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  • ItemOpen Access
    Characterizing the fluorescence intermittency of individual cadmium selenide/zinc sulfide quantum dot clusters with spatially correlated single molecule fluorescence spectroscopy and atomic force microscopy
    (Colorado State University. Libraries, 2008) Yu, Ming, author; Van Orden, Alan K., advisor
    In this thesis, I describe work done to study the optical behaviors of CdSe/ZnS quantum dots, especially the fluorescence blinking behavior of small quantum dot clusters. QDs have unique optical properties that impart several key advantages over molecular dyes. However, when examined at the single-molecule level, QDs emission exhibit novel fluorescence intermittency, or "blinking," behavior. This blinking is believed to be caused by trapping and de-trapping of the photoexcited carriers, causing the QDs to fluctuate between emissive and non-emissive states. A spatially correlated single molecule fluorescence spectroscopy and atomic force microscopy (AFM) apparatus was used to carry out these studies. Single molecule spectroscopy examines the blinking behavior of individual, isolated QDs and QD clusters, while the AFM images the nanometer scale topography of the particles. When multiple isolated QDs were probed simultaneously, the fluorescence behavior was consistent with independent blinking of the individual QDs. However, when close-packed QD clusters were probed, the fluorescence intermittency became much more rapid and intense than could be explained by the summation of multiple particles blinking independently. This suggests when the small QDs aggregate together, they become electronically coupled in some way that enhances the fluorescence blinking. Subsequently, we studied variations of the emission wavelengths of isolated small QD clusters possessing the enhanced blinking behavior. The emission wavelength of the coupled enhanced blinking is red shifted relative to that of normal blinking. We propose that red-shifting in emission is one of the characteristics of electronic coupling in the QD clusters and resulted from the quantum confinement Stark effect. In the following chapters, environment and substrate dependence were also studied. Compared with ambient air, dry nitrogen decreases the population, intensity and/or durations of "on" times. Both CTAB- and Mg 2+-mica substrates quench the fluorescence of single QDs and QD clusters, which is due to the dissociation of electron hole pairs of excited QDs by the electron attractive sites in CTAB molecules and Mg2+ ions.
  • ItemOpen Access
    Enantioselective rhodium-catalyzed [2+2+2] and [4+2+2] cycloaddition reactions of alkenyl heterocumulenes: applications to alkaloid synthesis
    (Colorado State University. Libraries, 2009) Yu, Robert Tzu Hsiang, author; Rovis, Tomislav, advisor
    An intermolecular rhodium-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and internal alkynes has been developed. In the presence of a catalytic amount of [Rh(C2H4)2Cl]2 and P(4-MeO-C6H4)3, the cycloaddition produces substituted indolizinones and quinolizinones with newly formed sp 3-stereocenters. Depending on the alkynyl partners, a CO migration process can be involved during the cycloaddition to furnish cycloadducts possessing vinylogous amide functionality. The use of TADDOL-based phosphoramidite ligands on rhodium allows for the incorporation of terminal alkynes in a highly enantioselective [2+2+2] cycloaddition with alkenyl isocyanates. Terminal alkyl alkynes provide bicyclic lactams, while the use of aryl alkynes provides complementary access to vinylogous amides through a CO migration process. Product selectivity seems to be governed by a combination of electronic and steric factors, with smaller and/or more electron-deficient substituents favoring lactam formation. The synthetic utility is demonstrated in an expedient asymmetric total synthesis of the alkaloid (+)-lasubine II. A highly enantioselective rhodium-catalyzed [2+2+2] cycloaddition of terminal alkynes and alkenyl carbodiimides has been realized. The cycloaddition with aryl alkynes provides complementary selectivity to the reaction previously described using isocyanates. In addition, this reaction demonstrates the feasibility of olefin insertion into carbodiimide-derived metalacycles, and provides a new class of chiral bicyclic amidines as the major products. A new catalyst system has been realized. The use of chiral biphenyl-based phosphoramidite ligands on rhodium provides an efficient cycloaddition between terminal alkyl alkynes and alkenyl isocyanates. The cycloaddition proceeds through a CO migration pathway, and generates various 5-alkyl indolizinone products with high enantiomeric excess. A four-step asymmetric synthesis of indolizidine (-)-209D has been achieved. A highly enantioselective rhodium-catalyzed [4+2+2] cycloaddition of terminal alkynes and dienyl isocyanates has been developed. The cycloaddition provides a rapid entry to highly functionalized and enantioenriched bicyclic azocines. This reaction represents the first [4+2+2] cycloaddition strategy to construct nitrogen-containing eight-membered rings.
  • ItemOpen Access
    Combinatorial discovery and optimization of novel metal oxide materials for photoelectrolysis using visible light
    (Colorado State University. Libraries, 2008) Woodhouse, Michael, author; Parkinson, Bruce, advisor
    Efficient and inexpensive production of hydrogen from water and sunlight has been the "holy grail" of photoelectrochemistry since Fujishima and Honda first demonstrated the feasibility of the process by illuminating TO2 single crystals with UV light. While it was a great proof of concept, a more suitable material will most likely be an oxide semiconductor containing multiple metals that will each contribute to the required properties of stability, light absorption, and being catalytic for hydrogen or oxygen evolution. Therefore we developed a high throughput combinatorial approach to prepare overlapping patterns of metal oxide precursors onto conducting glass substrates that can be screened for photolectrolysis activity by measuring the photocurrent generated by rasterng a laser over the materials while they are immersed in an electrolyte. A ternary oxide containing cobalt, aluminum and iron, and not previously known to be active for the photoelectrolysis of water, was identified using the combinatorial technique. The optimal composition and thickness for photoelectrochemical response of the newly identified material has been further refined using quantitative ink jet printing. Chemical analysis of bulk and thin film samples revealed that the material contains cobalt, aluminum and iron in a Co3O 4 spinel structure with Fe and Al substituted into Co sites with a nominal stoichiometry of Co3-x-yAlxFeyO4 where x and y are about 0.18 and 0.30 respectively. The material is a p-type semiconductor with an indirect band gap of around 1.5 eV, a value that is nearly ideal for the efficient single photoelectrode photoelectroylsis of water. Photoelectrochemical measurements indicate that the material has a respectable photovoltage but the photocurrent is limited by the slow kinetics for hydrogen evolution. This new cobalt iron aluminum oxide is most likely not the "holy grail" of photoelectrochemistry that we seek, but our methodology gives a rational approach for future materials discovery and optimization.
  • ItemOpen Access
    Indirect electrochemical detection of DNA hybridization based on catalytic oxidation of cobalt(II) and concentration gradient formation in redox conducting polymers
    (Colorado State University. Libraries, 2008) Xue, Di, author; Elliott, C. Michael, advisor
    Since the new concept was introduced back in 1993, efforts to develop electrochemical methods for detecting nucleic acid hybridization (e.g., DNA) have mushroomed. Compared with nearly all other analytical techniques, electrochemical instrumentation is inexpensive, robust, and relatively simple to operate. The first part of the dissertation (Chapter 1 to Chapter 4) describes the development of a novel electrochemical DNA sensor based on catalytic oxidation of a cobalt bipyridine "mediator molecule" on an ITO electrode. Interaction of the surface bound DNA probe with the DNA target results in formation of hybrid duplex, which subsequently brings redox catalyst molecules from solution to the electrode surface. The mode of selective catalyst binding is intercalation between base pairs of ds-DNA. This surface-bound catalyst "turns on" the redox chemistry of the mediator molecule which is otherwise kinetically inert to oxidation on ITO. With this approach, we demonstrate detection of a 20-mer DNA target oligonucleotide at picomolar concentrations with outstanding signal-to-noise. The second part of our research (Chapter 5) mainly concerns redox polymer films containing permanently locked concentration gradients. Upon redox gradient formation, the conducting polymer displays interesting properties, such as solid diode behavior and electroluminescence. Previous methods explored drying and/or cooling the film to physically immobilize its gradient. Unfortunately, this preservation was temporary, and underwent degradation over time. Our work is aimed to overcome this limitation by covalently attaching counterions to the polymer backbone and thus permanently locking the redox gradients. Both parts of this dissertation utilize heteroleptic metal complexes possessing redox potentials close to zero (vs SSCE). Compounds with highly negative potentials are strongly reducing and highly positive potentials means strong oxidizing capabilities, which exerts strict requirements on supporting electrolytes and solvents, including high impurity, broad potential window as well as exclusion of environmental interference. Thus, the closer the potential to zero (vs SSCE), the more stable (electrochemically) the complex and the easier the electrochemical measurements.
  • ItemOpen Access
    Asymmetric epoxidation of various olefins catalyzed by fructose- and glucose-derived ketones
    (Colorado State University. Libraries, 2009) Wong, On Lo Andrea, author; Shi, Yian, advisor
    Numerous laboratories have studied dioxirane- and oxaziridinium-mediated epoxidations during the past two decades. Many chiral ketone and iminium salt catalysts, bearing a wide variety of structural features, have been investigated. Out of the systems studied a fructose-derived ketone has been proven to be one of the most general and practical catalysts. This catalyst epoxidizes trans- and trisubstituted olefins in good yield and enantioselectivity, and it has been employed in the syntheses of many complex molecules. In efforts to expand the substrate scope a series of glucose-derived, oxazinolidine-bearing ketones were reported to be excellent catalysts for the epoxidation of conjugated cis-olefins. The stereodifferentiation in the epoxidation transition state originates from the attraction between the N-substituent of the oxazolidinone and the RÏ€ substituent on the olefin. The existence of this interaction was supported by the observation that 6-substituted chromenes were epoxidized with higher enantioselectivities than 8-substituted chromenes. Using this glucose-derived ketone system, substituted chiral styrene oxides could be obtained in 80-92% ee. Fluoroolefins were investigated as epoxidation substrates with several fructose- and glucose-derived ketone catalysts. A fluorine substituent was found to improve enantioselectivity in some cases but was detrimental to enantioselectivity in others. The substrate scope of a diacetate-containing ketone was expanded. High enantioselectivities were obtained for the epoxidation of trans- and trisubstituted olefins, and cis-olefins bearing a bulky substituent. The optical rotations of the resulting cis-epoxides were opposite to those obtained using glucose-derived ketones. 1,1-Disubstituted terminal olefins were epoxidized in good enantioselectivities with a glucose-derived morpholinone ketone. From the absolute configuration of the resulting epoxides, the major transition state appears to be a planar-like transition state. Also studied was a glucose-derived dimethylmorpholinone ketone that has the combined features of several of the previously studied ketones. This catalyst epoxidizes trans- and trisubstituted olefins in high enantoselectivities, but compared to the oxazolidinone-containing ketones gives slightly lower enantioselectivities with cis- and 1,1-disubstituted olefin substrates. Lastly, the epoxidation transition state model was studied using 18O-labeled ketone catalysts, and the results support the currently accepted transition state model.
  • ItemOpen Access
    Oxidation of unfunctionalized olefins involving three-membered heterocycles and its related applications
    (Colorado State University. Libraries, 2008) Wang, Bin, author; Shi, Yian, advisor
    Typically three-membered heterocycles are highly strained molecules. They can exist as stable functional groups or very reactive intermediates. This dissertation discusses three types of three-membered heterocycles including dioxiranes, epoxides, and diaziridines. Dioxirane, a three-membered ring peroxide, is a very powerful oxidant which transfers an oxygen atom to a variety of functional groups including heteroatoms, π-bonds, X-H δ-bonds (X = C or Si), and organometallic compounds. Our group has been interested in the asymmetric epoxidation of unfunctionalized olefins using chiral dioxiranes generated from chiral ketones and Oxone. Asymmetric epoxidation produces chiral epoxides, a very useful three-membered heterocycle, which can be opened and rearranged to form more complex chiral molecules. A glucose-derived ketone with an oxazolidinone moiety has been employed in asymmetric epoxidation of conjugated tri- and tetrasubstituted olefins. The asymmetric epoxidation and subsequent epoxide rearrangement produced the enantioenriched aryl-substituted epoxides, cyclopentanones, cyclobutanones, and γ-butyrolactones in good yields and enantioselectivities. In addition to the above chiral products, chiral allylic alcohols can also be produced via asymmetric epoxidation catalyzed by fructose-derived ketone and base-mediated epoxide isomerization in good yields, high enantioselectivities, and high stereoselectivities. It was proposed that the isomerization of acyclic silyl epoxides to give the (Z)-allylic alcohols proceeds through an unusual silicon-assisted E1cb mechanism based on deuterium-labeling experiments and other observations. A practical synthesis of a diacetate chiral ketone was developed. The application of this diacetate ketone in asymmetric epoxidation of trans- and trisubstituted olefins, as well as its related mechanism, are discussed. A ketone with two oxazolidinone rings proved to be a robust catalyst for asymmetric epoxidation. The catalyst loading can be reduced to 1 mol %, and high enantioselectivities can still be achieved. A glucose-derived ketone with a lactam ring has been employed in the epoxidation of 1,1-disubstituted olefins with good enantioselectivities. Studies indicated that the epoxidation of 1,1-disubstituted olefins with the lactam ketone proceeds mainly via a planar-like transition state. The α, α-dimethyl substituted lactam ketone shows different reactivity from those without substitutions. It is an effective catalyst for asymmetric epoxidation of trans- and trisubstituted olefins. A study on the structural effect of ketone catalysts on asymmetric epoxidation revealed that the nitrogen atom in the spiro ring of the oxazolidinone-containing ketone is an important structural element in asymmetric epoxidation of cis-olefins. N,N'-di-t-butylthiadiaziridine 1,1-dioxide, a nitrogen analogue of dioxiranes, was explored as a nitrogen source for Pd-catalyzed dehydrogenative diamination of unfunctionalized olefin. The diamination is likely to proceed via Pd-catalyzed allylic amination and subsequent cyclization. This diamination is mechanistically distinct from the previously studied process using di-t-butyldiaziridinone as nitrogen source, thus resulting in different regioselectivity.
  • ItemOpen Access
    Trimeric coiled-coils as viral fusion protein mimics
    (Colorado State University. Libraries, 2008) Travisano, Philip, III, author; Kennan, Alan J., advisor
    α-Helical coiled-coils, a protein structural motif formed by supercoiling of two or more component polypeptide strands, are ubiquitous mediators of biological structure and function. Their characteristic primary heptad repeat, denoted abcdefg, makes these complexes attractive scaffolds for studying self-assembly and molecular recognition. Assembly of these structures is driven by the hydrophobic effect in which the hydrophobic sidechains associated with positions a and d are specifically packed together. Recently we have described methods for controlling the assembly of 1:1:1 heterotrimeric coiled-coils using only interior hydrophobic core residues. These core residues assemble according to steric matching, one large sidechain packs against two small sidechains. In the following text we have explored new sidechain parings. This steric matching strategy affords maximal sequence flexibility in the patterning of exterior surface residues, which we have exploited to create mimics of therapeutically significant protein-protein interfaces. The Human Immunodeficiency Virus (HIV) envelope protein gp41 facilitates infection by promoting fusion of cellular and viral membranes. At the heart of its function is formation of a trimer-of-hairpins structure in which a C-terminal ligand peptide binds to an N-terminal coiled-coil surface. This interaction is reminiscent of those in numerous other viral systems, including visna, the sheep analog of HIV. The design of protein mimics for viral systems by installation of key contact residues onto heterotrimer coiled-coils will be further discussed. The following text will highlight the structural verification of these mimics through various spectroscopic techniques. Also the validation of these mimics will be tested by exposure to known viral inhibitors. The work included in this text builds on previous research conducted in our laboratory, but it provides new avenues for future projects to explore the detailed interactions within the viral fusion mimics. This will hopefully lead to a better understanding of the viruses being studied as well as the underlying molecular interactions taking place.
  • ItemOpen Access
    NMR investigation of the behavior of chlorpyrifos and methyl parathion sorbed on clays, and quantitative carbon-13 NMR analysis of sequence distributions in poly(ethylene-co-1-hexene)
    (Colorado State University. Libraries, 2008) Seger, Mark R., author; Maciel, Gary E., advisor
    Chapters 1 and 2 (and Appendix). Decomposition of chlorpyrifos and methyl parathion on kaolinite and various cation-exchanged montmorillonites (at room temperature, in the dark) was monitored by 31P NMR. Decomposition products included the results of hydrolysis reactions, isomerization reactions and oxidation reactions; mineralization also appears to occur in some cases. Assignments of 31P peaks was based mostly on literature values of chemical shifts of similar structures and 31P NMR experiments on DMSO-d6 extracts of the pesticide/clay samples. When initially sorbed onto the clay, both pesticides appear by solid-state 31P NMR to exhibit significant motion on the molecular level, resulting in almost liquid-like spectra. Over a period of days or weeks, the signal due to unreacted pesticide diminishes and was replaced by new 31P NMR signals arising from various decomposition products. The rate of pesticide decomposition was found to vary greatly, depending on the cation present in montmorillonite. The fastest initial decomposition (disappearance of unreacted pesticide) occurred with the Cu2+-exchanged montmorillonites. Higher hydration levels of Al-exchanged montmorillonite were found to reduce the decomposition rate of methyl parathion; similarly, chlorpyrifos decomposed more quickly when sorbed on Zn-montmorillonite with lower hydration levels. Chapter 3. Different 13C NMR methods of determining triad distributions in two poly(ethylene-co-1-hexene) copolymers are examined using high signal-to-noise 126 MHz 13C spectra of the copolymers dissolved in deuterated 1,2,4-trichlorobenzene at 398K. This examination includes three integration techniques, the experimental impact of decoupler sidebands and significantly non-equal 13C nOe values. A least-squares regression analysis technique for solving for triad mole fractions is tested and appears to be more reliable than two published algebraic expressions. The resultant triad mole fractions are compared to sequence distribution parameters expected by Bernoullian and first-order Markovian statistical models. On the basis of 13C NMR-determined average reactivity ratios, the copolymer designated sample H (5.3 mol % 1-hexene) appears to be a Bernoullian copolymer resulting from a single-site catalytic system. The copolymer designated sample L (3.6 mol % 1-hexene overall) is better described as a mixture of polyethylene and a Bernoullian copolymer with 6.4 mol % 1-hexene content.
  • ItemOpen Access
    Bipyridyl cobalt complex mediators in dye-sensitized solar cells
    (Colorado State University. Libraries, 2008) Scott, Michael J., author; Elliott, C. Michael, advisor
    Dye-sensitization of semiconductor substrates allows for efficient charge injection into the semiconductor conduction band. Dye-sensitized solar cells (DSSCs) exploit this for conversion of light into electrical energy. By employing mesoporous TiO2 a significant portion of visible light can be absorbed. The mesoporous TiO2, deposited on a transparent conducting oxide (TCO) medium, constitutes the photoanode of the DSSC. A wide range of materials may be used as a cathode. A redox electrolyte solution completes the cell. Typically, the I-/I3- redox couple has been employed in DSSCs. The use of bipyridyl cobalt complexes allows for tuning of the cell's electrochemistry, exploration of diverse cathode materials, and investigation of mediator solution additives. Cobalt complexes with alkyl, ester, and amide functionalities were considered throughout this body of work. The cobalt complexes were investigated on the basis of time dependence and electrode dependence. The cobalt complexes are stable for at least a period of one week when dissolved in γ-butyrolactone. Gold, carbon and modified TCO cathodes perform well in cells employing the alkyl substituted complex. Gold cathodes alone provide the best performance with cells employing the ester and amide substituted complex. An optically transparent cathode was developed for use in stacked DSSCs, allowing light that is not absorbed by the first DSSC in a stack to be absorbed by a second cell. A spectrally complementary dye in the second cell extends the light absorption to longer wavelengths. Spatial current images were obtained to investigate the local current behavior of cobalt mediated cells. Intentional electrode damage was visualized, and the effects of increased pressure on the cell were discussed. The use of phenothiazine (PTZ) moieties as co-mediators in cobalt mediated DSSCs was investigated. An anionic PTZ salt was most effective at reducing the photo-oxidized sensitizing dye. This PTZ salt enhanced the performance of DSSCs employing the alkyl substituted cobalt complex. Poor electronic coupling and decreased driving force prevents the PTZ salt from enhancing the performance of DSSCs employing the cobalt complexes with withdrawing functionalities.
  • ItemOpen Access
    Synthesis and electrical property measurements of individual layered transition metal dichalcogenide nanotubes and nanowires
    (Colorado State University. Libraries, 2008) Seley, David B., author; Parkinson, Bruce, advisor
    Nanotubes of the layered transition metal dichalcogenides (LTMDs) including MoS2, WS2, ReS2, and ReSe 2 have been synthesized. Additionally, nanowires of WS2 have been synthesized. All of the 1-dimensional structures synthesized used some form of a template to structurally direct 1-dimensional growth. The synthesis of the nanotubes of MoS2, WS2, and ReS2 utilized the pores of anodic aluminum oxide membranes to direct nanotube growth. WS 2 nanowires were grown with the assistance of the surfactant cetyltrimethylammonium bromide. ReSe2 nanotubes were synthesized by using Se nanotubes as a sacrificial template. The nanotubes and nanowires were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive spectroscopy (EDS), and X-ray diffraction (XRD). Information about the shape, identity, and nanostructure was gained utilizing these techniques. Electron beam lithography was used to make electrical contacts to the nanowires. Once the contacts were made, two point room temperature current voltage curves were recorded for MoS2, ReS2, and ReSe 2 nanotubes. The current voltage characteristics displayed I-V curves that were nearly linear, nearly symmetric, and nearly rectifying for these systems. The currents passed through these nanotubes ranged from nanoamperes to microamperes. Additional experiments on ReSe2 nanotubes indicated a change in resistance with exposure to ammonia and photocurrent generation when exposed to light.
  • ItemOpen Access
    Predicting the physical stability of biopolymers by self-interaction chromatography
    (Colorado State University. Libraries, 2008) Payne, Robert W., author; Henry, Charles S., advisor
    Biopolymers, including proteins and peptides, are increasingly taking the place of small molecules in manufacturing, health and home applications. The advantage of using biopolymers over small molecules for therapeutic applications include high activity, high specificity and low toxicity. The disadvantages of using biopolymers include large scale production, chemical instability and physical degradation. A biopolymer that shows promise for a specific application will not advance past early development if the protein lacks either chemical or physical stability. Of these two parameters, physical stability is often harder to predict and/or measure. The physical stability of a biopolymer can be improved by site-directed mutagenesis, glycosylation, post-translational modification and adjusting the solvent/co-solvent system. Quantitatively measuring the change in the physical stability of a protein in different solvent/co-solvent systems can increase the number of early developmental stage proteins that advance to commercial scale. Physical stability of proteins can be described by protein-protein interactions and measured by the osmotic second virial coefficient (B). However, current methods used to measure B such as static light scattering are not practical for large screening studies because of large protein consumption, low throughput, method variability and analyte size limitations. An alternative method to measure B is Self-Interaction Chromatography (SIC), which requires less protein, shorter analysis time, allows for miniaturization and capable of measuring B for small size biopolymer. The ability of SIC to measure B for a therapeutic protein, a peptide and membrane proteins in different solvent/co-solvent systems has been demonstrated in this dissertation.
  • ItemOpen Access
    Synthesis of stereochemically controlled functionalized vinyl polymers and polyesters by metallocene-based catalysts
    (Colorado State University. Libraries, 2009) Ning, Yalan, author; Chen, Eugene Y.-X., advisor
    The research presented herein studies the polymerization of functionalized alkenes (methacrylates and acrylamides) and cyclic esters (lactide and lactone) catalyzed by group 4 metallocene complexes. Key findings of this study include: (1) development of the novel diastereospecific ion-pairing polymerization effected by a catalyst system comprising a chiral C 2-zirconocene bis(ester enolate) and two equiv of lewis acid Al(C 6F5)3, producing polymers with isotactic, syndiotactic, and isotactic-b-syndiotactic multiblock microstructures, (2) development of the highly syndiospecific polymerization by C s-ligated ansa-zirconocene bis- and mono(ester enolate) complexes at room temperature, and (3) development of quantitatively isospecific polymerization of L-lactide by Cs-ligated ansa-zirconocene bis- and mono(ester enolate) complexes. The broad focus of this dissertation concerns the kinetic and mechanistic studies of the polymerization of functionalized alkenes and cyclic esters, which provided several novel and useful polymerization systems.
  • ItemOpen Access
    Part I. Fitting protein aggregation kinetic data relevant to neurodegenerative diseases with an "Ockham's Razor" model en route to meaningful rate constants and mechanistic insights. Part II. Dioxygenases: the development of new, and the reinvestigation of prior, precatalysts
    (Colorado State University. Libraries, 2009) Morris, Aimee M., author; Finke, Richard G., advisor
    This dissertation is presented in two parts. Part I starts with a review of models that have been used to curve-fit or obtain rate constants for protein aggregation kinetic data. Following the review, the research presented in Part I is primarily focused on fitting protein aggregation literature relevant to neurodegenerative diseases using the Finke-Watzky (hereafter F-W) 2-step model of nucleation and autocatalytic growth. Part I includes: (i) the fits to the F-W model and resultant nucleation and growth rate constants of 14 representative data sets of amyloid-β, α-synuclein, and polyglutamine aggregation relevant to Alzheimer's, Parkinson's, and Huntington's diseases, respectively; (ii) the fits of 27 data sets of yeast and mammalian prion aggregation, along with the resultant rate constants and interpretation of factors that contribute to nucleation and growth of prion aggregates; and (iii) a re-examination of variable temperature and variable pH α-synuclein aggregation data in which the insights are elucidated that: (a) the processes of nucleation and growth are energetically similar, (b) the net charge of the protein affects nucleation, and (c) the lag-time does not, as previously thought, correspond to the rate of nucleation. Part II begins with a brief review of the importance of dioxygenases followed by an introduction to two important synthetic dioxygenases, the catechol dioxygenase [VO(3,5-DTBC)(3,5-DBSQ)]2 (where 3,5-DTBC = 3,5-di- tert-butylcatechol and 3,5-DBSQ = 3,5-di-tert-butylsemiquinone) and the claimed polyoxometalate dioxygenase, [WZnRu2(OH)(H 2O)(ZnW9O34)2]11-. The synthesis and characterization of a new dioxygenase, V(3,6-DBSQ)(3,6-DTBC) 2, along with the initial catalytic results with the H2(3,6-DTBC), substrate are given. Next is a full report of the dioxygenase activity with H2(3,5-DTBC) and H2(3,6-DTBC) substrates of three d 0 metal precatalysts: [VO(3,5-DTBC)(3,5-DBSQ)]2, V(3,6-DTBC) 2(3,6-DBSQ), and [MoO(3,5-DTBC)2]2. The d 0 vanadium bound to a semiquinone ligand in both V-precatalysts appears to be an important component for obtaining dioxygenase products from the H 2(3,5-DTBC) and H2(3,6-DTBC) substrates. Finally, Part II concludes with a reinvestigation a claimed dioxygenase, [WZnRu2(OH)(H 2O)(ZnW9O34)2]12- (1). Three independent samples of 1 from two different laboratories, samples that also give the same catalysis results as previously reported, are all consistent with the composition of the parent, Ru-free polyoxometalate, [WZn3(H2O)2(ZnW9O34) 2]12- (2). Also, simple mixtures of 2 plus [Ru(DMSO)4Cl2] is a ca. 2-fold more efficient catalyst than "1", placing in serious doubt a prior Nature paper detailing the claim that "1" is a Ru-based, all-inorganic dioxygenase.
  • ItemOpen Access
    Two novel fluorescent immunoassays for multianalyte detection
    (Colorado State University. Libraries, 2009) Murphy, Brian M., author; Henry, Charles S., advisor
    Since their inception several decades ago, immunoassays have become the workhorse technology for measuring both proteins and small molecules in complex biological matrices. Immunoassay technologies have become important tools in the field of medicine, where measurement of a variety of analytes in media such as urine, blood, or serum is essential. To diagnose many diseases and conditions, clinicians rely on the quantification of several biomarkers in a sample. However, common immunoassay systems such as ELISA can measure only a single analyte at a time, and can take hours to complete. This dissertation details two new immunoassay methods designed to simultaneously quantify several analytes from a single sample, Protein patterning on a silicon nitride wafer is performed for a micromosaic fluorescent immunoassay in which the thyroid hormone thyroxine (T4), inflammation biomarker CRP, and BSA-conjugated 3-nitrotyrosine (3NT) are assayed in the competitive format. The assay for 3NT is then combined with a sandwich immunoassay for superoxide hi dismutase (SOD) and catalase (CAT), demonstrating that micromosaic immunoassays can be used to simultaneously quantitate small and large targets. In a second approach, a unique capillary electorphoresis immunoassay is performed for 3NT, carboxy-methyl lysine (CML), and thyroxine (T4). Termed a cleavable tag immunoassay (CTI), the method relies on bioconjugation of IgGs to unique chemically cleavable fluorophores which serve as reporter groups for each analyte. A novel method for bioconjugation of IgG to fluorophore to produce the conjugates is presented. Microchip CE with fluorescence detection is demonstrated and resolution is optimized for the separation of three different CTI conjugate fragments. This dissertation will argue for the viability of both methods as relevant in the development of true multianalyte clinical diagnosis assays.
  • ItemOpen Access
    The Stetter reaction: scope and mechanistic investigation
    (Colorado State University. Libraries, 2009) Moore, Jennifer Lynn, author; Rovis, Tomislov, advisor
    Since the isolation and characterization of stable imidazolinylidene carbenes by Arduengo in 1991, chemists have been increasingly fascinated by their potential as modifying ligands on transition metals. However, it was not until Ukai demonstrated the efficacy in the benzoin reaction that the use of stable nucleophilic carbenes as catalysts was used for organic transformations. The last 10 years in particular have seen a tremendous explosion of interest in this area, with new reactivity manifolds having been developed across a range of reaction subtypes. The highly enantioselective intramolecular Stetter reaction has been expanded to include the formation of tetrasubstituted stereocenters. The reaction is mild, general, and tolerates aromatic, aliphatic, sulfur, oxygen, and nitrogen tethering of aldehyde and Michael acceptor. The current substrate scope includes compounds with varying electronics and sterics. A mechanistic investigation into the intramolecular Stetter reaction has been conducted. The rate law of the reaction was determined and coupled with kinetic isotope effects, competition experiments and calculations to suggest that proton transfer is rate determining. These results provide the foundation for future development of better catalysts and expansion of substrate scope. The inherent tunability of nucleophilic carbenes as catalysts promises great latitude in overcoming issues associated with functional group compatibility, turnover frequency, turnover number and, naturally, expansion of substrate type. This suggests that nucleophilic carbene catalysts will likely remain useful tools in organic synthesis for the foreseeable future.
  • ItemOpen Access
    Catalytic asymmetric Stetter reaction: intramolecular desymmetrization of cyclohexadienone and intermolecular reaction of glyoxamide
    (Colorado State University. Libraries, 2009) Liu, Qin, author; Rovis, Tomislav, advisor
    A series of cyclohexadienones were synthesized through dearomatization of phenols. The asymmetric intramolecular desymmetrizations of these substrates via Stetter reactions afford hydrobenzofuranones in good yields and excellent selectivities. Up to three contiguous stereocenters, as well as quaternary stereocenter, have been generated. An asymmetric intermolecular Stetter reaction of glyoxamides with alkylidenemalonates has been successfully developed. These reactions are catalyzed by a pyrrolidinone-derived carbene catalyst, and proceed in good yields with high asymmetric induction. When alkylidene ketoamides are employed, the reactions afford desired β-ketoamides in good yields, excellent enantioselectivities, and good diastereoselectivities. A carbene-catalyzed asymmetric redox reaction of ynal has been investigated. Cyclohexadienone-tethered ynal and alkylidenemalonate-tethered ynal were demonstrated as suitable substrates for the redox reaction. The desired products were obtained with moderate yields and modest selectivities.
  • ItemOpen Access
    Selective two-electron reductive defluorination of 1-Me-CB(11)F(11-) and related anions: synthesis and characterization of salts of 1-Me-12-R-CB(11)F(10-) and related anions
    (Colorado State University. Libraries, 2008) Kobayashi, Yoshihiro, author; Strauss, Steven H., advisor
    In this dissertation, a method to selectively defluorinate and functionalize the antipodal B-F bond in 1-R-CB11F11-anion is described. The defluorination reaction mechanism using sodium naphthalenide to form an intermediate anion was investigated by 19F{ 11B} NMR, cyclic voltammetry, and computational analysis. The stoichiometric amount of sodium naphthalenide to reduce 1-Me-CB11F11 - was determined to be two. 19F{11B} NMR of the intermediate did not show a peak due to the antipodal fluorine atom, which suggested that the B-F bond is broken. Cyclic voltammetry of 1-Me-CB 11F11- showed a reversible one-electron reduction. In presence of excess Na+, the reduction occurred as an irreversible two-electron process, but at the same potential as the one-electron process. The addition of excess 18-crown-6 restored the reversible one-electron process. This suggested that Na+ is probably incorporated in the structure of the intermediate. Based on these results, two structures were proposed, one with B···F···Na+ linkage the other with B···Na+···F - linkage at the antipodal position. The intermediate did not show electron-exchange between the intermediate and the starting material, 1-Me-CB 11F11-. This suggested that the structure with B···F···Na+ is unlikely. Computational analysis of the proposed structures predicted that the latter structure is 55 kJ/mol more stable than the former. From these results, the structure of the intermediate was suggested to be (1-Me-CB 11F11···Na+···F -)2-. Using various electrophiles, several derivatives of 1-Me-12-R-CB 11F10-. For example, when methyl iodide was added to the intermediate solution, the major product was 1,12-Me2-CB 11F10-. An isomer, 1-Me-7-X-CB11F 10- was formed as one of the byproducts, however, the isomeric ratio of the 12-isomer and the 7-isomer was 9:1. X-ray crystal structures of four new compounds NMe4(1,12-Me 2-CB11F10), Cs(1-Me-12-I-CB11 F10), Cs(1-Me-12-SiPh3-CB11F10), and Ag2(1-Me-12-SiPh3-CB11F 10)2·C6H6 were obtained. The characteristics of each structure are described. One of them, Ag2(1-Me-12-SiPh 3-CB11F10)2·C6H 6, contained two Ag+ with different coordination spheres. One of them was the first example of tetrahediral Ag(arene)4 +. In order to investigate the effect of substitution on the B12 vertex of 1-Me-CB11F11- on the coordinating and ion-pairing abilities of the anions, DFT calculations were performed with 1-Me-CB11F11-, 1,12-Me2-CB 11F10-, and 1-Me-12-H-CB11F 10-. The calculations predicted that both 1,12-Me 2-CB11F10- and 1-Me-12-H-CB 11F10- had slightly less ion-pairing ability than 1-Me-CB11F11-. Especially, significant change was observed on the B 12-X direction on the ion-pairing ability. The solution conductivities of N(n-Bu)4(1-Me-CB 11F11) and N(n-Bu)4(1,12-Me 2-CB11F10) also showed that N(n-Bu) 4(1,12-Me2-CB11F10) is 16% more conductive than N(n-Bu)4(1-Me-CB11F11). The DFT-predicted relative energies of the 12-, 7-, and 2-isomers of Fe(Cp)(CO) 2(1-Me-CB11F11), Fe(Cp)(CO)2(1,12-Me 2-CB11F10), and Fe(Cp)(CO)2(1-Me-12-H-CB 11F10) were also calculated. For Fe(Cp)(CO)2(1-Me-CB 11F10), the 12-isomer was predicted to be the most stable. This suggests that the B12-vertex is the most strongly coordinating. For Fe(Cp)(CO) 2(1,12-Me2CB11F10), the strongest coordinating site is on the B7-F7 direction, however, the difference between the 12- and 7-isomers was only 1.8 kJ/mol. For Fe(Cp)(CO)2(1-Me-12-H-CB 11F10), 12-isomer was the most stable, and 7- and 2- isomers were predicted to have much higher energies than the 12-isomer.
  • ItemOpen Access
    Bioanalytical applications of capillary electrophoresis and microfluidics: from metabolomics to biofuels
    (Colorado State University. Libraries, 2010) Holcomb, Ryan E., author; Henry, Charles S., advisor
    Capillary electrophoresis (CE) and related microfluidic technologies are increasingly being utilized as state of the art analysis tools in the field of bioanalytical chemistry. The following dissertation highlights selected applications of CE and microfluidics for metabolomics and microalgal-based biofuels research. Metabolomics research focused on targeted metabolic profiling and fingerprinting of biofluids using both conventional and microchip CE. Metabolite analysis in biofluids was of interest as this can be a useful clinical tool for monitoring disease states and treatment efficacy. Initial work in this area focused on targeted metabolic analysis of the cardiovascular disease biomarker homocysteine (Hcys). In this work, serum Hcys was analyzed using microchip CE (MCE) coupled with pulsed amperometric detection. Using this system, Hcys could be resolved from other electrochemically active serum components in under a minute by employing appropriate separation conditions. Following this targeted metabolic analysis, research shifted to a more comprehensive metabolic fingerprinting study of dogs undergoing chemotherapy for diffuse large B cell lymphoma. Urine samples from diseased and non-diseased dogs were obtained at various clinical time points and analyzed using CE with UV detection. The resulting fingerprints were compared for differences in metabolite make-up using multivariate statistical techniques. In an attempt to conduct this type of research at the microscale, a MCE device was developed with an integrated electrode array detector for resolving the multiple components present in biological samples. Selective detection and electrochemical resolution of co-migrating analytes could be facilitated with this device via judicious choice of detection potential at the multiple working electrodes. Improvement in detection capability of this system compared to single electrode MCE systems should allow for its use in rapid metabolic fingerprinting and profiling analyses. The final area of research presented in this dissertation involved use of microfluidics for culturing and screening cellular lipid accumulation in microalgae exposed to various environmental stressors. A microfluidic device was developed which contained integrated valves for facilitating cell culture and conducting imaging assays on-chip. Lipid accumulation in stressed microalgae was determined using fluorescence microscopy techniques. Additional experiments were conducted using gas chromatography to determine the types of lipids being accumulated in these stressed microalgae.
  • ItemOpen Access
    Concise syntheses of notoamides B-E and stephacidin A
    (Colorado State University. Libraries, 2008) Grubbs, Alan Whitfield, author
    Presented herein are concise syntheses of the cytotoxic alkaloids notoamides B-E. A highly convergent synthesis is outlined from commercially available 6-hydroxy indole and naturally derived L(-)-Proline or L(-)-cis-3-hydroxy Proline. Also presented is a 16 step synthesis of (±)-11-epi -norgeamide B and finally a concise 17 step synthesis of stephacidin A. The synthesis of each member of the norgeamide and notoamide family of natural products is proposed via the tunable activation or deactivation of the 1,7-dihydropyrano[2,3-g]indole ring system in order to exploit a mild Pinacol-type rearrangement en-route to notoamides A-C and norgeamides A and B, or the prevention thereof, to allow access to the pyrroloindole scaffold of norgeamides C and D or notoamide D.
  • ItemOpen Access
    [1,3]-oxygen to carbon rearrangement for the construction of carbon-carbon bonds between adjacent rings and 1,3-dioxepines in synthesis
    (Colorado State University. Libraries, 2007) Frein, Jeffrey Daniel, author; Rovis, Tomislav, advisor
    Several methods for the stereoselective formation of carbon-carbon bonds between contiguous rings where a stereogenic center is already present have been examined. The approaches investigated were: a [1,3]-oxygen to carbon rearrangement of cyclic vinyl acetals; an intermolecular enolsilane addition into an in situ generated oxocarbenium ion; an intramolecular conjugate addition of tethered alkoxy enones; and epimerization of several α-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have enabled formation of both the traps: anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. The C2-C2' relative stereochemistry of the carbon-carbon bond between the adjacent rings was proven via a chemical correlation. The versatility of 1,3-dioxepines as precursors to the formation of 1,4-diols and 1,2,4-triols has been examined. The rapid synthesis of unsymmetrical 1,3-dioxepines and the installation of a 4-acetoxy substituent as a synthetic handle for further functionalization has been realized. The Lewis acid mediated addition into in situ generated oxocarbenium ions has been developed for variety of different nucleophiles. Furthermore, a highly trans -diastereoselective Heck reaction has been performed on unsymmetrical 1,3-dioxepines and their synthetic utility as precursors to the formation of 2,3,4-alkyl substituted tetrahydrofurans and 2-methoxy-4,5-alkyl substituted tetrahydrofurans have been exploited.