Theses and Dissertations - Department of Chemistry & Biochemistry

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Air-stable palladium(II) precatalysts: synthesis, properties, and applications in cross-coupling reactions
(University of Alabama Libraries, 2017) Barnett, Kerry Lynn; Shaughnessy, Kevin H.; University of Alabama Tuscaloosa
Palladium catalyzed cross-coupling reactions are a versatile tool in organic chemistry to produce small molecules. Current research interests involve the development of new catalyst systems for various palladium catalyzed reactions. Previous work has suggested the active species for palladium-catalyzed cross-coupling reactions to be a mono-ligated palladium(0) species when sterically demanding ligands are used. Therefore, the my work focused on the synthesis of precatalysts with an established 1:1 L:Pd. Specifically, we were focused on the synthesis of mono-ligated palladium(II) precatalysts of general formula [(R_3P)PdCl_2]_2, using di-tert-butylneopentylphosphine (DTBNpP), tert-butyldineopentylphosphine (TBDNpP), and trineopentylphosphine (TNpP) as ligands. Under optimized conditions, both [(DTBNpP)PdCl_2]_2 and [(TNpP)PdCl_2]_2 were effective precatalysts for the Suzuki cross-coupling of a wide range of aryl bromides. Comparison studies with the air-stable precatalysts versus the in-situ generated catalyst showed the precatalysts to have improved conversions and higher rates of reaction under both inert and ambient atmospheres. The precatalyst activation pathways were investigated by 31P NMR spectroscopy. The spectra obtained from 31P NMR experiments revealed a side reaction resulting in a catalytically inactive palladacycle species. The results obtained from the mechanistic investigations led to further optimization of reaction conditions to decrease the amounts of catalytically inactive side products formed.
The anionic ring-opening polymerization of cyclic imines
(University of Alabama Libraries, 2019) Reisman, Louis; Rupar, Paul A.; University of Alabama Tuscaloosa
One important class of polymers is polyimines. Polyimines have a wide range of applications such as CO2 capture and non-viral gene-transfection. Despite their many applications, the use of these polymers is limited due to difficulties in controlling the polymerization. To increase the feasibility of polyimines in the aforementioned high-value applications, the research in this dissertation focuses on controlled routes to produce linear polyimines using living anionic ring-opening polymerization (AROP). The early work of this dissertation focuses on an AROP route to linear polyethylenimine (LPEI). Due to the insolubility of p(N-sulfonylaziridine)s (i.e. non-2-substituted) in all common solvents, this was achieved using a copolymerization strategy. Utilizing two N-sulfonylaziridines, N-(methanesulfonyl)aziridine (MsAz) and N-(sec-butylsulfonyl)aziridine (sBsAz), with similar reactivities, a soluble random copolymer with narrow molecular weight distributions is produced. Removal of the sulfonyl groups of p(MsAz-r-sBsAz) affords the first example of LPEI by living, controlled AROP. The later work in this dissertation focuses on the AROP of N-sulfonylazetidines in route to linear poly(trimethylenimine) (LPTMI). Initially, the polymerization of N-(methanesulfonyl)azetidine (MsAzet) was investigated. The kinetics of this polymerization were studied, and the reaction found to be first order with respect to monomer and the number of active chain ends remains constant throughout the polymerization. Interestingly, activation occurs at the methanesulfonyl group, leading to polymer branching. This branching precludes p(MsAzet) from being a precursor to LPTMI. By more judicial selection of N-sulfonylazetidine monomers, a living, controlled AROP approach to LPTMI was achieved by copolymerizing two similar N-sulfonylazetidines, N-(p-tolylsulfonyl)azetidine (pTsAzet) and N-(o-tolylsulfonyl)azetidine (oTsAzet), to produce a statistical copolymer. Copolymerization was required as the homopolymers resulting from these monomers were insoluble in all common solvents. The copolymerization is living and controlled, producing polymers with narrow molecular weight distributions. The kinetics of the copolymerization, and the reactivity ratios of the two monomers, were studied and the sulfonyl groups of the polymer were removed to provide the first example of LPTMI by living, controlled AROP. Finally, the high barrier to polymerization of N-sulfonylazetidines was utilized to produce block copolymers, containing no homopolymer impurities, in a closed system in which all monomers are present in solution at the time of initiation.
Application of hydrogen deuterium exchange mass spectrometry in protein-ligand and protein-protein interactions
(University of Alabama Libraries, 2016) Guan, Siqi; Frantom, Patrick A.; University of Alabama Tuscaloosa
Proteins are not static objects. They have a great variety of internal motions with different amplitudes and different timescales. These internal motions play an important role in catalytic processes. Therefore, the existence of an intimate relationship between protein dynamics and protein function is widely accepted. Due to the significance of protein dynamics, techniques have been developed to study protein dynamics including nuclear magnetic resonance (NMR) spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, and mass spectrometry (MS). Compared with NMR and EPR spectroscopy, MS has less stringent sample requirements, including protein concentration and protein size. Moreover, the mass accuracy, sensitivity, and faster data analysis also have contributed to the rapid growth of MS based techniques. Hydrogen-deuterium exchange mass spectrometry (HDX-MS), a combination of HPLC and MS, has become a common and sensitive tool to probe protein structural flexibility and solution dynamics. In this dissertation, HDX-MS was applied to study dynamic changes of proteins due to substrate binding and protein-protein interactions. The GT-A glycosyltransferase glucosyl-3-phosphoglycerate synthase from Mycobacterium tuberculosis (MtGpgS) catalyzes the first step of biosynthesis of 6-O-methylglucose lipopolysaccharides (MGLPs), which are essential to growth and existence of mycobacterium. The HDX-MS data revealed that the two substrates UDP-glucose (UDPG) and 3-phosphoglycerate (3PGA) can bind to MtGpgS independently, disagreeing with the previous proposal that 3PGA can only bind to MtGpgS after UDPG. Moreover, 3PGA was found to bind to or allosterically affect the UDPG binding site. Furthermore, the HDX-MS data revealed that MtGpgS may provide a necessary conformation for UDPG binding, while it goes through a large conformational change on 3PGA binding. The GT-B glycosyltransferase MshA from Corynebacterium glutamicum (CgMshA) catalyzes the initial step of mycothiol biosynthesis. A large conformational change was observed in CgMshA on nucleotide binding by superimposing APO structure of CgMshA and complex structure with UDP. HDX-MS was utilized to study conformational changes of CgMshA on substrate binding from the aspect of dynamics, providing a complementary to static structures. The HDX-MS data showed that both substrates uridine diphosphate glucose-N-acetylglucosamine (UDP-GlcNAc) and 1-L-myo-inositol-1-phosphate (I1P) can bind to CgMshA independently, but the I1P binding is not productive since it binds to an uncorrect site. Moreover, the I1P binding can lead to dynamic changes of CgMshA, while only UDP-GlcNAc can induce the major conformational change of CgMshA. Furthermore, the 3PGA binding cannot induce further dynamic changes of CgMshA in the presence of UDP. HDX-MS was also employed to study dynamic changes of protein complex SufBC2D from Escherichia coli on ADP/Mg2+ binding. This complex is responsible for Fe-S cluster assembly under oxidative stress. The crystal structure of SufBC2D complex has been determined, while little dynamic information is known. So HDX-MS was applied to study dynamic changes of the SufBC2D complex. The HDX-MS data revealed that SufC has a significant conformational change, which may be required by ATP binding and hydrolysis. Moreover, SufB and SufD are detected to have dynamic changes due to SufC conformational changes. These dynamic changes suggest that SufB-SufD protomer may have a conformational change in order to provide a suitable conformation for Fe-S cluster assembly. This work demonstrates that HDX-MS can be effectively used to study protein-ligand and protein-protein interactions, as well as the accompanying changes in structural dynamics. HDX-MS data detects substrate binding mechanism and conformational changes that are not available through x-ray crystallography. With these advantages, HDX-MS has been applied in study of protein structure and dynamics, studying protein-ligand and protein-protein interactions, protein folding, as well as protein therapeutics discovery and development.
Carbohydrate sensing using boronic acid modified polymers
(University of Alabama Libraries, 2019) Liang, Xiaoli; Bonizzoni, Marco; University of Alabama Tuscaloosa
Polyelectrolytes have attained a more prominent role in the design of supramolecular systems in recent years. In particular, commercially available poly(amidoamine) (PAMAM) dendrimers have been widely used because they have high loading capacities and good solubility in water. We focus here on using optical spectroscopy to investigate the application of PAMAM dendrimer derivatives as receptors in carbohydrate sensing, and to study the multivalent behavior of receptors covalently appended to the surface of these macromolecules. We then extended the design principles obtained from this work to linear water-soluble anionic polyelectrolytes developed in collaboration with the Kharlampieva group at the University of Alabama at Birmingham (UAB), using polymethacrylate-acrylamide co-polymers synthesized by their group. In chapters 2 and 3, we describe a carbohydrate sensing system that can operate in neutral water, using covalently modified polyelectrolytes as receptors, and common commercially available dyes as optical signaling units. Particularly, in chapter 2, boronic acid modified PAMAM dendrimers were used as receptors to differentiate common monosaccharides in water at millimolar concentration. This is a significant improvement in affinity and sensitivity over simple boronic acid receptors, particularly for work in aqueous environment, which is considered a challenging medium for carbohydrate detection. In chapter 3, these design concepts were also extended to using boronic acid modified polymethacrylate-acrylamide copolymers synthesized at UAB. Binding affinity trends of carbohydrates to boronic acid moieties were then investigated from a fundamental perspective. In chapter 4, the multivalent behavior of boronic acid moieties on surface-modified PAMAM dendrimers was characterized in detail to determine the factors influencing the onset of multivalent behavior, including the surface density of receptor sites and the overall size of the polymeric scaffold.
Catalytic small molecule reduction using late transition metal complexes of carbon and nitrogen donor chelates
(University of Alabama Libraries, 2017) Siek, Sopheavy; Papish, Elizabeth T.; University of Alabama Tuscaloosa
Hydrogenation reactions can be used to store energy in chemical bonds, and if these reactions are reversible that energy can be released on demand. A new bidentate chelating ligand was designed and synthesized for this project, using an N-heterocyclic carbene ring bound directly to a pyridinol ring (NHC-pyOR). This new ligand was used to make iridium complexes that were studied as catalysts for the hydrogenation of CO2 and dehydrogenation of formic acid. For comparison, analogous bipy derived iridium and ruthenium complexes were also tested. In general, the NHC-pyOR complexes demonstrated modest activity, where hydroxyl-pyridines found in the bipy derived systems are more active for CO2 hydrogenation under basic conditions. However, the trends were quite different for formic acid dehydrogenation reaction which will be discussed in Chapter 2. Other ruthenium (II) and iridium (III) complexes of the NHC-pyOR ligand with difference counter anions from above complexes were also synthesized. The ruthenium complexes were tested for their ability to accelerate CO2 (de)hydrogenation, but our studies show that these complexes all undergo transformations in solution and thus they are not true catalysts, but rather pre-catalysts. The use of new tridentate pincer ligands derived from NHC and pyridinol is also described. A new ligand containing (NHC-pyOR-NHC) rings binding to a metal with the pyridinol derivative were synthesized. A series of metal complexes of the type LnM were synthesized (n = 1 and 2; M = Fe2+, Co3+, and Ru2+). Preliminary results of photocatalytic reduction of CO2 to CO show that ruthenium complexes are the most active catalysts followed by cobalt and iron, respectively. The activation of carbon dioxide and nitrite utilizing bio-inspired and proton responsive catalysts were also studied with tris(triazolyl)hydroborate (Ttz) complexes of zinc(II) and copper(II). For the biomimetic zinc complexes for CO2 activation, the synthetic result was found to be greatly depend on the steric bulk of Ttz ligand which will be discussed in detail in Chapter 6. Moreover, the electrochemical reduction of Ttz-Cu(II) complexes in the presence and absence of a proton source shows processes that are relevant to enzymatic nitrite reduction which also will be studied in Chapter 7.
Characterization and catalytic applications of silver nanoparticles supported on hierarchically porous SiO_2 and Co_3O_4 monoliths
(University of Alabama Libraries, 2017) Yildirim, Yasemin; Bakker, Martin G.; University of Alabama Tuscaloosa
Hierarchically porous materials are of great interest in such applications as catalysis, drug delivery, chromatography, and electrochemical sensor arrays due to properties such as high surface area, large void volume, and tunable surface chemistry. In this study, we give the detailed report of the synthesis of supported Ag nanoparticles by nanocasting on to hierarchically porous SiO2 (silica) and Co3O4 (cobalt oxide) monoliths, as well as the use of these materials as heterogeneous catalysts for the hydrogenation and oxidation reactions. In the preliminary work, we investigated the synthesis of Ag supported on hierarchically porous SiO2 and Co3O4 monoliths, and the catalytic activity of these monoliths for the hydrogenation of MB (methylene blue) and MO (methyl orange) dyes in the presence of NaBH4 (sodium borohydride). The SiO2 monoliths were synthesized using a sol-gel technique. The Co3O4 monoliths were prepared by nanocasting, using the SiO2 monoliths as a template. The loading of Ag nanoparticles on the SiO2 and Co3O4 monoliths was done by a solution infiltration method using aqueous AgNO3 (silver nitrate) solution followed by reduction with ethylene glycol and hydrazine hydrate. Such monoliths also were used as continuous flow monolithic microreactors for the catalytic activity and stability studies for the hydrogenation of EO (eosin-Y) dye in the presence of NaBH4. Finally, the use of these monoliths for the oxidation of cyclohexene was investigated including the effects of temperature, oxidant, catalyst loading, and substrate to oxidant ratio. All these studies are presented in different sections depending on the different synthesis, procedures, and catalytic activity occurring in each heterogeneous catalyst.
Chromium, question of essentiality for mammals: its subcellular mechanism, toxicity, uses as a probe for DNA binding
(University of Alabama Libraries, 2011) Rhodes, Nicholas Ryan; Vincent, John B.; University of Alabama Tuscaloosa
Chromium was proposed to be an essential trace element over 50 years ago and was accepted as an essential element for over thirty years. Several studies were performed to address the question of essentiality. Male Zucker lean rats were housed in specially designed metal-free cages for six months and fed the purified AIN-93G diet with no added chromium in the mineral mix component of the diet, the standard purified AIN-93G diet, the standard purified AIN-93G diet supplemented with 200 Μg Cr/kg, or the standard purified AIN-93G diet supplemented with 1000 Μg Cr/kg. This study revealed that a diet with as little chromium as reasonably possible had no effect on body composition or glucose metabolism or insulin sensitivity compared to a chromium "sufficient" diet. The diets supplemented with Cr had beneficial effects on the rats; the effects at these doses are pharmacological effects, the mechanism of which requires further research. Zucker obese and Zucker diabetic fatty (ZDF) rats were used to establish whether rats under stress (diabetes and obesity associated insulin resistance) have altered levels of chromium absorption compared to Zucker lean rats. If these conditions lead to increases in chromium absorption, then increased urinary Cr losses resulting from the conditions are unlikely to lead to chromium deficiency. The study revealed that increases in urinary Cr loss associated with insulin resistance or diabetes are offset by increased absorption. Together with the results of other recent studies, these results clearly indicate that chromium can no longer be considered an essential element. Chromium(III) picolinate, [Cr(pic)_3 ], is a commonly used nutritional supplement in humans, that has also been approved for use in animals. Health concerns have arisen over the use of [Cr(pic)_3 ] in high doses. Male CD-1 mice were used to further assess the potential for reproductive or developmental toxicity at a dose of 200 mg/kg/day [Cr(pic)_3 ]. The results suggest that paternal dietary exposure to [Cr(pic)_3 ] has little potential for adverse reproductive effects. Studies with chromium nicotinate and chromium basic carboxylate complexes containing trifluoroacetate, 3-fluoropyridine, 3-trifluoromethylpyridine, and 4-trifluoromethylpyridine are described.
Chromium: binding studies with transferrin and peptide eeeegdd and its effect on colorectal cancer
(University of Alabama Libraries, 2016) Deng, Ge; Vincent, John B.; University of Alabama Tuscaloosa
Chromium as the trivalent ion has been proposed as an essential element for decades. Although that status has recently been discredited, doses of Cr3+ have been shown to generate improvements in insulin sensitivity and blood cholesterol levels in animals that have problems with their glucose and lipid metabolism systems, especially in type 2 diabetic rodent models. The mechanism for these effects at a molecular level is unknown. Transferrins are a class of protein that can reversibly bind 2 equivalents of metal ions. Biologically, transferrins are the main iron transport proteins in plasma. A role for transferrin in the delivery Cr3+ from plasma to tissues has been proposed. Studies have shown that Cr3+ readily binds to the two metal-binding sites in the two lobes of apotransferrin. The Cr3+ binding is accompanied by intense changes in the transferrin’s ultraviolet spectrum. This intense changes arises from chromic ion binding to two tyrosine residues in the two iron-binding sites of transferrin and allow the binding of Cr3+ to transferrin to be monitored. The rate at which Cr3+ binds to transferrin and the stability of Cr-transferrin recently has received considerable attention. In vitro spectroscopic studies previously found that the generation of Cr2-transferrin needs two weeks to guarantee a stoichiometric amount of Cr3+ binding. However, this study indicates that in the presence of 25 mM (bi)carbonate, the concentration in human blood, two Cr3+ ions bind rapidly and tightly to apotransferrin. Glycation of transferrin alters how tightly the protein binds iron and may alter the conformation of diferric transferrin, presumably changing its ability to deliver the iron to tissues. Given that Cr3+ complexes has been proposed as nutritional supplements to improve symptoms of type 2 diabetic subjects, understanding the ability of glycated transferrin to bind and transport Cr is significant, especially for determining the appropriate dose of Cr. This study examined the binding ability of Cr3+ to glycated serum transferrin and the transport of Cr in vivo by glycated transferrin. The results suggest that glycation of transferrin in subjects with elevated blood glucose levels should lower the ability of Cr from pharmacological agents to enter tissues. Additionally, these studies with glycated transferrin also indicate that heat treatment of transferrin makes dramatic change on its conformation and Cr binding ability.
Computational studies of atmospheric chemical processes, flexible catalysts, and of new materials for chemical hydrogen storage
(University of Alabama Libraries, 2014) Garner, Edward B.; Dixon, David A.; University of Alabama Tuscaloosa
Advanced electronic structure methods on high performance computers have been used to study new materials for technology applications and for atmospheric chemical processes of the halogens. Chapter 2 is focused on the thermodynamics of halogen oxides relevant to stratospheric ozone depletion chemistry. We calculated the thermodynamic properties of various key species to better understand what is happening in the atmosphere to help minimize our impact on the environment. This research is particularly important because of the lack of experimental data on these species. Chapter 3 is focused on the design of flexible catalysts for single electron transfer reactions using neutral Group 6B (Cr, Mo, W) pentacarbonyl complexes M(CO)5-L. It was found that various P-ligands such as phosphines, phosphalkenes, and phospha-quinomethanes can form radical cations and anions under redox conditions and that the radical site can be localized either on the metal or on the "non-innocent" ligand. More polar solutions will drive single electron transfer reactions to form the cationic and anionic metal based complexes with the appropriate oxidizing and reducing agents. Chapter 4 is the study of chemical hydrogen storage systems with a focus on borane amines. The goal was to develop economically viable and energy efficient processes to regenerate spent fuel formed by the release of hydrogen from ammonia borane. The thermodynamics for fuel regeneration processes of spent ammonia borane fuel, modeled as polyborazylene, were accurately predicted. A method using a modified Pictet-Trouton rule and calculated boiling points was used to estimate heats of formation of liquids for the prediction of the thermodynamics of reactions in the liquid phase. An effective tin catalyst with the potential to lower the cost for ammonia borane regeneration at an industrial scale was designed in collaboration with Los Alamos National Laboratory. However, it was found that at an industrial scale the process was limited due to the cost of transporting the tin catalyst around the spent fuel regeneration plant. Therefore, it was necessary to find a new method for regenerating spent ammonia borane fuel, and hydrazine was found to work very effectively in a one pot approach.
Computational studies of Lewis acidic gas adsorption to transition metal oxide nanoclusters and metal organic frameworks
(University of Alabama Libraries, 2017) Flores, Luis Antonio; Dixon, David A.; University of Alabama Tuscaloosa
Computational studies of the interaction of Lewis acid gases with metal oxide clusters and metal organic frameworks show how these gases interact with and degrade these materials at the molecular level. The calculations were done at the levels of density functional theory and correlated molecular orbital theory ((CCSD(T))). Group VI metal oxides clusters physisorb CO_2 near or below to 298K, and chemisorption of CO_2 by carbonate formation is an endothermic process. SO_2 physisorbs to Group VI clusters near or below 298K. Group VI metal oxides chemisorb SO_2 by forming sulfites with positive free energies of binding at 298K. The formation of sulfates is thermodynamically allowed for Cr clusters because Cr clusters have a higher reducibility than do Mo or W clusters. Group IV metal oxide clusters prefer chemisorption of both gases by carbonate and sulfite formation. Mo and W oxides may function as long lived sorbents for these gases, whereas Cr and Group IV metal oxides would degrade upon exposure to these gases as sulfites, sulfates, or carbonates form on their surfaces. Uranium trioxide clusters are predicted to chemisorb CO_2 by uranyl carbonate formation. The exposure of nuclear waste to CO_2 could cause uranium oxides to degrade leading to ground water contamination. The physisorption of the Lewis acid gases (CO_2, SO_2, H_2O, H_2S, CO, and NO_2) to M-MOF-2 systems (M = Zn, Cu, Co), was investigated. The MOFs are predicted to bind H_2O, H_2S, and SO_2 more strongly than the other gases. The binding energies are larger for Zn and Co than for Cu. Zn-MOF-2 clusters will degrade faster than Cu.
Computational studies of solid state materials for practical applications
(University of Alabama Libraries, 2012) Stott, Amanda C.; Dixon, David A.; University of Alabama Tuscaloosa
The Ni-rich Ni55Ti45 composition of the NiTi alloy is a promising material for aerospace bearing materials. Spiral orbit tribometry friction tests performed on Ni-rich Ni55Ti45 titanium ball bearings indicate that this alloy is a promising candidate for future aerospace bearing applications. Microstructural characterization of the bearing specimens was performed using transmission electron microscopy and energy dispersive spectroscopy, with NiTi, Ni4Ti3, Ni3Ti, and Ni2Ti4Ox phases identified within the microstructure of the alloy. Density functional theory (DFT) was applied to predict the electronic structure of the NixTiy phases, including the band structure and site projected density of states. Ultraviolet photoemission spectroscopy was used to verify the density of states results from the density functional theory calculations, with good agreement observed between experiment and theory. Plane wave ab initio DFT calculations of the B2 NiTi (100), (110), and (111) surfaces, the B2 and B19´ phases of NiTi, and the supercell structures of NiTi, Ni4Ti3 and Ni3Ti are also reported. Electronic energies from the electronic structure calculations are used to assess relative stability of the different surface and supercell geometries. DFT was applied using a plane wave approach for solids to determine the band gap energies in a series of Pb3C6X6 semiconducting extended-network organic structures, to determine the phase stability in the NiTi alloy system, and to study the surface of the (bcc) B2 phase of NiTi. To reveal the molecular structure and optoelectronic properties of these materials, a detailed ab-initio theoretical investigation of the solid-state properties was performed. Density functional theory was applied to predict the electronic structure of the NixTiy phases, including the band structure and site projected density of states. Organo-metallic compounds are also an important class of materials for organic electronic devices due to their semiconducting properties. Ground state geometries, band structure, density of states, and charge density were calculated using density functional theory using the PBE exchange-correlation functional as well as the Heyd-Scuseria-Ernzerhof (HSE06) hybrid functional. The results show that the optical properties and band gap energies can be easily tuned by chemical modifications of the substituent X atom in Pb3(C6X6). Calculations of substituent atoms S, O, Se, and Te are presented. TiV-based alloys are promising candidates for NiMH batteries, as it is well established that the V-based (bcc) solid solution phase acts as the major hydrogen absorbing phase wguke the (hcp) Ti phase acts mainly as a catalyst for electrochemical hydrogenation and dehydrogenation. To achieve improved electrochemical performance a precise knowledge of the microstructure is required. Therefore, the influence of the interfacial energy on the material phase stability was investigated for a series of TiV multi-laminate thin films. Experiments revealed that at a higher layer thickness, the α (hcp) phase is the most stable. As the layer thickness is reduced, a transformation from the α (hcp) phase to the ß (bcc) phase occurs. Atomic-scale characterization of the transformed specimen by atom probe tomography reveals V interfacial diffusion between the layers. Equivalent crystal theory based calculations confirm the V interfacial diffusion mechanism. The predicted segregation profiles match those obtained experimentally.
Computational studies of the catalytic reactions of group ivb and vib transition metal oxide clusters
(University of Alabama Libraries, 2014) Fang, Zongtang; Dixon, David A.; University of Alabama Tuscaloosa
Computational chemistry approaches have been used to study the reactivity of Group IVB and VIB transition metal oxide clusters. The hydrolysis of MCl₄ (M = Zr, Hf) as the initial steps on the way to form zirconia and hafnia nanoparticles has been studied with density functional theory (DFT) and coupled cluster [CCSD(T)]theory. Instead of the direct production of MOCl₂ and HCl or MO₂ and HCl, the hydrolysis reaction starts with the formation of oxychlorohydroxides followed by the release of HCl due to the large endothermicities associated with the direct path to form gas phase MO₂. The formation of MO₂ nanoparticles by the high temperature oxidation method is complicated and is associated with the potential production of a wide range of intermediates. The interaction between H₂O and small (MO₂)n (M = Ti, Zr, Hf, n = 1−4) nanoclusters has been studied for the first step to understand the reaction mechanism of photocatalytic water splitting with the presence of (MO₂)n as catalysts. Both the singlet and the first excited potential energy surfaces (PESs) are studied. The hydrolysis reactions begin with the formation Lewis acid-base adducts followed by proton transfer from H₂O to the nanclusters. The reactions are highly exothermic with very small activation energies. Thus, H₂O should readily decompose to generate two OH groups on (MO2)n nanoclusters. The generation of H₂ and O₂ starting from the hydroxides formed in the hydrolysis step has been studied with the same computational methods as used for the hydrolysis study. The water splitting reactions prefer to take place on the first excited triplet potential energy surface (PES) due to its requirement of less energy than that on the singlet PES. A low excess potential energy is needed to generate 2H₂ and O₂ from 2H₂O if the endothermicity of the reaction is overcome on the first excited triplet PES using two visible photons. Hydrogen generation occurs via the formation of an M−H containing intermediate and this step can be considered to be a proton coupled, electron transfer (PCET) reactions with one or two electrons being transferred. Oxygen is produced by breaking two weak M−O bonds on the triplet PES. Ethanol (CH3CH2OD) conversions on cyclic (MO3)3 (M = Mo, W) clusters have been studied experimentally with temperature programmed desorption and computationally with both DFT and CCSD(T) methods. The addition of two alcohol molecules is required to match experiment. The reaction begins with the elimination of water with the formation of an intermediate of dialkoxy species for further reaction. The dehydration reaction proceeds through a β hydrogen transfer to a terminal MVI = O atom without the involvement of a redox process. The dehydrogenation reaction is through an α hydrogen transfer to an MoVI = O with redox involved or a WVI avoiding redox. The same computational methods have been used to study the other alcohol species such as methanol, n-propanol and isopropanol. The reactions with single, double and triple alcohols per M3O9 cluster have been studied. The dehydrogenation and dehydration for single alcohol reactions is via a common intermediate of metal hydroalkoxide formed by the dissociation of alcohol. The dehydration is through a β hydrogen transfer to OH group. The lowest energy pathway for dehydrogenation is the same for different alcohols in both single and double alcohol reactions. Three alcohols involved condensation reaction may lower the reaction barrier tremendously by the sacrifice of an alcohol to form a metal hydroalkoxide, a strong gas phase Brønsted acid. This is a Brønsted acid driven reaction different from dehydrogenation and dehydration reactions governed by the Lewis acidity of the metal center and its reducibility.
Computational studies of the fundamental thermodynamic properties of amino acids and small peptides
(University of Alabama Libraries, 2015) Stover, Michele Leigh; Dixon, David A.; University of Alabama Tuscaloosa
In 2011, the Human Proteome Project (HPP) was launched with the main goal of experimentally mapping the entire human proteome. Determining a protein’s sequence is a first step to understanding its structure and function, which are of great importance in biological, biochemical, and medical studies. The sequencing of peptides and proteins by mass spectrometry (MS) has become a major tool in proteomics research because it is a cost effective and highly reproducible analytical technique. The analysis of biomolecules by mass spectrometry requires an understanding of proton transfer reactions because the two most commonly used ionization techniques, electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI), involve the addition and removal of protons. The sites of proton transfer reactions can affect the fragmentation patterns of peptide ions, which consequently impacts the sequence information that can be obtained from mass spectrometry experiments. Thermodynamic values, such as the gas-phase acidity (GA or ∆Gacid), the ΔG for the deprotonation reaction AH → A- + H+, provide valuable information to help in understanding the less studied negative ion peptide fragmentation mode by mass spectrometry. The study of gas-phase proton transfer reactions provides unique insights into the structures and energetics of the peptides. Changing the protonation state can impact the hydrogen bonding in the molecule and result in decreased or increased properties such as solubility, hydrophobicity, and electrostatic interactions. By combining these experimentally obtained results with the results from high level electronic structure theory calculations, an improved understanding of the structures and energetics of polypeptides can be obtained. Herein we describe computational studies using reliable, correlated molecular orbital methods of the gas-phase properties, including acidities and heats of formation, and solution-phase acidities of amino acids (AAs) and small peptides including substituted molecules such as AA amides and phosphorylated AAs. This dissertation will focus on the prediction of fundamental thermodynamic properties of AAs and small peptides that are of interest in the area of biochemistry, proteomics, and the Human Proteome Project.
Construction of chiral polysubstituted oxacycles by novel jocic reactions and synthesis of a new cytochrome-p450 photoaffinity label
(University of Alabama Libraries, 2016) Entrekin, Jordan Thomas; Snowden, Timothy S.; University of Alabama Tuscaloosa
The preparation of a novel cytochrome P-450 photoaffinity label is described. The targeted azidoquinone was to be used as a photo-reactive label to specifically identify peptides associated with the oxidation binding site within cytochrome bc1, and consequently determine the unique catalytic mechanism of quinol oxidation processes and the intermediates involved. The synthetic route features a Diels-Alder cyclization/alkylation/decyclization approach to prepare the mimic of naturally occurring ubiquinone. The synthesis is accomplished in 6 steps from commercially available 4-methylcatechol and involves incorporation of azide in the final synthetic step to prepare the novel azidoquinone. (S)–Wynberg lactone was used to prepare the potent CERT inhibitor (1R,3S)-HPA-12. The route featured the preparation of an optically active azidolactone through a Corey-Link reaction accompanied by nucleophilic acyl substitution. The synthesis was accomplished in 5 steps, and proceeded in 33% overall yield from (S)–Wynberg lactone. (R)-Wynberg lactone was used to prepare chiral polysubstituted oxacycles through a novel Jocic-type reaction. The route featured a directed 1,3-reduction of a β-hydroxyketone followed by ruthenium-catalyzed cross metathesis and osmium-catalyzed asymmetric dihydroxylation. A modified olefin metathesis procedure to suppress undesired byproduct formation is described in detail. A variety of functionalized olefins were prepared by the modified procedure in yields commonly exceeding 80%. Functionalized tetraols were prepared by a modified Sharpless asymmetric dihydroxylation reaction with yields commonly exceeding 80%, and diastereomeric ratios typically exceeding 85:15. Stereoselectivity in the dihydroxylation of terminal mono-substituted olefins can be enhanced with a pre-formed phenyl boronic ester adduct. Conditions for enhancing the stereoselectivity with this class of substrates are described in detail. The final synthetic step en route to the targeted tetrahydopyran derivatives involves intramolecular cyclization through a novel Jocic-type reaction, and commonly proceeds in > 80% yield. Work towards the cyclization of all classes of prepared tetraols is currently in progress. Terminal alkylsulfanyl alcohols were prepared in one step from an aliphatic trichloromethyl carbinol in yields exceeding 85%. These results further demonstrate the utility of gem-dichloroepoxide intermediates in Jocic-type reactions, and lay the groundwork for future transformations. Work in this area is currently underway.
Control of molecular geometries using new photo-electro-switchable azobenzenes
(University of Alabama Libraries, 2015) Saint-Louis, Carl Jacky; Blackstock, Silas C.; University of Alabama Tuscaloosa
There has been a recent growing interest in azobenzene derivatives because of their ability to isomerize when visible light is absorbed. This unique property allows azobenzenes to undergo reversible conformation change between the trans and cis forms upon absorbing light and slowly thermally relaxing from the cis to the trans form. By adding a redox-active (RA) group to the azobenzene skeleton, we have developed a series of new redox appended azo switches capable of efficient photo “folding” and catalytic electron transfer mediated “opening” on exposure to an oxidant or a small amount of voltage as an electrical trigger. We utilized an aryl amino group as our redox auxiliary moiety because of its excellent redox properties- it is chemically stable in both neutral and radical cation forms. The basic premise of our work is that the cationic state of the RA-azo will be much more reactive toward azo isomerization (cis-to-trans) than its neutral form. Thus, upon one electron removal from the cis-RA-azo to make cis-RA•+-azo, the azo group will immediately unfold. How well the redox activation of azo unfolding works may depend on where the RA group is located. Thus, we have prepared RA-azo substrates with the RA group linked at the para and meta positions of the azobenzene ring to test their relative abilities to support redox activation of azo unfolding. Because the oxidized radical cation state of the RA group (RA•+) is so chemically stable, it should be able to exchange an electron with other neutral cis-RA-azo molecules thereby generating a catalytic cycle for azo unfolding. Based on this study, we hypothesized a new photo-electro isomerization catalysis mechanism that accounts for the fast relaxation from “folded” cis to “open” trans. To date, we have successfully synthesized six different RA-azo in which the placement of the RA moiety is varied on the azobenzene ring and we observed that redox activation of the RA-azo unfolding process works catalytically with rate increases relative to thermal azobenzene unfolding of ≥ 105 and turnover numbers in the 100-1000 range.
The determination of Cr(III)'s mode of binding dna
(University of Alabama Libraries, 2019) Brown, Silas Earl; Vincent, John B.; University of Alabama Tuscaloosa
Chromium(VI) complexes are potent mutagens and carcinogens when inhaled, while the potential of these complexes to generate similar effects when taken orally is an area of active debate. The focus on this work is to investigate how chromium binds to DNA on a molecular level. The exact mechanism(s) of action of this activity is unknown, but potential mechanisms can be grouped into two categories. The first is mechanisms associated with redox chemistry during reduction of Cr(VI). Numerous studies have been focused on studying this potential mechanism. The second mechanism is based on the generated Cr(III) binding to DNA to form binary and ternary complexes. Virtually no data on the molecular level structure of these Cr(III)- DNA complexes exists. Such studies are complicated by the spectroscopic and magnetic properties of Cr(III). Second, previous studies have used plasmid DNA, DNA polymers, calf thymus DNA, or DNA isolated from cultured cells, which because of their size and complexity, present numerous potential Cr-binding sites with a range of binding constants. What is required to determine the preferential sites for Cr-binding and to characterize the structure of these sites is the use of DNA oligomers significantly smaller in size whose base sequences can be carefully designed and which can be synthesized in appreciable quantities. Results of spectroscopic and magnetic studies (1H and 31P nuclear magnetic resonance spectroscopy including multidimensional techniques, pulsed electron paramagnetic resonance spectroscopy, and infrared spectroscopy) to characterize the binding of Cr(III) to such DNA oligomers indicate that Cr(III) as [Cr(H2O)5]3+ can bind specifically to the guanine N7 position of B-form double stranded DNA without direct interaction with the phosphate backbone and resulting in minimal distortions in iii the structure of the DNA. A potential Cr(III)-based inter-strand crosslink of DNA has been characterized. Preliminary steps to synthesize and characterize ternary Cr(III)-small molecule- DNA compounds have been investigated.
Development and applications in computational chemistry for inorganic catalysis
(University of Alabama Libraries, 2013) Chen, Mingyang; Dixon, David A.; University of Alabama Tuscaloosa
A robust metadata database called the Collaborative Chemistry Database Tool (CCDBT) for massive amounts of computational chemistry raw data has been designed and implemented. It performs data synchronization and simultaneously extracts the meta data. The indexed meta data can be used for data analysis and data mining. A novel tree growth - hybrid genetic algorithm (TG-HGA) was developed to search the global minimum of small clusters. In the TG algorithm, the clusters grow from a small seed to the size of interest stepwise. New atoms are added to the smaller cluster from the previous step, by analogy to new leaves grown by a tree. The initial structures for the search for the global minimum of TiO_2 nanoclusters were generated by TG-HGA, and new low energy structures that have not been previously reported were found. Low energy isomers of Agn, n = 2 - 99, were studied at different computational level depending on the size of Agn. The geometries of Agn, n = 2 - 8, were optimized using density functional theory (DFT), and the energies were calculated at the CCSD(T)/CBS level. The Agn, n = 9 - 20, were initially generated by the TG-HGA builder with an EAM potential, and optimized using the DFT method. The relative energies and normalized atomization energies for the optimized structures were calculated at the CCSD(T) level with a small basis set. For larger Agn, 20 < n < 100, the low energy structures were generated using TG-HGA with an EAM potential, and the energies were calculated at the DFT level with a small basis set. A range of DFT functionals were benchmarked with the normalized atomization energies at the CCSD(T) level for the small Agn clusters. PW91 and ω-B97XD provided best results for predicting the normalized atomization energies. The normalized atomization energies for Agn start to converge slowly to the bulk at n = 55. At n = 99, the normalized atomization energy is predicted to be ~50 kcal/mol. The low energy isomers of the Irn(CO)m complexes (n=1, 2, 3, 4, and 6) were investigated using electronic structure methods at the density functional theory and coupled cluster (CCSD(T) theory levels. Ir4(CO)12 is predicted to be the most favored complex for reactions of Irn(CO)m with CO at low temperature, and Ir6(CO)16 is predicted to be formed above room temperature. Smaller Irn(CO)m clusters will nucleate to form Ir4(CO)12 spontaneously. Low-lying structures of the small iridum clusters Irn (n = 2 - 8) were optimized using DFT methods. Ir2 and Ir3 were also optimized using the CASSCF method. MRCI-SD (for Ir2) energies and CCSD(T) (for Ir2 and Ir3) energies of the leading configurations from the CASSCF calculations were done to predict the low-lying states. The normalized atomization energies for Irn (n = 2 - 8) were calculated at the CCSD(T) level up to the complete basis set (CBS) limit in some cases using the B3LYP optimized geometries. Inclusion of the spin orbit corrections in the normalized atomization energies for Irn is critical and will decrease the normalized atomization energies by ~ 15 kcal/mol for n ≥ 4. Several molecular models were used to characterize various binding sites of the metal complexes in the zeolites. The calculated structures and energies indicate a metal-oxygen (M(I)-O) coordination number of two for most of the supported complexes but a value of three when the ligands include C2H5 or H. The results characterizing various isomers of supported metal complexes incorporating hydrocarbon ligands indicate that some carbene and carbyne ligands could form. A set of ligand bond dissociation energies is reported to explain reactivity trends. The Pd-L ligand bond dissociation energies (BDEs) of cis- and trans-[L-Pd(PH3)2Cl]+ were predicted using coupled cluster CCSD(T) theory and a variety of density functional theory (DFT) functionals at the B3LYP optimized geometries. For cis-[L-Pd (PH3)2Cl]+ complexes, the Pd-L bond energies are 28 kcal/mol for CO; ~40 kcal/mol for AH3 (A = N, P, As, and Sb), norbornene, and CH3CN; and ~53 kcal/mol for CH3NC, pyrazole, pyridine, and tetrahydrothiophene at the CCSD(T) level. The benchmarks show that the dispersion-corrected hybrid, generalized gradient approximation, DFT functional ω-B97X-D is the best functional to use for this system. Use of the ω-B97X-D/aD functional gives predicted BDEs within 1 kcal/mol of the CCSD(T)/aug-cc-pVTZ BDEs for cis-[L-Pd(PH3)2Cl]+ and 1.5 kcal/mol for trans-[L-Pd(PH3)2Cl]+ . Lanthanide metal atoms, produced by laser ablation, were condensed with CH3F in excess Ar at 8 K. New infrared absorption bands are assigned to the first insertion CH3LnF and oxidative addition methylene lanthanide hydride fluoride CH2LnHF products on the basis of 13C and deuterium substitution and density functional theory calculations of the vibrational frequencies. For Ln = Eu and Yb only CH3LnF is observed. CH3LnF in the Ln formal +2 state is predicted to be more stable than CH2LnHF with the Ln in the formal +3 oxidation state. CH3-LnF forms a single bond between Ln and C and is a substituted methane. The calculated potential energy surface for the CH3F + La → CH3-LaF/CH2-LaHF shows a number of intermediates and transition states on multiple paths. The reaction mechanism involves the potential formation of LaF and LaHF intermediates.
DNA complexes containing novel aromatic residues
(University of Alabama Libraries, 2016) Dong, Wenzhao; Woski, Stephen A.; University of Alabama Tuscaloosa
The investigation of DNA complexes containing novel aromatic residues was performed. In the first part of this work, a series of novel nucleosides possessing a C1’-carboxamide linkage between the aryl moiety and the sugar group were successfully introduced into a single strand DNA oligonucleotide. The results of the thermal denaturation studies indicate that the incorporation of the modified nucleosides into DNA complexes destabilizes the DNA duplexes. However, the “bulged” complexes are only slightly destabilized and they are the most stable complexes among all the DNA complexes containing novel aromatic residues. This suggests that the carboxamide motif may be a general method for the insertion of non-natural residues into DNA for applications such as spectroscopic probes. The second part of this study involves a seven step synthesis of novel aryl C-nucleosides. The aromatic residues are directly linked to the deoxyribose moieties through a carbon-carbon connection instead of the original carbon-nitrogen glycoside bond. Three novel C-nucleosides containing 4-substituted phenyl residues were successfully synthesized by following this synthesis scheme. The isomer problem involved in the multi-step synthesis of aryl C-nucleoside was resolved and as a result, the β-aryl C-2′-deoxynucleoside can be successfully separated from the α-aryl C-2′-deoxynucleoside. The synthesized aryl C-nucleoside can be introduced into a DNA oligonucleotide as a non-natural nucleobase. The third part of this research was focused on the determination of the structure of DNA oligonucleotide duplexes containing aryl C-nucleoside using 2D NMR techniques and computational methods. 2D NMR experiments including COSY and NOESY were performed, followed by resonance assignment and structure calculation to construct the preliminary 3D structure of DNA oligonucleotide duplex containing aryl C-nucleoside. Due to the limitation of the obtained restrains from NMR experiment, the study of molecular modeling has been performed to compensate the ambiguous of the preliminary structure. Conflicts between the calculated duplex structure and the data from the NMR experiment were observed, so an alternate possible structure of hairpin was proposed. The results of thermal denaturation study and molecular modeling may indicate that the hairpin structure is more preferred than the duplex structure for the non-natural DNA oligonucleotide containing aryl C-nucleoside.
Effects of transition metal cationization on peptide dissociation by mass spectrometry
(University of Alabama Libraries, 2011) Watson, Heather Malone; Cassady, Carolyn J.; University of Alabama Tuscaloosa
Peptide sequencing is fundamental to understanding a protein's structure and function. The field of proteomics is dedicated to how these aspects relate to human health and disease. Unfortunately, the majority of peptides and proteins are not fully sequenced. In mass spectrometry, this is often due to spectral complications and incomplete fragmentation. There is a need to develop new sample preparation techniques or dissociation methods to increase sequence information. The dissociation of transition metal-cationized peptides by collision-induced dissociation (CID), electron-transfer dissociation (ETD), and electron-transfer collisionally activated dissociation (ETcaD) has been investigated in a quadrupole ion trap (QIT). The resulting mass spectra provide a wealth of information about the primary structures of the peptides. Using transition metal ions as cationizing reagents proves beneficial to peptide sequencing by CID and, in some cases, is better than the analysis of protonated species. For instance, spectra obtained from CID of singly and doubly charged Cu(II)-heptaalanine ions, [M + Cu - H]^+ and [M + Cu]^2, are complementary and together provide cleavage at every residue and no neutral losses. This contrasts with protonated heptaalanine, [M + H]^+, which results in fewer backbone cleavages by CID and does not allow sequencing of the first three residues. Multiply charged precursor ions are required in order to carry out ETD and ETcaD. This can be problematic for acidic or neutral peptides. This work demonstrates that addition of transition metals as a cationizing reagent allows peptides to be submitted to ETD and ETcaD that do not otherwise form multiply charged precursors. ETD spectra were less complex than those produced by CID. ETcaD increases backbone cleavages for all samples studied relative to ETD. In addition, complexes that result in very few cleavages by CID are cleaved at every residue when submitted to ETcaD. Evidence for macrocyclic metallated a- and b-ions is found in ETD and ETcaD spectra in the form of nonsequential product ions. The sequence (pEEEEGDD) of the peptide component of biologically derived low-molecular-weight chromium binding substance (LMWCr) is obtained as a result of extensive mass spectrometric studies. LMWCr is proposed to be involved in carbohydrate metabolism. The sequencing of the peptide component of LMWCr by MS represents a potentially significant milestone towards understanding the pharmacological role of chromium at a molecular level.
Electrochemically assisted self assembly of mesoporous silica on conducting substrates as templates for electroactive metal oxides
(University of Alabama Libraries, 2012) Cordes, Nikolaus Lynn; Bakker, Martin G.; University of Alabama Tuscaloosa
Three dimensional, conductive, macroporous nickel foams and mesoporous carbon aerogels have been utilized as skeletal supports for an electrochemically assisted deposition of mesoporous silica particles and films. Substrate-supported mesoporous silica particles were synthesized directly onto the conducting supports using a combined sol-gel/electrochemical method, termed Electrochemically Assisted Self Assembly (EASA). The EASA method resulted in mesoporous silica/nickel foam composites exhibiting high specific surface areas (20-120 m^2 g^-1) and narrow silica mesopore size distributions (2.6-3.8 nm), as determined by nitrogen physisorption characterization. Increasing the EASA deposition time resulted in the increase of mesoporous silica particle diameters (from less than one micron for deposition times of 80 seconds to greater than one micron for deposition times of 3600 seconds), as well as an increase in the number of particles deposited and substrate surface coverage, as determined by scanning electron microscopy (SEM) and cyclic voltammetry, respectively. Transmission electron microscopy (TEM) analysis revealed that silica particles deposited by EASA possess a worm-like disordered morphology, due to poor surfactant ordering during the EASA process. Mesoporous silica particles on carbon aerogels resulted in an increase in electrochemical capacitance, from 7 F g^-1 for a bare carbon aerogel substrate to 20 F ^-1 for a mesoporous silica/carbon aerogel composite. Mesoporous silica/nickel foam composites were utilized as substrate-supported templates in a metal oxide nanocasting procedure. Aqueous and ethanolic cobalt nitrate infiltration and thermal decomposition produced Co3O4/mesoporous silica/nickel foam composites. Removal of the mesoporous silica particle template resulted in hierarchically porous Co_3 O_4 /nickel foam composite electrodes, as determined by X-ray diffractometry (XRD) and nitrogen physisorption. Co_3 O_4 /nickel foam composite electrodes fabricated from aqueous cobalt nitrate nanocasting exhibited relatively high surface areas (37-44 m^2 per gram of electrode), small micropore volumes, and broad mesopore size distributions. Co_3 O_4 /nickel foam composite electrodes fabricated from ethanolic cobalt nitrate nanocasting resulted in Co_3 O_4 /nickel foam electrodes with lower surface areas of 12-29 m^2 per gram of electrode. The electrochemical pseudocapacitance of Co_3 O_4 /nickel foam composite electrodes were investigated by galvanostatic constant current chronopotentiometry, with specific capacitances of 298-845 F per gram of deposited Co_3 O_4 at low current densities.

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