The photochemistry of several tribromo-compounds, R−CBr3 (R = CH2OH, CH2OC(O)CF3, COOH) have been studied by utilizing nanosecond transient absorption (ns-TA) and femtosecond transient absorption spectroscopy. Femtosecond transient absorption experiments showed that isomer species R−CBr2−Br were formed after excitation of R−CBr3 within several picoseconds. The absorption band of the isomers R−CBr2−Br showed a strong solvent dependence upon changing the solvent from cyclohexane to acetonitrile. The absorption wavelength of the proposed isomer intermediates and the spectral shift in cyclohexane and acetonitrile were consistent and supported by results from time-dependent density functional theory (TDDFT) calculations. The decay of the isomer intermediates were significantly shortened by the presence of water and alcohols which indicated that R−CBr2−Br intermediates are likely to react with water and alcohols. Second-order Møller-Plesset perturbation theory (MP2) calculations were employed to investigate the structures and energies of the OH-insertion reactions of R−CBr2−Br when water/alcohol molecules (up to three) were explicitly involved in the reaction complex. The reaction mechanisms examined were found to be dramatically catalyzed by the hydrogen bonding of the water molecules causing the molecule to undergo decomposition. The calculations indicate that the isomer species are able to react with water and alcohol via a water catalyzed OH-insertion/HBr elimination reaction to produce a R−CBr2(OH) product. The ab initio calculations suggested that the R−CBr2(OH) product can undergo a similar water catalyzed reaction mechanism to form R−C(O)Br. The acyl bromide type compounds were also studied using ab initio calculations. The dependence on the substituent group R was found to influence the decomposition pathways that form various final products. The results of the experimental and computational results discussed in this thesis were summarized and some issues were detailed that could be prospects for further study in the future. / published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Thesis (Ph. D.)--University of Wisconsin--Madison, 1962. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references : leaf 72.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1951. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves [110-111]).

No description available.

Thesis (PhD) -- University of South Australia, 1995

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

A vast number of halogenated natural products have been isolated to date that contain unique structural and electronic characteristics due to the installed halogen. These properties not only aid in their bioactivity, but also put into question nature's biosynthesis of these complex molecules. Nature's ability to install halogens in a direct and concise manner has inspired our group to seek out chemical transformations that accomplish the same efficiency in the context of synthesizing complex natural products. Specifically, our group has targeted challenges in the areas of halonium-induced polyene cyclization, asymmetric halonium addition to alkenes, and medium-sized bromoether formation, as having access to such transformations would further facilitate total syntheses of these halogenated isolates. Only a few electrophilic iodonium reagents have proven capable of inducing polyene cyclization of linear terpene precursors, though, to date, these only include substrates with electron rich functional groups. Due to this, we targeted development of a new iodonium reagent, IDSI. This easily synthesized, isolable solid has promoted cyclization of both electron rich and poor linear polyene precursors in good yields and diastereoselectivities. The produced iodinated cores allow for further diversification as demonstrated in the formal synthesis of loliolide, stemodin, and K-76. In general, the use of IDSI in previous routes decreases step count, increases overall yields, and avoids the use of stoichiometric amounts of toxic metals. In addition, the chloronium variant, CDSC, completed the first polyene cyclization ever to be initiated by a chloronium electrophile. With the development of our halonium reagents, BDSB (the bromonium variant), IDSI, and CDSC, we next varied the synthesis of each reagent to include an asymmetric component. While their use in polyene cyclization only produced racemic materials, the iodohydroxylation of simple alkenes provided up to 63% ee with only a select substrate. Yet, this chiral IDSI reagent is one of only a handful of strategies capable of transferring an iodonium electrophile with moderate enantioselectivity (above 50% ee). By analyzing the hypothesized biosynthesis of the Laurencia natural isolates, we realized the proposed direct 8-membered bromoetherification from a linear precursor was most likely an unfavorable event, leading us to investigate an alternative idea. Discovery of a unique bromonium-induced ring expansion method generated 8-membered bromoethers diastereoselectively in a single step in good yields. From easily prepared tetrahydrofuran precursors, a variety of diastereomers of 8-endo and 8-exo bromoethers were generated selectively, modeling the cores of over half of the medium-sized isolates. This method was then expanded to include diastereoselective synthesis of 9-membered bromoethers, also found in the Laurencia family. The BDSB-induced ring expansion strategy was then used as the key step in the completed formal total synthesis of laurefucin, an 8-endo bromoether in the Laurencia natural products. By utilizing this method, we have developed the shortest synthesis of any 8-membered bromoether isolate in the family to date. Due to the breadth of products this transformation has generated, we believe this bromonium-induced ring expansion may have biosynthetic relevance. Our proposed biosynthesis could account for generation of not only the 8-membered bromoethers, but also additional 5-, 7- and 9-membered ethers found in the family. Additional experiments were completed to support this pathway, including mimicking enzymatic conditions as well as intercepting the proposed intermediates.

Graduation date: 1991

Bacterial degradation is an important way to detoxify environmental pollutants haloacids, and the key enzyme involved is dehalogenase. In contrast to the well characterized dehalogenases, haloacids transporters that mediate uptake of haloacids are poorly understood. The deh4p gene in a haloacids-degrading bacterium Burkholderia species MBA4 is the first reported haloacids transporter gene. It is located downstream of the dehalogenase gene deh4a and the two forms a haloacids operon. The role of Deh4p as a haloacids transporter was confirmed by heterologous expression. It was later found that a mutant of MBA4 without functional Deh4p was still able to grow in monochloroacetic acid (MCA), and Deh4p seems to be not the only haloacids transporter in MBA4. This study aimed at gaining a deeper understanding of the haloacids transport process in MBA4, and establishing the role of a newly identified gene dehp2 as a conserved haloacids transporter gene in the Burkholderia genus. Disruption of deh4p in MBA4 caused a 32% decrease in MCA uptake rate, confirming the role of Deh4p as a haloacids transporter, but not the only one. A gene showing homology to deh4p in MBA4 was identified and named dehp2. The role of Dehp2 as a second haloacids transporter in MBA4 was confirmed by both gene disruption and heterologous expression. Like deh4p, the expression of dehp2 is also MCA-inducible. A double mutant with both deh4p and dehp2 disrupted only retained 36% MCA uptake rate, further confirming the roles of Deh4p and Dehp2 as haloacids transporters. Dehp2 and Deh4p were also shown to be the two major haloacids transporters. Both Dehp2 and Deh4p are specific toward acetate and its halogenated derivatives, but Dehp2 has a broader spectrum of substrates than Deh4p. Deh4p was found to be a better MCA transporter than Dehp2, and also has a higher affinity for MCA. The effects of protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) and pH on MCA uptake supported the symport of proton(s) and the inclusion of both Dehp2 and Deh4p in the metabolites:H+ symporter family. Orthologs of dehp2 are widely found in the Burkholderia genus, and phylogenetic analysis showed that they were conserved in the genus. The roles of dehp2 orthologs in haloacids transport in three non-pathogenic Burkholderia species were studied. The three species were engineered to gain the ability to utilize MCA as the sole carbon source, and were shown to have MCA-inducible MCA uptake activities. Expressions of the dehp2 orthologs in them are MCA-inducible, strongly suggesting their relationship with MCA uptake. Fusion analysis with lacZ as a reporter gene confirmed the presence of MCA-inducible promoter activity in the upstream non-coding region of dehp2, and the results of electrophoretic mobility shift assay (EMSA) suggested a positive regulation of dehp2. This study established Dehp2 as a second haloacids transporter in MBA4, and also confirmed dehp2 as a conserved haloacids transporter gene in the Burkholderia genus. The presence of at least two haloacids transporters in MBA4 demonstrated the complexity of this process, and future work should figure out the transport mechanisms. / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Bioactivation of organohalogen xenobiotics produces reactive intermediates which alkylate macromolecules. The activation of carbon tetrachloride, trichloroethylene, and methylene chloride was studied in isolated rat hepatocytes by examining alkylation of lipid, protein, RNA, and DNA. All organohalogens alkylated lipid and protein. Carbon tetrachloride and trichloroethylene, but not methylene chloride, alkylated RNA and DNA. Methylene chloride was more highly activated in an oxygen containing atmosphere by hepatocytes, consistent with a proposed formation of formyl chloride as its reactive intermediate. Trichloroethylene was also shown to be more highly activated in an oxygen containing atmosphere, consistent with a proposed trichloroethylene epoxide reactive intermediate. Carbon tetrachloride was shown to be more highly activated in an oxygen-free atmosphere, consistent with a proposed trichloromethyl free radical reactive intermediate. Hepatocytes from rats pretreated with phenobarbital to induce cytochrome P-450 mixed function oxidase activated carbon tetrachloride and trichloroethylene to alkylating intermediates greater than did hepatocytes from non-induced rats. The interaction of carbon tetrachloride metabolites with fatty acids was studied in a chemical activation model system. The thermal decomposition of benzoyl peroxide produced free radicals which activated carbon tetrachloride. The resulting trichloromethyl free radicals abstracted a hydrogen from methyl stearate resulting in chloroform and fatty acid free radicals. Using chemical ionization mass spectrometry, it was discovered that the fatty acid free radical abstracted a chlorine from carbon tetrachloride resulting in chlorinated fatty acid esters. When methyl oleate was used as a substrate in the benzoyl peroxide model system, it was discovered that the trichloromethyl free radical binds covalently, resulting in a fatty acid adduct radical. This radical then abstracted a chlorine to produce chloro, trichloromethyl stearic acid methyl ester, identified by chemical ionization mass spectrometry. Carbon tetrachloride radiolabeled with ¹⁴C or ³⁶Cl in dual label binding experiments in the benzoyl peroxide model system confirmed the mass spectral data. Methyl stearate bound ³⁶Cl- and ¹⁴C-carbon tetrachloride in the ratio of approximately 10 to 1, whereas methyl oleate bound in the ratio of approximately 3.5 to 1. The existence of fatty acid radicals due to hydrogen abstraction or covalent binding by trichloromethyl free radicals was demonstrated in microsomal preparations. In the presence of tritiated water and ¹⁴C-carbon tetrachloride, dual-label analysis demonstrated that the tritium incorporation into microsomal lipids approximately equalled the sum of carbon tetrachloride metabolites bound covalently to microsomal lipids and chloroform production.