This thesis describes the development of a new microwave-mediated methodology for C–S bond formation and the issues regarding scaling up heterocyclic transformations. Chapter 1 provides an overview on the current understanding of microwave-mediated synthesis and on the use of microwave technology in copper- and palladium-mediated synthesis. A separate part is dedicated to the current advancements in the use of flow reactors within the chemical community. Chapter 2 describes the application of the current batch and continuous flow technology for the scale-up of selected heterocyclic transformations, starting with the well known Bohlmann- Rahtz pyridine synthesis and moving to other reactions, including pyrimidine and Hantzsch dihydropyridine synthesis. Chapter 3 describes the development of a new methodology for the microwave-mediated C–S bond formation, starting from an investigation on the current available methods and moving to the application of new methodology to the synthesis of a library of compounds. Further application was found in the synthesis of a drug candidate with anti-ageing properties and in the synthesis of a new class of anti-HIV compounds.

Marine sedimentation from the Adélie Land continental margin of East Antarctica provides unique high resolution records of Holocene environmental change. The subannually resolved sediment cores MD03-2601 (66°03.07’S, 138°33.43’E) and IODP-318-U1357B (66°24.7990′S, 140°25.5705′E) from the Dumont d’Urville Trough,Adélie Land, document atmospheric and oceanic processes impacting on biogenic sedimentation on the Adélie Land continental shelf during the Holocene. Resin embedded, continuous polished thin sections from each core were analysed for diatom content and sediment microfabric using scanning electron microscope backscattered electron imagery. The sediments contained repeating sequences of seasonal diatom-rich laminae which enabled multi-taper method time series analysis. Time series analysis shows that in the Hypsithermal there appears to have been an external (solar) control on interannual sedimentation as well as internal controls (e.g. the southern annular mode, SAM, and El Nino-southern Oscillation, ENSO); whilst in the Neoglacial internal climatic modes exerted a much stronger control. Quasi-biennial (2 – 3 year) peaks commonly occurred in analysis of both Hypsitherml and Neoglacial sequences. The distribution of resting spore-rich laminae in these sections suggests that a multidecadal (>50-years) variation between phasing of the SAM and ENSO systems may exert an important control on interannual environmental variability in the sections analysed. The distribution of diatom-derived biomarker proxies, namely C25 highly branched isoprenoid (HBI) alkenes, was compared to the diatom lamina-based record in core MD03-2601. At the Holocene scale, HBI diene and triene molecules have a positive association to sea ice associated diatom-rich laminae, with greater abundances of both HBI molecules and sea ice associated diatom laminae in the Neoglacial interval. However, at a sub-annual resolution there is no strong association between lamina type and HBI concentrations. This is attributed to a combination of: (i) the HBI alkenes recording a different signal to that of the diatom-rich laminae; (ii) interannual variation in HBI export that is greater than inter-seasonal variation, for which there is little modern data for comparison; (iii) possible diagenetic alteration of the HBI signal.

This thesis consists of the exploration of a novel oxygenation procedure and its applicability in the preparation of synthetically useful compounds.

The ‘Silicic Acid Leakage Hypothesis’ (SALH) is a mechanism by which the increased supply of silicic acid to the low latitude ocean allows diatoms (silica producers) to outcompete coccolithophorids (carbonate producers). This would result in a decrease in the export of carbonate, and drawdown of atmospheric CO2 through changes in surface- and whole-ocean alkalinity. Here I test the SALH as a potential cause of CO2 drawdown during glacial Marine Isotope Stage (MIS) 4 (~70-59 ka). Firstly, I measure opal (biogenic silica) accumulation rates in a suite of cores from the equatorial Atlantic, to determine whether the export productivity of diatoms increased during MIS 4. I found that opal accumulation rates increased ~100% in MIS 4 relative to interglacial MIS 5a (~84-77 ka), in agreement with the SALH; however the timing of the changes make the SALH unlikely to be the direct cause of the CO2 drawdown. I then measured the calcium carbonate accumulation rates in the same suite of cores and found that carbonate accumulation decreased in MIS 4 relative to MIS 5a, also in agreement with the SALH. However, I found that this decrease may have been the result of enhanced carbonate dissolution. I also tested the SALH directly by reconstructing changes in the silicic acid concentration of AAIW, by using neodymium and silicon isotopic ratio measurements. I found that AAIW conveyed an increased amount of silicic acid into the western tropical Atlantic during MIS 4, and that the timing of this increase was coeval with increases in both low latitude opal accumulation, and also opal accumulation in the northwest Atlantic. Lastly, I tested the amount of atmospheric CO2 drawdown which could have been attributed to the SALH mechanism during MIS 4 by using a box model, and I estimated that ~35-50 ppmv of CO2 drawdown is achievable.

The first chapter focuses on the introduction of iodine mediated carbocyclisations and their applications continue to present a stimulating challenge in target- and diversity-oriented synthesis. The second chapter discusses applications and brief literature overview about classical approaches towards the syntheses of indene derivatives. Herein the syntheses of 3-iodo-1 H-indene derivatives via iodonium-promoted 5-endo-dig carbocyclisation of 2-substituted ethynylmalonates as a key starting material are described. Within this study, we were able to show that the 3-iodo-1 H-indene can be used as a synthetic platform not only for the palladium chemistry but also as a catalyst for the in situ generation of [text unavailable] hypervalent iodine reagent. Additionally, 3-iodo-1 H-indene derivatives have the potential to perform asymmetric synthesis. Third chapter demonstrates tandem iodine mediated carboannulation of the stilbene malonate derivatives via either 5-exo- or 6-endo-trig mode under basic reagents with subsequent lactonisation to structurally complex indanes and tetrahydronaphthalenes with three new stereogenic centres. In the present study, a unique stereochemistry was observed in the case of tetrahydroindenofuranones and confirmed by single crystal X-ray analysis. These cyclisations proceed exclusively with the retention of configuration to form tetrahydroindenofuranones. Both the compounds formed as a single diastereomers as judged from their 1H and 13C NMR spectrum. In fourth chapter the synthesis of novel simplified analogues of IBA by oxidation of [text unavailable] diiodoacrylic acids are described. Additionally, the ligand exchange resulted in tosylate derivative. The new reagents have been utilized in various well established oxidative transformations with superior or similar reactivity as conventional hypervalent iodine(III) reagents.

Ab initio, density functional (DFT), semi-empirical and force field methods are used to predict non-covalent interactions between peptides and major histocompatibility complex (MHC) class II receptors. Two ab initio methods are shown to be in good agreement for pairwise interaction of amino-acids for myelin basic protein (MBP)- MHC II complex. These data are then used to benchmark more approximate DFT and semi-empirical approaches, which are shown to be significantly in error. However, in some cases significant improvement is apparent on inclusion of an empirical dispersion correction. Most promising among these cases is RM1 with the dispersion correction. This approach is used to predict binding for progressively larger model systems, up to binding of the peptide with the entire MHC receptor, and is then applied to snapshots taken from molecular dynamics simulation. These methods were then compared to literature values of IC50 as a benchmark for three datasets, two sets of IC50 data for closely structurally related peptides based on hen egg lysozyme (HEL) and myelin basic protein (MBP) and more diverse set of 22 peptides bound to HLA-DR1. The set of 22 peptides bound to HLA-DR1 provides a tougher test of such methods, especially since no crystal structure is available for these peptide-MHC complexes. We therefore use sequence based methods such as SYFPEITHI and SVMHC to generate possible binding poses, using a consensus approach to determine the most likely anchor residues, which are then mapped onto the crystal structure of an unrelated peptide bound to the same receptor. This shows that methods based on molecular mechanics and semi-empirical quantum mechanics can predict binding with reasonable accuracy, as long as a suitable method for estimation of solvation effects is included. The analysis also shows that the MM/GBVI method performs particularly well, as does the AMBER94 forcefield with Born solvation. Indeed, MM/GBVI can be used as an alternative to sequence based methods in generating binding poses, leading to still better accuracy. Finally, we investigated the influence of motion in implicit and explicit solvents for a set of 22 peptides. Binding free energies were calculated by Molecular Mechanics Generalized -Born Surface Area (MM/GBSA) method, but it was found that the results are worse than MM/GBVI on MOE, which show that the MM/GBVI approach can deliver reasonable predictions of peptide-MHC binding in a matter of a few seconds on a desktop computer.

CuAu/SiO2 catalysts were prepared in a number of ways, the main route being incipient wetness impregnation, but other methods, like deposition precipitation and high dispersion, were also used. Bimetallic and monometallic catalysts were prepared for this investigation and most were characterised by various techniques such as XRD, SEM, TPR, BET, UV visible and TEM. Theoretical and characterisation studies of CuAu catalysts have generated considerable interest. However, little research has been carried out on their catalytic activity. Therefore, propene oxidation was chosen as the principal reaction, as it was previously examined by Chimentao and group.1 This study showed that the reduction of the catalysts in H2/Ar was fundamental to alloy formation. The most active catalyst was made by a sequential procedure that deposited the copper onto the silica support by high dispersion, followed by depositing gold onto the support by deposition precipitation. The catalyst was then treated by a Sinfelt thermal treatment which involved a reduction in H2/Ar at 315oC for 2h followed by a high temperature calcination at 676oC in air for 15h. Propene oxidation was performed in the presence of hydrogen and a propene conversion of 10% was observed at 320oC, with a selectivity towards acrolein (90%) and some carbon dioxide (10%). The purpose of this study was to obtain an understanding of the nature of these CuAu/SiO2 catalysts and to determine if there were any relationship towards their activity for propene oxidation.

Surfactant templating provides a facile route to mesoporous materials with tuneable architectures, whilst simultaneously allowing control over complementary macro and micro porosity. The impact of these varying physical properties, on both catalyst synthesis and during catalytic reactions, was one principal area of investigation. Catalyst series were prepared on mesoporous SBA-15, SBA-16 and KIT-6, meso-macroporous SBA-15, true liquid crystal templated SBA-15 and a commercial low surface area silica support. Additionally two mesoporous alumina series, with mesoporosity akin to SBA-15, were produced. The catalytic activity of the materials was screened for the selective oxidation of allylic alcohols, which represents a class of industrially relevant chemical upgrading reactions. Nanoparticulate palladium is widely recognised as an able catalytic species, although the active site nature is still debated with both metallic and oxidic surfaces proposed. Further insight into the active species was another major area of investigation. Extensive characterisation confirmed successful support synthesis and mesopore stability after palladium impregnation. Irrespective of support, decreasing metal loading elevates dispersion (particles sizes are typically less than 2nm), which correlates with the increase of surface PdO content. In relation to the silica supports these trends escalate via support transition in the order of: Pd/low surface area commercial silica < Pd/true liquid crystal templated SBA-15 < Pd/SBA-15 < Pd/mesomacroporous SBA-15 < Pd/KIT-6 ≈ Pd/SBA-16. Initially increasing support surface area is critical and later rising mesopore accessibility dictates. Catalytic activity, for cinnamyl and crotyl alcohol selective oxidation, reveals significant rateenhancements with PdO content, with turnover frequencies providing compelling proof of a PdO active species. Alumina supports, even with lower surface areas than equivalent silicas, allow further gains in metal dispersion, surface oxidation state and resulting catalytic activity. In conclusion, tuning the physical and chemical properties of the support is paramount if highly active catalysts are to be produced.

Chapter one provides an overview of nonstatistical dynamics and the methodology presented in this work to search for such effects. Chapters two and three discuss a singlet biradical which was specifically designed to search for nonstatistical effects in the ring opening of a cyclopropylmethyl radical. These effects could be seen experimentally by observing the reactivity of the biradical as a function of the pressure of the supercritical fluid solvent. While several syntheses were designed to synthesise the biradical precursor, they were ultimately unsuccessful. Computational study of the biradical system highlights the convenience and accuracy of density functional theory in studying singlet biradicals. Molecular dynamics carried out on the biradical system is then discussed. The molecular dynamics confirms that this biradical should be a useful systems to search for nonstatistical dynamics. Chapters four and five discuss cyclopentadiene. When cyclopentadiene is formed from bicyclo[2.1.0]pent-2-ene, it can undergo a [1.5] hydrogen shift. We proposed that this hydrogen shift shows evidence for nonstatistical dynamics. Molecular dynamics calculations at the density functional theory level showed that hydrogen shift breaks the expected symmetry of the system. This symmetry breaking is caused by normal mode coupling which is a hallmark of nonstatistical dynamics. We have proposed a mechanism for the transformation of bicyclo[2.1.0]pent-2-ene into cyclopentadiene that explains the oscillatory behaviour of the hydrogen shift which is able to break the symmetry. We have also proposed isotope-labelling experiments that can be used to confirm the existence of nonstatistical behaviour for the cyclopentadiene system.

No description available.