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Item Exploitation of Biomass for Applications in Sustainable Materials Science(North Dakota State University, 2019) Serum, Eric MichaelBiorefinery may be defined as the process of accessing chemical commodities from living systems; consequently, biomass becomes the antecedent for renewable resources through biorefinery. Advantages to this process over petroleum refinery include: (1) increased potential for sustainable products, (2) increased diversity in chemical structure including heterocycles, and (3) potential for regional resource independence. Despite these clear advantages, adoption of biorefined commodities can be limited by the risk associated with small initial application portfolios and concomitant uncertainties. The strategies adopted by our dynamic and collaborative research team entail continuous engagement of those issues by: (1) preparing renewable polymers, (2) chemical diversification of biomass-derived platform chemicals, (3) direct modification of biopolymers, and (4) development of petroleum replacements. Battling the inveterate proclivity towards portents of gloom need not solely justify investigations into biorenewable feedstock chemicals; the ramifications of bioinspired molecular inquiry create opportunities to go beyond mere sustainability through innovation. This dissertation includes specific examples which illustrate utilization of three types of biomass: (1) oil seeds, (2) lignin, and (3) carbohydrates. Each class of biomass-derived materials offered unique advantages as well as challenges associated with their varied structures. The presentation has been divided into five sections: (1) biomass, sustainable chemistry and design thinking; (2) styrene replacements and their application in renewable vinyl ester thermosets; (3) catalyst-free lignin valorization by acetoacetylation; (4) chemical diversification of 5-(hydroxymethyl)furfural; (5) valorization of cellulose-derivable platform chemicals by cycloaddition with a potentially bioderivable reactive intermediate: benzyne.Item 4-Dimethylamino Pyridine (DMAP) Catalyst with Fluxional Chirality: Synthesis and Applications(North Dakota State University, 2016) Ma, GaoyuanOrganocatalysis using small organic molecules to catalyze organic transformations, has emerged as a powerful synthetic tool that is complementary to metal-catalyzed transformations and remarkably promote stereoselective synthesis. Our group has designed useful templates, ligands, and additives that use fluxional groups to control and/or enhance stereoselectivity in a variety of asymmetric transformations. A key feature of this strategy is that the size of the fluxional substituent can be varied readily. As an extension of this strategy we became interested in developing efficient and broadly applicable and adjustable 4-dimethylaminopyridine (DMAP) organocatalysts. In our design, we surmised that a fluxional group would be effective in relaying stereochemical information from the fixed chiral center to the catalytic center of DMAP. Presented herein the synthesis of novel fluxionally chiral DMAP catalysts and their application in the acylative kinetic resolution of secondary alcohols and axially chiral biaryls, dynamic kinetic resolution of chiral biaryls with low rotation barriers and allylic substitution reactions. In the beginning, a comprehensive study of the chiral relay concept in enantioselective transformations was reviewed and the historic and current story of the chiral relay concept is covered. The design and synthesis of fluxionally chiral 4-dimethylaminopyridine catalysts was introduced. The key issues addressed in this chapter include the design concept regarding a stereoselective fluxionally 4-dimethylaminopyridine catalyst and muti-step synthesis strategies developed for catalyst synthesis. The development of fluxionally chiral 4-dimethylaminopyridine catalysts in the acylative kinetic resolution studies of secondary alcohols as well as axially chiral biaryls is investigated. Six different secondary alcohols are resolved with good selectivity factors (6-37) and ten biaryl substrates are resolved with moderate to high selectivity factors (10-51). Dynamic kinetic resolution has more practical applications to organic synthesis than simple kinetic resolution. The dynamic kinetic resolution of atropisomeric biaryls using the novel fluxionally chiral 4-dimethylaminopyridine catalysts was explored and the corresponding acylated products were obtained with 11-80 %ee. The newly designed DMAP catalysts containing fluxional groups as a stereocontrol unit could also be effectively applied as a nucleophilic catalyst in asymmetric allylic aminations. A range of α-methylene-β-amino esters were obtained with good yields and selectivities (up to 72 %ee).Item Investigating the role of BECN2 CCD interactions in canonical and non-canonical autophagy(North Dakota State University, 2024) Bueno, ElizabethAutophagy is a conserved cell-survival pathway wherein old, damaged or harmful cellular components are surrounded by a double membrane vesicle called the autophagosome for lysosomal degradation and recycling. All eukaryotes have a conserved BECN homolog, a key coiled-coil domain (CCD)-containing autophagy protein. Mammals are unique as they have two BECN homologs, BECN1 and BECN2, both of which have the same domain architecture and function in autophagy. BECN2 has been shown to also function in non-canonical autophagy. My research focused primarily on investigating selected interactions of the BECN2 CCD. We investigated interactions of the BECN2 CCD with two CCD-containing proteins known to bind to BECN1: UVRAG, an important autophagy protein, and TAB2, a protein important for inflammatory responses. We show that the BECN2 and UVRAG CCDs interact, but were unable to purify stable complexes for structural studies. In comparison, the CCDs of BECN2 and TAB2 bind with an affinity tighter than that of BECN2 homodimerization, forming a well-folded elongated heterodimer. These preliminary results provide information regarding interactions that enable BECN2 to regulate autophagy, in a manner analogous to BECN1. We also show that, unlike BECN1, BECN2 facilitates non-canonical autophagy involving ATG9A-bearing vesicles, via interactions with the STX6 SNARE domain. We show that the STX6 SNARE domain binds to BECN2 residues 181-250 (BECN2(181-250)) within the BECN2 CCD. The STX6 SNARE is disordered in the absence of interacting partners but becomes helical when in complex with BECN2. The BECN2(181-250):STX6 SNARE complex is also more stable than either the BECN2(181-250) or the BECN2 CCD homodimer. We determined the 2.65 Å X-ray crystal structure of the STX6 SNARE bound to BECN2, showing that the complex is a heterotrimeric helical bundle, consisting of one helix comprising BECN2(181-250) and two STX6 SNAREs that are anti-parallel to each other. The heterotrimer interface is stabilized by 15 layers of three residues, each contributed by a different helix, of which, six layers are entirely hydrophobic, including two consisting of three leucines each. We verified the importance of these hydrophobic layers using point mutations and affinity pulldowns, showing that mutations of the hydrophobic layers either significantly or completely disrupt the interaction between BECN2(181-250) and STX6 SNARE domain. This 3-helix bundle likely represents an intermediate during the formation of the full SNARE complex, thereby providing mechanistic insights into the process by which ATG9A-bearing vesicles transport lipids to the growing phagophore. Together these studies help explain the role of the BECN2 CCD in canonical and non-canonical autophagy, providing clues as to why mammals have two BECN paralogs.Item Achiral Templates in Asymmetric Catalysis: Applications in Construction of All Carbon Quaternary Centers(North Dakota State University, 2018) Subramanian, HariharaputhiranConjugated olefins are readily available and inexpensive starting materials and their functionalization offers a rapid access to many important building blocks for organic synthesis. The functionalization of these olefins by asymmetric catalytic methods for the formation of C-C and C-X bonds is an active area of research. Major advances in this field are not only triggered by the development of new catalysts but also by engineering of new acceptor olefins. In our lab we have successfully developed acceptor olefins appended to alkoxyimidazoles as a novel template. Using these templated acceptors, we demonstrated methodologies to construct all carbon-quaternary centers, one of the demanding tasks in synthetic methodology development. We have also made significant efforts towards understanding the solution structures of the intermediates involved in the catalytic asymmetric reactions developed in our lab. In chapter 1, the importance of templated acceptors in the field of chemical synthesis with special emphasis on acylimidazoles is reviewed. The versatility of the N-alkylimidazole templates is showcased by their utility in several organic transformations. In chapter 2, modes of activation of acceptor olefins by catalysts, need for templated acceptors and challenges associated with designing an asymmetric catalytic process is described. Our approach in designing novel acceptors based on imidazoles is also described. In chapter 3 the synthetic utility of these novel N-alkoxyimidazole based acceptors is shown by enantioselective construction all carbon quaternary centers by Lewis-acid catalysis. We also compare the effectiveness of other templates such as oxazolidinone and N-methylimidazoles in the Lewis-acidic catalyzed Friedel-Crafts alkylation reaction. The effect of various parameters such as Lewis acid, chiral ligands, temperature, additives and solvents on the conjugate addition of Friedel-Crafts nucleophiles are presented in this chapter. In chapter 4, our research efforts toward understanding solution structures of intermediates involved in catalytic asymmetric reactions are presented. A combination of Diffusion Ordered Spectroscopy (DOSY), heteronuclear NMR spectroscopy, mass spectrometry and X-ray crystallography has been used to study the solution structure of intermediates involved in asymmetric catalytic reactions. In chapter 5, a future outlook on templated chemistry developed in our laboratory is presented. Some preliminary results pertinent to future projects are presented.Item Interactions of Light with Organic Chromophores: A Photochemical and Photophysical Investigation(North Dakota State University, 2018) Clay, Anthony MarcelOver the past century, light has emerged as a useful tool finding utility in various fields such as device fabrication, the medical field, as well as utility as an energy source. Chemist have adopted this abundant energy source to do work in material applications and to mediate simple chemical transformations. In regards to the latter, light utilized as a traceless benign reagent for organic transformations has proven fruitful and therefore unequalled in its ability to afford structural complexity from simple starting material(s). Photon absorption of the correct energy elevates organic molecules to a high energy excited state of “short” finite lifetime. In order to afford photoproducts of high selectivity or merely dictate the outcome of a desired photoreaction, control must exist during this short-lived excited state. This dissertation describes a complementary approach to already established photochemical methodologies by which excited state control can be employed in efforts to afford photoproducts of enhanced selectivity. By employing the NEER principle (Non-Equilibrating Excited State Rotamers) and exploiting axial chiral substrates and thereby implementing rotamer control in the excited state, photoproducts of high chemoselectivity, diastereoselectivity and enantioselectivity can be accessed. Additionally, by judicious choice of chromophore control over the excited state process can be gained affording materials of desired physical properties. It was determined that altering the functionality of bio-based feedstocks afforded photoresponsive molecules with altered photoreactivity. Photoacids and photoinitiators were synthesized and their photophysical properties were investigated. Photoinitiators were evaluated for their efficacy towards photochemical polymerization. This dissertation details synthesis, characterization and photophysical investigations of various organic chromophores in efforts to provide mechanistic rationale regarding atropisomeric photoreactions and utility of biobased photoresponsive molecules.Item Stereoselective Carbon-Carbon Bond Construction Using Indium and Bismuth: New Methods in Green Chemistry(North Dakota State University, 2012) Balasubramanian, NarayanaganeshSelective chemical reactions that can be accomplished with minimal waste using non-toxic catalysts and reagents will allow for new greener chemical processes for future environmentally sustainable technologies. This work will present an account on enantioselective nucleophilic addition to carbon-nitrogen and carbon-oxygen double bonds mediated by the environmentally benign indium and bismuth metals. The dissertation entitled “ Stereoselective carbon-carbon bond construction using indium and bismuth: new methods in green chemistry” is divided into three chapters Chapter one outlines a few concepts in green chemistry and background information on the vital role of indium and bismuth in present day organic synthesis. The development of a procedure for using allylic alcohol derivatives for ümpolung type allylation of chiral hydrazones is described in chapter two. This procedure affords homo allylic amines in good yields and excellent diastereoselectivity. An interesting study with respect to the mechanism of the reaction has been conducted. Switching gears towards the end of this chapter, ultrasound-promoted indium-mediated Reformatsky reaction of chiral hydrazones is described. This chapter describes a potential green chemical method for making β-amino acids. In chapter three, indium mediated enantioselective allylation of α-ketoamides is described. The developed procedure is applied in the allylation of linear and cyclic α- ketoamides. Overall, an operationally simple and environmentally benign stratergy development has been explained. The later section of this chapter discusses the Reformatsky reaction in isatin series using the same protocol applied for imines. To fully explore any organometallic reaction, it is important to understand the mechanism with which they operate at molecular level. Chapter three outlines some of our attempts to understand the enantioselective indium and bismuth mediated allylation and the nature of chiral- indium and bismuth Lewis acids. A postive non-linear effect has been observed and studied in bismuth-mediated allylation. Key findings obtained in each chapter and their implications to the future of our research is also discussed in each chapter. The chapters also details on what we understood about the potentials of organoindium and organobismuth chemistry towards developing new green chemical methods.Item Applications of Dithieno [3,2-B2',3'-D] Pyrroles and its Analogues to Conjugated Materials(North Dakota State University, 2014) Mccausland, Casey B.The promise of semiconducting materials with tunable electronic and optical properties that share the same mechanical flexibility, low production costs and ease of processing displayed by traditional polymers fuels the intense interest seen in developing devices employing conjugated polymers (CPs). Many examples of -conjugated systems have been studied and reported in the literature, of which Rasmussen and coworkers have advanced the field with their work involving N-alkyl, N-aryl, and N-acyl-dithieno[3,2-b:2',3'-d]pyrroles (DTPs). Using DTP as a template current investigations are targeting two analogues: pyrrolo[3,2-d:4,5-d’]bisthiazole (PBTz) and difuro[3,2-b:2’,3’-d]pyrroles (DFP). In comparison to polymers of DTP, the electron-deficient nature of thiazoles is known to stabilize HOMO levels of PBTz-based polymers. Furan-based oligomers exhibit many of the properties displayed by DTPs and it is a reasonable assumption that the properties of DFPs would be comparable to DTPs. The synthesis and characterization of PBTz and DFPs and a comparison to DTP-based materials will be presented.Item Visual Detection of Cancer Biomarkers with Aptamer-Functionalized Gold Nanoparticles(North Dakota State University, 2015) Gurung, Anant SinghCancer biomarkers may hold the key for the early detection of cancer, distinguishing between benign and malignant cells, and differentiating tumor types. The detection of cancer biomarkers can be used for cancer diagnosis, monitoring the response to therapy, and providing real-time prognostic information for cancer patients. Most of the traditional cancer biomarker detections are based on specific antibodies or expensive instrumentations/complex operations. In this dissertation, we have developed aptamer-based bioassays for visual detection of cancer protein biomarkers with low-cost and short assay time. Aptamers with specific sequences are immobilized on gold nanoparticle (AuNP) surface through self-assembling process. Combining the excellent molecular recognition properties of aptamers and the unique optical properties of AuNPs, colorimetric assay for carcinoembryonic antigen (CEA) and mucin 1 (MUC1) (breast cancer biomarkers) and lateral flow assay for platelet-derived growth factor (PDGF) and thrombin have been developed. The methods were applied to detect protein biomarkers in human plasma and blood successfully. The sensitivities of the assays were further improved by using enzyme-coated AuNP dual labels and designing the cross-flow test strips. The developed approaches have the potential to be extended for detecting other biomarkers, and show great promise for point-of-care or in-field detection.Item Synthesis, Photophysics, Reverse Saturable Absorption, and Photodynamic Therapy of Iridium(III) Complexes Bearing Different Degrees of p-conjugation on the Ligands(North Dakota State University, 2019) Liu, BingqingOctahedral d6 iridium(III) complexes possess rich photophysical properties. The most distinct phtotphysical properties of the Ir(III) complexes are their high triplet excited-state formation quantum yields, long-lived triplet excited states, and feasile structural modifications. To better understand the impact of ligand -conjugation on the photophysics and reverse saturable absorption (RSA) or PDT of the Ir(III) complexes, six series of Ir(III) complexes bearing various bidentate or terdentate ligands were designed and synthesized in this dissertation. In Chapter 1, the photophysical principles, typical electronic transitions in Ir(III) complexes, the prototypes of the tris-bidentate and bis-terdentate Ir(III) complexes, the state-of-art on exploring Ir(III) complexes for RSA and PDT, and the materials design criteria are reviewed. In Chapters 2 and 3, sixteen cyclometalated cationic Ir(III) complexes were synthesized and investigated to understand how the benzannulation site on diimine ligands influences the characteristics of the excited states of these complexes. The site−dependent benzannulation influenced the spectral feature and intensity of the triplet transient absorption (TA) and T1 lifetimes, and their RSA strength. In Chapter 4, ten 2-phenylpyridine based Ir(III) complexes with varied degrees of π-conjugation and sites of benzannulation were synthesized. Benzannulation at the different sites of 2-phenylpyridine exerted a different effect on the energies of the S1 and T1 excited states, the TA spectral features, and the RSA performances of the complexes. In Chapter 5, the synthesis, photophysics, and RSA of three Ir(III) complexes with different degrees of -conjugation on the diimine ligands were discussed. The impact of this structural variation on the RSA at 532 nm was demonstrated. In Chapter 6, five Ir(III) complexes bearing terpyridine-capped fluorenyl bridging ligands and different terminal terdentate ligands were investigated to reveal the effects of different terminal ligands on the S1 and T1 excited states. Their in vitro theranostic PDT effects toward the SKMEL28 cells were evaluated. In Chapter 7, the photophysics and in vitro PDT studies of five neutral Ir(III) complexes incorporating BODIPY-substituted N-heterocyclic carbene (NHC) ligands were studied. The attachment position of the BODIPY substituent did not alter the photophysical properties significantly but changed the dark- and photo- cytotoxicity of these complexes toward SKMEL28 cells.Item Designing Ru Catalysts for Selective C-H Bond Oxidation Reactions(North Dakota State University, 2020) Herath, Hashini Nuradha KumariTypically, C-H bond oxidation proceeds via formation of high-valent metal oxo species. Attaining a high oxidation state of the metal complex is critical as it is the key step for many catalytic processes. Understanding ligand effects on structural and electronic changes of the metal complexes towards designing more robust catalysts is an effort of this dissertation. It will highlight initial attempts at developing novel ruthenium (Ru) catalysts and an analysis of their structural, electrochemical and spectroscopic properties. The catalytic behavior of the resulting complexes towards C-H bond hydroxylation reaction will also be shown. Chapter I introduces the background of C-H bond activation and hydroxylation reactions by Ru catalysts. Also, this chapter details the study of C-H bond hydroxylation mechanisms, reaction intermediates, the importance of C-H bond hydroxylation, electronic effects of ligands, and the pioneering work in this field. Chapter II describes development a of new Ru complex containing the pyridine alkoxide ligand, of general formula [Ru(tpy)(pyalk)Cl] (tpy = 2,2’:6’2”-terpyridine, pyalk = 2-(2′-pyridyl)-2-propanol). This chapter outlines the detailed synthesis, structural, electrochemical and spectroscopic properties of the complex by electrochemical techniques, UV Visible spectroscopy, NMR, mass spectrometry and X-ray crystallography. In order to overcome some limitations on project 1, new ruthenium complexes [Ru(MepyPO3H)(tpy)Cl] (1, tpy = 2,2’:6’2”-terpyridine , MepyPO3H = (pyridine-2-ylmethyl)phosphonic acid) and [Ru(bpyPO3H)(bpy)Cl] (2, bpy(PO3H2) = 2,2-bipyridine-6-phosphonic acid, bpy = 2,2-bipyridine) bearing phosphonate ligands were prepared and fully characterized. Catalytic properties of the complexes have been evaluated by testing their ability to catalyze C-H bond oxidation using a variety of sacrificial oxidants.