Theses and Dissertations at Montana State University (MSU)

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The expansion and optimization of ZN(II)-mediated intramolecular metalloamination and subsequent CU(I)-catalyzed functionalization for the construction of pyrrolidines and piperidines
(Montana State University - Bozeman, College of Letters & Science, 2023) Frabitore, Christian Ames; Chairperson, Graduate Committee: Thomas S. Livinghouse; This is a manuscript style paper that includes co-authored chapters.
Nitrogen-containing heterocycles (azacycles) are ubiquitous in pharmaceutical agents. Their ability to moderate and modulate the activity of drugs in the body make them especially powerful, and thus sought after, synthetic targets. While the synthesis of many popular azacycles has been greatly improved in recent years, the production of pyrrolidines and piperidines has not received as much attention despite their standing as the 1st and 5th most common azacycles in FDA-approved drugs. The intramolecular Zn(II)-mediated metalloamination/cyclization of N,Ndimethylhydrazinoalkenes provides structurally diverse pyrrolidines and piperidines with the added advantage of a subsequent functionalization step, efficiently building molecular complexity in one reaction sequence. Herein, this method is optimized and improved by the addition of a new hydrazone reduction method, the inclusion of 1-bromoalkynes in the functionalization step, and multiple key discoveries in the reagents used to effect these transformations. Furthermore, preliminary results adding N,N-dimethylhydrazinoallenes as substrates for this powerful method are presented.
Conversion of biomass sugars to platform chemicals by homogeneous acid catalyst in organic water mixtures
(Montana State University - Bozeman, College of Engineering, 2022) Scheffel, Aidan James; Chairperson, Graduate Committee: Stephanie Wettstein; This is a manuscript style paper that includes co-authored chapters.
Lignocellulosic biomass could serve as an alternative to petroleum for the production of platform chemicals that can be upgraded to bio-based plastics, chemicals, and fuels. The polysaccharides present in the cellular structure of biomass can be hydrolyzed into common sugars, which can be further reacted into important chemical intermediates such as furfural, 5-hydroxymethylfurfural, and levulinic acid. However, current commercial processes typically result in low yields. This work aimed to study the conversion of model sugars (glucose, xylose, and arabinose) into platform chemicals using a homogeneous acid catalyst in a variety of organic-water mixtures, and compare those findings to reactions carried out using biomass under the same conditions. Reactions were performed in 50-50 solvent-water mixtures using sulfolane, tetrahydrofuran (THF), or gamma-butyrolactone (GBL) as the solvent and using a sulfuric acid catalyst. Intermediate wheatgrass was used in the biomass reactions and its composition was determined using standard NREL methods. Similar trends were observed in both pure sugar and biomass reactions in which the solvent choice had little effect on maximum yield of furfural, HMF, or levulinic acid. However, the THF/water solvent achieved maximum yields at lower severities than the other solvent mixtures indicating that a combination of less time, lower temperature, and/or less acid could be used in the THF reactions compared to the others. Compared to previously published research that found the solvent polarity correlated with product yields of furfural in reactions with no acid present, the effects of solvent properties may be minimized by the presence of the acid catalyst. Higher yields were achieved in biomass reactions than in pure sugar reactions, possibly due to unaccounted for reaction pathways or lowering of degradation reaction rates due to a lower initial reactant weight percent.
How biological catalysts activate oxygen to realize its full potential
(Montana State University - Bozeman, College of Letters & Science, 2021) Ellis, Emerald Sue; Chairperson, Graduate Committee: Jennifer DuBois; Daniel J. Hinchen, Alissa Bleem, Lintao Bu, Bennett R. Streit, Quinlan V. Doolin, William E. Michener and Brandon C. Knott were authors and Sam J.B. Mallinson, Mark D. Allen, Melodie M. Machovina, Christopher W. Johnson, Gregg T. Beckham, John E. McGeehan, Jennifer L. DuBois were co-authors of the article, 'Engineering a biocatalyst for demethylation of lignin-derived aromatic aldehydes' in the journal 'Journal of the American Chemical Society Au' which is contained within this dissertation.; Luke MacHale, Robert K. Szilagyi and Jennifer L. DuBois were co-authors of the article, 'How chemical environment activates anthralin and molecular oxygen for direct reaction' in the journal 'Journal of organic chemistry' which is contained within this dissertation.; Dissertation contains an article of which Emerald Sue Ellis is not the main author.
Dioxygen is a potent oxidant, inexpensive, and environmentally-friendly compared with most industrial oxidants, but intrinsic energy barriers to reaction limit its utility. Biological catalysts can activate O 2 by generating dangerous reactive oxygen species intermediates. The fundamental chemistry of two diverse O 2-utilizing enzyme systems were examined: GcoAB, a cytochrome P450 which catalyzes the O-demethylation of aromatic alcohols using heme to activate O 2, and NMO, an antibiotic biosynthesis monooxygenase which catalyzes cofactor-independent monooxygenation of an organic substrate. The enzyme active site environments and the reactions catalyzed therein were investigated with mutagenesis, X-ray crystallography, molecular dynamics simulations, fluorescence and UV/visible spectroscopy, cyclic voltammetry, electrode-based measurement of O 2 consumption, high-performance liquid chromatography, and simulations of homogenous solvation using quantum chemistry composite methods. The substrate range of GcoAB was expanded by rational design engineering to include two aromatic aldehydes commonly found in chemically-processed lignin. Only a single-point mutation was needed for GcoAB to catalyze demethylation of each new substrate. The reaction catalyzed by NMO can be called 'substrate-assisted' because the substrate mimics the role of the organic cofactor flavin in activating O 2. The physics of this reaction were probed using Marcus Theory, which relates the activation energy of the reaction to the free energy and the reorganization energy. By measuring the differences in the activation energy and free energy of the reaction within and without the enzyme, we found that the enzyme mainly acts on the reorganization energy term. The reaction was then examined in several homogenous solvents chosen based on their chemical similarity to individual amino acids. Homogenous solvation is much less computationally expensive to model than a protein active site, especially at higher levels of theory. By this approach, we discovered a plausible mechanism by which the chemical environment alone can boost the O 2-activating capacity of NMO's substrate--particularly by stabilizing the deprotonated anion which can transfer an electron to O 2 more easily than the neutral molecule. In summary, this work demonstrates that, while cofactors are responsible for activating O 2 in most oxidases, full appreciation of how an oxidase catalyzes reactions requires that neither the enzyme environment nor the substrate be ignored.
Organocatalytic approaches to claisen rearrangements of acid sensitive substrates
(Montana State University - Bozeman, College of Letters & Science, 2021) Casey, Aoife; Chairperson, Graduate Committee: Matthew Cook
Cyclopentanes and cyclopentenes are present in many natural products and pharmaceuticals. Despite their presence in many natural products and pharmaceuticals there are few general methods to synthesize highly functionalized 5-membered carbocycles. Using substituted allyl vinyl ethers, highly functionalized 5-membered carbocycles can be accessed through a Claisen rearrangement followed by an intramolecular Sakurai reaction. Due to the acid sensitive nature of these allyl vinyl ethers, Lewis acid catalysis is not a viable reaction pathway but the use of H-bond donors as organocatalysts is an attractive method to develop a synthetic methodology to access 5-membered carbocycles. Through NMR and computational studies, the activation parameters of a these HBD catalyzed Claisen rearrangement has been studied and further knowledge into the mechanism of these reaction pathways has been gained.
Effect of aryldimethylphosphine electronics on rate of oxidative addition of aryl electrophiles at Ni 0
(Montana State University - Bozeman, College of Letters & Science, 2019) Giroux, Michael James; Chairperson, Graduate Committee: Sharon Neufeldt
An analysis of kinetics related to the selectivity of aryldimethylphosphine-nickel complexes for reaction at carbon--chlorine versus carbon--tosylate bonds is reported. A series of aryldimethylphosphine ligands bearing electronically-varied substituents were investigated. The rate constants for oxidative addition of ligand-nickel complexes to either aryl chloride or aryl tosylate substrates were calculated. These rate constants were used to construct Hammett plots describing the susceptibility of oxidative addition at both types of electrophiles to electronic influence from the ligand. Oxidation of catalyst to aryl tosylates yields a plot with a negative slope, while addition to aryl chlorides produces a positive slope. With this, we see that electron donating groups accelerate the addition of catalyst to aryl tosylates, while electron withdrawing groups may change the rate determining step of addition to aryl chlorides.
Aluminate spinels for use as catalyst enhancement of solid oxide fuel cells
(Montana State University - Bozeman, College of Engineering, 2019) Zachariasen, Marley Sarria; Chairperson, Graduate Committee: Stephen W. Sofie
The growing necessity to find clean, efficient power sources has led to the advancement of technology in various fields of renewable energy. The field of electrochemical energy conversion, better known has Hydrogen Fuel Cell energy, has shown promise in replacing fossil fuels. This technology is fuel flexible, emits no harmful products, and generates power at efficiencies double or triple that of the Carnot combustion cycle widely used in automotive propulsion and large scale combustion power generation. However, the power production is limited by the short life expectancy of the components used to convert the chemical energy of the fuel into an electrical current. Two mechanisms work simultaneously during fuel cell operation to degrade the anodic electrode of the cell. The coarsening of the catalyst metal particles reduces the total active area of the anode while contaminants from the fuel deposit on the anodes remaining active areas, blocking fuel from the locations where the reaction takes place. Recent studies have shown that doping the industry standard fuel cell anode, Ni/YSZ, with a compound known as Aluminum Titanate (ALT) increases the overall resiliency of the cell. When heat-treated, ALT disassociates in to aluminum and titanium oxides which are then able to go into solution with the material components of the anode. These new secondary phases were shown to increase the strength and overall power output of the cell while decreasing the rate at which the catalyst coarsens. The electrochemical enhancements were attributed to the aluminum based secondary phase, known as nickel aluminate, a spinel structured compound which undergoes unusual reduction and catalytic transport kinetics. This work assesses the viability of transferring these enhancement effects to various other cermet anode systems by individually exchanging the ceramic ion conductor and metal electrocatalyst. The electrochemical performance and degradation, as well as mechanical properties, were evaluated for Ni/GDC anodes doped with ALT and alumina. In addition, synthesis and reduction behavior of cobalt and copper aluminate spinels were analyzed for similarities with nickel aluminate.
Solid acid catalysts for biomass and sugar upgrading to furans
(Montana State University - Bozeman, College of Engineering, 2019) Romo, Joelle Elise; Chairperson, Graduate Committee: Stephanie Wettstein; Nathan V. Bollar, Coy J. Zimmermann and Stephanie G. Wettstein were co-authors of the article, 'Conversion of sugars and biomass to furans using heterogeneous catalysts in biphasic solvent systems' in the journal 'ChemCatChem' which is contained within this thesis.; Ting Wu, Xinlei Huang, Jolie Lucero, Jennifer L. Irwin, Jesse Q. Bond, Moises A. Carreon and Stephanie G. Wettstein were co-authors of the article, 'SAPO-34/5A zeolite bead catalysts for furan production from xylose and glucose' in the journal 'ACS omega' which is contained within this thesis.
Platform chemicals derived from biomass provide a viable alternative to petroleum-based fuels, chemicals, and materials. The efficient production of chemical building blocks, such as 5-hydroxymethylfurufral (HMF) and furfural, requires an optimized catalyst and reaction system, as well as an efficient system in which catalysts and products can be easily recovered. While homogeneous acid catalysts have historically been a popular choice for furan production, additional safety, material, and corrosion considerations motivates the exploration of heterogeneous solid acid catalysts. Furthermore, biphasic reaction systems, which use an organic solvent to continuously extract products, have shown increased furan yields over aqueous and monophasic systems and can allow for easy product recovery if the boiling point is selected carefully. One class of heterogeneous catalysts known as zeolites, has unique potential for furfural and HMF production with its controlled acidic and structural properties. A novel SAPO- 34/5A zeolite bead is presented in this thesis, showing promise in catalyst design for activity, product selectivity, and stability. The combination of optimized solvent systems with carefully designed solid acid catalysts lays a framework for the progression of platform chemical production from biomass. Additionally, a comprehensive review of heterogeneous catalysts for furan production in biphasic systems is presented here, which informs decisions on optimized solvent selection.
The reactive form of a C-S bond-cleaving CO 2-fixing flavoenzyme
(Montana State University - Bozeman, College of Letters & Science, 2019) Mattice, Jenna Rose; Chairperson, Graduate Committee: Jennifer DuBois; Thesis includes a paper of which Jenna R. Mattice is not the main author.
Atmospheric carbon dioxide (CO 2) is used as a carbon source for building biomass in plants and most engineered synthetic microbes. Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), the most abundant enzyme on earth, is used by these organisms to catalyze the first step in CO 2 fixation. 1,2 Microbial processes that also fix carbon dioxide or bicarbonate have more recently been discovered. My research focuses on a reaction catalyzed by 2-KPCC (NADPH:2-ketopropyl-coenzyme M oxidorectuase/ carboxylase), a bacterial enzyme that is part of the flavin and cysteine-disulfide containing oxidoreductase family (DSORs) which are best known for reducing metallic or disulfide substrates. 2-KPCC is unique because it breaks a comparatively strong C-S bond, leading to the generation of a reactive enolacetone intermediate which can directly attack and fix CO 2. 2-KPCC contains a phenylalanine in the place where most other DSOR members have a catalytically essential histidine. This research focuses on studying the unique reactive form of 2-KPCC in presence of an active site phenylalanine.
A molecular, structural, and cellular multiple-level study aimed at understanding the unique reaction catalyzed by the last enzyme in the heme-biosynthesis pathway of gram-positive bacteria, coproheme decarboxylase (CHDC)
(Montana State University - Bozeman, College of Letters & Science, 2018) Celis Luna, Arianna I.; Chairperson, Graduate Committee: Jennifer DuBois; Bennett R. Streit, Garrett C. Moraski, Timothy D. Lash, Gudrun S. Lukat-Rodgers, Kenton R. Rodgers and Jennifer L. DuBois were co-authors of the article, 'Unusual peroxide-dependent, heme-transforming reaction catalyzed by hemQ' in the journal 'Biochemistry' which is contained within this thesis.; George H. Gauss, Bennett R. Streit, Krista Shisler, Garrett C. Moraski, Kenton R. Rodgers, Gudrun S. Lukat-Rodgers, John W. Peters and Jennifer L. DuBois were co-authors of the article, 'A structure-based mechanism for oxidative decarboxylation reactions mediated by amino acids and heme propionates in coproheme decarboxylase (hemQ)' in the journal 'Journal of the American Chemical Society' which is contained within this thesis.; Dissertation contains two articles of which Arianna I. Celis Luna is not the main author.
Heme b is one of nature's most ancient and versatile co-factors and is essential for aerobic life. As such, heme b is synthesized by almost every living organism and plays a major role in bacterial virulence. A pathway for heme b biosynthesis, which is unique to some of the most primitive gram-positive bacteria including many important pathogens, was recently discovered. This pathway, now known as the coproprophyrin-dependent (CPD) branch, ends in a step catalyzed by an unusual enzyme known alternately as coproheme decarboxylase (ChdC) or HemQ. This research aimed to understand ChdC function at the molecular, structural, and cellular levels. Using the ChdC enzyme from Staphylococcus aureus (SaChdC) and a variety of biochemical and analytical tools (conventional and stopped-flow UV-Vis spectroscopy, resonance Raman, HPLC, LC-MS, site-directed mutagenesis, EPR, and X-ray crystallography), the work presented here describes how the coproheme substrate is accommodated in the SaChdC active site and poised for reactivity. The cumulative results show that ChdC catalyzes the oxidative decarboxylation of coproheme III to generate heme b in a sequential and clock-wise fashion, generating harderoheme III in the process. This reaction is H 2 O 2-dependent and the mechanism involves the formation of the high-valent Fe(IV) intermediate (Compound I) and a tyrosine radical (Tyr °). The coproheme-bound ChdC structure revealed a helical-loop that is flexible and moves in towards the active site in the presence of substrate. This loop is hypothesized to act as an 'active site gate' which mediates substrate entry and product egress. Due to the cytotoxicity of heme and its porphyrin precursors, we proposed that the metabolite flux in this pathway is controlled by transient protein-protein interactions. Using the UV-Vis characteristics of porphyrins and phenotype characterization of the deltachdC knock-out strain of S. aureus complemented with ChdC point mutants, we present preliminary evidence for an interaction between ChdC the preceding enzyme of the pathway, CpfC. The same approaches also implicated potential interactions between ChdC and an unidentified heme-chaperone, which delivers heme to its final cellular destination. We propose that this chaperone is HemW. Experiments to test this hypothesis are outlined. This work elucidates yet different way that nature has equipped cells to perform radical chemistry in order to accomplish essential molecule transformations, such as that of decarboxylation and the simultaneous generation of CO 2, and emphasizes the importance of substrate/product post-catalysis cellular trafficking.
Characterization of CpI and CpII [FeFe]-hydrogenases reveals properties contributing to catalytic bias
(Montana State University - Bozeman, College of Letters & Science, 2016) Artz, Jacob Hansen; Chairperson, Graduate Committee: John W. Peters; Dissertation contains two articles of which Jacob Hansen Artz is not the main author.; David W. Mulder, Michael W. Ratzloff, Saroj Poudel, Axl X. LeVan, S. Garrett Williams, Michael W. W. Adams, Anne K. Jones, Eric S. Boyd, Paul W. King and John W. Peters were co-authors of the article, 'Potentiometric EPR spectral deconvolution of CPI [FeFe]-hydrogenase reveals accessory cluster properties' submitted to the journal 'Journal of the American Chemical Society' which is contained within this thesis.; David W. Mulder, Michael W. Ratzloff, Saroj Poudel, Axl X. LeVan, Michael W. W. Adams, Eric S. Boyd, Paul W. King, and John W. Peters were co-authors of the article, 'EPR and FTIR spectroscopy provides insights into the mechanism of [FeFe]-hydrogenase CPII' submitted to the journal 'Journal of the American Chemical Society' which is contained within this thesis.
The need for food, fuel, and pharmaceuticals has been increasing at a growing rate as the world's population increases and lifestyles improve. All of these needs are highly energy dependent, and, to a significant degree, rely on an inefficient use of fossil fuels. In order to break free of this dependence, new understanding is required for how to efficiently generate the products humanity needs. Here, a model system of two closely related [FeFe]-hydrogenases, CpI and CpII, is employed in order to understand how biology is able to efficiently control the formation of reduced products, in order to further delineate the limits of control, and the extent to which biology may be co-opted for technological needs. CpI, one of nature's best catalysts for reducing protons to hydrogen gas, is compared to CpII, which functions catalytically to oxidize hydrogen to protons and electrons. Oxygen sensitivity, midpoint potentials, catalytic mechanisms, and catalytic bias are explored in-depth using electron paramagnetic resonance, Fourier Transform Infrared spectroscopy, and protein film voltammetry. CpI and CpII have been found to function under different metabolic conditions, and key amino acids influencing their distinct behavior have been identified. The conduit arrays of hydrogenases, which direct electrons to or from the active site, have been found to have distinct midpoint potentials in CpII compared to CpI, effectively reversing the favored electron flow through CpII in comparison to CpI. In order to probe the contributions of the protein framework on catalysis, analysis of site-specific amino acid substituted variants have been used to identify several determinants that affect the H-cluster environment, which contributes to the observed differences between CpI and CpII. This has resulted in a deeper understanding of the hydrogenase model system and the ability to directly influence catalytic bias. Thus, the work presented here represents key progress towards developing unidirectional catalysts, and demonstrates the possibility of targeted, rational design and implementation of unidirectional catalysts.

Theses and Dissertations at Montana State University (MSU)

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