Doctoral Degrees (Chemistry and Polymer Science)
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- ItemFundamental Palladium Catalyzed Oxidative Addition Reactions(Stellenbosch : Stellenbosch University, 2023-11-28) Moloto, Bryan Phuti; Esterhuysen, Catharine; Bickelhaupt, F Matthias; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: This thesis focuses on investigating fundamental oxidative addition (OA) reactions catalysed by palladium (see Chapter 1). OA, being the first and rate determining step in cross-coupling reactions, is a reaction of vital importance in synthetic chemistry. Palladium-catalysed crosscoupling reactions are widely used in industrial applications, such as in catalytic converters and the synthesis of pharmaceuticals. Besides these applications, palladium is widely used as a versatile catalytic reagent in many different chemical processes. Considering the importance of oxidative addition reactions catalysed by palladium, a deep understanding of the underlying mechanism is crucial to designing new catalysts and improving the existing ones. In a nutshell, the main focus is on understanding the mechanism behind the oxidative addition step and the trends in activation barriers upon variation of either the catalyst or substrate structure. The following summary will discuss only the most important findings from the chapters involved. As explained in Chapter 2, the findings in this thesis were successfully obtained using the Activation Strain Model of chemical reactivity (ASM, discussed in section 2.3) in combination with computations based on Density Functional Theory (DFT) as implemented in the ADF program. The ASM model is a fragment-based approach that characterizes reactions in terms of the rigidity and the bonding capabilities of the original reactants , and the extent to which the reactants must deform along the reaction pathway of a particular reaction mechanism. Thus, the total energy profile of a particular chemical reaction can be decomposed into contributions from the deformation of the reactants (the strain energy) and their mutual interaction (the interaction energy). The interaction energy can then be further decomposed using the canonical energy decomposition analysis (EDA) of ADF into electrostatic interactions, destabilizing Pauli repulsion, and stabilizing orbital interactions. In Chapter 3, with the aim of understanding the underlying mechanism and trends found by the oxidative addition, we detailed our quantum chemical exploration of the palladiummediated activation of C(spn )–X bonds (n = 1–3; X = F, Cl, Br, I) in the archetypal model substrates H3C–CH2–X, H2C=CH–X, and HC≡C–X by a model bare palladium catalyst. First and foremost, we investigated the bond dissociation enthalpies (BDEs) of the bonds to be activated. So, we started from the C(sp3 )–X moving to C(sp2 )–X and then to C(sp)–X bonds for each of the selected set of X atoms above. We found that as we move down group 17, the C(spn )–X bond becomes weaker and as such easier to break. Based on our state-of-the-art analyses, we discovered that as we vary the substituent X, going down Group 17 from X = F to Cl to Br to I on the C(spn )–X substrate, the oxidative addition barriers drastically decrease. This favorable activation barrier stabilization originates from two factors: (i) a less destabilizing activation strain; and remarkably (ii) a more favorable electrostatic attraction between the catalyst and the substrate. When changing the substrate from C(spn )–F to C(spn )– I, consequently, the electrostatic interaction between the catalyst and substrate also becomes more favorable. Iodine, being the largest halogen of the selected substituents, has a more diffuse and electron-rich density and a higher nuclear charge that in turn engage in favorable electrostatic attractions with the palladium nucleus and electron density, respectively. This effect makes the oxidative addition reaction involving the C(spn )–X bond with a larger halogen atom correspond to a more stabilizing interaction and hence lower reaction barrier. Next, in Chapter 4 we have quantum chemically investigated the palladium-mediated activation of HnA–AHn bonds (AHn = CH3, NH2, OH, F) by catalysts PdLn with Ln = no ligand, PH3, (PH3)2. Herein, we found that as we move from C to F along the period, i.e., from H3C– CH3 to H2N–NH2 to HO–OH to F–F, the activation barriers decrease and more interestingly the activation of the F–F bond is even barrierless. As we move from C to F on the selected substrates, the number of the substituents around the A–A bond become less and as such enabling the catalyst to approach the substrate with ease, thereby resulting in a decreasing activation barriers. The causal effects of this barrier stabilizations stem from: (i) a reduced activation strain due to a weaker HnA–AHn bond; (ii) a decreased Pauli repulsion as a result of a difference in steric shielding of the HnA–AHn bond; and (iii) an enhanced backbonding interaction between the occupied 4d atomic orbitals of the palladium catalyst and * acceptor orbital of the substrate. The findings in this thesis have the potential to equip experimentalists with detailed mechanistic insight that can facilitate a deep understanding into the trends in reactivity of palladium-mediated oxidative addition reactions.
- ItemDeveloping marker technologies to probe complex polymers and products(Stellenbosch : Stellenbosch University, 2022-11) Liprini, Marehette Suzanne; Van Reenen, Albert; Lutz, Marietjie; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: Fluorescent imaging has proven to be a valuable tool across a wide variety of applications. It can help with detecting, locating and observing the interactions between different molecules. This study used fluorescence to evaluate interactions, provide detection and trace different components within complex polymer systems. Cellulose nanowhiskers (CNW) were isolated and characterized, then labelled using fluorescent labelling with fluorescein 5(6)-isothiocyante (FITC) and rhodamine B (RhB). The attachment of the fluorescent dyes was easily observed with fluorescence microscopy. Fluorescently labelled cellulose nanowhiskers (CNW) were incorporated into different crystalline fractions of two different types of polypropylene impact copolymers (CMR 648 and CMR 348). This part of the study focused on the visually assessing the interactions between the different crystalline fractions within polypropylene impact copolymers. The different fractions of the copolymers were first evaluated in the form of solvent-cast films. The solvent-cast films showed strong associations between the 30 oC fraction and the 60 oC fraction, as well as between the 60 oC fraction and the 80 oC fraction. The fluorescent images showed no strong association between the 30 oC fraction and the 80 oC fraction in the absence of the 60 oC fraction. The fraction interactions were also evaluated after mechanical agitation in the melt, followed by injection moulding. The injection-moulded samples showed the same interactions visually as observed with the solvent-cast films. The visual assessment after extracting the labelled 30 oC fraction and 60 oC fraction also showed that the labelled CNW did not migrate out of the fractions into which they were incorporated. The next section of this study focused on the detection of fluorescently labelled markers within paint samples. CNW labelled with fluorescent dyes were incorporated into two types of paint. The paint films were evaluated with confocal fluorescence microscopy and the different paint samples could be identified. The fluorescent markers could still be detected within the paint films even after accelerated weather testing by implementing confocal fluorescence microscopy (CFM), lambda scanning, and unmixing. The last part of the study focused on the release of ethyl formate from different polymer films of polylactic acid (PLA) and polyethylene glycol (PEG). The intrinsic fluorescence associated with the ethyl formate precursor, PLA and PEG was used to track the release of the ethyl formate after exposure to humidity and humidity with citric acid. The release could easily be tracked visually with CFM.
- ItemBonding interactions in congested molecules: a study of the interatomic forces and the molecular electrostatic potential(Stellenbosch : Stellenbosch University, 2022-09) von Berg, Stuart Raymond Colenzo; Dillen, Jan; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: The purpose of this research is to apply the quantum theory of atoms in molecules (QTAIM) to the molecular electrostatic potential (MEP) field and use the topology of the MEP to determine whether a stabilising interaction occurs between two hydrogens in a congested molecule. A method for comparing bond strength using the ratio of the nuclear and electronic components of the MEP is developed and applied to the congested molecules. The MEP ratio was used to associate the bond strength of the hydrogen-hydrogen interaction in congested molecules to that of a hydrogen bond between water molecules. Despite this result, analysis of the electron density, laplacian and kinetic energy created an equally compelling argument against the interaction being stabilising.
- ItemComputational and experimental investigation of factors affecting the quality of multi-component crystals(Stellenbosch : Stellenbosch University, 2022-03) Akerele, Oluwatoyin Omolara; Esterhuysen, Catharine; Haynes, Delia; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: A series of six substituted benzoic acid and fifteen substituted pyridine compounds have been crystallised together to form multi-component co-crystals or salts. The crystal structures obtained from single-crystal X-ray diffraction show that the hydrogen bond between the carboxylic acid group and pyridine nitrogen is strong, resulting in a robust synthon that is present in all the co-crystals and salts formed. The nature of the synthon, including hydrogen bond strengths and geometries and the co-planar of the acid and base in the multi-component crystals was investigated using both experimental and computational approaches. The hydrogen-bond energy between the acid and base is related to the Npyr-Ocarb distance as we found low distances correspond to strong interactions and vice versa in both co-crystals and salts. It was found that in the presence of NH2 substituents ortho to the pyridine an 𝑅22(8) hydrogen-bonded ring forms that leads to co-planarity of the two molecules. This is likely to promote the formation of a slip plane, which in turn may improve the tabletability of such salts or co-crystals. These results were confirmed by a Cambridge Structural Database search that showed that the properties identified are also generally relevant for the 879 related multi-component crystal structures previously reported. These crystal structures were then used as a basis for the identification of intrinsic factors that affect the crystal quality. The hydrogen-bond energies between the acid-base unit in salts is stronger than those in co-crystals, suggesting that salts are more stable than co-crystals. Similar observations were obtained for the lattice energies, the free energies of interactions, polarisation energies, and the strengths of hydrogen bond donor and acceptor. This means the presence of ionic components makes these interactions stronger and thereby stabilises the multi-component crystal. However, in salts this does not automatically translate into a good-quality crystal as we observed good- and poor-quality crystals for both salts and co-crystals. This means ionicity does not determine the formation of quality crystals. Further investigation revealed that the factors influencing crystal quality depend on the chemical species involved; there is no common factor that cut across all the compounds. The interactions associated with the packing of the crystal structures, and not necessarily the hydrogen bond between the acid-base pair were most commonly found to be responsible for the formation of good-quality salt crystals. The quality of co-crystals is influenced by both the strength of the hydrogen bond within the acid-base unit and the interactions with molecules surrounding the unit. The absence of a substituent at the para position in the acid component was found to hinder the formation of good-quality co-crystals. Comparison of two similar compounds that produce crystals of different quality reveals that the strong lattice energy, electrostatic energy, a small difference in the strength of hydrogen bond donor and hydrogen bond acceptor of acid and base, the presence of strong interactions around the benzoic-acid…pyridine synthons, are the factors that influence the formation of good-quality crystals. These interactions that play a role are typically strong hydrogen bonds, π- π stacking, and C-H…O bonds; the greater the number of interactions with high energy in a complex, the better the quality of crystals that will be formed. Finally, the organic bases used in this study were found to impact crystal formation, for instance, 2-amino-4-methyl pyridine and 2-amino-5-nitropyridine are good co-formers that generally facilitate strong interactions and give rise to good-quality crystals, while co-formers such as 4-cyanopyridine and 2-amino-6-methylpyridine typically form weak interactions, resulting in poor-quality crystals.
- ItemPolymer-coated magnetic nanoparticles and polymer nanoparticles for the treatment of Mycobacterium tuberculosis (Mtb)(Stellenbosch : Stellenbosch University, 2022-04) Smit, Marica; Lutz, Marietjie; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.ENGLISH ABSTRACT: Tuberculosis (TB) can be classified as a neglected disease where an estimated one fourth of the world’s population could be infected with Mycobacterium tuberculosis (Mtb) in the form of latent TB. Combinations of three or more anti-tuberculosis (anti-TB) drugs are required during a long treatment period (between 6 months and 2 years) to effectively eliminate Mtb. The long treatment duration with concentrated anti-TB drugs has lead to side-effects, low patient adherence and resulting possible drug resistance. Orally administered anti-TB drugs have difficulty effectively reaching the lung and alveolar macrophages. Concentrated anti-TB drugs are thus orally administered daily in tablet form but anti-TB drug loaded polymer nanoparticles could possibly prevent rapid drug degradation via sustained release. There is thus a need to decrease the necessary concentration of the administered anti-TB drugs, which could be achieved via pulmonary inhalation which directly treats TB in the lungs. Polymer coated superparamagnetic iron oxide nanoparticles (SPMNs) could possibly enable targeted drug delivery via injection. The nanoparticles can be controlled with an external magnetic field to Mtb infected areas, followed by drug release from the anti-TB drug loaded polymer coating. In this thesis, biocompatible polymers namely chitosan, carrageenan, alginate, dextran sulfate and poly(lactide-co-glycolide) (PLGA) were utilized for anti-TB drug loading. Quaternary ammonium chitosan (CS-qC12) and quaternary ammonium poly(styrene-alt- maleic anhydride) (SMI-qC12) were also synthesized due to the known improvement in antimicrobial activity and mucoadhesion, due to the quaternary ammonium functional groups, compared to pristine chitosan and poly(styrene-alt-maleic anhydride). Several commonly administered anti-TB drugs such as isoniazid (INH), rifampicin (RIF), ethambutol (EMB), streptomycin (STM), ethionamide (ETA) and ofloxacin (OFX) were utilized for anti-TB drug loading. Chitosan (CS) based anti-TB drug loaded nanoparticles were synthesized via ionic gelation where polymer and anti-TB drug is dissolved, followed by the addition of crosslinking agent or polymer to prepare the nanoparticles (distributing anti-TB drug throughout the polymer matrix). PLGA nanoparticles were prepared via an “oil-in-water” emulsion followed by solvent evaporation. Sustained drug release (aqueous acetic acid solution, pH 5, UV-Vis spectrophotometry) over 7 days was seen for all the drug loaded nanoparticles, except with ofloxacin loading. The SPMNs were produced via co-precipitating with Fe2+ and Fe3+ in one step (CS SPMNs and CS-qC12 SPMNs) or two steps (chitosan-alginate-carrageenan (CS-Al-Car) SPMNs and chitosan-dextran sulfate (CS-DS) SPMNs). PLGA SPMNs and SMI-qC12 SPMNs were synthesized by activating the pristine iron oxide nanoparticles with oleic acid and (3-aminopropyl)triethoxysilane (3-APTES), respectively, before polymer coating. The polymer coated SPMNs were ex situ drug loaded by dispersing the SPMNs in anti-TB drug solution. Sustained drug release over 8 days was observed for the INH, ETA and RIF loaded polymer coated SPMNs. The resazurin microtiter assay (REMA) against TB mimic Mycobacterium Smegmatis (M. Smeg) was utilized to quantify the antimicrobial activity, via minimum inhibition concentration (MIC) determinations. The CS-DS nanoparticles were determined to be the optimal drug carrier with lower MIC values (CS-DS-OFX = 0.2441 μg/mL) compared to the free drugs (OFX = 0.5859 μg/mL).