Document Type

Dissertation

Date of Degree

Fall 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Chemistry

First Advisor

Leonard R. MacGillivray

Abstract

Crystal engineering is a rapidly developing area of research with goals aimed at designing molecular solids with desired physical and chemical properties. By utilizing reliable intermolecular interactions, the principles of supramolecular chemistry are exploited in the solid state in order to achieve favorable arrangements of molecules in a crystal lattice. We have applied crystal engineering strategies to further develop the strategy of template-directed reactivity in the solid state. An evaluation of catechol, a regioisomer of the commonly used resorcinol template, was performed. Co-crystallization of the template candidate with a bis-pyridyl olefin produced a discrete self-assembled architecture wherein hydrogen-bonded dimers of catechol pre-organize the olefins for a [2+2] photodimerization in the solid state. The dimerization was determined to proceed quantitatively and X-ray studies of a partial single-crystal-to-single-crystal reaction supported the hypothesis of the reaction proceeding exclusively within the discrete assemblies, despite the infinite stacking of the olefins.

A study of substituent effects on the conformational bias of additional catechol- based template candidates was carried out. Candidates with bulky substituents a the 3- and 4-positions were observed to adopt a favorable syn-anti or syn-gauche conformer in most cases. Though conformational bias was induced and discrete assembly achieved, only one of the synthesized cocrystals met the geometric requirements for a photodimerization, however, extended UV exposure produced no evidence of product formation.

We discuss the fortuitous discovery of a catechol-based cocrystal system that produces an infinite linear assembly. The fluorine atom of 3-fluorocatechol was observed to be too small to induce conformational bias in the template candidate. However, the

system was observed to progress through a three-step solvent-mediated phase transformation. The second and third crystal phases were isolated and characterized by single-crystal X-ray diffraction. The X-ray data revealed that the zig-zag assembly of the first phase spontaneously transforms to a double helix topology in the second phase, before transforming to the final phase, which exhibits a quadruple helix topology.

In our studies of pharmaceutical cocrystals, we sought to perform a systematic study of the solid-state behavior of the anti-cancer drug 5-fluorouracil. Inspired by previously published cocrystal structures, we performed co-crystallization experiments with a small series of structurally similar coformers. Comparison of the three structures revealed an inconsistent degree of synthon disruption between the coformers. Curiously, one of the cocrystals obtained displayed a packing arrangement consistent with the requirements of a [2+2] cycloaddition. Irradiation of the sample with UV light resulted in the quantitative formation of a cross-photocycloaddition product. The product was characterized as a pyrimidine-fused cyclobutane, the first reported synthetic derivative of 5-fluorouracil obtained from a solid-state reaction.

Lastly, we utilize crystal engineering strategies to study the behavior of 2- iodohippuric acid, a common radio-imaging target. The pharmacokinetic properties of 2- iodohippuric acid make it an ideal target for renal imaging. We sought to approach a solid formulation of the target in a similar manner to that of a drug or other metabolized pharmaceutical. In doing so, we hoped to study the compound’s behavior in the solid state so that we may eventually use co-crystallization as a means of altering the properties of the target for the purpose of generalizing its use in imaging the body.

Keywords

crystal engineering, pharmaceutical cocrystals, solid-state reactions, supramolecular chemistry

Pages

xviii, 155 pages

Bibliography

Includes bibliographical references (pages 121-138).

Comments

This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: http://www.lib.uiowa.edu/sc/contact/

Copyright

Copyright © 2017 Andrew Jacob Edward Duncan

Included in

Chemistry Commons

Share

COinS