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

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Light Controlled Bio-inspired Small Molecules

Date created: 
2016-12-12
Abstract: 

The work presented in this thesis examines the design, preparation and evaluation of light controlled biologically inspired small molecules. Incorporation of light sensitivity was achieved through the introduction of a photoresponsive diarylethene group, into a specific position within the molecular structure of a biologically relevant compound. The diarylethene class of photoresponsive molecules can absorb light of a specific wavelength, and subsequently undergo a reversible, light induced isomerization reaction, to generate a new structure with a unique set of chemical and physical properties. This photoisomerization process, also referred to as photoswitching, allows for reversible manipulation of the modified biomolecule’s properties, and consequently its ability to interact with a target using light. During this thesis, two examples utilizing the diarylethene framework are presented as a means to control the properties; either geometric (steric) or electronic, of photoresponsive small molecules using light energy. In the first example, featured in Chapter 2, light is used to alter the binding affinity (and thus inhibitory potency) of a photoswitchable enzyme inhibitor. The design relies on the structural and geometrical changes that accompany photoswitching of the central diarylethene to achieve this. A series of inhibitor candidates, based on the bisindolylmaleimide class of protein kinase inhibitors, were synthesized and investigated. A number of challenges were encountered during the design process, including the poor photochemical performance and limited aqueous stability of the inhibitor candidates. Although, during the course of the project, two light controlled inhibitors with differing inhibition mechanisms were discovered. One derivative exhibited good in vitro inhibition, and its inhibitory activity could be switched from an inactive, “off” state, to an active, “on” state, with brief exposure to non-damaging visible light. A second derivative, self-assembled into large aggregate particles and interestingly, exhibited light dependent (more specifically, structure dependent) solubility in aqueous media. The aggregates were found to inhibit enzyme function in vitro, although through a non-specific adsorption mechanism. The aggregate assembly could be disrupted with exposure to visible light, which generated the water soluble isomer, and restored enzyme activity. In the second example, featured in Chapter 3, light is used to control the electronic properties of a photoisomerizable Pyridoxal 5’-phosphate (PLP) mimic and influence the rate of a racemization reaction. The design combines the essential structural features of PLP, which are an aldehyde and a pyridinium, with a diarylethene photoswitch. The inherent changes that take place to the structure of the diarylethene with photoisomerization, effectively allowed for reversible modulation of the degree of electronic connection between the aldehyde and pyridinium. Consequently, control over the cofactor mimic’s reactivity towards substrate was possible. In the inactive state, communication between the pyridinium and aldehyde are minimal, and as a result, the ability to convert a substrate to product is poor. Whereas in the active state, the extended communication pathway formed between the pyridinium and aldehyde, lead to a more efficient catalyst for substrate conversion.

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

Designing artificial electron transfer pathways in dioxygen-activating metalloenzymes

Date created: 
2016-07-26
Abstract: 

This thesis describes efforts to introduce new redox reactivity into two classes of dioxygen-activating enzymes. First, I investigated modified cytochrome c peroxidase (CcP). Here, a series of Trp residues were introduced between the heme active site and the surface of the enzyme to serve as a hole transfer wire. The addition of two mutations (A193W and Y229W) introduced new oxidation chemistry to CcP, as evaluated using aromatic substrate oxidation assays. This enzyme is a functional model for lignin peroxidase enzymes and provides a strong foundation for the development of new protein-based oxidation catalysts. Second, we investigated cyanobacterial aldehyde deformylating oxygenase (cAdo) enzymes. Here, we characterized and investigated three Ru-cAdo models. To provide the four electrons required for catalysis, we introduced a Ru-tris(diimine) photosensitizer to solvent exposed cysteine residues. Through NMR and GC-MS, we gained an insight into the catalytic activity of Ru-cAdo. This work highlights the nature of protein based electron transfer and points toward other underlying factors that dictate catalytic efficiency.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dr. Jeffrey J. Warren
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Synthesis and characterization of lead-free perovskite solid solutions

Date created: 
2015-08-19
Abstract: 

Piezo-/ferroelectrics form an important class of functional materials that can transduce mechanical energy to electrical energy and vice versa. They have large impacts in medicine (ultrasound imaging), in naval exploration/defence (sonar) and in consumer products (random access memories, capacitors). Currently, there is high interest in the development of new lead-free materials due to health and environmental risk factors of high-performance lead-based materials, such as Pb(Zr,Ti)O3. One promising lead-free system is the (K,Na)NbO3 (KNN) solid solution, as it has a high Curie temperature, which allows for a wide operating temperature range for devices. In order to better understand the structure and property relations, single crystals are needed. In this work, single crystals of K0.1Na0.9NbO3 (KNN) and 0.98K0.8Na0.2NbO3 – 0.02LiNbO3 (KNN-LN) have been grown using a high-temperature solution growth method with K2CO3 and B2O3 as flux. Polarized light microscopy was used to study the Na-rich KNN crystals, and the phase diagram on the Na-rich end of the (1-x)KNbO3 - xNaNbO3 solid solution has been updated. With the intention of addressing the issue of composition segregation, a modified vapour transport equilibration technique has been developed and demonstrated to be a viable approach to increase the Li-content in the KNN-LN crystals. In addition, a new ternary solid solution of y(K0.5Na0.5)NbO3 – (1-y)[(1-x)Bi0.5K0.5TiO3 – xBaTiO3] has been synthesized in the form of ceramics with compositions of y = 0.96 to y = 0.98 and its partial phase diagram has been established. Aside from KNN-based materials, translucent ceramics of (1-x)(Na0.5Bi0.5)TiO3 – xAgNbO3 (NBT-AN) and (1-x)(Na0.5Bi0.5)TiO3 – xAgTaO3 (NBT-AT) have been successfully prepared via a solid state method under ambient pressure. The dielectric permittivity as a function of temperature is found to be constant for compositions of x > 0.12 (e.g. its variation is within ±10 % for both NBT-AN and NBT-AT (x = 0.16) between 0 °C and 350 °C), while the polarization versus electric field relation shows pure capacitive behaviour up to 250 °C. With these properties, NBT-AN and NBT-AT are promising candidates for electro-optics and/or high-temperature capacitors.

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

Tandem Organocatalytic α-Chlorination−Aldol Reactions: A Powerful Tool for Carbohydrate and Iminosugars Synthesis

Date created: 
2015-08-05
Abstract: 

Carbohydrates play a vital role in regulating biological events that range from cell recognition to pathogen/host adhesion. Not surprisingly, inhibitors of carbohydrate binding and cleaving processes, such as iminosugars, have been identified as leads in various therapeutic areas and several glycomimetic drugs have been approved for use in humans. Despite several clinical successes, their de novo synthesis remains a significant challenge that also limits their integration within modern high-throughput screening technologies. Progress in glycomimetic research is often closely tied to advances in the de novo synthesis of unnatural carbohydrates, with much success being realized through the use of organocatalytic reactions. Our continued interest in the use of α-chloroaldehydes as building blocks for natural product synthesis led us to probe their organocatalytic aldol reactions with 2,2-dimethyl-1,3-dioxan-5-one. These efforts resulted in the discovery of a one-pot α-chlorination—aldol reaction that involves the dynamic kinetic resolution of an in situ generated α-chloroaldehyde. This process provides direct access to novel, enantiomerically-enriched building blocks (β-ketochlorohydrins) that are well-suited for the synthesis of carbohydrates and C-glycoconjugates. In this thesis, a unique synthetic strategy to convert a wide range of acetaldehyde derivatives into imino-C-nucleoside analogues in two or three straightforward transformations is described. We also show that this strategy can be readily applied to the rapid production of indolizidine and pyrrolizidine iminosugars. The high levels of enantio- and diastereoselectivity, excellent overall yields, convenience and broad substrate scope make this a promising process for diversity-oriented synthesis and should enable drug discovery efforts. Finally, the synthesis of configurationally divergent iminocyclitols is presented. This study led to the identification of potent, selective and brain penetrant OGA inhibitors as lead candidates for the treatment of Alzheimer’s disease.

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

Molecular Modeling of Structural Transformations in Ionomer Solutions and Membranes

Date created: 
2016-08-04
Abstract: 

Different functions are expected from the polymer electrolyte membranes used in fuel cells. They work as a proton conduction medium, as a separator, and as an electronic insulator. The current membrane materials of choice are perfluorosulfonic acid (PFSA) ionomers such as Nafion. The two main challenges that PFSAs still face, after three decades of extensive research, are a limited lifetime and a lack of basic structural understanding. To investigate the chemical degradation phenomena, we devised a kinetic model of radical formation and attack to PFSA ionomers. Analytical relations are derived to obtain the content of aggressive radicals as a function of iron ion content and hydrogen peroxide. The mean-field type, coarse-grained ionomer model distinguishes ionomer headgroups, side chains, and ionomer backbone. The model is used to study the impact of different degradation mechanisms and ionomer chemistries on PEM degradation. Application of the model to degradation data of various PFSAs highlights the important role of radical attack to the ionomer headgroups. The insufficient understanding of the membrane structure thwarts further forays in degradation modeling. To this end, we undertook molecular dynamics simulations of the conformation of single chain ionomers as a function of different structural parameters. This study revealed the nonmonotonic effect of the side chain length and density on the conformational behaviour and rigidity of ionomer backbones. We discuss how the changes in these architectural parameters change the ionomer affinity to counterions and the corresponding ion mobility. Studying the aggregation of ionomer chains revealed their spontaneous aggregation in dilute solution. We explored the effect of various parameters such as ionomer hydrophobicity and side chain content on ionomer bundle formation. Minimization of the surface free energy of hydrophobic backbones is the driving force of ionomer aggregation, while the repulsion of anionic headgroups opposes the aggregation. The results rationalize the experimental studies and highlight the role ionomer bundles as the prevailing structural motif in PFSA materials.

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

Development of chemical tools for studying human O-GlcNAcase activity

Author: 
Date created: 
2015-11-18
Abstract: 

In recent years, the post-translational modification of nuclear and cytoplasmic proteins with O-linked N-acetylglucosamine (O-GlcNAc) has emerged as playing diverse roles in health and disease. Interestingly, this modification is regulated by only two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). A method to study the effects of elevated levels of O-GlcNAc is to selectively target OGA. Herein, we describe the structure-activity relationships of a family of 2'-aminothiazoline-based inhibitors, one of which shows to be among the most potent inhibitors of human OGA (hOGA) known to date. We present the selectivity ratios of these compounds for hOGA over the structurally-related lysosomal β-hexosaminidases, define them as transition state analogues and rationalize their potencies by using linear free energy analyses. We also identify two fluorescence quenched substrates for hOGA bearing thioamide quenchers having different fluorogenic leaving groups, which reveal design features for substrates to monitor hOGA activity in live cells.

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

Platinum electrocatalysis: Novel insights into the dissolution mechanism and oxygen reduction reaction

Date created: 
2016-07-29
Abstract: 

Formation of hydrogen peroxide and oxygenated radical species are the leading cause of chemical degradation observed in polymer electrolyte membranes (PEM) in polymer electrolyte fuel cells. Recent experimental studies have shown that Pt nano-deposits in the PEM, which originate from Pt dissolution in the catalyst layer, play an important role in radical-initiated membrane degradation. Surface reactions at Pt particles facilitate the formation of reactive oxygen species. The net effect of Pt surface processes on membrane degradation depends on the local equilibrium conditions around the Pt nano-deposits, specifically, their equivalent local electrode potential. In this thesis, we first present a multi-step theoretical approach, validated by a collaborative experimental study, to understand the impact of environmental conditions around the Pt nanodeposits on membrane chemical degradation. In the first step, we developed a physical analytical model for the potential distribution at Pt nanodeposits in the PEM. Given the local potential, we identify the surface adsorption state of Pt. Thereafter, density functional theory (DFT) was used to investigate the influence of the Pt adsorption state on the mechanism of oxygen reduction reaction (ORR), particularly the formation of hydrogen peroxide and hydroxyl radical as the two important reactive oxygen species for membrane degradation. In a separate work, we employed DFT to study the atomistic mechanism for interfacial place-exchange between surface Pt atom and chemisorbed oxygen at oxidized Pt (111)-water interfaces. Understanding the criteria for Pt oxide growth is a crucial step to comprehend the mechanisms of Pt dissolution during electrochemical processes.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Dr. Michael H. Eikerling
Department: 
Science: Department of Chemistry
Thesis type: 
(Dissertation) Ph.D.

Total Synthesis of Tetrahydrofuranol-Containing Natural Products and Studies Toward Eleutherobin

Date created: 
2016-08-23
Abstract: 

An extension of previously developed methodology towards the synthesis of tetrahydrofuranol rings is demonstrated in the total synthesis of amphirionin-4 in 11 steps comprising the first total synthesis of this natural product. Furthermore, we were able to exploit this methodology toward the total synthesis and structural reassignment of laurefurenyne A. The development of a flexible and concise synthesis allowed for access to the proposed stereostructure of the natural product and, following analysis of spectral data, indicated this structure had been misassigned. Further synthetic efforts completed the synthesis of the correct structure of laurefurenyne A and enabled investigations into the biosynthesis of this natural product. An additional study describes efforts toward the synthesis of the promising anti-cancer natural product eleutherobin. As part of these efforts we have developed a cyclobutanone α-arylation/ring expansion strategy that affords access to α-tetralones. This methodology has been expanded toward the synthesis of a wide range of α-arylcyclobutanones and α-tetralones including the incorporation of heterocycles. Our efforts towards the synthesis of the core of eleutherobin through an α-tetralone intermediate are detailed including a radical cyclization method to form a vital C-C bond required for a proposed retro-aldol fragmentation. Furthermore, we have exploited this approach in our efforts toward the total synthesis of coniothyrinone D. While ultimately unsuccessful in accessing the natural product, this synthesis has demonstrated the utility of this approach towards the synthesis of this natural product scaffold.

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

Smartphone-readable barcode assays for quantitative analysis

Date created: 
2016-07-25
Abstract: 

In the literature, there has been a recent surge in smartphone-based bioanalytical techniques, particularly for point-of-care and medical diagnostics. These devices aim to have certain characteristics such as affordability, sensitivity, be user friendly and equipment-free. To add to the growing field, a smartphone-readable, bona fide barcode assay is demonstrated; the work performed to develop the app to read colorimetric assays and the design of the barcode assay is discussed. Paper-printed tests and direct biotin-streptavidin assay were used to test the initial app. Barcode reading abilities in the app allowed for the validation of the barcode assay (for the pregnancy hormone, hCG), which proved to be both qualitative and quantitative when scanned and imaged using a smartphone-app combination. No external accessories are required, thereby highlighting its potential to boost the research and development of POC devices, particularly by minimizing the need for specialized instrumentation and providing instant testing results on-site.

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

Electron Density-Matching Diamido Ligands to 1st Row Transition Metals: Coordination and Reactivity Trends

Author: 
Date created: 
2016-04-29
Abstract: 

Amido-based ligands can employ a variable R-group which can be used to “tune” the steric and electronic properties of the resulting metal complex, targeting bond activation and catalytic applications. This thesis explored how the chelating diamido ligand {(tBuNSiMe2)2O}2- interacts with the early transition metals scandium(III), titanium(III) and vanadium(III), to discern how the number of d-electrons affects the coordination and reactivity of the complexes. The coordination motif is oxidation state-dependent, and structural differences are observed as the number of d-electrons changes. Alkylation yielded interesting results: the vanadium complex formed the dinitrogen species {[(tBuNSiMe2)2O]VR}2(μ-N2) (R = CH2SiMe3, CH2Ph), while scandium produced the expected complex, {[tBuNSiMe2]2O}ScCH2SiMe3•THF. Concurrently, a diamido ligand containing electron-withdrawing –CF3 groups, {[3,5-(CF3)2PhNSiMe2]2O}2-, was examined to probe how the altered electronic profile affects the overall coordination and reactivity of later transition metal iron(III) and cobalt(II) complexes. Unusual structural motifs indicated that this ligand warrants additional research.

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