Date of Award

2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry

Specialization

Organic Chemistry

Department

Chemistry

First Advisor

Mindy Levine

Abstract

The overall theme of my graduate research is to understand forces involved in supramolecular, hydrophobically-driven interactions, primarily in cyclodextrin systems and to use those interactions in applications ranging from fluorescence-based sensing to supramolecular catalysis. This research has included a highly interdisciplinary research project exploring the effects of cation-π interactions on surfactant/lipid bilayer vesicles for delivery applications. Cyclodextrins, which are commercially available, torus-shaped cyclic oligoamyloses, have been selected as the supramolecular hosts in these studies because of their well-defined hydrophobic interior cavity. The hydrophilic exterior, in turn imparts substantial aqueous solubility. Moreover, the primary and secondary hydroxyl groups of the cyclodextrin provide a myriad of synthetic handles for further modification and chemical derivatization.

Cyclodextrin-based catalytic systems have been envisioned for mild, environmentally friendly transformations in high-impact organic reactions. The basis of this research stems from the ability of cyclodextrins to form hydrophobic complexes with small molecules, thereby lowering the entropic barrier for the formation of a transition state in selected organic reactions. Moreover, the hydrophobic complexes of cyclodextrin with small molecules have also been shown to be more reactive from the perspective of many organic transformations.

The first manuscript “Cyclodextrin-promoted Diels Alder reactions of a polycyclic aromatic hydrocarbon under mild reaction conditions” describes Diels Alder reactions of a model polycyclic aromatic hydrocarbon (PAH), 9-anthracenemethanol with N-substituted maleimides under mild reaction conditions (aqueous solvent, 40°C) in the presence of commercially available cyclodextrins. In this system, hydrophobic complexation of the N-substituent in turn modifies the electronics of the alkene double bond, resulting in its enhanced reactivity. We found that cyclodextrin complexation of the N-substituent on the maleimide (driven by hydrophobic interactions) was the key factor in determining the rate of the reaction and the overall conversion to product. Optimal results were found using N-cyclohexylmaleimide with a methyl-β-cyclodextrin host, with 94% conversion obtained in 24 hours. A proposed model of the complexation with methyl-β-cyclodextrin has been proposed, with cyclodextrin encapsulation perturbing the electronics of the dienophile double bond and enhancing its reactivity. Results of these experiments were published in Tetrahedron Letters in 2015, and this publication has already been cited multiple times.

The second manuscript “An Environmentally Friendly Procedure for the Aqueous Oxidation of Benzyl Alcohols to Aldehydes with Dibromodimethylhydantoin (DBDMH) and Cyclodextrin - Scope and Mechanistic Insights” discusses the cyclodextrin-promoted oxidation of benzyl alcohols to benzaldehydes using an inexpensive, commercially available reagent, 1,3-dibromo-5,5-dimethylhydantoin (DBDMH). This newly developed reaction has two notable advantages compared to previously reported benzylic oxidation reactions: (a) more environmentally friendly (i.e. “greener”) methodology through the use of an aqueous solvent system and mild reaction conditions; and (b) high specificity for benzyl alcohol substrates with limited side reactivity, including over-oxidation and aromatic bromination, observed. This reaction proceeds with moderate to good yields for a broad scope of benzyl alcohol substrates, with the cyclodextrin additive accomplishing two main objectives: (a) enhancement of the desired reactivity as a result of the activation of the benzylic protons via interactions with the cyclodextrin rim; and (b) limitation of the undesired aromatic bromination side products as a result of steric shielding of the aromatic ring in the hydrophobic cyclodextrin pocket. Catalyst reusability up to three consecutive runs has been observed without substantial loss of product yield and selectivity, which further enhances the atom economy of this method. Results of these experiments were published in Synthetic Communications in 2016.

Non-covalent energy transfer has been used as a highly sensitive investigative tool in a wide variety of supramolecular systems. Owing to its exquisite sensitivity and dependence on a host of factors, this strategy has also been employed to study dynamic conformations of biomolecules such as nucleic acids and peptides. Our group has developed highly efficient energy transfer systems using γ-cyclodextrin as a supramolecular host for promoting non-covalent energy transfer from small molecule aromatic toxicants to high quantum yield fluorophores. Although γ-cyclodextrin has a cavity size that is well-known to be able to accommodate two small molecule guests simultaneously, limitations of γ-cyclodextrin include its limited specificity and ill-defined host: guest stoichiometry, as a result of its larger cavity size. There is neither control of the orientation of the guest molecule inside the cavity, nor selective binding of a single analyte in the presence of other competitive guest molecules, which often leads to sub-optimal detection sensitivity and anomalous false positive signals. In the third manuscript “Array based detection of isomeric and analogous analytes employing synthetically modified fluorophore attached β-cyclodextrin derivatives.” the scope of the cyclodextrin host has been expanded beyond that of γ-cyclodextrin, which permits us to tailor and tune the hydrophobic domain of the hosts optimally to the size of specific guest molecules. This expansion in turn offers improvements in selectivity and sensitivity for the detection for a given analyte. The chapter highlights the synthesis of a series of fluorophore-appended β-cyclodextrins with specific degree of functionalization and high levels of regioselectivity. These are powerful architectures in our group’s ongoing attempts at developing highly selective sensors for the efficient detection of persistent organic pollutants (POPs) at concentrations close to their environmental concentrations and literature-reported limits of concerns. By covalently linking a fluorophore directly to the cyclodextrin host, we obtained higher levels of system control in the cyclodextrin-promoted binding leading to unique fluorophore responses in the detection of several isomeric and analogous toxicants, including DDT pesticide analogues and polychlorinated biphenyl (PCBs) congeners. Advantages of using β-cyclodextrin include the smaller cavity size, which directly enables greater selectivity in binding as well as more efficient host-guest interactions, the lower cost of β-cyclodextrin compared to the γ-cyclodextrin isomer, and more straightforward methods for synthetically modifying the cyclodextrin host structure. We have demonstrated the ability of three architecturally distinct combinations of perbenzylated-β-cyclodextrin/fluorophore sensor molecules to distinguish three isomeric and two analogous classes of analytes with 100% accuracy using linear discriminant analysis (LDA) of the fluorescence response signals. Each analyte-sensor binding event results in the modulation of the associated fluorophore, generating a unique chemical signature for each isomer across all the three sensors in an array based sensing strategy. Results of this work have recently been accepted for publication in New Journal of Chemistry.

Additionally, the synthesis of a series of cyclodextrin-incorporated higher order architectures has also been described in the fourth manuscript “Synthetic β-cyclodextrin dimers for squaraine binding: Effect of host architecture on photophysical properties, aggregate formation and chemical reactivity.” These architectures have been designed to exhibit higher binding affinity towards larger hydrophobic analytes like stilbene, tamoxifen and biphenyls based on hydrophobic binding of the guest from two or more distinct ends of the molecule. Two cyclodextrins were tethered by aromatic/alkyl amide linkages, and binding properties of these novel receptors were investigated for high quantum yield fluorophores (squaraine dyes in this case). A comparison of the binding constants of the different hosts was drawn to reveal the contribution from a flexible aromatic linker in the binding of hydrophobic guests. Investigation of the supramolecular interactions of hosts with a series of N-alkyl-N-methylanilino squaraines of progressively increasing alkyl chain length has produced a few notable results, including: (A) the ability of the dimers to suppress the squaraine H- and J- aggregate formations in solution very effectively (a phenomenon reported by Chen et. al. previously with β-cyclodextrin); (B) the ability of the dimers to protect the squaraine core from aqueous hydrolysis, thereby prolonging its halflife (a phenomenon previously reported by Smith and co-workers for squaraine pseudo-rotaxanes with synthetic tetralactam macrocycles) and finally (C) a particular dimer being able to act as an enzyme mimic for the aqueous hydrolysis of a squaraine dye with high selectivity and turn-over numbers (TON). The results of this work are being prepared for submission to the journal Chemical Science.

To develop sensitive and selective sensors, efforts have even been extended to synthetic macrocycles for the efficient binding of PAHs and other analytes. The fifth manuscript “A highly versatile fluorenone-based macrocycle for the sensitive detection of polycyclic aromatic hydrocarbons and fluoride anions” entails the synthesis and application of a fluorenone integrated triazolophane for the efficient binding of PAHs and fluoride anions. UV-vis and 1H-NMR spectroscopy results showed that the macrocycle has high sensitivity for selected PAHs and binds fluoride anions in a 1:2 stoichiometry. The bilateral symmetry of the macrocycle creates two binding pockets for the relatively small fluoride anion. This conclusion is well supported by the binding curve fitting of 1H-NMR titrations and Job’s plot analysis of the chemical shift of the triazole proton. A high association constant value of 104 M-2 is observed for the binding of fluoride anion in DMSO. Results of these experiments have been published in a co-first author publication in RSC Advances in 2016.

The final chapter of the thesis describes the application of basic supramolecular science in an industrial setting. In cosmetic industries, hydrated surfactant vesicles are used to deliver encapsulated perfume ingredients and counter skin dryness. However, addition of small concentrations of perfume-raw-materials (PRMs) has a drastic effect on vesicular suspensions, perturbing their microstructures and altering their rheological properties. In the sixth manuscript entitled, - “Impact of Nearly Water-Insoluble Additives on the Properties of Vesicular Suspensions” two model perfume-raw-material (PRM) compounds, linalyl acetate (LA) and eugenol, have been identified to have very different impacts on a multilamellar vesicular suspension made of diethylester dimethylammonium chloride (DEEDMAC) surfactant. While the former has negligible effect, the latter triggers a change from multilamellar to unilamellar vesicles, resulting in a sharp rise in the suspension viscosity. Employing time-resolved cryogenic transmission electron microscopy, microstructural changes related to viscosity variations were observed. In addition, 1H-NMR spectroscopy was used to examine the interactions between the additives and DEEDMAC, revealing the underlying mechanisms behind the structural transformations. To provide additional insights, changes induced upon addition of non-allyl substituted structural analogs of eugenol with increasing aromaticity, cyclohexanol, phenol, catechol and guaiacol, to DEEDMAC suspensions were investigated. These molecules are therefore characterized as ‘intermediate’ between LA and eugenol, in terms of transitioning from the non-aromatic character of LA to the highly aromatic character of eugenol. By examining NMR results from all the additives, strong interaction of the π electrons in aromatic rings with the cationic DEEDMAC head groups was determined to play a significant role in vesicular exfoliation phenomena. Such interactions are strong in eugenol but not present in LA. Results of these experiments were published in a co-first author publication in Industrial & Engineering Chemistry Research in 2016.

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