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

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Modeling of Water Sorption and Swelling in Polymer Electrolyte Membranes: Diagnostic Applications

Date created: 
2015-04-23
Abstract: 

The polymer electrolyte membrane (PEM) fulfills vital functions as separator, proton conductor, and electronic insulator in a polymer electrolyte fuel cell (PEFC). The well-studied and practically used solid polymer electrolyte membranes are perfluorosulfonic acid (PFSA) polymer membranes such as Nafion. These membranes offer high proton conductivity, high mechanical strength and good chemical stability. The efficiency of the chemical-to-electrical energy conversion in a PEFC critically depends on the ability of the PEM to transport protons from the anode to the cathode. Proton conductivity of the PEM is a key parameter to achieve high power density and performance. The main variable to characterize the state of a PEM and determine its transport properties is its water content. In particular, the proton conductivity is highly sensitive to the level of hydration. Membranes experience continuous stresses and consequently continuous loss of performance throughout their operational life. Chemical degradation alters the chemical structure of the PEM, which affects the water distribution in it. A consistent description of water sorption and swelling under conditions relevant for the PEFC operation lies at the heart of understanding transport properties, performance and degradation phenomena. This work expands on a previously developed poroelectroelastic model of water sorption in PEMs [Soft Matter 7, 5976 (2011)]. The theory relates the charge density at the pore walls to a microscopic swelling parameter. Extended to the water sorption equilibrium in a pore ensemble, the model reconciles microscopic swelling in a single pore with macroscopic swelling of the membrane. This work provides a generalized treatment of elastic effects in PEMs. Different deformation modes of polymeric pore walls are used to derive stress-strain relationships that determine the law of swelling. Moreover, this work enhances the diagnostic capabilities of the model; it provides the statistical pore size distribution as well as a statistical distribution of microscopic fluid and elastic pressures inside the PEM. Thereafter, the model is applied to different sets of water sorption data for PEMs that had undergone either hygrothermal aging or chemical degradation. The model-based analysis provides mechanistic explanations of structural changes and their impact on microscopic distributions of charge density and elastic properties in PEMs.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Michael Eikerling
Department: 
Science:
Thesis type: 
(Thesis) M.Sc.

Total synthesis of 5,5-spiroacetal natural products and studies toward the total synthesis of eleutherobin

Date created: 
2015-04-20
Abstract: 

A novel chlorohydrin-based spirocyclization reaction has been developed that complements contemporary approaches to spiroacetals. The discovery and optimization of a silver(I)-promoted cyclization of ketochlorohydrins enabled the synthesis of a wide range of 5,5-, 5,6-, and 5,7-spiroacetal compounds. In addition, this strategy was applied in the total syntheses of (+)-cephalosporolide E and (−)-cephalosporolide F, which were accomplished in six steps. Further extension of this methodology culminated in the first total synthesis and full stereochemical assignment of (+)-ascospiroketal A. Specifically, a silver(I)-promoted cyclization cascade was developed that effected both a spirocyclization as well as an oxetane rearrangement, and generated a quaternary all-carbon stereogenic centre with complete stereocontrol. This unique reaction sequence was a critical component of the eventual total synthesis of (+)-ascospiroketal A and several diastereomers that were made available in fourteen steps. An additional study detailing efforts geared toward the total synthesis of eleutherobin, an anti-cancer natural product, is also presented. By utilizing a cyclobutanone α-arylation/Haller-Bauer fragmentation/Friedel-Crafts acylation strategy, a tetralone intermediate for the synthesis of eleutherobin was made available on multi-gram-scale. Efforts to convert this material into the bicyclo[8.4.0]tetradecane core of eleutherobin are described including the identification of an intramolecular aza-Michael strategy that secured the carbon complement of eleutherobin.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Robert Britton
Department: 
Science: Chemistry
Thesis type: 
(Thesis) Ph.D.

Investigation of Protein-ligand Interactions by Molecular Dynamics and Saturation Transfer Difference NMR Spectroscopy

Author: 
Date created: 
2015-03-26
Abstract: 

Protein-ligand interactions form the molecular basis of many biological processes. The study of their interactions from a structural perspective can provide not only insights into the molecular recognition between the protein and the ligand but also clues to the design of better ligands that can serve to mediate the biological events. This thesis investigates such interactions for four proteins that are (potential) therapeutic targets. Techniques used in this thesis include molecular dynamics (MD) simulations, saturation transfer difference (STD) NMR spectroscopy, and complete relaxation and conformational exchange matrix (CORCEMA) analysis that calculates theoretical STD effects. MD simulations are employed to study the binding of two designed glycopeptides with SYA/J6, a monoclonal antibody specific for the O-polysaccharide of the Shigella flexneri Y bacterium, as well as the binding dynamics and strengths of a series of inhibitors against human lactate dehydrogenase A (LDHA), an enzyme implicated in the cell energy metabolism of various cancers. The computational results from both cases are consistent with experimental data, predicting that neither glycopeptide would bind to SYA/J6, and clarifying ambiguities in the binding modes of two well-known LDHA inhibitors. Furthermore, binding models of two inhibitors against the enzyme UDP-galactopyranose mutase (UGM), a potential target for the treatment of tuberculosis, and two substrates of UDP-N-acetylgalactopyranose mutase (UNGM), a potential target against diarrheal disease, are constructed by a protocol that combines MD, STD NMR, and CORCEMA calculations. The collective results indicate a unique binding mode for a UGM inhibitor and explain the bifunctionality of UNGM.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Gary Leach
Department: 
Science:
Thesis type: 
(Thesis) Ph.D.

An in-depth examination of the properties and behaviour of Au(III)-based [AuX2(CN)2]- (X = Cl, Br, I) as a coordination polymer building block

Date created: 
2014-11-27
Abstract: 

This thesis primarily focuses on the synthesis and characterization of [AuX2(CN)2]- (X = Cl, Br, I), a square planar Au(III)-based compound, and its use as a coordination polymer building block. K+, nBu4N+ and PPN+ salts of [AuX2(CN)2]- and the Au(I/III)-based double salts K3[Au(CN)2]2[AuBr2(CN)2]-H2O and K5[Au(CN)2]4[AuI2(CN)2]-2H2O were prepared and structurally characterized. All compounds exhibited many structure-defining weak interactions such as X-X, Au-X (X = Br, I) and Au(I)-Au(I) interactions, as well as a rare Au(I)-Au(III) interaction with an intermolecular distance of 3.58 A; no Cl-Cl interactions were observed. [AuX2(CN)2]- was introduced to solutions containing a variety of divalent metals (Mn, Fe, Co, Ni, Cu, Zn, Pb) and ancillary N-donating chelating ligands such as 1,10-phenanthroline or bridging ligands such as 4,4'-bipyridine. In most cases, an ionic material resulted, containing a metal cation coordinatively saturated by ligand and an unbound [AuX2(CN)2]- (X = Cl, Br) anion. In some cases, [AuX2(CN)2]- did bind, but in a pendant, non bridging fashion. With ethylenediamine and 4,4'-bipyridine ligands, and Ni(II) and Co(II) or Zn(II), respectively, an [AuBr2(CN)2]--bridged coordination polymer resulted; no [AuCl2(CN)2]--bridged materials were observed with added ancillary ligands. In the absence of ancillary ligand, several [AuX2(CN)2]--bridged (X = Cl, Br) formed; all reactions involving [AuI2(CN)2]- resulted in decomposition of the [AuI2(CN)2]- molecule. Exposing [AuX2(CN)2]- to temperatures above 80 C or UV light resulted in the reductive elimination of halogen, yielding [Au(CN)2]-. Kinetics (thermal and photochemical) studies revealed pseudo first-order rate kinetics with. Heating some [AuBr2(CN)2]--containing coordination polymers to 125 C converted them to analogous [Au(CN)2]--containing materials. The ligand-free Cu[AuX2(CN)2]2 materials exhibited a vapochromic response when exposed to H2O, DMF, DMSO, pyridine, 1,4-dioxane and ethyleneglycol; they also exhibited distinct IR and Raman vCN patterns. Using Raman analysis, these vCN patterns can be effectively used to detect and identify between DMF, DMSO and pyridine. A series of Cu(I) and Ag(I)-based coordination polymer materials containing bridging [AuX2(CN)2]-, [Au(CN)4]- and [Au(CN)2]- were synthesized and characterized. M[Au(CN)4] (M = Cu, Ag) exhibit negative thermal expansion with expansion coefficients between -11e-6 and -24e-6 K-1. M[Au(CN)2] are isomorphous to known AuCN, and exhibit turquoise (Ag) and red (Cu) emission. Incorporating pyridine, THT, PPh3 and Me2S in the Cu(I)/[Au(CN)2]- reaction yielded materials with distinct emissive properties; Cu(SMe2)[Au(CN)2] emits white light. Thus, Cu[Au(CN)2] shows potential as a sensor for P- or S-donor solvents.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Daniel Leznoff
Department: 
Science: Chemistry
Thesis type: 
(Thesis) Ph.D.

Method Development for an Easy and Direct Quantitation of Protein Adsorption by Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis (SDS-PAGE)

Date created: 
2014-11-20
Abstract: 

The current proteomic approach is to identify and analyze proteins of interest, which can potentially be disease biomarkers. However, these important proteins usually exist in very low concentration, making them vulnerable to sample loss by adsorption during any laboratory manipulations. A simple method, sodium dodecyl sulfate polyacrylamide gel electrophoresis coupled with direct protein adsorption analysis (SDS-PAGE/DPA), is presented here for the quantitation of adsorption-caused protein loss. No complicated steps and expensive equipment are involved; this method for protein study enables measurement of proteins adsorbed on vials at extremely low concentrations (in pg/μl). We used this method to characterize the effects of concentration, time, and volume on adsorption. We also applied this method to discover differential sample loss in protein mixtures and its utility in developing preventive strategies of adsorption. This method is further being employed for studying different aspects of adsorption-caused peptide loss.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Bingyun Sun
Department: 
Science:
Thesis type: 
(Thesis) M.Sc.

Ab Initio Studies on 2D Array Of Acidic Surface Groups as a Model For Polymer Electrolyte Membranes.

Date created: 
2014-08-25
Abstract: 

Polymer electrolyte fuel cells (PEFCs) are touted as the next generation of energy delivering devices. Within a decade, PEFC-driven powertrains are expected to become a viable alternative to internal combustion engines in vehicles. Moreover, PEFCs could provide power to a plethora of portable and stationary applications. The critical component in a PEFC is the polymer electrolyte membrane (PEM). Current PEMs require a high level of hydration in order to provide sufficient proton conduction. Of particular interest in this field is the synthesis of advanced functional membranes that could attain high proton mobility at minimal hydration and at elevated temperature (> 100ºC). At these temperatures, structural correlations and proton dynamics at acid-functionalized polymer aggregates could be vital for membrane operation. Theoretical predictions should guide the efforts in the design of advanced PEMs. Our model system consists of a minimally hydrated interfacial array of acid-terminated surface groups. The density of these surface groups is the main variable parameter of the model; moreover, we have evaluated different chemical architectures of surface groups. We have employed ab initio calculations based on density functional theory to study interfacial energies, structural correlations and transitions in the hydrogen bonded network of hydronium ions and protogenic surface groups.The first part of this thesis focuses on rationalizing the effect of various parameters of highly acid-functionalized interfaces in PEMs, such as density, chemical architecture, and conformational flexibility of acidic surface groups on interfacial structural correlations and transitions. At high surface group density and under minimal hydration, with one water molecule per surface group, sulfonic acid head groups are perfectly dissociated. They assemble into a highly ordered condensed surface state with two sublattices; one of them is formed by hexagonally ordered sulfonate anions; the other sublattice corresponds to interstitial hydronium ions. Sulfonate anions and hydronium ions form a hydrogen bonded network. The saturation of hydrogen bonds renders the network in a superhydrophobic state. Lowering the surface group density triggers a sequence of transitions to states with decreasing long range order, decreasing the number of interfacial hydrogen bonds and the degree of dissociation. Moreover, the interface becomes hydrophilic. The same sequence of transitions was found for arrays with varying length and chemical structure of surface groups. These findings emphasize the importance of 2D correlation effects at polymer-water interfaces in PEMs. The second part of the thesis focuses on the impact of a second monolayer of water molecules on stability, interfacial structural correlations and and transitions of the hydrated array of acidic surface groups. Upon increasing the surface group spacing, the bonding energy of additional water increases, undergoing a transition from superhydrophobic to hydrophilic wettability. At sufficiently large surface group separation, a hydronium ion is seen to transfer from the minimally hydrated interfacial network to the second water layer, where it is then observed to form a Zundel ion.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Michael, Eikerling
Department: 
Science:
Thesis type: 
(Thesis) Ph.D.

The Cyclotron Production and Cyclometalation Chemistry of 192-Ir

Date created: 
2014-12-11
Abstract: 

The goal of this thesis is to demonstrate the cyclotron production, radiochemical isolation, and cyclometalate chemistry of radio-iridium isotopes. In recent work, Luminescence Cell Imaging (LCI) has been combined with radioisotopes leading to compounds that can be imaged with both optical microscopy and nuclear techniques. Radiometals excel in this multifunctional setting, providing ideal chemical and nuclear properties for luminescence, biological targeting, nuclear diagnostics, and therapy. Iridium cyclometalate compounds have demonstrated potential in LCI with excellent photophysical properties. Independently, low specific activity 192-Ir has been successfully applied in brachytherapy as a high-intensity beta (-) emitter. Despite this, radio-iridium has not been applied to cyclometalate chemistry, nor a radiochemical isolation method developed for its cyclotron production. Herein is demonstrated the feasibility of the production and isolation of radio-iridium, and its application to cyclometalate chemistry as a potential tool for nuclear medicine research. Natural osmium was electroplated onto a silver disc from basic media, and the thin deposits obtained were weighed and characterized with scanning electron microscopy. These targets were irradiated using the TRIUMF TR13 cyclotron, delivering 12.7 MeV protons to the target disc to access the A-Os(p,n)A-Ir reaction channels. Three irradiations were performed at 5 microamps for 1 hour, and one at 20 microamps for 2 hours. Gamma spectra of the targets were collected and the range of iridium isotopes (186-190, 192) identified and quantified. The irradiated material was then oxidized, dissolved from the target backing, and separated via anion exchange. Once isolated, the isotopes were applied to an adapted cyclometalation procedure, and the compounds were identified and quantified against non-radioactive standards using high performance liquid chromatography with coupled gamma-ray and ultraviolet detectors. The procedure developed here has enabled the study of radio-iridium cyclometalates, a potentially new class of theranostic compounds for nuclear medicine.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Corina Andreoiu
Paul Schaffer
Department: 
Science:
Thesis type: 
(Thesis) M.Sc.

Pre-concentration of positron-emitting [18F]fluoride and radiosynthesis of fluoride-based prosthetic compounds for PET imaging using magnetic droplet microfluidics (MDM)

Date created: 
2014-12-09
Abstract: 

The radioisotope 18F is often considered the best choice for PET imaging, owing to its desirable chemical and radiochemical properties. However, nucleophilic 18F fluorination of large, water soluble biomolecules, based on C-F bond formation, has been difficult. Thus, several aqueous fluorination approach have been developed which offers significant development in radiopharmaceutical synthesis. Furthermore, since 18F decays rapidly, production of these 18F-labelled compounds requires an automated process to reduce production time, reduce radiation exposure and also minimize transfer of reagents during tracer synthesis to reduce sample transfer loss. Herein, a method called magnetic droplet microfluidics (MDM) has been developed which aims to conduct [18F]fluoride pre-concentration and synthesis of 18F-labeled compound on a microfluidic platform. Using this method, we have demonstrated 18F pre-concentration in a small-volume droplet through the use of anion exchanging magnetic particles. By using MDM, the pre-concentration step took approximately 5 min. and the [18F]fluoride solution was pre-concentrated by 15-fold from a volume of 1 mL to 0.05 mL. After the pre-concentration step, an 18F-labelling reaction was performed on the MDM platform using the S-F bond formation in aqueous conditions to produce an arylsulfonyl [18F]fluoride which can be used as a prosthetic group to label PET targeting ligands. The high radiochemical purity of 95 ± 1% was comparable with 96% which was previously reported using conventional method. In addition, when using MDM, the total synthesis time was improved to 15 min. with lower reagent volumes (50-60 µL) used. The MDM method was also used to produce an 18F-labelled aryltrifluoroborate through B-F bond formation. The synthesis of aryltrifluoroborate compound at low activities (~5 mCi), gave radiochemical purities which were low for both MDM (5.8%) and conventional method (6.0%).

Document type: 
Thesis
File(s): 
Senior supervisor: 
Paul Li
Paul Schaffer
Department: 
Science:
Thesis type: 
(Thesis) M.Sc.

Chlorine as an auxiliary in asymmetric aldol reactions and photocatalytic fluorination of C-H bonds

Date created: 
2015-01-20
Abstract: 

Organohalides are ubiquitous in organic chemistry, with broad utility ranging from their use as building blocks in multistep syntheses, to fluoropharmaceuticals that can oftentimes provide more favourable properties to drug molecules. In this regard, two new synthetic methods have been developed that involve the use or preparation of organohalides: chlorine as an auxiliary for asymmetric aldol reactions, and the photocatalytic fluorination of C-H bonds. The aldol reaction is an important carbon-carbon bond forming reaction in organic chemistry, the product of which is a β-hydroxyketone, which is a functionality often encountered in drugs and natural products. As many pharmaceuticals, agrochemicals and bioactive compounds have increased activity as single enantiomers, asymmetric variants of aldol reactions are sought. Herein, an auxiliary strategy is demonstrated for the stereoselective addition of lithium enolates to aldehydes in which the auxiliary itself is not chiral, but a single chlorine atom introduced via organocatalytic asymmetric α-chlorination. The stereodirecting influence of the chloromethine is then exploited prior to its removal by radical reduction. This strategy is demonstrated in the synthesis of various optically enriched β-hydroxyketones (92-99% ee), as well as the natural products (+)-dihydroyashabushiketol and (+)-solistatin. Fluorination reactions are essential to modern medicinal chemistry, and can provide a means to block site-selective metabolic degradation of drugs and access radiotracers for positron emission tomography imaging. Despite current sophistication in fluorination reagents and processes, the fluorination of unactivated C-H bonds remains a significant challenge. Reported herein is a convenient and economic process for direct fluorination of C-H bonds that exploits the hydrogen abstracting ability of a decatungstate photocatalyst in combination with the mild fluorine atom transfer reagent N-fluorobenzenesulfonimide. This operationally straightforward reaction provides direct access to a wide range of fluorinated organic molecules, including structurally complex natural products, acyl fluorides, and fluorinated amino acid derivatives.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Robert Britton
Department: 
Science: Chemistry
Thesis type: 
(Thesis) Ph.D.

Mechanistic Insights into Transition States of Sialidases

Date created: 
2013-08-14
Abstract: 

Sialic acids, a family of nine carbon sugars, are important components of many biomolecules, and they play important roles in many biological processes. For example, they modulate cellular responses such as differentiation, proliferation and apoptosis. These critical carbohydrates are usually positioned on glycoconjugates as the terminal sugar and they are removed by a family of enzymes called sialidases. In mammals, there are several sialidases that are involved in various biological pathways; however, some human sialidases such as NEU3 have shown to be up-regulated in cancer. Also, certain viruses, bacteria, and trypanosomes have developed sialidases as part of their weaponry. Therefore, it is crucial to design selective and potent inhibitors against these enzymes, with minimal side effects. Development of such selective therapeutics involves a comprehensive understanding of the mechanism by which sialidases catalyze the removal or transfer of sialic acid moieties from glycoconjugates. A key component when studying enzymes mechanisms involves characterization of the transition state(s) (TS) through which the enzyme:substrate complex (ES) is converted to the enzyme:product complex (EP). Hence, the focus of this thesis involves characterization of the transition states (TSs) for sialidase-catalyzed cleavage of alpha-sialosides (sialic acid residues covalently attached to glycoconjugates), by employing three distinct mechanistic tools. These techniques include Brønsted analysis, linear free energy relationship (LFER), and kinetic isotope effects (KIEs). Of note, chapter 4 of this thesis describes the development of a new 2D-NMR technique for measuring multiple kinetic isotope effects simultaneously as a first step in the process of solving transition state structure(s) of sialidase-catalyzed reactions.

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