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Design of Well-Defined Mesoporous Silicas via Surfactant Templating Method Enhanced by the Use of Swelling Agents
Year of Dissertation:
Surfactant-templated ordered mesoporous materials continue to attract tremendous attention as these materials are characterized by reproducibility and predictability of their synthesis as well as their wide range of potential applications, which serve as future opportunities for additional advancement. The main purpose of this dissertation is to advance the understanding how to control the structural features and properties in the synthesis of well-defined porous materials via surfactant templating method, while keeping in mind that the uniformity of pore size and structural ordering are essential characteristics for these well-defined materials. The work was primarily focused on the issue of the unit-cell size and pore size adjustment in the large-pore domain (that is, for pore diameters above 12 nm) for two-dimensional hexagonal silica structures with cylindrical pores (referred to as SBA-15 silicas). The use of common poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), PEO-PPO-PEO, surfactants, commercially known as Pluronics® in combination with appropriate hydrophobic micelle swelling agents was pursued. The main hypothesis was that it is possible to judiciously select surfactant/swelling agent pairs to achieve optimal structural adjustment capabilities. Moreover, it was hypothesized that different surfactant/swelling agent pairs may work most effectively in certain temperature intervals. The choice of Pluronic tri-block copolymer as main templating agent, the selection of micelle expanders, the adjustment of initial synthesis temperature (including room temperature conditions), and the adjustment of the amount of silica precursor (tetraethylorthosilicate) can systematically affect the structure of porous silica materials formed via the surfactant-micelle-templating synthesis approach. The advancement in pore size tailoring discussed in this dissertation focuses on the above aspects. In particular, considerations based on the extent of solubilization of organic compounds in Pluronic surfactants paved the way to the identification of new excellent swelling agent for the synthesis of large-pore SBA-15. Ordered SBA-15 silica with d100 interplanar spacing of up to about 30 nm has been successfully synthesized. Modifications in the synthesis approach in terms of shortening the duration of the synthesis to as little as six hours and eliminating the need for temperature control to carry out the SBA-15 synthesis were found effective for the synthesis around room temperature. Highly ordered face-center-cubic silica materials have also been synthesized using surfactants with moderate content of the hydrophilic PPO domains challenging our current understanding of viable selections of surfactants for the synthesis of materials with spherical mesopores. These materials exhibited increased mesopore volumes when compared to the silicas obtained via the traditional synthesis of materials with spherical pores involving block copolymers with a high fraction of the hydrophilic PEO domains. Overall, the dissertation demonstrates that the synthesis mixture composition and synthesis conditions can be predictively selected to achieve particular structural properties (such as unit-cell size) or to observe formation of material under particular conditions. Moreover, some additional opportunities emerge as we explore the predictability of the synthesis pathways.
Large-pore mesoporous organosilicas and related polymer nanocomposites
Year of Dissertation:
The research work in this dissertation covers the synthesis of mesoporous organosilicas and (organo)silica/polymer nanocomposites. The content can be divided into 4 parts (8 chapters). The first part of the dissertation is the introduction, which covers the background and progress in the field of mesoporous silicas, periodic mesoporous organosilicas and related inorganic/polymer nanocomposites. The second part of the dissertation (Chapter 2-5) involves the synthesis of mesoporous organosilicas from different organosilane precursors at mild acid concentration (0.1 M HCl) and low temperature (0 or 7 °C) using Pluronic F127 (EO106PO70EO106) as a surfactant template. Chapter 2 focused on the synthesis of large-pore periodic mesoporous organosilicas (PMOs) with ethylene bridging groups using 1,2-bis(triethoxysilyl)ethane (BTEE) and 1,2-bis(trimethoxysilyl)ethane (BTME) as well as phenylene- bridged PMOs using 1,4-bis(triethoxysilyl)benzene (BTEB). The use of different micelle swelling agents was also discussed. The resulting PMOs in many cases had face-centered cubic structure with large pore diameters, pore volumes and unit-cell parameters. In Chapter 3,the synthesis of large-pore ethenylene (-CH=CH-) bridged PMOs with tunable pore sizes and face-centered cubic structures (Fm3m symmetry) using 1,2-bis(triethoxysilyl)ethylene (BTEEn) was discussed. The unit-cell parameters were tuned from 27 to 40 nm and the pore diameters were tuned from 13 to 22 nm by carefully adjusting the amount of swelling agent in the reaction mixture. Chapter 4 covered the synthesis of biphenylene-bridged PMOs using 4,4′-bis(triethoxysilyl)-1,1′-biphenyl (BTEBP) under the above mentioned conditions. The resulting materials had an ordered structure with pore diameters around 8.5 nm. Because of the presence of large aromatic groups in the framework precursor, the materials display a high molecular scale periodicity, which may contribute to the unique sheet type particle morphology. Chapter 5 discussed the synthesis of mesoporous organosilicas with pendant methyl groups using methyltriethoxysilane (MTES) as an organosilica precursor. These organosilicas have one methyl group attached to each silicon atom. The organosilicas have the pore diameters around 10 nm with cylindrical pores arranged in two-dimensional (2-D) hexagonal structure. The mesoporous organosilicas with accessible pores (through framework micropores) were thermally converted to closed-pore mesoporous organosilicas, without any degradation (or with minor degradation) of methyl groups. The closed-pore mesoporous organosilica materials usually have low dielectric constant, and so if a similar pore closing without organic group degradation can be accomplished for materials in a thin-film form, the resulting materials could be very useful in electronics industry. The third part of the dissertation covers the synthesis of inorganic/polymer nanocomposites. In Chapter 6, poly(N-isopropylacrylamide) (PNIPAAm) brushes were grafted on the surface of large-pore methylene-bridged periodic mesoporous organosilica using surface-initiated activators regenerated by electron transfer (ARGET) atom transfer radical polymerization (ATRP). The loading of the polymer can be controlled over a wide range by changing the polymerization time. A high loading of polymer (up to ~35 wt. %) was achieved without the mesopore blocking. This research demonstrates that the range of ordered mesoporous materials suitable as supports for polymer brushes extends beyond pure-silica materials into hybrid organic-inorganic frameworks. In Chapter 7, poly(2-(2’-methoxyethoxy)ethyl methacrylate) (PMEO2MA), poly(oligo(ethylene glycol) methacrylate) (Mn=300 g/mol) (PMEO5MA) and P(MEO2MA-co-MEO5MA) brushes were grafted on the surface of ultra-large-pore SBA-15 silica using ARGET ATRP. It was seen that loading of the polymer can be controlled over a wide range by changing the polymerization time. High loading of polymer (up to ~34 wt.%) was achieved without the pore blocking. The last part of the dissertation (Chapter 8) covers the conclusions from all the chapters.
Ultra-Large-Pore Ordered Mesoporous Organosilicas and Related Hollow Nanoparticles
Year of Dissertation:
My dissertation describes the synthesis of ultra-large-pore ordered mesoporous organosilicas and related hollow nanoparticles. In the first part, we developed a versatile approach through which a series of periodic mesoporous organosilicas (PMOs) with 2-dimensional hexagonal structure and different bridging groups can be synthesized. The bridging groups are methylene (-CH2-), ethylene (-CH2CH2-), ethenylene (-CH=CH-), and phenylene (-C6H4-). For this purpose, a combination of a commercially available triblock copolymer Pluronic P123 (EO20PO70EO20) with judiciously chosen micelle swelling agent (cyclohexane, or 1,3,5-triisopropylbenzene) was used as a miceller template, and the initial step of the synthesis was performed at temperature between 10 and 18 oC, followed by hydrothermal treatment at 100-150 oC. The PMOs were characterized using small-angle X-ray scattering (SAXS), nitrogen adsorption, transmission electron microscopy, and solid-state 29Si NMR. For all PMO compositions, the formation of 2-D hexagonal structures with (100) interplanar spacing, d100, up to 21-26 nm was achieved, which is at least seven nanometers larger than d100 reported earlier for any PMO with 2-D hexagonal structure. The nominal (BJH) pore diameters up to 20-27 nm were achieved for the considered compositions of PMOs with with 2-D hexagonal ordering, while even larger pore sizes were sometimes attained for disordered or weakly ordered structures. The mesopores exhibited constrictions or narrow entrances that were widened by increasing the hydrothermal treatment temperature. The pore diameter tended to increase as an initial synthesis temperature decreased, allowing for the pore size adjustment, but the useful temperature range depended on the bridging groups. The present work suggests that the low-temperature micelle-templated synthesis with judicious selected swelling agents is a general pathway to ultra-large-pore 2-D hexagonal PMOs with both aliphatic and aromatic bridging groups. In the second part, we have demonstrated the synthesis of large-pore ethylene-bridged periodic mesoporous organosilica with face-centered-cubic structure. This was achieved by the use of judiciously chosen swelling agents and Pluronic F127 block copolymers at sub-ambient temperature (~ 15 oC). While our work confirmed that 1,3,5-trimethylbenzene (TMB) which was already employed by other researchers, is a facile swelling agent for Pluronic F127-templated ethylene-bridged PMOs with cubic Fm3m structure and our optimization of the synthesis afforded hitherto unreported unit-cell size and pore size for this PMO, it was also demonstrated that swelling agent predicted to have a higher extent of solubilization in Pluronics than TMB provide vast new opportunities. In particular, xylene was found to afford highly ordered materials with large unit-cell size and pore diameter, and a wide range of moderately or weakly ordered materials with very large unit-cell parameters (up to ~ 50 nm) and some with very large pore diameters (up to ~ 20 nm). In this case, the pore size and unit-cell size was tunable by adjusting the amount of inorganic salt (KCl) in the synthesis mixture. The use toluene allowed for the increase in the primary mesopore volume and also afforded large-pore PMOs in the absence of an inorganic salt. The use of the latter was also not required when benzene was used as a swelling agent. The identification of new swelling agents for ethylene-bridged PMO with spherical mesopores is likely to be extendable on PMOs of other framework compositions and for other related materials. In the third part, based on understanding of the condition for the formation of ordered mesoporous organosilicas, we were able to synthesize hollow nanoparticles with different organic bridging groups. Different organic bridging groups such as methylene, ethylene, ethenylene, and phenylene were incorporated in the organosilica walls of the hollow nanoparticles. Further, we were able to synthesize hollow nanotubules comprising of these bridging groups in the walls.
Polymer Pen Printing: A Tool for Studying 2D Enzymatic Lithography and Printing 3D Carbon Features
Year of Dissertation:
Polymer Pen Lithography (PPL) is a promising molecular printing approach which combines the advantages of both microcontact printing (low cost, high-throughput) and the dip pen lithography (DPN) (arbitrary writing, high-resolution) into one cohesive lithography method to create 2 dimensional (2-D) patterns with micro/nano-features on different substrates. The goal of this dissertation is to design and develop a new tool based upon PPL, which is not limited to forming 2D parallel patterns, but can also create 3D complex microstructures, finding applications in both biotechnology and Micro-Electro-Mechanical systems (MEMS) technology. This novel approach is named Polymer Pen Printing. Different from PPL using traditional dry-ink printing methods, an inking step is added to each printing repetition in the polymer pen printing process. Thus a wide range of ink materials with diverse viscosities can be transferred to substrates to create functional 2D and 3D microstructures. The polymer pen printing apparatus used in this thesis has been accomplished and introduced in Chapter 2. As a preliminary attempt, the single polymer pen printing approach was developed by simply attaching a solid polydimethylsiloxane (PDMS) pen tip to a multi-axis robot for small microarray fabrication. Compared to the single pen printing method, multi-pen printing can create large arrays of features. Therefore, an improved apparatus for polymer pen printing with high-throughput was discussed and built. Silicon molds, which consist of hundreds of uniform pyramidal openings, were photolithographically defined and etched using hydrofluoric acid (HF) followed by potassium hydroxide solution; after surface-modification with fluorosilane, these silicon molds were used to cast arrays of PDMS pyramidal pen tip. The cast PDMS pen array was mounted to a hollow holder with a 45° mirror inside. Therefore, each PDMS pen can be observed and monitored from the microscope on the side. To achieve prints less than 1 micron across, a Z axis stage with nanometer resolution was incorporated; and to control the compression of PDMS pen tips, a force gauge was also incorporated to detect 1 mg of applied force from the tips. The printing process for the multi-pen system is almost the same as single pen system. PDMS pens are coated with ink solution before each printing cycle by dipping into an inkwell and then brought into contact with the substrate surface. Thus multiple patterns, one from each tip, are created in parallel simultaneously. Furthermore, with control of the printing force, feature sizes could be controlled over the range submicron to tens of microns. Three ink candidates have been printed by polymer pen printing approach to fabricate 2D&3D microstructures. The first ink material is Barium Strontium Titanate (BST) nanocrystallites dispersed in a furfuryl alcohol (FA), which was printed by the single PDMS pen with 100 µm tip diameter (Chapter 3). After printing, samples were heated to crosslink FA monomers, forming a stable polymeric matrix with embedded BST nanocrystallites. Without shear-thinning properties, BST/FA ink cannot be used to build 3D posts, but it has the capability to create circular patterns with different thickness by the single or multi-tier deposition method. It was found that the thickness of film increased linearly with the number of deposits without changing the diameter significantly. This encouraging result could enable the formation of microcapacitors with multi-tiered structure. Moreover, the study of printing parameters, including printing height and ink pick-up position, shows that changes to the pen positions in the ink reservoir or substrate have essentially no impact on deposit thickness or diameter. Beyond that, the effect of surface chemistry of PDMS pen and silicon wafer have also been studied. The plasma treated hydrophilic PDMS pen can pen transfer more BST/FA than untreated one; and the larger diameters with smaller thickness were obtained on a hydrophilic silicon wafer. The second ink candidate is a dilute aqueous solution of enzyme Candia antartica lipase B (CALB), which is known to catalyze the decomposition of poly (ε-caprolactone) (PCL) films. By bringing enzymes into contact with pre-defined regions of a surface, a polymer film can be selectively degraded to form patterned features that are requited for applications in biotechnology and electronics. This so-called “enzymatic lithography” is an environmentally friendly process as it does not require any actinic radiation or synthetic chemicals to develop required features. But the need to restrict the mobility of the enzyme in order to maintain control of feature sizes poses a significant challenge. In Chapter 4, after writing 2D enzyme patterns onto a spin-cast PCL film by single pen printing, samples with CALB were incubated at 37 °C and 95% relative humidity (RH) for up to 7 days to develop features. The CALB selectively degraded the PCL film during incubation, forming openings through the film. The size of these features (10 to 50 µm diameter) is well suited for use as biocompatible micro-reactors. Previous study of patterning CALB by single polymer pen printing technique resulted in slow etch rates, low throughput and poor image quality. In Chapter 5, I present an improved enzymatic lithography approach, still based on enzyme CALB and PCL system, which can resolve fine-scale features (< 1 µm across) in thick (0.1 – 2.0 µm) polymer films after 5 minutes to 2 hours of incubation at 37 °C and 87% RH. Immobilization of the enzyme on the polymer surface was monitored using fluorescence microscopy by labeling CALB with FITC. The crystallite size in the PCL films was systematically varied; small crystallites resulted in significantly faster etch rates (20 nm/min) and the ability to resolve smaller features (as fine as 1 µm). The effect of printing conditions and RH during incubation is also presented. Patterns formed in the PCL film were transferred to an underlying copper foil demonstrating a “Green” approach to the fabrication of printed circuit boards. In parallel, the third ink material is a mixture of 25 wt% graphite dispersed in a high viscosity phenolic resin n-methyl-2-pyrrolidone (NMP) solution, which can be converted into carbon/carbon composites after a pyrolysis process. The 3D polymeric posts were created by depositing multilayers of thixotropic phenolic ink on a silicon substrate by single polymer pen printing method with a 10 µm radius PDMS pen tip (Chapter 6). After pyrolysis at 1000 °C in a nitrogen (N2) atmosphere, the polymeric features were converted to the glassy carbon/graphite features with a high aspect ratio (>2). These features may be used as microelectrodes. Last, arrays of needle-shaped glassy carbon have been developed by a drawing approach using multi-pen printing technique followed by simple pyrolysis process (Chapter 7). To build polymeric needles with ultra-high aspect ratio, the polymeric ink was prepared by dissolving phenolic resin in the high boiling point (204 °C) solvent NMP without fillers to achieve good printability and suitable viscosity. By slowly lifting up the print head from substrate, liquid needle structures were formed and then solidified on silicon substrates or gold electrodes due to the solvent evaporation. In addition, suspended resin fibers connected to two electrodes have also been fabricated by precisely controlling the movement of the PDMS pen. After pyrolysis, these resin features were converted to glassy carbon and the 3D structures remained. The electrical characterization results showed that glassy carbon made by this method had relatively low resistivity (2.5 ⨯ 10-5 Ωm). Therefore the glassy carbon based microneedles are well-suited to be electrodes for electrochemical sensors for biological applications.
Aqueous Solvation of Protein Secondary Structures: Density Functional Theory Study
Year of Dissertation:
In recent years, van der Waals forces have received considerable attention among the scientific community. It is hard to overestimate the significance of dispersion forces which are thought to play important roles in the energetics of biological molecules, such as DNA and peptides. However, the weakest of interactions is also the most difficult to approach by theoretical methods and has been troubling computational chemists for at least last two decades. In my thesis I will answer how well recently developed density functionals deal with the dispersion in the case study of dispersion-enhanced induction complexes, relative stability of pi-stacking and hydrogen bonded dimers, and protein secondary structures. The presented results undermine the belief that recent widely-parametrized and/or dispersion-corrected functionals outperforms older well-established functionals, like famous B3LYP. In the second part of my thesis I will focus on the influence of aqueous solvent on protein structures. Water is present in all biological systems, where it is not only a static medium of the reaction, but also an active part of the process called life, and it requires careful treatment. I compare models of implicit and explicit solvation for beta-turns, alpha-helices, and beta-sheets. I find that solvation by small water clusters can alter the molecular properties of gas phase molecules and continuous methods are not able to model all effects.
Oxocarbenium Ion and Alkene Metathesis Strategies for the Synthesis of Complex Cyclohexanes
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ABSTRACT Oxocarbenium Ion and Alkene Metathesis Strategies for the Synthesis of Complex Cyclohexanes. by Clayton Mattis Mentor: Professor David R. Mootoo Highly oxygenated cyclohexanes comprise the structures of a number of pharmacologically interesting molecules, including potently bioactive natural products and carbapyranosides. The latter, which are unnatural analogues of carbohydrates in which the ring oxygen of the parent sugar is replaced with a methylene group, have attracted interest as hydrolytically stable mimetics of their parent O-glycosides. This research reports the development of two general methodologies for the synthesis of highly oxygenated cyclohexanes: (1) Oxocarbenium Ion Cyclization (OCC) and (2) Ring Closing Metathasis (RCM). Chapter one gives a review of the literature on the synthesis for highly oxygenated cyclohexanes. Previous results from this laboratory have shown that OCCs on cyclic oxocarbeniums derived from 1-thio-1,2-O-isopropylidene precursotrs are highly stereoselective for cyclohexanes and tetrahydropyrans with cis 3,4-diols. To expand the scope of the OCC methodology, the goal was to evaluate the OCCs on non-cyclic oxocarbenium ions derived from mixed thioacetal precursors. Chapter two describes reactions with alkene nucleophiles. In particular, the OCC on an alkene-mixed thioacetal precursor aimed at the cyclohexane core of the immunosuppressive agent FR65814, was examined. This study revealed that OCCs on non-cyclic oxocarbenium ions could deliver cyclohexanes with trans 3,4-diols in high stereoselectivety. As for the previous observations on OCCs with cyclic oxocarbenium ions, these results can be explained in terms of conformational arguments. Chapter three discusses OCCs for non-cyclic oxocarbenium ions and enol-ether nucleophiles. These reactions were expected to give highly oxygenated cyclic enol ether precursors for carba- and C- pyranosides with trans 3,4-diols. However, in all cases, complex mixtures of products that suggested multiple deleterious pathways from the initial formed cyclization intermediates, was observed. This result contrasts to the successful OCCs involving cyclic oxocarbenium ions and enol ethers, and suggests that conformational rigidity is an important requirement for OCCs involving enol ether nucleophiles. Therefore, the OCC strategy appears to be limited to the synthesis of carba- and C- pyranosides with cis-3,4-vicinal diols. Chapter four describes a more general synthesis of carbapyranosides, which is based on the RCM of an enol ether - alkene substrate. This reaction delivers a six-membered cyclic enol ether in which the enol ether oxygen is exocyclic, and contrasts with a related cyclization from the Postema group that provides C-1-substituted glycals, i.e. cyclic enol ethers with an endocyclic enol ether oxygen. This RCM strategy for carbapyranosides was applied to the carba-arabinose and carba-xylose analogues of the sugar residues in the potent antitumor steroidal glycoside OSW-1.
The Development Of New Organocatalysts and New Organocatalytic Cascade Reactions
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Organocatalysis is the use of small organic molecules to catalyze chemical reactions. They are generally cheaper, less toxic, and easier to handle on a laboratory and industrial scale than more traditional metal-based catalysts. This dissertation discusses the development of new organocatalysts and organocatalytic methods for the asymmetric synthesis of useful small molecules. The research conducted has specifically focused on the use of chiral diarylprolinol silyl ether organocatlysts and their ability to catalyze a variety of useful cascade reactions through iminium and enamine catalysis. Cascade reactions are useful in that a great deal of molecular complexity may be generated in a one-pot process using simple, readily available building blocks. Herein, is provided a comprehensive background on the use of diarylprolinol silyl ethers in the catalysis of iminium-initiated cascade reactions. The research conducted has focused on three main topics: 1.) The development of a novel class of bifunctional bissulfonamide organocatalysts for the asymmetric conjugate addition of dicarbonyls to nitroolefins. 2.) The use of diarylprolinol silyl ether organocatalysts to catalyze a novel Michael-Michael cascade reaction which generates fused carbocycles. 3.) The discovery and development of a novel organocascade kinetic resolution reaction using diarylprolinol silyl ether organocatalysts, which can be used for the synthesis of chiral 2,6-disubstituted tetrahydropyrans and chiral 2,5-disubstituted tetrahydrofurans.
SPECIATION OF TECHNETIUM-99 INCORPORATED INTO METAL OXIDE MATRICES: A MOLECULAR LEVEL UNDERSTANDING OF Tc-99 REDUCTION AND ITS COMPLEXATION INTO POLYOXOMETALATES
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Technetium-99 (99Tc) is a long-lived (T1/2 = 2.13 x 105 years) β-emitting (Emax = 294 KeV) radionuclide formed during the fission of 235U and fallout from nuclear weapons testing. It exists in relatively high concentrations in nuclear waste tanks, and the pertechnetate (TcO4-) anion has been shown to leach into surrounding subsurface soils and groundwaters. Due to its long half-life and the high mobility of the pertechnetate (TcO4-) anion, 99) Tc management is an issue for both waste characterization and long-term storage. A better understanding of both its extensive redox chemistry and the parameters that affect the speciation and coordination environment of Tc will promote the development of more appropriate methods for the separation of Tc from nuclear waste tanks as well as more fitting mediums for storage. Polyoxometalates (POMs) are early transition metal oxide clusters that are chemically robust. They have homogeneous crystalline structures and are known to be good model systems for metal oxide solid-state materials such as the glasses and ceramics used to house nuclear waste. The synthesis of pure 99Tc-POM compounds, however, is complicated by both the unwanted hydrolysis of the Tc(V) starting material and difficulties with the separation of the free POM ligand from the desired 99Tc-POM complex. We have developed methods for the clean synthesis of the 99Tc - (α1-P2W17O61)10-) and (α2-P2W17O61)10-) Wells-Dawson POM compounds (as both organic and aqueous soluble complexes) and characterized them using various spectroscopic techniques. POMs also have unique, tunable, electron transfer abilities and can be reduced, both electrochemically and photochemically in the presence of a sacrificial electron donor, by multiple electrons while maintaining their structural integrity. To this end we have investigated a number of POMs; Keggin ions, (XW12O40n-), X=P, n=3; Si, n=4; Al, n=5), the Wells-Dawson lacunary isomer (α2-P2W17O61) 10-), and a "wheel" POM, P8W48O18440-), for their ability to reduce pertechnetate and sequester low valent 99Tc. The resulting low valent Tc species have been characterized by physical methods including multinuclear NMR and electrochemistry.
Studies Toward a General Synthesis of Poly-Substituted Alpha-Hydroxytropolones
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ABSTRACT Studies Toward a General Synthesis of Poly-Substituted Alpha-Hydroxytropolones by Christine Meck Advisor: Prof. Ryan P. Murelli, Ph.D. Chapter 1: This chapter gives a brief history of α-hydroxytropolones, how they were discovered and unique properties of these substrates. Included is a background on the bioactivity of these substrates in cellular targets such as bacteria, fungi, parasites, tumors and toxicity, as well as their ability to inhibit various metallo-based enzymes. Structure activity relationships studies are reviewed on important metalloenzymes HIV-Reverse Transcriptase (RT) and Inositol monophosphatase (IMPase). Finally the chapter finishes with a synthetic overview of α-hydroxytropolones including natural product targets such as puberulic acid, puberulonic acid, β-thujaplicinol, and α-hydroxytropolone. Chapter 2: A brief review on β-hydroxy-γ-pyrone based oxidopyrylium cycloadditions will be presented as well as important oxidopyrylium cycloaddition/ring opening procedures to yield natural tropolone products. Research from the Murelli laboratory will be highlighted. This chapter will discuss a new synthetic route toward functionalized α-hydroxytropolones. A β-hydroxy-γ-pyrone intermolecular oxidopyrylium cycloaddition with a range of alkynes that was optimized to an efficient and high yielding process will be discussed. Next two ring catalyzed ring openings will be discussed; one that utilizes boron trichloride that attains α-hydroxytropolones and 7-methoxytropolones, and a triflic acid mediated sequence that yields exclusive 7-methoyxtropolones and furans. Finally, a new reaction with the oxidopyrylium species will be highlighted that shows the exchange of alcohols in these reactive species. Chapter 3: Chapter three describes the background on three specific medicinal targets: ANT (2”)-Ia, HIV RT RNase H, and HBV RT RNaseH and preliminary structure activity relationship studies with α-hydroxytropolones synthesized in this research are outlined.
Benzophenone photoprobes for chemical proteomics and drug target identification
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Benzophenone photoprobes are widely used in photoaffinity-labeling studies, especially for the characterization of ligand-receptor interaction. Photolabeling studies using benzophenone, however, are by no means routine experiments. It is not uncommon that carefully designed photoligands fail to label target proteins. In order to get insights into the important factors that affect the photolabeling efficiency, we conducted a structure-activity relationship study (SAR) on adenine-benzophenone photoligands. The study suggested that conformational flexibility was the determining factor that controls the photolabeling efficiency by benzophenone photoprobes. In theory, photoaffinity-labeling can also be used for target identification of small molecules. However, the complexity of proteins in biological samples, such as cell lysate, tissue homogenates and serum samples, limits the use of benzophenone photoprobes in drug target identification and chemical proteomics. By using so called "blocking strategy" we were able to systematically classify the list of proteins identified from photoaffinity-labeling studies using benzophenone. The findings of this study enabled us to refine the experimental protocol for drug target identification and chemical proteomics using benzophenone photoprobes. During the affinity purification of phochemically biotinylated proteins, we discovered that monomeric avidin resin can selectively enrich heat shock proteins (Hsps) from complex proteomes. Although such serum Hsps or circulating Hsps, has been linked to various diseases, including cancer and cardiovascular diseases, their characterization have been hampered be the abundant proteins in serum such as albumin and immunoglobulings. The development of simple and reproducible method for Hsp enrichment opens a new opportunity to define the roles of circulating Hsps in various diseases.