Doctoral Degrees (Chemistry and Polymer Science)

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A 195Pt Nuclear magnetic resonance and molecular dynamics computer simulation study of the solvation of simple platinum (IV) chlorido complex anions in water and water-miscible solvent mixtures
(2017-03) Engelbrecht, Leon de Villiers; Koch, Klaus R.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: A combined 195Pt NMR spectroscopy and Molecular Dynamics (MD) computer simulation study of the solvation of the octahedral Pt(IV) complex [PtCl6]2‒ in binary mixtures of water and the fully water-miscible organic solvents methanol, 2-methoxyethanol and 1,2-dimethoxyethane has been carried out. A recent 195Pt NMR chemical shift-trends study indicated a preferential solvation of the aforementioned platinum complex by the organic solvent component in such solvent mixtures. The solvent dependence of the intrinsic 1Δ195Pt(37/35Cl) NMR isotope shifts of [PtCl6]2‒ in pure solvents indicate a slight increase in magnitude ~7 ppb in the order water < methanol < 2-methoxyethanol < 1,2-dimethoxyethane. In selected equimolar binary mixtures of water and organic solvents, 1Δ195Pt(37/35Cl) is found to be similar in magnitude to that in the pure organic solvents, supporting the proposed preferential solvation of the platinum complex. 195Pt NMR T1 spin relaxation times and pulsed gradient spin echo (PGSE) translational diffusion measurements were performed for [PtCl6]2‒ in selected solvents and binary mixtures. The results were interpreted in the context of hydrodynamic continuum models of molecular diffusion; while these were found to be not strictly appropriate, the rotational and translational dynamics results appear to be notionally consistent with the preferential solvation phenomenon as indicated. A series of classical MD computer simulations were performed for [PtCl6]2‒ in these equimolar binary solvent mixtures, using a recently revised force field developed by Naidoo et al. The results using the standard force field indicate a strong preference for water in the primary solvation shell region of the complex in all solvent mixtures studied. A similar result is obtained for [PtCl4]2‒ in an equimolar water‒methanol mixture. Simulations were repeated with ionic charges scaled according to the recently developed Molecular Dynamics in Electronic Continuum (MDEC) theory, which is intended to account for the dielectric screening of charges in condensed phases. In these MDEC simulations, a significant reduction in the contribution of water to the primary solvation shells of both complexes is observed; this is particularly evident in the solvation shell of [PtCl6]2‒ in mixtures of water with 2-methoxyethanol and 1,2-dimethoxyethane, for which a strong preferential solvation by the organic components has been indicated. Dynamic properties were also computed from MD trajectories, and are qualitatively consistent with experimental trends, but deviate due to the solvent model combination. Finally, an interpretation of the fascinating 35/37Cl and 16/18O isotope-induced fine structure in the 195Pt NMR spectra of complexes of the type [PtCln(OH)6‒n]2‒, n = 0‒5, is presented, based on the expected trans-influence series of ligands for Pt(IV) OH‒ > Cl‒ > H2O in aqueous solution.
59Co NMR, a tool for the study of the structure, reactivity and supramolecular chemistry of Co(III) complexes derived from a series of N-alkyl-N-alkyl(aryl)-N’-acyl(aroyl)thioureas
(Stellenbosch : Stellenbosch University, 2020, 2020-03) Barnard, Ilse; Koch, Klaus Robert; Gerber, Wilhelmus Jacobus; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: A large library of Co(III) complexes, derived from selected monopodal and bipodal N,N- dialkyl-N’-acyl(aroyl)thioureas, have been synthesized and characterized. These ligands form tris(chelated) complexes in the thermodynamically more stable fac geometry with the cobalt metal. The monopodal ligands, and their corresponding Co(III) complexes, were separated into two groups based on the two R substituents of the C(S)-NRR’ function. The first group were named the symmetrically substituted acylthiourea derivatives, where R = R’. Due to the increased stability provided by the chelate effect as well as the selective population of the lower-energy d-orbitals, such complexes are generally expected to be kinetically stable in solution. Nonetheless, the ‘symmetrical’ Co(III) complexes were utilized for the study of the unexpected, slow and spontaneous ligand exchange reaction between non-identical homoleptic pairs of low-spin d⁶ octahedral fac-[Co(LA-κS,O)3] and fac-[Co(LB-κS,O)3] complexes in organic solvents. The exchange reaction between these complexes result in mixtures of their corresponding heteroleptic fac-[Co(LA-κS,O)2(LB-κS,O)] and fac-[Co(LA-κS,O)(LB-κS,O)2] complexes in solution. This discovery was followed by a quantitative determination of the ligand exchange equilibria as well as a relative rate study, as a function of temperature, of the reaction using rp-HPLC. It was then established that the high chemical shift sensitivity of ⁵⁹Co NMR is a powerful tool for the easy characterization of the Co(III) complexes derived from symmetrically substituted acylthioureas in solution. The utility of ⁵⁹Co NMR as a spectroscopic tool was exemplified after utilizing this technique for further additional studies of factors shown to dramatically affect the relative rate of ligand exchange in these complexes, specifically light and solvent. The second group of monopodal acylthiourea ligands investigated were named the asymmetrically substituted acylthioureas, where R ≠ R’. The partial double bond character in the C-N bond of the C(S)-NRR’ function results in the E,Z configurational isomerism of these ligands in solution. The isomerism is expressed as duplicate resonances in the ¹H NMR spectra of the uncoordinated ‘asymmetrical’ acylthiourea ligands. The Z to E isomer ratio varies depending on the two R and R’ substituents of the thiourea moiety. Notably, the isomerism in the uncoordinated ligands is passed on to the Co(III) chelates after coordination. As for the symmetrically substituted acylthiourea Co(III) complexes, we find that the ⁵⁹Co NMR chemical shift is very sensitive to the structure of the asymmetrical fac-[Co(Lⁿ-κS,O)3] complexes in solution. Significantly, the presence of the four, theoretically possible, fac- [Co(EEE-Lⁿ-κS,O)3], fac-[Co(EEZ-Lⁿ-κS,O)3], fac-[Co(EZZ-Lⁿ-κS,O)3] and fac-[Co(ZZZ-Lⁿ- κS,O)3] isomers is readily observable by means of ⁵⁹Co NMR, which shows four well-resolved resonances. From the relative peak integrals of the ⁵⁹Co NMR peaks, a semi-quantitative estimate of the relative amounts of the configurational isomers in solution was possible, although assignment of the isomers is not trivial. The assignment of the ⁵⁹Co peaks to each of the EEE, EEZ, EZZ and ZZZ configurational isomers of the asymmetrical fac-[Co(Lⁿ-κS,O)3] complexes were based on the relative E/Z ratio of the uncoordinated ligands, which was established from their ¹H NMR spectra. However, this assignment assumes that the relative E/Z ratio does not vary significantly during coordination to cobalt and remains therefore ambiguous. The distribution of the EEE, EEZ, EZZ and ZZZ configurational isomers was shown to be dependent on the solvent used during the analyses. Moreover, we evaluated the temperature needed to lift the barrier to rotation in the C-N bond of the coordinated ligands. Finally, the ⁵⁹Co NMR trends of several complexes isolated for single crystal X-ray diffraction analysis were complemented by DFT linear transit calculations of their configurational isomers. Finally, we investigate the interesting coordination chemistry of the well-ordered and multinuclear coordination systems of the bipodal acylthiourea analogues, namely aroylbis(N,N-dialkylthioureas). Two ligands were selected for this purpose, including isophthaloylbis(N,N-diethylthiourea) and a bipodal ligand with a modified aromatic spacer derived from catechol. These were utilized as pre-programmed chelating ligands to form metallamacrocyclic octahedral facial Cobalt(III) complexes via self-assembly. The latter catechol-spaced ligand was used for the synthesis of a number of oligometallic Co(III) complexes by one-pot reactions of the ligand, Co³⁺ and a variety of monovalent cations, to form metallacryptates of type {M⁺ ⊂ [Co2(L-κS,O))3]}(PF6), M⁺ = K⁺, Rb⁺, Cs⁺ and NH4+. A significant discovery, owing to the unique sensitivity of the ⁵⁹Co nucleus, was the instrumental role ⁵⁹Co NMR played in our attempt to characterize the metallacryptates and to determine their conditional stabilities in solution. This was achieved by way of several biphasic exchange experiments of cations between an aqueous and non-aqueous phase. This is a novel discovery that has allowed for the study of various factors shown to effect the stability of the metallacryptates in solution.
Adamantane copolymers
(Stellenbosch : Stellenbosch University, 2001-12) Coetzee, Liezel; Van Reenen, A. J.; Stellenbosch University. Faculty of Science. Dept. of Chemistry & Polymer Science.
ENGLISH ABSTRACT: This study concerns the incorporation of adamantane containing monomers 3-(1-adamantyl)-1-propene and 1-(1-adamantyl)-4-vinylbenzene into ethene, propene and higher a-olefins using different catalytic systems. The effect of the incorporation of the adamantane monomer on the physical and thermal properties of the polymers was investigated. A thorough study on the background of adamantane in general, as well as polymerization reactions involving the above-mentioned monomers and a-olefins was done. 3-(1-Adamantyl)-1-propene as well as 1,.(1-adamantyl)-4-vinylbenzene was sucessfully synthesized. The homo polymers of each monomer were made. The above-mentioned monomers were also polymerized: • . 3-( 1-adamantyl)-1-propene with ethene, propene and higher a-olefins, • 1-(1-adamantyl)-4-vinylbenzene with ethene and styrene. The copolymers of 3-(1-adamantyl)-propene as well as 1-(1-adamantyl)- 4-vinylbenzene were characterized as far as possible to show the influence of the incorporation of the adamantane group on the physical and chemical properties of the polymers. A series of 3-phenyl-1-propene copolymers with higher a-olefins were synthesized to compare the influence of the phenyl group to the adamantyl group on the relevant properties of the polymers.
Advanced analytical methods for the analysis of complex polymers prepared by RAFT and RITP
(Stellenbosch : Stellenbosch University, 2015-04) Wright, Trevor Gavin; Pasch, Harald; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Synthetic polymers are complex compounds that have multiple distributions with regard to molar mass, chemical composition, functionality and molecular architecture. Therefore, the molecular complexity of these compounds can only be analysed using a combination of analytical techniques. Well-defined complex polymers can be prepared by different types of living radical polymerisation, including reversible addition–fragmentation chain transfer polymerisation (RAFT) and reverse iodine transfer polymerisation (RITP). Using these techniques, several different homopolymers and copolymers have been prepared. However, there is still space for some more extended research. Many different types of multifunctional RAFT agents have been reported in literature. A tetrafunctional RAFT agent was prepared in our laboratory and used for the first time in the polymerisation of styrene. The polymerisation reaction was followed using in situ 1H nuclear magnetic resonance (NMR) and the molar masses of the resultant polymers were determined using size exclusion chromatography (SEC). The molar masses of the star-shaped polystyrenes (PS) were found to be less than the theoretical molar masses. This was due to the fact that SEC was calibrated with linear PS standards, while the samples under investigation are branched. Linear and branched polymers have different hydrodynamic volumes at similar molar masses. In order to prove that the star-shaped polymers were in fact four-armed, the samples were cleaved by aminolysis to yield the linear PS arms. The molar masses of the arms were in agreement with the theoretical arm molar masses based in the fourarmed structure. RITP is a relatively new living radical polymerisation technique. Various monomers have been prepared using RITP, including acrylates, methacrylates and styrene. The polymers formed using this technique have been characterised by techniques such as SEC, NMR and mass spectrometry (MS). However, very little advanced characterisation work has been done on polymers synthesised via RITP. Polystyrene-block-poly(n-butyl acrylate) (PS-b-PBA) block copolymers were prepared via RITP and the microstructure analysed by in situ NMR and other advanced analytical techniques. The chromatograms from gradient HPLC of the PS-b-PBA block copolymers showed a separation based on chemical composition. The preparation of deuterated polymers via RITP has not been reported in literature. Hydrogenous-polystyrene-block-deuterated-polystyrene (hPS-b-dPS) was synthesised via RITP and analysed using liquid chromatography at critical conditions. An isotopic separation was achieved when critical conditions were established for hydrogenous PS (h-PS). A separation of the block copolymer from the first block was also achieved under chromatographic conditions where the block copolymer eluted in SEC mode while the first block eluted in LAC mode. The separation according to the block structure was confirmed by two-dimensional liquid chromatography.
Alternating hetero-arm copolymer molecular brushes as scaffolds for inorganic nano-wires
(Stellenbosch : Stellenbosch University, 2013-03) Hadasha, Waled Ajili; Klumperman, Bert; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: This study describes the synthesis and self-assembly of hetero-arm molecular brushes (hetero-arm MBs). These MBs consist of two polymeric side chains (SCs) of different natures, alternatingly distributed along the main chain (backbone). Two different types of hetero-arm MBs were prepared: first, alternating amphiphlic hetero-arm MBs (AMBs), and second, alternating hetero-arm MBs (AHMBs). Hetero-arm AMBs were synthesized via two strategies: (I) via a combination of “grafting through” and “grafting onto”, and (II) via “grafting through”. In approach (I), poly[vinyl benzyl (polyethylene glycol)-alt-N-alkyl-maleimide)] (poly[VB-(PEG12)-alt-N-(CnH2n+1)-MI]) was prepared via radical copolymerization of vinyl benzyl-terminated polyethylene glycol (VB-PEG12) with maleic anhydride (MAnh) (grafting through), which produces graft copolymers with PEG SCs and reactive succinic anhydride repeat units alternatingly distributed along the backbone. These graft copolymers were then modified by nucleophilic substitution (imidization) with alkyl amines (CnH2n+1-NH2) on the succinic anhydride residues (grafting onto). Three different primary amines possessing different alkyl chain lengths (n = 4, 12 and 16) were used in the modification process. In this way, hetero-arm AMBs with different hydrophilic to hydrophobic ratios were obtained. In approach (II), similar hetero-arm AMBs were prepared in a one-step grafting through approach. In this case, poly[VB-(PEG17)-alt-N-(CnH2n+1)-MI] (n = 10, 16 and 20) was prepared via radical copolymerization of VB-PEG17 with N-dodecylmaleimide, N-hexadecylmaleimide and N-icosylmaleimide. Following the synthesis step, self-assembly of these hetero-arm AMBs in arm-selective solvents was investigated in relation to the alkyl chain length. The morphology of the obtained assemblies was characterized by Field Emission gun-Scanning Electron Microscopy (FE-SEM), Transmission Electron Microscopy (TEM) and Fluorescence Microscopy (a fluorescent dye was encapsulated). Cylindrical-like aggregates, length 10 μm and diameter ~ 250 nm, were obtained upon hetero-arm AMBs self-assembly. The second type of hetero-arm MBs was hetero-arm AHMBs, in which the SCs consist of PEG and poly(N,N-dimethylamino-ethyl methacrylate) (PDMAEMA). These hetero-arm AHMBs were prepared via a combination of grafting through and grafting from approaches. In this case, poly[vinyl benzyl-(polyethylene glycol)-alt-N-(poly(N,N-dimethylamino-ethyl methacrylate) maleimide] (poly[VB-(PEG17)-alt-N-(PDMAEMA)-MI) was prepared in the following steps: (1) alternating poly[vinyl benzyl-(polyethylene glycol)-alt-N-(4-hydroxyphenyl) maleimide] (poly[VB-(PEG17)-alt-N-(HPh)-MI]) was synthesized via radical copolymerization of VB-PEG17 with N-(4-hydroxyphenyl) maleimide (N-HPhMI). (grafting through), (2) the hydroxyl sites were esterified with 2-bromoisobutyryl bromide to afford poly [vinyl benzyl-(polyethylene glycol)-alt-N-(4-(2-bromobutyryloxy)phenyl) maleimide] (poly[VB-(PEG17)-alt-N-(BrPh)-MI]) (macroinitiator) and (3) an atom transfer radical polymerization (ATRP) reaction of 2-(N,N-dimethylamino)ethyl methacrylate (DMAEMA) was initiated from the obtained macroinitiator. This approach afforded poly[VB-(PEG17)-alt-N-(PDMAEMA)-MI] hetero-arm AHMBs with two water soluble SCs; however, one is water soluble at all pHs and temperatures (i.e. PEG), while the other is a pH- and temperature-sensitive polymer (i.e. PDMAEMA). Initial attempts were made to fabricate cylindrical organo/silica hybrid materials based on these AMHBs as the organic template and tetra-ethylorthosilicate as the silica precursor. Preliminary results indicate the formation of silica nano-wires, ~ 8 μm in length and ~45 nm in diameter. The self-assembly behavior of these AHMBs in water at a temperature above the lower critical solution temperature of PDMAEMA (> 55 °C) was also investigated. Fibril morphology (~ 30 nm in diameter) was observed. This study addresses initial attempts to fabricate organic/inorganic hybrid materials with controlled size and morphologies via densely grafted hetero-arm molecular brushes.
Amine end-functional poly(N-vinylpyrrolidone) as amMacroinitiator for L-lysine N-carboxyanhydride polymerization - towards the preparation of pH-responsive micelles for drug delivery
(Stellenbosch : Stellenbosch University, 2015-03) Ilchev, Alexander; Klumperman, Bert; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Cancer is a notorious affliction that knows no age, gender, ethnic, racial, or species bounds and is responsible for over 14% of annual worldwide human deaths. There is no universal cure and the treatments that exist have poor probabilities of success. Chemotherapy is often considered the staple for cancer treatment as it can enter areas of the body that are unsafe for surgery and can treat tumors that are too small to be detected, even with modern imaging techniques. However, chemotherapy can induce many harmful and fatal side-effects. It can also lose its therapeutic effect if the cancer mutates to become multi-drug resistant. These shortcomings can be linked to the poor selectivity and pharmacokinetics of conventional chemotherapy drugs. Modern research focusses on improving these aspects of existing chemotherapy regimens through the incorporation of drug delivery principles. This dissertation focusses on the development of a novel, polymeric, pHresponsive drug delivery system for chemotherapy that incorporates the chemotherapeutic drug as well as a cell-penetrating peptide in a prodrug formulation. The system was designed to inhibit the release of its components into healthy tissues while selectively accumulating, through the enhanced permeability and retention effect, and releasing its payload, through reversible hydrolysis of imine bonds, within tumor tissues. Poly(L-lysine) was chosen as the cell-penetrating peptide since it is able to form imine bonds through its ε-amine functional groups on its residues. It was prepared by the primary amine-initiated ring-opening polymerization of Nε-(benzyloxycarbonyl)-L-lysine Ncarboxyanhydride at 0 °C and pressures lower than 1 mbar as these conditions allow for a controlled, living polymerization to occur. The benzyloxycarbonyl end-group was removed by acidolysis with HBr in a mixture of dichloromethane and 1,4-dioxane at 0 °C. The initiator used for the ring-opening polymerization was poly(N-vinylpyrrolidone) with a primary amine end-group, prepared by RAFT-mediated polymerization with O-ethyl-S-(phthalimidylmethyl)xanthate. This RAFT agent was shown to display slow pre-equilibrium kinetics which was linked to the lower relative stability of the phthalimidylmethyl radical compared to the poly(N-vinylpyrrolidone) propagating radical. The pre-equilibrium and main equilibrium kinetics of the RAFT polymerization were optimized by performing the polymerization in semi-batch mode. During the semi-batch polymerization, the monomer to RAFT agent ratio could be controlled by adjusting the monomer feed. This ratio was shown to be inversely proportional to the probability of radical transfer from the propagating radical to the phthalimidylmethyl radical. The phthalimide end-group could be converted to a primary amine both by reacting with hydrazine in methanol as well as reduction with sodium borohydride in water followed by hydrolysis in 1 M HCl at 60 °C. Doxorubicin and benzaldehyde could be conjugated, via imine bonds, to the poly(N-vinylpyrrolidone-block-L-lysine) copolymer spontaneously in methanol. Both types of conjugates would self-assemble into micelles when dispersed in water. However, the Doxorubicin conjugates were unstable, precipitating out of solution within 24 hours. The benzaldehyde conjugates were stable in water for over 24 hours. This suggested that a formulation of Doxorubicin and benzaldehyde conjugated to the block copolymer may be sufficiently stable under the physiological conditions of blood plasma.
Analysis of complex tannins by multidimensional techniques
(Stellenbosch : Stellenbosch University, 2019-03) Venter, Pieter; De Villiers, Andre J.; Pasch, Harald; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Hydrolysable tannins are plant derived (poly)phenolics which for centuries have been used in tanning, the transformation of animal hides into leather. In addition to their industrial applications, epidemiological evidence suggests that the consumption of hydrolysable tannins can be linked to disease prevention and treatment, although their mode of action at a molecular level is still unknown. In order to investigate their biological and chemical properties, the determination of the molecular composition of hydrolysable tannins in plant material is a critical step. Liquid chromatography hyphenated to mass spectrometry (LC-MS) is the preferred analytical approach to obtain this information, although conventional methods often provide insufficient performance for highly complex mixtures of hydrolysable tannins. The goal of the work reported in this thesis was, therefore, to develop improved multidimensional methods for the analysis of hydrolysable tannins. In the first part of the study, a methodology for the comprehensive analysis of ellagitannins and gallotannins in chestnut and tara using reversed phase liquid chromatography (RPLC) and hydrophilic interaction chromatography (HILIC) combined with ultraviolet (UV), ion mobility (IM) spectrometry and high-resolution mass spectrometry (HR-MS) detection is reported. Good chromatographic performance was achieved using both HILIC and RP-LC for chestnut tannins, with the complementary separation mechanisms proving useful for particular compound classes also pointing to the potential of the combination of HILIC and RP-LC in a comprehensive two-dimensional separation. In contrast, RP-LC provided much better separation of tara gallotannins than HILIC. Incorporation of IM into the LC-MS workflows offered several advantages for such non-targeted screening analyses, including improved mass spectral quality by filtering MS data according to IM arrival time, the availability of an additional identification criterion in the form of collisional cross section (CCS) values obtained from arrival times, and an improved MS duty cycle and, therefore improved sensitivity. Furthermore, additional isomeric species were resolved by IM and, in combination with UV spectral data, IM provided a simple methodology to differentiate between positional isomers. In the second part of the study, an on-line comprehensive two-dimensional HILIC×RPLC method was developed for the analysis of hydrolysable tannins by kinetic optimisation of the relevant experimental parameters. The use of a weak make-up flow to dilute the HILIC effluent and avoid second dimension injection band broadening resulted in excellent performance, with practical peak capacities in excess of 1000 determined for both samples. Despite on-column dilution and the short second dimension analysis times ultimately limiting the number of compounds detected in chestnut and tara, the group-type separations obtained show promise for the fast fingerprint analysis of hydrolysable tannins. Building on previous findings, the final part of the work evaluated the potential of IM spectrometry as a third dimension in a comprehensive three-dimensional HILIC×RPLC×IM configuration. Apart from the inherent advantages of IM alluded to above, the additional separation step offered by IM contributed to an increase in practical peak capacity by a factor of 13 when integrated into the LC×LC workflow. Certain instrumental constraints which limit the ultimate performance of LC×LC×IM-HR-MS are highlighted. Despite these, this approach shows significant promise for the high resolution separation of highly complex mixtures.
Analysis of hydroformylation catalysis mechanisms of rhodium catalyst precursors by computational and instrumental means.
(Stellenbosch : Stellenbosch University, 2021-05) O'Kennedy, Sean James; Gerber, Wilhelmus J. ; Mapolie, Selwyn Frank ; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The most industrially prevalent hydroformylation catalysts are based mainly on cobalt or rhodium with various combinations of carbonyl, halide or tertiary phosphine ligands and derivatives thereof. Recently, catalyst designs have branched out to include nitrogenous ligands such as pyridines, imines, triazoles and pyrazoles as well as multidentate combinations of either nitrogen, oxygen and/or tertiary phosphine donor ligands. This dissertation focuses on the mechanistic pathways of hydroformylation catalyst in absence of a detectable hydride intermediate. Due to the transient nature and low abundance of the catalytic intermediates, the study is focused primarily on in situ and in silico modelling of proposed mechanistic pathways. In order to investigate the kinetic trans effect in transition metals an example reaction of the transformation of [RhCl6]3􀀀 was investigated. It has been well documented that the transformation of [RhCl6]3􀀀 to [Rh(H2O)6]3+ is slow (equilibration takes more than 10 years) in acidic solutions at room temperature. However, on the addition of base to the solution, the [RhCl6]3􀀀 complex initially forms the [RhCl5(OH)]3􀀀 complex which then rapidly converts to [Rh(OH)6]3􀀀. We show using computational methods that the transformation of the [RhCl5(OH)]3􀀀 to [Rh(OH)6]3􀀀 occurs via labilisation of the trans chloride to form a 5 coordinate [RhCl4(OH)]2􀀀 species that can readily react with another hydroxide. The transformation to a hydroxido complex causes a cascade of rapid transformations to form the final [Rh(OH)6]3􀀀 complex. The domain based localized pair natural orbital coupled cluster singles doubles and virtual triples (DLPNO-CCSD(T)) was used to calculated accurate transition state energies that agreed well with the experimental data and corroborated our proposed dissociative ligand exchange mechanism. Hydroformylation is a well understood catalytic reaction for the more prevalent cobalt and rhodium phosphine based catalysts that follow a pathway where the catalyst spends most of the catalytic cycle in the Co(I) or Rh(I) oxidation state, respectively. However, we show an alternative pathway where oxidative addition of hydrogen directly to the precursor forms a Rh(III) dihydride which remains in the octahedral geometry throughout most the catalytic cycle. The oxidative addition of hydrogen is shown to form low abundances of transient rhodium dihydride species by computational chemistry, explaining the lack of spectroscopically detectable species in situ. In addition, it is shown via computational fragment analysis and a local energy decomposition scheme that the double electron transfer to form the dihydride occurs on relaxation from the transition state towards the dihydride octahedral complex and not at the transition state itself. The overall catalytic mechanism for a the [[N-(pyridine-_N-methyl)-N0-(3-imine-_N-p-tolyl)]rhodium(I)(_4-1; 5-cyclooctadiene)]+ complex was investigated using in situ 1H NMR in conjunction with UHPLC-MS. The spectroscopic results indicated possible transamination of the imine ligand by reaction with wither the acetone solvent or the formed aldehyde product. Computational chemistry was used to model the proposed hydroformylation mechanism for the [[N-(pyridine-_N-methyl)-N0-(3-imine-_N-p-hydroxyphenyl)]dicarbonylrhodium(I)]+ and [N--(pyridine-_N-methyl)-N0-(3-imine-_N-p-hydroxyphenyl)]chlorocarbonylrhodium(I) complexes, using the [Rh(CO)4]+ and [RhCl(CO)3] complexes as model precursors. The computational results indicated that the overall mechanism is feasible with a dissociative step at each point except that of the alkene addition. Each 5-coordinate intermediate of the proposed dissociative mechanism was stabilised by agostic interaction between the vacant site and the hydrogen of the proximate coordinated alkyl or acyl ligand. Throughout the mechanism, competition is seen between the chloride, hydride, alkyl and acyl ligands. This trans influence was found to destabilise the complex isomers where these ligands are in the trans position. No steric or chiral specificity is expected in these complexes from computationally calculated geometries as there is no hindrance to the coordination of either the linear or branched alkyl ligand explaining the lack of n-iso specificity in experimental results.
Analysis of vegetable oils, seeds and beans by TGA and NMR spectroscopy
(Stellenbosch : University of Stellenbosch, 2011-03) Retief, Liezel; Koch, Klaus R.; McKenzie, Jean; University of Stellenbosch. Faculty of Sciences. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Due to the commercial, nutritional and health value of vegetable oils, seeds and beans, the analysis of their components is of much interest. In this dissertation oil-containing food products, specifically vegetable oils, seeds and beans, were investigated. Selected minor components of three locally produced vegetable oils, namely apricot kernel, avocado pear and macadamia nut oils were investigated using 31P NMR spectroscopy. These minor components, including 1,2 diacylglycerols, 1,3 diacylglycerols and free fatty acids, were identified in the 31P NMR spectra of each of the three vegetable oils for the first time. Two approaches were used for the quantification of the minor components present in the spectra. A calibration curve approach used known concentrations of standard minor components to establish calibration curves while a direct correlation approach calculated the unknown concentration of minor components in the vegetable oils using a known amount of standard compound within the analysis solution. These approaches aided in determining the concentration of minor components during storage studies in which vegetable oils were stored in five different ways: exposed to light, in a cupboard, in a cupboard wrapped in tin foil, at -8 °C and at 5 °C. It was found that determining the best storage condition for each oil was difficult since individual minor components were affected differently by the various storage conditions. However, in general the best storage conditions appeared to be 5 °C and -8 °C. The oil, protein and carbohydrate contents of sesame, sunflower, poppy, and pumpkin seeds, and soy, mung, black and kidney beans were analysed by thermogravimetric analysis and 13C NMR solid state NMR spectroscopy. It was shown that the first derivative of TGA data for seeds and beans can give valuable information about the carbohydrate, moisture, protein and fat content. This has not been previously demonstrated. For the seeds, the integration of a region between 270–480 ºC was equal to the sum of the oil and protein content and compared well to quantitative results obtained by other conventional methods. For beans the integration of a region between 180-590 ºC, gave a value which represented the sum of the oil, protein and carbohydrate content. 13C solid state NMR spectroscopy, including SPE-MAS, CP-MAS and variable contact time experiments, was carried out on these seeds and beans and gave valuable information on the solid-like and liquid-like components. To our knowledge these seeds and beans have never been previously analysed using this technique. 13C SPE-MAS NMR spectroscopy indicated that the seeds contained more liquid-like components than the beans. In turn the 13C CP-MAS NMR spectra indicated that beans had higher levels of solid-like components than the seeds. These conclusions correlated well with the quantities of liquid-like components and solid-like components that were determined by conventional methods and TGA. Preliminary studies using T1pH experiments on the components present in the seeds and beans led to a few observations. Most interesting is that a model using a two- phase fit in order to determine T1pH values appears to be more accurate than a one-phase model.
Applicatins of liquid chromatography-tandem mass spectrometry to wine analysis : targeted analysis and compound identification
(Stellenbosch : Stellenbosch University, 2012-12) Alberts, P.; Stander, M. A.; De Villiers, A. J.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The wine industry is an important sector of agriculture and wine analysis forms the basis of assessing compliance of its commodities with regulatory standards and research in this field. Liquid chromatography (LC) is extensively used for the determination of a wide range of nonvolatile wine components, but conventional detectors impose performance limitations on the technique that prevents its application to sophisticated analytical problems. In particular, conventional detectors for LC often lack the sensitivity and specificity for the determination of many wine compounds, especially trace level analytes, and furthermore, do not possess spectral capabilities for compound identification or structure elucidation. The hyphenation of mass spectrometry (MS) to LC has led to the introduction of a range of detectors that confers high levels of sensitivity and selectivity to the technique. In addition, a wide variety of MS architectures are available that are inherently suited for targeted analysis or structure elucidation studies. In this dissertation, the potential benefits of liquid chromatography – tandem quadrupole mass spectrometry (LC-MS/MS) to solve analytical problems relevant to the wine industry are explored. LC-MS/MS is a particularly versatile analytical technique because both mass analysers can be operated in full-spectrum mode or selected-ion monitoring, which, together with optional fragmentation, gives rise to four modes of operation that may be used for highly specific and sensitive targeted analysis or spectral investigations. In multiple reaction monitoring (MRM) mode, both analysers are set at single ion frequencies specific for the compound under investigation and one or more of its product fragments, respectively. MRM mode is ideally suited for trace level analysis in complex mixtures, even in cases where the target components are not resolved from interferences. In this study, MRM detection was used to solve challenges relevant to the wine industry for the selective quantitation of target analytes that could not be analysed by conventional LC methods. The application of this approach for the analysis of natamycin, ethyl carbamate (EC) and 3-alkyl-2- methoxypyrazines (MPs) in wine is demonstrated. Natamycin is an antimicrobial preservative that is not permitted in wine in the European Union. A rapid and sensitive method for the determination of natamycin was developed, and has been used since 2009 to regulate this vitally important sector of the South African wine export industry. EC is a natural carcinogen that occurs at trace level amounts in alcoholic products. It also has the potential to accumulate in wines and can occur in very high concentrations in some fruit brandies. The determination of EC is complicated by its physicochemical properties, and available analytical methods suffer from drawbacks such as the requirement for elaborate extraction procedures and high solvent consumption. A novel method for the determination of EC in wines, fortified wines and spirits is described and it was applied to perform an audit of the South African industry as well as to investigate factors responsible for its accumulation in alcoholic beverages. This work forms an integral part of the food safety mandate of the State and it ensures that export products comply with international norms for trade. MPs are ultra-trace-level aroma compounds that contribute to the varietal character of Sauvignon blanc wines. Their analytical determination is challenging due to their low levels of occurrence. The loading capacity of LC combined with the sensitivity and resolving power of MS was exploited to analyse concentrated extracts, in order to achieve very low limits of detection. The performance of the LC-MS/MS method enabled the quantitation of these compounds at their natural levels of occurrence, including the first quantitation and spectral confirmation of 3- ethyl-2-methoxypyrazine in wine. Extensive data pertaining to South African Sauvignon blanc wines are reported and statistical analysis is performed, reporting the correlation of variables such as vintage and origin as well as wine parameters such as malic acid with wine MPs. Furthermore, the application of LC-MS/MS for structural elucidation and screening of target classes of analytes was demonstrated for the analysis of red wine anthocyanins. The anthocyanidin-glycosides are responsible for the colour of red grapes and wine, contribute to the sensory properties of wine, and are also of interest due to their beneficial biological properties. Their determination is complicated by their large numbers and structural diversity, further exacerbated by diverse reactions during wine ageing as well as the lack of reference standards for most members of this class of compounds. Tandem MS in scan mode was used for the highly selective detection of glycosylated anthocyanins and derivatives, exploiting the predictable elimination of the sugar moiety in neutral loss mode. Concurrent survey scan experiments were used to unambiguously identify neutral loss detected compounds. The method therefore follows a simplified and structured approach for unambiguous peak identification based on elution order and mass spectral information to impart a high level of certainty in compound identification. In summary, the work presented in this dissertation demonstrates that LC-MS/MS is a versatile and powerful analytical approach for the analysis of diverse compounds of relevance to the wine industry. The sensitivity and specificity of MRM mode, and the selectivity and spectral capabilities of neutral loss and survey scan modes of MS/MS detection, is amply demonstrated by the applications presented in the dissertation.
Application of modern analytical techniques and chemometric methods to the chemical characterisation of South African wines : determination of non-volatiles
(Stellenbosch : Stellenbosch University, 2004-12) De Villiers, A. J. (Andre Joubert); Sandra, P. J. F.; Crouch, A. M.; Stellenbosch University. Faculty of Science . Dept. of Chemistry & Polymer Science.
ENGLISH ABSTRACT: The present study deals in the first instance with the improvement of current analytical techniques for the analysis of the non-volatile content of wines. An improved sample preparation method, using solid phase extraction (SPE), was initially developed for the analysis of organic acids, sugars and phenolic compounds. Consequently, modem analytical methodologies were assessed to obtain optimal techniques for the separation of various non-volatile compounds. A capillary electrophoresis (CE) method, demonstrably more reliable than currently used high performance liquid chromatography (HPLC) and CE methods, is proposed for the analysis of organic acids. HPLC with refractive index (RI) or evaporative light scattering detection (ELSD) proved more suitable than CE for the analysis of sugars in dry wines. Liquid-chromatography-mass spectroscopy (LC-MS) offered superior sensitivity and resolution compared to the relatively new technique of CE-MS for the analysis of wine phenolics. LC-MS was further applied for the efficient and sensitive analysis of non-coloured phenolics and anthocyanins in wine. Negative- and positive electrospray ionisation, respectively, were used in conjunction with an ion-trap mass analyzer, for the identification of 34 phenolics and 31 anthocyanins in red wine samples. Complementary CE and LC methods were developed to allow the identification of artificial dyes in red wines, added illegally to improve their colour. Also, the application of stir bar sorptive extraction (SBSE) with liquid desorption and micellar electrokinetic chromatography (MEKC) for the analysis of bitter acids in beer is reported. In the second part of the thesis, the analytical results obtained for South African red and white wines were evaluated. Following comparison of the results with literature reports, several pattern recognition techniques were employed. A classification function obtained by linear discriminant analysis (LDA) was used to classify both red and white wines according to variety, based on their chemical composition. This classification is achieved independent of the factors of wine age or geographical origin, making it useful for authenticity evaluation.
Application of modern chromatographic technologies for the analysis of volatile compounds in South African wines
(2009-12) Weldegergis, Berhane Tekle; Crouch, A. M.; De Villiers, A.; University of Stellenbosch. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The present study was initiated by the wine industry of South Africa to overcome the lack of available information on the flavor and aroma of South African wines. The aim was to develop new analytical methods and improve existing ones for the analysis of volatile compounds in the South African wines. Initially a new analytical method based on stir bar sorptive extraction (SBSE) in the headspace mode for the analysis of 37 pre-selected volatile compounds was developed and validated. Consequently, the method was improved by making important modifications and increasing the number of compounds analyzed to 39. This method was successfully applied to a large number of Pinotage wines of vintages 2005 and 2006. The quantitative data of these wines were subjected to chemometric analysis in order to investigate possible co- /variances. A clear distinction was observed between the two vintages, where the 2005 wines were more characterized by wood-related compounds and the 2006 wines by the fermentation compounds. The developed method was further applied to other cultivars of vintage 2005, including two white (Sauvignon Blanc and Chardonnay) and three red (Shiraz, Cabernet Sauvignon and Merlot) cultivars. In a similar fashion, the quantitative data of the six cultivars of vintage of 2005 were analysed by chemometric methods. Significant differences were observed between the two white cultivars and among the four red cultivars. It was shown that among these cultivars, the major role-players were the wood and fermentation related volatiles. A striking observation was the confirmation of the unique character of the Pinotage wines compared to the other red cultivars, mainly influenced by the high level of isoamyl acetate and low level of isoamyl alcohol, the former being categorized as a varietal compound for Pinotage expressed by a fruity (banana) odor. In addition, advanced chromatographic technology in the form of comprehensive twodimensional gas chromatography (GC × GC) coupled to time-of-flight mass spectrometry (TOFMS) was investigated for the detailed analysis of volatile compounds in young South African wines. This work focused primarily on Pinotage wines. In the first instance, solid phase micro extraction (SPME) in the headspace mode in combination with GC × GC-TOFMS was used. Due to the high resolution and large peak capacity of GC × GC, more than 200 compounds previously reported as wine components were identified. These compounds were dominated by the highly volatile and less polar compounds, mainly due to the characteristics of SPME. In an attempt to further extend these results, another selective extraction method, solid phase extraction (SPE) was used in combination with GC × GC-TOFMS analysis. Using this technique, more than 275 compounds, most of them unidentified using the previous method, were detected. These groups of compounds include volatile phenols, lactones as well as mostly aromatic esters and norisoprenoids, which can potentially influence the aroma and flavor of wine. The techniques developed as part of this study have extended our knowledge of the volatile composition of South African wines.
Applications of superparamagnetic nanoparticles for the separation and recovery of PGM metals from acidic wastewater solutions
(Stellenbosch : Stellenbosch University, 2018-12) Khutlane, Joyce Tsepiso; Malgas-Enus, Rehana; Koch, Klaus R.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: South Africa is one of the leading countries in the production of precious metals (Au and PGMs). The refinery final stages for recovering precious metals makes use of two hydrometallurgical processes: solvent extraction and extraction with ion exchangers. Even though both methods improved the recovery of these metals from the ore, they still suffer from setbacks ranging from large amounts of secondary waste solutions, expensive solvents and resins, and filtration in terms of the use of ion exchange resins for extraction. Therefore, a need for the development of simple and environmentally friendly refining processes is required to minimize the recurrence of the abovementioned setbacks. Naked magnetic iron oxide nanoparticles (MIONs) are promising materials for adsorption studies of metal ions/complexes from wastewater due to their versatile magnetic properties, which allow a facile remote control, separation and analyte recovery from solution. This work makes use of magnetite nanoparticles (MIONs) which are superparamagnetic and less expensive compared to adsorbents used by the South African refineries for extraction of Au(III)-Cl, Pd(II)-Cl and Pt(IV)-Cl complexes from acidic aqueous solutions. Synthesis of naked MIONs was carried out by using the chemical co-precipitation method. Naked MIONs successfully sorbed Au(III), Pd(II) and Pt(IV) complexes from acidic aqueous solutions, showing a higher adsorption affinity for Au(III)-Cl species compared to Pd(II) and Pt(IV) species. The adsorption kinetics of the three metal complexes using naked MIONs followed a pseudo-second-order kinetic mode, indicating that the chemical adsorption was the rate-limiting step. The equilibrium adsorption of Au(III)-Cl species onto naked MIONs at pH 1.0, pH 3.0 and pH 5.0, was fitted with Langmuir adsorption isotherms. It was found that the experimental data was in reasonably good agreement with the Langmuir model, suggesting that Au forms a monolayer coverage on the surface of naked MIONs. The adsorption capacities were as follows: 10.44 mg.g-1, 18.98 mg.g-1, and 27.25 mg.g-1 respectively. The proposed mechanism responsible for adsorption of Au(III), Pd(II) and Pt(IV) complexes onto naked MIONs was governed by the electrostatic attractions and metal reduction. These naked MIONs were found to be unstable at pH1, which is usually the conditions used for extraction in the mining industry. To circumvent this problem, the surface of MIONs was functionalised with aliphatic carboxylic acids, dendrimer micelles and then with both carboxylic acids and dendrimer micelles. Characterisation of naked MIONs and functionalised MIONs was carried out by IR, PXRD, FESEM, HRTEM and ICP-OES. Competitive adsorption of Au(III), Pd(II), and Pt(IV) complexes onto naked MIONs and functionalised MIONs was explored by varying solution pH and the contact time. The dendrimer micelles played a vital role in adsorption of Pd(II) and Pt(IV) complexes. Adsorption kinetics followed a pseudo-second-order kinetics model. The adsorption isotherms all obeyed the Langmuir model in the case of Au(III), Pd(II), and Pt(IV) complexes by naked MIONs and, adsorption isotherm for Au(III) and Pd(II) complexes using modified MIONs obeyed Langmuir, while adsorption of Pt(IV) species followed the Freundlich model. The desorption studies showed that the best desorption reagents were 1.0 M HNO3 and 1.0 M HNO3/0.5 M thiourea. The modified MIONs were stable at low pH, even at pH1, and the extraction potential of the modified MIONs were comparable to that of the naked MIONs.
Bioactive compounds inspired by nature: synthesis, stability & delivery
(Stellenbosch : Stellenbosch University, 2020-01) Van der Westhuyzen, Alet E; Van Otterlo, Willem A. L.; Klumperman, Bert; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Historically, natural products (NPs) have served as a dominant contributor to the discovery of medicinal agents. Their invaluable role in modern drug discovery is emphasized by the major impact NP-inspired scaffolds and NPderivatives/mimics have had on the inception of clinically approved drugs. Evidently, Nature continues to influence human innovation in the design and development of new therapeutic agents. Since NPs have been programmed to interact with biological targets, they are thought of as evolutionary-chosen, privileged structures. In this regard, NPs serve as a structural ‘muse’ for the design of new biologically active small molecules. Moreover, the unique characteristics of NPs can be leveraged and fine-tuned to enhance potency and drug-like properties of therapeutic candidates. Owing to the tremendous impact of NPs in the field of medicinal chemistry, the inspiration gained from their scaffolds has provided a strong impetus for the development of new antiproliferative agents. The research explored in this dissertation comprised a multi-disciplinary project with the golden thread throughout the various scientific ventures being the development of bioactive anticancer agents inspired by Nature. In its entirety, the research was aimed at investigating two common challenges experienced during drug development –poor aqueous solubility and hysicochemical instability of NP/NP-inspired compounds. The two NP families whichmotivated these endeavours were the rigidins and sphaeropsidins (specifically SphA). The rigidins are marine-derived alkaloids which have been developed and optimized into a potent class of 7-deazahypoxanthines. A major breakthrough regarding the synthesis of the rigidins and their NP-inspired analogues, involved a crucial multi-component reaction (MCR) furnishing the tetrasubstituted 2-amino pyrrole precursor. The implementation of the MCR has permitted the rapid assembly of molecular diversity, serving as an attractive strategy towards the 7-deazahypoxanthines. These rigidin-inspired analogues are capable of disrupting microtubule dynamics in cancer cells and cell lines associated with MDR. However, like many other anticancer agents, the potent 7-deazahypoxanthines suffer from poor aqueous solubility. To address this impediment, two strategies were envisaged – polymeric micelle encapsulation and the introduction of solubilizing appendages. The first approach was directed towards the synthesis of a specific 7-deazahypoxanthine analogue and its covalent conjugation onto a hydrophilic polyvinylpyrrolidone (PVP) polymer via a Michael addition reaction. Although the resulting drug-polymer conjugate was successfully furnished, research efforts evolved towards the design of a more amphiphilic PVP polymer capable of loading multiple 7-deazahypoxanthine molecules. This led to the attempted synthesis of an α-substituted Nvinylpyrrolidone monomer. The next strategy aimed at enhancing the aqueous solubility of the 7-deazahypoxanthines involved incorporation of water-solubilizing groups (WSGs) within the pyrrolo[2,3-d]pyrimidine backbone. Building on a previously identified lead compound, the synthetic strategy was directed towards the addition of WSGs on the aryl rings prior to the MCR. Evaluation of the final compounds revealed that the introduction of WSGs derived from the sulfonamido acetophenone components led to a retention or improvement of nanomolar activity. Inspection of the growth inhibitory activity (GI 50 ) against HeLa cells identified a new front-runner amongst the family of rigidin-inspired analogous. This particular 7-deazahypoxanthine, 6-[4-(2-ethoxyethoxy)benzoyl]-2-(pent-4-yn-1-yl)-5-phenyl-1,7- dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, bearing a glycol ether solubilizing appendage, exhibited an exceptional GI 50 of 15 nM against HeLa cancer cell lines. Although the aqueous solubility of the most potent 7-deazahypoxanthines were assessed based on their hydrophobicity (log D), it was suspected that the poor solubility was rather attributed to the solid-state characteristics arising from the network of strong intermolecular forces. Building on this work, a collaborative project on the prodrug behaviour of N9-substituted 7-deazahypoxanthines was undertaken. Stability studies conducted in cell medium via LC-MS analysis revealed the conversion of the N9-substituted 7-deazahypoxanthines into their unsubstituted potent variants. Thereby, substitution at the N9 position of the 7-deazahypoxanthine presented an additional potential tactic for aqueous solubility enhancement. The other NP which motivated this project is the fungal metabolite SphA. This tetracyclic diterpenoid demonstrates potent cytotoxicity towards apoptotic- and multidrug-resistant cancer cell lines. SphA’s unique mechanism of action has been ascribed to the disruption of ion homeostasis in cancer cells through the impairment of regulatory cell volume increase (RVI). Unfortunately, the potential success of SphA as an anticancer agent is hindered due to its poor physicochemical stability in cell medium. As such, the research of this section was directed towards two objectives – analysis of the degradation behaviour of SphA and the impetus towards improved stability. Initially, SphA was incubated in cell medium with sample analysis taken at varying time intervals using LC-MS. Owing to the complexity of the LC-MS data, a complementary simplified buffer solution was implemented. Extensive LCMS analysis revealed possible SphA degradation metabolites based on their molecular ions, with several corresponding to SphA degradation product-amino acid adducts. Most noteworthy was the presence of a major SphA degradation metabolite (SphA-Met), which increased in concentration over extended incubation periods. Subsequently, scale-up degradation experiments and use of preparative HPLC resulted in the isolation of SphA-Met. Finally, successful structural elucidation of this major degradation metabolite was achieved via extensive 2D NMR spectroscopy and innovative NMR spectroscopy protocols. Bioactivity evaluation of SphA-Met revealed a loss in activity compared to the parent SphA NP, thereby further motivating the necessity to address its undesired degradation behaviour. With the hope of enhancing antiproliferative activity, as well as stability, a semi-synthetic SphA derivative was furnished using olefin cross-metathesis. Although significant improvement in potency was established by our collaborators, stability issues of the semi-synthetic derivative in cell medium persisted. Thus, a final research thrust was directed towards the synthesis of an amphiphilic block copolymer capable of physical encapsulation and protection of the SphA derivative. Pleasingly, the desired PVP-b-PDLLA copolymer was successfully generated and polymeric micelle formation was confirmed. Ultimately, this dissertation encompassed several scientific disciplines focussed on the advancement of rigidin- and SphA-inspired research. In addition to contributions made to the small-molecule synthetic arena, integrated knowledge from separation science, structural elucidation and polymer chemistry was applied towards the different research ventures. Considering the findings, the development of these NP-inspired compounds as efficacious anticancer agents holds much promise.
Biodegradable polymeric prodrugs for the delivery of antimalarial combination therapy
(Stellenbosch : Stellenbosch University, 2019-12) Fortuin, Lisa; Klumperman, Lubertus; Pfukwa, Rueben; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The design and synthesis of a novel polymeric prodrug was achieved for the synergistic antimalarial drug combination of artemether and lumefantrine. To this end, a lumefantrine-conjugated amphiphilic block copolymer (BCP) was self-assembled into micelles with artemether entrapped within the hydrophobic core of the micelles. To develop this, different acid-labile linkages were investigated for their ability to selectively cleave under the low pH conditions of the parasitophorous food vacuole within a Plasmodium-infected red blood cell and remain stable in the neutral pH conditions of serum. The β-thiopropionate ester, amide and maleimide linkages as well as the acetal linkage were studied using 1H NMR spectroscopy-based kinetic analysis, by synthesising seven model drug compounds, where the model drug (aromatic group) was linked to RAFT-made poly(N-vinylpyrrolidone) (PVP). The model system based on the acetal linkage had a t12⁄ of 107 h at pH 5.0, and remained stable at pH 7.4, providing the impetus for its use in the synthesis of the antimalarial polymeric prodrug. The parent BCP of PVP-block-poly(δ-valerolactone) (PVP-b-PVL) was explored and the synthesis optimised to aid in the development of PVP-block-poly(α-allylvalerolactone) (PVP-b-PAVL), used as the polymer carrier in the drug delivery system. To achieve this, hydroxy-functional PVP was applied as the macroinitiator in the ring-opening polymerisation of δ-valerolactone or its allylated derivative, where triazabicyclodecene was found to be the more effective organocatalyst compared with diazabicycloundecene and cocatalyst thiourea. The crystallisation-driven self-assembly (CDSA) behaviour of PVP-b-PVL was studied in detail where spherical micelles, cylindrical micelles and lamellar micelles were observed using TEM analysis. A novel method to induce micellar morphological transitions was developed in the form of the freeze-thaw process. Lumefantrine was conjugated to the BCP in a ‘click’-type reaction via an acetal linkage, after PVP-b-PAVL was carboxylated and functionalised with EGVE. Artemether was physically entrapped within the core of spherical micelles (114 nm in diameter from DLS) using the cosolvent technique with THF as the non-selective solvent and water as the selective solvent for the hydrophilic block, PVP. The targeting ligand, a low molecular weight peptide with sequence ‘GSRSKGT’ was modified to bear thiol groups using succinimidyl 3-(2-pyridyldithio)propionate (SPDP) modification (quantitative) and it was bioconjugated to the BCP prodrug micelles using disulfide exchange (12 ± 3 mol%). The prodrug micelles had a drug loading content of 20.5 wt.%, a critical micelle concentration of 2.0  10-3 mg·mL-1 indicating thermodynamic stability, and remained stable in a simulated physiological environment for up to four days. Negligible haemolysis to RBCs and non-cytotoxicity to HepG2 cells were found. The prodrug micelles can be classified as having good activity towards P. falciparum parasites; however, they exhibit a higher IC50 value of 1021.8 ± 270.9 nM compared with the free drug combination. The developed drug delivery system is robust, tuneable and non-toxic to healthy cells, indicating that it holds potential for its application and further development in therapeutic nanosystems.
Block and graft copolymers as flocculants for wastewater treatment
(Stellenbosch : Stellenbosch University, 2018-03) Narsingh, Udi; Klumperman, Lubertus; Pfukwa, Rueben; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Water pollution, due to toxic metals and organic compounds, remains a serious environmental problem. Many of the contaminants found in industrial and municipal wastewaters are known to be toxic or carcinogenic. Heavy metals are not biodegradable and tend to accumulate in living organisms, causing various diseases. The treatment of these wastewaters involves, among other steps, flocculation to remove, not only the suspended, colloidal particles but also heavy metals and other contaminants that get adsorbed on them. In this research, graft and triblock copolymer flocculants were synthesized to flocculate the suspended solids. For graft copolymerized flocculants, acrylamide was grafted onto cellulose. Cellulose is inexpensive and most abundantly available from plant and microbial resources. Polyacrylamide is a synthetic polymer that is polar and widely used for the treatment of wastewaters. Acrylamide was grafted onto cellulose using a conventional chemical free-radical initiation, as well as microwave-assisted and microwave- initiated methods. The synthesis procedure for each of the methods was optimized for percentage grafting using experimental design with response surface methodology. The optimally synthesized graft copolymer, Cell-g-PAM, from each of the synthesis methods was compared with highly recommended polyacrylamide based commercial flocculants for the flocculation of a model kaolinite suspension. The flocculant synthesized via the microwave-assisted method outperformed all flocculants tested. For triblock flocculants, two ABA type triblock copolymers were synthesized using single electron transfer living radical polymerization (SET-LRP). For both copolymers, the central block was poly(ethylene glycol) (PEG). PEG is a hydrophobic, pH insensitive polymer that adsorbs strongly onto colloidal particles. The first outer block was poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA). PDMAEMA is temperature and pH responsive and known to interact strongly with anionic colloidal particles and heavy metals. The second outer block was polyacrylamide. Various molecular weight triblock copolymers were synthesized and used for the flocculation of a kaolinite suspension. The mechanism of flocculation changed from patch to bridging as the length of the flocculants increased. The graft copolymer flocculants performed better than the block copolymer flocculants in the flocculation of kaolinite.
Bonding 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.
Carbene and coordination complexes of gold, palladium, platinum and manganese derived from N-containing heterocycles
(Stellenbosch : Stellenbosch University, 2001-12) Deetlefs, Maggel; Raubenheimer, H. G.; Stellenbosch University. Faculty of Science. Dept. of Chemistry & Polymer Science.
ENGLISH ABSTRACT: Please refer to fulltext for abstract
Carbene ligand and complex design directed towards application in synthesis and homogeneous catalysis
(Stellenbosch : Stellenbosch University, 2008-12) Stander-Grobler, Elzet; Raubenheimer, H. G.; Cronje, S.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
Alkylated acetonitrile that forms during the synthesis of the sulfonium salt, [(Me3)2(MeS)S][BF4], is involved in the formation of new , -unsaturated Fischer-type carbene complexes from (CO)5M=C(OMe)CH2Li (M = Cr, W). Metal migration observed when the substitution product obtained from the reaction of the anionic carbene complexes (CO)5M=C(NMe2)CºC¯ (M = Cr, W) with Ph3PAu+ was left in solution, was also kinetically and theoretically investigated. 1H NMR and quantum mechanical (at the B3LYP level of theory) data indicated a complicated mechanism. The a,b-unsaturated Fischer-type carbene complex, (CO)5Cr=C(OMe)CH=C(Me)NH(Me), obtained from the reaction of (CO)5M=C(OMe)CH2¯ with alkylated acetonitrile, was transformed into the new remote one-N, six-membered, carbene ligand (rN1HC6) complex, (CO)5Cr=C(CH=C(Me)N(Me)CH=C(nBu). The carbene ligand unprecedentedly preferred the softer Rh(CO)2Cl moiety to the Cr(CO)5 metal fragment and transferred readily. A new series of remote and abnormal square planar compounds [r/a(NHC)(PPh3)2MCl]CF3SO3 (M = Pd or Ni) was prepared by oxidative substitution. The various positions for metal-carbon bond formation on a pyridine ring to furnish various ligand types i.e. C2 for nN1HC6, C3 for aN1HC6 or C4 for rN1HC6 received attention. The ligands were arranged in increasing order of carbene character, aNHC < nNHC < rNHC and trans influence, nN2HC5 ~ aN1HC6 ~ nN1HC6 < rN1HC6. In competitive situations, oxidative substitution occurred selectively at C4 of the pyridine ring rather than at C2 and on the aromatic ring containing the heteroatom (C4), rather than on an annealed aromatic ring (C7). Crystal and molecular structure determinations confirmed the preferred coordination sites. Quantum mechanical calculations (at the RI-BP86/SV level of theory) indicated that the chosen carbene ligand has a much larger influence than the metal on the BDE of the M-Ccarbene bond; the farther away the N-atom is from the carbene carbon, the stronger the bond. In complexes that also contain additional external nitrogen atoms, e.g. trans-chloro(N-methyl-1,2,4- trihydro-2-dimethylaminepyrid-4-ylidene)bis(triphenylphosphine)palladium(II) triflate and transchloro( N-methyl-1,2,4-trihydro-2-dimethylaminepyrid-4-ylidene)bis(triphenylphosphine)nickel(II) triflate, stabilisation originates from both the nitrogens. 2-Chloro-1-methyl-1H-pyrid-4-ylidenephenylammonium triflate afforded complexes with both remote as well as normal nitrogen atoms. New azole complexes of palladium and nickel with remote heteroatoms were also prepared from N-methyl-4',4'-dimethyl-2'-thiophen-3-chloro-2-yl-4,5-dihydro-oxazole. Employing the compound 1,5-dichloroanthraquinone, the product of a double oxidative substitution on two Pd centra could be isolated but not alkylated. The fact that the chemical shift of the metal bonded carbon in the 13C NMR spectrum can not be used as absolute measure of carbene character, was emphasised in a compound where the heteroatom was situated seven bonds away from the carbon donor. In efforts to synthesise a sulphur-bridged complex that contains carbene ligands, crystals of transdi- iodobis(1,3-dimethyl-imidazoline-2-ylidene)palladium were obtained. Bridged thiolato complexes with N1HC6 ligands were unexpectedly found in the attempt to substitute the halogen on chosen square planar carbene complexes of palladium, widening the application possibilities of N1HC6 ligands in organometallic chemistry beyond that of catalysis. A trinuclear cluster, [(PdPPh3)3(μ-SMe)3]BF4 was isolated as a by-product of these reactions. A series normal and abnormal thiazolylidene complexes of nickel and palladium were prepared by oxidative substitution of the respective 2-, 4- and 5-bromothiazolium salts with M(PPh3)4 (M = Pd or Ni), and unequivocally characterised. In a preliminary catalytic investigation, all the thiazolinium and simple pyridinium derived palladium complexes showed activity in the Suzuki-Miyaura coupling reaction. Little variation in activity in the order a (N next to carbon donor) > n > a (S next to carbon donor) was found for the former series, whereas decreased activity was exhibited in the sequence r > a > n of the latter group. The pyridinium derived complexes showed superior activity to the thiazolinium ones. The rNHC complex, trans-chloro(N-methyl-1,2,4-trihydro-2- dimethylaminepyrid-4-ylidene)bis(triphenylphosphine)palladium(II) triflate, showed similar Suzuki-Miyaura activity to the standard N2HC5 carbene complex precatalyst, trans-chloro[(1,3- dimethyl-imidazol-2-ylidene)triphenylphosphine]palladium(II) triflate.
Cation-π induced association and nano-structured aggregate formation of water-soluble [PtII(diimine)(Ln-S,O)]+ complexes examined with high-resolution 1H and DOSY NMR : towards understanding their potential antimalarial activity
(Stellenbosch : Stellenbosch University, 2013-12) Kotze, Izak Aldert; Koch, Klaus R.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Please refer to full text for abstract

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