Chemistry - Doctoral Theses
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Item Hydrogenation and other palladium mediated transformations for the construction of important molecular frameworks(University College Cork, 2024) Kehoe, Roberta A.; Mcglacken, Gerard P.; Science Foundation Ireland; Synthesis and Solid State Pharmaceutical Centre; Higher Education AuthorityThis thesis is presented as a thesis by publication and includes two peer-reviewed published chapters and a third chapter to be submitted, pending external nanoparticle analysis. The numbering of the compounds, schemes and figures are unchanged and are as per the published manuscripts. Therefore, compound, figure and scheme numbering etc. is independent for each chapter. This work mostly describes the use of palladium catalysts in hydrogenation reactions to form molecular structures of interest in pharmaceuticals and medicine. Chapter 2 Building molecular complexity usually requires numerous synthetic steps, isolations, and purifications. In addition, many reagents/solvents can be required, and the processes can take a lot of time. Designing one-pot tandem reaction methods is an environmentally friendly approach to building complexity which negates the need for intermediate isolation/purification and saves on time and costs. In this chapter, a one-pot Mizoroki-Heck/direct arylation/hydrogenation sequence was developed to access biologically significant alkylated benzofuroquinolines, benzofuropyridines and dibenzofurans. This one-pot method combines three mechanistically distinct palladium-catalysed reactions from a single pre-catalyst without the need for exogeneous ligands and inorganic base. A library of novel compounds was synthesised, including a deuterated derivative, and some green metric calculations were carried out. Chapter 3 Extended aromatic systems exhibit an associated 2D character which is often not conducive to clinical success. Compounds with more 3D (sp3) character often progress further in clinical studies. Introducing this ‘3-dimentionality’ at a late-stage allows for initial access to the unparalleled scope and broad applicability of sp2-sp2 cross-coupling which is then followed by hydrogenation to add a third dimension. This work describes the use of simple hydrogenation reagents and conditions to selectively reduce tetracyclic benzofuroquinolines, incorporating more sp3 character into the target compounds at ‘late stage’. Deuterium was also incorporated to form deuterated derivatives. Additionally, the deuteration provided some interesting insights into the source of the deuterium/hydrogen in this reaction. The role of the oxygen atom in benzofuroquinoline was also explored. Chapter 4 The Z-alkene motif is ubiquitous in chemistry and is found across pharmaceutical, agricultural and materials industries. The selective formation of Z-alkenes by hydrogenation methods remains a challenge, as isomerisation to the E-alkene can occur in addition to over-reduction to the respective alkane. The widely used Lindlar’s catalyst facilitates the selective hydrogenation of alkynes to Z-alkenes. However, there are many problems associated with the use of this catalyst. The use of ligand stabilised nanoparticles can facilitate the formation of Z-alkenes with low catalytic loadings and increased reproducibility. This chapter describes the development and use of ligand stabilised palladium-dodecanethiolate nanoparticles for the semi-hydrogenation of alkynes to form Z-selective alkenes. These nanoparticles also facilitate the introduction of deuterium into the alkene bond while maintaining selectivity and excellent deuterium incorporation.Item Multiferroic investigations of Aurivillius phase thin films(University College Cork, 2023) Colfer, Louise; Keeney, Lynette; Long, Brenda; Royal Society; Science Foundation IrelandIn recent years, the amount of data being created and processed is growing at a much faster rate than the rate of computational storage technology development. With CMOS technologies reaching their miniaturisation limits, new disruptive materials are needed to increase data storage capabilities. Technological road-maps have identified room temperature, non-volatile magnetoelectric multiferroic materials as promising candidates for memory scaling within future memory storage devices. Although multiferroic memory devices have the potential to revolutionise memory storage technologies, commercial devices successfully utilising multiferroics have not yet come to fruition. The focus of this thesis is to understand and optimise a rare example of a room temperature magnetoelectric multiferroic, Bi6TixFeyMnzO18 (B6TFMO; x = 2.80 to 3.04; Y = 1.32 to 1.52; Z = 0.54 to 0.64). Aurivillius phase materials, (Bi2O2)(An−1BnO3n+1), where ferroelectric perovskite units are interleaved between dielectric [Bi2O2]2+ layers, are flexible scaffolds for technological applications. While earlier studies indicated that B6TFMO is a promising material for future memory devices, my thesis presents significant advances in the characterisation, understanding and optimisation required towards implementing the material in fully realised devices. In this work, correlation between the octahedral tilting and atomic-level structural distortions with functional electronic and magnetic properties of B6TFMO were determined, revealing that crystal field splitting of the Ti4+ octahedra is influenced by its position within the Aurivillius unit cell. Theoretical calculations determined that this is predominantly driven by changes in the extent of tetragonal distortion along the c-direction. Atomic scale mapping of polar displacements reveals this has a direct impact on the ferroelectric properties. Polarisation is largest towards the outer perovskite cells, correlating with an increased extent of local tetragonal distortion of octahedral geometries. Experiments demonstrate that tilting of the BO6 octahedra competes with the extent of tetragonal distortion of the TiO6 octahedra, where the degree of octahedral tilting increases towards the central layers of this Aurivillius system, where the magnetic cations preferentially partition. This work presents the first indication that octahedral tilting might be an important enabler of long-range magnetic interactions and subsequent multiferroic behaviour in B6TFMO. Delving deeper into fundamental understandings of B6TFMO’s antipolar and magnetic behaviour, the purposeful inclusion of structural defects within the layered structure of B6TFMO and how they can impart elastic strain and electrostatic energy changes which in turn influence polar behaviour is explored. The findings show that the vicinal sapphire substrates (mis-cut angle 0.2 o to 10 o) are successful for promoting the propagation of sub-unit-cell defects and disruptions to the periodicity of the Aurivillius phases. This has a marked effect on the film morphology and ferroelectric properties. Macroscopic and local measurements show that defect, crystal grain and ferroelectric domain density increases with increasing substrate mis-cut angle. Atomic resolution polarisation mapping showed that charged domain walls alongside exotic polar vortices are facilitated by OPBs when two OPB defects are spaced 5 nm apart. This work provides insight into methods for successfully controlling defect levels and how polar vortex domain walls and charged domain walls are promoted within layered multiferroics by tailoring the underlying substrate that the film is grown on. Moving on from vicinal sapphire surfaces, patterned sapphire with 3D domes were used to encourage the growth of the Aurivillius grains towards an upright geometry. An increased number of non-(00l) reflections were present in the B6TFMO films on patterned sapphire along with evidence from STEM imaging showing that B6TFMO grains grow along the incline of the patterned sapphire domes. With the growth of the crystal grains towards an upright geometry it would be expected that access to the major a-axis polarisation via out-of-plane measurement would be improved, however with a maximum inclination angle of 60 ° achieved with the 3D dome architectures, the out-of-plane piezoresponse of the samples remained weaker than the in-plane piezoresponse. Studies of the magnetic properties of the films demonstrated that the B6TFMO samples were ferromagnetic at room temperature. These findings provide further evidence of room temperature multiferroic behaviour in B6TFMO. Lastly, the role of bismuth excess and substrate strain were investigated to optimise the epitaxial growth of B6TFMO via DLI-CVD. A single-step deposition method on epitaxial substrates was developed to allow the successful synthesis of continuous 45 nm thick B6TFMO films at thicknesses relevant to applications as piezoelectric actuators, sensors and energy harvesters. These films nucleated via a layer-by-layer growth mode and were found to have a strong in-plane ferroelectric response with isotropic domains. Film purity was enhanced with utilisation of epitaxial substrate with appropriate lattice match to B6TFMO and by optimising the amount of bismuth precursor used. In this work, progress was made towards the optimisation of epitaxially grown B6TFMO films, allowing greater control of film orientation and augmenting strain-induced enhancement of multiferroic properties in future data storage devices. Overall, this research has increased understanding of the fundamental mechanisms governing the ferroelectric and ferromagnetic properties of B6TFMO. The work has elucidated some of the key requirements fundamental to the manifestation of polar topologies and has created strategies for the tailoring of novel polar topologies. This combination of new material understanding and new growth optimisation of room temperature multiferroics contributes to solving the ‘big data’ problem. Application of B6TFMO in future technologies based on ultra-high density, energy efficient memory devices, spintronic devices, multilevel resistance control (memristive and synaptic devices) and energy-efficient neuromorphic “brain inspired” devices are envisioned.Item Ordered macroporous metal oxides and carbonaceous composites for Li-ion and beyond Li-ion batteries(University College Cork, 2023) Carroll, Aoife; O'Dwyer, Colm; Irish Research CouncilThis thesis provides an in-depth investigation of three-dimensional ordered macroporous materials, specifically inverse opal materials, for electrochemical energy storage systems, particularly rechargeable batteries. Exploring the potential of composite structures, this research focuses on TiO2/GeO2 nanocomposites and C/TiO2 inverse opal anodes in Li-ion batteries, and carbon inverse opal anodes in Na-ion and K-ion batteries. Employing comprehensive characterization techniques, this research studies intricate material properties and electrochemical responses inherent in these structures. The composite materials exhibit promising features such as enhanced electrolyte penetration, improved specific capacities and coulombic efficiency, and robust structural integrity during extended charge-discharge cycling. The study findings shed light on the unique advantages of inverse opal composites for application in next-generation battery technologies. Highly ordered, macroporous inverse opal structures were fabricated as TiO2/GeO2 nanocomposites with varying GeO2 content, showcasing coulombic efficiency and capacity retention. The overall capacity of these interconnected binder-free anodes was affected by the Ge content and its distribution at both slow and fast rates. Characterization techniques such as X-ray diffraction, high-resolution transmission electron microscopy (HRTEM), selected area electron diffraction, energy-dispersive X-ray spectroscopy, and electron energy loss spectroscopy were employed to analyse these anodes. The electrochemical response over 2000 cycles and at various rates elucidated the impact of the composite on key metric in battery cells. The results indicated that a composite of intercalation and alloying compounds yielded good specific capacity and excellent coulombic efficiency (>99%), even with low quantities of the GeO2. The cycling life reveals an increase in capacity with improved coulombic efficiency with suspicion that the GeO2 material becomes electrochemically active within the composite matrix, undergoing modifications during cycling. C/TiO2 composite were synthesized from sucrose as the carbon precursor to form interconnected, porous inverse opal structures. Material characterization revealed amorphous TiO2 and disordered carbon with a large pore size of ~400 nm. An atomic ratio of ~8:1 in favour of carbon yielded promising electrochemical responses with high specific capacity and capacity retention at 150 mA/g rate. Diffusion processes were shown to be the dominant contributor to current responses for all scan rates, with double-layer capacitance accounting for less than ~45 % even at the high scan rate of 1000 mV/s. When compared to individual carbon and TiO2 inverse opals the composite demonstrated improved coulombic efficiency and high-rate performance attributed to the synergistic benefits of combining these two intercalation materials. Carbon inverse opals were fabricated in a similar way from sucrose to study the effect of the macroporous structure on performance in sodium-ion and potassium-ion batteries. Composed of disordered carbon with short-range graphitic regions, the storage mechanism involved primarily diffusion processes at lower scan rate with capacitive behaviour governing the current response at faster scan rates. Structural integrity was maintained in all cells after 250 cycles showcasing impressive resistance to structural stresses. Comparing the inverse opal material to thin films of the same composition highlighted the improved capacity retention and cycling stability inherent to the three-dimensional ordered macroporous structure.Item Multifaceted computational modelling in pharmaceutical research and development(University College Cork, 2023) Vinay Kumar Reddy, Cheemarla; Tiana, Davide; Lawrence, Simon; Swiss Forum for International Agricultural Research; National Institute of Neurological Disorders and StrokeDrug development is a multi-step process and takes around 12 to 15 years for a new drug to get approved. In the current scenario, to accelerate the drug development process and to reduce the time frame, most pharmaceutical companies have in-house developed workflows comprised of a hybrid use of computational and experimental approaches. This thesis was focused on employing state-of-the-art molecular modelling methods in three significant areas of pharmaceutical research and development. This thesis comprises an introductory part (chapter 1) and a productive part (chapter 3 to chapter 5). The first chapter of this thesis is the literature review, outlining the foundational studies and research framework used in chapters 3 to 5. The second chapter describes the thesis structure and objectives of the other three chapters. The third chapter explores the hit identification process, utilising docking to screen a small database of phytopharmaceuticals against sclerostin protein followed by an investigation of the stability of the protein-ligand complexes through standard molecular dynamics and funnel meta dynamics. The fourth chapter involves the modelling of adsorption and diffusion of doxorubicin, paclitaxel, carboplatin, and gemcitabine anticancer drugs and also drug combinations such as doxorubicin with carboplatin, paclitaxel with gemcitabine and carboplatin employing NUIG-4 metal-organic framework as drug delivery agents. In this chapter, the comprehensive understanding of molecular interactions governing drug adsorption and diffusion was studied using Grand Canonical Monte Carlo (GCMC) and Molecular Dynamics (MD) simulations. The fifth chapter focuses on investigating the mechanism of chiral Bronsted acid catalysed asymmetric synthesis of homoallyl alcohols from ortho vinyl benzaldehydes and allyl boron pinacol ester using density functional theory methods (DFT), QTAIM, and NCI analysis. Furthermore, a comparative analysis of transition structures of Ortho vinyl and ortho alkynyl benzaldehyde substrates was studied.Item Studies in synthesis using CO2 and H2 gases(University College Cork, 2023) Lowry, Amy; Mcglacken, Gerard P.; Byrne, Peter; Irish Research Council; Higher Education AuthorityThis thesis is split into two parts based on two different areas of research. Part 1 Part 1 is sub-divided into four chapters. Chapter 1 involves a review of the existing research conducted in this area. Chapter 2 provides details on the research carried out in this project on the development of a Wittig CO2 utilisation methodology for the synthesis of α,β unsaturated carboxylic acids. Chapter 3 involves discussion on the development of protocols for purification of the α,β-unsaturated carboxylic acids synthesised. The Conclusions and Future Work section relating to this area of research is found at the end of Chapter 3. Chapter 4 outlines the experimental work for Part 1. CO2 utilisation continues to capture the attention of chemists due to the ever-increasing levels of CO2 and the negative effects of global warming. CO2 is an inexpensive and environmentally friendly C1 building block, which can be used in the synthesis of value-added chemicals. Many medicinally important compounds and natural products contain the elements of CO2 within their structure, including carboxylic acids, enoates, and carbamates. In particular, α,β unsaturated carboxyl compounds are typically accessed by metal-catalysed transformations or condensation reactions, which often require hydrolysis of the ester product to furnish the corresponding acid. In this project, a telescoped process was developed, that not only achieves CO2 activation, but exploits a novel application of the Wittig reaction, enabling direct installation of the carboxyl group by two successive carbon-carbon bond forming events. Reaction optimisation and purification studies were carried out and 34 α,β-unsaturated carboxylic acids were synthesised using the method, containing a wide range of functional groups, as well as a number of pharmaceutical precursors, in moderate to excellent yields. As part of this work, a novel method for purification of α,β-unsaturated carboxylic acids was developed. Part 2 Part 2 is sub-divided into three chapters. Chapter 5 involves a discussion on the background of the project and a review of the existing research conducted in the area. Chapter 6 involves a discussion of the research carried out in this project on the dearomatisation of benzofuroquinolines by a Pd-catalysed hydrogenation reaction. The Conclusions and Future Work section relating to this part of the thesis is found at the end of Chapter 6. Chapter 7 outlines the experimental work for Part 2. Within the McGlacken group, development of C-H activation methodologies has been a large area of research, and, in particular, benzofuroquinolines have been synthesised via direct intramolecular arylation of 4-phenoxyquinolines. The quinoline nucleus is one of the most frequently occurring ring systems in approved drugs, and hydrogenation of the quinoline nucleus and the selectivity thereof, has been reported in the literature. In addition, increasing interest in the concept of ‘escaping flatland’, whereby the saturation of compounds is increased, allowing for the exploration of more architecturally complex molecules that will potentially give rise to enhanced biological activities. In this part of the thesis, a range of differently substituted benzofuroquinolines were hydrogenated to generate 18 selectively dearomatised benzofuroquinolines. Investigations were carried out into different reaction conditions tolerated by the reaction, and the fate of halogen substituents in the reaction. In addition, a double reduction product side-product was identified and characterised, opening up the methodology to the formation of a new class of novel compounds.