This project has been part of an ongoing interest in metabolites with a cyclic tricarbonyl motif 1, usually enolised. Coleophomones A C have a unique architecture with the cyclic tricarbonyl motif embedded in an 11-membered ring: A & B exist in aldol equilibrium, B & C are geometric isomers, and D lacks the macrocycle.1,2 Antifungal & antibiotic activity, and inhibition of human heart chymase & bacterial cell-wall transglycosylase, has generated synthetic interest. In an approach distinct from reported studies,3 we propose 4-carbonyl-substituted isoxazoles, from dipolar cycloaddition of nitrile oxides, as building blocks for the tricarbonyl framework. During this investigation precursors to the macrocycles of coleophomones A, B, C and analogues were developed. En route to these precursors we have uncovered and probed a facile and highly unusual benzisoxazole to oxazole rearrangement. *Schemes and figures relating to the abstract can be found within the document proper.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Master / Master of Philosophy

The recent development of materials with autonomous repair capabilities has opened an exciting new field of polymer science expected to impact nearly every facet of modern society. Similar to natural systems, these "self-healing" materials sense when their structural integrity has been compromised (e.g., due to wear or damage) and respond with a viable repair mechanism. Despite the extraordinary number of successes and advances in this area, a means to ascertain instantaneous knowledge of a material's structural integrity, and more importantly, when it has been compromised, remains a considerable challenge in current systems and materials. To address this challenge, we report recent efforts toward the development of an electronically conductive material that is structurally dynamic and responds to various types of external stimuli. In particular, we have developed new synthetic methodology to prepare a variety of organometallic polymers containing a novel benzobisimidazolylidene or bis(benzoimidazolylidene) ligand, which is comprised of two linearly opposed N-heterocyclic carbenes (NHCs) annulated to a common linker, and various types of transition metals in the polymer's main-chain. Using this approach, polymers with molecular weights up to 10⁶ Da were prepared and cast into robust thin films. Using four-point probe technique, the inherent conductivities of these materials were found to be on the order of 10⁻³ S/cm. Secondly, the dynamics of these polymers were probed in solution using gel permeation chromatography. At specific cross-linker loadings, thermally-responsive gels were obtained. Collectively, these experiments suggested that the essential features for a thermally-responsive, structurally dynamic, conjugated organometallic polymer were developed. Efforts toward probing their ability to display self-healing characteristics in the solid-state are described. The inherent conductivity of the polymers permitted the healing behavior of thin films to be observed by scanning electron microscopy in the absence of a dopant. Long range goals of implementing and utilizing these materials in electronic circuits and other advanced devices are also described. An additional approach towards a dynamic material utilized functional imidazolium-based ionic liquids. A series of functional ionic liquids were produced by appending N-substituents containing pendant halides, alkynes, azides, furans and maleimides. These functional groups allowed for polymerization and crosslinking. The physical properties of the imidazolium monomers, as well as the resulting polymers, could be tuned by altering the anion. When a trifunctional monomer is used in conjunction with the polymerization of difunctional ionic liquids an insoluble crosslinked material forms. This behavior, combined with NHCs ability to bind transition metals as ligands and catalyze various organic transformations, provides potential for this system to be used as a method for catalyst recovery and ultimately catalyst recycling. / text

Chemistry / The efforts described in this thesis were bifurcated along two distinct projects, but generally were directed toward the development of new materials to solve outstanding issues in contemporary electrochemical applications. The first project involved the synthesis and application of redox-switchable olefin metathesis catalysts. N-heterocyclic carbenes (NHCs) bearing ferrocene and other redox-active groups were designed, synthesized, and incorporated into model iridium complexes to evaluate their intrinsic electrochemical and steric parameters. Using these complexes, the ability to switch the electron donating ability of the ligands via redox processes was quantified using a variety of electrochemical and spectroscopic techniques. The donicity was either enhanced or attenutated upon reduction or oxidation of the redox-active group, respectively. The magnitude of the change in donicity upon reduction or oxidation did not vary significantly as a function of the proximity of the redox-active group from the metal center. Thus, other factors, including synthetic considerations, sterics, and redox potential requirements, were determined to guide ligand design. Regardless, redox-active NHCs were adapted into ruthenium-based olefin metathesis catalysts and used to gain control control over various ring-opening metathesis polymerizations and ring-closing metathesis reactions. The second project was focused on the development of new basic polymers for acid/base crosslinked proton exchange membranes intended for applications in direct methanol fuel cells. Polymers containing pendant pyridinyl and pyrimidinyl groups were obtained via the post polymerization functionalization of UDEL® poly(sulfone) and then blended with sulfonated poly(ether ether ketone) (SPEEK). Fuel cells containing these blends were found to exhibit reduced methanol crossover, higher open circuit voltages, and higher maximum power densities compared to plain SPEEK. The differences in fuel cell performance were attributed to the basicity and sterics of the pendant N-heterocycles. / text

Imidazo[1,5-a]pyridines are an important and versatile class of N-heterocyclic compounds due to their stability, unique biological, and photochemical properties. Due to the conjugation and charged structure, their properties are extended to conducting electricity and also have electronic properties. They can be used for chelating transition metals especially heavy metals that can be harmful to living things (including human). The aim of this research was to develop more useful imidazo[1,5-a]pyridines which are stable in both free and complexed state. A variety of imidazo[1,5-a]pyridyl compounds was synthesized following three useful methods namely (i) The first route includes the isolation of imine intermediates which were then treated with phosphorus oxychloride in one case and hydrochloric acid in another case as catalysts. Both cases resulted in the yield of the same imidazo[1,5-a]pyridyl compounds. (ii) The second route was the development on the first route for those imine intermediates that could not be isolated and only hydrochloric acid catalyst was used. In both the first and second routes, paraformaldehyde was used for the ringclosure step of the reaction. The last route for the formation of imidazo[1,5-a]pyridyl compounds did not involve the use of the paraformaldehyde reagent. The suitable routes were followed depending on the nature of the targeted products and the reaction yields were moderate to excellent. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg,2010.

Routes to novel heterocyclic azo compounds and components of use as potential inkjet dyes were investigated. A new route to fluorenones from biphenyl acid chlorides using FVP (Flash Vacuum Pyrolysis) has been discovered. Fluorenone and 4-methylfluoren-9-one were prepared by FVP of 2-phenylbenzoyl chloride and 2-methylbiphenyl-2-carbonyl chloride respectively. Xanthen-9-one and thioxanthen-9-one were also prepared by FVP from the corresponding acid chlorides. 9-Phenanthrol could also be prepared via the FVP of biphenylacetyl choride and the application of this method to a heterocylic thiophene system afforded naphtho[1,2-b]thiophen-4-ol. Naphtho[2,1-b]thiophen-4-ol and naphtho[1,2-b]furan- 4-ol could be obtained in low yields by the FVP of (2-thiophen-3-ylphenyl)acetic acid methyl ester and (2-furan-2-ylphenyl) acetic acid methyl ester over a tungsten trioxide catalyst. Coupling of these systems with the diazonium salt of Acid Yellow 9 afforded the corresponding azo compounds. New heterocyclic dyes were also prepared from the condensation of heterocyclic hydrazines with 4,9-disulfophenanthrenequinone. Pyridine, pyridazine, phthalazine, isoquinoline and 2-quinoline disulfophenanthrene quinone metallised 2:1 nickel complexed magenta dyes were prepared. Industrial tests by standard methods revealed the pyridazine dye has a particularly impressive balance of light and ozone fastness over similar magenta dyes. The reaction of an arylnitro compound with 2-aminopyridine appeared to be an attractive and high yielding route to 2-(phenylazo)pyridine. However, application of this reaction to substituted and naphthalene systems failed. This afforded byproducts due to nucleophilic substitution of groups such as methoxy and the relatively uncommon nucleophilic substitution of hydrogen with none of the required azo products obtained. Therefore it appeared that the reaction of a nitro and amine was not a robust and versatile route to heterocyclic azo compounds. An alternate route to heterocyclic azo compounds involved the use of the Mills reaction by the condensation o-anisidine, p-chloroaniline, 2-aminophenol, 3- aminophenol, naphthylamine, 8-amnioquinoline and 2-acetylamino-5-aminobenzenesulfonic acid with 2-nitrosopyridine afforded the heterocyclic azo products in moderate to high yields. The Mills reaction does appear to be the favored route to heterocyclic azo compounds. Several factors were identified which affect the process of bisazo coupling of chromotropic acid and products obtained. Reaction at the ipso position of monoPACAs (2-phenylazochromotropic acid) leading to increased yields of the ipso substitution monoPACA by-product as opposed to the expected bisazo coupling position was a major problem. Studies indicated reactivity at the ipso position was greatly reduced by the presence of electron withdrawing groups around the phenyl ring of the monoPACA. Further study indicated reaction at the bisazo coupling position increased with the strength of the diazonium salt used in bisazo coupling. Therefore the electronic nature of the monoPACA starting material and the diazonium salt used in bisazo coupling greatly affected the products obtained. Reaction pH studies also revealed attack at the bisazo coupling position increases with pH and at lower pH (5.0 – 8.0) attack at the ipso position dominated. Reactivity of the monoPACA starting material also increased with pH. The influence of steric effects upon bisazo coupling revealed, in the cases where ortho sulfonic acid groups were present in the monoPACA, a reduction in attack at the ipso position. Hence the reaction appeared to be directed towards the required bisazo coupling position.

The halogenated derivatives of heterocyclic compounds (haloarenes) are highly utilized in many fields of chemistry, including drug discovery, medicinal, and material chemistry. There are a variety of ways to functionalize an aromatic system and introduce halogen substituent into the ring. However, electrophilic aromatic substitution (EAS) has been the focus of growing attention, particularly for electronrich substrates. Electrophilic aromatic bromination protocols are one of the most important electrophilic aromatic substitution reactions. However, preparation of bromoarenes classically recommends the use of highly oxidative agents along with utilizing various metal catalysts in a halogenated solvent. The corrosive and toxic nature of these reagents and need of harsh conditions for these protocols make their utility less desirable in current practice. Furthermore, lack of regioselectivity for most substituted aromatics is the other distinguished drawback, since most products contain ortho/para directors which afford a mixture of isomers. The innovation of our procedure for the bromination of various substituted aromatic compounds is twofold in that highly regiospecific para-bromination of activated aryls by treatment with NBS has been accomplished. Although various reaction mediums, such as cyclohexane, acetone, and acetonitrile has been used in this procedure, the significant high yields of the product formation along with the very short reaction times using acetonitrile make this approach more attractive. That this regiospecific p-substitution takes place under such mild conditions leads us to question whether it is EAS.

Master of Science / Food Science Institute / J. Scott Smith / Heterocyclic amines (HCAs) are cancer causing compounds formed during the cooking of meat. Previous studies show that incorporating antioxidant spices into meat as well as marinating meat with antioxidant spices reduces formation of HCAs. The purpose of this study was to determine if commercially available spices applied to the surface of meat could effectively reduce HCA formation. Two commercially available spice blends and one blend of spices with known quantities of antioxidant spices were sprinkled onto the surface of beef just prior to pan-frying. The quantities of spices used were based on the amounts customarily consumed in typical Western cooking. The results of direct application were then compared to marinating with the same types and amounts of spices. The antioxidant potential of the spices was analyzed using DPPH and total phenolics methods. Results indicated that the spices would be effective antioxidants. Low recovery rates and problems during the extraction process made results inconclusive, but suggest that further research may find that applying spices directly to the surface of meat in consumer acceptable quantities may be as effective as marinating at reducing the formation of HCAs.

Thesis advisor: James P. Morken / Sesquiterpene quinones are a prolific class of marine natural products that are particularly interesting due to their antibacterial, antiviral, and anti-inhibitory properties. Hundreds of these biologically active molecules are based on decalin frameworks, both cis- as well as trans-fused, however, significantly less synthetic work has focused on targeting the cis-fused series of compounds. In this chapter, progress towards an asymmetric, general route to various sesquiterpene quinones in the cleordane family of natural products will be described. The key steps of the synthesis include a highly convergent and diastereoselective reductive alkylation to forge both the requisite cis-ring fusion well as the all carbon quaternary center, as well as a scandium-catalyzed ring expansion of a 6,5-ring system to deliver the decalin core of the molecule. Additionally, the chapter includes the development and substrate scope of both methodologies utilized in the key complexity building reactions. Iron complexes ligated by bis(imino)pyridine ligands are remarkably active catalysts for a vast range of organic transformations including polymerization, hydrogenation, hydrosilylation, and hydroboration. Whereas much work has been done to probe the importance of the imine-substituents on catalysis, significantly less information is known about the nature of the central pyridine donor. To study the effects of a more donating ligand in which the pyridine is replaced with an N-heterocyclic carbene, a series of novel ligands and their corresponding iron complexes were synthesized and characterized. Whereas imidazole-derived complexes exhibited exclusively bidentate binding modes, 4,5,6-trihydropyrimidylidene-based ligands adopted a tridentate pincer conformation analogous to complexes of bis(imino)pyridines. Bonding in the five-coordinate bis(imino)-N-heterocyclic carbene complex displayed considerably contracted iron-ligand bond distances compared to the analogous bis(imino)pyridine iron complex. The study of physical and electronic structure and bonding in organometallic compounds is a critical for understanding and predicting complex behavior and reactivity. Having synthesized a completely new type of N-heterocyclic carbene (NHC) ligand and the corresponding iron complex, a rigorous study of metal-NHC bonding, magnetism, and redox activity in bis(imino)-NHC (or carbenodiimine, CDI) complexes of iron was carried out. A series of oxidation and reduction reactions on CDI complexes of iron were performed, enabling access to complexes spanning from formally iron(0) to iron (III) oxidation states. A battery of spectroscopic and computational methods, including X-ray crystallography, Mössbauer spectroscopy, SQUID magnetometry, and EPR spectroscopy established the CDI ligand as a redox active chelator. Additionally, a unique iron-carbene interaction was discovered, in which the metal center antiferromagnetically couples with the carbon of the NHC. Intent on developing CDI complexes of iron into practical catalysts for both synthetic organic transformations and polymerization, a series of stoichiometric as well as catalytic reactions were carried out to evaluate the reactivity profile of the novel complexes. Halide atom abstraction generated a new cationic species, which demonstrated different coordination chemistry compared to the bis(imino)pyridine analogue. Furthermore, the addition of a hydride or alkyl lithium reagent to the parent (CDI)FeCl2 species resulted in interesting and unexpected reactivity involving the carbene ligand. Preliminary catalytic hydrogenation experiments established (CDI)FeCl2 as a competent catalyst for the reduction of simple alkenes in the presence of Na(Hg) as a reductant under 80 psi of hydrogen. Additionally, the dichloride species could be readily converted into bis(aryloxide) complexes that were active for the polymerization of lactide to produce poly(lactic acid). The polymerization is very controlled (PDI values are <1.3), and polymers with molecular weights of around 35 kDa can be obtained after 3 hours at room temperature. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.