58 research outputs found

    AB INITIO MODELING OF THE SELECTIVITY AND REACTIVITY OF BOTH THERMAL AND LIGHT MEDIATED ORGANIC AND ORGANOMETALLIC TRANSFORMATIONS

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    The mechanism of a reaction is the collection of events that take place that lead to the products of a chemical transformation. Though there are some events in a chemical reaction that can be observed by experiment, such long-lived intermediates, many of the events are too short lived to be measured. Due to these restrictions and the advancements in the development of moderately scaling computational tools, it is becoming commonplace to use quantum mechanical software packages to model the mechanism of a reaction. Here, I used quantum mechanical calculations alongside experimental evidence provided by multiple collaborators to understand the reactivity of both heat- and light-mediated organic transformations. In chapter 2, I investigated the role of electron donor-acceptor complexes in the generation of alkyl and acyl radicals in the presence of visible light. In addition, the pathways to the experimentally observed products, alkyl and acyl thioethers, were modeled. The lowest energy pathway to product, post-radical generation, was radical addition to the radical electron donor-acceptor complex. For a photoredox-catalyzed method to cyclopropanes from a novel halomethyl radical precursor (Chapter 3), computations strongly supported a redox-neutral reductive radical/polar crossover mechanism over radical pathways, consistent with experimental trends. Investigation of the isomerization of cinnamyl chloride to cyclopropane via a commonly used photoredox catalyst (Chapter 4) revealed that the reaction was mediated via dexter energy transfer between photocatalyst and substrate over the more commonly proposed electron transfer, affording diastereoselective product formation. A dual nickel/photoredox-catalyzed coupling of sulfinate salts and aryl halides gave a mixture of aryl sulfide and aryl sulfone products (Chapter 5), suggesting that disproportionation of sulfone radical was leading to the formation of thiyl radical. Modeling the product determining steps indicated that the product distribution was controlled by radical addition of the thiyl radical to the nickel(II) species versus reductive elimination of the sulfone bound to the nickel(III) catalyst. A bicyclo[1.1.1]pentane diborylated with pinacolboryl groups, one at the arm and head position, was found to have reactivity only at the bridgehead position (Chapter 6). Calculations of a hydrozone coupling reaction performed by the Qin group found that the reactivity was due to the unique hybridization of the bridgehead position as well as increased steric interactions at the arm position. Finally, a sulfoxide synthesized from a sulfinate salt could be activated with Grignard reagent, affording coupling of the substituents originally bound to the sulfoxide. DFT calculations validated the role of the sulfurane intermediate acting as a mediator to the coupled product

    New methods for the construction of fluorinated cyclic amines and amides

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    In recent years, photoredox catalysis has emerged as a powerful tool for the synthesis of complex building blocks. Fluorine-containing saturated nitrogen heterocycles are desirable structures in medicinal and biological chemistry, as the incorporation of fluorine can be used to influence key properties of a compound such as conformation, basicity and bioavailability. This thesis explores the utilisation of a photoredox-catalysed cyclisation/hydrogen atom transfer reaction of bromodifluoroethylamines, using a modular, two-step approach. The first chapter provides an introduction to photoredox catalysis, notable developments in the area and relevant examples from the literature of photoredox-mediated radical cyclisation reactions. Following this, the importance of fluorination in drug discovery is discussed, along with traditional methods for the introduction of the geminal difluoro- group. The second chapter describes a photoredox radical cyclisation protocol using bromodifluoroethylamines, which are prepared through a three-component coupling. The reaction is applicable to a wide range of alkenyl- and alkynyl amines, and the utility of the products are demonstrated. Mechanistic investigations established the role of the tertiary amine base and the additional hydrogen-atom donor in the reactions. The success of the described approach relies on the strongly electron-withdrawing nature of fluorine, which prevents oxidation of the amine substrates and products under the reaction conditions. This eliminates the need for electron-withdrawing protecting groups on nitrogen and promotes cyclisation. The third chapter builds on the developed photoredox catalysed cyclisation for the mild and efficient synthesis of γ- and δ-lactams. The protocol is applicable to a range of amide substrates, and a mechanism for the reaction is proposed, supported by computational calculations

    Natural Gas

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    Natural gas as a non-renewable hydrocarbon is used as an energy source for cooking, heating, vehicle fuel, and electricity generation. It is also used as a chemical feedstock in the manufacturing of plastics and organic chemicals. This book brings together new perspectives and future developments in natural gas. Chapters address such topics as adsorbed natural gas, fermentation processes for producing value-added products from natural gas, processes for separating C3+ hydrocarbon from natural gas, natural gas dehydration, and much more

    Mechanistic insights and in silico studies on selected G protein-coupled receptors implicated in HIV and neurological disorders.

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    Doctoral Degree. University of KwaZulu-Natal, Durban.G protein-coupled receptors (GPCRs) are the largest membrane protein receptor superfamily involved in a wide range of physiological processes. GPCRs form the major class of drug targets for a diverse array of pathophysiological conditions. Consequently, GPCRs are recognised as drug targets for the treatment of various diseases, including neurological disorders, cardiovascular conditions, oncology, diabetes, and HIV. The recent advancement in GPCR structure resolutions has provided novel avenues to understand their molecular basis of signal transduction, ligand recognition and ligand-receptor interactions. These advances provide a framework for the structure-based discovery of new drugs in targeting GPCRs implicated in the pathogenesis of various human diseases. In this thesis, the interactions of inhibitors at two dopamine receptor subtypes and C-C chemokine receptor 5 (CCR5) of the Class A GPCR family were investigated. Dopamine receptors and CCR5 are validated GPCR targets implicated in neurological disorders and HIV disease, respectively. The lack of structural information on these receptors limited our comprehension of their antagonists’ structural dynamics and binding mechanisms. The recently solved crystal structures for these receptors have necessitated further investigations in their ligand-receptor interactions to obtain novel insights that may assist drug discovery towards these receptors. This thesis comprehensively investigated the binding profiles of atypical antipsychotics (class I and class II) at the first crystal structure of the D2 dopamine receptor (D2DR). The class I antipsychotics exhibited binding poses and dynamics different from the class II antipsychotics with disparate interaction mechanistic at D2DR active site. The class II antipsychotics were remarkably observed to establish a recurrent and vital interaction with Asp114 via strong hydrogen bond interactions. Furthermore, compared to class I antipsychotics, the class II antipsychotics were found to engage favourably with the deep hydrophobic pocket of D2DR. In addition, the structural basis and atomistic binding mechanistic of the preferential selective inhibition at D3DR over D2DR were explored. This study investigated two small molecules (R-VK4-40 and Y-QA31) with substantial selectivity (> 180-fold) for D3DR over D2DR. The selective antagonists adopted shallow binding modes at D3DR while demonstrating a deep hydrophobic pocket binding at D2DR. Also, the vital roles and contribution of critical residues to the selective binding of R-VK4-40 and Y-QA31were identified in D3DR. Structural and binding free energy analyses further discovered distinct stabilising effects of the selective antagonists on the secondary architecture and binding profiles of D3DR relative to D2DR. Furthermore, the atomistic molecular interaction mechanism of how slight structural modification between novel derivatives of 1-heteroaryl-1,3-propanediamine (Compd-21 and - 34) and Maraviroc significantly affects their binding profiles toward CCR5 were elucidated. This study utilised explicit lipid bilayer molecular dynamics (MD) simulations and advanced analyses to explore these inhibitory disparities. The thiophene moiety substitution common to Compd-21 and -34 was found to enhance their CCR5-inhibitory activities due to complementary high-affinity interactions with residues critical for the gp120 V3 loop binding. The study further highlights the structural modifications that may improve inhibitor competitiveness with the gp120 V3 loop. Finally, structure-based virtual screening of antiviral chemical database was performed to identify potential compounds as HIV-1 entry inhibitors targeting CCR5. The identified compounds made pertinent interactions with CCR5 residues critical for the HIV-1 gp120-V3 loop binding. Their predicted in silico physicochemical and pharmacokinetic descriptors were within the acceptable range for drug-likeness. Further structural optimisations and biochemical testing of the proposed compounds may assist in the discovery of novel HIV-1 therapy. The studies presented in this thesis provide novel mechanistic and in silico perspective on the ligand-receptor interactions of GPCRs. The findings highlighted in this thesis may assist in further research towards the identification of novel drug molecules towards CCR5 and D2-like dopamine receptor subtypes.List of thesis publications on page vi-vii. Research Output on page viii-ix

    Synthesis of Highly Branched Polystyrene Model Systems with Superior Strain Hardening and their Influence on Foaming Properties

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    Die molekulare Struktur bestimmt maßgeblich die Verarbeitbarkeit eines Polymers in der Schmelze und die daraus resultierenden makroskopischen Eigenschaften des Endprodukts, die wiederum über seine Anwendung entscheiden. Viele dieser Anwendungen beruhen auf dünnen Film- und Faserstrukturen, von denen polymere Schäume mit ihrer porösen Zellmorphologie ein wichtiger Vertreter sind. Die Schmelzefestigkeit ist entscheidend für die Expandierbarkeit eines Schaums, da sie die Zellwände und Verstrebungen auf mikro- und nanoskaliger Ebene stabilisiert. Verzweigungen, insbesondere Langkettenverzweigungen sind eine Schlüsseleigenschaft eines Polymers um eine gute Schmelzefestigkeit in Dehnströmung zu erreichen. Es ist von großem Interesse, den Einfluss der Topologie eines Polymers auf das rheologische Verhalten zu verstehen und die Struktur-Eigenschafts-Beziehung vorherzusagen und letztendlich effizient zu nutzen. Die hier vorgestellte Arbeit untersucht den Einfluss von mehrfach verzweigten Polymerarchitekturen auf die Schäumbarkeit, speziell auf die Volumenexpansion und korreliert die erzielten Schaumeigenschaften mit der Molekularstruktur mittels dem Fließverhalten aus der Scher- und Dehnrheologie. Um einen systematischen Ansatz zu ermöglichen, werden definierte Modellpolystyrole (PS) mit Kamm- und Dendrigraft-Topologie und einer variierenden Anzahl von Verzweigungen mittels anionischer Synthese hergestellt. Die Schmelzeeigenschaften werden in oszillatorischer Scherung und uniaxialer Dehnung rheologisch charakterisiert. Das Batch-Schäumen wird bei 180180 und 500bar500\,\text{bar} unter Verwendung von Kohlendioxid (CO2_2) als physikalisches Treibmittel durchgeführt. Die resultierenden Schäume werden hinsichtlich ihrer Volumenausdehnung, Zellgröße und Zelldichte analysiert. Es wird eine Reihe von Kamm-PS mit gut verzweigten, aber unterschiedlicher Anzahl von Langkettenverzweigungen synthetisiert, die von spärlich verzweigt bis hin zu flaschenbürstenartiger Strukturen reichen. Die Korrelation der rheologischen und der Schaumeigenschaften zeigt einen Bereich optimaler Verzweigungszahl, die in einen maximalen Volumenexpansionskoeffizient von 40 bei gleichzeitig maximalem Dehnverfestigungsfaktor (\textit{strain hardening factor}) von SHF=200\text{SHF}=200 resultiert, wobei die Nullscherviskosität auch am niedrigsten ist. Dendrigraft-PS werden aus einem langkettenverzweigten Kamm-PS synthetisiert, auf den eine Korona aus Kurzkettenverzweigungen aufgepfropft wird. Die sogenannte ``branch-on-Branch\u27\u27 (bob)-Architektur weist molekulare Parameter auf, die eindeutig drei verschiedene Relaxationsmodi zeigen, die jeder Verzweigungsgeneration zugeordnet werden können und auf die hierarchische Kettendynamik hinweisen. In uniaxialer Dehnung wird ein enormer Dehnungsverfestigungfaktor bis zu SHF=700\text{SHF}=700 erreicht. Dabei zeigt sich die Dehnrate als ein wichtiges Kriterium dafür, ob eine hohe Dehnverfestigung zu einer verbesserten Schäumbarkeit führt. Dies wird durch das Schäumen eines kurzkettenverzweigten Kamm-PS validiert, der sich durch eine Dehnverfestigung von SHF=200\text{SHF}=200 bei schnellen Dehnungsraten von ε˙H=310s1\dot\varepsilon_\text{H}=3\text{--}10\,\text{s}^{-1} auszeichnet und im Vergleich zu Dendrigraft- und langkettenverzweigten Kamm-PS konstant höhere Volumenexpansionen liefert, insbesondere bei hohen Schäumungstemperaturen und schnellen Druckentlastungsraten. Weiterhin werden bimodale Kamm-Lineare PS-Blends hergestellt, um das Zusammenspiel zwischen verzweigter und linearer Kettentopologie zu untersuchen. Die Schmelzrheologie gibt einen Einblick in Relaxationsdynamiken und deren Skalengesetze und zeigt das Potenzial von verzweigt-linearen Blends zur Einstellung und Optimierung der Schmelzeeigenschaften für Verarbeitungsprozesse in Dehnung oder Scherung

    Recent advances in gold(III) chemistry: Structure, bonding, reactivity and role in homogeneous catalysis

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    Over the past decade the organometallic chemistry of gold(III) has seen remarkable advances. This includes the synthesis of the first examples of several compound classes that have long been hypothesized as being part of catalytic cycles, such as gold(III) alkene, alkyne, CO and hydride complexes, and important catalysis-relevant reaction steps have at last been demonstrated for gold, like migratory insertion and β-H elimination reactions. Also, reaction pathways that were already known, for example the generation of gold(III) intermediates by oxidative addition and their reductive elimination, are much better understood. A deeper understanding of fundamental organometallic reactivity of gold(III) has revealed unexpected mechanistic avenues, which can open when the barriers for reactions that for other metals would be regarded as "standard"are too high. This review summarizes and evaluates these developments, together with applications of gold(III) in synthesis and catalysis, with emphasis on the mechanistic insight gained in these investigations.
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