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Regioselective modification of amino acid derivatives / Tan Eng Wui
No full textBibliography: leaves 187-202204 leaves ; 30 cm.Thesis (Ph.D.) -- University of Adelaide, Dept. of Organic Chemistry, 199
1-Tetradecylpyridinium bromide monohydrate
No full textIn the title compound, C19H34N+·Br−·H2O, the dihedral angle between the trans-planar alkyl side chain and the pyridinium ring is 52.73 (7)°. In the crystal structure, O—H...Br, C—H...Br and C—H...O hydrogen bonds form a network, while the hydrophobic alkyl chains interdigitate, forming bilayers
Synthesis and study of Quaternary Nitrogen Surfactants
No full textThe effect of head group modification on the solubility and antimicrobial potency of some quaternary nitrogen surfactants (QNSs) was investigated. Using high yielding Menshutkin reactions, a homologous series of monomeric, dimeric and polymeric QNSs based on aliphatic ammonium and aromatic pyridinium head groups were synthesised. The hydrophilicity of the head groups was increased via hydroxymethyl addition and decreased using ethyl substitution. The tails used were saturated, straight alkyl chains ranging from 6 to 22 carbons in length.
The hydrophobicity of the QNSs was established by calculating their predicted partition coefficient in an octanol/water mix (Log P) and by measuring their critical micelle concentration (cmc). As anticipated, the QNSs with longer alkyl tails were more hydrophobic with lower cmc and increased Log P values. Alterations to the head groups showed predictable results for all head groups except the hydroxymethyl addition on the pyridinium head group. The Log P value predicted an increased hydrophilicity, while the cmc suggested an increased hydrophobicity. This difference (lower cmc) was postulated to be due to decreased repulsion of the head groups allowing for micellisation at lower concentrations. This theory was supported by crystal structure analysis which showed that the hydroxymethyl addition caused the QNSs to pack more closely. Measurement of limiting molar conductivity (Λo) also showed that the hydroxymethylpyrdinium compounds were unexpectedly less solvated than the unsubstituted counterparts, and the micelle size was increased by the presence of the hydroxymethyl group. This data as a whole suggested the hydroxymethyl group was not solely acting to decrease the hydrophobicity.
The antimicrobial activity of each QNS was assessed against three Gram positive bacteria (Staphylococcus aureus, Listeria innocua, Bacillus subtilis); three Gram negative bacteria (Pseudomonas aeruginosa, Yersinia enterocolitica, Escherichia coli); a fungus (Aspergillus niger); and a yeast (Saccharomyces cerevisiae), using a minimum inhibitory concentration (MIC) assay. The longer chain compounds were generally found to be more effective against the bacteria with a cut-off seen in many cases at the hexadecyl derivative. The charge of the bacteria cell surface (ζ-potential) became increasingly positive at higher concentrations of QNS and transmission electron microscopy (TEM) showed that at concentrations above the MIC the cytoplasmic membrane had been compromised. These studies suggested the primary mode of action of the QNS against the bacteria was due to the attraction of the QNS to the cytoplasmic membrane of the bacterial cell which resulted in its destabilisation. Destabilisation of the bacterial cytoplasmic membrane occurred at lower concentration for QNSs with longer alkyl tails. It was therefore postulated that the hydrophobicity of a QNS could be used to predict its antimicrobial potency. However, when the MIC was related to Log P using a quantitative structure activity relationship (QSAR) it was demonstrated that the relationship was not linear, and that while parabolic and bilinear models provided a better approximation to the observed data no model sufficiently accounted for all the data.
The research presented in this thesis has shown that the physical properties and antimicrobial activity of QNSs varies greatly with altered head group hydrophobicity. It has been demonstrated that very small changes to the head group can lead to unexpected physical properties which changes their interactions with micro-organisms. The antimicrobial action of these compounds has been shown to rely on the attraction of the cationic head group to the cytoplasmic membrane which is then destabilised by the alkyl tail. Findings from this project will help in the development of more potent QNSs and a greater understanding of the interaction of QNSs with cytoplasmic membrane
Triggered Solute Release from Prosurfactant Incorporated Liposomes
No full textSwitchable surfactant (SS) triggered release of encapsulated solute from liposomes was investigated. A range of redox and pH head group sensitive SSs were synthesised and characterised. Redox triggered SSs were derived from the nicotinamide moiety while pH triggered SSs incorporated amidine and imidazoline functional groups.
The prosurfactant (PS) form of the SSs were incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes at ratios of up to 20 mol% for pH SSs and 15 mol% for redox SSs. The switching characteristics of the incorporated SSs were investigated. The pKa of the pH SSs decreased, and redox potential of the redox SSs increased, over their respective free forms suggesting stabilisation of the PS due to the non-polar nature of the bilayer.
SS triggered release studies from liposomes using the fluorescent molecule carboxyfluorescein (CF) indicated that SS incorporation of 10% induced the most CF release with additional SS altering the membrane character and suppressing release. An amidine SS with a C14 alkyl tail length was found to induce the greatest CF release which was thought to be due to the optimal compromise between packing parameter and hydrophobicity. Compared to imidazoline and redox SS, amidine derived SS also induced greater amounts of CF release possibly due to the greater hydrophilicity of the head group causing ejection of the surfactant from the bilayer, which also causes the system to be irreversible. In contrast, the imidazoline SS remained in the bilayer due to its hydrophobicity, and repeated triggering of the system induced CF release. Despite the greater pKa of the amidine compared to the imidazoline head group CF release was observed between similar pH ranges of between 9.0 and 7.0 when the pH of the system was decreased incrementally from pH 12.4.
Of the redox SSs, only one was able to be effectively triggered, and was observed to induce significant CF release upon the addition of a molecular oxidant at elevated temperatures (25-30 °C). This was attributed to increased hydrogen bonding through the amide of the head group which stabilised the membrane.
CO2(g) was demonstrated as an alternative trigger for pH SS incorporated liposomes. Where sparging with CO2(g) decreased the pH of the systems, triggering CF release. The imidazoline switched system was found to be reversible when the CO2 was displaced with argon.
A coupled triggering mechanism was demonstrated with the incorporation of a photoacid generator (PAG) as a secondary trigger in imidazoline-liposomes. Upon irradiation with light the PAG generated acid which proceeded to protonate the PS, inducing CF release. By employing this method pH SS induced CF release was demonstrated at constant pH
Triggered Solute Release from Prosurfactant Incorporated Liposomes
No full textSwitchable surfactant (SS) triggered release of encapsulated solute from liposomes was investigated. A range of redox and pH head group sensitive SSs were synthesised and characterised. Redox triggered SSs were derived from the nicotinamide moiety while pH triggered SSs incorporated amidine and imidazoline functional groups.
The prosurfactant (PS) form of the SSs were incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes at ratios of up to 20 mol% for pH SSs and 15 mol% for redox SSs. The switching characteristics of the incorporated SSs were investigated. The pKa of the pH SSs decreased, and redox potential of the redox SSs increased, over their respective free forms suggesting stabilisation of the PS due to the non-polar nature of the bilayer.
SS triggered release studies from liposomes using the fluorescent molecule carboxyfluorescein (CF) indicated that SS incorporation of 10% induced the most CF release with additional SS altering the membrane character and suppressing release. An amidine SS with a C14 alkyl tail length was found to induce the greatest CF release which was thought to be due to the optimal compromise between packing parameter and hydrophobicity. Compared to imidazoline and redox SS, amidine derived SS also induced greater amounts of CF release possibly due to the greater hydrophilicity of the head group causing ejection of the surfactant from the bilayer, which also causes the system to be irreversible. In contrast, the imidazoline SS remained in the bilayer due to its hydrophobicity, and repeated triggering of the system induced CF release. Despite the greater pKa of the amidine compared to the imidazoline head group CF release was observed between similar pH ranges of between 9.0 and 7.0 when the pH of the system was decreased incrementally from pH 12.4.
Of the redox SSs, only one was able to be effectively triggered, and was observed to induce significant CF release upon the addition of a molecular oxidant at elevated temperatures (25-30 °C). This was attributed to increased hydrogen bonding through the amide of the head group which stabilised the membrane.
CO2(g) was demonstrated as an alternative trigger for pH SS incorporated liposomes. Where sparging with CO2(g) decreased the pH of the systems, triggering CF release. The imidazoline switched system was found to be reversible when the CO2 was displaced with argon.
A coupled triggering mechanism was demonstrated with the incorporation of a photoacid generator (PAG) as a secondary trigger in imidazoline-liposomes. Upon irradiation with light the PAG generated acid which proceeded to protonate the PS, inducing CF release. By employing this method pH SS induced CF release was demonstrated at constant pH
Synthesis and study of Quaternary Nitrogen Surfactants
No full textThe effect of head group modification on the solubility and antimicrobial potency of some quaternary nitrogen surfactants (QNSs) was investigated. Using high yielding Menshutkin reactions, a homologous series of monomeric, dimeric and polymeric QNSs based on aliphatic ammonium and aromatic pyridinium head groups were synthesised. The hydrophilicity of the head groups was increased via hydroxymethyl addition and decreased using ethyl substitution. The tails used were saturated, straight alkyl chains ranging from 6 to 22 carbons in length.
The hydrophobicity of the QNSs was established by calculating their predicted partition coefficient in an octanol/water mix (Log P) and by measuring their critical micelle concentration (cmc). As anticipated, the QNSs with longer alkyl tails were more hydrophobic with lower cmc and increased Log P values. Alterations to the head groups showed predictable results for all head groups except the hydroxymethyl addition on the pyridinium head group. The Log P value predicted an increased hydrophilicity, while the cmc suggested an increased hydrophobicity. This difference (lower cmc) was postulated to be due to decreased repulsion of the head groups allowing for micellisation at lower concentrations. This theory was supported by crystal structure analysis which showed that the hydroxymethyl addition caused the QNSs to pack more closely. Measurement of limiting molar conductivity (Λo) also showed that the hydroxymethylpyrdinium compounds were unexpectedly less solvated than the unsubstituted counterparts, and the micelle size was increased by the presence of the hydroxymethyl group. This data as a whole suggested the hydroxymethyl group was not solely acting to decrease the hydrophobicity.
The antimicrobial activity of each QNS was assessed against three Gram positive bacteria (Staphylococcus aureus, Listeria innocua, Bacillus subtilis); three Gram negative bacteria (Pseudomonas aeruginosa, Yersinia enterocolitica, Escherichia coli); a fungus (Aspergillus niger); and a yeast (Saccharomyces cerevisiae), using a minimum inhibitory concentration (MIC) assay. The longer chain compounds were generally found to be more effective against the bacteria with a cut-off seen in many cases at the hexadecyl derivative. The charge of the bacteria cell surface (ζ-potential) became increasingly positive at higher concentrations of QNS and transmission electron microscopy (TEM) showed that at concentrations above the MIC the cytoplasmic membrane had been compromised. These studies suggested the primary mode of action of the QNS against the bacteria was due to the attraction of the QNS to the cytoplasmic membrane of the bacterial cell which resulted in its destabilisation. Destabilisation of the bacterial cytoplasmic membrane occurred at lower concentration for QNSs with longer alkyl tails. It was therefore postulated that the hydrophobicity of a QNS could be used to predict its antimicrobial potency. However, when the MIC was related to Log P using a quantitative structure activity relationship (QSAR) it was demonstrated that the relationship was not linear, and that while parabolic and bilinear models provided a better approximation to the observed data no model sufficiently accounted for all the data.
The research presented in this thesis has shown that the physical properties and antimicrobial activity of QNSs varies greatly with altered head group hydrophobicity. It has been demonstrated that very small changes to the head group can lead to unexpected physical properties which changes their interactions with micro-organisms. The antimicrobial action of these compounds has been shown to rely on the attraction of the cationic head group to the cytoplasmic membrane which is then destabilised by the alkyl tail. Findings from this project will help in the development of more potent QNSs and a greater understanding of the interaction of QNSs with cytoplasmic membrane
Donor-Acceptor Cyclopropanes as Building Blocks for the Synthesis of Natural Product Scaffolds
No full textThe first chapter of this thesis provides an introduction to natural products and describes how they are a valuable source of bioactive compounds, which feature heavily in clinically used drugs. The recently reported bioactive natural product maoecrystal V was introduced followed by the chemistry of cyclopropanes, which were intended to be used in the synthesis of maoecrystal V.
Synthetic strategies towards the synthesis of maoecrystal V were investigated in chapter 2. A retrosynthetic analysis of maoecrystal V was proposed, which featured a cyclopropane ring expansion. Using a model system, the key step, an intermolecular Diels-Alder cycloaddition was used to construct the [2.2.2]-bicyclooctane scaffold of maoecrystal V. Concurrently to this work, Baran and co-workers completed the synthesis of maoecrystal V and found that it possessed little to no bioactivity against a wide range of cancer cell lines.
An introduction to spiroketals and the less common benzannulated spiroketals followed by the methodology to construct them are described in chapter 3. Based on some preliminary results from another study, attention was turned to utilising donor-acceptor cyclopropanes in the synthesis of benzannulated n,5-spiroketals (n = 6 or 5), which are found in numerous bioactive natural products.
Chapter 4 details a new synthetic strategy to gain access to the benzannulated 6,5-spiroketals in a highly efficient manner, using donor-acceptor cyclopropanes. Vinyl cyclopropanes 312 were smoothly converted to the corresponding benzannulated 6,5-spiroketals by treatment with palladium(0). A series of benzannulated 6,5-spiroketals 313 with three or four stereocentres embedded were synthesized in good to excellent yields from simple, commercially available starting materials 321. The requirement of two chromatographic separations over six or seven steps and mild reaction conditions make this methodology attractive. Chapter 4 also presents a synthetic study towards berkelic acid, which has a benzannulated 6,5-spiroketal scaffold embedded. The successful construction of this model system indicates the practical value of this methodology and its potential in the total synthesis of natural products containing benzannulated 6,5-spiroketal moieties.
In Chapter 5, the synthesis of benzannulated 5,5-spiroketals via vinyl and phenyl cyclopropanes is described. In the presence of Pd(0), different benzannulated 5,5-spiroketals were formed from vinyl cyclopropanes 353.
While the phenyl cyclopropanes required Lewis acid catalysts to proceed. Various phenyl substituted benzannulated 5,5-spiroketals 372 were obtained from the corresponding 1,3-diketones or -keto esters 386
Donor-Acceptor Cyclopropanes as Building Blocks for the Synthesis of Natural Product Scaffolds
No full textThe first chapter of this thesis provides an introduction to natural products and describes how they are a valuable source of bioactive compounds, which feature heavily in clinically used drugs. The recently reported bioactive natural product maoecrystal V was introduced followed by the chemistry of cyclopropanes, which were intended to be used in the synthesis of maoecrystal V.
Synthetic strategies towards the synthesis of maoecrystal V were investigated in chapter 2. A retrosynthetic analysis of maoecrystal V was proposed, which featured a cyclopropane ring expansion. Using a model system, the key step, an intermolecular Diels-Alder cycloaddition was used to construct the [2.2.2]-bicyclooctane scaffold of maoecrystal V. Concurrently to this work, Baran and co-workers completed the synthesis of maoecrystal V and found that it possessed little to no bioactivity against a wide range of cancer cell lines.
An introduction to spiroketals and the less common benzannulated spiroketals followed by the methodology to construct them are described in chapter 3. Based on some preliminary results from another study, attention was turned to utilising donor-acceptor cyclopropanes in the synthesis of benzannulated n,5-spiroketals (n = 6 or 5), which are found in numerous bioactive natural products.
Chapter 4 details a new synthetic strategy to gain access to the benzannulated 6,5-spiroketals in a highly efficient manner, using donor-acceptor cyclopropanes. Vinyl cyclopropanes 312 were smoothly converted to the corresponding benzannulated 6,5-spiroketals by treatment with palladium(0). A series of benzannulated 6,5-spiroketals 313 with three or four stereocentres embedded were synthesized in good to excellent yields from simple, commercially available starting materials 321. The requirement of two chromatographic separations over six or seven steps and mild reaction conditions make this methodology attractive. Chapter 4 also presents a synthetic study towards berkelic acid, which has a benzannulated 6,5-spiroketal scaffold embedded. The successful construction of this model system indicates the practical value of this methodology and its potential in the total synthesis of natural products containing benzannulated 6,5-spiroketal moieties.
In Chapter 5, the synthesis of benzannulated 5,5-spiroketals via vinyl and phenyl cyclopropanes is described. In the presence of Pd(0), different benzannulated 5,5-spiroketals were formed from vinyl cyclopropanes 353.
While the phenyl cyclopropanes required Lewis acid catalysts to proceed. Various phenyl substituted benzannulated 5,5-spiroketals 372 were obtained from the corresponding 1,3-diketones or -keto esters 386
Interfacial behaviour of non-ionic surfactants
No full textThe research presented in this thesis explores the behaviour of non-ionic surfactants at air/solution and silica/solution interfaces. The aim was to gain insight into this behaviour to improve the efficacy of detergent and rinse aid surfactant behaviour in dishwashing performance. The project was driven by both academic and commercial foci due to the project being funded through a collaboration between Fisher&Paykel, the University of Otago and the Ministry of Business Innovation and Employment (NZ). The project aims to create methodologies employable on-site at Fisher&Paykel’s product development centre derived from academic insight garnered during the work.
Analysis of non-ionic surfactant behaviour at the silica/solution interface was predominantly interrogated by attenuated total internal reflection infrared (ATRIR) spectroscopy. Such a technique is surface sensitive and informs of both molecular details of surfactant adsorption at this interface and the kinetics of such a process. Two different methodologies were employed to examine non-ionic surfactant adsorption at the silica/solution interface using ATR-IR. The first employed silica particle films, and the second a silicon prism. Particle films were employed to determine conformational behaviour of surfactants and silicon prisms were used for kinetic analysis of the adsorption process.
Stable silica films were formed by decreasing the silica suspension pH from 10 to 2.5 eliminating of electrostatic repulsive forces. Such films were easily prepared and experiments were found to be replicable. IR spectral interpretation of surfactant adsorption to silica films was aided by analyzing the spectral response of silica films exposed to differing relative humidities. Such work spectroscopically
illustrated the room temperature interconversion of surficial siloxane groups to hydrogen-bonded silanols groups. The data gathered gave insight into the IR response of the main νas(Si-O-Si)TO mode at ∼1080 - 1040 cm−1, with a bipolar band noted.
Surface forces experienced in foam and wetting films formed in surfactant solution were studied with the newly developed interferometric atomic force microscopy (i-AFM). Such a technique gives the synchronous measurement of force and separation distance of deformable surfaces, not previously possible using colloid probe AFM. Due to the the micrometer size of bubbles used no deformation of bubble surfaces were observed owing to increased Laplace pressure. Such results were supported by analysis of surfactant adsorption behaviour at silica/solution and gas/solution interfaces using ATR-IR, ellipsometry and interfacial tension measurements. These techniques provided information about surfactant packing, adsorbed layer thickness and phase behaviour at both of these interfaces.
Finally this work presents the extension of analytical methodologies employed to examine fundamental non-ionic surfactant interfacial behaviour to the real world application of machine dishwashing. A methodology for the determination of adsorption rate constants utilizing UV-visible spectroscopy was developed. These measurements gave replicable results and will be utilized in testing the effect of altering product design on surfactant adsorption behaviour within the dishwasher. In addition foam column measurements determined foam stability of detergents formulated with different non-ionic surfactants. Such measurements gave good indications about desired surfactant properties to mitigate foaming in addition to providing an analytical tool that Fisher&Paykel can use on-site
Interfacial behaviour of non-ionic surfactants
No full textThe research presented in this thesis explores the behaviour of non-ionic surfactants at air/solution and silica/solution interfaces. The aim was to gain insight into this behaviour to improve the efficacy of detergent and rinse aid surfactant behaviour in dishwashing performance. The project was driven by both academic and commercial foci due to the project being funded through a collaboration between Fisher&Paykel, the University of Otago and the Ministry of Business Innovation and Employment (NZ). The project aims to create methodologies employable on-site at Fisher&Paykel’s product development centre derived from academic insight garnered during the work.
Analysis of non-ionic surfactant behaviour at the silica/solution interface was predominantly interrogated by attenuated total internal reflection infrared (ATRIR) spectroscopy. Such a technique is surface sensitive and informs of both molecular details of surfactant adsorption at this interface and the kinetics of such a process. Two different methodologies were employed to examine non-ionic surfactant adsorption at the silica/solution interface using ATR-IR. The first employed silica particle films, and the second a silicon prism. Particle films were employed to determine conformational behaviour of surfactants and silicon prisms were used for kinetic analysis of the adsorption process.
Stable silica films were formed by decreasing the silica suspension pH from 10 to 2.5 eliminating of electrostatic repulsive forces. Such films were easily prepared and experiments were found to be replicable. IR spectral interpretation of surfactant adsorption to silica films was aided by analyzing the spectral response of silica films exposed to differing relative humidities. Such work spectroscopically
illustrated the room temperature interconversion of surficial siloxane groups to hydrogen-bonded silanols groups. The data gathered gave insight into the IR response of the main νas(Si-O-Si)TO mode at ∼1080 - 1040 cm−1, with a bipolar band noted.
Surface forces experienced in foam and wetting films formed in surfactant solution were studied with the newly developed interferometric atomic force microscopy (i-AFM). Such a technique gives the synchronous measurement of force and separation distance of deformable surfaces, not previously possible using colloid probe AFM. Due to the the micrometer size of bubbles used no deformation of bubble surfaces were observed owing to increased Laplace pressure. Such results were supported by analysis of surfactant adsorption behaviour at silica/solution and gas/solution interfaces using ATR-IR, ellipsometry and interfacial tension measurements. These techniques provided information about surfactant packing, adsorbed layer thickness and phase behaviour at both of these interfaces.
Finally this work presents the extension of analytical methodologies employed to examine fundamental non-ionic surfactant interfacial behaviour to the real world application of machine dishwashing. A methodology for the determination of adsorption rate constants utilizing UV-visible spectroscopy was developed. These measurements gave replicable results and will be utilized in testing the effect of altering product design on surfactant adsorption behaviour within the dishwasher. In addition foam column measurements determined foam stability of detergents formulated with different non-ionic surfactants. Such measurements gave good indications about desired surfactant properties to mitigate foaming in addition to providing an analytical tool that Fisher&Paykel can use on-site
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