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