Year of Award

2018

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Chemistry (Organic Option)

Department or School/College

Department of Chemistry and Biochemistry

Committee Chair

Christopher Palmer

Commitee Members

Orion Berryman, Nigel Priestley, Mark Cracolice, Andrea Stierle

Keywords

Active site, Anion receptor, Halogen Bonds, Hydrogen Bonds, Organocatalyst

Abstract

Molecules interact in numerous ways. Halogen bonding is one of the most newly discovered and poorly understood non-covalent interactions. However, this attractive force may be a useful tool for chemists in various disciplines. The directional nature, and competitive strength of the interaction makes it a promising alternative to hydrogen bonding based molecules. Indeed, through crystal structures and solution phase anion titrations, this work has shown that a halogen bonding scaffold can outperform its hydrogen bonding analogue not only in overall interaction strength, but also in resistance to inactivation from polar solvents (an important feature in anion receptors, organocatalysts, and many other applications).

Crystal structures of another bidentate, halogen bonding receptor revealed an orthogonal binding mode within the active site. This previously unseen orientation is also found in biological catalysts that contain an oxyanion hole. This finding prompted small molecule solid-state investigations and solution phase catalysis screens in an attempt to mimic biological oxyanion-hole geometry.

Due to the synthetic obstacles related to modifying the halogen bonding molecule, a different scaffold was developed to explore orthogonal binding of oxyanions. Urea based receptors were designed to be conformationally locked, with systematically increasing steric groups affixed just next to the active site. The increasing sterics were correctly predicted to direct certain planar guests into orthogonal orientations, as determined through single crystal X-ray diffraction. The orthogonal guest binding of trifluoroacetate closely resembles the carbonyl substrate orientation in biological oxyanion holes. This similarity validated a reaction screen with various carbonyl guests in different reaction types. Additionally, the ureas were added to the reaction of N-methylindole and trans-β-nitrostyrene, a commonly screened reaction in organocatalyst development. The findings showed that urea catalytic activity decreases as the steric bulk adjacent to the active site increases. This finding was not present for the reaction with carbonyls, which showed no catalytic activity difference between the ureas.

The findings here demonstrate the numerous hurdles to overcome when designing a catalyst. The capabilities and advantages of halogen bonding receptors were explored, revealing high binding strength and solvent resistance. The unique solid-state data may foreshadow unknown or overlooked binding modes in future organocatalyst design.

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© Copyright 2018 Nicholas Blouin Wageling