Chemistry - Doctoral Theses
Permanent URI for this collection
Browse
Recent Submissions
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 Synthesis of novel IMPDH inhibitors(University College Cork, 2024) Upadhyay, Amit; O'Sullivan, Tim; Irish Research Council; Higher Education AuthorityInosine-5’-monophosphate dehydrogenase (IMPDH) is an important enzyme involved in the biosynthesis of guanine nucleotides. The use of IMPDH as a target for developing novel antimicrobial agents forms the basis of this research. Chapter 1 provides an overview of recently developed antimicrobial IMPDH inhibitors from the literature. The background to this project and the main aims and objectives are also outlined. Chapter 2 describes the development of synthetic routes to two related compound libraries. The first series comprises benzyl-containing urea analogues, while the second series all contain a common 3-nitro-4-chlorophenyl ring. The introduction of several heteroaryl/aryl rings via Suzuki- Miyaura coupling is also described. The synthesis of a third group of compounds incorporating a squaramide bioisostere in place of the urea group is discussed in Chapter 3. In silico analysis of all compounds is described in Chapter 4. Important ADME properties (e.g. LogP, TPSA, pKa) are calculated to determine the suitability of these compounds for future development. This chapter also details the screening of several compounds for activity against P. aeruginosa IMPDH, with a number of molecules displaying sub-micromolar activity. Additionally, biological evaluation of three potent candidates against S. aureus IMPDH and E. coli IMPDH is included in this chapter. A docking study of both synthesised and virtual inhibitors using the CpIMPDH enzyme as the target is contained in Chapter 5. Chapter 6 details the main conclusions of this work and proposes several avenues for future investigation. Chapter 7 contains all relevant experimental procedures, including spectroscopic and analytical data.Item Aromatic addition reactions of α-diazo-β-ketonitriles(University College Cork, 2024) Tyner, Ciara; Maguire, Anita; Collins, Stuart; Irish Research Council; Higher Education AuthorityThe central focus of this thesis is the intramolecular aromatic addition reaction of α-diazo-β-ketonitriles using rhodium and copper catalysts, and examination of the structural properties and reactivity of the resulting azulenones. In depth comparison of the reactivity and properties of the α-diazo-β-ketonitriles and the resulting azulenones to the analogous α-diazoketones and azulenones bearing a bridgehead methyl group in place of the nitrile is a key element of the work. The power of benchtop NMR spectroscopy to monitor labile intermediates is demonstrated in this work. Chapter One provides an overview of the literature related to this work with a particular focus on recent developments in aromatic addition reactions of α-diazocarbonyl compounds. Chapter Two describes the successful synthesis and characterisation of a series of α-diazo-β-ketonitriles (13 novel compounds) and their precursors. A number of synthetic routes were explored to lead to these compounds, each of which involved multiple reaction steps and required considerable optimisation. Conjugation with the nitrile unit contributed to the increased stability of the α-diazo-β-ketonitriles which could be readily stored for long periods without deterioration, while the precursor β-ketonitriles were labile and had to be used shortly after preparation. Chapter Three describes the investigation of the aromatic addition reactions of the novel α-diazo-β-ketonitriles using a range of rhodium and copper catalysts and, on one occasion, a ruthenium catalyst. The impact of the nitrile substituent on the reactivity of the α-diazocarbonyl is explored in detail resulting in cleaner reactions than with the corresponding α-diazoketones due to fewer side reactions, presumably due to the more stable carbenoid. Enantioselection in the aromatic addition process was successful using a copper bis(oxazoline) catalyst providing the corresponding azulenone with up to 75% ee. Interestingly, the presence of the nitrile on the carbene had little impact on the enantiofacial discrimination. The impact of the nitrile substituent on the stability and reactivity of the azulenones is very significant, increasing their lability towards rearrangement to form tetralones and, indeed in many cases, the azulenones could not be isolated or recovered from the reaction mixtures. The tetralones exist predominantly as the enol tautomers due to conjugation with the nitrile. One of the key advances in this study was successful trapping of the novel labile azulenones as cycloadducts through addition of PTAD to the aromatic addition reactions. Interestingly, the presence of PTAD did not impact negatively on the transition metal catalysed process. The impact of the nitrile substituent on the position of the norcaradiene-cycloheptatriene equilibrium is also explored in detail, principally through 1H and 13C NMR spectroscopy and IR spectroscopy at room temperature and in variable temperature NMR studies. The presence of the nitrile substituent has a very significant impact in shifting the equilibrium towards the norcaradiene relative to the position of the equilibrium in the corresponding azulenones with a bridgehead methyl substituent. Chapter Four describes the use of a benchtop NMR spectrometer to monitor the aromatic addition reactions of the α-diazo-β-ketonitriles to form labile azulenones followed by rearrangement to the tetralones, demonstrating the power of this technique for monitoring and detecting labile intermediates at relatively low field (80 MHz). The reactivity profiles of α-cyano-α-diazoacetamides were also monitored by benchtop NMR spectroscopy in both static and flow mode. Chapter Five contains the full experimental details and spectroscopic characterisation of the compounds synthesised in this work.Item Photochemical transformations of α-diazocarbonyl compounds in flow(University College Cork, 2024) O'Callaghan, Katie S.; Maguire, Anita; Collins, Stuart; Synthesis and Solid State Pharmaceutical CentreThis thesis describes a detailed investigation of the synthetic and mechanistic aspects of the reactivity of a series of α-diazocarbonyl compounds including aryldiazoacetates, α-diazo-β-ketoesters and an α-diazo-β-ketosulfone, under continuous flow photolysis. These photochemical transformations yielded 2,3-dihydrobenzofurans, γ- and β-lactones, oxazoles and Wolff rearrangement products indicating the synthetic versatility of these metal-free processes. Continuous flow technology was also applied to telescope sulfonyl azide generation, diazo transfer and subsequent photochemical reactions, enabling three steps to be carried out without the need to isolate or handle any hazardous materials. The use of Process Analytical Technologies (FlowNMR and FlowIR™) throughout this work provided key insights into reaction progress and offered improved process safety through reaction monitoring.Item Novel approaches to reducing resource use and waste generation in nucleophilic substitution reactions through low waste synthetic routes and reaction energy profile modelling(University College Cork, 2024) Ryan, David.; Mcglacken, Gerard P.; Byrne, Peter A.; Irish Research Council; Higher Education AuthorityThis thesis is split into two parts based on two different areas of research. Part I Part I relates to research conducted on the development of a sustainable protocol for the bromination of alcohols. It is divided into five chapters (including a dedicated chapter for the literature references across the entirety of Part I). Chapter 1 provides an introduction to the background of the project as well as a review of existing research conducted in this area. Chapter 2 provides details on the research carried out in this project on the sustainable synthesis of alkyl bromides by diphenyl H-phosphonate-mediated deoxygenative bromination of alcohols. The Conclusions and Future Work section relating to this area of research constitutes Chapter 3. Chapter 4 outlines the experimental work for Part I. All of the literature references for Part I are collected together to form Chapter 5. There also exists a dedicated Appendix containing images of all of the NMR spectra reported in Chapter 3, as well as Excel spreadsheets dedicated to the calculation of green metrics (CHEM21 worksheet) (details on how to access this are given in Section III below). The synthesis of complex value-added chemicals frequently employs reactive species such as alkyl halides. As the focus on implementation of green chemistry principles in industrial and academic chemical applications grows, the use of such species may be minimised but never truly eliminated. Conventional means for synthesising alkyl halides are highly problematic in that they are associated with vast amounts of waste generation and resource use. In 2007, and again in 2018, the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable designated the activation of alcohols toward nucleophilic substitution as one of their ten key research areas. The focus of the project described in Part I of this thesis was on development of a methodology addressing this challenge, focusing specifically on generation of alkyl bromides from alcohols using bromide ion as the nucleophile. The methodology reported herein, while valuable in its own right, was designed to be a ‘stepping-stone’ on the way to a general methodology for the nucleophilic substitution of alcohols i.e., the scope of nucleophiles may be readily expanded beyond the bromide ion. The methodology described in Part I constitutes the open-air, relatively low-temperature, one-pot activation and substitution of alcohols using benign materials of minimal environmental impact. It results in high yields and near complete stereoinversion (where applicable with enantiopure chiral alcohols). The methodology developed was applied to 34 alcohols containing a wide range of functional groups, in addition to several biologically active and pharmaceutically relevant substrates. A thorough analysis of the green metrics associated with the methodology is also presented, demonstrating an improvement on the state-of-the-art from a green chemistry perspective. Finally, exciting new research avenues are described which have the potential to further elevate the ‘greenness’ of this approach, in addition to the development of asymmetric variants or a general nucleophilic substitution platform. Part II Part II relates to research conducted on the development of a model for the prediction of Gibbs energies of activation and the generation of Gibbs energy profiles. It is divided into five chapters (including a dedicated chapter for the literature references across the entirety of Part I). Chapter 6 involves an introduction to the novel concept behind the model presented herein, as well as a review of existing research conducted in this area. Chapter 7 provides details on the research carried out in this project on modelling of the Gibbs energy profiles of SN2 reactions of nitrite anion as a representative nucleophile. The Conclusions and Future Work section relating to this area of research constitutes Chapter 8. Chapter 9 outlines the experimental work for Part II. Chapter 10 then contains the literature references for the entirety of Part II. There also exists an Appendix containing images of all NMR spectra reported (and not shown) in Chapter 9, as well as Excel spreadsheets containing intrinsic reaction coordinate data and Gibbs energy profile models for the reactions studied (details on how to access this are given in Section III below). A desire to understand and predict the factors that control the rates of chemical reactions has been at the heart of the field of Physical Organic Chemistry since its inception. Indeed, such factors determine the real-world behaviour of chemical species and so are of great importance. Since reaction parameters such as duration, temperature, concentration as well as factors such as selectivity and impurity generation all rely on the rates of chemical reactions, the ability to predict reaction rates would be a powerful addition to the organic chemist’s toolkit. In this project, a novel means of predicting Gibbs energies of activation (and by extension reaction rates) for reactions in solution is described. The approach described here avoids many of the issues associated with even the best modern computational approaches for determination of Gibbs energies of transition states (and hence Gibbs energies of activation) and also circumvents obstacles associated with theoretical treatments such as Marcus theory to predict the Gibbs energies of activation for 18 reactions with a high degree of accuracy. This was accomplished through a combination of robust computational data (values of ΔrG°, and Intrinsic Reaction Coordinate calculations performed at a high level of theory) and experimental measurements as a point of reference. Substantial kinetic measurements were undertaken in order to establish experimental values for the Gibbs energies of activation. These were used to validate the predictions of the model developed. The use of Intrinsic Reaction Coordinates also allowed for the generation of Gibbs energy profile diagrams which are likely to closely replicate the true Gibbs energy profiles for the reactions in question marking the first time that this has been achieved. A total of 22 Gibbs energy profile diagrams were generated. Access to these has enabled the measurement of reaction coordinate lengths and an in-depth analysis of the corresponding Gibbs energy profiles, enabling the comparison of a range of Gibbs energy profiles and their features. The ability to predict Gibbs energies of activation and understand the topologies of Gibbs energy profiles could have far reaching consequences for reaction planning and design. A further outcome may be the significant reduction in resource use and waste generation through the elimination of wasteful trial-and-error base approaches that are commonplace in modern approaches for process optimisation and synthesis planning.