No description available.

No description available.

In molecular transition metal catalyst architectures, ligand design plays a crucial role in enhancing the efficiency of catalytic reactions. Selected ligands can play a bifunctional role in ligand-assisted catalysis, providing first coordination sphere basic sites and facilitating formation of multinuclear species through monomer bridging, as well as through their electronic and steric effects. This research addresses the underutilization of SNS complexes in various catalytic cycles. Our aim is to expand their activity in different cycles, unlocking untapped reactivity. Specifically, we focus on SNS ligands with soft thiolate and hard amido donors, comparing their catalytic performance in diverse coupling reactions. This comparative study provides insights into the suitability of these ligands with different transition metals, contributing to the understanding of ligand-assisted catalysis. Chapter 1 introduces these concepts and outlines the relevant catalytic reactions studied herein. To gain a deeper understanding of the chemistry involved, a comparative analysis of the reactivity differences between transition metal complexes with similar coordination structures is conducted. This investigation is crucial as it provides valuable insights into the design of suitable ligands for transition metal catalysts. Specifically, Chapters 2 and 3 of this thesis delve into a comparison of the reactivity of coordination complexes with identical metal centers and similar ligands, or even the same molecular formula, in catalysis. In the second chapter, we introduce a new cobalt (II) complex bearing an (SNS) amido ligand for the bifunctional hydroboration of carbonyls. Following an unsuccessful attempt to mono-protonate the amido donor in the bis(amido) complex Co(SᴹᵉNSᴹᵉ)₂ (2.1) treatment with 1 equivalent of 1,3-bis(1-adamantyl)imidazolium chloride (IAd•HCl) resulted in the liberation of one protonated ligand, affording CoᴵᴵCl(SᴹᵉNSᴹᵉ)(a-IAd) (2.2) with an "abnormally" coordinated IAd ligand, i.e., specifically bound through C4 instead of C2 of the imidazole ring. Compound 2.2 exhibited excellent catalytic activity in the hydroboration of aldehydes, displaying high substrate tolerance under mild reaction conditions and short reaction times. Stoichiometric reactions of 2.2 with pinacolborane (HBpin) revealed a bifunctional catalyst activation step, generating free SNS-amine, ClBpin and the active cobalt dihydride catalyst. Generation of an analogous catalyst with a normally coordinated IAd ligand showed poor reactivity in the hydroboration of aldehydes and was unable to effect ketone hydroboration. In Chapter 3, two tetranuclear copper(I) complexes bearing thiolate [Cu(SNSᴹᵉ)]₄ (3.1) and amido [Cu(SNSᴹᵉ)]₄ (3.2) SNS ligands are synthesized and their catalytic activity in a base-free azide-alkyne cycloaddition is compared. Complex 3.1 (1 mol%) demonstrated excellent reactivity for performing this 'click' reaction in water, exhibiting a broad substrate scope and enabling the production of various triazole compounds, including bioactive compound 3.16, which holds potential as an anti-cancer drug. DFT calculations suggested a proton shuttle role for the thiolate donor in conversion of the Cu-coordinated terminal alkyne to the key Cu-alkynyl intermediate. On the other hand, complex 3.2 exhibited reactivity similar to copper chloride. This observation was attributed to the basic nature of the amido ligand, which undergoes protonation by the coordinated alkyne C-H bond, with subsequent dissociation of the SNS-amine from the copper. Without a ligand to stabilize the copper in the less stable +1 oxidation state, a disproportionation reaction occurs, leading to catalyst deactivation. Chapter 4 introduces two palladium(II) thiolate complexes: PdI(κ³-SNSᴹᵉ) (4.1) exhibits catalytic activity in promoting the Heck cross-coupling reaction, while Pd(κ²-SNSᴹᵉ)₂ (4.2) affords no coupling product. In concert with triethylamine base, catalyst 4.1 efficiently produces olefin products with excellent yields, even at low catalyst loadings, and exhibits broad substrate tolerance over a 5 h reaction period. In contrast, the limited catalytic activity of 4.2 can be rationalized by proposing the formation of a Pd(N₂S₂) complex through ligand imine coupling at elevated temperatures, a reaction reported previously for Ni and Co analogs. The tetra-coordinated ligand formed through this isomerization occupies critical coordination sites around the metal, thereby preventing oxidative addition of the organohalide substrate, a key step in the Heck reaction mechanism. This work sheds light on the divergent catalytic behaviors of these two intriguing complexes. Finally, in Chapter 5 we assess what has been learned and identify relevant implications for further work.

<p dir="ltr">LeadGlow (<b>LG</b>) was reported in 2009 for its ability to both sensitively and selectively detect Pb²⁺ in aqueous solutions. Utilizing the synthetic approach of <b>LG</b>, it is possible to generate a class of novel fluorophores. A derivative of first-generation <b>LG </b>was synthesized and reported here for the first time, intuitively named <b>LG2</b>. Both compounds contain interesting photophysical properties that have not been extensively researched prior to this work. Because of this, photophysical properties of both <b>LG</b> and <b>LG2</b> are unveiled here for the first time. These properties were investigated by determinations of quantum yield (QY), average fluorescence lifetime, and DFT calculations. <b>LG</b> was found to have a higher QY (0.057) than <b>LG2</b> (0.011); however, <b>LG2</b> displays an average fluorescence lifetime (3.186 ns) 5x greater than that of <b>LG</b>. Both <b>LG </b>and <b>LG2</b> are synthesized via Hg²⁺-facilitated desulfurization of their respective thiocarbonyls, resulting in a turn-on fluorescence feature. The thiocarbonyl-containing fluorophores (<b>SLG </b>and <b>SLG2</b>) display quenched fluorescence compared to their oxo-derivatives (<b>LG </b>and <b>LG2</b>), this work attempts to investigate the mechanism(s) responsible.<b> </b>A whole class of LeadGlow compounds can be synthesized and could be potentially used as fluorescence-based sensors.</p>

<p dir="ltr">Post-translational modification (PTM) is an important biological process by which cells regulate their signaling pathways. De-regulation of these signaling pathways often leads to many diseases. Protein AMPylation is a recently discovered PTM that caught a great amount of attention for its involvement in neurodevelopment and neurodegeneration. However, the mechanisms by which protein AMPylation modulates these biological processes remain mostly unknown. FIC domain protein adenylyltransferase (FICD)<b> </b>is one of the only two known AMPylators in eukaryotes, and its physiological role remains largely unexplored. By using a chemical approach, we identified two direct substrates of FICD: Peroxiredoxin 1 (PRX1) and Peroxiredoxin 2 (PRX2). These are antioxidant enzymes responsible for protecting cells from oxidative stress, which has been implicated in many neurodegenerative diseases. In addition, we found that FICD-mediated AMPylation increased PRX1 and PRX2 enzymatic activity <i>in vitro</i> and their protein levels in cells. These findings established a link between FICD-mediated AMPylation and oxidative stress, suggesting a potential neuroprotective role of FICD in neurodegenerative diseases.</p><p dir="ltr">Protein phosphorylation is another PTM that has been under extensive study due to its widespread role in cell signaling in many biological processes such as growth, division, metabolism, membrane transport, etc... Deregulation of protein kinases, which catalyze phosphorylation reaction, is often implicated in many diseases, including cancer. To elucidate disease mechanisms and explore alternative therapeutic targets, identifying direct protein substrates of a given disease-relevant kinase is crucial but remains a major challenge. Conventional methods to study phosphorylation involved the use of radiolabeled ATP, which poses health hazards and lacks reliability due to rapid decay of radioactive isotope. In this research, we developed an alternative method with a series of novel γ-modified ATP analog probes bearing a phospho-alkyne reporter handle, and their effectiveness and efficiency for<i> </i><i>in vitro</i> phosphorylation of recombinant proteins and proteomic substrate labeling in cell lysate were examined.</p>

AN ABSTRACT OF THE DISSERTATION OFElizabeth W. Salako, for the Doctor of Philosophy degree in Chemistry, presented on March 27, 2024, at Southern Illinois University Carbondale. TITLE: SYNTHESIS OF NOVEL PERFLUORINATED ION EXCHANGE MEMBRANES AGAINST HYDROGEN PEROXIDE DEGRADATION IN ELECTROCHEMICAL ENERGY STORAGE DEVICES MAJOR PROFESSOR: Dr. Yong GaoThe continuous burning of fossil fuels to meet the energy needs of the ever-growing population has extensive and enduring effects on the environment, human health, and the economy. Adopting cleaner and more sustainable energy sources is crucial to reducing the impact and tackling the difficulties posed by climate change. Renewable energy, which is derived from sources that are naturally replenished, presents a compelling solution to address these pressing challenges. Due to the inherent intermittency of renewable energy available, which relies on weather conditions and daylight hours, incorporating energy storage technology into the power grid can effectively handle unforeseeable power demands.An ion exchange membrane (IEM) is an important part of electrochemical energy storage and conversion devices like fuel cells, flow batteries, and electrolyzers. Without it, these devices would not work properly. The IEM has significantly enhanced these devices by enabling higher operating temperatures and improving their durability and efficiency. The proton exchange membrane (PEM) has been greatly studied, with Nafion® (a product of DuPont) as the state-of-the-art membrane. Even though Nafion®, which belongs to the perfluorosulfonic acid (PFSA) group, has been commercialized, it suffers from low working temperatures, high cost, low tolerance to fuel impurities, and most importantly, degradation of the membrane over a short period of time. The membrane undergoes three main types of degradation: mechanical, thermal, and chemical degradation. Although the mechanical and thermal degradation of the membranes can be managed, the chemical degradation is a more intricate and challenging issue to address. The degradation of Nafion® occurs through the process of radical-induced disintegration of the polymer structure. This selectively targets the weakest points in the polymer structure, thereby fragmenting the polymer and leading to a loss of ionic conductivity. These vulnerable sites include carboxylic acid groups, C-S linkages, tertiary carbons, and fluoro-ether groups. Studies have shown the fluoro-ether groups to be more susceptible to hydroxyl radical attacks. In our aim to reduce membrane degradation, we designed and synthesized novel fluoro-monomers void of the fluoro-ether groups. We used the emulsion polymerization process in a high-pressure reactor to polymerize our synthesized monomers with a commercially available monomer to make different ionomers with -SO3H and -PO3H2 ion exchange groups. We measured the molecular weight of the polymers through the viscometry method. The mechanical properties of the polymers were not as great, and it became difficult to cast them into a thin film. Polytetrafluoroethylene (PTFE) films were used as a support for the polymers to make them stronger and to also measure their ion conductivities in comparison with NafionTM 115. Fenton’s test was employed to measure the susceptibility of the polymers to hydroxyl radical attack. Our polymers were not as good at conducting ions as NafionTM 115, but they were better at protecting against hydroxyl radical attacks, both at room temperature and higher temperatures. The results showed an inverse relationship between the number of fluoroalkyl ether groups present in the polymers and their resistance to hydroxyl radical attacks.

Mono- and bis-aspidosperma indole alkaloid natural products have been shown to be cytotoxic against various cancer cell lines and are potential leads in therapeutics against diabetes and neurodegenerative diseases. Tabersonine, a monoterpene indole alkaloid isolated from the family Apocynaceae, was known to be the bio-synthetic precursor of its mono and dimeric analogs, including vindoline, conophylline, and vinblastine. The first synthesis of bis-aspidosperma indole alkaloid (–)-melodinine K was achieved in a chemoenzymatic fashion, featuring the T16H hydroxylation and the biomimetic dimerization via the Polonovski-Potier reaction. Moreover, eight tabersonine derivatives bearing one or two hydroxy or methoxy groups at C15-C17 were synthesized up to grams scale via a halogenation/borylation/oxidation sequence. These analogs exhibited potent inhibitory activities against cancer cells with GI50 values in the single digit micromolar level. This research on aspidosperma indole alkaloids could help guide the development of future cancer therapeutics as well as elucidate their biosynthetic pathways.Histone deacetylases (HDACs), regulating gene expression and multiple cellular activities, are important biomarkers and potential therapeutic targets. In this project, a group of fluorescent S-acetamidomethyl homocysteine-containing molecules were designed and synthesized to monitor HDAC’s activity and elucidate the temporal and spatial dynamics of HDACs in live cells. The free thiol warhead, released from the probe upon deacetylation by HDACs, would trigger an intramolecular Michael Addition to the coumarin-derived fluorophore and induce a blue shift for the fluorescence, which could be applied to the quantitative ratiometric study of HDACs. It provides a modular platform for discovering and developing class-/isoform-specific HDAC probes and future therapeutic lead compounds through modifications of fluorophores, C-terminal amino acids, and the capping acyl groups. / Chemistry

The increasingly complex world of illicit chemistry has created a need for rapid, selective means of determining the threat posed by new drugs as they are encountered by law enforcement personnel. To streamline this process, the entirety of the problem, from the production of illicit drugs all the way to the final analysis have been investigated. A series of N-alkylated phenethylamine analogues were synthesized in a shotgun method and subjected to direct-infusion analysis. A range of products were detected without the need for time-consuming purification steps, which was extended to novel pharmacological and receptor-binding assays where mass spectrometry is used as a detector. This direct-infusion technique was also applied to studies of methamphetamine and fentanyl production to preemptively determine improvements to common reaction conditions and explore the origins of common impurities. The ability to utilize these rapid techniques directly from the fume hood has also been critically reviewed to highlight gaps in current research and opportunities for improvement. When combined, these studies seek to provide a means for rapid, simplified analysis of illicit drugs to improve the quality of data and dramatically increase throughput.

Iminosugars are carbohydrate mimics, where the endocyclic ring oxygen has been replaced by nitrogen. This substitution affords these compounds their inhibitory activity towards sugar-processing enzymes (glycosidases) and, as a consequence, their chemotherapeutic potential in the treatment of a broad range of diseases. Several iminosugars are currently in clinical trials or have entered the market as approved drugs. This has consequently led to increasing levels of research into their synthesis and application, both in terms of the development of efficient methodology to access naturally occurring examples, and also to elaborate novel scaffolds. The presence of multiple chiral centres within iminosugars provides a considerable challenge in accessing these targets by asymmetric means, whereas carbohydrates pose a more attractive chiral pool. As such the majority of literature methods have employed this latter method. The focus of the thesis is on the elaboration of robust methodologies to access both naturally occurring and novel iminosugars, and their precursors, from readily available carbohydrate starting materials. Chapter 1 presents an introduction to iminosugars, including an overview of glycosidase inhibition by this class of sugar-mimic, their historical medical usage and the basis for their potential employment in treating diabetes, lysosomal storage disorders (LSDs) and cancer. This chapter also gives a general review of the methods employed in the literature for the assembly of iminosugar scaffolds. Chapter 2 is concerned with the synthesis of iminosugars from the carbohydrate glucuronolactone. This versatile chiron has previously allowed for access to many homochiral targets, and in this thesis is used to access DGJNAc on a gram-scale. This iminosugar has been shown to be a potent α-N-acetylgalactosaminidase inhibitor and is potentially extremely valuable in the treatment of late-stage cancer. Both enantiomers of glucuronolactone are also utilised in the divergent synthesis of every stereoisomer of two classes of five-membered iminosugars; the pyrrolidines (including DMDP), and the proline amides. These compounds demonstrate remarkable biological activity against a panel of glycosidases and hexosaminidases, allowing for the analysis of the structure-activity relationship between these compounds and the target enzymes. Chapter 3 describes the development of a novel, one-pot methodology - a tandem Strecker reaction and iminocyclisation - for the assembly of trihydroxy piperidine α-iminonitriles from a range of unbranched and branched pentose monosaccharides. These piperidine α-iminonitriles are precursors to pipecolic acids which may also be potentially valuable targets in the treatment of cancer.

This work describes developments in new azetidine and azetine chemistry; specifically, methods developed for the introduction of functionality α- to nitrogen in both ring systems, with additionally in situ formation of the latter system, from azetidine substrates. Chapter 1 discusses the growing importance of azetidines, and the current methods available for making substituted azetidines by ring formation. Further discussion comprises of current sp³ C–H activation approaches α- to nitrogen in heterocyclic compounds as potential methods for sp³ C–H activation on azetidines to give substituted azetidines. Previous work by the Hodgson group in this area is detailed. Chapter 2 describes the advance made towards 2,3-disubstituted azetidines using the thiopivaloyl protecting/activating group, where the latter plays a key role. Optimisation, scope, selectivity and mechanistic insight into the α-deprotonation–electrophile trapping of a 3-hydroxy azetidine system is discussed, which successfully gives access to a range of 3-hydroxy-2-substituted azetidines. Preliminary investigations with 3-alkyl-2-substituted azetidines are also described. Chapter 3 describes the development of a straightforward protocol to make 2-substituted-2- azetines, a rarely studied and difficult to access 4-membered azacycle subclass, from readily accessible azetidine starting materials using α-deprotonation–in situ elimination followed by further α-lithiation–electrophile trapping. Extension of this methodology by transmetallation from the intermediate organolithium to the organocuprate, resulting in greater electrophile scope, is also described.