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Item Embargo Cryo-electron microscopy of cloneable inorganic nanoparticles(Colorado State University. Libraries, 2024) Guilliams, Bradley Forrest, author; Ackerson, Christopher J., advisor; Sambur, Justin, committee member; Crans, Debbie, committee member; Stasevich, Tim, committee memberOur understanding of biology is best understood through direct, empirical measurements of biomacromolecules and biological systems. The functions of proteins are directly linked to both their structure and their intracellular organizations. Single particle cryo-electron microscopy has revolutionized modern structural biology by enabling the structural determination of proteins and protein-complexes in purified samples without the need to form large crystals as required by X-ray crystallography. With single particle cryo-EM, atomic and near-atomic resolution structures are now routine which offer insight into the functions of biomacromolecules. While these insights are invaluable, there is increasing momentum for integrative structural biology which aims to accomplish structural determination of biomacromolecules in their cellular, tissue, or organismal context. There remains a grand challenge in biological imaging where biological materials have low innate contrast. Cloneable contrast labels that impart contrast to discrete protein densities do not reliably exist for cryo-electron microscopy. In contrast, fluorescent proteins are reliable and routine for localizing fluorescent protein / protein of interest genetic fusions in visible-light microscopies. We have proposed and developed intracellularly synthesized inorganic nanoparticles called 'cloneable nanoparticles' as a solution to this grand challenge. Cloneable nanoparticles are inorganic nanoparticles, synthesized by a protein/peptide (or combination thereof) which controls and defines the properties of the inorganic nanoparticle. Here we have defined the cloneable nanoparticle paradigm and described the development of a cloneable selenium nanoparticle. Further, we show the application of the cloneable selenium nanoparticle as a cloneable contrast label for biological electron microscopy and correlative light-electron microscopy and detail progress towards adapting the cloneable selenium nanoparticle for use in cryo-electron tomography. With the aim to later expand cloneable nanoparticles to include a myriad of orthogonal cloneable contrast labels (analogous to different colored fluorophores), and to gain understanding about enzymatic nanoparticle synthesis, a single particle cryo-EM study is on-going. Lastly, we have shown the application of directed evolution for cloneable nanoparticles, suggesting that this is a viable path, alongside rational protein design, towards developing future cloneable nanoparticle cryo-electron microscopy labels.Item Open Access Does orientation matter? Controlling laccase orientation on planar gold electrodes(Colorado State University. Libraries, 2024) Perry, Collin, author; Ackerson, Christopher, advisor; Snow, Christopher, committee member; Dandy, David, committee member; Neale, Nathan, committee memberEnzyme electronics are becoming more common in modern life. Even though these technologies have been integrated into everyday life, the fundamental understanding of how an enzymes' orientation at the electrode surfaces affects the enzymes catalysis is still unknown. To understand this more we designed a library of laccase mutants, all with a single solvent exposed cysteine. These cysteine residues are used to bind to a gold electrode modified with a monolayer of sulfhydryl molecules capped with a maleimide binding group. Each mutants' single cysteine will bind to the maleimide group orienting each mutant differently at the electrode surface. The wild type enzyme (WT) and all the mutants, D113C, N264C, H470C all show activity toward a common substrate 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). Although each mutant does show catalytic activity in solution, we were unable to obtain an electrochemical response from the laccase library using the maleimide capped electrodes for either ABTS or oxygen. Modification of the electrodes via the deposition gold clusters makes the electrode surface more topographically complex. The cluster modified electrodes bound with WT laccase displayed an electrochemical response for the reduction of oxygen to water. The increased topography from using gold clusters allows for electron transfer with laccase enzymes, while the planar electrodes modified with the laccase enzymes in which we achieved an electrochemical response.Item Embargo Data-driven strategies for organic structure-property and structure-reactivity relationships(Colorado State University. Libraries, 2024) Santhanalakkshmi Vejaykummar, Shree Sowndarya, author; Paton, Robert, advisor; Prasad, Ashok, committee member; Kim, Seonah, committee member; Nielsen, Aaron, committee memberThe prediction of molecular properties plays a pivotal role in various domains, from drug discovery to materials science. With the advent of machine learning (ML) techniques, particularly in the field of cheminformatics, the prediction of properties for small organic molecules has witnessed significant advancements. This document delves into the diverse machine-learning strategies employed for the accurate prediction of properties crucial for understanding molecular behavior. In Chapter 1, I offer insights into the evolution of data-driven modeling through Quantitative Structure-Property Relationships (QSPR), highlighting promising advancements in utilizing chemical features to construct predictive models for molecular properties. In Chapter 2, I delve into the primary stage of modeling, focusing on data collection for predictive tasks. I illustrate how the integration of automation and computational tools' advancement can construct modular workflows for FAIR (Findable, Accessible, Interoperable, and Reusable) chemistry. This approach aims to enhance the usability and reproducibility of scientific data. In Chapter 3, I emphasize leveraging computational tools to access high-level data for small organic molecules. I showcase the creation of a novel metric for assessing organic radical stability, utilizing a comprehensive chemical database of radicals. This involves employing straightforward physical organic descriptors, namely fractional spin, and buried volume, computed through systematic computational workflows. In Chapter 4, I explore the progression of graph-based models designed to forecast molecular properties, specifically Bond Dissociation Energy. Additionally, I conduct a thorough examination of two particular applications pertinent to pharmaceutical and atmospheric chemistry. I demonstrate that utilizing a minimal number of molecules from the relevant chemical space can notably enhance large-scale machine-learning models. Finally, in Chapter 5, I combine the developed tools from Chapters 3 and 4, to perform goal-directed molecular optimization in identifying novel radicals for aqueous redox flow batteries using graph neural networks (radical stability, redox potentials, and bond dissociation energy) and reinforcement learning. This de novo molecular optimization strategy has successfully identified 32 new radical candidates. By amalgamating insights from diverse studies, this dissertation endeavors to offer a comprehensive grasp of how machine-learning strategies are transforming the terrain of molecular property prediction.Item Open Access Establishing base-catalyzed halogen transfer as a general platform for C–H functionalization(Colorado State University. Libraries, 2024) Bone, Kendelyn I., author; Bandar, Jeffrey, advisor; Crans, Debbie, committee member; Henry, Chuck, committee member; Belisle, John, committee memberIn contrast to traditional multi-step routes, C–H functionalization offers a resource and time efficient route to desired products. Current methods for oxidative C–H functionalization are developed on three predominate reactivity platforms (1) hydrogen atom transfer, (2) single- electron transfer, and (3) C–H insertion. Despite their synthetic power, methods built on these platforms are restricted to similar bond conversions, substrates, and selectivities. Thus, there remains a strong demand for new mechanistic approaches to oxidative C–H functionalization that offer a departure from traditional reactivity. In efforts to address this need, new methods for oxidative coupling based on a base-catalyzed halogen transfer (X-transfer) reactivity platform are described herein. Chapter one provides an overview on the development of a X-transfer enabled direct C–H hydroxylation of mildly acidic N-heteroarenes and benzenes. Hydroxylated (hetero)arenes are valued in many industries as both key constituents of end products and diversifiable synthetic building blocks. Accordingly, the development of reactions that complement and address the limitations of existing methods for the introduction of aromatic hydroxyl groups is an important goal. To this end, this chapter discusses the development of a protocol that employs an alkoxide base to catalyze X-transfer from sacrificial 2-halothiophene oxidants to aryl substrates, forming SNAr-active intermediates that undergo nucleophilic hydroxylation. Key to this process is the use of 2-phenylethanol as an inexpensive hydroxide surrogate that, after aromatic substitution and ii rapid elimination, provides the hydroxylated arene and styrene byproduct. Use of simple 2-halothiophenes allows for C–H hydroxylation of 6-membered N-heteroarenes and 1,3-azole derivatives, while a rationally designed 2-halobenzothiophene oxidant extends the scope to electron-deficient benzene substrates. Mechanistic studies indicate that aromatic X-transfer is reversible, suggesting that the deprotonation, halogenation, and substitution steps operate in synergy, manifesting in unique selectivity trends that are not necessarily dependent on the most acidic aryl position. The utility of this method is further demonstrated through streamlined target molecule syntheses, examples of regioselectivity that contrast alternative C–H hydroxylation methods, and the scalable recycling of the thiophene oxidants. Chapter two describes the elaboration the X-transfer enabled C–H functionalization platform to encompass benzylic C(sp3)–H bonds. Thus, a benzylic C–H oxidative coupling reaction with alcohols that proceeds through a synergistic deprotonation, halogenation and substitution sequence is discussed. In contrast to existing radical-based pathways for C–H functionalization, this process is guided by C–H acidity trends. This gives rise to new synthetic capabilities, including the ability to functionalize diverse methyl(hetero)arenes, tolerance of oxidizable and nucleophilic functional groups, precision regioselectivity for polyalkylarenes and use of a double C–H etherification process to controllably oxidize methylarenes to benzaldehydes.Item Embargo Understanding structure property relationships in niobium–based oxides for high-rate anodes(Colorado State University. Libraries, 2024) Salzer, Luke David, author; Sambur, Justin, advisor; Dong, Yuyang, committee member; Henry, Chuck, committee member; Weinberger, Chris, committee memberWith the growing usage of portable electronic devices, electric vehicles, and grid level storage, a diverse set of energy storage devices is required for each application. Current commercial level lithium-ion batteries commonly utilize graphite as the anode material. While graphite possesses impressive energy storage, graphite struggles with high (dis)charge applications. One class of materials of interest to replace graphite are niobium-based oxides, some of which fall into a group of materials called Wadsley-Roth crystallographic shear compounds. Wadsley-Roth (W-R) compounds possess unit cells with nxm blocks of edge-shared octahedra, which boast high-rate capabilities, having higher volumetric capacities than graphite at various (dis)charge rates. While various (W-R) compositions of have been synthesized and their electrochemical properties explored, the origin of the excellent rate capabilities and capacities is unclear. Herein, niobium-based anodes for high-rate lithium-ion batteries are investigated to understand the structure-property relationships in W-R materials with different block sizes, levels of disorder, and composition. Additionally, a niobium oxide polymorph falls into a unique class of energy storage materials called pseudocapacitors, which possess high energy density while the charge storage mechanism mimics that of a capacitor. Sections of this work describe current and future investigations of pseudocapacitive niobium oxide to better understand the origin of this interesting material. Chapter 1 begins with a brief introduction, background, and motivation on the need for high-rate, high-capacity anode materials as an alternative for graphite, to address the growing need for high-power, high-energy density materials. Chapter II describes the synthesis of three structurally similar W-R compounds with different block sizes and investigates the electrochemical performance of each material. Chapters III and IV investigate methods to improve the electrochemical performances of W-R compositions through defects and dopants. Chapter V investigates the pseudocapacitive niobium oxide that also exhibits high-rate capabilities through a process called pseudocapacitance, in which the material possesses electrochemical characteristic similar to both batteries and capacitors. In the final chapter, Chapter VI, concludes the dissertation by describing further directions necessary to better understand the structure property relationships resulting in high-rate, high-capacity niobium-based oxide anodes.  Item Open Access Synthesis of α,α-Difluorobenzylic structures via new base-promoted reductive and oxidative coupling reactions(Colorado State University. Libraries, 2024) Hooker, Leidy V., author; Bandar, Jeffrey S., advisor; Kennan, Alan, committee member; Finke, Richard, committee member; Reisfeld, Brad, committee memberα,α-Difluorobenzylic substructures have been a desired product in a variety of industries from pharmaceuticals to agrochemicals to electronic materials. This thesis highlights the traditional and fundamental challenges associated with accessing these valuable products from trifluoromethylarenes and difluoromethylarenes, respectively, with an emphasis on base-promoted strategies to facilitate these transformations. Both a general Lewis base-promoted reductive coupling strategy and a Brønsted base-promoted oxidative coupling strategy have been developed with the purpose of achieving more modular access to α,α-difluorobenzylic substructures. Chapter One describes the significance of defluorinative strategies on small molecule organofluorines and the background of defluorinative strategies on trifluoromethylarenes, specifically, including previous and current work by the Bandar Group. The monoselective defluorofunctionalization of trifluoromethylarenes has been a long-standing challenge within the chemistry community and in 2019 the Bandar Group began to expand this methodology to include Lewis-base promoted approaches to access value-added products. Chapter One is intended to be the foundation of this thesis and convey the importance of fluorinated small molecules in a variety of applications with a specific emphasis on defluorinative strategies to functionalize trifluoromethylarenes. Chapter Two describes the long-standing challenges for selective defluorofunctionalization of trifluoromethylarenes, specifically of electronically unactivated arenes. Insight gained from the Bandar Group's reported Lewis base-promoted strategy was used to pragmatically develop an approach for selective functionalization of electron-neutral trifluoromethylarenes. This chapter will provide background on the prevalence of trifluoromethylarenes, strategies that selectively functionalize unactivated systems, and my efforts to expand Lewis-base promoted functionalization to this class of arenes. Chapter Three describes the fundamental challenge of deprotonative strategies that result in unstable carbanions, particularly α,α-difluoromethylarenes and our approach to achieve their productive functionalization. Difluorobenzylic substructures are valuable in a variety fields such as pharmaceuticals, agrochemicals, and electronic materials. Our group's Halogen transfer platform provides an approach to rapidly capture unstable carbanions with base-stable halogen oxidants (2-halothiophenes) which was sequenced with substitution via in situ pronucleophiles. The scope is highly general and provides alternative selectivity to traditional nucleophilic fluorination or radical halogenation methods, while pronucleophiles can be aliphatic alcohols or aromatic alcohols and thiols to achieve value-added products.Item Embargo Analytical methods for evaluation of two classes of bioactive compounds(Colorado State University. Libraries, 2024) Haase, Allison Adelle, author; Crans, Debbie C., advisor; Jarosova, Romana, committee member; Menoni, Carmen, committee member; Peebles, Christie, committee memberAnalytical chemistry and techniques are the underlying support of most kinds of chemical research, as well as biological and environmental research in general, and is a broad field with many different methodologies and modalities. The major subdivisions of analytical chemistry stated in this dissertation are characterization, separation, identification, and quantification, though these fields can overlap. This dissertation focuses on two different research projects involving analytical chemistry, a project focusing on the characterization of novel compounds versus a project consisting of the separation, identification and quantification of compounds in a complex mixture. However, these different research projects are linked through their use of analytical chemistry and the fact that both research projects involve the study of bioactive compounds. Chapter 1 is an introductory chapter consisting of a discussion of the types of analytical chemistry mentioned in later chapters, as well as an overview of the projects that comprise the bulk of the dissertation. Chapter 2 details the studies used to characterize Vanadium complexes for potential use as anti-cancer agents, specifically focusing on the electrochemical evaluation of the complexes' redox properties using non-aqueous cyclic voltammetry. In addition, the hydrolytic stability of the complexes in both saline solution and DMSO was evaluated using ultraviolet-visible light spectroscopy. The potential relationship of these experimentally determined properties was compared to computed properties of the complexes calculated using the Chemicalize website. Vanadium complexes have been studied for various biological properties, as vanadium is a relativity non-toxic metal with various oxidation states. These complexes have been synthesized with a Schiff-base backbone and non-innocent catecholate ligands, which can provide a variety of redox activity on both the metal centers and the ligand. Some compounds in this class of complexes are effective against cancer cells, particularly those of dangerous brain cancers like glioblastoma, while not being overly toxic with long-term use due to the compound degrading into less harmful byproducts upon exposure to water. However, changing the catecholate ligand on these complexes significantly changes the stability and redox properties of the complexes. The potential source of the changes in hydrolytic stability and redox potentials were evaluated. Chapter 3 details the research involving the attempt to separate, identify, and quantify all 24 neutral hexoses from complex samples at very low concentrations using Gas chromatography–Mass spectrometry. It describes issues with separating enantiomers and intermolecular condensation forming rings and anomers, which further complicates separation when one does not use a chiral column. It delves into the scientific literature for possible separation methods without derivatization and why they were not used for this project. It then describes two derivatization methods for hexose separation. Chapter 4 is a concluding chapter that speaks of what was learned from these projects and the potential future directions of those projects.Item Embargo Cu-P-Se nanoparticles: understanding the reaction pathways for the colloidal synthesis of energy conversion and storage materials(Colorado State University. Libraries, 2024) Neisius, Nathan A., author; Prieto, Amy L., advisor; Finke, Richard, committee member; Herrera-Alonso, Margarita, committee member; Paton, Robert, committee memberNanotechnology has garnered considerable interest over the last 40 years, owing to the unique, desirable properties that can be targeted through established synthetic methods for tuning the size of materials at the nanoscale. As no one single material has properties suitable for a wide range of applications, property driven synthesis has been at the forefront of the nanoparticle (NP) field. Particularly, colloidal NP syntheses provide a large synthetic landscape to explore as a result of the vast synthetic tunability to target specific parameters such as, particle size, morphology, composition, and defects. Although significant efforts have been made toward deciphering the transformation processes of unary and binary NPs, traditionally the colloidal NP field has been driven by a top-down approach, driven by trial-and-error methods, limiting the design of desired, complex materials. Thus, to further progress nanoparticle technology, understanding the underlying transformation processes occurring throughout the formation of colloidal nanoparticles is essential to develop novel materials as well as control the structure/property relationships. The copious amounts of both organic and inorganic interactions, as well as the complexity of capturing the transformation from molecular to the solid-state regime, complicates the reaction landscape for more complex, ternary phases. The purpose of the work included and explained in this dissertation is to develop stoichiometric syntheses for both Cu-P-Se ternary phases, Cu3PSe4 and Cu7PSe6, and to then understand the reaction pathways for an improved retrosynthetic analysis and enable translation of the synthetic knowledge to other systems. Cu-P-Se ternary chalcogenide NPs are of particular interest, owing to the synthetic complexity of navigating a rich phase space with thermodynamically stable binary phases close in energy to the desired ternary phases, as well as applicable structural properties for thermoelectrics, photovoltaics, and battery applications. Therefore, to contribute to the progression of the nanoparticle field the general objectives of this study are, (1) analyzing the transformation of commonly employed precursors and solvents (2) capture the influence of precursor reactivity on ternary phase formation, and (3) perform careful characterization of speciation and final nanoparticles, all of which to establish a full scope of Cu-P-Se nanoparticle formation and the impact of individual synthetic parameters on chalcogenide-based precursors. In Chapter 1, the relevant literature for the following chapters is reported and reviewed to provide the essential background information. This chapter is divided into 6 subsections; (1) Need for renewable energy and how nanoparticles provide solutions, (2) State of nanoparticle synthesis field, current limitations, and progress towards developing a better understanding of nanoparticle reaction pathways, (3) Motivation for exploring the Cu-P-Se phase space, (4) Se reactivity in NP syntheses, (5) Cu3P – the required precursor for Cu-P-Se formation, (6) Dissertation overview, publications, and presentations. The first colloidal NP synthesis report on Cu3PSe4 was developed by a previous group member, Dr. Jennifer Lee, which demonstrated that the phase purity of Cu3PSe4 requires the use of Cu3P NPs and selenium powder (Se) in ODE as precursors. Alternate reaction precursors, and therefore pathways, were disproven throughout this study, leading to the working hypothesis that the interactions of Se and ODE were a necessary step to form active species that then react with Cu3P NPs. Although frequently employed in NP research, and heavily characterized, the implications of the Se/ODE solution on Cu3PSe4 phase formation are still misunderstood. Therefore, the studies presented in Chapter 2 are aimed at probing the Cu3PSe4 reaction landscape and the findings are separated into (1) ex situ reactions that are characterized with molecular and solid-state characterization techniques to determine the implications of the solution dynamics on Cu-P-Se NP phase formation, and (2) how different Se/ODE speciation can be isolated and subsequently favor the alternate, metastable Cu-P-Se phase, Cu7PSe6. A persistent limitation to the previous study is that ODE contaminates the final products, making the findings and analysis of Se/ODE rather difficult to interpret, thus requiring a simplified, cleaner reaction to produce phase pure Cu3PSe4. For that reason, Chapter 3 shifts the direction of the Cu3PSe4 synthesis towards a more stoichiometric, atom-economical reaction by eliminating ODE as the solvent. Rather, a long-chain, aliphatic solvent, octadecane (ODA) is employed that proves to be an operationally inert solvent under the standard synthetic conditions and produces cleaner, phase pure Cu3PSe4 NPs as determined by powder X-ray diffraction (PXRD) and transmission electron microscopy (TEM). If ODA was reacting with Se0 powder, the most favorable pathway, commonly cited in literature, is the formation of H2Se and oxidized ODA (alkene). Hence, molecular characterization techniques, nuclear magnetic resonance (NMR, 1H and 13C) and fast-Fourier infrared spectroscopy (FT-IR), were utilized to demonstrate the absence of oxidized ODA species, which is consistent with Se0 preferentially reacting with Cu3P, promoting a more direct reaction pathway. Eliminating the presence of alternate, competing reaction pathways in the ODE synthesis and establishing a near-stoichiometric reaction, allows us to capture the underlying transformation process of Cu3P to Cu3PSe4. From these systematic improvements, we hypothesize that Se0 powder is dispersed in ODA, which promotes a formal eight-electron transfer between Cu3P and 4 Se0. Extracting the synthetic information from the previous chapters to target the metastable Cu-P-Se phase, Cu7PSe6, provides the framework for Chapter 4. Previous methods to isolate Cu7PSe6 are based on traditional, solid-state techniques, where the elemental precursors are ground and subsequently heated to high temperatures (>1000K). Although a colloidal or solution-based synthesis has yet to produce phase-pure Cu7PSe6 particles, attempts explained in Chapter 2 provide a basis on the phase space complexity, where the products consisted of Cu7PSe6 but with thermodynamic byproducts, Cu-Se phases and Cu3PSe4 present. Therefore, an alternate Se precursor, diphenyl diselenide (Ph2Se2), is employed to form the metastable phase, which effectively avoids Cu3PSe4 formation. Importantly, an alternate route to form Cu3PSe4 is with analogous dialkyl diselenide precursor, dibenzyl diselenide, where a key finding is the presence of amorphous phosphorus (P) on Cu1-xSe binaries at low temperatures, which then efficiently reincorporates once the desired 300 ˚C reaction temperature is reached. Thus, in Chapter 4 we investigate why Cu7PSe6 is favored with Ph2Se2 as a precursor, which is predicated on the formation of byproduct species that effectively "trap" P. A proof of concept is explored to further demonstrate the dynamics of P in solution, where the Cu-P-Se phase space can be controllably toggled across by injecting P(5+) species. A drawback for the Cu-P-Se syntheses is the lack of compositional understanding of the pre-synthesized Cu3P NPs, thus further complicating the reaction stoichiometries. Chapter 5 first investigates the previously published synthesis by Liu et al., by thoroughly characterizing the final Cu3P nanoparticles under identical reaction conditions and exploring alternate reaction stoichiometries to reduce the presence of residue precursors. From such, it is determined that the particles substantially deviate from the stoichiometric Cu3P composition, with a Cu:P ratio around 1.5:1.0. Particular focus is also placed on monitoring the degradation of a green phosphorous source, triphenyl phosphite, P(OPh)3. Although triphenyl phosphite (TPOP) has been previously used for transition metal phosphide systems, a lack of systematic investigations leads to questions on the reduction of TPOP en route to forming Cu3P, a formal P(3+) to P(3-) event. Additionally, limited characterization of the final organic byproducts in the original synthesis, begs to question what, if any, byproducts could be contaminating the Cu3P NPs. Therefore, we develop and probe stoichiometric syntheses that isolate phase pure Cu3P NPs to avoid the original 30-fold excess of P. The transformation of hexadecylamine (reductant and ligand) and TPOP were characterized with 1H and 31P NMR to evaluate the role of each en route to forming Cu3P. As this is project is still developing, the necessary future directions are given to systematically approach this problem, with an emphasis on first-step experiments and essential characterization methods to completely grasp the decomposition mechanism of TPOP. Ultimately, this has implications when systematically applying TPOP to alternate transitional metal phosphide NP syntheses, as well as developing more precise Cu-P-Se syntheses. Finally, the work presented herein is summarized in Chapter 6 along with an outlook on the project as a whole. Specifically, future directions and preliminary insight into the underlying reaction pathways and mechanism of Cu3PSe4 formation are explored. Additionally, we explore preliminary data on an analogous material Ag-P-Se, which was plagued for years by the lack of a reproducible Ag-P precursor synthesis that limited our ability to extract the synthetic intuition from the Cu-P-Se system. However, recent literature findings on a potential Ag3P precursor provides promise on synthesizing Ag-P-Se phases in the future, which is critically analyzed to ensure that any bottlenecks in future syntheses are limited. Ultimately, the work provided in the following chapters is aimed at making strides to developing a more in depth understanding of precursor interactions between transition metals and main group elements, as well as properly monitoring such reactions to extract synthetic information to analogous systems. With the knowledge gained on the presented studies, we aspire to contribute to the NP field in order to continually improve NP synthesis and therefore nanomaterials. Finally, this work is supported by NSF Macromolecular, Supramolecular, and Nanochemistry (MSN #2109141).Item Open Access Mesoscopic revelations: studying the shape of AOT reverse micelles(Colorado State University. Libraries, 2024) Gale, Christopher D., author; Levinger, Nancy E., advisor; Krummel, Amber, committee member; Prieto, Amy, committee member; Buchanan, Kristen, committee memberAerosol-OT (AOT) reverse micelles are a quintessential model system for studying nanoconfinement, creating consistent reverse micelles with a repeatable and very small size (~1-10 nm) using just 3 components. These reverse micelles have been used for studying the behavior of water and solutes in nanoconfinement, modeling the behavior of key solutes and proteins in a system more analogous to in vivo work, synthesizing nanoparticles, and even as a vehicle for suspending proteins in a low-viscosity solvent for high quality NMR experiments. Despite their usefulness, AOT reverse micelle's shape is poorly understood, but important to understanding behavior within a reverse micelle. Interfacial properties have been found to be key to many aspects of behavior within AOT reverse micelles and distance from the interface as well as the actual amount of interface present are highly dependent on shape. Therefore, the study of shape is key to a better understanding of AOT reverse micelles and behavior in nanonconfinement. In this work, I develop a series of metrics for shape--- coordinate-pair eccentricity (CPE), convexity, and the curvature distribution--- and apply them to several simulations of AOT reverse micelles. The simulations were designed to test the impact of the force field on the shape and behavior of the reverse micelles, including the first parameterization of AOT into the OPLS force field. The system was extensively checked to ensure equilibration was achieved and the system was not biased by the starting configuration. To aid in the shape analysis, I have developed a model and a formal proof to predict how the CPE changes for an arbitrary shape as it grows to model the shape behavior of general core-shell structures. Additionally, I measured the dipole moment of AOT, the rotational anisotropy decay of water, and several radial distribution functions to provide experimental verification where possible and further explore the behavior of the AOT reverse micelle system. Several key findings emerge from this work. Most notably, I find that AOT reverse micelles are significantly aspherical and non-convex over every force field tested, providing robust evidence that AOT reverse micelles are aspherical at any given moment in time. This provides strong evidence in support of the idea that experimental observations of spherical particles are the result of ensemble averaging. I also observe that the shape at the AOT/oil interface is comparatively more spherical with a "Goldilock's" value of convexity, neither too high nor too low, compared to the water/AOT interface. My model predicts that the CPE should fall with the addition of a shell, here provided by the AOT surfactant layer, suggesting this is largely the result of geometry. There is great variation between simulations and metrics in their dynamics, but in general, the shape appears to change on the order of 10 ns. This provides a useful method of deducing which values may or may not be impacted by shape, based on the time scale. For instance, it can reasonably be said that shape likely has no impact on water dynamics based on the roughly four orders of magnitude difference in the time scales of each process, which is supported by my own findings. Across all metrics studied, there are noticeable differences between simulations, but none of the differences are consistent. I believe this observation has important implications for both the behavior and simulation of AOT reverse micelles. First, this implies that the forces and interactions giving rise to different aspects of the reverse micelle are complex and largely independent, and that there is a disconnect between molecular-level measurements like radial distribution functions and and mesoscopic-level measurements like shape. Second, this implies that any simulation parameterized on one measure has no guarantee that it reproduces any other aspect of the reverse micelle accurately.Item Open Access The development of new synthetic methods and techniques using strong Brønsted bases(Colorado State University. Libraries, 2024) Hoteling, Garrett A., author; Bandar, Jeffrey, advisor; Miyake, Garret, committee member; Menoni, Carmen, committee member; Peebles, Christie, committee memberBrønsted bases are indispensable tools in synthetic chemistry and, as such, deprotonation serves as a ubiquitous mode of molecular activation. By pushing the boundaries of what is possible within the acid-base reaction paradigm, unique synthetic methods and techniques can be developed. The work described in this thesis focuses on gaining a fundamental understanding of strong-base chemistry in efforts towards the development of new base-promoted synthetic methods. Herein, Brønsted bases have been investigated in two ways; 1) the design and application of benchtop-stable precatalyst salts for valuable organic superbases; and 2) the implementation of base-promoted halogen-transfer to develop benzylic oxidative coupling reactions with alkyl (hetero)arenes. This dissertation consists of five chapters. Chapters One and Three provide background and motivation for the work disclosed in this dissertation. Chapters Two, Four and Five represent project areas I have developed with Chapter Two adapted from published work and Chapters Four and Five as drafts of unpublished work. Below is a list of the chapters including a summary of the content for each. Chapter One describes the importance of organic superbases and their relevance to the synthetic community and the Bandar Group as a whole. Presented here will be the various classes of superbases and their unique properties that distinguish them from other classes of bases. Additionally, applications and known limitations to use of these bases will be discussed here. Chapter Two describes work along with Dr. Stephen J. Sujansky on the development of benchtop-stable organic superbase salts and the method for their facile in situ activation. Here, air-sensitive organic superbases form salts when mixed with carboxylic acids that are indefinitely stable on the benchtop. When combined with an epoxide additive, the carboxylate will react to open the epoxide and generate an alkoxide that can neutralize the superbase conjugate acid. This strategy is effective at promoting catalytic Michael-type additions and polymerizations as well as stoichiometric substitution and Pd-catalyzed cross-coupling reactions. This strain-release mechanism not only provides an accessible precatalyst for air-sensitive superbases but provides a new opportunity for controlling base concentration in situ. Chapter Two describes the development of the Bandar Group’s base-promoted halogen transfer research program. The history and importance of this mechanistic platform will be discussed as well as previous reports in the area by our group. In this chapter, the mechanism of base-promoted halogen-transfer is described, which enables the exchange of weakly acidic C–H bonds for C–X bonds that can be subsequently substituted with a pronucleophile in situ. This section will also provide the necessary background and motivation for Chapters Four and Five. Chapter Four describes the development of a new method for the synthesis of benzylic amines from alkyl (hetero)arenes. The development, optimization, and scope investigation of this reaction are described herein. The results of this work represent the first general approach for benzylic C–H amination, functioning on a broad scope of alkyl (hetero)arenes and amine coupling partners. Chapter Five describes the use of base-promoted halogen-transfer to enable alkyl (hetero)arene desaturation. With ethyl- and longer alkyl-substituted arenes, after benzylic halogenation, elimination takes place in the presence of excess base, a process that is competitive iv with the substitution protocol described in Chapter Two. Here, this reactivity has been exploited to develop a general desaturation technique for alkyl (hetero)arenes. Under desaturation conditions, an amine pronucleophile can be added, at which point β-addition followed by subsequent desaturation affords the β -aryl enamine, which is a diversifiable functional handle. This chapter describes the development of desaturation, cascade enamine formation, and the modification of enamine products.Item Open Access Ring-conversion and functionalization of nitrogen-containing heterocycles(Colorado State University. Libraries, 2024) Josephitis, Celena M., author; McNally, Andrew, advisor; Bandar, Jeff, committee member; Chung, Jean, committee member; Reisfeld, Bradley, committee memberPyridines and related azines are ubiquitous in pharmaceuticals and agrochemicals development. Chemist rely on the development of new synthetic methods to modify these heterocycles. Described herein are the development of methods to functionalize azines and convert pyridines and diazines into new heterocycles. Novel hydrogenation and molecular editing strategies were designed and leveraged to accomplish this goal. Chapter one introduces the importance of pyridines and related heterocycles in pharmaceuticals as well as methods to access and functionalize these molecules. Both classical and contemporary methods for functionalization and hydrogenation of pyridines are discussed to provide context for this work. Chapter two describes a novel method to selectively reduce pyridines to dihydropyridines, tetrahydropyridines, and piperidines. This method offers a complementary alternative to current hydrogenation or reduction methods, in which the degree of saturation cannot be controlled, and applies to complex azine starting materials. Chapter three explains the importance of structure-activity relationship (SAR) studies and its implications on the drug-discovery process. It also describes classical and contemporary strategies that apply to SAR diversification including de novo heterocycle synthesis and molecular editing strategies. Finally, chapter four presents a novel method for SAR diversification of pyrimidine containing molecules using a deconstruction/reconstruction approach.Item Embargo Investigations of low-temperature reaction pathways in solid-state reactions(Colorado State University. Libraries, 2024) Tran, Gia Thinh, author; Neilson, James R., advisor; Prieto, Amy L., committee member; Sambur, Justin B., committee member; Chen, Hua, committee memberAdvances in our technology are limited by our knowledge of functional materials, and access to new, possibly better, functional materials is limited by our synthesis methods. This dissertation discusses different synthesis methods for a variety of solid state materials. At the core of this thesis are metathesis reactions i.e. double displacement reactions. Metathesis reactions allow for control over product selectivity and reaction kinetics with choice of the spectating ions. We demonstrate these characteristics with different spectating ions in metathesis and cometathesis (e.g., combining 2 halides) reactions. LaMnO3 was chosen to probe the product selectivity of anion cometathesis towards specific off-stoichiometries of LaMnO3. The metathesis reaction for BiFeO3 illustrates that prediction of thermodynamic selectivity is important, but reaction kinetics remain important as well. Kinetic studies of metathesis reactions that form YMnO3 demonstrate the importance of crystalline intermediates to modulate the reaction rates. The complexity of solid-state kinetics their kinetic regimes within a reaction can be identified through synchrotron X-ray diffraction. We attempted to synthesize LiMoO2 as precursors for the proposed phase LaMoO3. We demonstrate our considerations on the synthesis challenges and offer gained insights into alternative Mo-based systems (nitrides). Aside from metathesis reactions, we employ learned concepts to flux reactions to influence the chemical potential of N2. Synthesis of Li-Fe-O-N and Li-Mn-O-N phases was attempted under the hypothesis that alkali halide salt mixtures solubilize nitrogen and pin nitrogen's chemical potential to prevent N2 formation. Cs2SbCl6 was chosen as a single crystal target to gain clearer insights into the electronic structure. Single crystals were synthesized via hydrothermal synthesis, but preliminary conductivity measurements suggest that Cs2SbCl6 has a photoconductance below our limit detection.Item Embargo Site-selective pyridine functionalization via nucleophilic additions to activated pyridiniums(Colorado State University. Libraries, 2024) Nguyen, Hillary M. H., author; McNally, Andrew, advisor; Bandar, Jeff, committee member; Chung, Jean, committee member; Shoemaker, Mark, committee memberPyridines and diazines are important heterocycles commonly found in pharmaceuticals, agrochemicals, ligands, and various other organic molecules. Pyridines existing in these molecules usually have multiple bonds connected to them that contribute to their reactivity and characteristics. Therefore, there are ongoing efforts l to find new methods to functionalize these heterocycles. Our lab has contributed to this field by developing methods to functionalize pyridines directly from the C–H bond through phosphonium salts or Zincke imines. Chapter One gives an overview of the current methods for pyridine functionalization and their limitations. Chapter Two describes the synthesis of N-Tf Zincke imines and their use for regioselective 3-position pyridine functionalization. Bipyridines and pyridine-piperidine coupled products are accessed through this method. Chapter Three discusses using N-Tf Zincke imines to form 15N pyridines and coupled with deuteration forms higher mass isotopologues. Chapter Four describes the formation of N-alkyl pyridinium salts from N-Tf Zincke imines. This chapter focuses on optimizing the ring-opening of 2-ester pyridines and ring-closing them with amino esters to access pipecolic esters for macrocyclization. Chapter Five highlights direct nucleophile additions to the 4-position of N-Tf pyridinium salts for pyridine functionalization. 4-aminated pyridines are formed with both aliphatic amines and anilines from the C–H bond. The regioselectivity of this amination is controlled by the basicity of the reaction. In addition, 4-NH2 pyridines are achieved through this method by adding benzophenone imine, an ammonia surrogate. This reaction extends to adding in heteroatom nucleophiles including alcohols, thioesters, amides, and sulfonamides.Item Embargo Leveraging bio-based monomers, chemical recyclability, and sustainable polymerization techniques for sustainable polymer synthesis(Colorado State University. Libraries, 2024) Bernsten, Simone Noelle, author; Miyake, Garret, advisor; McNally, Andy, committee member; Reynolds, Melissa, committee member; Reisfeld, Brad, committee memberPolymeric materials have become vital to everyday life since their commercialization. Although polymers are integral to many industries and consumers, their synthesis and use brings with them a myriad of environmental concerns. Unsustainability can arise even before polymer synthesis in that many synthetic polymers are made from petroleum-derived monomers which are inherently nonrenewable. Next, many polymers are synthesized using one or more unsustainable components such as precious metals including iridium and ruthenium. Finally, at the end of a polymer's useful life, options for recycling are limited by the inability to make virgin-quality materials that can be used for the same application as the original polymer. The work described in this thesis aims to address each of these issues. The polymerizations of several bio-based monomers are described. The use of organic photoredox catalysis to enable polymerization represents sustainable synthesis of polymers. Polymers exhibiting chemical recyclability are also investigated, wherein end-of-life materials can be depolymerized and used to produce virgin- quality materials. Ultimately, this work represents a diverse array of methodologies for increasing the overall sustainability of polymeric materials.Item Embargo Charge carrier dynamics of 2-dimensional photoelectrodes probed via ultrafast spectroelectrochemistry(Colorado State University. Libraries, 2024) Austin, Rachelle, author; Sambur, Justin, advisor; Krummel, Amber, advisor; Rappe, Anthony, committee member; Prieto, Amy, committee member; McNally, Andrew, committee member; Brewer, Samuel, committee memberThe integration of hot charge carrier-based energy conversion systems with two-dimensional (2D) semiconductors holds immense promise for enhancing the efficiency of solar energy technologies and enabling novel photochemical reactions. Current approaches, however, often rely on costly multijunction architectures. In this dissertation, I present research that combines spectroelectrochemical and in-operando transient absorption spectroscopy measurements to unveil ultrafast (<50 fs) hot exciton and free charge carrier extraction in a proof-of-concept photoelectrochemical solar cell constructed from earth-abundant monolayer (ML) MoS2. Theoretical analyses of exciton states reveal enhanced electronic coupling between hot exciton states and neighboring contacts, facilitating rapid charge transfer. Additionally, I discuss insights into the physical interpretation of transient absorption (TA) spectroscopy data in 2D semiconductors, comparing historical perspectives from physical chemistry and solid-state physics literature. My perspective encompasses various physical explanations for spectral features and experimental trends, particularly focusing on the contribution of trions to TA spectra. Furthermore, I examine how different physical interpretations and data analysis procedures can yield distinct timescales and mechanisms from the same experimental results, providing a comprehensive framework for understanding charge carrier dynamics in 2D semiconductor-based optoelectronic devices.Item Open Access Understanding selectivity in organic reactions through density functional theory(Colorado State University. Libraries, 2024) de Lescure, Louis Raymond Philibert, author; Paton, Robert, advisor; McNally, Andrew, advisor; Bandar, Jeffrey, committee member; Kennan, Alan, committee member; Herrera-Alonso, Margarita, committee memberThe success of chemical reactions is often expressed through the lens of selectivity, defined as the preference for a desired reaction pathway over an undesirable one. A profound understanding of the rationale behind the selectivity of chemical reactions is crucial for the progression of synthetic methodologies in organic chemistry. Utilizing quantum chemical approximations, density functional theory (DFT) calculations offer unparalleled insights into the electronic structures and mechanisms of reactions, which can be correlated with observed empirical selectivities. This dissertation demonstrates the significant utility of DFT, in tandem with experimental evidence, in elucidating the intricate mechanisms of reactions. Chapter 1 defines the thematic and methods used throughout this thesis. Chapters 2 and 3 detail collaborative work with the McNally group at Colorado State University. Here, we developed innovative methods for the halogenation of pyridines and advanced modifications of pyrimidine rings utilizing redesigned Zincke chemistry. This chapter focuses on the factors influencing the regioselectivity of halogenation processes and provides mechanistic insights into the formation of crucial intermediates. Chapter 3 outlines a joint project with the Race group at the University of Minnesota, where we explored the homologation of benzylic carbon-bromide bonds. Our investigations centered on the ring-opening of phenonium intermediates, a critical step in determining the success of the reaction. Chapter 4 presents a collaboration with the Aggarwal group at the University of Bristol. This chapter examines the nuanced interplay between kinetic and thermodynamic factors that govern the enantioselectivity of the reaction discussed. This comprehensive study underscores the integration of theoretical and experimental approaches in advancing our understanding of complex chemical reactions.Item Embargo The design and synthesis of super reducing organic photocatalysts through mechanistic understanding with application towards unactivated arene activation(Colorado State University. Libraries, 2024) Green, Alexander Richard, author; Miyake, Garret, advisor; Paton, Robert, committee member; Bailey, Travis, committee member; Reisfeld, Brad, committee memberThe work described in this dissertation focuses on the understanding of an organic photocatalyst system through a degradation and mechanistic study, leading to development of a new class of organic photocatalyst and improved application. The design of new organic photocatalysts is crucial for eliminating the need to use rare and expensive ruthenium and iridium that have dominated the field of photoredox catalysis for the past decade. Additionally, most of the catalysts describe here-in operate through a unique two electron, one proton activation mechanism to generate a closed shell species which enables direct quenching towards unactivated arenes such as benzene, without the use of a stoichiometric amount of reductant such as solvated electrons coming from pyrophoric metals. The progress described within this dissertation provides a deeper understanding of tunable organic reductants and their function.Item Embargo Application and effects of metal-based therapeutics on cancer cell lines in tissue culture(Colorado State University. Libraries, 2024) Klugh, Kameron Leigh, author; Crans, Debbie, advisor; Paton, Robert, committee member; Menoni, Carmen, committee memberIn recent years, metal-based drugs have emerged as significant players in the field of therapeutics, leveraging the unique properties of metals to enhance medical treatments. These compounds, incorporating transition metals such as vanadium and platinum, have shown remarkable efficacy in treating various conditions, most notably cancer. The ability of such metals to form complex structures with organic molecules allows for precise targeting and modulation of biological pathways, leading to improved drug efficacy and reduced side effects. Thus, this approach has opened new avenues for designing advanced therapeutics such as vanadium(V) Schiff base catecholate complexes for the treatment of cancer. This thesis aims to explore the potential of non-innocent Schiff base vanadium(V) catecholate complexes as promising agents against glioblastoma, an aggressive form of brain cancer. Two catecholate ligands, 3,5-di-isopropyl catechol and 3,4,6-tri-isopropyl catechol, were synthesized and coordinated to both known and novel vanadium(V) Schiff base scaffolds. Upon testing on glioblastoma T98g cell lines, two of the new complexes, namely [VO(3-tBuHSHED)(TIPCAT)] and [VO(3,5-tBuHSHED)(TIPCAT)], showed remarkable antiproliferative activity. Parallelly, the manuscript delves into the therapeutic applications of platinum-based drugs and how the resistance of platinum-based chemotherapeutics remains a significant challenge. This area of the manuscript identifies the newly discovered role of long non-coding RNAs in platinum-resistance in gastrointestinal cancer treatment. The interaction of these drugs with cellular RNA, in addition to DNA, contributes to this resistance. This manuscript examines the speciation of cisplatin and oxaliplatin, their interactions with DNA and RNA, and the resulting physiological responses of long non-coding RNAs. It identifies aberrantly expressed lncRNAs in platinum-resistant gastrointestinal cancer cell lines, including those from oral cavity, esophageal, gastric, and colorectal cancers. Despite testing different cell lines, similar patterns of aberrant expression compared to normal cells suggest consistent changes in gene expression and cellular pathways. Understanding these changes may help develop new therapeutic strategies for gastrointestinal cancer patients. Together, the vanadium(V) complex investigations and the new insights into platinum-resistance underscore progress in the understanding of the molecular interactions of metal-based drugs, offering pathways to enhance their efficacy and overcome resistance in cancer therapy.Item Embargo Comparative analysis of the role of redox active molecules on bioenergetically active membranes(Colorado State University. Libraries, 2024) Dolan, Connor Cathal, author; Crans, Debbie, advisor; Kennan, Alan, committee member; Chicco, Adam, committee memberTransition metals play crucial roles in various biological processes, with vanadium and manganese being prominent examples due to their redox activity and impact on oxidative stress, mitochondrial function, and disease progression. This manuscript focuses on the role of transition metals, particularly vanadium, in biological functioning, with an emphasis on oxidative stress and mitochondria. Chapter 1 of this thesis discusses the respective role that vanadium plays on oxidative stress and how that influences biological systems. Due to its variety of speciation states and its ability to redox cycle as well as its structural and electronic properties, vanadium can affect biological systems in a variety of ways. These include the generation of reactive oxygen species, lipid peroxidation, protein inhibition, changes in membrane fluidity and potential. DNA damage and cell death. The effects that vanadium has is highly dependent on the speciation and state that they exist in. this can impact the system that is being affected and the outcome. Species such as decavanadate have a unique and profound biological effect. Changing of the species, oxidation state and complexation can alter the biological consequences associated with vanadium. Chapter 2 of this thesis explores the differences and similarities between vanadium and manganese on cardiac mitochondrial dysfunction and oxidative stress. Using varying vanadium and manganese compounds, we investigated the effects they had on isolated cardiac mitochondria using high resolution respirometry and UV-Vis spectroscopy. We found similarities between metal salts on inhibition of respiration as well as significant differences on the metals iii effect on mitochondrial swelling. We further investigated the role of transport proteins on vanadium induced swelling and found that the mitochondrial calcium uniporter played an important role in vanadium induced mitochondrial swelling. We further investigated the differences in species and oxidation state on function. We tested the difference between VV and VIV on mitochondrial swelling and found that VIV led to significantly greater swelling. We also found that there the VO(OH)3 - monomer and dimer were present in both VIV compounds and the Mn2+ ion was present in both manganese compounds. This speciation similarity between compounds may account for some of the similar effects seen within the same metal compounds as well as the differences seen when comparing manganese and vanadium together.Item Embargo Advancements in the chemical recyclability of acrylic polymers through investigation of monomer design(Colorado State University. Libraries, 2024) Gilsdorf, Reid Anthony, author; Chen, Eugene, advisor; Miyake, Garret, committee member; Shores, Matthew, committee member; Herrera-Alonso, Margarita, committee memberDepolymerization is a key avenue of state-of-the-art recycling of polymeric materials. Although many polymers have been investigated for their ability to depolymerize, a subset of polymers has been widely left out of the conversation, polyolefins, or polymers containing C-C bonds in the polymer main-chain. Acrylic polymers are an important class of polyolefins used throughout the world in a variety of applications. One of the key drawbacks of the polymer, however, is their unfavorable depolymerization conditions, requiring high temperatures in expensive reactors. Although much work has been performed on the depolymerization of the most widely used acrylic polymer, poly(methyl methacrylate) (PMMA), there have been few reports on trying to improve upon the recycling methods, such as decreasing depolymerization temperature or gaining control over the depolymerization mechanism. In this work, key mechanistic steps of acrylic polymer depolymerization are investigated to gain fundamental understanding on the limitations faced during depolymerization and try to improve upon them. When poly(α-methylene-γ-butyrolactone) (PMBL) and poly(α-methylene-γ-methyl-γ-butyrolactone) (PMMBL) were investigated, the suppression of side reactions that occurred with PMMA depolymerization were identified, attributed to the pendant lactone tethering radical species together. Employing this tethering effect, the design of new polymers with pendant lactones and lower equilibrium polymerization temperatures (ceiling temperature or TC), was carried out, overall decreasing depolymerization temperatures and improving polymer recyclability. Finally, these new polymers were incorporated into the design of copolymers with PMMA and PMMBL in order to exploit the new polymers' depolymerizability without hindering thermomechanical properties. Overall, this work has shed light onto the importance of polyolefin design in, not just thermomechanical properties, but also polymerization and depolymerization behavior which will benefit the continued development of recyclable-by-design polymers.