Department of Chemistry and Polymer Science

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Controlled polymerization of amino acid derivatives
(Stellenbosch : University of Stellenbosch, 2008-03) Van Kralingen, Leon; Bredenkamp, M. W.; Sanderson, Ron D.; University of Stellenbosch. Faculty of Science. Dept. of Chemistry and Polymer Science.
This dissertation can be broken into two parts comprising different strategies to synthesise novel poly-amino acid based polymers. The use of recently developed nickel(0) and cobalt(0) metal catalysts for the living polymerization of α-amino acid-N-carboxyanhydrides (NCAs) to synthesise novel poly-amino acid polymers, comprising a polar, hydrophilic block and a neutral hydrophobic block, were investigated in the first part of this study. The hydrophilic block was made up of a random sequence of arginine (Arg, R), glycine (Gly, G) and aspartic acid (Asp, D) - poly-RGD. This was followed by a polyleucine (Leu, L) hydrophobic block. Success was limited with this system due to polymer precipitation during the polymerization reaction. Because of this precipitation, the amino acid composition of the hydrophilic block was changed to a random sequence of glutamic acid (Glu, E), cystein (Cys, C) and aspartic acid – poly-ECD. Here also, the success was limited because of polymer precipitation. A novel approach to the synthesis of hybrid poly-amino acid – synthetic polymer materials constitutes the second part of this study. The final polymeric structure can be described as a carboxylic acid functionalized polyethylene glycol (PEG) sheathed polylysine polymer. The technology involves the synthesis of a lysine NCA functionalized at the ε-amino group with an α,ω-bis(carboxymethyl) ether PEG. The distal carboxylic acid group was protected as a benzyl ester during synthesis and subsequent polymerization of the PEG-lysine-NCA macro-monomer. The polymerization was successfully initiated using n-butyl amine to form short homopolymer strands. Copolymerization with lysine-NCA was also achieved as well as the successful initiation using a generation 1.0 dendritic amine initiator, N,N,N’,N’-tetrakis(3-aminopropyl)-1,4-butanediamine (DAB-Am-4). These polymers were characterized by 1H NMR.
Ligand modification of Pluronic F108 for use in immobilized metal affinity separation of bio-macromolecules
(Stellenbosch : Stellenbosch University, 2002-03) Van Kralingen, Leon; Adendorff, H. J. A.; Bredenkamp, M. W.; Stellenbosch University. Faculty of Science. Dept. of Chemistry & Polymer Science.
ENGLISH ABSTRACT: Inthis work we aim to put into place a system to separate or immobilise biomacromolecules by means ofimmobilised transition metal ions like nickel(II) or copper(II). Although the concept of immobilised metal affmity chromatography (IMAC) has been around since the early 1960's, the metal ions were always immobilised by covalent modification of the support matrix. Recently the concept of IMAC was applied to membranes, and again the metal ion was immobilised by covalent modification of the membrane surface. Inthis study we covalently modified the support matrix by attaching a linear, EDTA type ligand to the hydroxy end groups of a tri-block copolymer (polyethylene oxide (PEO)m = 129 - polypropylene oxide (PPO)n = 56 - polyethylene oxide (PEO)m= 129), Pluronic® F108. The middle block of this polymer, which is hydrophobic, will non-covalently adsorb onto the membrane surface through hydrophobic interaction. The hydrophilic outer blocks, with the ligand modified end groups, will associate with the aqueous substrate exposing the chelated metal ion for interaction with the bio-macromolecules. This affords a system which is recyclable, without replacing the membranes, simply by stripping the expired ligand modified-polymer and adsorbing fresh polymer. A series of model ligands and their complexes were synthesised and characterised, to study the coordination of the ligand around the metal ions. The model compounds were also essential in characterising the final product - the ligand modified Pluronic. Finally the ligand modified Pluronic was tested for its metal binding capabilities. This was done in aqueous solution by qualitatively comparing the UV-VIS spectra of the modified Pluronic with that of the model ligands and complexes. The spectra indicate that metal coordination does take place.
Self-assembly of new porous materials
(Stellenbosch : University of Stellenbosch, 2009-03) Jacobs, Tia; Barbour, Leonard J.; Bredenkamp, M. W.; University of Stellenbosch. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The primary objective of the work was to prepare and investigate new porous materials using the principles of crystal engineering. Both organic and metal-organic systems were studied and the work can best be divided into two separate sections: 1. The crystal engineering of Dianin’s Compound, a well-known organic host. 2. The design and synthesis of a series of related porous coordination compounds consisting of discrete, dinuclear metallocycles. The first section discusses the synthetic modification of Dianin’s compound in order to engineer a new clathrate host with an altered aperture size. Although this study ultimately failed to isolate the host material in its porous guest-free form, the work led to the discovery of a chiral host framework that aligns guest molecules in a polar fashion, and consequently displays non-linear optical properties. These findings are unprecedented in the long history of crystal engineering of Dianin’s compound and its analogues. This section also describes desorption studies of the new inclusion compound, as well as the known thiol analogue of Dianin’s compound. Systematic characterisation of these desorbed phases has raised interesting fundamental questions about desolvation processes in general. The second section constitutes the major portion of the work. A series of related isostructural coordination metallocycles were synthesised and their structure-property relationships were investigated using a variety of complementary techniques. These metallocyclic compounds all crystallise as solvates in their as-synthesised forms, and different results are obtained upon desolvation of the materials. In each case, desolvation occurs as a single-crystal to single-crystal transformation and three new “seemingly nonporous” porous materials were obtained. A single-crystal diffraction study under various pressures of acetylene and carbon dioxide was conducted for one of the porous metallocycles. This enabled the systematic study of the host deformation with increasing equilibrium pressure (i.e. with increasing guest occupancy). The observed differences in the sorption behaviour for acetylene and carbon dioxide are discussed and rationalised. Gravimetric gas sorption isotherms were also recorded for the three different porous materials and the diffusion of bulkier molecules through the host was also investigated structurally. Finally, a possible gas transport mechanism is postulated for this type of porous material (i.e. seemingly nonporous), and this is supported by thermodynamic and kinetic studies, as well as molecular mechanics and statistical mechanics simulations.
Structure activity relationship studies of ochratoxin A analogues
(Stellenbosch : Stellenbosch University, 2002-03) Gabrielli, William Fullard; Bredenkamp, M. W.; Steyn, P. S.; Stellenbosch University. Faculty of Science. Dept. of Chemistry & Polymer Science .
ENGLISH ABSTRACT: Mycotoxins have assumed worldwide importance due to the ubiquitous occurrence of toxigenic fungi, their infestation of plant-based foods and feeds and the subsequent economical and health impact it because of their contamination of commercial products. Ochratoxin A (OA) is a nephrotoxic mycotoxin produced by isolates of Aspergillus ochraceus and Penicillium verrucosum and occurs frequently in nature. The major target for toxicity of OA in mammalian species is the kidneys and it has been the major cause of Danish Porcine Nephropathy. OA has also been extensively implicated in the aetiology of Balkan Endemic Nephropathy and Chronic Interstitial Nephropathy in Northern-Africa. Furthermore, OA has been identified as a carcinogen, an immunosuppressant and a teratogen with respect to the foetal central nervous system. Although a large amount of research has been conducted into the chemical nature of the toxicity of OA, the exact molecular mechanism of action of OA is not yet conclusive. Numerous structure activity relationship studies have suggested that the toxicity of OA may be assigned to three major processes: (i) inhibition of ATP production; (ii) inhibition of protein synthesis; and (iii) the disruption of hepatic microsomal calcium homeostasis through the promotion of membrane lipid peroxidation. It is the aim of this thesis to gain a better understanding, through the synthesis ofOA analogues, of the chemical structure responsible for the toxic function of the ochratoxins. The halogen-group has extensively been implicated in the toxicity of the ochratoxins. This is evident in ochratoxin B (OB), the dechloro analogue of OA, which is approximately ten times less toxic than OA. Preliminary tests have indicated that bromo-ochratoxin B(BrOB), the bromo analogue of OA, is more toxic than ochratoxin A to renal cells. Fluoro-ochratoxin B and other analogues of OA, where other amino acids are incorporated, should provide invaluable information on the structure-activity relationships and the mode of action of the ochratoxins. Our research effort addresses both these aspects (i) fluorination of the dihydroisocoumarin moiety and (ii) the coupling of different amino acids and dipeptides to the non-toxic hydrolysed product of OA, ochratoxin a. Chapter one includes a review of the important biological aspects of OA that has served as a guideline to the synthesis of effective OA analogues. An overview of the relevant chemistry involved in the modification of OA will conclude the chapter. Chapter two entails a discussion of fluorine in bio-organic chemistry. This includes an overview of the impact that fluorine substitution has on the biological reactivity of molecules. A review on the synthesis of organofluorine compounds, which forms the emphasis of this study, concludes the chapter. Chapter three elaborates on the different methodologies used in our attempts to synthesise fluoro-ochratoxin B and other analogues. These included the direct electrophilic fluorination of OB and different analogous aromatic model compounds by xenon difluoride, N-fluorobenzenesulfonimides and Selectfluor™ as fluorinating agents. Also involved is an investigation into an alternative route for the synthesis of fluoro aromatic compounds from bromo and chloro analogues by means of palladium catalysed trimethyl- and tributylstannyl and trimethylsilylation which in tum may be substituted with fluorine by means of xenon difluoride. Efforts towards the direct catalytic fluorosubstitution of aryl halides are also investigated. The synthesis of a key intermediate, fluoroacetoacetaldehyde, in a de nova synthetic route to fluoroochratoxin B is also discussed. Furthermore, the synthesis of novel OA analogues with respect to the replacement of the L-phenylalanine moiety is addressed. This includes the conversion of OA to Oa, by acid hydrolysis, followed by the coupling of ortho-, meta- and para- substituted DL-fluorophenylalanine to the lactone acid. This is followed by the synthesis of histidylhistidine methyl ester and attempted coupling to Oa. The coupling of halosalicylic acids and salicylic acid to L-phenylalanine, for use as model aromatic substrates for fluorination, IS discussed. Peptide coupling by dicyclohexylcarbodiimide carboxyl activation, with reference to the protection of the phenolic hydroxyl group in 5-chlorosalicylic acid for application to Oa, concludes this work.
Synthesis and electrochemistry of biodegradable ligands - iminodiglutaric acid and iminoglutaricsuccinic acid - and their complexes with selected metal ions (Zn²⁺, Cd²⁺, Cu²⁺)
(Stellenbosch : Stellenbosch University, 2004-12) Yohannes Desta, Yonas; Crouch, A. M.; Bredenkamp, M. W.; Stellenbosch University. Faculty of Science. Dept. of Chemistry & Polymer Science.
ENGLISH ABSTRACT: Two new potentially biodegradable aminopolycarboxylic acid ligands, iminodiglutaric acid tetra sodium salt (IDG-4Na) and iminoglutaricsuccinic acid tetra sodium salt (IGS- 4Na), were synthesized in reasonably good yield and purity. The commercially unavailable precursor for the two ligands, ethyl p-aminoglutarate, was synthesised in high yield and purity, and together with the two ligands were fully characterized by means of melting point measurements and various spectrometric techniques CH-NMR, 13C-NMR, MS and IR). For the first time, an electrochemical study has been conducted on the complexes of these ligands with selected transition metal ions (Zn2+, Cu2+ and Cd2+). An electrochemical technique, cyclic voltammetry (CV), was utilized on the study of the complexing ability of the ligands to the selected metal ions. An electrochemical cell comprising three electrodes was employed: thin film mercury coated carbon microelectrode was used as the working electrode, a Platinum wire as the auxiliary electrode, and a Ag/AgCI as the reference electrode. CV has been used and proven to offer a convenient route towards the determination of metal-ligand complex stability constants in aqueous media". The values of the logarithms of the metal-ligand formation constants obtained by this technique, when compared with other widely used aminopolycarboxylic acids (APCAs), show better complexing ability of the ligands with the transition metal ions. When the two ligands are compared, IGS showed greater affinity towards the selected transition metal ions. This is due to the fact that, in aqueous media, as the side chain ligators decrease, the stabilization energy of the complex increases. The formation stability constants were determined by plotting the change in the reduction potential (ΔE) against solution pH. A process making use of a modification of lingane equation was used.
Synthesis of chiral thiourea ligands and their transition metal complexes
(Stellenbosch : Stellenbosch University, 2003-12) Ghebregziabiher Berhe, Haile; Koch, K. R.; Bredenkamp, M. W.; Stellenbosch University. Faculty of Science . Dept. of Chemistry & Polymer Science.
ENGLISH ABSTRACT: Modification of chitosan with benzoylisothiocyanate was attempted, however due to solvent problem the study was left incomplete till appropriate solvent is designed. N,N-diethyl-N -camphanoylthiourea (HL8), N-piperidyl-N '-camphanoylthiourea (HL9), N-pyrrolidyl-N -camphanoylthiourea (HL10) and N,N-diethyl-N -adamantylcarbonyl thiourea (HL11)have been synthesised and characterised for the first time. Two of these ligands HL8 and HL11, were used to form a number of transition metal complexes, namely H30+{fae-[Co(L8-S,Obn, cis-[Ni(L8-S,0)2], trans-[Cu(L8-S,0)2], translcis-[Zn(L 8_S,0)2], translcis-[Pt(L 8_S,0)2], Ag2[(HL8-S)(L-J.1-S,O)]2, translcis- [Ni(L11-S,O)2]and translcis-[Cu(L11_S,O)2]. The new products are fully characterised by means of MS, IR spectroscopy, NMR spectroscopy, elemental (C, H, Nand S) analysis and melting point determinations. The H30+{fae-[Co(L8-S,Obn, cis-[Ni(L8- S,O)2], trans-[Cu(L8-S,O)2] and Ag2[(HL8-S)(L-J.1-S,O)]2 are also characterised by Xray diffraction analysis. The structure of the new chiral N,N-dialkyl-N' -camphanoylthiourea ligand (HL8) has a significant effect on its coordination chemistry with transition metal ions. This ligand forms H30+ {fae-[Co(L8-S,Obn, cis-[Ni(L8-S,0)2], trans-[Cu(L-S,O)2] and Ag2[(HL8- S)(L8-J.1-S,O)]2 complexes with the Co(II), Ni(II), Cu(II) and Ag(I) metal ions respectively. The spectroscopic and X-ray diffraction results of these complexes indicate a bidentate mode of coordination of the ligand (with its Sand °donor atoms) to the Co(II), Ni(II) and Cu(II) metal ions. The reaction of this ligand with silver(I) however affords the formation of a binuclear silver(I) complex exhibiting monodentate and bidentate modes of coordination within the same complex. The exclusive formation of trans-[Cu(L8-S,0)2] is a new phenomenon for the HL type thiourea ligands with Sand °donor atoms. Up to this point a maximum of 15 % trans-isomer has been reported in ltterature." All the transition metal complexes made with HL8and HL11are air stable in both the liquid and solid states except the H30+{fae-[Co(L 8-S,Ob]} Interestingly the deep green fae- H30+{fae-[Co(L8-S,Obn complex is air sensitive and the Co(II) oxidizes to Co(III) in the complex by atmospheric O2. The oxidation of Co(II) to Co(III) in the complex is confirmed by 1Hand 13CNMR spectra as well as by UV-Visible spectra of the complex. The NMR spectra of the complexes indicated the presence of one isomer in each complex except for the NMR spectra of the platinum complex of the HL8 ligand. The presence of the minor trans-[Pt(L8-S,Q)21 isomer in combination with the major cis-[Pt(L8-S,Q)21 isomer in the platinum complex was indicated by the 1H, 13Cand 195ptNMR spectra of the complex.
Synthesis, structure and coordination chemistry of new monopodal and bipodal thiocarbamic esters and acyl(aroyl)-substituted ureas with Ni(II), Pd(II), Pt(II) and Cu(II)
(Stellenbosch : Stellenbosch University, 2006-12) Blewett Gavin; Koch, Klaus R.; Bredenkamp, M. W.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: N-acyl(aroyl)-N',N'-dialkylthioureas have resulted in a number of potential industrial and analytical applications within the platinum group metals (PGM) industry. N-acyl(aroyl)thiocarbamic-0-alkyl esters and N-acyl(aroyl)-N',N'-dialkylureas are remarkably similar in connectivity and molecular geometry to the N-acyl(aroyl)-N',N'-dialkylthioureas and are therefore of interest as structural analogues. A systematic study was made of the influence of variation of the N-acyl(aroyl) moiety, as well as the 0-alkyl moiety of N-acyl(aroyl)thiocarbamic-0-alkyl esters, on the coordination geometry of this class of ligand to nickel(II), palladium(II) and platinum(II). Numerous single crystal X-ray analyses were undertaken on both the non-coordinated ligands as well as the resultant complexes in order to elucidate the effect these variations have on the molecular structures and the overall crystal lattices. Particular attention was paid to the effect that these variations have in the solid state on the carbon-nitrogen bond lengths within the non-coordinated ligands as well as the derived metal complexes. A systematic study was also undertaken of the steric and electronic influences of electron rich substituents introduced onto the aroyl moiety of the N-acyl(aroyl)thiocarbamic-0-alkyl esters on the metal-oxygen bond lengths within the derived 0-alkyl-N-aroyl-thiocarbamato complexes. A parallel investigation was carried out on a series of N-acyl(aroyl)-N',N'-dialkylureas to elucidate the effect of the variation from bidentate (S, 0)-donor atoms sets to the ( 0,0 ')-donor atom sets. The molecular structures of several N-acyl(aroyl)-N',N'-dialkylureas as well as several copper(II) complexes thereof were determined and used to investigate the steric and electronic influences the N',N'-dialkyl and N-acyl(aroy) variations within this series have on the coordination of this class of ligand. The resultant scarcity of trans- or anti-( 0, 0 ') chelates was also investigated from an electronic and steric perspective of the ligands and their coordination mode to the metals investigated. The first example of a trans- or anti-( 0, 0 ') copper complex of this class of ligand was successfully isolated and fully characterised. Furthermore, the theme has been expanded to incorporate the preparation and characterisation of bipodal equivalents to the simple monopodal N-acyl(aroyl)thiocarbamic-0-alkyl esters. These bipodal compounds potentially add a 'supramolecular' and 'self assembly' dimension to the Nacyl( aroyl)thiocarbamic-0-alkyl ester motif. The first crystal structures of this type are reported and include an interesting case of polymorphism. The coordination of this class of bipodal ligand to several platinum group metals as well as copper was investigated.
Tin-bemiddeling van inositolderivatisering
(Stellenbosch : Stellenbosch University, 2000-03) Prinsloo, Mare-Loe; Bredenkamp, M. W.; Stellenbosch University. Faculty of Science. Dept. of Chemistry & Polymer Science .
ENGLISH ABSTRACT: The aim of this thesis is to use tin-mediated reactions to differentiate between the four zones in the myo-inositol ring that consists of five contiguous equatorial and one axial hydroxyl groups. It is expected to give chemical control over the hexitol that can be put to good use in commercializing the phosphate derivatives of myo-inositol that are of pharmaceutical value. As point of departure 1,2-0-cyclohexylidene-myo-inositol (II.I) was synthesized that contains a tetrol with one end adjacent to an axial acetal oxygen and the other end adjacent to an equatorial acetal oxygen. The selective protection of position 3 (Dmyo- inositol) was investigated. Various problems lead to the selective silylation of the acetal at position 5. The silane forms the basis of the subsequent investigation because the cyclitol is now divided into an isolated mono-ol and a trans-diol allowing for easier differentiation between the various hydroxyl groups. It was indeed possible to differentiate the trans-diol from the mono-ol by using carbonylation and allylidenation. Ring closure occurs in both cases. In the carbonylation case the resultant five-membered ring is less stable than that of the allylidene due to the Sp² hybridized carbon atom of the carbonate compared to theSp³ hybridized carbon of the allylidene group. Preliminary work was done on the racerrue 1,2-0-cyclohexylidene-myo-inositol (II.VII) in order to use the acquired technology on the chiral camphor analog. The transition from racemic to chiral proved problematic since the camphor acetal is difficult to prepare and its selective silylation differs from that observed for cyc1ohexylidene. The camphor acetal itself was silylated in the process. (S)-( -)-Camphanic chloride was therefore used as chiral auxiliary in the protection of position six of the racemic 1,2,3,4,5-protected myo-inositol, thus solving the problems encountered in the protection of position six whilst combining the protection and chiral induction steps. The resultant diastereomers could both be used in the synthesis of IP₃ and IP₄ respectively, eliminating the disposal of half ofthe product. This project lead to the development of useful chiral differentially protected myoinositol derivatives, which could be useful in synthesis of various other myo-inositol derivatives. Besides the synthesis of useful chiral differentially protected myo-inositol derivatives, this investigation developed new applications in the tin-mediated derivatization of sugars. The following compounds were synthesized during this investigation. Bold numbers indicates novel compounds.

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