Theses (Chemistry)

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Fate and distribution of atmospheric volatile organic compounds from wastewater treatment facilities
(2025) Michalchuk, Trevor; Krogh, Erik
Malodourous volatile organic compounds (VOCs) are found throughout the environment, from biogenic, geochemical and anthropogenic sources. A concerning anthropogenic source of malodours are wastewater treatment plants (WWTPs), where elevated levels of VOCs including several organosulfur compounds with low odour detection thresholds are produced and emitted. The ability to measure this class of malodourous compounds specifically, methanethiol (CH3SH), dimethyl sulfide (CH3SCH3), and dimethyl disulfide (CH3SSCH3) by mobile mass spectrometry has enhanced our understanding of their fate and distribution in the environment surrounding wastewater treatment facilities. Organosulfur compounds can impact the environment including human health either through toxic effects, malodours, and/or as a source of sulfur dioxide (SO2), thus lowering air quality. This thesis summarizes the use of direct mass spectrometry in a purpose-built research vehicle to investigate odour control systems at three wastewater facilities on Vancouver Island both on-site in foul air collection ductwork and on-road in ambient air in the neighbouring community. The three WWTPs investigated varied in age, size, location, and odour control technology. VOCs were measured using proton-transfer time-of-flight mass spectrometry (PTR-TOF-MS) with concentrations of methanethiol (m/z 49.01), dimethyl sulfide (m/z 63.02), and dimethyl disulfide (m/z 94.99) assessed in real-time. Other VOCs known to contribute to the odour profile include oxygenated hydrocarbons (e.g., acetaldehyde, acetic acid, butanal) as well as monoterpenes were also monitored. Supplemental measurements taken with sorbent tubes on-site were evaluated with lab-based thermal desorption-gas chromatography-mass spectrometry, to assess the identity of compounds such as dimethyl sulfide and ethanethiol. The distribution of atmospheric gases emitted from these facilities varied depending on the treatment methods employed as well as on the location, topography, and meteorology. On-site measurements were aimed at assessing the efficiency of odour control technologies and the on-road measurements provided insight into the spatiotemporal distributions of malodourous VOCs. Concentrations of reduced sulfur compounds in the collected foul air ranged from 102 – 104 parts per billion by volume (ppbv). The odour control systems included physical adsorption by activated carbon and biological treatments using biofilters and bioreactor systems. A chemical scrubber and a pilot scale UV advanced oxidation treatment process were also evaluated during this study. Efficiencies of odour control techniques are described, with methanethiol removal efficiency consistently being the greatest, with typical removal of 70-90% by odour control technologies. Using biological and physical treatments, dimethyl sulfide and dimethyl disulfide were found to be modestly removed, with removal efficiency of dimethyl sulfide at <40% and dimethyl disulfide removal efficiencies being low (<20%) to negligible. In some cases, we observed increases in dimethyl disulfide concentrations. On-road measurements in the local communities around the WWTPs were also investigated for potential impacts from WWTPs. This includes mapping VOC concentrations over time and space, tracking plumes, and determining whether other sources of odours exist in the sample area. Typical ambient concentrations recorded at and within 2 km of WWTPs in the 0.2 -5 ppbv range for reduced sulfur compounds and 2 – 10 ppmv for methane. On-road concentrations for benzene, toluene, ethylbenzene, and xylenes (BTEX) associated with vehicle emissions were typically observed in the 0.5 – 5 ppbv range. Results from the drive portion of the campaign allowed for visualization of VOC distributions and produced neighbourhood scale information, including geospatial averages mapped at 50x50m, with detection of odourous VOCs within 1 km of WWTPs above odour thresholds under some conditions. Sources other than the WWTPs were also identified including pump stations, conveyance structures, and estuarine marine locations. This work illustrates the application of mobile real-time measurements to better understand the fate and distribution of VOCs in the community as well as characterize the effectiveness of mitigation strategies for malodourous compounds.
Deriving function from complex linked equilibria: systems chemistry with self-assembled p-sulfonatocalix[n]arenes in aqueous solution
(2025) Selinger, Allison J.; Hof, Fraser Alan
Building systems of increasing complexity can give rise to emergent properties that are otherwise unobtainable. The design and development of macrocyclic-based systems that function in aqueous solution has many applications in detection, delivery and reversal of biologically relevant molecules. This dissertation focuses on synthetic analogs of the macrocyclic host p-sulfonatocalix[n]arene, as key building blocks in the creation of self-assembled complex systems, covering applications in therapeutic design and differential sensing in aqueous solution. Chapter 1 sets the stage for this work, introducing current synthetic and systems strategies employed in biorelevant host-based sensing. An advanced property addressed in this dissertation is the ability to achieve pan-selectivity — binding well across a whole class of target analytes while maintaining good selectivity against other chemically similar analytes. Synthesizing a host that selectively binds a target analyte can be an inefficient and arduous task. In Chapter 2, I report on the templated synthesis of new bivalent hosts, Super-sCx4 and Super-sCx5, as pan-selective binders of neuromuscular blocking agent’s (NMBA’s). Synthesis was achieved using a bisquaternary amine NMBA template, self-assembling two highly anionic p-sulfonatocalix[n]arene building blocks for covalent linkage. These bivalent anionic hosts bind by engaging both quaternary amines present on a variety of NMBA’s, making them potential candidates for host-based NMBA drug reversal. We report low μM binding to alkyl, steroidal, curarine and benzylisoquinoline NMBA’s, with selectivity over endogenous monovalent hydrophobic amines. Another advanced property addressed in this dissertation is the ability to produce useful sensing outputs for a variety of analytes, without programming specific molecular recognition events. Differentiation of analytes by supramolecular sensors is typically achieved through sensor arrays, relying on pattern recognition responses from a large panel of isolated sensors. The differentiation of highly similar analytes poses an ongoing challenge. In Chapter 3, I explore a new one-pot systems chemistry approach to differential sensing in biological solutions. This systems approach relies on a network of three cross-assembling DimerDye p-sulfonatocalix[n]arene sensors, containing different integrated fluorophores. This robust approach exploits complex interconnected host•host and host•analyte equilibria, producing emergent supramolecular and photophysical responses unique to each analyte. We apply this inherently information-rich systems approach to the discrimination of closely related serum albumin proteins and protein mixtures, without relying on targeted recognition elements. We show that a single adaptive sensing solution provides better analyte discrimination than an analogous sensor array. Macrocyclic host-based sensors are often limited to detecting a single class of interacting analytes because they tend to bind molecules with similar properties. In Chapter 4, I address this challenge, reporting a mixed host system that detects analytes from many different classes, including cationic, neutral, and anionic. We show that co-assembling two different macrocyclic scaffolds, DimerDye p-sulfonatocalix[4]arenes and cucurbit[n]urils (n = 7 and 8), effectively increases the scope of analyte binding interactions and sensor outputs. This simple strategy exploits cross-reactive noncovalent host•host interactions through a synthetically integrated reporter dye. Emergent photophysical responses are produced by analyte interactions to either host. We demonstrate the advantages of mixed host co-assembled sensors in an array-based platform, differentiating a range of illicit drugs and common adulterating substances. The potential of this approach is further applied in profiling real-world multi-component illicit street drug samples.
Mechanistic investigations of palladium-catalyzed cross-coupling reactions using advanced mass spectrometric methodologies
(2025) Chagunda, Ian C.; McIndoe, J. Scott
This dissertation explores the application of mass spectrometry (MS) as a tool for investigating the mechanisms of palladium-catalyzed cross-coupling (PdCC) reactions. By integrating advanced MS techniques with reaction monitoring methodologies, this work provides insights into catalytic activation processes, the role of intermediates, and the limitations of MS in analyzing complex chemical systems. The research is presented across five chapters, each examining specific aspects of MS in the context of organometallic catalysis. The first chapter establishes the foundational context, detailing the principles of MS and its role in studying PdCC reactions. A particular focus is placed on electrospray ionization mass spectrometry (ESI-MS) and pressurized sample infusion (PSI), highlighting their advantages and challenges in capturing transient catalytic species. Chapter 2 discusses the inherent limitations of MS in characterizing high molecular weight polymers, a common product of PdCC reactions. Factors such as diminishing signal-to-noise (S/N) ratios, isotope pattern broadening, and ionization inefficiencies are examined, and strategies for improving polymer analysis via MS are proposed. Chapter 3 evaluates the performance of ESI-MS across different instruments, particularly in detecting fragile organometallic complexes. A multi-instrument comparative study reveals significant variability in instrument performance, emphasizing the necessity for optimizing instrument parameters to preserve weakly bound catalytic species. Chapter 4 critically re-examines the mercury drop test, a widely used method for distinguishing between homogeneous and heterogeneous catalysis. This analysis demonstrates that mercury interacts with Pd intermediates through redox-transmetallation and amalgamation processes, leading to potential misinterpretations of catalytic activity. Finally, Chapter 5 investigates a new-generation palladium precatalyst, (DMPDAB)Pd(CH2SiMe3)2, providing mechanistic insights into ligand substitution, catalyst activation, and oxidative addition processes. The combination of PSI-ESI-MS and real-time monitoring enabled the identification of key catalytic intermediates, contributing to the development of more efficient and selective Pd-based catalysts. Collectively, this dissertation advances the understanding of MS as a tool for elucidating catalytic processes, offering methodological improvements and new perspectives on PdCC reaction mechanisms. The findings have broad implications for catalyst design, sustainability, and the continued evolution of mass spectrometric techniques in organometallic chemistry.
Palladium catalyzed C–O bond activation
(2024) Gaube, Gregory; Leitch, David
Carboxylate C–O bonds are atom-economical, robust in synthesis, and easily accessible, but have traditionally been ineffective synthetic handles for Pd catalysis. In this thesis the utility of these cross-coupling handles in Pd catalysis has been established. As global climate issues necessitate an alternative to oil-based processes, the development of Pd-catalyzed C–O bond activation chemistry, such as the chemistry explored in this thesis, has the potential to aid in biomass becoming a common future feedstock. This thesis is divided into three research chapters. Firstly, we evaluated the mechanism of an air-stable, base-free, Pd-catalyzed cross coupling of enol carboxylates and aryl boronic acids that was first developed within the Leitch Lab. This experimental evaluation uncovered key intermediates that allowed us to propose a cationic Pd(II)-only mechanism. Secondly, the knowledge gained in evaluating the mechanism was applied to Miyaura borylation of various enol carboxylates. In this study we uncovered that the nature of the enol carboxylate and the boron source greatly impacted the reactivity in the initial synthesis as well as any future desired reactivity of the enol boronate. Finally, by identifying active pharmaceutical ingredients, specifically pyrido[1,2-a]pyrimidin-4-ones, that could be used in future C–O activation chemistry, we systematically approached their synthesis to create and characterize a library of substituted molecules. We demonstrated that we could functionalize these molecules with both pivalate and tosylate synthetic handles. Because the fundamental reactivity of these carboxylate C–O bonds is established, these three chapters have created myriad potential research projects that are discussed in Chapter 5.
Generation and reactivity of transient aminoboranes and phosphinoboranes: Intermediates in the formation of inorganic polymers
(2024) Wiebe, Matthew A.; Manners, Ian; Wulff, Jeremy Earle
Polymers are ubiquitous. From the infamous plastic water bottle, typically made of polyethylene terephthalate, to chitin, a polysaccharide, polymeric materials are produced on massive scales in both industry and the biosphere. Most known polymers consist of long chains containing C–C, C–O, or C–N bonds. However, inclusion of elements other than carbon, oxygen, or nitrogen, can introduce valuable properties into the resulting bulk material. For example, the first boot to make contact with the moon had a sole comprised of silicone rubber, a material that can remain rubbery at even lunar temperatures. The ability of this material to remain pliable at such low temperatures is largely due to the inorganic Si–O bonds in its main-chain, which allow for greater conformational flexibility compared to polymers comprised primarily of C–C bonds. The work described in this thesis focuses on a different class of inorganic polymers, polyaminoboranes and polyphosphinoboranes. These polymers feature main-chains of alternating nitrogen and boron or phosphorus and boron atoms. • Chapter 1 provides a general introduction to inorganic polymers as well as a more detailed survey of polyaminoboranes and polyphosphinoboranes. • Chapter 2 explores the synthesis of polyphosphinoboranes via the generation of transient phosphinoboranes (PhRP–BH2; R = H, Ph, Et) through the deprotonation of PhRPH•BH2(NTf2). These transient phosphinoboranes then undergo an addition polymerization. • Chapter 3 describes the solution generation, observation, and subsequent reactivity of primary aminoboranes (RNH=BH2; R = tBu, Me, CPh3), a class of species that has only otherwise been isolated on solid argon matrices or observed as a complex mixture of products by 11B NMR spectroscopy. These aminoboranes were generated via the deprotonation of RNH2•BH2(NTf2) and observed at –78 °C as the sole 11B containing species, allowing for subsequent reactivity studies. • Chapter 4 explores the role of catalysts in the catalytic dehydropolymerization of phosphine-borane adducts, where it is discovered that high molar mass, low dispersity polymers can be accessed using commercially available salts such as LiOTf or by adding catalytic amounts of BH3•SMe2. Further, a new potential mechanism for phosphine-borane dehydropolymerization is discussed. • Chapter 5 ties together the themes of phosphinoboranes and aminoboranes, revealing that sterically unencumbered aminoboranes can accept hydrogen from phosphine-borane adducts, producing amine-borane adducts and phosphinoboranes. These transient phosphinoboranes then undergo subsequent reactivity to form dehydrocoupled products. • Chapter 6 summarizes the findings of the research, discusses future research directions, and provides an overall outlook.
Synthesis of densely-functionalized multicyclic ring systems from bicyclobutanes
(2024) Woelk, Kyla; Leitch, David
The discovery and development of novel small molecule drug candidates is essential to the advancement of the pharmaceutical industry. One area of focus for drug development is increasing the molecular complexity and number of Csp3 centers in pharmaceutical candidates. Saturated multicyclic structures have been proposed as bioisosteres to replace portions of pharmaceutical molecules that lack these Csp3 centers. Incorporating these bioisosteres in existing pharmaceuticals has been shown to improve pharmacokinetic properties and in some cases even increase the drug’s potency. The syntheses to access these bioisosteres is limited and thus, efforts to develop more syntheses of these motifs is crucial in progressing the development of new drugs. This thesis explores the development of new methods to access these saturated multicyclic bioisosteres, specifically bridging bicycloalkanes. Bicyclo[1.1.0]butanes are used as a common starting material to access the different bicyclic compounds. Focus is placed on the use of readily available starting materials and straightforward reaction conditions. Reaction discovery, optimization and viability is reported for a variety of different bicyclic compounds. The types of bicyclic compounds that were synthesized include 2-azabicyclo[2.1.1]hexanes, 2-oxo-bicyclo[2.1.1]hexanes and 3-azabicyclo[3.1.1]heptanes. High-throughput experimentation was used to aid in reaction discovery and optimization in a streamlined manner. Reaction scopes were developed to demonstrate the applicability of these methods. Finally, this thesis demonstrates the potential for application of these bicyclic bioisosteres in pharmaceuticals via target-based synthesis. This was done through the functionalization of the products synthesized. This demonstrates their ability to be modified so they can be incorporated into drug candidates. With more syntheses of these bioisosteres available to medicinal chemists, the ability for these motifs to be applied in future drug development processes can be improved.
A single-atom upgrade to polydicyclopentadiene
(2024) Godwin, Benjamin; Wulff, Jeremy Earle
Polydicyclopentadiene (PDCPD) is an engineering plastic produced through the ring-opening metathesis polymerization (ROMP) of dicyclopentadiene (DCPD), a petrochemical waste product. Owing to its high glass transition temperature, high storage modulus, high tensile strength, and general robustness to chemical or physical attack, PDCPD has enjoyed commercial use for making body panels for automobiles and heavy machinery. However, PDCPD is a simple polyolefin composed of only hydrogen and carbon atoms; it is thus low surface energy and not chemically tunable. The low surface energy also makes the application of paints and adhesives challenging. Herein I describe a ketone-functionalized derivative of dicyclopentadiene (oxaDCPD). When polymerized oxaPDCPD displays a unique non-canonical hydrogen bond between the ketone and an adjacent vinyl hydrogen within the polymer. Partly as a result of this interaction, the thermoset polymer has an increased glass transition temperature, storage modulus, Young’s modulus, compression strength, and surface functionality compared to the native material. I also describe the copolymerization of dicyclopentadiene with the novel oxa-dicyclopentadiene monomer to produce copolymers. These copolymers display remarkably tunable (and improved) mechanical and thermal properties. Additionally, the copolymers have improved surface functionality and display resistance to oxidative embrittlement. Many thermosets—including PDCPD and oxaPDCPD—are produced in a process called reaction injection molding (RIM) wherein neat monomer is directly transformed to solid polymer using a catalyst. In these polymerizations the crosslinks between the polymer chains form alongside the polymer, rapidly forming a solid. It is therefore challenging to study these kinds of processes. I have developed a method suitable for laboratory-scale studies of these reactions. This method is high-throughput and low cost. Remarkably, not only can various initiators be compared but the mechanical and thermal properties of the final material can be generally predicted. Finally, despite PDCPD’s industrial niche remaining in the body panel market for decades there is a large volume of high-impact research dedicated to it. As part of a Natural Sciences and Engineering Research Council of Canada (NSERC) Lab to Market (L2M) Grant I conducted stakeholder interviews to determine industry pain points and determine a path towards commercialization of new PDCPD technologies.
The role of interactions between cucurbit[7]uril and small molecules in the sodium deoxycholate hydrogel
(2024) Rahbari Asr, Nikou; Bohne, Cornelia
The structure of bile salts has hydrophilic (hydroxyl groups) and hydrophobic (alkyl groups) regions, resulting in amphiphilic properties. Bile salts can form aggregates and these aggregates can act as supramolecular hosts for small molecules and encapsulate guest molecules within their structure. Unlike other bile salts, sodium deoxycholate (NaDC), can form supramolecular hydrogels through molecular self-assembly processes by adjusting the pH to around neutral and controlling the temperature. The aim of this work, was to investigate how cucurbit[7]uril (CB[7]), affects the properties of NaDC hydrogel. Cucurbit[n]urils (CB[n]s) are a family of macrocyclic molecules characterized by their pumpkin-shaped structure and a symmetrical hydrophobic cavity. By studying the interactions of CB[7] in NaDC hydrogels, the aim was to understand the potential role of CB[7] in modifying the hydrogel's properties and to determine if CB[7] can serve as a carrier for guest molecules from the NaDC hydrogel to the surrounding medium. To gain a better understanding of the effect of CB[7] and its localization within the NaDC gel, two projects were developed. The objective of the first project was to study how the presence of NaDC aggregates affects the binding dynamics of berberine, a natural isoquinoline alkaloid fluorophore, with the host CB[7] in the presence of mobile aggregates of the NaDC. The presence of NaDC aggregates creates a more heterogeneous environment for the host-guest interactions, potentially affecting the dissociation of berberine from CB[7]. The results showed that the addition of NaDC aggregates changed the distribution of berberine, causing berberine to bind to both CB[7] and NaDC aggregates. The results also revealed that the addition of NaDC aggregates to the berberine@CB[7] complex accelerated the apparent dissociation rate constant of berberine from CB[7]. The objective of the second project was to understand how the presence of CB[7] affects the structure of the NaDC hydrogel and the release of a small molecule from the hydrogel into the surrounding medium, and how this effect differs from the effect of cucurbit[6]uril (CB[6]). To study these effects, I studied the hydrogel's structure using berberine, a hydrophobic and positively charged guest, and rhodamine 6G, a hydrophilic and positively charged dye. The release of rhodamine 6G from the NaDC hydrogel into the surrounding medium was also studied in the presence of CB[7] and CB[6]. The results showed that the presence of CB[7] in the NaDC hydrogel caused the transformation of the spherical aggregates into elongated structures, whereas CB[6] led to the formation of fibrous structures, as observed in previous research conducted by our group. Also, the release profile of rhodamine 6G from the NaDC hydrogel was not significantly affected by the addition of either CB[6] or CB[7].
The study of Ruthenium(II) half-sandwich phosphido complexes containing Pentamethylcyclopentadienyl (Cp*) ligand
(2024) Akar, Afsaneh; Rosenberg, Lisa
The catalyst Ru(η5-Cp*)(PPh2H)2(PPh2) was developed by the Rosenberg group for the hydrophosphination of activated alkenes with primary and secondary phosphines. Our group’s recent publication about this system described high activity of this catalyst and preliminary mechanistic studies indicated that the intramolecular proton transfer from the cis-coordinated PPh2H should be the turnover-limiting step for this system. My work started with further investigating the alkene scope for this system to see the activity and generality of the Cp*Ru catalyst toward a variety of alkenes and to get evidence to support the proposed mechanism for a model hydrophosphination reaction catalyzed by the new catalyst. The activity of the catalyst toward electron-deficient alkenes supported that the mechanism includes the nucleophilic addition of the Ru-PPh2 at the alkene. This investigation also gave evidence that was consistent with the existence of an equilibrium in the proposed mechanism. I did a kinetic study to obtain the experimental reaction order for substrates involved in the hydrophosphination of methyl methacrylate with PPh2H catalyzed by the Cp*Ru catalyst. The results from this study supported our proposal that the last substitution step is not the turnover-limiting step in this system as it was for the indenyl analogue. Also, an isotope labeling experiment was conducted to get evidence for the proposed turnover-limiting step in the proposed mechanism. Since the Cp*Ru complexes used to catalyze the hydrophosphination reactions were challenging to isolate due to their high solubility and substitutional lability, they were generated in situ throughout all investigations. The presence of PPh3 ligand in the starting material led to the formation of an orthometallated product during the attempted isolation, so I replaced PPh3 with 1,5-cyclooctadiene (COD) to prevent the orthometallation process and was able to isolate this complex for R = Ph.
Uniform, 1-dimensional polymer nanofibers for applications in nanomedicine
(2024) Parkin, Hayley; Manners, Ian; Bohne, Cornelia
Polymer nanomaterials have garnered increased attention over the past several decades due to their ability to perform in a variety of applications, depending on the chemical functionality of the material used. Of note, polymers have been used increasingly for biomedical applications, from drug and gene delivery vehicles, to contrast agents and therapeutics themselves. Living crystallization-driven self-assembly (CDSA) provides a novel pathway for the preparation of morphologically pure, length-controlled, 1-dimensional (1D) polymer nanofibers. In this thesis, the applications of these nanofibers for applications in nanomedicine is explored. Chapter 1 provides an introduction into polymer self-assembly, living CDSA, and a brief literature review of nanoparticles explored for biomedical applications. Chapter 2 describes the synthesis and self-assembly of biodegradable and cationic poly(fluorenetrimethylenecarbonate)-block-poly(dimethylaminoethylmethacrylate) (PFTMC-b-PDMAEMA) 1D nanofibers, and evaluates the length and shape dependence on antibacterial activity against Escherichia coli. A comparison to neutral 1D poly(ethylene glycol) nanofibers is made. Chapter 3 then investigates the antibacterial mechanism of action of 1D nanofibers relative to nanospheres of identical composition. This pathway is explored through the use of confocal laser scanning electron microscopy and flow cytometry, as well as transmission electron microscopy and scanning electron microscopy. Chapter 4 expands upon preliminary drug-loading results to explore the addition of the anticancer therapeutic paclitaxel to the core-corona interface of PFTMC-b-PDMAEMA seed nanofibers. These are then evaluated as a delivery vehicle in 2D and 3D cell models containing glioblastoma cells. Chapter 5 then extends the scope of antibacterial activity of 1D PFTMC-b-PDMAEMA nanofibers against gram-positive Staphylococcus epidermidis, as well as explores the ability of these nanofibers for treating the extremely drug-resistant organism Burkholderia vietnamiensis. Chapter 6 concludes this thesis with an outlook as well as proposes future directions that could expand on the projects presented herein.
Mechanistic investigation of the effect of S-based poisons on Pd-catalyzed cross-coupling reactions
(2024) Pitipana Achchige, Nadini Thushara; McIndoe, J. Scott
Catalyst poisons are unwanted components in a reaction mixture that lead to the partial or total deactivation of a catalyst. Most previous work on homogeneous catalyst poisoning has focused on identifying the poisons in a catalytic cycle and their effects on catalyst performance, therefore, chemists can take measures to avoid or exclude these types of poison from the system. The chemical behavior of catalyst poisons and how the poisons bind to the catalyst are under-explored areas. Hence, an improved understanding of homogeneous catalyst poisoning is crucial because it can be applied to the systems where the reaction needs to be terminated at a certain point in a catalytic cycle, by deliberately introducing the poison into the reaction mixture. Furthermore, such studies will give molecular insight into the poisoning in homogeneous catalysts, providing the necessary understanding of the catalyst poisoning behavior. In this work, pressurized sample infusion - electrospray ionization - mass spectrometry (PSI-ESI-MS) was used to introduce a poison into a reaction flask containing a Pd cross-coupling reaction solution, which was monitored in real-time. The combination of mass-to-charge ratio (m/z), isotope pattern, and fragmentation behavior was used to characterize the newly formed Pd-poisoned species. Tetrakistriphenylphosphine palladium(0) was used as the catalyst, and three S-based poisons: 1,2-benzenedithiol, thiourea, and N-acetylcysteine were used in this analysis. Poisoning experiments were conducted on the precatalyst Pd(0) solution and on the complexes generated after oxidative addition of an aryl halide to make Pd(II) complexes. All three of the poisons reacted rapidly with Pd(0), all via oxidation of the Pd to Pd(II) and deprotonation of the poisons, revealing significant changes in the Pd complexes. Newly formed Pd-poisoned species were identified using tandem mass spectrometry (MS/MS). Mass spectrometry quantification of these poisoned species was a significant challenge during these studies, since MS quantification is complex due to the frequent occurrence of non-linear responses with increasing analyte concentrations. Therefore, a key part of these investigations was ensuring the instrument used was always well-calibrated. Developing calibration curves for quantification is a time-intensive task. A novel project designed to make calibration faster and easier: A one-experiment approach to calibration, details real-time continuous calibration method was the subject of Chapter 3. The same PSI-ESI-MS technique was used in this collaboration project to construct a highly accurate and precise continuous calibration curve for achieving high-quality analytical results in both mass spectrometry and UV-Vis spectroscopy. The results were sufficiently encouraging that this method has wide scope for any analytical method that allows continuous monitoring of a solution. Overall, this work provides the molecular insight into the field of catalyst poisoning, as well as providing a novel continuous calibration method for future use in analytical chemistry.
High-throughput compatible catalyst development towards sustainable direct alkenylation reaction discovery and optimization
(2024) Pipaon Fernandez, Nahiane ; Leitch, David
The direct C–H functionalization of heteroaromatic compounds such as pyridine, furan, thiophenes, thiazoles, and others have been developed as effective methods for making Csp2–Csp2 linkages which are often found in biologically active compounds and π-conjugated functional materials. More specifically, the development of palladium catalysts that can selectively activate specific C–H bonds is key for late-stage functionalization of pharmaceutically-relevant compounds. Mechanistic studies of the catalytic system, reaction intermediates and evaluation of the reaction parameters allows chemists maximize the reaction performance. This thesis explores direct C–H alkenylation reactions from both a catalyst and substrate perspective, and exploits modifications to the generally accepted direct alkenylation mechanism. Furthermore, this work shows how systematic, hypothesis-driven High-Throughput Experimentation of reaction conditions, palladium sources and ancillary ligands enables the development of new reactivity, optimization of catalytic systems and exploration of the chemical space of direct alkenylation of heterocycles. Finally, this work also highlights the versatility of palladacyclic precatalysts in the selective C–H functionalization of challenging but pharmaceutically relevant heterocycles such as pyrazoles and thiazoles. New synthetic procedures have been described toward the development of single component precatalyst systems, and they have been used for the synthesis of two pharmaceutical compounds: GSK3368715, a PRMT1 inhibitor, and fatostatin, a lipid accumulation inhibitor.
Chemometric strategies for the detection of bromazolam and xylazine in illicit opioids using surface-enhanced Raman and infrared spectroscopy
(2024) Martens, Rebecca Robinton; Hore, Dennis Kumar
The detection of trace adulterants in opioid samples is an important aspect of drug checking, a harm reduction measure that is required as a result of the variability and unpredictability of the illicit drug supply. While many analytical methods are suitable for such analysis, community-based approaches require techniques that are amenable to point-of-care applications with minimal sample preparation and automated analysis. We demonstrate that surface-enhanced Raman spectroscopy, combined with a random forest classifier, is able to detect the presence of two common sedatives, bromazolam (0.32--36% w/w) and xylazine (0.15--15% w/w), found in street opioid samples collected as a part of a community drug checking service. The Raman predictions, benchmarked against mass spectrometry results, exhibited high specificity for the compounds of interest (88% for bromazolam, 96% for xylazine) and sensitivity (88% for bromazolam, 92% for xylazine). We additionally provide evidence that this exceeds the performance of a more conventional approach using infrared spectral data acquired on the same samples. This demonstrates the feasibility of surface-enhanced Raman spectroscopy for point-of-care analysis of challenging multi-component samples containing trace adulterants. Surface-enhanced Raman spectroscopy and infrared spectroscopy were integrated into two data fusion strategies - hybrid (concatenated spectra) and high level (fusion of high outputs from both models) - to enhance the predictive accuracy for xylazine detection. Three advanced chemometric approaches - random forest, support vector machine, and k-nearest neighbor algorithms - were employed and optimized using a 5-fold cross-validation grid search for both fusion strategies. Validation results identified the random forest classifier as the optimal model for both fusion strategies, achieving high sensitivity (88% for hybrid, 84% for high level) and specificity (88% for hybrid, 92% for high level). We demonstrate the enhanced practicality of the high level fusion approach, effectively leveraging the surface-enhanced Raman data with a 90% voting weight, without compromising prediction accuracy when combined with infrared spectral data. This highlights the viability of a multi-instrumental approach using data fusion and random forest classification to improve the detection of various components in complex opioid samples for community-based drug checking.
Using living crystallization-driven self-assembly to form functional π-conjugated nanostructures for potential optoelectronic device applications
(2024) Vespa, Marcus A.; Manners, Ian; Leitch, David
At the micro- and nanoscale, mimicking the level of complex organization observed in nature is difficult, and reproduction of these materials has been a key challenge in the fields of materials science and synthetic chemistry. Solution self-assembly of amphiphilic block copolymers (BCPs) is a promising route towards the construction of nanoscale assemblies with various sizes, morphologies, and material properties. Living crystallization-driven self-assembly (CDSA) of polymers with a crystallizable core-forming block has emerged as a valuable method to exert control over the dimensions of one- and two-dimensional (1D and 2D) nanostructures. This method reliably produces nanostructures with predictable sizes and low size distributions. Due to the variety of BCPs capable of crystallization, a wide array of hierarchically organized nanostructures have been fabricated which show promising potential for application to a broad assortment of fields such as optoelectronics, biomedicine, and catalysis. The work presented in this thesis focuses on expanding the library of materials known to be compatible with living CDSA by introducing a new crystallizable π-conjugated core-forming block. This work also seeks to extend controlled self-assembly techniques in systems where precise nanoscale control is highly sought-after and deepen our understanding of the processes that govern π-conjugated block copolymer self-assembly by establishing structure-property relationships; the practical realization of which are all key goals in modern energy, materials, and nanoscience research.
Depth dependant dielectric constant and second order response at aqueous interfaces
(2024) Yang, Peter; Hore, Dennis Kumar
Aqueous interfacial environments have unique properties as a result of their inherent anisotropy; however, analysis of interfacial regions remains challenging. Sum-frequency generation measurements can be used for their study, although determining the linear-optical properties, and the molecular electronic structure required for quantitative analysis remains difficult. From classical molecular dynamics simulations we found the orientation distribution to be invariant with increasing surface number density; we can also therefore expect the ordering of cyanophenol to be a result of interfacial water. We describe the necessity of depth dependence to the sum-frequency response by using interfacial structure from classical molecular dynamics. By exploiting symmetry, we can derive linear relationships between elements of the $\chi^{(2)}$ tensor which shed light on future sum-frequency based orientational measurements. The range of possible values for the interfacial hyperpolarizability ratio has been significantly narrowed with the aid of classical molecular dynamics simulations. We also propose a technique for experimentally measuring the hyperpolarizability ratio that has been derived by exploiting the polarisation null angle method. By using Raman spectra derived from interfacial and bulk-phase \textit{ab initio} simulations we conclude there to be little difference in the hyperpolarizability ratio in the interfacial or bulk environments; by comparing with experimental Raman measurements we also report the existence of asymmetric broadening in the C--N mode.
Water-soluble photoswitchable supramolecular hosts based on the hemiindigo chromophore
(2024) Kliuchynskyi, Anton; Hof, Fraser
The constant search for new and unusual hosts is what pushing supramolecular chemistry forwards. The scope of their applications is immense: drug recognition and reversal, novel materials, catalysis, purification and separation of chemicals etc., not to mention a fundamental insight into chemical and biological systems that can be gained by studying them. Sulfonated calixarenes constitute an important family of such hosts. Their exceptional binding properties coupled with water-solubility, high stability and endless potential for synthetic modifications make them perfect candidates for study. There are numerous examples of those macrocycles, modified in a way that introduces a fluorescent chromophore, enabling them to be used as detectors for various guests. Yet, cases of them being able to change their properties upon irradiation with light – having a photoswitchable chromophore – remain particularly scarce. This work attempts to present such system – a pair of sulfonated calixarenes, calix[4] and calix[5]arene with a hemiindigo moieties installed on the upper rim. Here we demonstrate their synthesis, as well as a study into their photophysical and supramolecular properties. Various advanced NMR techniques such as DOSY and NOESY were used in conjunction to demonstrate differences in their aggregation.
Mechanism of photosolvolytic rearrangement of p-hydroxyphenacyl esters : evidence for excited state intramolecular proton transfer as the primary photochemical step
(1998) Zhang, Kai
The photosolvolytic rearrangement of p-hydroxyphenacyl alcohols 56, 57, p- hydroxyphenacyl esters 58a-d, 59a-d, and p-methoxyphenacyl derivative 60 has been studied in aqueous solution using product studies and nanosecond laser flash photolysis. The p-hydroxphenacyl moiety has recently been proposed as a new and efficient photoactivated protecting group in aqueous solution. However, although their practical applications have been amply demonstrated, much less is known about the mechanism of photoreaction. Our data support a novel mechanism in which the primary photochemical step from the singlet excited state is intramolecular proton transfer from the phenolic proton to the carbonyl oxygen of the distal ketone, to generate the corresponding p-quinone methide phototautomer, which subsequently expels the ester group with concerted rearrangement to a spiroketone intermediate leading to the final observed product, p-hydroxyphenylacetic acid. Irradiation of these p-hydroxyphenacyl derivatives in 1: 1 (v/v) H20-CH3CN produced the corresponding p-hydroxyphenyl acetic acid (31) or its di-tert-butyl derivative 61 as the only photoproduct. Conversion to 31 or 61 can be taken to quantitative yield upon prolonged photolysis for all of these compounds without the formation of significant by-products. These results rule out the involvement of C-OCOR bond homolysis in the mechanism. All of these p-hydroxyphenacyl derivatives were unreactive in neat CH3CN indicating that H20 is necessary for the reaction. p-Methoxyphenacyl acetate (60) failed to give any observable reaction under the same conditions, which shows that the phenol HO group is required. Quantum yield measurements showed that neither acid nor base catalyzed the reaction. All of the above results are indicative of the involvement of excited state intramolecular proton transfer (ESiraPT) in the mechanism. Such a mechanism would be expected to generate p quinone methide (p-QM) intermediates. Direct evidence was provided by laser flash photolysis (LFP), which gave observable transients at 330 and 360 nm assignable to p QM 67a and 67b, respectively.
Space focusing and mass selection of transition-metal-chlorine and -sulfur clusters generated through laser ablation
(2001) Yu, Yongzhi
The goal of this study was to develop a laser ablation-TOF mass spectrometer system suited to the generation of transition metal -chlorine and -sulfur clusters. A detailed characterization of the plasma generated by laser ablation was accomplished. Positive clusters were shown to have a slower original flight speed than negative clusters from the same source. The approximate time window during which clusters reached the repeller with the maximum density was measured as well. A functional triggered TOF-Mass spectrometer was built with adjustable space focusing parameters. This setup works to space focus the positive or negative clusters generated by the laser ablation. The optimized mass resolution this setup can provide is about 300. A functional mass gate was built. The mass gate can isolate a particular mass peak with about 95% purity for clusters with flight times that differ by 1.1 µs. Many ionic transition metal-chlorine and -sulphur clusters were synthesized and identified, and a systematic survey of the transition metal-chlorine clusters was conducted. Trends were evident in the formation of negative clusters that can be explained by a simple building block model. To a lesser extent, the building block model can be applied to some of the positive clusters. The formation of transition metal -sulphur clusters was far more complicated.
Pyrene and ʺ-cyclodextrin complexes : chiral discrimination and ternary complex formation
(1994) Yang, Hong
Photogeneration and chemistry of o-quinone methides
(1994) Yang, Cheng

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