphazene)s were converted to cationic and anionic derivatives via a,w-thiolated alkylamines and alkylcarboxylates, respectively. Simultaneous co-incubation of alkylamine- and alkylcarboxylate-poly(phosphazenes) with nucleic acids generated polyelectrolyte complexes which were more compact than poly(alkylamino-phosphazene):DNA analogues but with similar positive surface charges. Screening of a series of these complexes for transfection of U87MG glioblastoma cells, showed that 6-mercaptohexanoic acid substituted poly(phosphazene)s mixed in the polycation/DNA complexes resulted in the highest luciferase expression in the cells. These data were consistent with an increased buffering capability of the 6-mercaptohexanoic acid substituted polymer across the early endosomal pH range in comparison with other anionic side-chain substituted polymers. Transfection assays in 3D spheroid models and in subcutaneous xenograft U87MG tumours confirmed higher transgene expression for these mixed cationic and anionic poly(phosphazene)s compared to the related poly(alkylamino-phosphazene)-DNA complexes, and also to PEI-DNA complexes. Extension of the approach to siRNA delivery showed that the mixed cationic and anionic poly(phosphazene)s were able to silence a gene encoding for a kinase implicated in tumour progression (DYRK1A), resulting in a reduced renewal ability of U87MG cells in vitro and in delay of tumour growth in a xenograft model.