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Polymer architecture is a key area for polymeric materials design and new chemistries that offer novel architectures are of wide interest amongst the macromolecular community, in both academia and industry. Telomerisation was very important to the growth of controlled radical polymerisation techniques, although it has been significantly overlooked for advanced materials in recent times. The introduction of Transfer-dominated Branching Radical Telomerisation (TBRT), a new approach to high molecular weight branched polymer synthesis that utilises radical telomerisation chemistries is presented. Despite the homopolymerisation of multi-vinyl monomers (MVMs) being long considered as an impossible task according to the Flory-Stockmayer theory, over the last decade homopolymerising MVMs has become increasingly attractive for the synthesis of soluble hyperbranched polymers. Nevertheless, current methodologies present significant drawbacks which minimise their applicability for industrial use such as the utilisation of metal catalysts, inflexibility of functionalities and large quantities of initiator. The homopolymerisation of divinyl monomers, under TBRT conditions, avoided all drawbacks of previous technologies and generated soluble hyperbranched materials. Successful polymerisation was achieved at 70 ?C using ethylene glycol dimethacrylate and dodecanethiol as the divinyl taxogen and telogen respectively and 2,2-azobis(2- methylpropionitrile) as the initiator, yielding densely branched (a < 0.340) polymers with high molecular weights (up to Mw = 1, 820, 000 g mol-1 ). A detailed and extensive programme of mechanistic and architectural analysis was undertaken to provide robust evidence for the novelty of TBRT, employing a range of leading-edge techniques including the application of diffusion ordered spectroscopy. The effect of reaction concentration was investigated by conducting a series of reactions at various solid contents, and the effect of intramolecular cyclisation at high dilution on the resulting polymer properties was also investigated. Successful polymerisations were also extended to the transfer-dominated branching radical cotelomerisation of ethylene glycol dimethacrylate with a mixture of telogens, dodecanethiol and 4-tert-butylbenzyl mercaptan. Studies to understand the competition between the two telogens and the effect of this on the resulting polymeric structures and their properties was undertaken. Additionally, reactions with a mixture of divinyl taxogens, ethylene glycol dimethacrylate with bisphenol-A-dimethacrylate was also investigated. Comparisons to their homopolymers were too made. Exploring bio-derived taxogens and their applicability in the generation of hyperbranched polymers via this novel method was also performed. The versatile nature of TBRT makes it a potentially efficient tool for achieving intricate structures unachievable via other polymerisation techniques; therefore, the potential impact and application of this methodology on the future synthesis of hyperbranched polymers in industry is of considerable interest. This belief was confirmed in the summer of 2020, with the research conducted in this thesis securing an investment of £1million to form a joint venture, Polymer Mimetics, between the University of Liverpool and Scott Bader Co. Ltd.

Reduction of carbonyl and N-heteroaromatic compounds is a fundamental transformation in organic synthesis to produce valuable products in both academia and industry. Transfer hydrogenation using non-H2 hydrogen source is a convenient and safe alternative to direct hydrogenation with hazardous hydrogen gas. Compared with other N-heterocyclic compounds, transfer hydrogenation of pyridine derivatives is less developed, especially in obtaining high enantioselectivity. Chapter 1 provides a brief introduction of catalytic transfer hydrogenation and the use of formic acid and methanol as hydrogen sources. It also describes previous achievements on the TH of carbonyl and N-heteroaromatic compounds. Chapter 2 extends our previously reported method for the preparation of chiral piperidines to more valuable chiral fluorinated piperidines with excellent enantioselectivities. A chiral amine is incorporated into the pyridine ring via transamination during the reduction process and induces the chirality on the ring. Chapter 3 describes a simple and efficient method for the switchable synthesis of N-aryl piperidines and pyrrolidines from pyridinium salts, providing an alternative to the traditional C-N cross coupling methods. The key to the preparation of pyrrolidines is the introduction of a leaving group on the pyridine substrates, which leads to the ring contraction during the ring-closing step after transamination. Chapter 4 demonstrates the preliminary attempts on the asymmetric transamination of pyridinium salts with achiral amines. Imidazoline iridacycle and rhodacycle have been found to be active for the reaction, although the enantioselectivity currently achieved still needs to be improved. Chapter 5 presents a highly efficient cyclometaled rhodium complex for the transfer hydrogenation of various aldehydes at near room temperature using methanol as hydrogen source. The hydroxy functionality on the imino ligand is shown to be crucial for this remarkable activity. Chapter 6 summarise all works covered in this thesis and provides an outlook for the future work.

With the rise of antibiotic resistance many alternatives to antibiotic treatments have been suggested, among which is photodynamic therapy. Photodynamic therapy uses a compound (photosensitiser) which is not toxic without light, but becomes toxic when irradiated by light. Over the past few decades photodynamic therapy has seen a marked progress as an anticancer treatment while antimicrobial photodynamic therapy has remained relatively stagnant. Porphyromonas gingivalis and Pseudomonas aeruginosa are bacteria responsible for causing severe periodontal disease and skin infections, respectively. The diseases caused by these pathogenic bacteria are difficult to irradicate not only because they are difficult to access but also because they can develop resistance to antibiotics very quickly and/or can invade host cells to escape the action of both host immune responses and therapeutic agents. An effective antibacterial agent would need to be able to penetrate the host cell membrane, and target bacteria inside the host cells whilst remaining non-toxic to the host cells themselves. Herein we introduce a novel aPDT conjugate - a new mononuclear iridium(III) complex which is cell-permeable, that is modified with an antibacterial agent metronidazole, that in itself cannot penetrate membrane of mammalian cells. The Ir(III) moiety acts as light-absorber and photosensitizer, whilst also carrying the antibiotic moiety across the cellular membrane. We demonstrate the effective antimicrobial properties of this conjugate against P gingivalis & P.aeruginosa. We show that: (i) The dosage required to achieve 99.9% killing of bacteria is extremely low; (ii) the conjugate works under visible light; (iii) the treatment does not damage host cells.

This thesis describes investigations into the application of N-oxyazoles as reactive dienes in [4+2] cycloaddition reactions, followed by elimination of nitroxyl (HNO), for the synthesis of aromatic scaffolds. First an overview of the current state of the art in the use of [4+2] cycloaddition/elimination methodology for the synthesis of aromatics is provided. The review is broken down by the class of heteroaromatic diene used in the Diels-Alder reaction and highlights the advantages and drawbacks of each class in detail, providing exemplar published examples as evidence. Limited by unique drawbacks associated with each substrate, there is currently no class of heterodiene that is used as a 'go to' coupling partner for this type of Diels-Alder/elimination methodology, and so there is still significant demand for new classes of synthetically tractable heterodienes with good reactivity profiles towards a broad range of dienophiles that can be used to produce diverse libraries of aromatic products. Chapter 2 describes investigations into the use of N-oxypyrroles as reactive dienes in Diels-Alder reactions, followed by cheletropic elimination of their [4+2] cycloadduct products to produce polysubstituted aromatics. O-TBS protected N-hydroxypyrroles are identified as optimal substrates for the cycloaddition reaction, producing stable cycloadducts which can separately be aromatised using typical fluoridic conditions for the deprotection of silyl ethers. A range of N-hydroxypyrroles are synthesised using literature and novel syntheses and subjected to the optimised conditions with highly electron deficient dienophiles to produce their corresponding aromatic products in good yields. Chapter 3 details the use of Lewis acid catalysis to overcome reactivity limitations in the [4+2] cycloaddition reaction of N-silyloxypyrroles with alkynes. Stoichiometric diethylaluminium chloride is found to dramatically enhance the rate of reaction of O-TBS-N-oxypyrroles with mildly electron deficient alkynes, with kinetic studies carried out at the University of Bath Dynamic Reaction Monitoring (DReaM) facility to elucidate the origins of the requirement for stoichiometric catalyst to achieve good yields. Chapter 4 describes investigations into the reaction of N-oxyazoles with arynes for the synthesis of polyaromatic scaffolds. Having identified that less reactive N-oxypyrroles are required for reaction with highly reactive arynes, O-pivaloyl-N-oxypyrroles were reacted with Kobayashi aryne precursors, followed by cheletropic elimination of the cycloadducts to produce polyaromatic compounds. Finally, an example of an N-oxyimidazole was reacted with benzyne to produce a polysubstituted isoquinoline. Chapter 5 discusses the application of aza-norbornadienes as Nitroxyl Releasing Molecules (NORMs). The production of nitroxyl from the cheletropic elimination of aza-norbornadiene is first detected utilising diaminonaphthalene (DAN) as an exogenous fluorescent sensor and subsequently the aromatic product of the cheletropic elimination of aza-norbornadiene TBS-NORM is configured to be a fluorophore DiPhen, which is used as a turn on sensor for detection of fluoride in solution. Finally, the potential of NORMs for the site selective release of HNO for the treatment of disease is discussed.

The development of Heterobifunctional molecules in the field of targeted degradation is a hot topic, with various modalities appearing over the past 20 years, with examples such as; PROTACs, SNIPERs, dTAGs, HaloTags, AUTACS, ATTECs and LYTACs. In 2019 alone there were 107 PROTAC publications, an increase of 55 from the previous year. ISOX-DUAL is an inhibitor of both BRD4 (IC50 = 1.5 µM) and CBP/p300 (IC50 = 0.65 µM) bromodomains and, as such, is a useful chemical probe for research into epigenetics.2 The published and our in-house protocols toward this target molecule were poor yielding and not amenable to scale-up. Here, synthetic routes towards the title compound were re- investigated, and now achieves an overall yield of 42%, compared to the literature published 1%. Using literature co-crystal structures in the bromodomains of BRD4 and CBP/p300 of the, structurally similar, inhibitor BDOIA383, two solvent exposed exit vectors were discovered for potential linkage to E3 recruiters. ISOX-DUAL was then re-designed with the optimised synthetic route to afford two degrader precursors (3.07) and (3.27) which were designed through replacement of the N,N-dimethylpropylamine to a propyl carboxylic acid (3.07) and the replacement of the morpholine moiety to a piperazine (3.27). Degrader mimics (3.09, 3.29) were synthesised from these compounds and showed no loss in binding affinities to the bromodomains of BRD4 or CBP/p300. A small library of 20 ISOX-DUAL based degraders were synthesised, guided by predicted physiochemical properties. Select degraders (4.69-4.72) were subjected to cell-free ubiquitination assays, to which, confirmed induction of ubiquitination of the target. The 20 synthesised degraders were initially treated in HeLa cells and 4.68 caused a reduction in BRD4 (75%) and CBP (73%), the most potent degrader in this assay. The investigation goes on to highlight the importance of cell lines when assessing these compounds and describes a series of future experiments, which, should be performed.

Pyrimidines are amongst the most common heterocycles found in biological systems, they are constituents of nucleic acids and countless other biologically significant molecules, including many pharmaceutical and agrochemical products. They can be prepared by annulation or direct functionalisation of the preformed ring, but stable intermediate pyrimidines bearing organometallic functionality are rare in the literature. Such intermediates allow for potential production of numerous analogous pyrimidines for screening purposes via e.g. cross-coupling reactions without the need for a de novo synthesis each time. We addressed this gap in the literature by preparing (amino)pyrimidin-6-yl trifluoroborate salts from the corresponding ynone trifluoroborate salts via an operationally simple and chromatography-free condensation procedure. The (amino)pyrimidin-6-yl trifluoroborate salts were amenable to classic boron chemistry at the trifluoroborate unit, including SuzukiMiyaura cross coupling, oxidation and halodeboronation. In addition, transformations that were orthogonal to the trifluoroborate unit allowed the further elaboration of these intermediates while keeping the boron functionality intact for later derivatisation. Fluorine is the most abundant halogen found in the Earth's crust. Despite this, organofluorine compounds are almost non-existent in biological systems and are created almost entirely by synthetic methods. Trifluoromethyl (CF3) – substituted (hetero)aromatic compounds are a privileged substructure in medicinal chemistry and can be accessed by direct (C-H, "innate")) trifluoromethylation or by ("programmed") trifluoromethylation of an in-built functional group such as a halogen or organometallic. Less well-studied are cycloaddition approaches to their preparation, which sidestep limitations in both innate and programmed methods. We developed a directed cycloaddition approach to fluoroalkyl-substituted (hetero)aromatic compounds that is mild, regiospecific and affords stabilised boronate products that are amenable to further functionalisation. This was achieved by preparing fluoroalkyl-substituted alkynyl trifluoroborate salts and subjecting them to substituted dienes/dipoles in the presence of a Lewis acid promoter. DFT calculations were conducted to investigate further the influence of the CF3 group on this process.

De novo design is a subdiscipline of chemoinformatics concerned with designing novel chemical entities in-silico that fit a pre-defined property profile. A fundamental limitation of de novo design is creating molecules that chemists can readily synthesise. Reaction vector-based de novo design aims to overcome this limitation by utilising reaction transformations mined from chemistry literature to build molecules of interest. However, de novo design utilising reaction vectors has been limited due to the reliance on complete enumeration, leading to a combinatorial explosion of products. Moreover, issues with local optima along sequential paths of reaction vectors have led to poor performance. This project details the development of a novel tree search algorithm utilising reaction vectors. The Monte Carlo tree search (MCTS) was first identified as a promising approach to overcoming the limitations of reaction vector-based de novo design. The MCTS approach was implemented utilising the reaction vector methodology. To test the approach, a validated benchmark was constructed. The reaction vector-based Monte Carlo tree search (RVMCTS) performance was then investigated via a series of ablation studies utilising the validated benchmark. The studies revealed several limitations of the approach, which provided fruitful avenues for further modification. First, the simulation component of the RVMCTS approach was investigated and modified by leveraging machine learning techniques. A further series of modifications were then investigated, including improved tree traversal and reaction vector prioritisation utilising reinforcement learning. These modifications were screened against the validated benchmark and combined to form REACTS (REACtion Tree Search), a novel tree search algorithm. Finally, REACTS was tested against a series of de novo design problems from the literature. REACTS demonstrated comparable performance against established deep learning-based approaches. Thus, REACTS demonstrated it can effectively chart a path through chemical space utilising the sequential application of reaction vectors to regions of interest.

The PhD thesis describes a research project that focuses primarily on a series of dysprosium metallocenium single-molecule magnets containing cyclopentadienyl and fulvalenyl ligands. The project aims to discover the influence of the various ligand types on the magnetic properties, including the exchange coupling. An introduction to SMMs is described in the first chapter, which mainly shows a historical perspective, current theoretical models and synthesis strategies. Inspired with the previous achievement of cyclopentadienyl sandwich SMMs in the Layfield group, I have successfully synthesized several dimetallic and trimetallic dysprosium metallocene SMMs containing the bulky pentafulvalenyl ligand [(C5tBu2H2)2]²⁻, with the complexes also containing bridging borohydride ligands, as described in Chapters 2 and 3, respectively. The bridged polynuclear structures show a periodic improval in the SMM properties, such as an increase in the effective energy barrier to reversal of the magnetization, which is thought to be a consequence of the gradually diminishing influence of the borohydride ligands. The magnetic measurements and theoretical calculations also indicate that the quantum tunnelling of the magnetization (QTM) process is suppressed in the polynuclear system due to magnetic exchange. In Chapter 4, I describe a dysprosocenium-based single-ion magnet, which is sandwiched by a mono-phospholyl ligand and a Cp* ligand. The near-linear metallocenium compound displays an excellent blocking temperature of 70 K and two separate energy barriers of 1410 cm⁻¹ and 747 cm⁻¹ due to two distinct Orbach processes. According to the AC magnetic susceptibility measurements, the compound unexpectedly gives two range of maxima in magnetic susceptibility (c'M and c''M), which is not observed in other reported phospholide samples. In Chapter 5, two dimetallic uranocenium compounds are reported based on the fulvalenyl ligand, with additional iodide bridges. The dimetallic U(III)-U(III) sandwich structure gives distinct chemical reactivity as the iodide ligand cannot be removed, but resulting in a mixed-valence U(III)-U(IV) cation.

This thesis includes the development of indicator displacement assays (IDAs) with a boronic acid receptor, used for the differentiation of Z and E alkene mixtures. An IDA protocol was developed which is ammenable to high-throughput screening and can successfully identify Z and E alkene mixtures with an average absolute error of eight percent. The second research chapter includes the synthesis and analysis of shape-switching cyclophane hosts with a range of molecular guests. This research serves as a contribution towards the field of molecular machines and switches which may gain utility in the fields of drug delivery or catalysis.

This thesis aims at both electrochemically investigating mainly at the single entity level the physicochemical properties of metal-based nanoparticles and seeking to study unusual electrochemical activity of metal nanoparticle ensembles by using mainly an optical approach. Three experimental stages are presented accordingly: (1) Electrochemical detection and sizing of single metallic nanoparticles with a critical focus on the study of the quantitative methodology; (2) Further investigations of the surfaces (composition, structure and catalytic activity) of metal-based core-shell nanoparticles both at the particle ensemble and single particle level; (3) Opto-electrochemical investigation of a substrate-mediated electrochemical dissolution of metal nanoparticle ensembles. To begin with, the first chapter briefly reviews the key basics of fundamental electrochemistry, and the second chapter introduces the metal-based nanoparticles, the major electrochemical technique of 'nano-impacts' and the alternative technique of dark field microscopy used in this thesis. Chapter 3 reports a generic quantitative methodology for electrochemically detecting and sizing individual nanoparticles using the complete oxidation of silver nanoparticles in halide solutions as a model system. In particular, this established methodology of nano-impacts emphasises the use of lower filtering frequencies in the data acquisition (prior to any analysis) for the accurate description of the charge passed during a transient nano-event. For the critical comparison between electrochemical and electron microscopic measurements, the effect of the nanoparticle diffusion coefficient on the probability of it being observed in the electrochemical responses and the effects of non-spherical shapes of nanoparticles visible in the microscopic images are also discussed. On this basis, Chapter 4 further shows the advantages of applying the nano-impact technique for sizing small (d < 30 nm), multimodal-sized nanoparticles that are inherently beyond the measuring capacity of the conventional light scattering methods of dynamic light scattering and nanoparticle tracking analysis. Chapter 5 next demonstrates the electrochemical characterisation of the surface compositions of Co@Co(OH)2 nanoparticles at the single particle level. By contrast, the very thin surface layer of Co(OH)2 is not characterised by either X-ray diffraction or transmission electron microscopy. Moreover, the aggregation of the nanoparticles in aqueous solutions is implied via the impact electrochemistry. Chapter 6 focuses on the mechanistic study of the mediated hydroxide ion oxidation by Co₃O₄ nanoparticles in alkaline conditions. Hydrogen peroxide, rather than dioxygen, is found to be the predominant initial oxidation product of the electron transfer. The nano-impact results further point out the rate determining step and the limiting kinetics of the catalytic reaction. Furthermore, as the work next compares the electrochemical behaviour of bare Co3O4 with that of core-shell Co₃O₄@SiO₂ nanoparticles, the surface silica of the synthesised core-shell particles is inferred to be highly porous or broken. This is not otherwise easily distinguished, for example, by electron microscopy. Chapter 7 reports a substrate-mediated electrochemical dissolution into aqueous solution of silver nanoparticles driven via electron transfer to trace dissolved oxygen. Investigation of a range of solid materials (glass, indium titanium oxide, glassy carbon and platinum) used to support the nanoparticles shows that conductive supports greatly catalyse the dissolution and by means of complementary and synergistic optical and electrochemical measurements it is inferred that the electron transfer can occur at locations on the support surface remote from the silver nanoparticles.

Chapter 1: Introduction: The introduction gives an overview of C-C bond forming reactions, highlighting their applications within the thesis. The historical development of C-C bond forming hydrogen borrowing reactions is then reviewed, with an emphasis on work by the Donohoe group involving Ph* methyl ketone, as well as examples in the chemical literature utilising earth-abundant metal catalysts. Finally, the role of nitrogen-containing compounds within both natural products and pharmaceuticals is discussed. Chapter 2: Hydrogen Borrowing Reactions of Aziridino Alcohols: The hydrogen borrowing reaction between various aziridino alcohols and Ph* methyl ketone is explored, along with the formation of lactams upon removal of the Ph* group with Br2. A number of N-Boc aziridines are synthesised and converted into their corresponding N-Bn aziridino alcohols via structurally complex aziridino aldehyde dimers. The unexpected reactivity of trisubstituted aziridino alcohols under hydrogen borrowing and Br2 cleavage conditions is also explored. Chapter 3: Total Synthesis of (-)-γ-Lycorane: Utilising a key C-C bond forming hydrogen borrowing reaction, and a subsequent Br2-mediated Ph* cleavage/lactam formation/ring opening cascade, the total synthesis of (-)-γ-Lycorane is completed in 9 steps, 4% overall yield and in 99:1 er. An alternative pericyclic approach to (-)-γ-Lycorane is also explored, with a number of small and highly functionalised amine and aziridine substituted cyclopentanes being successfully synthesised. Chapter 4: Hydrogen Borrowing Reactions of Amino Alcohols: The hydrogen borrowing reaction between enantioenriched 1,2-amino alcohols, derived from both natural and unnatural amino acids, and Ph* methyl ketone was investigated. The use of a bulky trityl group was found to be effective in protecting the reaction intermediates against racemisation, leading to the isolation of a large number of 1,4-amino ketone products in good yields and with high levels of enantioenrichment. The use of HCl in HFIP was found to be effective for cleavage of both the Ph* and trityl groups, giving 1,4-amino acid products in excellent yields and with no loss in enantioenrichment. The use of column chromatography could be entirely avoided by performing the two steps in sequence without intermediate purification. Chapter 5: Experimental: This chapter contains the experimental procedures and spectroscopic data for all compounds described within the thesis. Appendix 1: X-Ray Crystallographic Data: The X-ray crystallographic data for compounds 312, 351, 368, 381, 410, 553, 591, 665, and 719 can be found in this appendix. Appendix 2: Experimental Procedures by Indi Marriott: Experimental data for compounds 411 and 410 prepared by Indi Marriot. Appendix 3: References: The references cited within the thesis can be found in this appendix.

The thesis looks at the development of a multiplexed assay, i.e. detection of multiple targets by advancing methods, conjugation chemistries and recognition ligands. The thesis develops an electrochemical analytical technique, Resistive Pulse Sensing (RPS) for the analysis of the nanocarriers used in the development of the assays. The thesis consists of ten chapters that are each separated out to follow a chronological order in the development of a multiplexed assay using RPS. To improve the current methods, the work first: 1) redevelops new ways to use biorecognition ligands to nanocarrier surfaces, 2) use new biorecognition ligands that bind to the nanocarrier surface differently, 3) using multiple particle sizes of the same shape nanocarrier to enhance multiplex detection, 4) using new particle shapes for analysis with RPS to improve the complexity of the assays that can be analysed using RPS. Chapter 1 stands as the introduction chapter that explains the structure of the thesis and outline of the subsequent chapters. Chapter 2 explores the literature review around the characterisation of nanomaterials using numerous techniques and comparing them to the technique of using RPS and the limitations and drawbacks of the techniques. Chapter 2 explores the nanopore sensing abilities and the comparison of biological, solidstate, hybrid and tunable nanopores that can be used for various applications and each nanopore structure has its advantages and disadvantages depending on the application needs of the nanopore. Chapter 2 looks at the literature limitation of the multiplexed assays and the techniques that have previously been used for the development of the assays for targets of interest. Chapter 3 covers the fundamental theory of the electrochemistry technique, RPS and the analysis of the output signal as a nanocarrier translocates through a nanopore and causes a blockage of current. Chapter 3 explains the electrophoretic, electroosmotic and gravitational forces that are seen in the nanopore set up and how they affect the extraction of the signal to determine the size, concentration, charge and shape of the nanocarrier that is being analysed. Chapter 4 builds on the work that has been published in literature by the Platt research group where aptamers have been used for the detection of proteins, heavy metal ions, drug molecules and DNA of disease states and their interactions with the targets of interest. The work in Chapter 4 shows a universal aptamer sensing strategy, that utilises the same unique sequence on the nanocarrier surface, but different aptamers can be attached to the surface of the nanocarrier. This universal aptamer was developed in collaboration with the Aptamer Group, York, UK. The hypothesis was that using conjugation chemistries and known aptamer interactions, a universal aptamer could be utilised with all known aptamer sequences that have been isolated, regardless of being a shape changing aptamer upon binding to the target. Chapter 4 explores how a universal anchor aptamer is attached to the surface of the nanocarrier and how a complementary aptamer that has the complementary sequence to the end of its sequence will allow for binding to the anchor on the nanocarrier's surface. Chapter 4 looks at the detection of chemotherapeutic and antibiotic drug molecules that are present and how they can be analysed by changing the complementary aptamer sequence and keeping the nanocarrier modified with the anchor aptamer the same. The outcome of Chapter 4 enables a user of RPS to make use of all known DNA aptamers identified without the need to know whether the DNA aptamer would change in its tertiary structure and cause a change in the zeta of the nanocarrier. The work presented in Chapter 4 has been submitted in pre-print publication in ChemRxiv in August 2020. Chapter 5 hypothesis expands on the modification techniques that increases the library of targets that can be analysed using RPS technique. Chapter 5 looks at a technique that helps to broaden the target library using Peptide aptamers as well as using DNA aptamers on RPS. Chapter 5 showed that Peptide aptamers were difficult to use with RPS due to a low inherent charge, but the incorporation of a charge to the nanocarrier surface using surface chemistries helped. Chapter 5 looked at using a DNA aptamer and a Peptide aptamer for C-reactive protein (CRP) which is used as an indicator protein for inflammation and numerous disease states such as acute myocardial infarction. Chapter 5 looks at the signals that were obtained by changing the outer skin of the nanocarrier surface with the DNA and peptide and how that was used to increase the target library. Chapter 4 and Chapter 5 both explored how the target library is expanded using RPS and all identified peptides and the DNA aptamers can be used on RPS with very limited restrictions. The work presented in Chapter 5 was published in Medical Sensors & Devices, 2020, DOI: 10.1002/mds3.10059. The work in Chapter 6 aimed to increasing the number of nanocarriers that can be analysed at a given time using a single nanopore that would pave the way for the development of a multiplexed assay for multiple targets. Chapter 6 identifies the manufacturers and suppliers of the nanocarriers that can be purchased worldwide and using the specification data provided by these companies, a distribution of the nanocarriers and their sizes is plotted. Chapter 6 looks at using the collated data along with the theoretical capability of the polyurethane nanopore and identifying the best cocktail of nanocarrier sizes that would be analysed on a nanopore provided by Izon Science, New Zealand. Chapter 6 looks at comparing the theoretical size distributions with an experimental size distribution that can be seen in a single nanopore, which was four particles with no blockage. Chapter 7 combines the findings from Chapter 6 and the knowledge from Chapter 4 using the universal aptamer sensing strategy for the development of a multiplexed assay for detection of multiple analytes using a single assay. Chapter 7 looks at using surface modifications on the nanocarrier sizes identified in Chapter 6 and attaching the aptamer of interest to the nanocarrier surface. Chapter 7 showed that in the presence of the target analyte, the nanocarrier size that had the respective aptamer attached to the surface, showed a change in signal and the other nanocarrier sizes that were present in the assay remained the same and the signal from these nanocarriers was unchanged when the assay was run through the RPS device. Chapter 7 shows that multiplexed assay of various size nanocarriers showed a signal in the presence of the antibiotic drug molecule that was present in the one pot. Chapter 8 is about how the capabilities of RPS can be further improved by incorporating a shape analysis algorithm. The shape analysis algorithm was developed in collaboration with the Mathematics department at Loughborough University. Chapter 8 shows that the capability of RPS to determine the size, charge and concentration of nanocarriers could be improved to being able to determine the shape of the nanocarrier. Chapter 8 shows that a single nanocarrier that translocates through the nanopore could be characterised as a spherical nanocarrier or a non-spherical nanocarrier and this was shown experimentally when a mixture of spherical and rod nanocarriers were mixed in an assay a run through the device. Chapter 8 shows that the characterisation of a nanocarrier based on shape only was as good as 90% accurate, showing potential for shape based assays. Chapter 9 of the thesis outlines the conclusion findings from the five experimental chapters. Chapter 10 looks at the future work that can build on from the five experimental chapters.

The crystal engineering of metal-organic materials is an active area of research in the field of materials science with a wide variety of diverse functions, properties, and promising applications. Prominent work has been pioneered over the last few decades in crystal engineering where structure directing components have been systematically built into molecular building blocks. However, this has not been fully exploited, particularly in the field of magnetically switchable materials. The numerous interesting properties of spin crossover (SCO) active systems, combined with the current trend to develop molecular electronics and machines has resulted in a dramatic increase in the exploration compounds exhibiting this phenomenon. Modifying the solid-state interactions between metal complexes is essential for controlling the nature of the SCO event. One approach to achieve this is to use supramolecular chemistry to assemble complexes into high ordered arrays through non-covalent supramolecular interactions. Hydrogen bonding is typically the main tool used to control the formation of networks in crystal engineering due to its reproducible, well defined, and directional properties. Previous work has investigated the effect that hydrogen bonding and halogen bonding has on the cooperative nature of the SCO event, which proposed that other supramolecular interactions can also alter the nature of this cooperativity. The focus of this work is on utilising π⋯π interactions to systematically modify the SCO transition. The use of π⋯π stacking interactions has been become prevalent since the discovery that the electron density within the π systems defines the strength of the interaction. The established order of stability in the interaction of two π systems is π-deficient⋯π-deficient > π-deficient⋯πrich > π-rich⋯π-rich. A key aim of this project is to exploit π⋯π stacking interactions for the engineering of magnetically switchable metal-organic supramolecular networks. Naphthalimide-based functional groups were identified as the target for this project because of: a) their inherent ability to induce SCO in Fe(II); b) the long range ordering achieved through πstacking and c) the interesting photophysical properties of the 1,8-naphthalimide moiety. The electron deficient 1,8-naphthalimide systems have not only been utilised as ligand scaffolds for metal complexes, but also investigated as non-coordinating anions to incorporate this structure directing group into the lattice. While systematically varying the nature of substituents on naphthalimide backbone, we will use quantum crystallography methods to develop an understanding of how subtle changes in electron withdrawing/donating substituents influence the nature of interactions, and accordingly how π⋯π interactions influence magnetic properties. The calculation of the intermolecular interaction energies has resulted in an array of information which provides insights, that we wish to develop into detailed structure function relationship, thereby increasing control over the behaviour of magnetic materials.

The ring-opening copolymerisation of carbon dioxide and epoxides, yielding aliphatic polycarbonates, is a useful means to valorise waste gas and to reduce pollution in polymer manufacturing. Key to the success of this polymerization is the catalyst controlling both rate and selectivity. This thesis details the synthesis, characterisation and application of various inorganic complexes as homogeneous catalysts for these copolymerisations. Two different classes of catalysts are examined: (1) Heterodinuclear complexes, combining Mg(II) and various first-row transition metal(II) elements, are investigated to understand the potential for bimetallic synergy. Overall, the thesis provides insight into catalyst mechanisms and future design options. (2) Mononuclear indium(III) complexes. Chapter 1 contains a literature review of existing catalysts and mechanisms. It ends with an overview of the thesis aims and rationale for the selection of the catalysts. Chapter 2 provides an overview of selected material characterisation methods relevant to both the inorganic catalysts and the polymerisation catalysis. Chapter 3 compares catalysis using a series of heterodinuclear complexes of the form MgM where M = Mg(II), Cr(II), Mn(II), Fe(II), Co(II), Ni(II), Cu(II) and Zn(II). The most active catalysts are MgFe or MgCo ‒ both show very high activity and selectivity for cyclohexene oxide/carbon dioxide ROCOP. The catalysts are also active using vinyl cyclohexene oxide, cyclopentene oxide and 3,4-epoxytetrahydrofuran/CO2 and for norbornene anhydride/CHO. Chapter 4 describes the synthesis and characterisation of a series of salen and salan In(III) catalysts. The influence of electron donation of both the imine backbone (C=N, C‒N and C‒NMe) and para-phenolate position (tBu, OMe and Me) upon the catalysis are compared. The optimum catalysis conditions are under 40 bar carbon dioxide pressure and with a PPNCl cocatalyst. Chapter 5 provides and overall conclusion and outlook to the research presented in this thesis. Chapter 6 describes the experimental methods and techniques used in this thesis.

Far from thermodynamic equilibrium, many precipitation reactions can generate complex membrane structures. Such membranes are of great research interest in fields ranging from chemical engineering to geophysics, and even biology where they are thought to have played a vital role in the origin of life. Usually, the transport of chemicals by combined buoyancy, osmotic and diffusive mechanisms, support the precipitation reaction. In order to study these transport processes across a growing selective membrane, we use reactions forming chemical gardens. We focus on four studies: one in a micro-fluidic reactor where flow is forced by a pump and others in a Hele-Shaw cell where the flow is driven by the membrane itself. In the first, with externally forced flow, the growth of a wavy precipitate membrane is observed. We establish that its growth is controlled by transverse diffusion and dispersion of the ions in solution. We develop a precipitation model, taking into account diffusion of ions through the precipitate and through an adjacent gel layer. Results from our theory are in excellent agreement with the measurements and show that a wavy precipitate surface can enhance the transverse transport of ions by extracting energy from a longitudinal flow field. In the second study, the chemical gardens are formed in a horizontal Hele-Shaw cell. We examine the changes of the membrane morphology associated with the concentration of reactants. We also survey the growth rate of membrane, which is determined by the osmotic flow as well as by concentration effects. The motion of the fluid is visualized in order to understand the transport process. The pressure inside the membrane structure is measured and different patterns of pressure changes are identified. A pressure-concentration model is proposed to explain the harmonic pressure changes of this system. In our third study, we observe that a chemical garden confined to two dimensions is a clock reaction involving a phase change, so that after a reproducible and controllable induction period it explodes. The explosion of chemical garden is caused by the decreasing permeability of membrane, owing to the gradual blocking of its pores by the precipitate. A pressure-concentration-thickness model is developed to analyse the explosive system. In our final study, we return to a classic chemical garden where gravity force is of relevance. Oscillatory growth of tubes in the vertical direction is witnessed. The chemical gardens explode at a late phase of experiments, with longer life times than the corresponding horizontal cases. We also observe descending flow with a surrounding precipitation structure, which is controlled by gravity.

Lithium-ion Batteries (LIBs) are an important facet of modern society. They are the subject of much research interest due to the increased demand for electric vehicles and their prevalent use in portable electronics, such as mobile phones and laptops. There are many ways in which battery performance can be improved, once such route is through the use of electrolyte additives. This project, in collaboration with Sony and Murata Manufacturing, focuses on electrolyte additives that affect the formation of the solid electrolyte interphase layer (SEI), a film that forms upon and protects electrodes.

Mesoporous materials have been widely applied in the field of separation and catalysts. Surfactant templating is one of the widely used methods for the preparation of mesoporous materials. Many methods based on surfactant templating, such as spin coating, dip coating and co-precipitation, have been developed to prepare mesoporous materials. Free-standing film synthesis method using the surfactant templating method, which has been extensively studied by our group, enables the investigation of the change in the surface structure while the film is growing using surface sensitive techniques. Previously used silica precursors (tetramethyl orthosilicate and tetraethyl orthosilicate), produce organic species that disrupt the organisation of the micelles. Sodium silicate solution, used in this work produces water instead so is a potential precursor that could give better control of the pore size and the strength of the film. The growth of the film was followed using cutting-edge techniques: in situ X-Ray Reflectivity (XRR) and in situ Grazing Incidence Small Angle X-Ray Scattering (GISAXS), which suggest a possible growth mechanism. Functionalisation of mesoporous materials is required to improve their catalytic properties. Novel surfactants (POM-2Cn, n is the carbon number of the hydrocarbon chain length, n= 12, 14, 16 and 18) were designed and were prepared through grafting double hydrocarbon chains onto a Dawson structured polyoxometalates ([P2W17O61] 10-), to use these species as both templates and a source of polyoxometalate to functionalize the mesoporous materials prepared. The self-assembly of the prepared surfactants and their mixture with commercial nonionic surfactants (C12EO6 and C12EO8) in water have been studied using Small Angle Neutron Scattering (SANS) and Small Angle X-Ray Scattering(SAXS). The pure POM-2Cn molecules form less elongated micelles in water with increasing hydrophobic tail length, suggested by the SANS analysis. The micelles formed by POM-2Cn were used to template titanium dioxide. The prepared materials, denoted as POM-TiO2, have been proven to bear POM units well-dispersed in the porous TiO2 materials using Energy Dispersive X-Ray Analysis (EDX). The POM-TiO2 materials showed enhanced photodegradation properties for rhodamine B compared to the unfunctionalised TiO2 materials. This is attributed to the charge transfer from TiO2 conduction band to POM that prevent the recombination of the photo-excited holes and electrons during the photodegradation process. The insertion of the nonionic surfactant into the POM-2Cn system induces a micellar growth. The comparison of SANS studies of the two binary surfactant systems (POM-2Cn/C12EO6 and POM-Cn/C12EO8) have shown that the micellar growth caused by nonionic surfactant with a smaller polyethylene oxide group is more pronounced than that caused by that with a larger hydrophilic headgroup. The POM-2Cn/C12EO8 mixtures form Liquid Crystal P hases (LCP) when the total concentration is increased to 133 mM. The type of LCP formed depends on the mixing mole ratio of the POM-2Cn and C12EO8. The POM-2Cn rich mixtures form a cubic phase, while the C12EO8 rich mixtures form a lamellar phase. The lamellar phase formed by the mixture was then used to template long-range ordered silica. Porous silica was obtained after the organic part of the template was removed, with a relatively small surface area (ca. 313 m2/g) and small pore size (1 nm - 4 nm). This work includes several individual systematic investigations, the understanding of the growth of the silica film using sodium silicate solution, the basic understanding of surfactant behaviour of the POM-2Cn surfactants and their mixtures with C12EOm (m = 6 and 8). Their applications in fabricating hybrid porous materials with enhanced properties were also studied. It is hoped that these results could give a good understanding of the surfactant behaviour of both traditional and novel surfactants and would contribute to the future study of the functionalisation of inorganic materials using a surfactant templating method.

It was hypothesised that significant (above 1.0 Å) bond elongation can occur as a result of protonation at the oxygen of ether or ester groups. The hypothesis was tested on a set of 23 small (under 700 Da) agrochemical and pharmaceutical molecules. The computational data was analysed together with a set of positive ion electrospray mass spectra to identify correlation between product ion and predicted change in C-O bond length. The change of the C-O bond (predicted by computational modelling) close to or above 1.0 Å was in agreement with observed product ions in mass spectra. Density functional theory (DFT)(B3LYP 6-31+G*) and semi-empirical (PM3) methods showed potential to predict fragmentation upon ionisation, which occurs as result of the protonation event and not because of in-source CID. The success rate for the prediction of proton-induced fragmentation is 48% by semi-empirical and 39% by DFT calculation. The observed effect is a proton-induced dissociation (fragmentation upon ionisation). The application of DFT for the prediction of MS/MS fragmentation of diastereomers was also investigated, as the development of a method to identify diastereomers will be beneficial for a high-throughput environment. A combination of high resolution MS/MS data andDFT calculations has the potential to provide such information. Two metabolic diastereomers were successfully distinguished based on the difference in the fragmentation of sodiated and protonated molecules. Computational modelling showed a difference in ground state energies and geometries of those compounds, explaining the observed differences. Application of DFT calculationsto tandem mass spectra of sodiated and protonated molecules allows the assignment of stereochemistry to diastereomers. The performance of the DFT calculationsin predictingMS/MS fragmentation was evaluated using a set of 12 agrochemical compounds. The variety of the chemistries highlighted a need for analysis of a bigger data set. Computational modelling showed better performance for prediction of MS/MS in time (~60% success rate) whereas only ~50% of product ions were correctly predicted for MS/MS in space. The observed difference can be explained by the presence of secondary product ions in MS/MS in space data. A way to improve performance of the predictive approach through modelling of product ions and analysis of their geometries was suggested. DFT calculations have potential to predict differences between MS/MS in time and in space.

Reversed-Phase High Performance Liquid Chromatography (RP-HPLC) is one of the most widely used techniques for provision of analytical measurement information in the pharmaceutical industry from discovery through to development, clinical and manufacturing analytical laboratories. The pharma industry has been for many years attempting to transform the efficiency of method development and increasingly attention has turned to using in silico methodologies. Pfizer have been at the forefront of developing streamlined workflows and more recently, models for retention time prediction so as to reduce the amount of experimental effort in method development. Many of the in-silico strategies used rely on calculated parameters of the molecules under investigation and to some extent the characteristics of the RP-HPLC stationary phases, but no models yet have captured any measures that capture any description of the multiple and complex analyte - stationary phase-mobile phase interactions within any one RPHPLC method condition. To accomplish this, 1H high resolution magic angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spin-lattice (T1) and spin-spin (T2) relaxation measurements were carried out to probe site-specific molecular motion of a series of aromatic compounds and reversed phase HPLC stationary phases in two different mobile phases. The NMR relaxation measurements provided insight about the nature of the site-specific interaction between the compounds with different stationary phases.

The development of theranostic agents capable of the combined treatment of diagnosis of disease has seen a growing interest within the research community. The combination of diagnostic and treatment modality onto a single construct will allow the careful monitoring of the biodistribution of drug molecules, allowing optimisation of treatment, paving a way towards personalised medicines. Photodynamic therapy (PDT) is a promising treatment technique for cancer. It is minimally invasive and shows little or no toxicity which proves advantageous over traditional anti-cancer techniques. It involves the administration of a non-toxic drug known as photosensitiser and the irradiation with visible light to activate the photosensitisers. The activated photosensitiser will generate reactive oxygen species that can deal oxidative damage to surrounding tissues, culminating in cell death. Hence, the selective accumulation of the photosensitiser into diseased tissues is of utmost importance for photodynamic therapy. This make photosensitisers for photodynamic therapy an ideal candidate to be combined with a diagnostic modality, allowing the monitoring of accumulation of photosensitisers, improving treatment outcomes by irradiation when photosensitiser levels are maximal. Therapeutic abilities of porphyrin as a photosensitiser are undisputed, their ease of synthesis and functionalisation made them the photosensitiser of choice to combine with a diagnostic modality. Magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission tomography (SPECT) are of particular interest as they are routinely used in clinics and allow the imaging of the distribution of the imaging agent. In this thesis, molecular- and nano-theranostic agents were investigated to combine PDT with MRI contrast agent, PET radioisotope, or SPECT radioisotope. A brief introduction of these treatment and diagnostic techniques along with the current advances in theranostic is given in chapter 1. The bioconjugation of cowpea mosaic virus, a biological nanoplatform, with porphyrin is described in chapter 2. Synthesis of polyacrylamide nanoparticles for the encapsulation and functionalisation of porphyrin and MRI contrast molecules is described in chapter 3. Molecular-theranostic agents is described in chapter 4 and chapter 5; chapter 4 describes a PDT/PET theranostic agent and chapter 5 describe two molecular theranostics. prostate-targeted and non-targeted PDT/SPECT theranostic agents. Successful synthesis and evaluation of these theranostic agents led to the in vitro and in vivo analysis to evaluate their efficacy in PDT treatment and MR/PET/SPECT imaging.