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A dissertation submitted in fulfilment of the requirements for the degree Master of Science in Molecular and Cell Biology in the Faculty of Science, University of the Witwatersrand, Johannesburg, South Africa, 2019 / Biocatalysis is the use of biological systems, such as enzymes, to perform chemical transformations on organic compounds. These enzymes catalyse reactions as whole cell systems or in isolated forms and have been found to exhibit high regio- and stereoselectivity towards chiral compounds. Lipases have been extensively used to catalyse kinetic resolutions of chiral compounds such as the Morita-Baylis-Hillman (MBH) adducts. The MBH adducts and their esters are important intermediates in organic synthesis and have been found to be valuable in the production of biologically active compounds. In this study, we expressed and partially purified the Pseudomonas fluorescens P26504 lipase in an active and soluble form to catalyse the kinetic resolution on MBH acetates to obtain enantiopure MBH adducts. The Pseudomonas fluorescens P26504 lipase was overexpressed in BL21 (DE3) pLysS cells at 25 °C for 16 hours, with 1mM IPTG concentration. Enzymatic assays were conducted after partial purification using p-nitrophenyl esters. The recombinant enzyme was highly active towards short chain esters and showed moderate activity towards medium chained esters. The Morita-Baylis-Hillman reaction was conducted, giving rise to racemic MBH adducts derived from benzaldehyde and hydro-cinnamaldehyde. The second step of the reaction was acetylation, producing chiral MBH acetates. A lipase-catalysed kinetic resolution was set-up, using the partially purified recombinant P. fluorescens P26504 lipase and the MBH acetates. TLC plate analysis showed that the recombinant lipase was able to hydrolyse both MBH acetates. However, further studies can be done to determine the enantioselectivity of the recombinant P. fluorescens P26504 lipase using chiral HPLC, which is more definitive. / TL (2020)

Heterobimetallic complexes present a unique approach to catalyzing challenging reactions. By having two metals in close proximity to each other, the metals are able to interact and alter their electronics in a way that simple organic ligands (carbon, nitrogen, sulfur etc.) cannot. Our studies of heterobimetallic complexes focus on a Pd–Ti complex. The complex features a dative interaction between the palladium and the titanium held together by a phosphonamide scaffold. This interaction increases the electrophilicity of the palladium and makes it a very suitable catalyst for allylic amination reactions. We have conducted extensive studies of this catalyst in allylic aminations, the results of which will be discussed. Our first studies with heterobimetallic Pd–Ti complexes focused on their potential to catalyze challenging allylic amination reactions. These studies showed that the Pd–Ti complex was effective at catalyzing allylic aminations with sterically hindered secondary amines, a reaction which had heretofore proved challenging. We then developed a method for synthesizing the catalyst in situ, greatly simplifying the procedure by which the catalyst is used and making it that much more accessible. We also tested the substrate scope and varied the structure of both the amine and chloride substrates. Our results demonstrated the high catalytic activity of heterobimetallic catalysts with most substrates, in spite of steric hindrance of notoriously challenging substrates. Next, investigated the origin of the fast catalysis we had observed with heterobimetallic Pd–Ti complexes. We confirmed the catalytic cycle and determined the activation barrier for the rate-determining step. We computationally investigated the reactivity of various control catalysts in which the Pd–Ti interaction was severed. These results were compared with the reactivity of the heterobimetallic catalyst. We found that the activation barrier for turnover-limiting reductive amine addition was lowered with the bimetallic complex because of an increased electrophilicity at palladium. We further supported our claim by synthesizing a phosphinoamide palladium complex lacking a titanium atom and testing it in the allylic amination reaction. Our findings in the lab corroborated our calculations. We also ensured that the Pd–Ti catalyst was not transformed prior to catalysts by examining various decomposition pathways and determining that they all resulted in higher energy pathways. We discovered that the Pd–Ti interaction is made possible only by the steric interaction provided by N-tert-butyl groups on the amines which sterically reinforce the Pd–Ti interaction. Lastly, we tested the catalytic activity of the complex with allylic acetates and found them to be ineffective due to catalyst decomposition. It is our hope that these findings can serve as guiding principles when designing heterobimetallic complexes for future catalytic applications.

Catalytic Investigations of Rhodium Acetate Derivatives to Develop Sturdier Insecticides Authors: Alexandria Marshall, Alain Beauparlant, Cassandra Eagle* Department of Chemistry, College of Arts and Sciences East Tennessee State University Johnson City, TN Permethrins are a class of naturally occurring, low-toxicity insecticides that are extracted from the chrysanthemum flower. This class of insecticides is primarily utilized for the treatment of head lice for humans and flea and tick treatment for pets. These naturally occurring permethrins have a low Lethal Dose for 50% (LD50) of the bug population and a high LD50 for mammalian species. Unfortunately, permethrins are sensitive to heat and light, which precludes their use in industries such as the Christmas tree industry and other outside sources of bugs. Pyrethroids, on the other hand, are lab-synthesized insecticides that have the same biological activity as permethrins but are light and heat stable. Rhodium acetate is a catalyst that is used during the synthesis of pyrethroids. This means rhodium acetate is a chemical that speeds up the rate of the reaction without getting consumed. The goal of this research is to understand the mode of action of rhodium acetate so that we can develop sturdier derivatives of permethrin insecticides that can be used in a wider variety of applications. Rhodium acetate catalyzes the most difficult step in the synthesis of pyrethroids, the formation of a cyclopropane ring where there are two bulky groups on the same side of the ring. The catalytically active species, a rhodium (II) acetate carbene species, where the carbene is created from ethyl diazoacetate, is, unfortunately, too unstable and short-lived to characterize thoroughly. We have synthesized a more stable model of the catalyst using nitrile and iso-nitrile adducts of the active site and have been able to study it with extreme precision using X-ray crystallography. The derivative we have synthesized is Rh2(OAc)4.2X, where OAc is the acetate group (the same active ingredient in household vinegar) and X is benzonitrile, NC-C6H5. This nitrile derivative is similar to a carbene in that they both have a lone pair of electrons capable of serving as a Lewis base to initiate sigma bonding with the dirhodium core. Another similarity they share is that both species have empty orbitals capable of accepting electron density to form pi-backbonds. The derivative was synthesized by using 10-30 mg of Rh2(OAc)4 in approximately 10 mL of ethanol. 1-200 equivalents of the benzonitrile are dissolved in ethanol in a separate container. Then, the Rh2(OAc)4 in ethanol and benzonitrile in ethanol were mixed together and kept in a container covered with a tissue to prevent dust from entering. The slow evaporation of the ethanol solvent results in high-quality crystals that are suitable for single crystal X-ray crystallography. The results from X-ray crystallography have provided us important information regarding the rhodium-rhodium bond distance, the rhodium-nitrogen bond distance, the nitrogen-carbon bond distance, and the rhodium-nitrogen-carbon bond angle. This data will poise us to determine the steric and electronic parameters of the cavity used for carbene coordination. The next steps of this project will be to apply these findings to actual carbene chemistry reactions to verify that the parameters are correct. Thus, it will reveal exactly what is necessary for a particular reaction to take place in terms of reactants.

Thesis advisor: Jeffery A. Byers / This dissertation covers the development of redox-switchable ring-opening polymerizations for the synthesis of copolymers of underutilized monomers. In Chapter one, the progress in the development of switchable methods for ring-opening polymerization and ring-opening copolymerizations. Chapter two describes a method for the redox-switchable copolymerization of L-lactide, propylene oxide and carbon dioxide. The benefits of this method are demonstrated through the facile synthesis of blocky and statistical copolymers of the three monomers. In Chapter three, a method for the redox-switchable polymerization of N-carboxyanhydrides is presented. A mechanistic analysis and copolymerizations of N-carboxyanhydrides and either lactones or epoxides follow the initial findings. Chapter four further expands the uses of N-carboxyanhydride redox-switchable polymerizations by immobilizing the catalysts onto semiconductor surfaces for the synthesis of surface bound polyamides. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

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Thesis advisor: Amir H. Hoveyda / The possibility of accessing altered frameworks wherein the spatial relationship between several organic fragments can be controlled can notably impact drug discovery and development. In this context, we introduce a strategy that can be used for programmable and divergent synthesis of a diverse and otherwise difficult-to-prepare set of cyclic amines and bridged bicyclic enamines wherein up to four exit vectors can be altered accordingly. Central to the approach is a catalytic multicomponent reaction that merges a nitrile, a trisubstituted allenylboronate and a silyl hydride, delivering multifunctional 1,4-aminoboronates that contain a versatile and stereochemically defined trisubstituted alkenyl boronate. We show that the products can be modified to afford an assortment of complex, drug-like, polycyclic amines. What is more, a new cyclization strategy, involving the triflic anhydride-mediated reaction of a trisubstituted alkene and a nearby amide, was developed for synthesis of the corresponding bridged bicyclic scaffolds. These resulting bridged enamines and various derivatives are evocative of the 1-azabicyclo[3.2.1]octane core, found in a variety of bioactive alkaloids. / Thesis (PhD) — Boston College, 2023. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Finding materials with high stability, high yield, and excellent catalytic performance has been an outstanding research challenge. Thiol-stabilized atomically precise metal nanoclusters (NCs) have attracted a lot of interest in recent years due to their unique properties and industrial applications, including catalysis, toxic metal-ion sensing, and magnetism. Unlike classical nanoparticles (NPs) which have larger sizes ranging between 10-100 nm, the size of nanoclusters typically ranges from 1 to 3 nm. Thus, nanoclusters represent good candidates to gain fundamental insights into optical and catalytic properties from the atomic to the molecular level. The majority of nanoclusters are based on Ag, Au, and more recently Cu. The major goal of this dissertation is the synthesis and structure determination of silver and copper nanoclusters. The first part of this dissertation addresses a shape-controlled synthesis strategy based on an isomeric dithiol ligand to yield the smallest crystallized silver nanocluster to date, formulated as Ag9. The second part discusses the preparation of different sizes of copper nanoclusters using a one-pot synthesis method and attempted to understand the structure-dependent catalytic pathways at the atomic level. Moreover, three novel Cu nanoclusters were developed: Cu29, Cu45, and Cu67. In terms of size, Cu67 represents a milestone towards high-nuclearity nanoclusters with interesting optical and structural properties. In terms of catalytic properties, Cu45 was found to be promising catalyst in hydroboration reactions of alkynes/alkenes and B2pin2, which affords hydroborated products with good to excellent yield. Mechanistic studies showed single-electron oxidation of an in-situ formed ate complex ([B2pin2]OH-) by the Cu45 catalyst, enabling hydroboration of unsaturated double bonds via a boryl-centred radical. These findings motivate us to extend the library of ligand-protected nanoclusters and focus deeply on exploiting metal nanoclusters based on Cu for catalysis.

There are numerous classes of N-heterocyclic carbenes (NHCs) that have been synthesized since the discovery of stable NHCs in 1988. Their application as ligands in metal complexes has received much attention because of their strong sigma-donor and poor pi-acceptor properties. Within these NHC metal complexes, we are interested in studying zirconium metal complexes with pincer NHC ligands. Recently, achiral CCC-NHC pincer zirconium complexes were synthesized and their catalytic activity in intramolecular hydroamination of aminoalkenes were reported. Herein is reported new reaction conditions which yield pure, chiral CCC-NHC Zr pincer mono(amido) dibromo complex. The enantiopure crystal structure of the same complex is reported. Attempts to synthesize chiral CCC-NHC Zr pincer bis- and tris- amido complexes with the iodo salt of the ligand precursor are summarized. Moreover, syntheses of chiral bis(imidazolinium) ligand precursors with different counter anions are reported with optimized reaction conditions.