Substituent effects on non-covalent interactions
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Date
29/07/2020Author
Burns, Rebecca Jayne
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Abstract
Non-covalent interactions play a vital role in biological and chemical systems,
underpinning important processes such as ligand–receptor binding and protein
structure. Substituent effects on these non-covalent interactions are often used to
influence the system and are generally predicted based upon empirically defined
constants.
Chapter 1 of this thesis provides a literature review covering the quantification of
substituent effects from Hammett’s seminal constants to their present-day treatment.
The contributions to the overall influence of a substituent on a chemical system via
through-bond and through-space effects is explored, culminating in the most recent
studies pointing towards the often overseen importance of the latter.
Chapter 2 utilises a combined computational and experimental approach to explore
the influence of through-space substituent effects on chemical equilibria. Synthetic
molecular torsion balances were employed for the experimental measurements of the
conformational equilibrium constants from which a new set of substituent constants
were derived. Computational modelling to obtain Electrostatic Potential (ESP)
surfaces and slices uncovered the origin of the experimental findings to be a through-space effect. In addition, this analysis provided evidence for the geometrical sensitivity
of through-space effects resulting in the demonstration of the tune-ability of such
substituent effects. Through-space substituent effects were shown to be sensitive to
solvent effects via a mathematical model applied to the experimental data obtained in
a range of solvents. The through-space substituent effects were greatly attenuated by
competitive solvents, due to the intrinsic electrostatic nature of through-space effects
with electrostatic effects being sensitive to changes in solvent.
Chapter 3 is a detailed examination of the transferability of the substituent constants
derived in Chapter 2 by comparing the constants to experimental reaction rates.
Through-space substituent effects on reactivity was not well predicted by the constants
derived in Chapter 2, showing the sensitivity of field effects to geometrical influences
in the transition state. Ultimately, this analysis showed that through-space substituent
effects are best understood via simple computational modelling.
Chapter 4 provides a detailed analysis into the nature of weak hydrogen bonding
interactions using molecular balances and Energetic Decomposition Analysis (EDA).
Substituents that are known to be weak hydrogen bond acceptors were observed to
perturb the hydrogen bonding interaction between an ortho hydroxyl group with a
carbonyl group via conformational free energies. The surprising competitive nature of
these substituents was investigated through EDA, which showed that the apparent
competitive hydrogen bonds to the adjacent substituents were instead driven by
repulsive interactions (e.g. between lone pairs of electrons). It is proposed that such
contacts are instead best described as “pseudo-hydrogen bonds”, which lack the
attractive characteristic of true hydrogen bonds