Chemistry - Theses, Dissertations, and other Required Graduate Degree Essays

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A microfluidic chip-based synthesis of carbon-11 radiotracers for the purpose of PET imaging

Date created: 
2011-01-17
Abstract: 

A microchip-based technique was developed for the radiolabeling process of positron emission tomography (PET) radiotracers using C–11. Due to C–11’s short half-life (20.4 min) it is beneficial to develop a rapid and efficient synthesis that can be done while the patient is waiting. The investigation began with the non-radioactive synthesis of raclopride ((2S)-(-)-3,5-dichloro-N-((1-ethyl-2-pyrrolidinyl)methyl)-6-hydroxy-2-methoxybenzamide), a compound used to study dopamine receptors. The reaction was optimized on the microchip achieving 2-times the yields using ~1/20th the precursor amounts and ~1/5th the reaction time compared to the conventional method. Consequently, optimal parameters were applied to the radiolabeling synthesis of L-[methyl-11C]-methionine achieving 100% relative activities while the [11C]raclopride synthesis resulted in lower relative activities. Therefore reaction conditions were investigated and a computational mass transfer study showed that the reaction kinetics of the radiolabeling process must be considered for the microchip design.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Paul C. H. Li
Thomas J. Ruth
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Towards control of phase segregation in donor-acceptor blends by post-functionalization of conjugated polymer

Author: 
Date created: 
2010-08-12
Abstract: 

π-Conjugated polymers are promising active materials on account of their properties, which include electronic conductivity, electroluminescence and light-harvesting. Post-functionalization of conjugated polymers is a facile approach towards tailed structures and properties of polymers. This thesis reports on the synthesis and characterization of post-functionalized conjugated polymers and control phase segregation in donor-acceptor blends by post-functionalization of conjugated polymers for photovoltaic applications A graft copolymer, poly(3-hexlthiophene) bearing poly(vinyltriazole) (P3HT-g-PVTAZ), was used as the primary model material to demonstrate a novel strategy for controlling the size, contiguous nature, and extent of phase segregation of donor and acceptor domains. The graft copolymer was obtained by nitroxide-mediated radical polymerization of a vinyl triazole onto a postfunctionalized poly(3-hexylthiophene) (P3HT) backbone. The graft copolymer was blended with a fullerene modified with a similar motif - a pendant triazole functionality (TAZC60). TEM analysis revealed that the graft polymer undergoes extensive mixing with the fullerene to form bicontinuous 10 nm phase domains. Graft polymer blends annealed for 1 h at 140 °C retain their nanometer phase separation and domain purity was enhanced. The chemical similarity of the triazole functionality attached to P3HT and the fullerene leads to the formation of films with uniform, stable, nanophase morphologies. Synthesis of a perylene-functionalized conjugated polymer was used to demonstrate the templated growth of 1-D assemblies of perylene diimides (PDI) formed within a conjugated polymer. The strategy is demonstrated with poly(3- hexylthiophene) (P3HT), partially functionalized at the 4-position with N-(1- hexylheptyl)-N’-(12-carboxylicdodecyl)perylene-3,4,9,10-tetracarboxylbisimide (PP3HT). The 1-D assemblies of PDI embedded in the optoelectronically active polymer are hundreds of nanometers wide, 10 – 20 nm thick, several microns in length, and run parallel to the surface of the substrate. Surrounding the 1-D structures is a heterogeneous PP3HT-PDI blend. These systems represent structures of multiple hierarchy, wherein nano-sized domains of a π-conjugated polymer and an n-type material are in intimate contact and which encapsulate 1-D assemblies of nanocrystallites that run parallel to the films surface. They offer an alternative route for the fabrication of innovative supramolecular structures for optoelectronic applications.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Steven Holdcroft
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Development of an in vitro mimic of the in vivo deposition of virus-containing particulate matter onto the bronchial epithelium

Date created: 
2010-08-18
Abstract: 

The association between exposure to particulate matter (PM) air pollutants and respiratory viral infection is well recognized. We developed an in vitro mimic of the in vivo event of exposure to PM contaminated with Respiratory Syncytial Virus (RSV). Concentration of an RSV stock without affecting its infectivity and a particle levitation apparatus were the foundations of the methodology developed to generate designer particles prior to their dry deposition directly onto human lung epithelial cultures. Ex vivo PM Mimics comprised of RSV and carbon (PC+RSV) remain capable of infection months longer than ex vivo PM Mimics comprised of RSV (ARSV). Cells dosed with ARSV, PC+RSV, or PMMimics comprised of carbon exhibited differential secretion patterns of IL-6 and IL-8. In conclusion, our system provides an approach to study the airway epithelial-environmental interaction and the PM-viral interaction in the pathogenesis of respiratory diseases involving inhalation of environmental agents.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Dr. George Agnes
Dr. Del Dorscheid
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Multiple electrophilic aromatic substitution reactions of phloroglucinol and studies towards the total synthesis of hopeanol

Author: 
Date created: 
2011-08-05
Abstract: 

An investigation of the triple electrophilic aromatic substitution (EAS) reactions of phloroglucinol (1,3,5-trihydroxybenzene) has led to the preparation of both symmetrical triple Mannich bases and structurally-complex polycyclic adducts. This research was based on two synthetic approaches that were developed separately for the total synthesis of the polycyclic and C3-symmetric natural product xyloketal A. The first systematic study led to the synthesis of a series of functionalized C3-symmetric dendrimer cores. In the second study, polycyclic analogues of xyloketal A were prepared via the triple EAS reactions of phloroglucinol with various carbon-based electrophiles. In addition, a novel C2-symmetric polycyclic quinone was isolated from the reaction of phloroglucinol with (+)-p-mentha-2-ene-1,8-diol. In a separate study, the total synthesis of the natural product hopeanol was undertaken. This involved the preparation of a 1,2-diketone precursor which was tested with an array of acid promoters in an attempt to complete this synthesis in a single synthetic operation.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Peter Wilson
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Structure-property relationships of PEMs using fluorous-ionic copolymers

Date created: 
2011-06-20
Abstract: 

Proton exchange membranes (PEMs) are a key component in PEM fuel cells, serving as both a fuel separator and an electrolyte. The goal of this thesis work is to investigate structure-property relationships in PEMs. Specifically, the role of polymer microstructure on membrane morphology and physicochemical properties is examined. This is achieved by the design, synthesis and characterization of model polymers with controlled chain architectures and chemical composition, leading to membranes with controlled nanophase-separated morphologies, from which the influence of morphology upon proton transport and other membrane properties is investigated. Two classes of model polymer systems were devised and studied: diblock copolymers of sulfonated poly([vinylidene difluoride-co-hexafluoropropylene]-b-styrene) [P(VDF-co-HFP)-b-SPS]; and graft copolymers of sulfonated poly([vinylidene difluoride-co-chlorotrifluoropropylene]-g-styrene) [P(VDF-co-CTFE)-g-SPS]. These model polymer systems are of interest due to chemical dissimilarity between the hydrophobic fluoropolymer segments and the hydrophilic sulfonated polystyrene segments, which promote phase separation into ionic and non-ionic domains. In addition, controlled radical polymerization techniques were employed to grow the polystyrene segments, which provide high degrees of structural control. Macromolecular structural parameters, such as block ratio, graft length and degree of sulfonation, were systematically varied to determine the effects of polymer microstructure on morphology and proton conductivity. One of the key findings obtained from this work is that block ionomers, whether linear or graft structure, with a lower content of the acid-bearing constituent block (i.e., polystyrene block) gave enhanced proton conductivity at a given ion content. This is attributed to the relatively high degree of sulfonation required and therefore, closer spatial proximity between sulfonic acid groups, which allows for the formation of purer and more percolated ionic aggregates within the proton-conducting domains. Additionally, direct comparison between the diblock and the graft copolymers revealed that the formation of smaller-scale ionic domains is preferable for PEMs because of reduced water swelling which mitigates acid dilution at high ion contents. Furthermore, membranes with smaller-scale ionic domains provided enhanced water retention and proton conduction under low humidity and high temperature conditions. The knowledge gained from this thesis work provides useful insights into aspects of membrane design and preferred structures.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Steven Holdcroft
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Reading disc-based bioassays for protein biomarkers with standard computer drives

Date created: 
2011-05-16
Abstract: 

Current methods of biomedical diagnosis are often limited to centralized laboratories due to the requirement of bulky, sophisticated instruments. This thesis project has the goal of improving the sensitivity and accessibility of existing diagnostic tools for protein biomarkers by combining the popular enzyme-linked immunosorbent assay (ELISA) method with the compact disc (CD) technology. The polycarbonate base of a CD can be activated with a mild UV/ozone treatment, and its feasibility for preparing and running DNA hybridization assays has been demonstrated. Commercially available CD-quality analysis software is capable of quantifying the biotin-streptavidin binding reaction, a model system for biomedical diagnostic assays. After the validation of the CD-based assay preparation and reading protocol, the detection of a blood-borne cancer marker, CA215, has been explored. The sensitivity of the technique is comparable to the conventional ELISA assay, and it undoubtedly improves the accessibility and reduces the cost of current biomedical tests.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Hua-Zhong (Hogan) Yu
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Computational modeling of supported catalyst systems: investigation of free catalyst nanoparticles and support effects

Author: 
Date created: 
2011-04-13
Abstract: 

Improvements in durability and performance of cathode catalyst layers in polymer electrolyte fuel cells require a fundamental understanding of the stability and electrocatalytic reactivity of Pt/support systems. The objective of this Ph.D. work was to investigate the effects of geometrical factors defining the properties of the catalyst as well as the impact of the support material on the thermal stability and catalytic behaviour of free Pt nanoparticles and Pt/support systems. This dissertation consists of three parts, dealing with the following phenomena: i) effects of atomic structure on the energetics and adsorption properties of free Pt nanoparticles, ii) effects of metal oxide support materials within Pt/NbxOy bilayer systems; iii) effects of the spillover of hydrogen from catalyst surface to support on the apparent hydrogen evolution reactivity in the systems of Pd nanoislands on an Au support. The first two parts of this work employed ab initio calculations based on density functional theory. The third part employed a mean field approach based on the Wigner-Seitz cellular method. In the study of free Pt nanoparticles, the calculated cohesive energies agree with the Gibbs-Thomson relation. These results imply that the cohesive energy of Pt nanoparticles is determined primarily by the particle size and not the particle shape. The calculated adsorption energies of atomic oxygen showed high spatial variation on all nanofacets. The adsorption energies depend on the atom arrangement at the reaction site. In the study of Pt/NbxOy bilayer systems, the degree of oxygen incorporation into NbxOy was observed to influence the distribution of electronic charge density and the formation of chemical bonds at the Pt|NbxOy interface. These results imply that the electronic and geometric structure of Pt is changed by interaction between Pt and support. The spillover effect was studied by developing a kinetic model of hydrogen evolution on an array of Au-supported catalyst particles. These results imply that the spillover effect could be a major cause of the enormous enhancement of the current density observed in experimental studies.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Michael Eikerling
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Saturation transfer difference NMR studies of protein-ligand interactions

Date created: 
2011-04-18
Abstract: 

The mycolyl–arabinogalactan–peptidoglycan complex coats the surface of Mycobacterium tuberculosis. It is a structure composed of galactofuranosyl (Galf) residues attached via alternating β-(1→6) and β-(1→5) linkages synthesized by bifunctional galactofuranosyltransferases, GlfT1 and GlfT2. We have used Saturation Transfer Difference (STD) NMR spectroscopy to examine the active site architecture of GlfT2 using trisaccharide acceptor substrates, β-D-Galf-(1→6)-β-D-Galf-(1→5)-β-D-Galf-O(CH2)7CH3 and β-D-Galf-(1→5)-β-D-Galf-(1→6)-β-D-Galf-O(CH2)7CH3. The STD NMR epitope maps demonstrated a greater enhancement toward the “reducing” ends of both trisaccharides, and that UDP-galactofuranose (UDP-Galf) made more intimate contacts through its nucleotide moiety. This observation is consistent with the greater flexibility required within the active site of the reaction between the growing polymer acceptor and the UDP-Galf donor. Competition STD NMR titration experiments with the trisaccharide acceptor substrates demonstrated that they bind competitively at the same site, suggesting that GlfT2 has one active site pocket capable of catalyzing both β-(1→5) and β-(1→6)-galactofuranosyl transfer reactions. STD NMR spectroscopy was also used to probe the bioactive conformation of the carbohydrate mimic MDWNMHAA of the O-polysaccharide of the Shigella flexneri Y bacterium when bound to its complementary antibody, mAb SYA/J6. The dynamic ligand epitope was mapped with the CORCEMA-ST (COmplete Relaxation and Conformational Exchange Matrix Analysis of Saturation Transfer) program that calculates STD-NMR intensities. Comparison of these predicted STD enhancements with experimental data was used to select a representative binding mode. The bound conformation was further refined with a simulated annealing refinement protocol known as STD-NMR Intensity-restrained CORCEMA Optimization (SICO) to give a more accurate representation of the bound peptide epitope. X-ray crystallographic data of MDWNMHAA when bound to mAb SYA/J6 indicated the immobilization of water molecules in the combining site. Water Ligand Observed via Gradient Spectroscopy (WaterLOGSY) was used in conjunction with STD NMR spectroscopy to provide insight into the presence of water molecules that exist at the interstitial sites between the peptide and the antibody. Molecular dynamics calculations have also provided a more accurate picture of the possibilities for bound-ligand conformations, and water molecules involved in providing complementarity between the peptide and SYA-J6.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Dr. B. Mario Pinto
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Probing the mechanistic specificities of sialidase-catalyzed hydrolysis reactions

Author: 
Date created: 
2011-04-11
Abstract: 

Sialic acids are a family of 9-carbon keto sugars found throughout nature. The most prevalent example is N-acetylneuraminic acid (Neu5Ac). This carbohydrate is commonly found capping the terminal ends of a variety of glycoconjugates and polysaccharides. The family of enzymes that catalyze the hydrolytic cleavage of Neu5Ac containing complexes are known as sialidases. Numerous studies have implicated the involvement of these enzymes in human diseases such as cancer, cholera and influenza. As such, sialidase inhibitors can function as tools to study these conditions or to serve as potential therapeutics. Rational drug design has emerged as a powerful tool used to develop such compounds. This process involves acquiring a comprehensive mechanistic understanding of the target enzyme. Particularly interesting are features manifested at the enzymatic transition state (TS) which include the extent of bond-formation/cleavage, charge development and geometry. Since sialidases operate via a double displacement mechanism, both glycosylation and deglycosylation TSs must be considered to fully understand this family of enzymes. Thus, a major component and objective of this thesis work was to use established techniques such as enzyme kinetics, mutagenesis and the measurement and analysis of multiple kinetic isotope effects (KIEs) to unravel the mechanism for various sialidases. With regard to KIEs, a novel NMR-based technique was developed and employed to measure competitive enzymatic KIEs on the sialidase-catalyzed hydrolysis reactions.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Dr. Andrew J. Bennet
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Polybenzimidazoles as Ion Exchange Membranes

Author: 
Date created: 
2011-02-09
Abstract: 

Two sets of soluble, benzimidazole-based polymers have been synthesized. One series containing sulfonic acid groups (sulfonated polybenzimidazole (SuPBI)) utilizes the basic character of polybenzimidazole to form acid-base cross-links that improve the mechanical integrity of proton conducting polymers. The other series shows how the benzimidazole segments in the polymer can be quaternized to produce a polymer (poly(1,3-dimethylbenzimidazolium) (PDMBI+)) capable of transporting anions.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Steven Holdcroft
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.