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.

Callophycolide A is a meroditerpene isolated from Callophycus serratus, a Fijian red macroalgae. Callophycolide A has been shown to inhibit bacterial growth, and it exhibits moderate cytotoxicity against multiple human cancer cell lines. Most importantly, it exhibits moderate activity against Plasmodium falciparum, the dead- liest malaria-causing parasite to humans. Due to its antimalarial action and the need for antimalarial drugs on the pharmaceutical market, efforts toward a modular approach to the total synthesis of callophycolide A are presented that incorporate inexpensive, commercially available starting materials, offer gram-level scalability, and utilize known chemistry, including copper-mediated aryl allylation, hydrolytic kinetic resolution, base-promoted epoxide ring-opening, and the Steglich esterification. Once completed, this synthetic pathway can be used as a template for the total synthesis of other related marine natural products, such as the callophycols, callophycoic acids, and the bromophycolides. Callophycoic acids, also isolated from C. serratus, are the first examples of diterpene- benzoic acids observed in macroalgae. In addition, these acids, particularly callophycoic acids G and H, exhibit modest antibacterial activity. Although they are not strongly potent against malaria, they share a trans-decalin core identical to callophycols A and B, which are halogenated diterpene-phenols isolated from C. serratus that do exhibit modest antimalarial activity. Due to their identical core and their simpler structure (i.e., trisubstituted olefin tail), if a divergent total synthesis of callophycoic acids G and H can be established, it can serve as a template for synthesizing natural products that have been identified to be more potent against malaria, such as the callophycols, which are more complex in structure. Herein, a total synthesis of callophycoic acids G and H is investigated, which consists of a Wittig reaction, nucleophilic addition, and a bromonium-induced cation-pi cascade cyclization, and the progress toward the target molecules in the current study will be disclosed. To access chiral intermediates for the aforementioned metabolites, catalytic methods were sought. Hydrolytic kinetic resolution (HKR) resolves racemic epoxides using water as the nucleophile and is most often catalyzed by chiral Co(III)-salens. Previous studies have shown that the counter-ion of the Co(III)-salen has a direct effect on the rate of the HKR; when catalyzed by a 50:50 mix of (R,R)-Co(III)-salen-OH and (R,R)-Co(III)-salen-SbF6, the fastest HKR rates occurred. It has further been shown that the enantioselectivity is primarily associated with the reaction of (R,R)-Co(III)-salen-OH on the activated epoxide. Based on the aforementioned origin of selectivity, a catalyst containing a 50:50 mix of (R,R)-Co(III)-salen-OH and (±)-trans-Co(III)-salen-SbF6 could, in principle, give high activities and enantioselectivities for HKR comparable to a mixed counter-ion system containing both (R,R)-Co(III)-salens. In this dissertation, a series of experiments are described that demonstrate that highly selective catalysis is only achieved using 100% enantiopure ligand and that mixtures of (R,R)-Co(III)-salen and (±)-trans-Co(III)-salen yield lower activity and selectivity. Control experiments demonstrate that this is due to rapid counter-ion scrambling under the reaction conditions, precluding the possibility of effectively co-utilizing enantiopure (expensive) and racemic (inexpensive) catalysts with differing counter-ions. The mechanistic investigations resolving the counter-ion scrambling are consistent with the currently accepted mechanism for catalysis, involving cooperative activity of the two Co(III)-salen species that activate the epoxide and water in the reaction. Moreover, the application of HKR in the progress toward the total synthesis of callo- phycolide A will be highlighted and discussed.

In asymmetric catalysis, interactions between multiple molecules of catalyst can be important for achieving high catalyst activity and stereoselectivity. In Chapter 1 of this thesis, we introduce catalyst-catalyst interactions in the context of the classic Kagan nonlinear effect (NLE) experiment, and present examples of the strengths and drawbacks of the NLE experiment. For the remainder of the thesis, we explore catalyst-catalyst interactions in the context of two different reactions. First, in Chapter 2, we apply a combination of reaction kinetics and computational chemistry to a reaction that is well known to require the cooperative action of two molecules of catalyst: the (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides. In our investigation, we demonstrate that stereoselectivity in the HKR is achieved through catalyst-catalyst interactions and provide a model for how high selectivity and broad substrate scope are achieved in this reaction. In Chapter 3, we focus our attention on the thiourea-catalyzed enantioselective alkylation of alpha-chloroethers with silyl ketene acetal nucleophiles, a reaction that was not known to require the cooperative action of two molecules of catalyst at the outset of our investigation. By using a wide range of physical organic chemistry tools, we established that the resting state of the optimal thiourea catalyst is dimeric under typical reaction conditions, and that two molecules of catalyst work cooperatively to activate the alpha-chloroether electrophile. The implications of this mechanism for catalyst design are discussed. / Chemistry and Chemical Biology

Catalysis is an important field of study in chemical engineering and chemistry due to its application in a vast number of chemical transformations. Traditionally, catalysts have been developed as homogeneous molecular species or as heterogeneous insoluble materials. While homogeneous catalysts are typically very active and selective, they are difficult to recover. Conversely, heterogeneous catalysts are easy to recover and reuse, but they generally are less selective. To address these issues, the immobilization of homogeneous catalyst analogs onto solid supports has been a subject of research for the past few decades. Nonetheless, the effects of immobilization are still not completely predictable, and so continued effort is required to develop new immobilized catalysts as well as to develop a better understanding of how different parameters affect catalytic behavior. This dissertation presents the synthesis, characterization, and evaluation of new immobilized catalysts for different applications. First, a solid base catalyst supported on silica was developed and studied in the synthesis of cyclic carbonates from epoxides and carbon dioxide. Next, polymer and silica supported vanadium Schiff base catalysts were developed and evaluated for use in the oxidative kinetic resolution of alpha-hydroxy esters, an enantioselective reaction. Lastly, salen catalyst analogs with amine reactive functional groups were synthesized and characterized for grafting onto aminosilicas with different degrees of amine group isolation. The grafted catalysts were then tested to determine how catalyst spacing on the surface affects their behavior. Throughout the presentation of these results, comparisons are made amongst the new supported catalysts and relevant existing catalysts to discern general trends which could be applied to a wider range of immobilized catalysts. Finally, research opportunities for further improvements in these areas are suggested.

L’objectif de ce travail étaient le développement de catalyseurs hétérogènes efficaces pour promouvoir des réactions asymétriques, en utilisant la polymérisation oxydante ou la formation de polymères de coordination. De nouveaux complexes de salen Co(III) chiraux modifiés par des groupements aromatiques sur les position 5, 5’ ont été préparés et testés dans le dédoublement cinétique hydrolytique (HKR) des époxydes terminaux en conditions homogènes. Ces complexes ont été ensuite engagés dans les polymérisations oxydantes électrochimiques ou chimiques, et une stratégie de copolymérisation a fourni des polymères chiraux très efficaces et stables pour catalyser l’HKR dans des conditions hétérogènes. Nous avons alors cherché à préparer un catalyseur capable de catalyser deux réactions en cascade, en copolymérisant deux complexes de salen portant des métaux différents. Pendant ces études, les complexes de salen Mn ont révélé leur participation active à la réaction d’HKR des époxydes terminaux catalysée par les complexes de salen Co(III), en augmentant l’excès énantiomérique du produit de façon significative. Les études mécanistiques ont été ensuite réalisées pour tenter de comprendre le rôle des complexes de Mn dans cette réaction. De plus, des complexes de salen fonctionnalisés par le groupement pyridine ou le groupement de type acide isophtalique ont été synthétisés. Ces complexes ont été utilisés pour préparer de nouveaux réseaux de polymères de coordination poreux chiraux (collaboration avec l’équipe LCI de l’ICMMO et l’Institut Lavoisier à Versailles), qui sont ensuite testés comme catalyseurs hétérogènes dans la réaction de Henry asymétrique et la réaction d’HKR. / The aim of this work was to prepare new chiral heterogeneous catalysts for asymmetric catalysis by oxidative polymerization of chiral organometallic complexes or by formation of chiral metal organic frameworks. New chiral salen Co(III) complexes modified by oxidizable aromatic groups at position 5,5’ have been prepared and tested as homogeneous catalysts in the Hydrolytic Kinetic Resolution (HKR) of terminal epoxides. These complexes have also been engaged into the oxidative electrochemical and chemical polymerization, and a copolymerization strategy has afforded very efficient and stable heterogeneous catalysts for the HKR. The idea of copolymerization has then been extended to the copolymerization of two salen complexes with different metals, which is expected to promote successively two different asymmetric transformations. During preliminary investigations, the salen Mn complexes have been found to be able to enhance the catalytic performance of salen Co(III) complexes in the HKR by increasing significantly the enantiomeric excess of the products. Mechanistic studies have thus been realized to understand the role of salen Mn complexes in this reaction. Besides, some chiral salen complexes functionalized by pyridine or isophtalic acid groups have been synthesized for the preparation of new chiral metal organic frameworks (collaboration with LCI of ICMMO and Institut Lavoisier of Versailles), which have also been tested in the asymmetric Henry reaction and the HKR as heterogeneous catalysts.