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School of Biological Sciences

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School of Chemistry and Biochemistry

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School of Earth and Atmospheric Sciences

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School of Mathematics

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Prebiotic inspiration to functional application: Synthetic and mechanistic investigations of glyoxylate and its formal dimer dihydroxyfumaric acid

(Georgia Institute of Technology, 2018-11-09) Ward, George William

The origins of life on earth has been a topic of study in the scientific community for many years. In recent decades, as an understanding of biochemistry developed, how the biomacromolecules that make up life were formed became a prominent question. Exhibiting plausible routes to generate these compounds from simple building blocks and under conditions that could reasonably have existed on the early earth is the focus of prebiotic chemists. Among the small building blocks of interest, glyoxylate along with its dimer dihydroxyfumaric acid (DHF), have been of particular interest. In this thesis, both glyoxylate and DHF are studied with the goal of both showing the possibility of prebiotic functions as well as taking novel chemistries discovered toward origins of life work and expanding them into functionally applicable methodologies for synthetic chemists. The physical organic properties of DHF are analyzed both experimentally and computationally followed by expansion of DHF nucleophilic chemodivergent reactivity to (hetero)aryl aldehydes is shown based on choice of base and solvent. Novel decarboxylation reactivity is used to synthesize the natural product C-veratroylglycol in a single step and is being used toward the synthesis of related lignan and neo-lignan natural products. Glyoxylate is investigated for its possibility to serve a prebiotic precursor to the phosphodiester linker in nucleic acid polymers. Results from these studies lead to a pivot of using glyoxylate derived mixed acetals as a novel alcohol protecting group. This work exhibits how prebiotic chemistry can be applicable to more than just origins of life chemistry and can be used to inspire new synthetic methodologies and syntheses.
Sustainable chemistry solutions for industrial challenges: mechanisms of PVC degradation and stabilization; reversible ionic liquids for CO₂ capture; efficient Suzuki coupling of basic, nitrogen containing substrates

(Georgia Institute of Technology, 2014-08-20) Rumple, Amber C.

The thermal degradation of polyvinyl chloride (PVC) is a significant processing challenge which can lead to deleterious mechanical and optical properties in a wide range of products. Synergetic studies on PVC model compounds and blends of bulk PVC provide unique insights into the thermal degradation and stabilization pathways in the presence of common additives. Model PVC compounds were selected to replicate specific defects (e.g., allylic, vicinal and tertiary) and tacticity (i.e., utilizing stereochemistry to investigate tacticity) commonly found in PVC. Model studies were conducted neat (solvent-free) with metal carboxylates. Experimental results highlight that the allylic and tertiary defects are more reactive than pristine PVC and isotactic sites are more reactive than their syndiotactic counterparts. Zinc stearate was found to act not in the role of substituent, but as a Lewis acid by facilitating dehydrochlorination of labile chlorides. This prevents the accumulation of hydrogen chloride and autocatalytic chain unzipping. In contrast, calcium stearate delayed the formation of zinc chloride, a much stronger Lewis acid than zinc stearate, through an ion exchange process to form calcium chloride. Thermal weight loss studies using blends of bulk PVC proved critical in transferring mechanistic insights into the context of a polymeric matrix. Post-combustion carbon capture has traditionally involved the use of aqueous alkanol amine solutions. The regeneration of such systems, however, can be costly and energy intensive. We have developed an alternative system utilizing silylated alkylamines to reversibly capture CO2 under near ambient conditions. The silyl amines developed capture CO2 through chemical reaction to form reversible ionic liquids (RevIL). RevILs utilize no added water and are tunable by molecular design allowing us to influence industrially relevant carbon capture properties such as viscosity, temperature of reversal, and enthalpy of regeneration, while maximizing overall CO2 capture capacity. We demonstrate a strong structure-property relationship among the silyl amines where minor structural modifications lead to significant changes in the bulk properties of the RevIL. Amine containing substrates are important building blocks for a variety of biological and pharmaceutical compounds. However, application of the otherwise versatile Suzuki reaction to these substrates has proved challenging due to either ligation of the amine to the palladium or to electronic effects slowing the oxidative addition step. Conventional methods to overcome these challenges involve protection-deprotection strategies or the use of designer ligands to facilitate reaction. We have shown that application of CO2 pressure and adjusting the water content of the reaction system facilitate the Suzuki coupling of 4-amino-2-halopyridines in high yield with the simple Pd(TPP)2Cl2 catalyst. The protocol was expanded to 2-halopyridines. The results of these investigations will be discussed.
Investigation of new synthetic reactions: the synthesis of hydrazines via the Aza-Lossen rearrangement, the synthesis of carbamoyl azides from amines, and deprotection reactions using water at elevated temperatures

(Georgia Institute of Technology, 2014-01-07) Mojica, Mike

This thesis explores three rare synthetic routes: the synthesis of hydrazines via the aza-Lossen rearrangement, the synthesis of carbamoyl azides from amines, and deprotection reactions using water at elevated temperatures. The aza-Lossen reaction was found to be ideal at “infinite dilution” conditions and could be performed with both aryl and alkyl example. Carbamoyl azides could be synthesized in high yields from both aryl and alkyl amines. The carbamoyl azide reaction was found to be much more efficient with Cs (+1) present. Lastly, water at elevated temperatures conditions was efficient at removing various amine and hydroxyl protecting groups.
Indole synthesis: Knoevenagel/Hemetsberger reaction sequence; Suzuki coupling reactions of basic nitrogen containing substrates

(Georgia Institute of Technology, 2013-06-14) Heaner, William

A series of substituted indoles have been synthesized by the sequential reaction of aromatic aldehydes with ethyl azidoacetate in the presence of sodium ethoxide to form the corresponding ethyl α-azido-β-arylacrylates (Knoevenagel process) followed by a solvent mediated thermolysis (Hemetsberger process). The isolated yields of the ethyl α-azido-β-arylacrylates were significantly increased when employing the sacrificial electrophile ethyl trifluoroacetate. 1H NMR and coupled 1H-13C NMR analysis of the ethyl α-azido-β-arylacrylates indicate that the condensation is stereospecific—only the Z-isomer could be detected. Solvent mediated thermal treatment of the meta-substituted ethyl α-azido-β-arylacrylates resulted in the formation of both the 5- and 7- substituted indoles—the 5-regioisomer being slightly favored over the 7-regioisomer. Analogous thermal treatment of (2Z, 2Z’)-diethyl 3,3’-(1,3-phenylene)bis(2-azidoacrylate) and (2Z, 2Z’)-diethyl 3,3’-(1,4-phenylene)bis(2-azidoacrylate) exclusively produced pyrroloindoles, diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate and diethyl 1,5-dihydropyrrolo[2,3-f]indole-2,6-dicarboxylate, respectively. Results are also reported which indicate that the α-azido-β-arylacrylates can be used in the subsequent Hemetsberger indolization process without prior purification. Organic substrates containing basic nitrogen centers have been problematic in achieving high yields in the Suzuki coupling process. The origin of this issue is attributed to the complexation of the basic nitrogen center with the palladium catalyst. As a consequence, the use of CO₂ at a variety of pressures was evaluated as a reversible protecting/activating reagent for basic nitrogen containing substrates. The following observations and conclusions were reached. (1) The use of small amounts of water significantly improves the rate and yield of Suzuki coupling reactions. (2) In the presence of aqueous CO₂, careful selection of the base is essential due to formation of bicarbonate and the associated decrease in the amount water. K3PO4 was found to be the most effective base in the presence of CO₂. (3) The yield of product in the Suzuki coupling of 4-amino-2-bromopyridine with phenylboronic acid was evaluated as a function of CO₂ pressure. Compared to reactions in the absence of CO₂, the yield of product increased at all pressures of CO₂ (6.8, 17, and 30.6 atm) - from 15% with no CO₂ to 73% with 30.6 atm of CO₂.
Silanes in sustainable synthesis: applications in polymer grafting, carbon dioxide capture, and gold nanoparticle synthesis

(Georgia Institute of Technology, 2012-10-02) Nixon, Emily Cummings

Vinyltrialkoxysilanes are grafted onto polyolefins via a radical mechanism; in a subsequent step, the pendant alkoxysilanes hydrolyze and condense upon exposure to water, resulting formation of crosslinks. Straight chain hydrocarbons were used as model compounds to investigate the regioselectivity of vinyltrimethoxysilane grafting. To stabilize the water-sensitive grafted products, the methoxy groups were substituted using phenyllithium. It was found that this reaction must be carried out for a minimum of three days to ensure full substitution. The grafted products were then separated on a weight basis using semi-preparative HPLC. Analysis of the di-grafted fraction using edited HSQC and HSQC-TOCSY NMR showed that radical propagation occurs via 1,4- and 1,5-intramolecular hydrogen shifts along the hydrocarbon backbone, resulting in multiple grafts per backbone. Post-combustion carbon capture targets CO₂ emissions from large point sources for capture and sequestration. A new class of potential carbon capture agents known as reversible ionic liquids (RevILs) has been synthesized and evaluated in terms of potential performance parameters (e.g. CO₂ capacity, viscosity, enthalpy of regeneration). These RevILs are silylated amines, which react with CO₂ to form a salt comprising an ammonium cation and a carbamate anion that is liquid at room temperature. Structural modifications of the basic silylamine skeleton result in drastic differences in the performance of the resulting RevIL. Systematic variation of the silylated amines allowed determination of a structure-property relationship, and continued iterations will allow development of an ideal candidate for scale-up. The properties and potential applications of gold nanoparticles (AuNP) are highly dependent on their size and shape. These properties are commonly controlled during liquid-phase synthesis through the use of capping agents, which must be removed following synthesis. Reverse micelles can also be used to control the morphology of AuNP during their synthesis. When RevILs are used in the formation of these reverse micelles, either as the disperse phase or as the surfactant, the built-in switch can be used to release the nanoparticles following their synthesis. This release on command could decrease the post-synthetic steps required to clean and purify AuNP prior to use. We have successfully synthesized AuNP using a number of different RevILs.
Two approaches to green chemistry in industrially driven processes: aluminum tert-butoxide as a rate enhancing Meerwein-Ponndorf-Verley reduction catalyst applied to the technological transfer from batch to continuous flow and structural modifications of functionalized trialkylsilylamines as energy efficient carbon dioxide capture solvents

(Georgia Institute of Technology, 2012-06-14) Flack, Kyle M.

Green chemistry principles have been applied to the enhancement of two industrial chemistry problems. An industrially used reaction to form alcohols from aldehydes and ketones, the Meerwein-Ponndorf-Verley reduction, was improved by introducing a new catalyst Al(OtBu)₃. Due to the lower state of aggregation of this catalyst versus the conventional Al(OiPr)₃ catalyst, reduction rates were found to be faster in both pure iPrOH and mixed solvent systems for three model compounds: benzaldehyde, acetophenone, and a complex, chiral ketone, (S)-CMK. This allowed for the successful implementation of two important milestones; lowering the amount of catalyst needed necessary to complete the reactions (an economic benefit and lower waste) and the conversion from traditional batch reactions to continuous flow (a processing benefit) whereby reactions can be scaled-out rather than scaled-up. Another industrially important field of research that was focused on was CO₂ capture. High energy demands from current CO₂ capture methods such as aqueous amine solvents, specifically from coal-fired power plant flue gas, led to the development of non-aqueous reversible ionic liquids based on silylated amines. Structural modifications of the substitution around the silicon atom, the length of the alkyl chain bonding the silicon and amine, branching along the alkyl backbone, and investigating secondary and primary amines within this class of silylated amines were completed. These amines were reacted with CO₂ and the CO₂ capacity, the ionic liquid viscosity, reversal temperature and reaction enthalpy were all considered as a function of structure. In all cases the capacity was found to be not only greater than that of monethanolamine, an industrial standard, but higher than theoretical predictions through the formation of carbamic acid. Viscosity, reversal temperature, and reaction enthalpy were all found to be tunable through structure. These modifications gave significant insight into the necessary direction for optimization of these solvents as energy-efficient replacements of current CO₂ capture technology.
Development of new chemistry for a dual use hydrazine thruster, switchable room temperature ionic liquids, a study of silane grafting to polyethylene and its model compounds, synthesis of the novel hydrazine replacement fuel molecules 1,1-dimethyl-2-[2-azidoethyl]hydrazine and 1,1-dimethyl-2-[2-azidoethyl]hydrazone

(Georgia Institute of Technology, 2010-04-13) Huttenhower, Hillary Anne

This thesis focuses on the development of new compounds or new processes that are more environmentally friendly and economical than those currently in use. The decomposition of hydrazine, a well established liquid rocket fuel for both the aerospace and defense industries, to the product ammonia is studied. Control of this reaction will allow hydrazine to be used as a propellant for both chemical and electric propulsion. From this a dual stage thruster will be developed that will be more efficient than current systems decreasing the amount of propellant needed and allowing for either a larger mission payload or a longer duration of individual missions. Hydrazine, while beneficial and well established, is also highly toxic, so other work in this thesis focuses on the synthesis of the novel molecule 1,1-dimethyl-2-[2-azidoethyl]hydrazine or DMAEH and its hydrazone intermediate 1,1-dimethyl-2-[2-azidoethyl]hydrazone or De-DMAEH as less toxic hydrazine replacements. Novel "switchable" ionic liquids have been investigated in this research. These are solvents that can change from molecular liquids to ionic liquids and back, simply with the addition or removal of CO₂ from the system. They can be used for a variety of applications, including as solvents for a reaction and separation system. Due to the recyclable nature of these solvents, waste is decreased making their development and implementation both environmentally and economically beneficial. Finally, the grafting reaction of vinyl silanes onto a hydrocarbon backbone is investigated. Fundamental work is being performed to study the graft distribution, selectivity and mechanism by which this reaction occurs. A more thorough understanding of how this reaction proceeds will allow for the development of a more efficient industrial process.
Studies in the asymmetric reduction of (3s)-3-amino-1-chloro-4-phenyl-2-butanone derivatives

(Georgia Institute of Technology, 2010-01-04) Kitagawa, Kristen

This thesis focuses on the asymmetric reduction of N-protected derivatives of (3S)-3-amino-1-chloro-4-phenyl-2-butanone to their corresponding diastereomeric alcohol products, which are key intermediates in the synthesis of HIV protease inhibitors. Although the stereoselective synthesis of the (S,S) alcohol product is easily achieved, preparing the (R,S) diastereomer is much more challenging. I investigated three diastereoselective reduction processes: 1) Meerwein-Ponndorf-Verley (MPV) reduction, 2) asymmetric transfer hydrogenation, and 3) boron reducing agents. The diastereoselectivity of the MPV reduction still favored the (S,S) product; however, I discovered a significant rate enhancement when the standard catalyst (aluminum isopropoxide) was replaced with aluminum tert-butoxide. Many reaction variables were investigated in the asymmetric transfer hydrogenation reaction and the diastereoselectivity was improved to give a ratio of the desired (R,S) diastereomer to the undesired (S,S) alcohol of 9.5:1. Using chiral oxazaborolidine catalysts, an unprecedented (R,S) to (S,S) ratio of 9.5:1 was achieved. Finally, I investigated the effect of the N-protecting group on the stereoselectivity of the reduction. When the original boc-protecting group was replaced with a phthalimide group, the diastereoselectivity of the MPV reduction was reversed to favor the desired (R,S) product.
Coupling reactions and separations for improved synthetic processes

(Georgia Institute of Technology, 2008-10-27) Charney, Reagan R.

This thesis showcases a work that focused on developing processes with improved economic and environmental signatures. It illustrates the strengths of chemists and chemical engineers working together towards sustainable solutions. The joint collaboration between Drs. Liotta and Eckert allows the combination of disciplines to overcome economic and environment obstacles. This thesis depicts the application of chemical engineering and chemistry for industrial processes towards reducing cost and environmental impact. In chapter 2, a synthetic sequence yielding a pharmaceutical precursor was optimized for continuous processing. The precursor was for the pharmaceutical drug Ro 31-8959, which acts as a human immunodeficiency virus (HIV) protease inhibitor. A continuous flow reactor was designed, built and utilized successfully for the two-step reaction of the diazoketone pharmaceutical precursor, (1-benzyl-3-chloro-2-hydroxy-propyl)-carbamic acid tert-butyl ester. The best configuration for the continuous flow reactor involved a single and double coiled stainless steel reactor packed with glass beads. The yield obtained for the diazoketone was quantitative. In chapter 3, the cleavable surfactant (cleavable surfactants decompose in non-surface active ingredients upon stimulus), n-octyl thiirane oxide was synthesized, characterized and its surface activity and loss of surface activity upon heating was demonstrated. The n-octyl thiirane oxide surfactant activity was measured using a dye, Suddan III, and compared to a commercially available surfactant sodium dodecyl sulfate. In chapter 4, 5-amino-1H-tetrazole was synthesized using two novel synthetic routes starting from benign chemicals. Both routes involved Sharpless click chemistry in the first step to form the tetrazole ring. Both routes also used hydrogen transfer as the last step for the formation of the 5-amino-1H-tetrazole. These syntheses eliminated the use of highly toxic and/or explosive chemicals such as cyanamide, hydrazoic acid, and hydrazine. Finally in chapter 5, phase transfer catalysis was used as a means to improve reaction rates and yields between a siloxylated reagent (in the liquid phase) and insoluble ionic reagents (in the solid phase). The activity of commercial phase transfer catalysts like tetra-n-butylammonium bromide was compared to the activity of two novel custom-made siloxylated phase transfer catalysts. Surprisingly, the tetra-n-butylammonium resulted in superior rate constants to the custom made siloxylated phase transfer catalysts.
Novel Switchable Systems and Applications

(Georgia Institute of Technology, 2007-08-24) John, Ejae A.

This work showcases the utility of switchable materials. Included are a switchable room-temperature ionic liquid, a switchable solvent, a switchable heterogeneous catalyst system, and a switchable gel. First, the switchable ionic liquid 2-butyl-1,1,3,3-tetramethylguanidium methylcarbonate is fully investigated. Its use in a complete chemical process (including reaction, separation, reformation, and recycle) is demonstrated with several reactions. Furthermore, its potential use for bitumen separation and purification and SO2 capture/isolation are discussed, and preliminary data is presented. Next, piperylene sulfone (PS), a switchable solvent, is synthesized and fully characterized. Anionic nucleophilic substitution reactions were performed in PS, the products were isolated in high yields, and then the PS was reformed for reuse. Then, we designed an immobilized fluorous microphase system that uses F-MonoPhos to induce high enantioselectivities as a switchable heterogeneous catalyst system. Finally, stable reversible polyethyleimine-CO2 gels have been synthesized with 1-octanol. Our findings indicate that PEI-1200/octanol/CO2 gels have potential as a possible drug carrier matrix for transdermal delivery applications.