Non-covalent interactions underpin the whole of chemistry and biology, but their study is extremely difficult in complicated biological systems. This thesis presents the application of synthetic molecular balances for gaining fundamental insights into the physicochemical phenomena that govern molecular recognition processes. Chapter 1 reviews the use of small synthetic molecules that exist in two conformational states via slow rotation of a bond, in the quantification of non-covalent interactions. Chapter 2 presents a new molecular torsion balance, based on a slowly rotating tertiary formyl amide for the study of non-covalent interactions. The incorporation of a fluorine atom in one of the rings allows the quantification of solvent effects in a wide range of solvents. Intramolecular electrostatic interactions and intermolecular solvation effects (but not solvophobic effects) are shown to be important in determining the position of the conformational equilibria. Correlations with calculated molecular properties show that solvent effects are fully dissected, revealing the idealistic behavior of the system in the gas phase. Chapter 3 discusses through-space substituent effects on the properties of aromatic rings. Electronic communication between both electron-rich and electron-deficient substituents with the electron density of an adjacent aromatic ring is predicted by molecular electrostatic potential calculations. The effect is confirmed to occur experimentally and is quantified using synthetic molecular balances. Chapter 4 describes the work done towards the investigation of solvent bridging interactions in molecular torsion balances. No experimental evidence of bridging interactions was observed. This might be attributed to the entropic penalty associated with this binding mode, or the non-ideal geometry of the potential bridging sites. Chapter 5 outlines a steric blocking effect observed in certain balances with bulky substituents in chloroform and dichloromethane. Chapter 6 presents synthetic procedures and compound characterisation including a thorough analysis of NMR data obtained in this study.

Predicting and quantifying solvent effects on non-covalent interactions is often very challenging, as they are influenced and modulated by multiple factors. In this thesis, a series of molecular torsion balances is used as a tool to tackle the complexities of noncovalent interactions in solution. Chapter 1 presents an up-to-date literature review on solvent effects on non-covalent interactions, with a particular focus on solvent effects on conformational equilibria and molecular torsion balances. Chapter 2 demonstrates the use of molecular torsion balances and a simple explicit solvation computational model to show that the electrostatic potential of the substituted aromatic rings is largely dependent on the explicit solvation of the substituent. The contribution of both bond polarisation and through-space field effects is also covered. Chapter 3 provides a literature review on the deuterium isotope effects on non-covalent interactions, presenting a range of contradictory findings. Molecular torsion balances are used here as a probe of H/D isotope effects on the conformational equilibria, solvent isotope effects and the solvophobic effect in aqueous mixtures. The balances are studied from thermodynamic and kinetic viewpoints, through which both intra- and intermolecular interactions are examined. It is shown here that H/D isotope effects on the presented system are either non-existent or negligibly small. Chapter 4 presents the use of molecular torsion balances to investigate carbonylcarbonyl interactions, taking into account steric and solvent effects. This is compared experimentally and computationally against two existing theories rationalising these interactions. In Chapter 5, a background of metal-ligand interactions is outlined, along the most widely utilised theories rationalising them. The electronic effects of Pt complexation by a pyridyl-substituted molecular torsion balance is analysed both experimentally and computationally, and the arising discrepancies are addressed. The applicability limits of the previously presented simple solvation models are determined using systems displaying extreme electronic effects.

Non-covalent interactions are fundamental to molecular recognition processes that underpin the structure and function of chemical and biological systems. Their study is often difficult due to the interplay of multiple interactions and solvent effects common in complex systems. Herein, chapter one provides some general background on the area before presenting a literature review of key, contemporary developments on the use of folding molecules for the quantification of non-covalent interactions. Chapter two investigates the magnitude and extent of energetic cooperativity in H-bond chains. Utilising supramolecular complexes and synthetic molecular torsion balances, direct measurements of energetic cooperativity are presented in an experimental system in which the geometry and number of H-bonds in a chain were systematically controlled. Strikingly, it was found that adding a second H-bond donor to form a chain can almost double the strength of the terminal H-bond, while further extension had very little effect. Computations provide insights into this strong, short-range cooperative effect in a range of H-bonding contexts. Chapters three and four build on the concepts and molecular models discussed in chapter two. Chapter three discusses the effects of interplay and competition between strong H-bond acceptors such as formyl groups and the weaker organofluorine H-bond acceptor. There has been some debate in recent literature about the latter’s ability to accept H-bonds, the work presented shows that although organofluorine is a weak H-bond acceptor, it can have a significant modulating effect on stronger interactions when in direct competition. Chapter four investigates deuterium isotope effects on conformational equilibria governed by non-covalent interactions. The results show that any deuterium isotope effect which exists is less than the margins of experimental error. Finally, chapter five discusses a molecular torsion balance designed to investigate halogen∙∙∙arene interactions. The interaction energies were investigated in a range of solvents and mixtures in order to dissect out the dispersive and solvophobic components of folding. Overall, these interactions were found to be weak. Nonetheless, a model was used to dissect trends in solvophobic and electronic contributions to the binding using multiple linear regression based upon the cohesive energy density and polarisabilities of the solvents.

A series of studies from our lab have investigated the threading polyintercalator approach to sequence specific DNA binding using a 1,4,5,8-naphthalene tetracarboxylic diimide (NDI) intercalating unit connected by flexible peptide linkers. Herein is a report of the sequence specificity, as well as a detailed kinetic analysis, of a threading NDI tetraintercalator. DNase I footprinting using two ~500 base pair DNA fragments containing one designed binding site for the tetraintercalator confirmed highly sequence specific binding. Kinetic analyses include 1H NMR, gel mobility-shift assays, and stopped-flow UV measurements to reveal a polyintercalation binding mode that demonstrates significant similarities between association rate profiles and rate constants for the tetraintercalator binding to its preferred versus a random oligonucleotide sequence. Sequence specificity was found to derive almost entirely from large differences in dissociation rates from the preferred versus random oligonucleotide sequences. Interestingly, the dissociation rate constant of the tetraintercalator complex dissociating from its preferred binding site was extremely slow, corresponding to a 16 day half-life at a benchmark 100 mM [Na+]. This dissociation result for the tetraintercalator is one of the longest bound half-lives yet measured, and to the best of our knowledge, the longest for a DNA binding small molecule. Such a long-lived complex raises the possibility of using threading polyintercalators to disrupt biological processes for extended periods. Current focus is given to deciphering a mechanism for the molecular recognition of the tetraintercalator preferred binding site within a long sequence of DNA. Initial DNase I footprinting results on an approximate 500mer DNA sequence containing three sequential preferred binding sites reveal that the tetraintercalator likely locates its designed binding site by a macro- or microscopic dissociation/re-association type of mechanism. Cooperativity is a possible ally to binding, leaving future studies to distinguish the mechanism for molecular recognition in a manner that is capable of circumventing cooperative binding. Taken together, the threading polyintercalation binding mode presents an interesting topology to sequence specific DNA binding. Extraordinarily long dissociation rates from preferred binding sites offers many future possibilities to disrupt biological processes in vivo. / text

The focus of this thesis is the question of how non-covalent interactions affect chemical systems' electronic and structural properties. Non-covalent interactions can exhibit a range of binding strengths, from strong electrostatically-bound salt bridges or multiple hydrogen bonds to weak dispersion-bound complexes such as rare gas dimers or the benzene dimer. To determine the interaction energies (IE) of non-covalent interactions one generally takes the supermolecular approach as described by the equation \begin{equation} E_{IE} = E_{AB} - E_{A} - E_{B}, \end{equation} where subscripts A and B refer to two monomers and AB indicates the dimer. This interaction energy is the difference in energy between two monomers interacting at a single configuration compared to the completely non-interacting monomers at infinite separation. In this framework, positive interaction energies are repulsive or unfavorable while negative interaction energies signify a favorable interaction. We use prototype systems to understand systems with complex interactions such as π-π stacking in curved aromatic systems, three-body dispersion contributions to lattice energies and transition metal catalysts affect on transition state barrier heights. The current "gold standard" of computational chemistry is coupled-cluster theory with iterative single and double excitation and perturbative triple excitations [CCSD(T)].\cite{Lee:1995:47} Using CCSD(T) with large basis sets usually yields results that are in good agreement with experimental data.\cite{Shibasaki:2006:4397} CCSD(T) being very computational expensive forces us to use methods of a lower overall quality, but also much more tractable for some interesting problems. We must use the available CCSD(T) or experimental data available to benchmark lower quality methods in order to ensure that the low quality methods are providing and accurate description of the problem of interest. To investigate the effect of curvature on the nature of π-π interactions, we studied concave-convex dimers of corannulene and coronene in nested configurations. By imposing artificial curvature/planarity we were able to learn about the fundamental physics of π-π stacking in curved systems. To investigate these effects, it was necessary to benchmark low level methods for the interaction of large aromatic hydrocarbons. With the coronene and corannulene dimers being 60 and 72 atoms, respectively, they are outside the limits of tractability for a large number of computations at the level of CCSD(T). Therefore we must determine the most efficient and accurate method of describing the physics of these systems with a few benchmark computations. Using a few benchmark computations published by Janowski et al. (Ref. \cite{Janowski:2011:155}) we were able to benchmark four functionals (B3LYP, B97, M05-2X and M06-2X) as well as four dispersion corrections (-D2, -D3, -D3(BJ), and -XDM) and we found that B3LYP-D3(BJ) performed best. Using B3LYP-D3(BJ) we found that both corannulene and coronene exhibit stronger interaction energies as more curvature is introduced, except at unnaturally close intermolecular distances or high degrees of curvature. Using symmetry adapted perturbation theory (SAPT)\cite{Jeziorski:1994:1887, Szalewicz:2012:254}, we were able to determine that this stronger interaction comes from stabilizing dispersion, induction and charge penetration interactions with smaller destabilizing interactions from exchange interactions. For accurate computations on lattice energies one needs to go beyond two-body effects to three-body effects if the cluster expansion is being used. Three-body dispersion is normally a smaller fraction of the lattice energy of a crystal when compared to three-body induction. We investigated the three-body contribution using the counterpoise corrected formula of Hankins \textit{et al.}.\cite{Hankins:1970:4544} \begin{equation} \Delta ^{3} E^{ABC}_{ABC} = E^{ABC}_{ABC} - \sum_{i} E^{ABC}_{i} - \sum_{ij} \Delta ^{2} E^{ABC}_{ij}, \end{equation} where the superscript ABC represents the trimer basis and the E(subscript i) denotes the energy of each monomer, where {\em i} counts over the individual molecule of the trimer. The last term is defined as \begin{equation} \Delta ^{2} E^{ABC}_{ij} = E^{ABC}_{ij} - E^{ABC}_{i} - E^{ABC}_{j}, \end{equation} where the energies of all dimers and monomers are determined in the trimer basis. Using these formulae we investigated the three-body contribution to the lattice energy of crystalline benzene with CCSD(T). By using CCSD(T) computations we resolved a debate in the literature about the magnitude of the non-additive three-body dispersion contribution to the lattice energy of the benzene crystal. Based on CCSD(T) computations, we report a three-body dispersion contribution of 0.89 kcal mol⁻¹, or 7.2\% of the total lattice energy. This estimate is smaller than many previous computational estimates\cite{Tkatchenko:2012:236402,Grimme:2010:154104,Wen:2011:3733,vonlilienfeld:2010:234109} of the three-body dispersion contribution, which fell between 0.92 and 1.67 kcal mol⁻¹. The benchmark data we provide confirm that three-body dispersion effects cannot be neglected in accurate computations of the lattice energy of benzene. Although this study focused on benzene, three-body dispersion effects may also contribute substantially to the lattice energy of other aromatic hydrocarbon materials. Finally, density functional theory (DFT) was applied to the rate-limiting step of the hydrolytic kinetic resolution (HKR) of terminal epoxides to resolve questions surrounding the mechanism. We find that the catalytic mechanism is cooperative because the barrier height reduction for the bimetallic reaction is greater than the sum of the barrier height reductions for the two monometallic reactions. We were also able to compute barrier heights for multiple counter-ions which react at different rates. Based on experimental reaction profiles, we saw a good correlation between our barrier heights for chloride, acetate, and tosylate with the peak reaction rates reported. We also saw that hydroxide, which is inactive experimentally is inactve because when hydroxide is the only counter-ion present in the system it has a barrier height that is 11-14 kJ mol⁻¹ higher than the other three counter-ions which are extremely active.

The Effective Fragment Potential (EFP) is a quantum-mechanical based model used to describe non-covalent interactions of small molecules or fragments. It can be used along with fully <i>ab initio</i> methods to study the electronic properties of complex systems, such as solvated chromophores or proteins. For this purpose, the system is divided into two regions: one modeled with quantum mechanics and the other with EFP. The interaction between the QM region and the effective fragments has popularly been described through electrostatics and polarization only. This thesis focuses on the development of the QM/EFP exchange-repulsion term, as well as the evaluation of the dispersion term and a charge-penetration correction. The goal of is to determine how these terms can increase the accuracy of QM/EFP calculations without an increase in their computational cost.

Non-covalent interactions taking place in solution are essential in chemical and biological systems. The solvent environment plays an important role in determining the geometry and stability of interactions. This thesis examines aromatic stacking interactions, alkyl-alkyl interactions, edge-to-face aromatic interactions, halogen bonds and hydrogen…hydrogen interactions in solution. Chapter 1 briefly introduces the different classes of non-covalent interactions, in addition to the state-of-the-art models and methods for investigating these weak interactions. The chapter finishes with a focus on dispersion interaction in alkanes and arenes. Chapter 2 investigates dispersion interactions between stacked aromatics in solution using a new class of complexes and thermodynamic double mutant cycles (DMCs). In extended aromatics, dispersion was detected as providing a small but significant contribution to the overall stacking free energies. Chapter 3 concerns the experimental measurement of alkyl-alkyl dispersion interactions in a wide range of solvents using Wilcox torsion balances. The contribution of dispersion interactions to alkyl-alkyl association was shown to be very small, with DMC, QSPR method and Hunter's solvation model. Chapter 4 studies edge-to-face aromatic interactions in series of solvents. In the open system, edge-to-face aromatic interactions were found to be sensitive to the solvent environment. The solvent effects were complicated and cannot be rationalised by a single parameter. Further analysis is needed. Chapter 5 describes a preliminary approach to investigate organic halogen…π interactions in solution using supramolecular complexes and torsion balances. Chapter 6 is a preliminary investigation of the ability of hydrogen atoms to act as H bond acceptors in silane compounds. Computations and 1H NMR demonstrated a weak interaction between silane and perfluoro-tert-butanol.

Non-covalent interactions in solution are subject to modulation by surrounding solvent molecules. This thesis presents two experimental molecular balances that have been used to quantify solvent effects on non-covalent interactions, including electrostatic and dispersion interactions. The first chapter introduces literature where non-covalent interactions have been studied in a range of solvents, particularly those where the effects of aqueous or fluorous solvents have been investigated. These solvents are of particular interest as they both invoke solvophobic effects on organic molecules, but have differing chemical and physical properties. The second chapter describes the adaptation of the Wilcox molecular torsion balance to study interactions between organic and fluorinated carbon chains in a range of solvents. Solvent cohesion was found to be the principle force driving both the alkyl and fluorous chains together in aqueous solvents, where no contribution to the interaction energy arising from dispersion forces could be detected. In fluorous and polar organic solvents evidence was found for weak favourable dispersion interactions between the alkyl chains. In contrast dispersion forces between the chains were found to be disrupted by competitive van der Waals interactions with surrounding solvent molecules in apolar organic solvents. Association of the fluorous chains was found to be solely driven by solvent cohesion. The final chapter describes the design and synthesis of a novel synthetic molecular-balance framework and describes its application to simultaneously measure solvent and substituent effects on the position of conformational equilibria. Despite the simplicity of the model system, surprisingly complicated behaviour emerged from the interplay of conformational, intramolecular and solvent effects. Nonetheless, a large data set of experimental equilibrium constants was analysed using a simple solvent model, which was able to account for both the intuitive and more unusual patterns observed. A means of dissecting electrostatic and solvent effects to reveal pseudo gas-phase behaviour has resulted from the analysis of experimental data obtained in many solvents.

No description available.

The D-A and π-π Interactions and Their Use in Self-Assembly Due to their well-defined shape, size and properties gold nanoparticles represent an advantageous platform for the study of non-covalent interactions between ligands anchored to their surface both in solution and in monolayers or thin films. The aim of this thesis was the synthesis of ligands for gold nanoparticles bearing an anchoring group at one end and a planar π-electron rich pyrene unit at the other. Six structurally variable ligands were prepared differing in the pyrene substitution pattern and the spacer between the aromatic part and the acetylated thiol function. Furthermore, a synthetic pathway leading to extended π-electron systems (both electron rich and electron poor) such as hexabenzocoronene derivatives and its fragments was explored. The key steps in the synthesis of these compounds are the cyclization reactions of alkynes leading to polycyclic intermediates and their ensuing cyclodehydrogenation (Scholl reaction). All of the prepared ligands and their intermediates were characterized by spectroscopic methods. The structure of the key hexakis(pentafluorosulfanyl-phenyl)benzene was confirmed by single crystal X-ray crystallography. The prepared ligands bearing a pyrene unit were deacetylated and anchored to the surface of...