Year of Award

2023

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Chemistry (Organic Option)

Other Degree Name/Area of Focus

Organic and Supramolecular Chemistry

Department or School/College

Department of Chemistry and Biochemistry

Committee Chair

Nigel D. Priestley

Commitee Members

Orion B. Berryman, Christopher P. Palmer, Bruce E. Bowler, Kasper B. Hansen

Keywords

anions, foldamers, halogen bonds, helix, noncovalent interactions, oligomers

Abstract

The ubiquity of folding in biopolymers to induce critical functions like information storage, signal transduction, catalysis, and selective binding has inspired chemists to create synthetic analogs called “foldamers” as materials which emulate and complement the remarkable complexity observed in nature. The ingenuity of chemists has yielded unique methodologies to induce secondary structure (folding) for diverse applications in materials science, medicine, and nanotechnology.

Anion foldamers are a specific class of foldamers engineered to recognize and specifically bind anions through noncovalent interactions. Using anions to induce folding has unique challenges. Anions have diverse topologies, pH dependence, and high free energies of solvation relative to smaller cations. Despite this, many examples of anion foldamers have been synthesized.

Still, anion-induced multi-strand helix assembly in solution remains rare. The association and folding of multiple oligomers (quaternary folding), as seen in DNA or multimeric proteins, necessitates overcoming significant entropy loss. Nevertheless, there are important reasons to design higher-order foldamers. Molecular assemblies with tertiary (involving multiple folding patterns) or quaternary (where multiple strands fold collectively) structures allow for multifunctionality, more specific guest targeting, and regulation of activity far greater than simpler systems. This dissertation explores controlling quaternary folding, where multiple synthetic oligomers fold together, using a novel approach that combines halogen bonding (XB) and hydrogen bonding (HB). We present the first anion templated double helices induced by XBs and stabilized by “hydrogen bond enhanced halogen bond” (HBeXB) interactions. Our findings demonstrate that the number and orientation of HB and XB donors significantly affects the quaternary structure and guest selectivity of two similar oligomers. This research offers new design elements for engineering foldamers with tailored quaternary structures for specific guest binding.

Chapter 1 introduces helical anion foldamers. A previous iteration has been published in Chemical Reviews (2020, 120, 5, 2759–2782) and currently has 3416 reads and 60 citations. It has been updated to provide a comprehensive collection of every known helical anion foldamer to date. Chapter 2 presents the design, synthesis, and study of the first HBeXB anion foldamers and includes research submitted for publication. Chapter 3 touches on preliminary work and future directions for the project.

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