Alumni Dissertations

 

Alumni Dissertations

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  • Chiral Sulfurization For Synthesis Of Antisense Oligonucleotides

    Author:
    Joshua Mukhlall
    Year of Dissertation:
    2010
    Program:
    Chemistry
    Advisor:
    William Hersh
    Abstract:

    Chapter 1: Antisense and RNA interference (RNAi) reagents are two of the most widely studied oligonucleotide-based therapeutics. Phosphorothioate oligonucleotide, an antisense reagent, has a stereogenic center at the phosphorothioate linkage and in the absence of enantioselective synthesis, a mixture of diastereomers results. Stereodefined phosphorothioates have shown greater antisense activity; however, only a few research groups have successfully designed methods for enantioselective synthesis of phosphorothioates with >98% de, albeit in low yields. This dissertation presents a conceptually different method for enantioselective synthesis of phosphorothioate oligonucleotides via a Curtin-Hammett system that requires epimerization of the phosphite triester on the reaction time scale and selective sulfurization of one of the equilibrating epimers with a chiral sulfurizing reagent. Chapter 2: 2-Cyanoethyl[5'-O-acetyl-2'-deoxythymylyl]-(3',5')-3'-O-(acetyl)-2'-deoxythymidine phosphite triester was found to invert at 150 ºC with ΔG = 33.0 ± 0.2 kcal/mol. Separation of the two diastereomers of the phosphite triester was successfully achieved via its 2-cyanoethyl[5'-O-(p,p'-dimethoxytrityl)-2'-deoxythymylyl]-(3',5')-3'-O-(tert-butyldimethylsilyl)-2'-deoxythymidine boranophosphate analogue. For the inversion study the p,p'-dimethoxytrityl and tert-butyldimethylsilyl groups were substituted with acetyl groups to reduce decomposition during heating. Attempts to induce inversion at lower temperature with acidic and radical species failed. Chapter 3: Chiral analogues of phenylacetyl disulfide (PADS) and 5-methyl-3H-1,2,4-dithiazol-3-one (MEDITH) were synthesized from the same α-alkylated carboxylic acids to give products with enantiomeric purities of 99.0 to >99.9% and 86.1-99.4%, respectively. X-ray diffraction results for one pair of enantiomers unequivocally establish the absolute configurations of two disulfides, and density functional theory (DFT) calculations suggest that the observed high specific rotations could be due to preferred retention of helicity about the S-S bond in solution. Chapter 4: Phosphite triesters with varying degrees of steric hindrance around the phosphorus atom (β-cyanoethyl, TMS, TBDMS, and TPS derivatives) were screened against chiral analogues of PADS and MEDITH. The RPS:SPS diastereomeric ratios of the resulting phosphite sulfides or phosphorothioates were determined by reverse-phase HPLC, and a numerical procedure was developed to express the diastereoselectivity of the reactions. The best selectivities to give RPS enriched and SPS enriched phosphorothioates were achieved with MEDITH analogues (S)-6d (naproxen derivative) (14.7% de) and (S)-6c (isopropyl group at the α position) (-7.9% de), respectively, when reacted with the phosphite triester bearing the TMS group.

  • SYNTHESIS, CHARACTERIZATION, RAMAN, AND SURFACE ENHANCED RAMAN STUDIES OF SEMICONDUCTOR QUANTUM DOTS

    Author:
    Yi Pan
    Year of Dissertation:
    2012
    Program:
    Chemistry
    Advisor:
    John Lombardi
    Abstract:

    The major contributions and discoveries of the dissertation include: (1) Homogeneous nucleation processes for the formation of nanocrystals can occur at low temperature and do not need to proceed at high temperature to overcome a high energy barrier. Monodisperse PbS quantum dots (QDs) obtained with nucleation and growth at 45°C support this finding. (2) Monodisperse single elemental Se QDs can be produced by simple solution crystallization from TDE (1-tetradecene) or ODE (1-octadecene). (3) TDE is a better non-coordinating solvent compare to ODE. STDE (S dissolved in TDE) and SeTDE (Se dissolved in TDE) are stable reagents with long storage time. They can be used as universal precursors for S-containing and Se-containing QDs. (4) QDs synthesis can be carried out at low temperature and relatively short reaction time using the simple, non-injection, one-pot synthetic method. (5) The one-pot method can be extended for the synthesis of QDs and graphene oxide nanocomposites and metal and graphene oxide nanocomposites. (6) PbCl2-OLA (oleylamine) is a universal system for the synthesis of Pb-chaclogenides QDs. (7) Surface enhanced Raman spectroscopy (SERS) is used to probe both size and wave length dependent quantum confinement effects (QCEs) of PbS QDs. (8) Raman spectroscopy is a powerful tool to elucidate crystal structure of Se nanoclusters with size of 1-2 nm. Semiconductor QDs have attracted considerable attention due to their potential for energy-efficient materials in optoelectronic and solar cell applications. When the radius of a QD is decreased to that of the exciton Bohr radius, the valence and conduction bands are known to split into narrower bands due to QCEs. QCEs are both size and wave length dependent. We have developed, synthesized and characterized a series of Pb-chaclogenide QDs, which all the sizes of the QDs are monodisperse and smaller than their respective exciton Bohr radius, to study the QCEs of these QDs. SERS is used as a crucial tool to investigate these QCEs. The QCEs are due to any of the following three resonances or a combination among them: interband resonance, molecular state resonance, and charge-transfer resonance.

  • Applications of Bionanotechnology

    Author:
    Christophe Pejoux
    Year of Dissertation:
    2011
    Program:
    Chemistry
    Advisor:
    Hiroshi Matsui
    Abstract:

    The aim of nanotechnology is to devise technologies at the crossroads of chemistry, physics and biology to shape matter at the atomic scale to form nanosized functional objects and to arrange them into intricate assemblies to elaborate new devices. Today, its biological aspect is largely emphasized to tackle biomedical issues such as pathogen identification, disease diagnosis and treatment. In this respect, interdigitated electrodes were employed to monitor the presence of harmful bacteria, then to attempt to detect human PC3 carcinoma prostate cells as well as the size variation of stimulus-responsive hydrogel beads designed for drug delivery. Our second project aimed at demonstrating the potential use of TiO2-labeled antibodies as substitute for horse-radish peroxidase-labeled antibodies for Enzyme-Linked ImmunoSorbent Assays (ELISA). Our last project revolved around harnessing the enzymatic activity of urease to grow silver-sulfide nanoparticles.

  • FACTORS AFFECTING THE REMOVAL OF AMMONIA FROM AIR ON CARBONACEOUS ADSORBENTS: INVESTIGATION OF REACTIVE ADSORPTION MECHANISM

    Author:
    Camille Petit
    Year of Dissertation:
    2011
    Program:
    Chemistry
    Advisor:
    Teresa Bandosz
    Abstract:

    Air pollution related to the release of industrial toxic gases, represents one of the main concerns of our modern world owing to its detrimental effect on the environment. To tackle this growing issue, efficient ways to reduce/control the release of pollutants are required. Adsorption of gases on porous materials appears as a potential solution. However, the physisorption of small molecules of gases such as ammonia is limited at ambient conditions. For their removal, adsorbents providing strong adsorption forces must be used/developed. In this study, new carbon-based materials are prepared and tested for ammonia adsorption at ambient conditions. Characterization of the adsorbents' texture and surface chemistry is performed before and after exposure to ammonia to identify the features responsible for high adsorption capacity and for controlling the mechanisms of retention. The characterization techniques include: nitrogen adsorption, thermal analysis, potentiometric titration, FT-IR spectroscopy, X-ray diffraction, Energy Dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy and Electron Microscopy. The results obtained indicate that ammonia removal is governed by the adsorbent's surface chemistry. On the contrary, porosity (and thus physisorption) plays a secondary role in this process, unless strong dispersive forces are provided by the adsorbent. The surface chemistry features responsible for the enhanced ammonia adsorption include the presence of oxygen- (carboxyl, hydroxyl, epoxy) and sulfur- (sulfonic) containing groups. Metallic species improve the breakthrough capacity as well as they lead to the formation of Lewis acid-base interactions, hydrogen-bonding or complexation. In addition to the latter three mechanisms, ammonia is retained on the adsorbent surface via Brønsted acid-base interactions or via specific reactions with the adsorbent's functionalities leading to the incorporation of ammonia into the adsorbent's matrix. Another mechanism involves dissolution of ammonia in water when moisture is present in the system. Even though this process increases the breakthrough capacity of a material, it provides rather weak retention forces since ammonia dissolved in water is easily desorbed from the adsorbent's surface.

  • PEPTIDE NANOTUBES AND THE EXPERIMENTAL DESIGN INTEGRATING NANOPARTICLES FOR USE IN NANOELECTRONICS

    Author:
    Precila Porrata
    Year of Dissertation:
    2009
    Program:
    Chemistry
    Advisor:
    Hiroshi Matsui
    Abstract:

    Scientists have just begun to explore the world of nanotechnology, as instruments become more sophisticated areas previously unable to be seen or probed can now be studied. Peptide nanotubes are often used in experiments since they are extremely versatile. They are nontoxic, self-assembled, they have available functional groups in order to bind to other compounds and the tubule structure allows for the exclusivity of inside or outside binding. The ability of the peptide tubes to bind to other compounds permits biomineralization and additionally creates an atmosphere of selective binding to desired locations. The importance in using peptide nanotubes for study becomes the ability to rely on consistency of the shape and size. Ph factors can regulate whether a tubule or sheet is formed in solution, while controlling the diameter has been achieved through the use of various membranes, such as polycarbonate and alumina oxide. One of the main goals in nanotechnology is the ability to create functional machines of decreased size, improved storage capacity and faster cooler electrical components, therefore, making peptide nanotubes with electrical properties is of extreme interest. This dissertation takes a look at the properties of peptides coated with FePt and Pt.

  • SELF-ORGANIZED PORPHYRIN NANOMATERIALS FOR SOLAR ENERGY HARVESTING

    Author:
    Ivana Radivojevic
    Year of Dissertation:
    2010
    Program:
    Chemistry
    Advisor:
    Charles Drain
    Abstract:

    New concepts in the design and function of organic dyes as sensitizers for solar energy harvesting are needed. Commercial viability constrains these designs: (a) cost effective synthesis, (b) long-term stability, and (c) an important goal is to reduce the environmental impact of the product at the end of its life cycle. Simple porphyrinoid dyes meet these constraints, but new modes of incorporation into devices are needed to increase the efficiency of charge separation that drives any photonic device designed to harvest light. In this thesis, we will show how complex material architectures on surfaces need not to be the result of complex molecular structures or strong intermolecular forces that form in solution and deposit intact onto surfaces. Varying environmental conditions we can dictate morphology of self-organized structures on surfaces. These studies provide further insights into the design principles, processing, and extent of electron and energy transfer in supramolecular porphyrin materials. We are also developing a new strategy to couple porphyrinoid dyes to oxide surfaces using hafnium and zirconium metalloporphyrins and metallophthalocyanines. The mode of dye attachment to oxide surfaces is a key parameter for the construction of efficient dye sensitized solar cells. Porphyrinoid dyes containing oxophylic group (IV) metal ions that protrude from on face of the macrocycle allow connections directly to oxide surfaces, wherein the metal ion serves as the conduit. Since the charge transport efficiency is mediated by appropriate matching of molecular HOMO-LUMO gaps to semiconductor band gaps, we will show characterized solution phase ground and excited redox potentials of these dyes, and also photophysical properties of dye excited state using transient absorbance spectroscopy.

  • Metal Nanoparticles Immobilized on Basic Supports as Catalysts for Hydrogenation and Dehydrogenation Reactions of Relevance to Cleaner Fossil Fuels and Alternative Sources of Energy

    Author:
    Reena Rahi
    Year of Dissertation:
    2014
    Program:
    Chemistry
    Advisor:
    Roberto Sanchez-Delgado
    Abstract:

    We developed a series of catalysts, composed of metal nanoparticles immobilized on basic supports for the hydrogenation of heteroaromatics of relevance to cleaner fossil fuels and biodiesel, and for the dehydrogenation of heteroaromatics of relevance to hydrogen storage in organic liquids. Our catalyst design involves nanostructured catalysts composed of metal particles immobilized on basic supports capable of ionic mechanism that may avoid catalyst poisoning and enhance catalytic activity. We prepared a new catalyst composed of Pd nanoparticles immobilized on MgO by NaBH4 reduction of Na2PdCl4 in methanol in the presence of the support. TEM measurements revealed well-dispersed 1.7 nm Pd particles attached to MgO, also characterized by XPS, XRD and hydrogen pulse chemisorption measurements. The new catalyst is efficient for the hydrogenation of the heterocyclic ring of quinolines, as well as for the mild reduction of a variety of alkenes representative of fuel components, and the partial saturation of biodiesel. In the second part, we switched our attention to ruthenium nanoparticles, with the aim of achieving higher activity and broader reactivity, supported on functionalized carbon nanotubes, of higher surface area. Our second catalyst was prepared by first attaching pyridine groups to the surface of the nanotubes, and then depositing the metal particles by NaBH4 reduction of RuCl3.3H2O. TEM, XRD and XPS analysis indicate the presence of 1.7 nm Ru(0) particles attached mainly to the surface of the nanotubes. The Ru/py-CNTs results in an unprecedentedly high activity for the selective hydrogenation of N-heteroaromatic compounds, with respect to other reported systems. The activity of this catalyst was extended also to plain aromatic compounds under mild conditions and to the challenging S-heteroaromatics under more forcing conditions. Lastly, we evaluated the efficacy of the catalyst for the dehydrogenation of 1,2,3,4-tetrahydroquinoline, which was achieved with reasonable turnover frequencies under moderate conditions. The hydrogenation/dehydrogenation reactions thus establish a cyclic process of possible utility in hydrogen storage in organic liquids. We screened other substrate pairs that may be adequate for hydrogen storage, by computational study of the thermodynamics of dehydrogenation, which allowed us to identify other N-heterocycles that may prove useful in future studies.

  • New Ruthenium (II)-Chloroquine Complexes and Metal-Free Aminoquinolines: Synthesis, Antimalarial Activity and Mechanism of Biological Activity

    Author:
    Chandima Rajapakse
    Year of Dissertation:
    2010
    Program:
    Chemistry
    Advisor:
    Roberto Sanchez-Delgado
    Abstract:

    New Ruthenium (II)-Chloroquine Complexes and Metal-Free Aminoquinolines: Synthesis, Antimalarial Activity and Mechanism of Biological Action by Chandima S. K. Rajapakse Advisor - Professor Roberto A. Sanchez-Delgado Malaria is widespread in many tropical and subtropical regions and causes between one and three million deaths annually. The disease is caused by a protozoan parasite of the genus Plasmodium that is transmitted primarily by the female Anopheles mosquito. Chloroquine (CQ) is the most commonly used antimalarial drug, but resistant strains of P. falciparum have emerged and thus improved chemotherapies are required. Modifications of the molecular structure of chloroquine led to other effective quinoline based drugs but unfortunately, resistance to these drugs is now also common in many parts of the world. The success of cisplatin and other platinum anticancer drugs has stimulated a renaissance of inorganic medicinal chemistry and the search for complexes of other transition metals with better biological properties. Among them, ruthenium complexes are attracting increasing attention as potential chemotherapeutic agents against a variety of diseases. Complexation of CQ to Ru has been previously shown by our group to enhance the activity against resistant strains of the malaria parasite, as for instance the complex [RuCl2(CQ)]2. In the first phase of this thesis we adopted a molecular design based on Ru(II) forming coordinate bonds to CQ through one of the basic nitrogen atoms. A series of new organo-RuII-CQ complexes were synthesized and characterized by use of a combination of NMR and FTIR spectroscopy with DFT calculations. All the new complexes were active against CQ-resistant (Dd2, K1, and W2) and CQ sensitive (FcB1, PFB, F32 and 3D7) malaria parasites (Plasmodium falciparum); importantly, the potency of these complexes against resistant parasites is consistently higher than that of the standard drug chloroquine diphosphate (CQDP). In order to understand the origin of the improved antimalarial activity, we have measured water/n-octanol partition coefficients, pKa values, heme binding constants, and heme aggregation inhibition activity of the new (π-arene)-Ru-CQ complexes. Measurements of heme aggregation inhibition activity of the metal complexes atq water/n-octanol interfaces qualitatively predict their superior antiplasmodial action against resistant parasites, in relation to CQ. Some interesting tendencies emerge from our data, indicating that the antiplasmodial activity is related to a balance of effects associated with the lipophilicity, basicity, and structural details of the compounds studied. We concluded that the increase in the lipophilicity of CQ caused by coordination to the Ru-containing fragments is beneficial for overcoming resistance but the reduction in basicity due to the blocking of one active nitrogen atom by the metal limits the therapeutic potential of the complexes. Therefore, new compounds combining the desired basicity and lipophilicity are needed. Based on this new model, two new metal free 4-aminoquinoline derivatives were synthesized and characterized by 1D/2D NMR spectroscopy, elemental analysis and mass spectrometry. Both compounds are highly active in vitro against CQ-resistant strains of P. falciparum (K1, K14 and Dd2) as well as a CQ-sensitive strain (D6). Both compounds are more basic and more lipophilic than the standard drug CQ. Our mechanistic studies demonstrate the validity of our hypothesis: that the structural and physicochemical modifications of 4-aminoquinoline imposed by the presence of the lipophilic substituent as a side chain lead to an enhanced activity against malaria parasites, while retaining heme aggregation as the main target of action.

  • De Novo Designed Safranine Enzymes

    Author:
    Gheevarghese Raju
    Year of Dissertation:
    2012
    Program:
    Chemistry
    Advisor:
    Ronald Koder
    Abstract:

    ABSTRACT DE NOVO DESIGNED SAFRANINE ENZYMES by Gheevarghese Raju Advisor: Professor Ronald L. Koder De novo designed safranine enzymes are functionally parallel to NAD(P)H: flavinnitroreductases. The non-natural redox cofactor safranine has a very low reduction potential, -290 mV versus flavins -190 mV. A difference of 100 mV provides an additional 2.3 Kcal/mol energy to drive reduction reactions. Also safranine has an intrinsic unstable semiquinone oxidation state providing a doorstep for hydride transfer mechanism. Hence safranine enzymes will perform the electron transfer reaction, which is similar to the natural nitroreductases avoiding all oxygen activating free-radical side reactions. We designed a whole series of safranine binding helical bundles which catalyzes NAD(P)H dependent nitroaromatic reduction. Latest studied saf-X and safX-Loop proteins hold promise towards fully functional artificial enzymes. A novel synthesis pathway of generating different safranine derivatives was developed. These derivatives differ in their characteristic reduction potentials, fluorescent and visible spectra. This will allow the amendment of reduction reaction towards any particular nitroaromatic substrate. Our goal is to create artificial safranine enzymes, which can be used for cancer prodrug activation, treatment of atherosclerosis, explosive sensing, biofuels as well as green chemical catalysis.

  • DESIGN AND SYNTHESIS OF SQUARAMIDE -BASED MOLECULAR MACHINES

    Author:
    Vijayakumar Ramalingam
    Year of Dissertation:
    2009
    Program:
    Chemistry
    Advisor:
    Prof. Rajeev Muthyala
    Abstract:

    Artificial molecular machines are sought after in a wide variety of fields. They are useful in the construction of nanodevices (molecular valves, brakes, nanocars, rotors and ratchets), for ion transport and also for optical data storage. In an effort to develop new ion-transportand drug delivery strategies we became interested in designing molecular machines based on amide derivatives of squaric acid (squaramides). In this study, we first determined that secondary diaryl squaramides, which exist in the extended ZZ conformation, are excellent neutral receptors for biologically important anions such as chloride, carboxylate, and dihydrogen monophosphate. Next, we envisioned a molecular valve approach to regulate anion binding to squaramides via changes in the external environment (for example, a change in solvent polarity). We reasoned that in non-polar solvents, intramolecular hydrogen bonding between the carbonyl groups and the squaramide NHs would block anion binding (OFF state) while in a polar solvent disruption of intramolecular hydrogen bonding and reorientation of the carbonyl allows anion binding (ON state). Using ortho benzoyl substituted squaramides, we successfully applied the molecular valve approach to chloride binding. We subsequently studied the generality of the molecular valve approach with other ortho substituents such as secondary and tertiary amides, esters, and nitro groups. We found that the success of the molecular valve approach depends on whether, in a given solvent, intra-molecular hydrogen bonding is stronger or weaker relative to intermolecular hydrogen bonding with chloride ion. A significant effort was also spent on developing tertiary squaramide-based molecular machines for drug delivery. Initial studies revealed that simple (for example, N, N'-dimethyl derivatives) tertiary diaryl squaramide exhibited a preference for folded EE conformation regardless of solvent polarity. For our goal of transforming these squaramides to functional molecular machines, we decided to exploit the hydrophobic effect. In nonpolar solvents we anticipated that the tertiary squaramides would exhibit a preference for EE conformation while in aqueous medium we reasoned that the conformation would switch to ZZ driven by the hydrophobic effect. However we soon experienced major synthetic challenges. The literature procedures for the synthesis of these tertiary aryl squaramides routinely resulted in low yields with significant squaraine impurities. We therefore developed a novel copper-based method to synthesize symmetrical tertiary diaryl squaramides. Importantly, this method also enabled synthesis of unsymmetrical tertiary diaryl squaramides. Syntheses, conformational preferences, and our attempts at developing hydrophobically driven molecular machines will also be discussed in this dissertation.