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

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Modeling novel ionenes for electrochemical devices with first principles and machine learning methods

Author: 
Date created: 
2020-04-06
Abstract: 

Polybenzimidazole-based ionenes are being developed for use in both alkaline anion-exchange membrane fuel cells and alkaline polymer electrolysers. The first part of this work explores the impact of the degree of methylation on the conformations and electronic structure properties of poly-(hexamethyl-p-terphenylbenzimidazolium) (HMT-PMBI), the materials of interest in this thesis. For this purpose, HMT-PMBI oligomers, from monomer to pentamer, are studied with density functional theory calculations. Next, molecular dynamics simulations are used to calculate the trajectory paths of all atoms of the fully methylated HMT-PMBI tetramer. Lastly, recurrent neural networks are explored as a means to accelerate the statistical sampling of molecular conformations of polymeric systems, thereby providing complementary tools for molecular dynamics simulations. It is demonstrated that these types of artificial neural networks can be learned from the distribution of the coordinates of atoms over molecular dynamics simulations. As shown, the trained multivariate time series model enables forecasting trajectory paths of atoms accurately and in much reduced time with over 96% accuracy.

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

Synthesis and assessment of ethylene diamine-based self-immolative linkers for use in the selective delivery of drugs to bones

Author: 
Date created: 
2019-04-30
Abstract: 

Self-immolative linkers containing bisphosphonates may be an ideal approach to delivering drugs to bone for treatment of diseases such as osteoporosis. Bisphosphonates can be used to target pro-drugs to bone and can be linked to active drugs via a self-immolative linker such as an ethylene diamine carbamate. Such prodrugs can be inactive until reaching and attaching to bone where they then slowly release the active drug. Several prodrug models with an ethylene diamine linker attached to a model drug, 1-phenyl-2,2,2-trifluoroethanol (which represents a structural component of a proprietary bone stimulating drug) were prepared and used to study the effect of the position of attachment of the model drug and the bisphosphonate and of substitutions on the linker on the rate of self-immolation and drug release. This study concluded that attachment of the bisphosphonate, steric hindrance, and steric compression (attributable to substitutions) can be used to alter the rate of self-immolation.

Document type: 
Thesis
Senior supervisor: 
Robert Young
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Multifunctional ligand design for modulating protein stability and aggregation for cancer treatment

Author: 
Date created: 
2020-03-30
Abstract: 

Referred to as the “guardian of the genome”, p53 is the most frequently mutated protein in cancer and accounts for over 50% of cancer diagnoses. p53 regulates the cellular network by signaling for the activation of various pathways including apoptosis and cell cycle arrest to avoid propagation of damaged cells. Consequently, in 50% of cancer diagnoses, single point mutations render the protein inactive, prohibiting its antiproliferative response and allowing for accumulation of damaged cells. The majority of mutations are localized to the DNA-binding domain, a domain that contains a Zn2+ ion that is essential for proper protein folding and function. These mutations typically affect the proteins’ tertiary structure, resulting in a loss or alteration of Zn-binding which can lead to unfolding and enhanced aggregation. As an overexpressed and tumour-specific target, the past two decades have seen considerable dedication to the development of small molecules that aim to restore wild-type function in mutant p53. Previous efforts have been monofunctional in design, targeting specific characteristics of a given p53 mutant including thermal denaturation, aggregation, or loss of zinc. This thesis explores small molecule design strategies to restore wild-type function in mutant p53. Considering the multifaceted nature of p53 mutants, a multifunctional approach was employed to simultaneously target various characteristics. Chapter 2 features a bifunctional scaffold targeting zinc loss and thermal denaturation. The utility of this scaffold in increasing intracellular zinc and restoring transcriptional function in mutant p53-Y220C is described. Modifications to the ligand scaffold to extend the structures into subsite cavities of this mutant are explored in Chapter 3. These modifications increased the cytotoxicity of the ligands and restored apoptotic activity, however, resulted in a loss in their ability to serve as zinc metallochaperones. Lastly, a combination of fragments targeting zinc loss and protein aggregation found success in restoring wild-type function in mutant p53 in Chapter 4. These studies highlighted the possible advantages of halogenation in modulating mutant p53 aggregation, as an iodinated scaffold limited mutant p53 aggregation and restored wild-type function. This work represents a foundation to simultaneously target the multiple characteristics of p53 mutants and provides important information for drug design moving forward.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Tim Storr
David Vocadlo
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Reaction of hydroxyl radicals with sulfonated phenylated polyphenylenes

Author: 
Date created: 
2019-04-18
Abstract: 

The perceived poor durability of non-fluorous, hydrocarbon solid polymer electrolyte membranes in the presence of reactive hydroxyl radicals remains a significant hurdle for their integration into electrochemical systems such as fuel cells. However, recent reports point to sulfonated phenylated polyphenylenes (sPPP) being considerably stable in accelerated fuel cell tests. In order to investigate the possible reaction of hydroxyl radicals with this promising class of hydrocarbon polymer electrolytes, a structurally-analogous oligophenylene model compound was synthesized and its degradation route was studied in the presence of hydroxyl radicals. Using NMR spectroscopy and mass spectroscopy, all significant degradation products are characterized and based on their chemical structures, along with changes in concentration over time, a degradation route is proposed. Hydroxyl-radical degradation was observed and found to be initiated by the oxidation of pendant phenyl rings to form fluorenone sub-structures which, upon further oxidation, lead to ring-opening of a main chain phenyl ring which, if occurring in sPPP, leads to chain-scission of the polymer backbone. In keeping with this hypothesis, molecular weights of sPPP were found to decrease when subject to hydroxyl radicals. Although degraded polymer NMR spectra remain unchanged, resonances consistent with the elimination of sulfobenzoic acid emerge. The results outlined in this work point towards a promising future for sPPP membranes and suggest a simple modification which should enhance their lifetime within fuel cell systems.

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

Synthesis of sulfo-phenylated terphenylenes: molecules, polymers and copolymers

Author: 
Date created: 
2019-04-16
Abstract: 

This thesis reports the synthesis and study of a new class of fluorine-free, acid-bearing polymers for potential usage in proton exchange membrane fuel cells. The polymers were prepared via the synthesis of a pre-sulfonated monomer, followed by homo- and co-polymerization by [4+2] Diels-Alder cycloaddition. Molecular structures were determined by mass spectrometry, infrared spectroscopy, 1H NMR and 2D COSY spectroscopies, and single crystal X-ray diffraction. Disulfonated tetracyclone and tetrasulfonated bistetracyclone molecules were used to synthesize two model compounds to determine the potential isomers present. Tetrasulfonated bistetracyclone was polymerized with 1,4-diethynylbenzene co-monomer. The resultant polymer, sPPP-HNEt3+, was prepared with a high molecular weight and converted into its acid form, prior to casting as a membrane. The membranes possessed a high ion exchange capacity (IEC) of 3.49 meq/g and a proton conductivity of 118 mS/cm at room temperature and at 95% relative humidity (RH), respectively, four and a half time superior as the current benchmark NRE 211®. The polymer film was found to become soluble during exposure to aggressive oxidative solutions no significant chemical changes were observed. The final part of this work focused on increasing the polymer film stability by judiciously tuning the hydrophilic content of the polymer. A family of random-copolymers was prepared based on the above monomers. The parameters for polymerization were studied and the optimal conditions were found using size exclusion chromatography to determine molecular weight. The measured IEC for these copolymers correlated well with the theoretical IEC, ranging from 1.86 to 3.50 meq/g. The conductivity of these polymers at 80°C and 95% RH was found to reach 338 mS/cm. Fuel cell tests were performed using the membranes and provided a peak power density of 770 mW/cm2.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Steven Holcroft
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Total synthesis of biselide A and studies towards the synthesis of a chimeric glycopeptide to probe peptide-carbohydrate mimicry

Date created: 
2019-12-11
Abstract: 

The primary focus of the research described in this thesis deals with the studies geared towards the total synthesis of biselide A and phormidolide A, two tetrahydrofuran containing natural products with potentially useful biological activities. Additionally, efforts towards the synthesis of a chimeric glycopeptide is described. Biselide A, is a chlorinated macrocyclic polyketide isolated from the Okinawan ascidian Didemnidae sp., possessing potent cytotoxicity against a variety of human cancer cell lines. The core molecular structure contains a densely substituted tetrahydrofuran ring and 5 stereogenic centres as a part of 14-membered macrolactone. To access this potentially useful marine macrolide we have utilized an asymmetric aldol reaction with enantiomerically-enriched chlorohydrins that affords a rapid and stereocontrolled access to the tetrahydrofuran core. The macrocycle was constructed through a series of transformations that include a cross metathesis, regioselective enzymatic acetylation, and Reformatsky macrocyclization. In this thesis we highlight a flexible and stereoselective total synthesis of biselide A. Phormidolide A is a complex macrocyclic polyketide isolated from the cyanobacteria Leptolyngbya sp. It possess a highly oxygenated side chain and a macrocyclic core with an embedded substituted tetrahydrofuran. We exploit our previously developed α-chlorination/aldol reaction strategy to access the tetrahydrofuran motif. Synthesis of three model acetonide tetrahydrofuran derivatives allowed for the NMR comparison with the same previously reported triacetonide derivative of phormidolide A. NMR spectroscopic analysis supports a reassignment of seven of the eleven stereogenic centres initially reported for phormidolide A. The second part of this thesis describes the progress made towards the synthesis of a chimeric glycopeptide. Two haptens, a pentasaccharide and a mimetic octapeptide bind with moderate affinity to a monoclonal antibody SYA/J6, specific for the O-polysaccharide of the S.flexneri Y bacterium. Based on the X-ray crystallography data and molecular docking studies, two chimeric glycopeptides (α-glycopeptide and β-glycopeptide) were designed in an attempt to improve the binding affinity to SYA/J6 antibody. Our group has previously synthesized α-glycopeptide and showed no inhibition of SYA/J6 antibody to the O-polysaccharide. Preliminary docking studies indicated that the β-glycopeptide might provide a better fit within the antibody combining site. The molecule consists of a rhamnose trisaccharide linked through a β-glycosidic linkage to an MDW moiety of a mimetic octapeptide. Our strategy involved linking three fragments, synthesized using solution and/or solid phase methodology. The key step in the synthesis was the formation of the thermodynamically less favoured β-linkage between the sugar and peptide. This was achieved following an ulosyl bromide approach. We herein describe our efforts towards the synthesis of a β-glycopeptide.

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

Design, synthesis and characterization of novel, lead-free multiferroic and relaxor materials

Author: 
Date created: 
2019-04-11
Abstract: 

New multiferroic solid solutions of (1-x)BiFeO3-xBaHfO3 (BF-BaHf) with x = 0.05 - 0.95 has been prepared by conventional solid-state reaction in the form of ceramics. X-ray powder diffraction revealed that the perovskite structure of BF-BaHf transfers from rhombohedral to cubic symmetry with the increasing concentration of BaHf, resulting in the formation of solid solution. Compared with pure BF, the ferromagnetism in the BF-BaHf solid solution is substantially enhanced by the structural distortion due to A-and B-site co-substitutions, with remanent magnetization Mr = 0.0469 ????" ⁄????. ???? in x = 0.15. Meanwhile, ferroelectric domains were observed by transmission electron microscopy for x = 0.15. This confirms the beneficial role of BaHf substitution in enhancing magnetic properties while maintaining ferroelectric properties of the BF-based multiferroic materials. Another new multiferroic solid solution of pseudo-binary system (1-x)[0.8BiFeO3- 0.2BaHfO3]-xBaTiO3 [(1-x)(0.8BF-0.2BaHf)-xBaT] has been successfully synthesized by solid state reaction with x = 0.15 - 0.95. All the composition studies showed a gradual phase transition from rhombohedral to tetragonal phase as the BaT concentration increases. A morphotropic phase boundary is found in the composition range of 0.70 < x < 0.80. Additionally, weak ferromagnetism at room temperature was observed in the composition range of 0.30 ≤ x ≤ 0.40. The dielectric loss tangent shows a significant decrease as the BaT component increases. Summarily, a phase diagram of the (1- x)[0.8BiFeO3-0.2BaHfO3]-xBaTiO3 solid solution has been established. Single crystals of lead-free BaZr0.275Ti0.725O3 (BZT) have been grown successfully by a high temperature solution growth method after 32 trials. The optimal flux combination to grow the BZT single crystals is a mixture of BaCO3, BaCl2 and B2O3. The size of the as- grown crystals varies from 0.5 to 1 nm. X-ray diffraction indicates a pure perovskite phase. Polarized light microscopy has shown that the crystals are of cubic symmetry at room temperature, suggesting that they are of relaxor behaviour, as initially expected. The BZT single crystal composition is determined by X-ray photoelectron spectroscopy to be consistent with the nominal composition. The atomic concentrations ratio of the elements Ti and Zr are 72.5 % and 27.5%, respectively. This work demonstrates that the BZT single crystal can be grown by high temperature solution growth method and this is the first successful growth.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Zuo-Guang Ye
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Synthesis and characterization of new Au-Ag plasmonic alloy materials

Author: 
Date created: 
2019-04-10
Abstract: 

Confining the delocalized fields of electromagnetic waves to the nanometer scale of metallic surface regions by exciting surface plasmons enables new methods of information transfer, energy conversion, red-ox chemistry and catalysis. Currently, Ag and Au are the most commonly used plasmonic materials, but neither is ideal. The goal of this work is to synthesize and characterize new Au- and Ag-based alloy materials with improved plasmonic response, low optical losses and high chemical stability by employing an electroless reduction method to deposit the alloys through co-deposition of silver and gold ions. The deposition kinetics of the ions in solution have been examined, followed by characterization of the resulting films to assess their quality, crystallinity and physical and chemical properties. We have employed spectroscopic ellipsometry (SE) to assess the optical and plasmonic properties, X-ray photoelectron spectroscopy (XPS) for film composition and electronic structure, X-ray diffraction (XRD) for film crystallinity, scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HRTEM) for their crystalline structure and morphology. The chemical stabilities of the alloy films have also been addressed by examining their stability upon exposure to various oxidants. Nanostructured alloy films deposited using the same chemistry on films patterned by electron beam lithography (EBL) yield large area, high quality, crystalline nanopillar arrays. These metamaterial arrays demonstrate plasmonic response which is determined by pillar diameter, periodicity and composition. The development of new high quality, crystalline, plasmonic alloy materials will enable new and improved performance in plasmonic and metamaterial research and application.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Gary Leach
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Evaluation of small molecules and metal complexes that modulate amyloid-beta aggregation of relevance to Alzheimer’s disease

Author: 
Date created: 
2019-11-28
Abstract: 

Alzheimer’s disease (AD) is the most common form of dementia, representing 50-75% of all cases worldwide. AD is a multifaceted disease that is characterized by increased oxidative stress, metal-ion dysregulation, and the formation of intracellular neurofibrillary tangles and extracellular amyloid-B (AB) aggregates. Cu(II), Zn(II) and Fe(II) have been shown to play a role in the aggregation and toxicity of the AB peptide, leading to the formation of reactive oxygen species (ROS) for Cu(II) and Fe(II). Different approaches have been used in this thesis to decrease the formation of ROS, modulate peptide aggregation and the interaction between bioavailable metal ions and the AB peptide. In the first approach, metal-protein attenuating compounds (MPACs) were designed to bind dysregulated metal ions thereby limiting metal ion binding to the AB peptide. The ability of 8-hydroxyquinoline Schiff-base ligands to inhibit peptide aggregation in the presence of Cu(II), and their antioxidant activity measured by a Trolox equivalent antioxidant capacity (TEAC) assay are described. The ligands were shown to form complexes with Cu(II), 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. The second approach investigated herein describes the use of metal complexes that are able to bind to the peptide, with potential to modulate aggregation and limit ROS formation. We report the high affinity binding of the Fe(III) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole complex FeL1 to the AB peptide (Kd ~ 10-7) and the ability of the bound FeL1 to act as a catalytic antioxidant in both the presence and absence of Cu(II) ions. Overall, FeL1 is shown to bind to the AB peptide, and modulate peptide aggregation. In addition, FeL1 forms a ternary species with AB-Cu(II) and impedes ROS generation. Finally, we report a series of four Ru(III) complexes, inspired by the antimetastatic NAMI-A complex. These complexes bind to AB, and were shown to modulate peptide aggregation. Overall, we highlight the promise of discrete metal complexes to limit the toxicity pathways of the AB peptide.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Tim Storr
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Synthesis of conformationally constrained inhibitors for glycoside hydrolases

Author: 
Date created: 
2019-09-10
Abstract: 

Glycoside hydrolase (GH) enzymes are clinically relevant biological targets for drug development. Disfunction of the two lysosomal GHs β-glucocerebrosidase and α-galactosidase can lead to Gaucher and Fabry’s disease, respectively. With knowledge of their mechanisms of action it is possible to create compounds that would effectively modulate their activity and potentially restore the activity of dysfunctional enzymes. Therefore, this work considers the approach to the synthesis of such compounds and determination of their mode of action. In the future, these compounds can be used for the development of drug candidates.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Andrew Bennet
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.