VTechWorks Repository :: Browsing by Author "Gandour, Richard D."

Browsing by Author "Gandour, Richard D."

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Ab initio and Direct Quasiclassical Trajectory Study of the F + CH₄ → HF + CH₃ and F + C₂H₆ → HF + C₂H₅ Reactions
Weiss, Paula (Virginia Tech, 2007-09-25)
The reparametization of semiempirical Hamiltonians is an emerging method used in direct dynamics studies. The use of semiempirical Hamiltonians in direct dynamics studies diminishes the computational cost of trajectory calculations and negates the need for an analytical potential energy surface when performing reaction dynamics studies. The reparametization of semiempirical Hamiltonians increases the agreement with experiment and high level ab initio theory. We have chosen to create one set of new parameters that apply to two related reactions, F + CH₄ → HF + CH₃ and F + C₂H₆ → HF + C₂H₅. We have performed an electronic structure study for these reactions. The ab initio data obtained from the electronic structure study is then used as the reference for a reparametization of the PM3 Hamiltonian. The reparametization has improved the ab initio and PM3 reaction energy and potential energy surface scan agreement. This new set of parameters for PM3 (SRP-PM3) is used to perform a direct quasiclassical trajectory study of the reactions. The vibrational and rotational HF distributions calculated using SRP-PM3 are compared with experiments. We have observed an improvement in the agreement with experimental vibrational distributions but have seen no change in the rotational distributions.
AFM surface force measurements between hydrophobized gold surfaces
Wang, Jialin (Virginia Tech, 2008-09-08)
In 1982, Israelachvili and Pashley reported the first measurements of a hitherto unknown attractive force between two mica surfaces hydrophobized in cetyltrimethylammonium bromide (CTAB) solutions. Follow-up experiments conducted by many investigators confirmed their results, while others suggested that the "hydrophobic force" is an artifact due to nanobubbles (or cavitation). Evidences for the latter included the discontinuities (or steps) in the force versus distance curves and the pancake-shaped nano-bubbles seen in atomic force microscopic (AFM) images. Recent measurements conducted in degassed water showed, however, smooth force versus distance curves, indicating that the hydrophobic force is not an artifact due to nanobubbles.1, 2 Still other investigators3, 4 suggested that the long-range attraction observed between hydrophobic surfaces is due to the correlation between the patches of adsorbed ionic surfactant and the patches of unoccupied surface. For this theory to work, it is necessary that the charged patches be laterally mobile to account for the strong attractive forces observed in experiment. In an effort to test this theory, AFM force measurements were conducted with gold substrates hydrophobized by self-assembly of alkanethiols and xanthates of different chain lengths. The results showed long-range attractions despite the fact that the hydrophobizing agents chemisorb on gold and, hence, the adsorption layer is immobile. When the gold surfaces were hydrophobized in a 1 Ã 10-3 M thiol-in-ethanol solution for an extended period of time, the force curves exhibited steps. These results indicate that the long-range attractions are caused by the coalescence of bubbles, as was also reported by Ederth.5 The steps disappeared, however, when the species adsorbed on top of the chemisorbed monolayer were removed by solvent washing, or when the gold substrates were hydrophobized in a 1 Ã 10-5 M solution for a relatively short period of time. AFM force measurements were also conducted between gold substrates coated with short-chain thiols and xanthates to obtain hydrophobic surfaces with water contact angles (ï ±) of less than 90o. Long-range attractions were still observed despite the fact that cavitation is thermodynamically not possible. Having shown that hydrophobic force is not due to coalescence of pre-existing bubbles, cavitation, or correlation of charged patches, the next set of force measurements was conducted in ethanol-water mixtures. The attractive forces became weaker and shorter-ranged than in pure water and pure ethanol. According to the Derjaguin's approximation6, an attractive force arises from the decrease in the excess free energy (ï §f) of the thin film between two hydrophobic surfaces.7 Thus, the stronger hydrophobic forces observed in pure water and pure ethanol can be attributed to the stronger cohesive energy of the liquid due to stronger H-bonding. Further, the increase in hydrophobic force with decreasing separation between two hydrophobic surfaces indicates that the H-bonded structure becomes stronger in the vicinity of hydrophobic surfaces. The force measurements conducted at different temperatures in the range of 10-40C showed that the hydrophobic attraction between macroscopic surfaces causes a decrease in film entropy (Sf), which confirms that the hydrophobic force is due to the structuring of water in the thin film between two hydrophobic surfaces. The results showed also that the hydrophobic interaction entails a reduction in the excess film enthalpy (Hf), which may be associated with the formation of partial (or full) clathrates formed in the vicinity of hydrophobic surfaces. The presence of the clathrates is supported by the recent finding that the density of water in the vicinity of hydrophobic surfaces is lower than in the bulk.8
Antibacterial and Laundering Properties of Ams and Phmb as Finishing Agents for Healthcare Workers Uniforms
Eberhardt, Darlene Michele (Virginia Tech, 2004-04-22)
The safety of healthcare workers (HCW) has become a serious concern; therefore, a need for protection against bacterial penetration and transmission is realized. The purpose of this research is to examine whether antibacterial finishes can effectively reduce the presence of bacteria that have the potential for penetration and transmission on healthcare workers uniforms (HCWU). The specific objective of this research is to compare the antibacterial properties (i.e., bacterial reduction), two descriptive properties (i.e., fabric weight, fabric thickness), and one durability property (i.e., breaking strength loss due to abrasion) of a 65/35% polyester/cotton blend fabric treated with two commercially available antibacterial agents (i.e., 3-trimethoxysilylpropyldimethyloctadecyl ammonium chloride) or AEGIS Microbeshield, (AMS) and polyhexamethylene biguanide (PHMB) or Reputexâ · before laundering and after 5, 10, and 25 laundering cycles. The independent variables were the treatments (i.e., AMS, PHMB, no treatment) and the laundering cycles (i.e., 0, 5, 10, 25). The dependent variables were the four fabric properties: (a) antibacterial properties against Staphylococcus aureus (S. aureus) and Klebsiella pneumoniae (K. pneumoniae) bacteria, (b) fabric weight, (c) fabric thickness, and (d) breaking strength loss due to abrasion. Multiple Analysis of Variance (MANOVA) and Two-way Analysis of Variance (ANOVA) were used to examine the effects of the independent variables and their interaction on each dependent variable. The results showed PHMB treated specimens had a significantly higher log reduction against both S. aureus and K. pneumoniae before laundering and after 5, 10 and 25 laundering cycles than AMS treated specimens and the no treatment specimens. Initially, AMS had some reduction against S. aureus and K. pneumoniae before laundering; however after laundering, the reductions against both bacteria were diminished greatly. As expected, the no treatment specimen had no reduction against S. aureus or K. pneumoniae before and after laundering. The addition of PHMB and AMS increased the fabric weight of 65/35% polyester/cotton fabric and kept the fabric thickness throughout 25 laundering cycles. The untreated specimens became thicker after 25 laundering cycles. In addition, the breaking strength loss due to abrasion indicated that treatments had no effect on fabric strength. In conclusion, adding antibacterial agents do have some influence on bacterial reduction for both Gram-positive and Gram-negative bacteria as well as descriptive properties (i.e., fabric weight, fabric thickness). However, there was no influence on durability property (i.e., breaking strength loss due to abrasion). More studies are needed to test both agents on other types of fabrics such 100% cotton and nonwoven to incorporate more treated HCWU in the marketplace.
Borylations and Silylations of Alkenyl and Alkynyl Carbonyl Compounds Employing a Mild and Environmentally Friendly Cu(II) Catalyst
Calderone, Joseph Anthony III (Virginia Tech, 2014-04-25)
An environmentally friendly, operationally simple copper-amine catalyst system is disclosed. Using this catalyst system, electron deficient alkenes and alkynes with diverse functional groups are borylated and silylated in high yields and with short reaction times. In the case of electron deficient alkynes the identity of the electron withdrawing group controlled diastereoselectivity. Esters and amides exclusively form E-product, while aldehydes and ketones favor Z-product. Mechanistic insights into the catalytic cycle as well as origin of diastereoselectivity are discussed.
Carnitine analogues as topical, microbicidal spermicides
(United States Patent and Trademark Office, 2003-12-02)
Acylcarnitine analogues having alkyl side chains of 10 to 30 carbon atoms display excellent spermicidal and anti-HIV activity, a well as being potent inhibitors of the growth of Candida albicans.
The Chemistry of Cyclopropylarene Radical Cations
Wang, Yonghui (Virginia Tech, 1997-02-06)
Cyclopropane derivatives are frequently utilized as "probes" for radical cation intermediates in a number of important chemical and biochemical oxidation. The implicit assumption in such studies is that if a radical cation is produced, it will undergo ring opening. Through a detailed examination of follow-up chemistry of electrochemically and chemically generated cyclopropylarene radical cations, we have shown that the assumption made in the use of these substrates as SET probes is not necessarily valid. While cyclopropylbenzene radical cation undergoes rapid methanol-induced ring opening (e.g., k = 8.9⁷ s⁻¹M⁻¹), the radical cations generated from 9-cyclopropylanthracenes do not undergo cyclopropane ring opening at all. The radical cations generated from cyclopropylnaphthalenes disproportionate or dimerize before undergoing ring opening. Utilizing cyclic, derivative cyclic, and linear sweep voltammetry, it was discovered that decay of radical cations generated from cyclopropylnaphthalenes in CH₃CN/CH₃OH is second order in radical cation and zero order in methanol. Anodic and Ce(IV) oxidation of all these naphthyl substrates in CH₃CN/CH₃OH led to cyclopropane ring-opened products. However, the rate constant for methanol-induced ring opening (Ar-c-C₃H₅⁺. + CH₃OH -> ArCH(·)CH₂CH₂O(H⁺)CH₃) is extremely small (<20 s⁻¹M⁻¹ for 1-cyclopropylnaphthalenes) despite the fact that ring opening is exothermic by nearly 30 kcal/mol. These results are explained on the basis of a product-like transition state for ring opening wherein the positive charge is localized on the cyclopropyl group, and thus unable to benefit from potential stabilization offered by the aromatic ring. Reactions of radical cations generated from 9-cyclopropylanthracenes in CH₃CN/CH₃CN have also been investigated electrochemically. The major products arising from oxidation of these anthryl substrates are attributable to CH₃OH attack at the aromatic ring rather than CH₃OH-induced cyclopropane ring opening. Ce(IV) oxidation of 9-cyclopropyl-10-methylanthracene and 9,10-dimethylanthracene further showed that radical cations generated from these anthryl substrates undergo neither cyclopropane ring opening nor deprotonation but nucleophilic addition. Side-chain oxidation products from Ce(IV) oxidation of methylated anthracenes arose from further reaction of nuclear oxidation products under acidic and higher temperature conditions. An analogous (more product-like) transition state picture can be applied for cyclopropane ring opening and deprotonation of these anthryl radical cations. Because of much higher intrinsic barrier to either nucleophile-induced cyclopropane ring opening or deprotonation of these anthryl radical cations, nucleophilic addition predominates. Stereoelectronic effects may be another additional factor contributing to this intrinsic barrier because the cyclopropyl group in these anthryl systems adopts a perpendicular conformation which may not meet the stereoelectronic requirements for cyclopropyl ring opening at either the radical cation or dication stage.
The Chemistry of Fullerenes, Polymers, and Host/Guest Interactions
Schoonover, Daniel Vernon (Virginia Tech, 2015-03-03)
The exploitation of the relationship between the chemical and physical properties of materials is the hallmark of advancing science throughout the world. The basic understanding of how and why molecules react and interact with each other in different environments allows for the discovery and implementation of new materials and devices that not only advance the state of human life but continually change the planet. The work described in this dissertation generally falls under three diverse categories: functionalization of fullerenes, investigation of host/guest interactions in solution, and the synthesis and characterization of ion containing polymers. The separation and functionalization of fullerenes is a recent and exciting area of research. The separation methods outlined are intended to increase the availability of endohedral metallofullerenes by decreasing their cost of production. Functionalized fullerene species were achieved through Bingel and Prato reactions to provide materials with novel functional groups. These materials may be further utilized in photovoltaic or other organic electronic devices. The characterization of noncovalent interactions between different molecules in solution is the focus of supramolecular chemistry. Isothermal Titration Calorimetry stands out as one of the best, among the many methods used to elucidate the characteristics of these systems. The binding of bis- imidazolium and paraquat guests with macrocyclic host molecules has been explored in this work. The measurements of the association constants for these systems will aid in the ongoing synthesis of new host/guest systems. Ion containing polymers were synthesized and characterized for their use in electroactive devices. Imidazolium containing polymers with bulky anions were synthesized on low glass transition polymer chains. These materials had enhanced ion conductivity and may eventually be used in electronic actuator materials.
Computational and Spectroscopic Determination of Lithiated Benzylic Nitriles in THF/HMPA Solution
Harmon, Henry Jason (Virginia Tech, 2008-09-10)
The synthetic utility of nitrile-stabilized carbanions as reactive intermediates for selective carbon-carbon bond formation has prompted numerous studies toward characterization of the solution structure of these nucleophiles. In hopes of eventually gaining a better understanding of the structural properties which may mediate reactivity and selectivity, researchers have designed elegant structure elucidation strategies. These studies have offered key advancements toward the characterization of these intermediates; however, contradictory evidence has hindered unambiguous structural determination—particularly for lithiated benzylic nitriles in low dielectric, ethereal media. Chapter 1 of this dissertation presents a review of the synthetic utility of metalated nitriles and the spectroscopic and computational techniques employed to characterize their solution structure. Also reviewed herein are the controversial determinations drawn from these efforts. The research and data which follow in Chapters 2 and 3 focus on resolution of the conflicting structural determinations drawn from multinuclear magnetic resonance (NMR) and vibrational (IR and Raman) spectroscopy. Employing a strategy to slow the lithium-nitrogen exchange rate in low dielectric media, new 7Li, 31P, and 15N NMR spectroscopic evidence (with support from computational modeling) lead us to amend our previous assessments and propose that lithiated arylacetonitriles adopt an aggregated triple-ion structure in THF/hexane with sub-stoichiometric HMPA. Due to the limitations of computer resources and the effect of non-linear scaling, theoretical modeling of aggregated and solvated lithiated benzylic nitriles became impractical at the 6-31+G(d) basis set. These limitations led to the use and comparative analysis of two alternative basis sets for the DFT analysis of lithiated benzylic nitrile derivatives' 6-31(+LiX)G(d) and 6-31â +â G(d). Defined upon the principal of resonance stabilization, these basis sets were constructed by application of varying levels of computational theory on a per-atom basis. By applying higher levels of theory only to the atoms most intimately involved in the electronic distribution, "accurate" replacement models for 6-31+G(d) structures were obtained with considerable savings in computational resources. This study in basis set economy is detailed fully within Chapters 4 and 5.
Computational study of HIV gp120 as a target for polyanionic entry inhibitors: Exploiting the V3 loop region
Hollingsworth, Louis R. IV; Brown, Anne M.; Gandour, Richard D.; Bevan, David R. (PLOS, 2018-01-18)
Multiple approaches are being utilized to develop therapeutics to treat HIV infection. One approach is designed to inhibit entry of HIV into host cells, with a target being the viral envelope glycoprotein, gp120. Polyanionic compounds have been shown to be effective in inhibiting HIV entry, with a mechanism involving electrostatic interactions with the V3 loop of gp120 being proposed. In this study, we applied computational methods to elucidate molecular interactions between the repeat unit of the precisely alternating polyanion, Poly(4,40-stilbenedicarboxylate- alt±maleic acid) (DCSti-alt-MA) and the V3 loop of gp120 from strains of HIV against which these polyanions were previously tested (IIIb, BaL, 92UG037, JR-CSF) as well as two strains for which gp120 crystal structures are available (YU2, 2B4C). Homology modeling was used to create models of the gp120 proteins. Using monomers of the gp120 protein, we applied extensive molecular dynamics simulations to obtain dominant morphologies that represent a variety of open-closed states of the V3 loop to examine the interaction of 112 ligands of the repeating units of DCSti-alt-MA docked to the V3 loop and surrounding residues. Using the distance between the V1/V2 and V3 loops of gp120 as a metric, we revealed through MD simulations that gp120 from the lab-adapted strains (BaL and IIIb), which are more susceptible to inhibition by DCSti-alt-MA, clearly transitioned to the closed state in one replicate of each simulation set, whereas none of the replicates from the Tier II strains (92UG037 and JR-CSF) did so. Docking repeat unit microspecies to the gp120 protein before and after MD simulation enabled identification of residues that were key for binding. Notably, only a few residues were found to be important for docking both before and after MD simulation as a result of the conformational heterogeneity provided by the simulations. Consideration of the residues that were consistently involved in interactions with the ligand revealed the importance of both hydrophilic and hydrophobic moieties of the ligand for effective binding. The results also suggest that polymers of DCSti-alt-MA with repeating units of different configurations may have advantages for therapeutic efficacy.
Dendronized Amphiphilic Copolymers Synthesized from Methacrylate Derivatives as Potential Topical Microbicides
Hardrict, Shauntrece Nicole (Virginia Tech, 2009-11-05)
The need for a preventative agent to curtail the rampant spread of HIV, other STDs and mucosal pathogens is urgent. Topical microbicides based on amphiphilic compounds have been identified as an attractive means toward this goal. Novel dendritic methacrylate macromonomers––di-tert-butyl 4-(2-tert-butoxycarbonyl-ethyl)-4-[3-(2-methacryoloxyethyl)ureido]heptandioate (MI) and di-tert-butyl 4-(2-tert-butoxycarbonylethyl)-4-[3-methyl-3-(2-methacryoloxyethyl)ureido]heptanedioate (MIII)––were synthesized, characterized, and subsequently polymerized via conventional free radical polymerization in acetonitrile employing AIBN as an initiator. Methyl 3-mercaptopropionate (MMP), a chain transfer agent, was employed to target low molecular weight (<10,000 g/mol) polymers. Dendronized homopolymers were prepared from MIII with varying MMP concentrations (0–10 mol%). MALDI-TOF MS characterized the homopolymer prepared with 10 mol% MMP (Mn = 2,481 g/mol). In the presence of MMP, MIII (5 to 25 mol%) was copolymerized with alkyl (methyl, ethyl, and n-butyl) methacrylates. Copolymer composition correlated well with monomer feed; Mns of 3–10K g/mol were observed. Ionizable polymers were achieved via acidolysis with trifluoroacetic acid; significant increases in Tg were observed. For the copolymers, the Tgs of the acids increased as the copolymer composition increased in MIII. For the homopolymers, Tgs decreased with increasing MMP concentration. The solubilities of carboxylic acid functional polymers were studied in 5 w/v % aqueous triethanolamine (aq TEA) at a concentration of 12.5 mg/mL. Clear, homogeneous solutions of the deprotected macromonomer, MIII(OH), homopolymer, PMIII(OH), and MIII(OH)/MMA copolymer series were observed; copolymer solubility decreased as the aliphatic chain length of the alkyl methacrylate increased. The amphiphilic dendronized polymer series incorporates many features shown beneficial in the pursuit of effective antimicrobial agents: amphiphilicity, multiple anionic functional groups, a polymer backbone, and aqueous solubility. Additionally, biological selectivity (e.g. cytotoxicity) is expected to be tunable through the control of molecular weight, alkyl chain length (n*), copolymer composition, and molecular architecture.
Desalination of Produced Water via Gas Hydrate Formation and Post Treatment
Niu, Jing (Virginia Tech, 2012-04-19)
This study presents a two-step desalination process, in which produced water is cleaned by forming gas hydrate in it and subsequently dewatering the hydrate to remove the residual produced water trapped in between the hydrate crystals. All experiments were performed with pressure in the range of 450 to 800psi and temperature in the range of -1 to 1°C using CO? as guest molecule for the hydrate crystals. The experiments were conducted using artificial produced waters containing different amounts of NaCl, CaCl₂ and MgCl₂ at varying temperature (T) and pressure (P). The results are presented as functions of %Reduction of difference chemical elements, CO? requirements and applied T and P conditions. The impact of dewatering techniques, including centrifuge and filtration process, on gas hydrate solid product is studied. The results showed that over 99% of dissolved NaCl and MgCl2 can be removed from artificial saline water in laboratory experiments. This was achieved in a process involving a single-stage hydrate formation step, followed by a single-step solid-liquid separation (or dewatering). The results also show that the %Reduction (percentage of the concentration decrease) of artificial produced water increases with centrifugation time and rotational speed (rpm). The %Reduction was increased considerably after hydrate crystals were crushed and filtered, indicating that the artificial process water was entrapped in between the hydrate crystals. It was found also that the finer the particle size, the higher the extent of salt removal. In general, filtration was a better than centrifugation for the removal of TDS (Total Dissolved Solids).
Design and Syntheses of Potential Drugs Based on GABA(A) Receptor Pharmacophores
Clement, Ella Chow (Virginia Tech, 2005-06-28)
Numerous previous studies of GABAAR ligands have suggested that GABAAR agonists must be zwitterionic and feature an intercharge separation similar to that of GABA (approx. 4.7-6.0 Ã ). We have demonstrated that monomeric, homodimeric and heterodimeric non-zwitterionic GABA amides are partial, full, or superagonists at the murine GABAA receptor (GABAAR). The agonism of these GABA amides is comparable to that of THIP, as shown by in vitro assay results. The assay data indicate that the agonism of GABA amides is tether length-dependent. Optimum agonism is achieved with a tether length of four methylenes in GABA amide dimers and in GABA amides bearing pendant amide or amino groups. We have further investigated the structure-activity relationship for GABA amides on the GABAAR by performing structural modifications to both the superagonist 2c and the agonist 6c. Synergism and [3H]muscimol binding experiments show that 2c binds to the same sites as GABA. Structural modification of 2c demonstrated that partial rigidification of the tether eliminated agonism and caused ligands to behave as weak competitive antagonists. We have also investigated the agonism of four ZAPA derivatives in 36Cl- uptake functional assay. Two of them are found to be as potent as GABA. In our studies of 1,4-benzodiazepines, our goal was to synthesize three different subtypes of quaternary 1,4-benzodiazepines by use of the memory of chirality (MOC) strategy. Disappointingly, most of the deprotonation/alkylations failed, due to various reasons. The failure of the reactions of (S)-alanine-derived tetrahydro-1,4-benzodiazepin-3-ones was probably due to either the unexpected side reactions or the steric hindrance of enolate alkylation. In the case of tetrahydro-1,4-benzodiazepin-2-ones, computational studies suggested that steric hindrance by both the benzo ring and N4-allyl group might retard deprotonation at C3 by bulky bases like KHMDS or LDA. Finally, (S)-serine-derived 1,4-benzodiazepin-2-ones and their elimination products (ï ¡-methylene benzodiazepines) were prepared. These proved unreactive towards deprotonation/alkylations and conjugate additions, respectively. The low reactivity of the ï ¡-methylene benzodiazepines towards nucleophiles was attributed to highly delocalized LUMOs that failed to direct nucleophiles to the ï ¢-carbons.
Design and Synthesis of Doxorubicin Conjugated Gold Nanoparticles as Anticancer Drug Delivery System
Xia, Long (Virginia Tech, 2016-06-24)
Doxorubicin is one of the most widely used and effective anticancer agents to treat a wide spectrum of tumors. But its success in cancer therapy is greatly compromised by its cumulative dose-dependent side effects of cardiotoxicity and tumor cell resistance. For the purpose of addressing these side effects, a gold nanoparticles-based anticancer drug delivery system was designed. Five novel thiolated doxorubicin analogs were designed and synthesized and their biological activities have been evaluated. These doxorubicin analogs and the poly(ethylene glycol) (PEG) stabilizing ligands were conjugated to gold nanoparticles via formation of a gold-thiol bond. The systems were evaluated in vitro and in vivo, and the results show that controlled drug release can be achieved either by acidic conditions or by reducing agents in cancer cells, depending on the design of the thiolated drug construct. The overall drug delivery system should achieve enhanced drug accumulation and retention in cancer cells and favorable drug release kinetics, and should demonstrate therapeutic potential and the ability to address some of the current problems of doxorubicin in cancer therapy.
Design, Preparation and Characterization of Novel Pseudorotaxanes, Semirotaxanes, Rotaxanes, Non-Covalent Supramolecular Polymers and Polycatenanes
Niu, Zhenbin (Virginia Tech, 2011-09-06)
Design and preparation of novel host/guest systems, such as pseudorotaxanes, semirotaxanes, rotaxanes and catenanes, with high association constants, enhanced yields and the abilities to respond to external stimuli are of great importance and significance due to their topological novelty and potential application. The convergence of supramolecular chemistry with polymer science provides an important way to extend the scope of polymer and material sciences by incorporating designed host/guest systems into polymers, and the resulting non-covalently linked supramolecular polymers are expected to have unusual properties due to their unique architectures compared with traditional polymers. After discovery of bis(meta-phenylene)-32-crown-10 (BMP32C10) derivative/paraquat complexes, for about a quarter century only “taco”-shaped complexes were observed by X-ray crystallography. Here, by the self-assembly of a BMP32C10 bearing two electron-donating groups (carbazoles) with electron-accepting paraquat derivatives, the first [2]pseudorotaxane and the first pseudocryptand-type poly[2]pseudorotaxane based on BMP32C10 were isolated as crystalline solids as shown by X-ray analyses. The first dual component pseudocryptand-type [2]pseudorotaxanes were designed and prepared via the self-assembly of synthetically easily accessible BMP32C10 pyridyl, quinolyl and naphthyridyl derivatives with paraquat. The formation of the pseudocryptand structures in the complexes remarkably improved the association constants by forming the third pseudo-bridge via H-bonding with the guest and π-stacking of the heterocyclic units. A pseudocryptand-type [2]pseudorotaxane was formed via the self-assembly of a dipyridyl BMP32C10 derivative and a paraquat derivative. Due to the basicity of the pyridyl group, which forms the third pseudo-bridge of the pseudocryptand, this pseudorotaxane represents the first system with acid-base adjustable association constants, i. e., finite both under acidic and neutral conditions. The first pseudocryptand-type supramolecular [3]pseudorotaxane was designed and prepared via the self-assembly of a bispicolinate BMP32C10 derivative and a bisparaquat. The complexation behavior was cooperative. In addition, the complex comprised of the BMP32C10 derivative and a cyclic bisparaquat demonstrated strong binding; interestingly, a poly[2]pseudocatenane structure was formed in the solid state for the first time. Two novel BMP32C10 cryptands, bearing covalent and metal complex linkages, were designed and prepared. By employing the self-assembly of these biscryptands, which can be viewed as AA monomers, and a bisparaquat, which can be viewed as a BB monomer, the first AA/BB-type linear supramolecular polymers with relatively high molecular weights were successfully prepared. Via the self-assembly of two BMP32C10-based cryptands, bearing covalent and metal complex (ferrocene) linkages, with dimethyl paraquat, novel [3]pseudorotaxanes were formed statistically and anticooperatively, respectively. From a hydroxyl-functionalized secondary ammonium salt a [2]semirotaxane and a [2]rotaxane were prepared successfully with dibenzo-24-crown-8 (DB24C8). X-ray analysis of a single crystal of the [2]semirotaxane confirmed its semirotaxane nature. In addition, the formation of the [2]semirotaxane can be reversibly controlled by adding KPF6 and 18C6 sequentially. This system affords a way to prepare novel supramolecular polymers. Dibenzo-30-crown-10 (DB30C10) derivatives and pyridine-based DB30C10 cryptands were prepared by employing the templating method established by our group. A [2]pseudorotaxane was prepared based on DB30C10 diol and paraquat diol. The [3]pseudorotaxane formed via the self-assembly between DB30C10 cryptand and bisparaquat diol occurred in a cooperative manner. In addition, a bromo-functionalized DB30C10 cryptand was successfully designed and prepared. An alkyne-functionalized DB30C10 cryptand was designed and is under preparation; its precursors have been prepared successfully. In the future, based on these functionalized cryptands and paraquat salts, AA and AB type monomers will be prepared. Via the self-assembly between these monomers, non-covalent supramolecular polymers with high molecular weight will be afforded. A novel DB30C10 cryptand bearing an organometallic bridge, ferrocene, was prepared via 1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) coupling of the crown ether diol with ferrocene dicarboxylic acid. The cryptand is dimerized in the solid state via π, π-stacking and hydrogen bonds. The ferrocene-based cryptand formed novel [2]pseudorotaxanes with paraquat and diquat PF₆ salts with association constants (Kₐ) of 1.7 ± 0.1 x 10³ and 4.2 ± 0.3 x 10⁴ M⁻¹ in acetone-d₆, respectively. In order to prepare linear polycatenanes, the preparation of which represent a real synthetic challenge, a series phenanthroline derivatives were designed and prepared. A “U” shaped monomer was successfully prepared in relative high yield with good solubility. In the future, real linear polycatenanes will be prepared. In addition, a novel diphenanthroline-based BMP32C10 derivative was prepared in high yield and the complexation behavior between it and dimethyl paraquat was studied.
Design, Syntheses and Biological Activities of Paclitaxel Analogs
Zhao, Jielu (Virginia Tech, 2011-01-31)
The conformation of paclitaxel in the bound state on the protein has been proposed to be the T-taxol conformation, and paclitaxel analogs constrained to the T-taxol conformation proved to be significantly more active than paclitaxel in both cytotoxicity and tubulin polymerization assays, thus validating the T-taxol conformation as the tubulin-binding conformation. In this work, eight compounds containing an aza-tricyclic moiety as a mimic of the baccatin core of paclitaxel have been designed and synthesized as water-soluble simplified paclitaxel analogs, among which 3.50-3.52 and 3.55 were conformationally constrained analogs designed to bind to the paclitaxel binding site of tubulin, based on their similarity to the T-taxol conformation. The open-chain analogs 3.41-3.43 and 3.57 and the bridged analogs 3.50-3.52 and 3.55 were evaluated for their antiproliferative activities against the A2780 cell lines. Analogs 3.50-3.52 and 3.55 which were designed to adopt the T-taxol conformation showed similar antiproliferative activities compared to their open-chain counterparts. They were all much less active than paclitaxel. In the second project, a series of paclitaxel analogs with various thio-containing linkers at C-2′ and C-7 positions were designed and synthesized in our lab. These analogs were attached to the surfaces of gold nanoparticles by CytImmune Sciences for the development of mutifunctional tumor-targeting agents. The native analogs and the gold bound analogs were evaluated for their antiproliferative activities against the A2780 cell line. All the compounds tested showed comparable or better activities than paclitaxel. Stability studies were performed for selected analogs in hydrolysis buffer, which showed that the analogs released paclitaxel in buffer over time. In the third project, the synthesis of a conformationally constrained paclitaxel analog which was designed to mimic the REDOR-taxol conformation was attempted. Two synthetic routes were tried and significant progress was made toward the synthesis of the conformationally constrained analog. However, both of the current synthetic routes failed to produce the key intermediate that would serve as the precursor for a ring-closing metathesis reaction to furnish the macrocyclic ring.
Development of Environmentally Friendly Non-Chrome Conversion Coatings for Cold-Rolled Steel
Zhang, Jinming (Virginia Tech, 2003-07-30)
Steel producers use various organic and inorganic coatings to protect cold-rolled steel (CRS) sheets from corrosion during shipment and storage. It is well known that CRS sheets can be protected from corrosion by galvanizing, phosphating, chromating, topcoating with organic, or their combinations. The chromate rinsing is particularly effective for preventing white rusting of galvanized steel. But there is an increasing interest in a replacement for the chromating process because of environmental and health concerns. The objective of the present work is to develop a chrome-free conversion coating for steel sheets. Various carboxylic acids and their salts have been studied for coating phosphated electrogalvanized (EG) steel sheets, including 10-undecenoic acid (UA), oleic acid (OA), and other fatty acids such as stearic acid (SA) and palmitic acid (PA). When they were used alone, or subsequently coated with resin, they could produce a highly hydrophobic surface and improve the corrosion resistance. Thiols such as 1-octadecanethiol (ODT) can form a self-assembled monolayer on metal substrates. This close-packed monolayer could provide an excellent corrosion resistance for EG steel sheets. It was capable of withstanding 50~60 hours of salt spray test (SST) although its thickness was only a few nanometers. The EG steel itself usually started rusting only after 2~4 hours of salt spray. In another coating system, thiols were mixed with a conventional resin to improve the corrosion resistance of EG steel. This new technique gave 100~120 hours of corrosion resistance. When the resin was applied directly on EG steel surface, its corrosion resistance was less than 72 hours. It was shown that further optimization of this technique increased the corrosion resistance to 200 hours and more in the standard SST.
Development of Metal-based Nanomaterials for Biomedical Applications
Roth, Kristina L. (Virginia Tech, 2017-04-21)
New synthetic advances in the control of nanoparticle size and shape along with the development of new surface modifications facilitates the growing use of nanomaterials in biomedical applications. Of particular interest are functional and biocompatible nanomaterials for sensing, imaging, and drug delivery. The goal of this research is to tailor the function of nanomaterials for biomedical applications by improving the biocompatibility of the systems. Our work demonstrates both a bottom up and a post synthetic approach for incorporating stability, stealth, and biocompatibility to metal based nanoparticle systems. Two main nanomaterial projects are the focus of this dissertation. We first investigated the development of a green synthetic procedure to produce gold nanoparticles for biological imaging and sensing. The size and morphology of gold nanoparticles directly impact their optical properties, which are important for their function as imaging agents or their use in sensor systems. In this project, a synthetic route based on the natural process of biomineralization was developed, where a designed protein scaffold initiates the nucleation and subsequent growth of gold ions. To gain insight into controlling the size and morphology of the synthesized nanoparticles, interactions between the gold ions and the protein surface were studied along with the effect of ionic strength on interactions and then subsequent crystal growth. We are able to control the size and morphology of the gold nanoparticles by altering the concentration or identity of protein scaffold, salt, or reducing agent. The second project involves the design and optimization of metal organic framework nanoparticles for an external stimulus triggered drug delivery system. This work demonstrates the advantages of using surface coatings for improved stability and functionalization. We show that the addition of a polyethylene glycol surface coating improved the colloidal stability and biocompatibility of the system. The nanoparticle was shown to successfully encapsulate a variety of small molecule cargo. This is the first report of photo-triggered degradation and subsequent release of the loaded cargo as a mechanism of stimuli-controlled drug delivery. Each of the aforementioned projects demonstrates the design, synthesis, and optimization of metal-based systems for use in biomedical applications.
Development of Transition Metal-Catalyzed Borylation Protocols using Symmetrical and Unsymmetrical Diboron Reagents
Peck, Cheryl Lynne (Virginia Tech, 2017-11-10)
The versatility of organoboron compounds has been demonstrated by their use as synthetic intermediates and more recently in therapeutic applications since the FDA approval of Velcade©. As a result, transition metal-catalyzed protocols to incorporate boron reagents into unsaturated compounds have been extensively researched. While an abundance of literature protocols have been reported, the majority utilize harsh reaction conditions in combination with expensive reagents. This dissertation discloses the author’s contributions to the development of efficient, cost-effective, and operationally simple transition metal-catalyzed borylation protocols with alkynes and diboron reagents. An open-to-air copper(II)-catalyzed aqueous borylation protocol of alkynoates and a symmetrical diboron reagent is reported. Conjugate addition of the boryl-copper species to the electrophilic β-carbon provided β-boryl-α,β-unsaturated esters in moderate to excellent yields. Exclusive (Z)-stereochemistry was confirmed by nOe experiments. The resulting vinyl boronate esters are useful cross-coupling partners. The scope of the aqueous β-borylation protocol was extended to the unsymmetrical diboron reagent, pinB-Bdan. This alternative protecting group has emerged as an orthogonal protecting group and alters the reactivity of the boron moiety. Activation of the pinacol moiety to form the Lewis acid-base adduct allowed for the chemoselective transfer of the 1,8- diaminonapthalene moiety to the β-carbon. An alternative novel synthesis of vinyl, allyl diboronate esters from propargylic alcohols has also been described. Formation of a leaving group in-situ with a palladium- and coppercatalyzed protocol can lead to several competing reaction pathways and the formation of multiple products. Fortunately, the resulting vinyl, allyl diboronate esters were stereoselectively synthesized in moderate GC yields despite significate decomposition during purification, as confirmed by stability studies. The terminal diboration of allenes was previously the only reported method for the synthesis of vinyl, allyl diboronate esters.
Dibenzo-30-crown-10: Synthetic optimization and studies of the binding conformation
Wessels, Hanlie R. (Virginia Tech, 2018-05-07)
Dibenzo-30-crown-10 (DB30C10) is one of the first-generation macrocyclic hosts discovered by Pedersen. Crown ethers originally attracted attention due to their ability to encapsulate metal cations and render them soluble in organic solvents. These studies helped to launch host-guest chemistry as a discipline within supramolecular chemistry. Crown ethers form complex molecules containing organic cations and neutral organic molecules. Additionally, they form components in supramolecular architectures such as catenanes, rotaxanes, and supramolecular polymers. They have been used as selective hosts in diverse applications such as wastewater treatment, switchable catalysis, therapeutic agents, sensors, molecular machines, and stimuli responsive materials "smart polymers". Despite the vigorous research activity in the field, DB30C10 has received surprisingly little attention. DB30C10 was reported in 1967 and has been commercially available since 1992; however, it has been mostly overlooked as a host in favour of smaller crown ethers such as DB24C8, B15C5, 18C6 and 15C5. Herein we present an improved synthetic route that improves the yield of the cyclization step in the synthesis of DB30C10 from 25% to 88% enabling us to prepare multiple grams of the material without the use of pseudo high-dilution techniques. The same methodology was applied to three other crown ethers with similar improvement in yield. Four new rotaxanes based on the DB30C10-paraquat binding motif were used to investigate the binding conformation of DB30C10 and paraquat. The new rotaxanes were characterized by 1H, 13C and 2D-NOESY NMR, mp, and HRMS. A single crystal X-ray structure of one of the [2]rotaxanes was obtained. To our knowledge, this is the first crystal structure of a rotaxane based on this particular binding motif. This result illustrated that DB30C10 was a suitable host for the construction of supramolecular systems and polymers. Our eventual goal is to use DB30C10 in the construction of supramolecular polymers with novel topologies. Therefore, the relative threading efficiency of DB30C10 in solution had to be determined. A series of segmented polyurethane poly(pseudorotaxanes) with paraquats in the backbone were synthesized with different crown ether or cyptand hosts. The threading efficiency was determined by 1H NMR.
Discovery and Delivery of Bioactive Natural Products
Du, Yongle (Virginia Tech, 2018-06-25)
As a part of search for bioactive natural products from the plants in collaboration with the Natural Products Discovery Institute (NPDI), ten plant extracts were investigated for their antiplasmodial activity against Plasmodium falciparum Dd2 strain. Twenty-eight compounds were isolated, and twelve of them were new compounds. The structures of all these compounds were determined by analysis of their mass spectrometric, 1D and 2D NMR, and ECD spectrum. Among these natural products, there were three compounds with good antiplasmodial activity, trichospirolide A with an IC50 value of 1.5 μM, malleastrumolide A with an IC50 value of 2.7 μM, and (+)-lariciresinol with an IC50 value of 3.7 μM. In addition to the studies of drug delivery of bioactive natural product, doxorubicin, a novel thiolated doxorubicin analog were designed and synthesized. Its analogs and PEG stabilizing ligands were then conjugated to gold nanoparticles and the resulting Au-Dox constructs were evaluated by TEM. The release of native drug can be achieved by the action of reducing agents, and that reductive drug release gave the cleanest drug release.

Browsing by Author "Gandour, Richard D."

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