UMD Theses and Dissertations
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Item Building Block Approach to the Synthesis of a Cucurbit[7]uril Derivative Bearing Sulfonate Functional Groups(2014) Brownlow, Lorene Elizabeth; Isaacs, Lyle; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Low aqueous solubility prevents 40-70% of new pharmaceutical agents from reaching their full potential. The use of molecular containers as solubilizing agents is one solution currently under development. Chapter 1 introduces molecular containers under investigation as drug delivery excipients. Synthetic approaches, properties and important derivatives of cyclodextrins and cucurbiturils are briefly reviewed. Chapter 2 describes the tested hypothesis that the addition of sulfonate functional groups to CB[7] will enhance the aqueous solubility of the CB[7] derivative as compared to CB[7] itself. The building-block approach to obtain a difunctionalized CB[7] derivative by the condensation of glycoluril hexamer (21) and ((¬CH2)4SO3Na)2 glycoluril bis(cyclic ether) (30) is described. The new CB[7] derivative had surprisingly low aqueous solubility (20.2 mM), but very similar molecular recognition properties to those of CB[7]. The CB[7] derivative was investigated for its use as an excipient for drug solubilization and found to have no enhancement compared to CB[7].Item Templated Synthesis of Glycoluril Oligomers and Monofunctionalized Cucurbit[6]uril Derivatives(2011) Lucas, Derick; Isaacs, Lyle D; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)The molecular recognition properties exhibited by molecular containers have inspired supramolecular chemists to generate diverse and specialized macrocycles. The family of hosts known as cucurbiturils (CB[n]) have become a popular platform for molecular recognition due to their high binding affinities and selectivity in water. As CB[n] branch into increasingly complex applications it becomes important to find efficient pathways to prepare monofunctionalized CB[n] derivatives bearing reactive functional groups. Chapter 1 presents a literature review of the synthesis, properties, mechanism of formation, and applications of the CB[n] family. We use this background information to explain our key hypothesis, that templated reactions offer potential routes to obtain glycoluril oligomer building blocks that allow the preparation of monofunctionalized CB[n] compounds. Chapter 2 describes the templated synthesis of glycoluril hexamer (6C) in a one step synthetic procedure on the gram scale using the p-xylylenediammonium ion (II-11). Hexamer 6C undergos cyclization with (substituted) phthalaldehdyes II-12, II-14, II-15, II-18 under acidic conditions at room temperature to deliver monofunctionalized CB[6] derivatives II-13, II-15, II-16, and II-19. Furthermore, the reaction kinetics for CB[6] cyclization between hexamer and formaldehyde or phthalaldehyde is influenced by the size and shape of ammonium ion templates. The larger size of the p- xylylenediammonium ion (II-11) allows it to act as a negative template by discouraging transformation of hexamer and paraformaldehyde to form CB[6]. However, II-11 and hexanediammonium ion (II-20) act as positive templates during the reaction of 6C and phthalaldehyde II-12 by giving (±)-II-21 as an intermediate along the mechanistic pathway to CB[6] derivative II-13. Finally, a fluorescence turn-on assay was investigated using the fluorophore and metal-ion binding (e.g., Eu3+) of naphthalene- CB[6] derivative II-19. The synthesis of monofunctionalized CB[6] derivatives in high yields has broad implications toward tailor-made approaches to CB[n] derived functional systems in the future. Chapter 3 describes the high yield synthesis of glycoluril pentamer (5C) by the 3,5- dimethylphenol induced fragmentation of bis-ns-CB[10] under acid conditions. The access to large quantities of 5C and 6C and previously reported tetramer III-4 allowed for a comparison of host-guest recognition properties of acyclic CB[n]-type receptors toward alkaneammonium ions in water.Item Acyclic Congeners of Cucurbit[n]uril and a Related Mechanistic Study on the Cucurbit[n]uril Forming Reaction.(2010) Ma, Da; Isaacs, Lyle D; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Supramolecular chemistry has been a very important research area in the past several decades. In this research field, molecular containers, such as cyclodextrin, attracts special attention due to their wide applications both in academia and industry. Cucurbit[n]uril (CB[n]), as a new generation molecular container, has selective and tight binding towards lots of cations and neutral molecules. A homologous family of CB[n] has been discovered including CB[5]-CB[8], CB[10], iCB[n], ns-CB[10] and ns-CB[6]. CB[n] analogues and derivatives have also been developed. CB[n] still has several issues, such as low solubility in water, difficulty to be functionalized, and slow association and dissociation kinetics. This thesis describes efforts to address these issues by developing new CB[n] type molecular containers and carrying out mechanistic investigations. Three chapters are included in this thesis. Chapter 1 is a literature review of molecular encapsulation and molecular container chemistry. We first introduced general concepts of molecular encapsulation and present examples of molecular container, such as cyclodextrin. This is followed by an introduction to CB[n] molecular containers and their supramolecular chemistry. Chapter 2 introduces new acyclic CB[n] congeners II-5a and II-5b. II-5a and II-5b are obtained from step-wise synthesis with reasonable yields. This step-wise synthetic route avoids difficult separation process. We measured the binding constants of II-5a towards a number of guests and found the binding affinity is usually comparable to CB[7]. The recognition property of II-5a is investigated in depth. We found that the length and functional groups of the guests greatly influence the binding affinity. Nevertheless, the charge and size of the guests do not have as a big influence on the binding constants as CB[7]. We discovered that the ionic strength of the buffer is critical for the binding constant. By comparing the recognition property of II-5a and II-6, it is discovered that the substituted o-xylyene walls are important for the tight binding compounds. II-5a and II-5b are new examples of CB[n] type molecular containers. They retain most of the good recognition property of CB[n] and have advantages compared to CB[n], including 1) aromatic walls that makes further functionalization possible; 2) acyclic structure that enables fast association and dissociation kinetics. Chapter 3 describes the mechanistic study of CB[n] forming reactions. Another possible way to synthesize CB[n] molecular container is to use aldehydes instead of paraformaldehyde. But neither previous researchers nor our work has succeeded to make the aldehydes participating CB[n] forming reactions happen. Mechanistic investigation was carried out to explain why this reaction simply does not occur. We used III-7 instead of glycoluril to avoid cyclization reactions. Several reasons are discovered: 1) side products are formed, such as III-SP1 and III-SP2; 2) S-shape intermediates are yielded, such as III-15S, III-16S, III-17S and III-18S, which are not able to continue the reaction to form macrocycles; 3) a small equilibrium constant for the chain grouth reaction. This study explains why aldehydes usually do not participate in CB[n] forming reactions. This work could also lead to the discovery of certain aldehydes that can form CB[n] type macrocycles.Item Discrete and Polymeric Complexes Comprising Bis-nor-seco-CB[10] and Oligoammonium Ions(2009) Nally, Regan; Isaacs, Lyle; Chemistry; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)ABSTRACT Title of Document: DISCRETE AND POLYMERIC COMPLEXES COMPRISING BIS-NOR-SECO-CB[10] AND OLIGOAMMONIUM IONS Regan C. Nally, Ph.D., 2009 Directed By: Professor Lyle D. Isaacs Department of Chemistry and Biochemistry Supramolecular architectures composed of multiple components are challenging to produce, as the enthalpic gain must be greater than the entropic penalty of strict geometrical arrangements. Therefore, it is the goal of supramolecular chemists to strategically design and synthesize molecules that will exhibit selectivity toward formation of a particular complex. This dissertation describes the formation of supramolecular architectures of increasing size and is organized in the following way. Chapter 1 introduces the reader to the field of supramolecular polymer chemistry. Chapter 2 describes the synthesis of a series of monovalent ditopic guests (II-1 - II-6) and their complexation properties toward double cavity cucurbituril host bis-ns-CB[10]. We observed the preferential formation of 1:1, 2:2, and oligomeric complexes rather than the desired n:n supramolecular polymers. Guest II-7 which contains a longer biphenyl spacer successfully precludes the formation of the 1:1 complex but results in the formation of the 2:2 complex (bis-ns-CB[10]2*II-72) rather than supramolecular polymer. Guest II-8 is heterovalent and ditopic and is shown to reversibly form 2:2 and 1:2 complexes (bis-ns-CB[10]2*II-82 and bis-ns-CB[10]*II-82) in response to changes in host:guest stoichiometry. Lastly, this equilibrium can be manipulated by the addition of exogenous CB[6] which selectively targets the hexanediammonium ion binding region of II-8 and delivers the penta-molecular complex bis-ns-CB[10]*II-82*CB[6]2. Chapter 3 describes the formation of a main chain supramolecular polymer from a mixture of poly(diallyldimethylammonium chloride) (III-1) and bis-ns-CB[10]. The bis-ns-CB[10] molecular container behaves as a molecular handcuff, bringing together two ends of individual polymers to form III-1n* bis-ns-CB[10]m, resulting in an extension of the length of polymer. The effect of bis-ns-CB[10] on the physical properties of the polymer was investigated using viscometry in aqueous solution. A decrease in the ηrel was observed upon increasing concentrations of bis-ns-CB[10] to a solution of III-1. Atomic force microscopy (AFM), and diffusion-ordered spectroscopy (DOSY) were performed to probe the mode of interaction between polymer III-1 and bis-ns-CB[10]. Collectively, the data supports the two roles for bis-ns-CB[10]: 1) as a deaggregation agent, and 2) as a molecular handcuff that non-covalently links individual polymer strands resulting in overall extension of the polymer.