Department of Chemistry and Polymer Science

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Applications of inherently chiral calix[4]arenes
(Stellenbosch : Stellenbosch University, 2013-03) Van Laeren, Laura Jane; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Calixarenes are large cyclic molecules that have a distinctive bowl-shaped geometry. The nonplanar nature of these molecules means that, by selectively functionalizing the calixarene on one side of the symmetry plane, one introduces inherent chirality. As with other varieties of chirality, this asymmetry can be utilised to impart stereoselectivity to the formation of new bonds through asymmetric catalysis. The evaluation of inherently chiral calixarenes has been hindered thus far by the difficulty in obtaining enantiomerically pure samples. Using a recently developed stereoselective methodology, incorporating chiral oxazoline directed ortholithiation, the synthesis of a series of upper-rim meta-substituted inherently chiral calixarenes is described. With the use of this methodology, the desired calixarene ligands are synthesised in high diastereoselectivity (from 75% de to >99% de). The inherently chiral meta-substituted bidentate thioether-oxazoline calixarenes synthesised were subsequently investigated as asymmetric ligands for palladium catalysed allylic alkylation. The debutylated series of calixarenes showed good catalytic efficiency, achieving high levels of conversion (>90% isolated yield). A rate enhancement relative to a planar model system was observed. Moderate levels of enantioselectivity (31% ee to 89% ee) were achieved. The influence of the central chirality of the chiral oxazoline was determined to be the predominant stereoselective effect. Increasing the steric bulk on this chiral carbon resulted in a significant increase in the stereoselectivity. Inherent chirality was found to have a subtle but significant effect. Increasing the steric bulk on the calixarene bowl, through the use of analogous tert-butylated calixarene, had an adverse effect on the catalytic efficiency. These ligands formed unstable complexes that decomposed before any appreciable yield of the desired product could be formed.
A C-H Activation Route Toward Inherently Chiral Calix[4]arenes
(Stellenbosch : Stellenbosch University, 2019-12) Visagie, Kevin Johan; Arnott, Gareth E.; Stellenbosch University. Faculty of Sciences. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT:The unique three-dimensional structure of the calixarene molecule allows it to possess, what is known as, inherent chirality. The compound, therefore, has potential application in various host-guest chemistry interactions. Our group is interested in developing new methods of synthesizing meta-functionalized inherently chiral calix[4]arenes. Recently, it has been demonstrated that ortho-halogenated N-aryl methyl carbamates may be selectively synthesized in acidic conditions through a Pd(OAc)2 assisted C-H activation. However, our research showed that when brominating a methyl (4-methoxyphenyl)carbamate without the inclusion of the catalyst, the regioselectivity of the reaction was not compromised. With this in mind, we investigated the role of the Pd(OAc)2 and the carbamate directing group when synthesizing meta-brominated inherently chiral calix[4]arenes. On a mono-substituted carbamate calix[4]arene system, we found that meta-brominated inherently chiral calix[4]arenes could be synthesized in high yields (85–90%), either through electrophilic aromatic substitution or C-H activation. After establishing the reaction conditions, we attempted to asymmetrically brominate the calix[4]arene by making use of a chiral 1(S)- (+)-menthyl carbamate directing group. For the reactions that included the catalyst, slightly higher yields were obtained compared to the reactions that did not. It was also found through alpha-D experiments that the Pd(OAc)2 assisted reactions resulted in a higher specific rotation. Unfortunately, no further evidence of diastereoselectivity could be obtained as the respective 1H NMR spectra showed no obvious differences and attempting to separate the diastereomers using HPLC proved unsuccessful. We also demonstrate for the first time that meta-functionalized inherently chiral calix[4]arenes of C4 symmetry can be synthesized through direct modification. This was achieved by making use of a methyl N-aryl carbamate directing group in an acid catalyzed electrophilic aromatic substitution. Purification was burdened with issues of isolating co-forming achiral stereoisomers, however, the desired inherently chiral calix[4]arene was finally isolated in yields as high as 40%.
Co-crystallisation with 1,2,3,5-dithiadiazolyl radicals
(Stellenbosch : Stellenbosch University, 2012-03) Robinson, Sean Wade; Haynes, Delia A.; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry & Polymer Science.
Please refer to full text for abstract
Inherently chiral calixarenes; methodology and applications
(Stellenbosch : Stellenbosch University, 2016-12) Castell, Dominic Christian; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The use of chiral directing groups has provided an efficient route to meta-functionalised inherently chiral calixarenes. Previously reported ortholithiation methods, incorporating chiral oxazolines have been reexamined, with the aim of revising the individual roles of the three major components of the reaction. The potential mechanistic ramifications of the solvent, additive and alkyllithium structure on the reaction outcomes were individually evaluated. The overarching complexity inherent in this chemistry, coupled with a wide scope of experimental results, point to a number of substrate, solvent and also reagent dependent reaction mechanisms. In addition to the oxazolines, the tert-butyl sulfoxide functional group has also been established as an effective chiral auxiliary for this ortholithiation strategy, yielding enriched diastereomeric mixtures of inherently chiral sulfoxide calixarenes. The absolute stereochemistry of these major and minor products were determined crystallographically. Despite restrictions in electrophile choice, an efficient desulfurization method afforded a route to a new class of meta-functionalised inherently chiral compounds. With the view to evaluating the potential of inherent chirality, oxazoline-directed ortholithiation methods were used to synthesize a new class of inherently chiral phosphine oxazoline ligands. The results from the application studies of these compounds, to both the Tsuji-Trost allylation and asymmetric Suzuki coupling reactions, suggested a definitive relationship between the configurations of the inherent chirality of the calixarene, and central chirality of the oxazoline auxiliary. A model of the -allyl palladium intermediate responsible for the enantioselection seen in the Tsuji-Trost reaction has been proposed for these calixarene ligands. The model was constructed using previously reported calixarene crystallographic data, in conjunction with numerous solid-state and computational studies of simpler Phox ligand systems. The experimental results obtained for this reaction were found to be in good correlation with the proposed model for the inherently chiral calixarene ligands. To confirm these observations, two additional inherently chiral Phox ligands, lacking a stereocenter on the oxazoline, were synthesized. Their preliminary application to the Tsuji-Trost allylation also yielded enantiomerically enriched product mixtures. These results point to a significant contribution made by the inherent chirality, toward the overall asymmetric induction observed in the reaction. These findings serve as a positive affirmation of the viability of inherently chiral calixarenes in the field of asymmetric catalysis, and create a platform for further development of new ligands containing this structural property.
Investigation into the bromination of calixarenes
(Stellenbosch : Stellenbosch University, 2020-08) Snayer, Trégen Michael; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science
ENGLISH ABSTRACT: Calixarenes are large bowl-shaped molecules consisting of an upper rim, lower rim, and methylene bridges. The most interesting feature of these compounds is that asymmetric modifications of these regions allows for the formation of inherent chiral calixarenes. Key to the formation of these compounds are the brominated calixarenes as the bromine group can easily be substituted via electrophilic aromatic substitution reactions. Most methods for achieving their synthesis involve debutylation of p-tertbutylcalixarene followed by careful addition of molecular bromine or N-bromosuccinimide. Recently, our group has discovered that bromination of p-tert-butylcalix[4]arene using chlorinated solvents show potential for the synthesis of ipso-brominated calix[4]arenes. This thesis reports the results of an investigation into the ipso-bromination of p-tert-butylcalix[4]arene. Initial attempts were made to synthesise mono- and dibromo calixarenes, but unfortunately efficient synthetic procedures could not be produced for these compounds. In the case of the monobromo compound, the synthesis proved challenging due the formation of spirocalixarenes when using chloroform as solvent while attempts in dichloromethane led to over-brominated products. Good conversion was achieved for the dibromo calix[4]arenes, however this always gave a mixture of distal and proximal calix[4]arenes with poor selectivity for either compound observed. Purification for all of these compounds also proved highly challenging. Successful synthesis of tri- and tetrabromo calix[4]arene was achieved with the pure compounds isolated in 60-64% and 85-90% yields respectively. Both compounds were found to be sensitive to temperature with the control of temperature key to achieving reproducibility. The role of light was carefully investigated as it was shown to heavily affect the ipso-bromination process. Reactions performed under a light source often resulted in benzylic bromination of toluene consequently hindering the ipso-bromination reaction. This led to the synthesis of these compounds being performed in the absence of light. While toluene was shown to affect the bromination process in the presence of light, it appeared to promote this process in its absence. This led to an investigation into its role, however there was no information found in literature or through experimental studies that helped to explain this phenomenon. The influence of radicals was also investigated with it being shown that their promotion negatively effects the bromination reaction due to increased bromination of toluene. Attempts at radical trapping proved unsuccessful as the trap used in this study proved to be inadequate for the trapping of bromine radicals. Importantly, the results of this study show that bromination of p-tert-butylcalix[4]arene can afford ipsobrominated product through a one-step synthesis.
An investigation into the functionalization of poly(styrene-co-maleic anhydride) with calixarenes and their potential applications
(Stellenbosch : Stellenbosch University, 2019-12) Eghbali Dogaheh, Seyed Babak; Arnott, Gareth E.; Mallon, P. E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: This work describes the development of a new method for the synthesis of a calixarene grafted polymer. The method involves synthesizing a mono-alkylated calixarene that contains an amino-tether suitable for grafting onto polymers such as the polystyrene-maleic anhydride copolymer (PSMA). The amino-tether was synthesized through a Gabriel synthesis on the parent phthalimide-derivatized calix[4]arenes. Having successfully optimized the method, the next stage investigated the potential applications for this technology. Two divergent applications were investigated: 1) a colorimetric mercury sensor, and 2) supramolecular hydrogel formation. The first application was based on the known sensing ability of functionalized calixarenes for the detection of different guests (cations, anions, neutral species, etc.). The most interesting one has been the colorimetric approach. Of interest in this work was the reported distal bis- allyl bis-arylazo calix[4]arene (also known as Chung’s sensor), which is capable of detecting mercury cations with a rapid color change in the solution media (yellow to pink). Therefore, a polymer-supported version of the same calix[4]arene was targeted for synthesis to facilitate the formation of a sensing instrument for mercury. Despite all efforts (trying eight synthetic routes), the required functionalized calixarene could not be obtained. Several suggestions for future work have been offered to solve this challenge. The second application aimed at in this project was to attach water-soluble calix[4]arenes to PSMA in order to make the polymer water soluble and to form a potential hydrogel. The most well-studied compound in this category has been the p-sulfonated calix[4]arene, which has been shown to form supramolecular complexes with bis-quaternary amines in aqueous solution. The possibility to achieve hydrogelation through a p-sulfonated calix[4]arene-grafted PSMA was therefore investigated. The primary amine-tethered p-sulfonated calix[4]arene was successfully synthesized and grafted onto PSMA. Unfortunately, the resulting grafts were unable to form a hydrogel in the presence of multiple quaternary amine-based compounds in spite of varying a large number of experiment parameters (i.e. stoichiometry, pH, temperature, concentration and so forth). One problem was that the grafts were not as water soluble as expected. Thus a second option was to replace PSMA with another polymer with higher water solubility upon grafting with the calix[4]arene. The polymer investigated was a polyvinylpyrrolidone maleic anhydride copolymer (PVP-MA). The grafting reaction was successfully carried out and much higher water solubility for the graft was achieved, but once again a hydrogel could not be formed. It is believed that this failure most likely is due to the conformational issue of the calix[4]arene or the low degree of functionalization for the grafts. Several solutions to this these failures have been proposed.
Oxazoline directed lithiation of Calix[4]arene and Ferrocene
(Stellenbosch : Stellenbosch University, 2011-12) Herbert, Simon Anthony; Arnott, Gareth E.; Stellenbosch University. Faculty of Sciences. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: The use of chiral oxazoline directed lithiation provides a highly diastereoselective (up to >99% de) route to meta functionalised inherently chiral calixarenes. This methodology can be used on both the butylated and debutylated calixarene systems and is tolerant of a wide range of different electrophillic quenches allowing access to a structurally diverse range of inherently chiral metafunctionalised calixarenes. The oxazoline directing group can be removed via hydrolysis, generating a range of functionalised calixarene carboxylic acids in high ee. We also demonstrate that the use of derivative alkyllithiums such as cyclopentyl lithium can provide significantly enhanced diastereoselectivity over the conventional organolithiums such as sec-butyl lithium, when employed in ortholithiation reactions of this nature. The differences in diastereoselectivity associated with the different alkyllithiums can be tied, in certain cases, to the steric bulkiness associated with the individual reagents. In this regard we have found that the use of the so called Tolman angle or cone angle approach allows quantification of the relative steric bulk of the alkyllithium. We also detail that the oxazoline directing group provides a hitherto unknown ability to be diastereoselectively tuned through the choice of the ligand system in the ortholithiation reaction. In this regard the development of a series of diglyme based ligands have proved to provide a highly diastereoselective means of inverting the chirality from that which the use of the conventional TMEDA ligand is able to generate (up to –92% de). The use of diglyme ligands to invert the sense of chirality is also shown to occur on the ferrocenyloxazoline system and presents an apparently general and hitherto unknown facet of asymmetric oxazoline directed ortholithiation. This diglyme induced inversion has been shown to be controlled through a secondary nitrogen coordinated mechanism that is able to operate with chiral oxazolines.
Resorcin[4]arene based N-heterocyclic carbenes as catalysts for carbon-carbon formation
(Stellenbosch : Stellenbosch University, 2016-12) Ngodwana, Lonwabo; Arnott, Gareth E.; Van Otterlo, Willem; Stellenbosch University. Faculty of Science. Chemistry and Polymer Science.
ENGLISH ABSTRACT: Resorcin[4]arenes are 3-dimensional cyclic tetramers belonging to a class of compounds called cyclophanes. Because of their properties, including several sites of functionalization and possession of a cavity, these compounds found their way into several applications. These include cation extraction, ion exchange mimics, molecular switches and catalysis. The latter is still at its infancy. This work was aimed at developing the first examples of resorcin[4]arene based Nheterocyclic carbene (NHC) complexes of palladium and evaluating their potential for catalysis of carbon-carbon bond formatting reactions. Using an ortholithiation technology that was developed in our group, a distally functionalized resorcin[4]arene di-ester was prepared. The reduction of the ester and bromination of the resulting di-ol led to a distal bromomethylresorcin[4]arene. The reactions of this new resorcin[4]arene with a variety of N-alkylimidazoles gave a small library of resorcin[4]arene imidazolium NHC precursor salts. Initially, the preparation of a bidentate palladium complex from the salts was attempted. The metal complex was isolated in 35% yield from an N-mesityl imidazolium salt. When the preparation of a dinuclear metal complex series, i.e. PEPPSI, was attempted, the compounds in this class could be isolated in yields over 90%. Although these compounds show the expected coordination modes (square-planer Pd center), they showed some variations in solid state conformations. Resorcin[4]arene NHC compounds, both pre-formed and prepared in situ, were evaluated for catalytic ability in the Suzuki-Miyauri and Tsuji-Trost reactions. These compounds could facilitate moderate to complete conversion of starting materials to products.
Selective distal functionalization of resorcinarenes via an ortholithiation approach
(Stellenbosch : Stellenbosch University, 2012-12) Ngodwana, Lonwabo; Arnott, Gareth E.; Van Otterlo, Willem; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Resorcinarenes are tetramers, belonging to a class of [1]4metacyclophanes, easily formed by the acid- or base-catalysed condensation of resorcinol and aldehydes. Properties include, amongst others; bowl-like shape, adhesion to hydrophilic surfaces and formation of hexameric capsules. Their uses are, to mention some: components in liquid crystals, photoresistors, selective membranes, surface reforming agents, HPLC stationary phases, ion-channel mimics, metal-ion extraction, molecular switches and ligands for metal catalysts. Selective functionalization of resorcinarenes has been explored and achieved via relatively inefficient methodologies which limit studies, structural architecture and new applications. In this work, synthesis of C4v symmetric resorcinarene ethers was performed which were used as templates in undertaking studies towards selective derivatisation of resorcinarenes via an ortholithiation approach. Conditions for the efficient synthesis of distally substituted resorcinarenes using ortholithiation were optimized and tested with a range of electrophiles, lower rim lengths, scale, base equivalents, reaction times and solvent effects. Ortholithiation gave distally substituted resorcinarenes in reasonable yields (>80%). Ortholithiation and its ability to form distal-resorcinarene esters could possibly be used as a way to synthesize distal-chloromethyl resorcinarene precursors whose further functionalization would furnish a range of distal-resorcinarene imidazolium salts, a class of distal bidentate carbene ligand staring materials for transition metal coordination.
Studies in the selective synthesis of bidentate resorcinarene ligands
(Stellenbosch : University of Stellenbosch, 2010-03) Kleinhans, Dewald Johannes; Arnott, Gareth E.; University of Stellenbosch. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Resorcinarenes are macrocyclic products formed from the condensation of aldehydes (aliphatic or aromatic) and resorcinol and have been used in a wide range of applications since their first synthesis. Applications include: HPLC stationary phases for the separation of pyrimidine bases, racemic drugs and isomers, the selective extractions of lanthanides and actinides, as molecular receptors, catalysis, NMR chiral shift agents, GC separations and as starting materials for the synthesis of macrocyclic compounds (e.g. cavitands and carcerands) to name but a few. The use of resorcinarenes in catalysis is still quite new and unexplored, while catalysis using calix[4]arenes, a related macrocycle, has been widely studied. In this thesis it was attempted to synthesise a C2v symmetric resorcinarene precursor that could be further functionalised to form distal bidentate ligands for coordination to transition metals. These compounds would then ultimately be used in catalytic testing, especially for Pd catalysed C-C bond formation. A dibromo resorcinarene precursor was synthesised starting from resorcinarene, using methodology developed by Shivanyuk. This molecule was functionalised with a small range of different electrophiles using lithium halogen exchange methodology, although low yields were returned for the expected distal resorcinarene compounds. Other methods of functionalisation of the resorcinarene, using an anionic ortho-Fries rearrangement and the reduction of a dinitrile resorcinarene to amine and aldehyde functionalities proved unsuccessful. Using a dithioether resorcinarene a di-nuclear coordination compound was formed with Pd(II). This compound was tested for catalytic activity with a Heck reaction, showing low yields for the coupling of styrene with bromobenzene.
Studies in the synthesis of benzoxazole compounds
(Stellenbosch : Stellenbosch University, 2015-12) Kleinhans, Dewald Johannes; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Benzoxazoles are an important class of π-electron-excessive, benzene-fused heterocyclic compounds found in natural products and display a wide range of pharmacological applications. It is therefore a widely used starting scaffold for drug and agrochemical discovery programs. Other applications include: chiral auxiliaries in asymmetric reactions, chiral receptors for the resolution of racemic mixtures, fluorescent whitening dyes, various photochromic materials and as ligands for a wide range of catalytic reactions. Due to our interests in resorcinarenes, we came across 4-hydroxybenzoxazoles, a structural motif that has not been explored as potential asymmetric ligands. In this thesis it was attempted to investigate the synthesis, functionalisation and coordination chemistry of these compound class and finally look at a method of synthesising chiral 4-hydroxybenzoxazoles from amino acids. A small library of achiral 4-hydroxybenzoxazoles were synthesised in good yields. These compounds were then reacted with various transition metals, of which only the Pd-salts proved to return any usable compounds. The first structural evidence of the bonding of 4- hydroxybenzoxazoles was recorded from single crystal X-ray diffraction analysis of the coordination compounds that formed. Different coordination modes were recorded, depending on the ligand and the Pd-salt used. The PdCl2 compounds were also tested for catalytic activity with a Heck reaction, showing good conversions for the reaction between iodobenzene and styrene to form stilbene. Further examination pointed to the ligands playing an insignificant role in the reaction and the products possibly due to only the PdCl2’s reactivity. During this period it was also attempted to functionalise the phenol group with P(III) groups and repeat the coordination and catalytic studies. Efforts to synthesise these compounds were not successful, with oxidation of the P(III) to P(V) groups or degradation of these compounds. Efforts to synthesise these via phosphorous protection, utilising BH3 or the in situ trapping of the compounds with transition metals, were also not successful. During the trapping experiments the phosphinite and Pd-salt formed a re-arranged product that is a known and useful catalyst on its own. Finally a small library of chiral benzoxazoles and 4-hydroxybenzoxazoles were synthesised, starting from amino acids and utilising a Mitsunobu reaction to perform the ring closing. Antimicrobial tests with these compounds did not return any appreciable results.
Studies towards the synthesis of the caulamidine core
(Stellenbosch : Stellenbosch University, 2021-09) Jurisch, Christopher David; Arnott, Gareth E.; Van Otterlo, Willem A. L.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Caulamidines A and B are trihalogenated marine alkaloids isolated from the bryozoan Caulibugula intermis that have an unprecedented structural scaffold. These compounds were shown to be nontoxic to human cells and displayed low micromolar antiplasmodial activities against both wild-type and drug-resistant strains of P. falciparum. Researchers have recently fully elucidated the complex carbon and nitrogen framework of these compounds. Although they have been isolated and fully characterised, the synthesis of caulamidines A and B has not yet been reported in the chemical literature. This provided an excellent opportunity to lay a foundation for the synthesis of these novel marine alkaloids and their analogues. Plans were therefore put into place to develop methods for the synthesis of the dimeric, hexacyclic amidine core structure of caulamidines A and B. The primary aim of this study was to synthesise a novel naphthyridine-1,5-dione that was envisaged to be a key precursor to the caulamidine core. The successful synthesis of this compound could provide access to a core scaffold that has the potential to serve as a synthetic building block for further functionalisation. Two synthetic strategies with slightly different disconnections were devised and investigated for the synthesis of the naphthyridine-1,5-dione precursor. The conjugate addition of a cyanomethyl nucleophile to the alkyne moiety of dimethylacetylene dicarboxylate, a key step of the primary synthetic strategy, was unfortunately unsuccessful despite extensive efforts. Focus was therefore shifted to the secondary synthetic strategy, which involved a Diels-Alder cycloaddition approach. Important findings were made along this route, and two novel dialdehyde dibisulfite adducts were synthesised. However, the secondary synthetic strategy was also ultimately unsuccessful. The secondary aim of the project was to investigate bond formation strategies for the synthesis of the caulamidine quaternary carbon centers, structural elements that were envisaged to be key for the synthesis of these compounds. A novel hexacyclic target compound that resembled the caulamidine core structure was identified and disconnected retrosynthetically to an enedione that mimicked the original naphthyridine-1,5-dione precursor. The enedione served as a model for quaternary carbon center formation and was successfully synthesised according to literature procedures. The primary strategy for the synthesis of the first quaternary carbon center via conjugate addition was thoroughly investigated but was unsuccessful. The first four rings of the target hexacyclic model compound were subsequently installed via an alternative indole-based strategy, which marked the successful synthesis of the first quaternary carbon center and a new hexahydrobenzo[d]carbazole derivative that was fully characterised as a new compound. Oxidation of this compound afforded a target hexahydrobenzo[d]carbazolone that has only been reported once before and was therefore fully characterised for the first time using modern analytical techniques. The subsequent synthesis of a key thermodynamic silyl enol ether was unsuccessful, which meant that the current synthetic strategy could not be investigated further. Focus was therefore shifted, and important foundations were laid for the synthesis of the dihydroquinoline fragment.
A study towards the synthesis of dithiadiazolyl functionalised calix[4]arenes
(Stellenbosch : Stellenbosch University, 2012-03) Applewhite, Malcolm; Arnott, Gareth E.; Haynes, Delia A.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Dithiadiazolyl heterocyclic radicals form part of an ever-growing research field in the quest for organic magnets and conducting materials due to the lone electron located within the heterocyclic ring. These compounds could potentially be used as electrical current conductors and transistors which may be developed into a molecular switch or other types of molecular devices. This thesis describes the successful synthesis of three nitrile functionalised calix[4]arenes, mono-, distal- and tetra-, as bulky scaffolds to be used as precursors in the synthesis of dithiadiazolyl functionalised calix[4]arenes. The crystal structures of these three nitriles are reported herein for the first time. Dithiadiazolyls tend to dimerise in the solid state, thus by selecting a calix[4]arene as a bulky R-group, it was hoped to inhibit dimerisation. Furthermore, synthesis of the radicals on different positions of the calix[4]arene may also inhibit dimerisation in the solid state. The typical reaction in the synthesis of dithiadiazolyls involves the reaction between a nitrile and lithium bis(trimethylsilyl)amide followed by the formation of the dithiadiazolylium chloride salt by the addition of sulfur dichloride. The salt is subsequently reduced giving the desired dithiadiazolyl. However, the addition of lithium bis(trimethylsilyl)amide to mono-nitrile calix[4]arene in the synthesis of the mono-dithiadiazolyl functionalised calix[4]arene was unsuccessful. To investigate the incompatible nature of the electrophile and nucleophile, computational and physical experiments were conducted on the mono-nitrile calix[4]arene derivative. These avenues were pursued to determine whether the unreactive nature of the nitrile in this case is due to electronic effects. Changes in the reaction conditions (i.e. temperature, solvent and the equivalents of nucleophile) were all varied, but this proved to be unsuccessful. Computationally, through charge calculations, it was determined that the electronic properties of the nitrile were similar to that of nitrile examples known to work in the literature. Therefore, it was established that steric effects of the calix[4]arene are playing a critical role in the unreactive nature of the nitrile. There are two non-degenerate LUMO orbitals for the nitrile as one is conjugated and the other is planar (LUMO + 1) to the aromatic system. It has been established that nucleophilic attack through the lowest energy LUMO would result in a high energy transition state due to the loss of conjugation and attack through the higher energy LUMO + 1 would result in a lower energy transition state. However, this was not possible due to the steric conditions surrounding its position relative to the nitrile. The results obtained from this study were, therefore, able to confirm that the normally suitable reaction procedure seems to be limited to less sterically encumbered nitriles.
Synthesis of distally substituted thioether resorcinarene ligands
(Stellenbosch : Stellenbosch University, 2017-12) Bhana, Ashlyn; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: In this thesis it is reported the attempts to synthesise a series of distal thioether functionalised resorcinarene ligands. Chapter 1 provides an overview in order to familiarize the reader about the history and synthesis of resorcinarenes as well as methods pertaining to the functionalization of resorcinarenes. In particular the synthesis of resorcinarenes for use as ligands in metal complexes as well as some examples of such resorcinarene-metal complexes are provided within this chapter. It is reported that resorcinarenes are mostly exploited within the application of host-guest complexes, but that only a few examples of resorcinarenes that are used as ligands for catalysis exist and are reported within the literature. Chapter 2 discusses the synthesis of parent resorcinarenes and the attempted synthesis of distal thioether resorcinarene ligands via the ortholithiation approach, using disulphides and sulfenyl chlorides as electrophiles. The ortholithiation procedure was compatible when using dimethyl disulphide as the electrophile; however the use of di-tert-butyl disulphide and benzenesulfenyl chloride as electrophiles returned negative results. Benzenesulfenyl chloride was successful when used as an electrophile within the ortholithiation procedure of the model system, 1,3-dimethoxybenzene, whereas di-tert-butyl disulphide was unsuccessful in this regard. Chapter 3 discusses the investigation into the attempted synthesis of a series of distal thioether resorcinarene ligands. This was attempted via transition metal catalysis as resorcinarenes can easily be functionalized with bromine which can be compared to aryl bromides which are commonly used as precursors in such coupling reactions. The literature suggested that copper and palladium would be good candidates to perform thioetherfication, the coupling of thiols to aryl bromides, on the resorcinarene. Copper mediated thioetherfication reactions were tested on the pre-functionalized model system, 2-bromo-1,3-dimethoxybenzene, and showed low conversion of starting materials. Palladium mediated thioetherfication reactions were also tested on the same model system, performed with the reportedly highly active [Pd(IPr*OMe)(cin.)(Cl)] catalytic species, and returned near quantitative yields of the coupled product. When the same catalytic species was tested on a distal dibromo resorcinarene precursor, however only starting material was isolated from the reaction. Chapter 4, Conclusions and Future Work, and Addendum A discusses work that was only preliminary and not thoroughly investigated due to time constraints. Future work towards the attempted synthesis of distal thioether resorcinarene ligands via catalysis, the use of sulphur nucleophiles or using different types of sulphur-derived electrophiles within the ortholithiation approach are also discussed within these two chapters.
Synthetic routes towards triazole cannabidiol analogues and substituted cycloparaphenylenes
(Stellenbosch : Stellenbosch University, 2019-12) Janse Van Rensburg, Mari; Van Otterlo, Willem A. L.; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Cancer is the leading cause of death worldwide and current treatment options often lead to painful and unpleasant side-effects. The active constituents isolated from medicinal plants have been successfully developed into various chemotherapeutic agents. The medicinal plant of interest in this research project, the cannabis plant, along with the constituents isolated, known as cannabinoids, have shown promising proapoptotic, anti-proliferative and anti-angiogenic effects. Interest in non-psychoactive cannabinoids, in particular cannabidiol (CBD), has significantly increased in recent years. CBD offers the hope of improved anticancer therapies that selectively target cancer cells without affecting normal cells, thereby eliminating the unwanted side-effects associated with conventional therapies. This project involved the design and synthesis of CBD analogues by mimicking the main pharmacophoric groups found on the structure of CBD. The main difference between the natural occurring cannabinoid and the analogues in this study, was the replacement of the benzene ring at the core of the structure with a 1,2,3-triazole ring using click chemistry. A triazole moiety can provide improved solubility and bioavailability, while helping to exploit the chemical space around the compound. Three different systems (Scaffold A, B and C) were explored throughout this project. The transitions between these systems involved systematic alterations of functional groups on the general structure of each system, as well as the introduction of stereochemistry in the synthesis of Scaffold C. Important reactions used during the synthesis of these scaffolds included an epoxide ring opening via nucleophilic substitution, a Michael reaction, an Appel reaction, a nucleophilic substitution reaction resulting in an inversion of stereochemistry, as well as copper- and ruthenium-catalyzed azide alkyne cycloaddition reactions. These reactions provided the 1,4- and 1,5-, as well as 1,4,5-polysubstituted 1,2,3-triazole CBD analogues. The anticancer activity of these compounds was subsequently evaluated against the MCF-7 cell line, as well as the HeLa cell line. None of the CBD triazole analogues of this study showed particularly appealing activity against these cancer cell lines. One analogue did however show potentially interesting activity against the MCF-7 cell line, and two analogues had an IC50 value below 100 μM against the HeLa cell line, with the most promising analogue providing an IC50 value of 74.3 μM. In addition, all compounds tested were completely devoid of toxicity below concentrations of 100 μM. The results obtained provide valuable insight into the future design of triazole CBD analogues. The synthesis of complex macrocycles and the study of the structural characteristics and properties displayed by these compounds is a fascinating research field. Cycloparaphenylenes (CPPs) are macrocycles which consist of benzene rings connected through para-linkages. This project focused on the synthesis of functionalized CPPs as these macrocycles could provide new host−guest possibilities, possible use in chemosensors and nanoporous materials and the option of connecting these CPP macrocycles to various surfaces. A method was developed for the synthesis of substituted [8]CPPs containing a thioether functionality, which provides the option of effortlessly transforming the substituents throughout the synthesis to give access to the previously synthesized ether-containing [8]CPP macrocycle. The series of reactions used during the synthesis of this CPP linker system included a Sonogashira coupling reaction, a dibromination reaction and a macrocyclization reaction, among others. A linear test system was developed with a similar backbone structure to the substituted CPPs. The synthesis of the linear test system allowed investigation of the optimum route for the formation of the thioether functionality, which was then directly applied to the CPP linker system to gain access to the sulfur-containing CPP macrocycle.
Towards light switchable surfaces
(Stellenbosch : Stellenbosch University, 2011-12) Reader, Paul; Klumperman, Bert; Arnott, Gareth E.; Stellenbosch University. Faculty of Science. Dept. of Chemistry and Polymer Science.
ENGLISH ABSTRACT: Polymeric nanofibrous membranes that act as surfaces offer two compelling properties; they have extremely large surface areas that can be modified and they can offer multiple reactive sites depending on which polymer they were electrospun from. Combining nanofibrous surfaces such as these with photochromic dyes can give remarkable, light responsive materials. In this study, a terpolymer was electrospun and crosslinked (to impart insolubility to the material) to produce a nanofibrous mat that contained surface secondary-hydroxyl units and benzyl chloride units, from which monomers could grow using surface-initiated atom transfer polymerization (SI-ATRP). The surface was further fluorinated though the secondary-hydroxyl moieties to produce a hydrophobic crosslinked nanofibrous surface. n-Butyl acrylate and a photochromic spiropyran dye were copolymerized from the surface using SIATRP, in order to produce a surface that exhibited reversible adhesion towards a water droplet using ultraviolet and visible light as a stimulus to change between the two states. This in principle would allow the droplet to roll off and stick to the surface respectively. Although the surface displayed a colour change when switched, proving that the SI-ATRP had taken place, the droplet of water remained attached to the surface in both states.

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