College of Science, Engineering and Food Science - Doctoral Theses
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Item Studies in palladium and rhodium catalysis: synthetic strategies for C–C bond formation(University College Cork, 2024) Power, Mark; Mcglacken, Gerard P.; Irish Research Council; Higher Education AuthorityThis thesis concerns studies in palladium and rhodium catalysis for carbon-carbon bond formation. Chapter 1 involves the synergistic use of tetrabutylammonium acetate (NBu4OAc) with palladium catalysis to expand on the synthesis of dibenzofurans via C-H activation. Dibenzofuran and its derivatives are ubiquitous and important medicinal and natural products. Many contain electron-rich aryl rings. Previously, we found that the wellestablished conditions, which promote C−H functionalisation through Concerted MetalationDeprotonation (CMD), proved unsatisfactory for electron-rich diarylether precursors. Herein, we report a Pd-catalysed C−H functionalisation protocol that works with electron-rich arenes. We suspect that tetrabutylammonium acetate can act as base, ligand and solvent, rendering this protocol a simple and efficient route to electron-rich dibenzofurans. A variety of functionalised dibenzofurans are successfully accessed through this protocol. The methodology can be applied to benzochromenes, with varying degrees of success. However, this protocol can be expanded to enable a robust, one-pot Buchwald-Hartwig, C–H activation sequence to access biologically relevant indoloquinoline scaffolds from simple building blocks. In Chapter 2, rhodium-catalysed asymmetric conjugate additions are performed with indolyl boronic acids. The indole ring system represents one of the most abundant and important heterocycles in natural products, Active Pharmaceutical Ingredients (APIs), drugs and other materials. The prominence of indole compounds makes efficient protocols to derivatise the heterocycle highly desirable. A particular importance is placed on asymmetric protocols and utilising unprotected (NH) variants. Herein, we report a Hayashi-Miyaura-type Rh-catalysed asymmetric conjugate addition using free NH indole boronic acids and enones. Each position on the carbocyclic backbone of indole can be accessed, with a variety of enones. Yield of up to 94%, and e.r. values up to 99:1 can be achieved using mild reaction conditions. Furthermore, a 1,2-addition to benzil can be performed in excellent yield and e.r. Finally, a one-pot conjugate addition and intramolecular cyclisation of 7-indolyl boronic acid allows for the synthesis of a novel tetracyclic indole, similar to that found in natural products.Item Experimental testing and finite element analysis of segmented water pipeline(University College Cork, 2024) Zhang, Qinglai; Li, Zili; Soga, KenichiUnderground pipeline networks are crucial for the serviceability of sustainable water distribution in contemporary society. Nonetheless, thousands of miles of segmented pipeline infrastructure are susceptible to substantial damage from natural disasters, such as earthquakes and landslides, particularly at the vulnerable joint sections. To enhance the resilience of the segmented pipelines, many previous studies have already investigated various types of pipeline joints and materials in both academia and industry. Over the years, Ductile Iron (DI) Pipes have already been widely used in buried underground infrastructure, owing to their durability and reliability under various soil and loading conditions. On the other hand, Polyvinyl Chloride-Oriented (PVCO) pipelines have emerged as a novel alternative in recent years due to its cost-effectiveness, environmental friendliness and easy installation. Both are valued for their adaptability to different local ground conditions. Continued advancements in both DI and PVCO pipeline technologies have led to significant improvements in the design and functionality of segmented pipelines. To evaluate the effectiveness of their recent innovations, it is crucial to conduct the corresponding experimental testing and develop computational models. Hence, this PhD study aims to comprehensively investigate the mechanical responses of modified jointed DI and newly designed segmented PVCO pipelines to earthquake-induced forces through a series of full-scale laboratory tests utilizing distributed fiber optic sensing (DFOS) technology for continuous strain measurement and conducting advanced three-dimensional (3D) finite element (FE) analyses. A series of laboratory tests were conducted on the 203-mm (8-in) diameter DI pipeline with a restrained axial joint, three critical states have been identified: axial tension, deflection and biaxial tension (combined tension and bending). The behavior in each state is influenced by the orientation, quantity, and installation of locking segments in bell-spigot joints, leading to variations in joint stiffness, flexibility, and capacity. The analysis was then further extended to an innovative surrogate model using bushing connectors to replace the complex bell-spigot joint configurations, aligning well with expected outcomes while significantly reducing simulation time. This is particularly beneficial for future soil-pipeline interaction studies at the system level. Similar to DI pipelines, a series of bending tests was also conducted on the 160-mm (6-in) diameter PVCO pipeline. The pipeline employs a 'Fittom-Coupler' fitting, sealed with an Ethylene Propylene Diene Monomer (EPDM) rubber and polypropylene ring gasket to connect two spigots securely and ensure water tightness. The results highlighted that performance is primarily influenced by bending stresses, leading to deflection and axial sliding. Validated models incorporating anisotropic properties and seal materials helped in conducting sensitivity analyses on varying wall thicknesses and fitting designs. Pipeline failure modes are shown typically involve mechanical disconnection at the joints and also local buckling related to variations in wall thickness. Such buckling can be reduced by altering the length or local shape of the fitting. Both segmented restrained DI pipes and PVCO pipes present unique advantages for seismic water infrastructure. DI pipes provide exceptional strength for high-load environments, whereas PVCO pipes, with thinner walls and enhanced circumferential strength allow greater deflection capability, suitable for areas requiring resilience to large deformations.Item Discovery and characterisation of bacteriocins from microbiomes(University College Cork, 2024) Hourigan, David; Ross, R. Paul; Hill, Colin; Science Foundation IrelandBacteria are social microorganisms that inhabit every corner of the world. They rarely live in isolation and are key members of the microbiome along with viruses, archaea, protozoa and algae. Microbiome research has exploded over the past 20 years, but we are only starting to disentangle the complexity and dynamic nature it holds. Bacteriocins are antimicrobial peptides produced by bacteria across the bacterial kingdom. They have gained attention as a suitable alternative or adjunct to traditional antibiotics due to low levels of documented resistance. However, the roles they play in shaping the microbiome or acting as selfish genetic elements are often overlooked when studying them through such a narrow scope. While it is widely accepted that these peptides can be exploited to target specific bacterial species, their abundance and diversity is often under explored. These factors will have a huge impetus on their suitability to be used as antimicrobials. In Chapter 1, we perform a literature review describing recent advancements in enterococcal genomics and how it’s advancements can aid in therapeutic strategy. Clinically problematic Enterococcus faecium are promiscuous with respect to horizontal gene transfer and are becoming a global healthcare issue. The ability to expand its own genome and rapidly mutate has made this bacterium resistant to multiple antibiotics. Therefore we explore non-antibiotic interventions, including bacteriocins, to tackle these pathogenic bacteria. However, in Chapter 2 we show that E. faecium APC1031 rapidly becomes resistant to the potent class IIa bacteriocin avicin A. We generated mutants at a frequency of approximately 1e-06 suggesting that class IIa bacteriocins alone may not be suitable to target such a “hardy” and adaptable bacterium. Over the past century bacteriocin research has been skewed towards the Bacillota. However, the Actinomycetota are gathering interest as an underexploited bacteriocin-producing phylum. In Chapter 3 we discover novel aureocin A53-like bacteriocins found within this phylum. We also show they are found in microbiomes. We then synthetise the first aureocin A53-like bacteriocins from Actinomycetota and show that they have antimicrobial activity. Chapter 4 explores the rumen microbiome as a source of novel bacteriocins by genome mining the Hungate1000 culture collection of rumen strains. We discover that between 30-70% of bacteria found in the rumen produce at least one bacteriocin which is more than double previous estimates of the bacteria found in mammalian gastrointestinal tract. Nisin is the most well studied bacteriocin. It is gathering attention as a suitable alternative to antibiotics. However, little is known of how widespread the genes responsible for its production are. In Chapter 5 we discover widespread nisin-like bacteriocin production genes and show they are on mobile genetic elements and present in bacteria of aetiological concern. We also show that some of these peptides can be heterologously expressed and that they have antimicrobial activity. We then show that nisin VP is a novel nisin variant from an anaerobic bacterium isolated from the pig gut. Chapter 6 shows that two Streptococcus devriesei strains have the genetic capability to produce a conserved novel circular bacteriocin. This novel bacteriocin streptocyclin BTW is an amylocyclicin-like bacteriocin found within the genus streptococcus. Both strains with the genetic capacity to produce this bacteriocin are found in the oral microbiota. The role of bacteriocins as antimicrobial peptides is a well-studied trait. However, little is known of the genetic systems that localise near them within genomes. In Chapter 7, we search for genes encoding protein families that have co-localised near lanthipeptide biosynthetic gene clusters and discover an enrichment of anti-phage defence systems. This suggests lanthipeptide production may be attribute to bacteriophage-bacteria interactions. This thesis explored the diversity of bacteriocin gene clusters that are found in microbiomes. We have shown that these peptides have antimicrobial activity in vitro. However, their abundance and diversity implies they play multiple roles in complex microbiomes.Item Studies in iridium and manganese catalysis in C-H activation and reductive transformations(University College Cork, 2024) Courtney, Eimear; Mcglacken, Gerard P.; Irish Research Council; Higher Education AuthorityHeteroaromatic compounds are fundamental building blocks in pharmaceutical, agrochemical and material chemistry. The efficient and selective derivatisation of heteroarenes is a critical tool for organic synthesis. C−H activation has emerged as an effective means to access diversified heteroaromatic motifs. In particular, iridium-catalysed C−H borylation has proven a useful means of heteroarene functionalisation, due to its ability to produce highly versatile aryl organoboronate intermediates. The quinoline nucleus is a ubiquitous, strategic target, given its role as a key scaffold in a plethora of synthetic and naturally occurring pharmacologically active compounds. Chapter 1 showcases a robust one-pot protocol which enables rapid late-stage functionalisation of this important class of pharmacophores. Chapter 1, Part I describes the direct borylation and transformation of the C-7 position of 6-fluoroquinolones in excellent yields. This protocol is further expanded upon in Chapter 1, Part II to include the borylation of the biologically significant N-ethyl 3-carboxylate-6-fluoroquinolone in good yields. Furthermore, we have identified a tuneable reactivity applicable to the N-substituted 3-carboxylate-6-fluoroquinolone motif, which can be controlled through judicious choice, and equivalents, of borylating agent employed. In recent years, earth-abundant 3d transition metal catalysts, such as manganese, have gained popularity as alternatives to expensive precious metals. This trend stems from the urgent need to develop new, efficient, and sustainable green methodologies. The use of readily available metals, instead of rare noble metals, is a key focus in green chemistry. Chapter 2 of this thesis explores the synthesis of various carbonyl manganese phosphine complexes and their applications in C–H activation. Chapter 2, Part I details the synthesis and characterisation of three carbonyl manganese phosphine complexes through spectroscopic methods and investigates their role in C–H activation reactions. Additionally, the formation of corresponding manganacycle complexes was studied to understand the fate of the ligand during the catalytic cycle. Chapter 2, Part II describes the preparation of a polymer-bound phosphine manganese complex from commercially available sources via a straightforward one-step process. This catalyst has shown broad applicability and promising results in protocols such as C–H activation, (de)hydrogenation, and hydrofunctionalisation, yielding valuable products ranging from chemical feedstocks to complex heteroaromatic motifs in moderate to good yields.Item The potential role of optical guidance for bone-related biomedical applications in orthopedics and neurosurgery(University College Cork, 2024) Li, Li Yao; Andersson-Engels, Stefan; Burke, Ray; Science Foundation IrelandOptical sensing technology was explored as a means of intraoperative guidance for bone-related procedures in orthopedics and neurosurgery. Specifically, the feasibility of diffuse reflectance spectroscopy (DRS), a non-invasive and real-time optical technique that measures diffusely reflected light off samples of interest, was investigated in the thesis to differentiate biological tissue types and inform tissue boundaries as an intraoperative safety measure for revision total hip arthroplasty. Feature selection (FS) frameworks based on DRS measurements were developed utilizing machine learning techniques to determine wavelength features of optimal discriminative power for bone-related surgical procedures. Four FS frameworks, incorporating principal component analysis (PCA), linear discriminant analysis (LDA), backward interval partial least squares and an ensemble approach (biPLS), were designed with high adaptability to facilitate modifications and applications to other clinical scenarios. A feature subset of 10 wavelengths was generated from each FS framework yielding promising balanced accuracy scores for the one-vs-rest binary classification task. For cortical bone versus the rest class labels, PCA, LDA, biPLS and ensemble -based FS framework computed balanced accuracy scores of 94.8 ± 3.47%, 98.2 ± 2.02%, 95.8 ± 3.04% and 95.8 ± 3.16, respectively. For bone cement versus the rest, 100% balanced accuracy scores were generated from all FS frameworks. Subsequently, an in-house designed optical probe integrating DRS sensing was engineered and examined in ex vivo experiments. The most discriminative DRS wavelengths, selected by the FS frameworks including 1200 and 1450 nm, were incorporated as the illumination light sources. Furthermore, the performance of DRS to predict drilling depths in cranial bones was evaluated for craniotomy. Two models including partial least squares (PLS) regression and feedforward neural networks (FNN) were examined for prediction of skull thickness ranging from 1 to 5 mm away from the brain, yielding a root mean squared error regression loss of 0.08 and 0.06 mm from PLS, and 0.2 and 0.1 mm from FNN by using all versus selected features as model inputs, respectively. The predicted depths served as a safety protocol to indicate lookahead distances. On the other hand, the potential of ultrafast lasers in bone-related surgical applications was reviewed and explored from multiple perspectives. The advantages offered by ultrafast lasers over conventional laser systems (continuous wave or long-pulse lasers) included superior precision and minimized collateral thermal damage to surrounding tissues. However, clinical translation of ultrafast lasers to surgical applications had been constrained by limitations in pulse average power and material removal rate. In contrast, the use in implant surface texturing had advanced substantially, effectively enhancing bioactivation and osteointegration within bone matrices. At the end, ambient mass spectrometry, which employed a picosecond laser system for plume generation, was additionally assessed for tissue differentiation in a preliminary study. The classification model employed PCA for dimensionality reduction and LDA for multi-class classification. By using the reduced mass spectra dataset, bone cement was distinguished from biological tissue types with 100% in different classification metrics (precision, recall, F1 score). The highest misclassification rate occurred between trabecular and cortical bone with 18 instances where trabecular bone was classified as cortical bone. Overall, the research presented in the thesis has demonstrated promising results to advance basic science and consequently set the foundation for translational study of integrating optical sensing into surgical tools in bone-related procedures with valuable insights. This work was supported by Science Foundation Ireland (SFI), Grant No. SFI/15/RP/2828 and Grant No. SFI/22/RP-2TF/10293.