The pure sodium salts of the toluenesulfonic acids were prepared by one of two ways. Both methods started with diazotization of the toluidine. In the first method, the diazonium solution was treated with sulfur dioxide and copper powder, and the resulting sulfinic acid was oxidized to the sulfonic acid with potassium permanganate. In the second method, the diazonium solution was treated with cuprous chloride and sulfur dioxide to give the sulfonyl chloride which was hydrolyzed to the sulfonate. Toluene was sulfonated by SO3 (enriched with S-35) in refluxing SO2 solution. The isotope dilution technique was used to determine the isomer distribution as 5.6 ± 0.6% ortho, 9.7 ± 0.4% meta, and 84.8 ± 1% para. A mixture of benzene and toluene was sulfonated as before, and the isotope dilution technique was employed to give the rate of sulfonation of toluene relative to that of benzene as 25 ± 7. This value with the isomer distribution gave partial rate factors in the sulfonation of toluene as of 4.2, mf 7.3, and pf 127. Some a-anilinoketones were prepared starting with the appropriately substituted benzaldehydes. The benzaldehyde was condensed with nitroethane to give a 1-phenyl-2-nitropropene, which was treated with acid and iron powder to give the phenylacetone. The phenylacetone was brominated in acetic acid and the resulting a-bromophenylacetone was treated with the appropriately substituted aniline to give the a-anilinophenylacetone. The anilinoketones prepared in this manner were 1-(4-chloroanilino)-1-(4-chlorophenyl)-2-propanone, its dibromo analog, and 1-(3-chloroanilino)-1-(3-chloropbenyl)-2-propanone. These anilinoketones were subjected to rearrangement conditions: refluxing ethanol, refluxing ethylene glycol, ethylene glycol heated at 105° by a refluxing toluene bath, or ethylene glycol heated at 150° by a refluxing bromobenzene bath, with γ-picoline hydrobromide as catalyst. No rearrangement was detected (ultraviolet analysis) in any of the conditions used in this work. The kinetics of the addition of bromine to cyclohexene in dichloromethane solution was studied at 0° and -22.9° using vacuum line techniques. The product was shown to be trans-1, 2-dibromocyclohexane by comparison of physical constants found with those in the literature and by use of a gas chromatograph. The order of the reaction as determined by the differential method was found to be 1.7 at 0° and 1.4 at -22.9°. The rate constants were calculated to be 80 ± 16 liter 0.7/mole 0.7 sec. at 0° and 48 ± 9 liter 0.4/mole 0.4 sec. at -22.9°. These results indicate a complex system with competing reactions. A possible mechanism is suggested as a explanation for the results.

No description available.

No description available.

<p>This thesis describes the initial steps towards the use of dipeptidyl acyloxymethyl ketones as a platform to develop molecular imaging (MI) probes for cancer. Initially the synthesis of an AOMK was performed following a literature procedure which resulted in an epimerized product. This issue was addressed by optimizing an alternative method yielding all intermediates in yields similar or better to those reported in the literature (final product yield of 67%). An AOMK derivative that can be used to evaluate target expression levels was synthesized by linking a fluorescent dye to the ε-amine group of lysine in accordance to a literature procedure describing the synthesis of an optical imaging probe in 24% yield. A second generation derivative AOMK was prepared by linking 4-fluoro-benzoic acid to the same amino group yielding a model of a PET MI probe.</p> <p>An endpoint colorimetric assay was developed and optimized to test cathepsin B inhibitors. Due to the fact that the AOMKs exhibit time-dependent inhibition these assay conditions did not prove to be adequate for the assessment of the cathepsin B binding. Steps toward developing a continuous assay that would be better suited for these compounds were achieved. Factors such as the relationship between the formation of the assay product vs enzyme concentration and determination of the Michelis-Menten constant (K_m = 390 ± 30 nM) were established. These parameters can be used to determine the optimal enzyme and substrate concentration that should be used to test the AOMK based probes.</p> / Master of Science (MSc)

M.S.

The reaction of sodium azide with 2-p-chloro- and 2-p–methoxyphenyl–3,4,5-triphenyl–2,4-cyclopentadien– Iâ one was studied to determine if the substituent would have any appreciable effect on the product distribution of the corresponding l,5,7,8–tetraphenyl-2,3,4–triazabicyclo[3.3.0]octa-2,7-dien-6-ones and the 3,4,5,6–tetraphenyl–2(lH)â pyridinones that were formed by an acid catalyzed rearrangement. It was found that the chloro substituent had no effect on the reaction. The methoxy substituent had a moderate effect in that the product arising from the stabilized intermediate cation was favored by a ratio of approximately 3 to l. The two simple linear analogs studied were l,2,3,3–tetraphenyl-2-propen-l-one and 3,4,4-triphenyl-3–buten–2â one. These compounds did not react with azide, presumably due to charge delocalization. Also studied as a cyclic analog was 2,7-diphenyltropone which did not react due to the aromatic character of the tropone ring system. A reaction did occur with diphenylcyclopropenone to give an unidentified product. However, the reaction did not take place in the same fashion as for the tetracyclones. / Master of Science

no abstract provided by author / Master of Science

In a recent study of cyclodehydrogenation reactions of potential carcinogenic or carcinolytic hydrocarbons Zajac pointed out that ring closure of 12-(3-methylphenyl)- benz[a]anthracene might take place at either of the two ortho positions or the phenyl ring. These positions are not equivalent with respect to the methyl group and ring closure might yield either 2-methyldibenzo[a,1]pyrene or 4-methyldibenzo[a,1]pyrene or both. The objectives of the present investigation are to study possibilities and methods to prepare 2-(2-naphthylmethyl)- 2'-chloro-5'-methylbenzophenone in a sufficient yield so that a study of the cyclization reaction under a variety of conditions can be made in order to prepare 2-methyldibenzo[a,l]pyrene. During the course of the investigation an improved synthetic route to prepare 2-bromonaphthalene was secured. Three methods utilizing Grignard reagents were approached in order to prepare 2-(2-naphthyl~ethyl)-2'halobenzophenones necessary for the study to obtain 2-(2-naphthylmethyl)-2'-chloro-5'-methylbenzophenone. The only successful preparative method for the above ketones was found to be the reaction between a Grignard reagent and an acid halide. This procedure was applied to the preparation of the following new ketones: 2-(2-naphthylmethyl)-2'-fluorobenzophenone, 2-(2-naphthylmethyl)- 2'-chlorobenzophenone, and 2-(2-naphthylmethyl)- 2'-chloro-5'-methylbenzophenone. Investigation of the sealed tube method revealed that the above ketones could be cyclized at 180° with a mixture of hydrobromic and acetic acids in seven hours. Under these conditions the new compounds 12-(2-fluorophenyl) benz[a]anthracene, 12-(2-chlorophenyl)benz[a]- anthracene, and 12-(2-chloro-5-methylphenyl)-7,12-dihydrobenzo[ a]anthracene were obtained. Further study showed that 12-(2-chloro-5-methylphenyl)-7,12-dihydro-benz[a]anthracene could be obtained in a much better yield when the above procedure was altered by using a mixture of hydriodic and acetic acids. In order to obtain 2-methyldibenzo[a,1]pyrene 12-(2-chloro-5-methylphenyl)-7,12-dihydrobenzo[a]anthracene was reacted with potassium hydroxide and quinoline. Although the results were not definite the qualitative tests and the ultraviolet and infrared spectra suggest an intermediate dihydro compound. The ultraviolet and infrared spectra of six new compounds were recorded. / Master of Science

Malaria continues to cause significant mortality in sub-Saharan Africa and elsewhere, and existing vector control measures are being threatened by growing resistance to pyrethroid insecticides.  With the goal of developing new human-safe, resistance-breaking insecticides we have explored several classes of acetylcholinesterase inhibitors.  In vitro assay studies have shown that trifluoromethyl ketones (TFK's) are potent inhibitors of An. gambiae AChE (AgAChE), that inhibit the enzyme by making a covalent adduct with the catalytic serine of the enzyme.  However research in the Carlier group has shown that trifluoromethyl ketones bearing benzene and pyrazole cores have shown very little toxicity to An. gambiae, perhaps due to hydration and rapid clearance. Focus was directed towards synthesis of oximes, oxime ethers, and hydrazones as potential prodrugs to prevent immediate hydration and reach the central nervous system.  The synthesis of various oximes, oxime ethers, and hydrazones has been shown to give cimpounds toxic to Anopheles gambiae within 3- to 4-fold of the toxicity of propoxur. However, thus far we have not been able to link the toxicity of these compounds to a cholinergic mechanism.  Pre-incubation studies suggest that significant hydrolysis of these compounds to TFKs does not occur or 22 h at pH 7.7 or 5.5.   Future work will be directed towards TFKs that have better pharmacokinetic properties.  Work will also be directed at synthesis of oxime and hydrazone TFK isosteres to determine the mechanism of action of these compounds. / Master of Science

Three 2, 5-dialkyl-1, 3, 4-triphenyl-2, 4-cyclopentadien-1-ols and 2, 5-di(t-butyl)-1, 3-diphenyl-2, 4-cyclopentadien-1-ol were prepared from their precursor ketones using phenyllithium and Grignard reagent. In general, the phenyllithium reagent produced products faster and in better yield and purity than the Grignard reagent. The alcohols were rearranged thermally to obtain the appropriate ketones and to obtain information about the relative rates of the rearrangement. The rearrangement of the three 2, 5-dialkyl-1, 3, 4-triphenyl-2, 4-cyclopentadien-1-ols were studied kinetically and the results compared with those obtained from similar studies on 1,2,3,4,5-pentaphenyl-2,4-cyclopentadien-1-ol. The alcohols all possessed energies of activation and enthalpies of activation which were essentially identical, these supporting earlier theory that no linear free energy relationship (LFER) exists in these rearrangements and that a purely concerted mechanism exists in these cases. The rate of reaction for 15,16,17—triphenylbicyclo[12.2.1] heptadeca-14,16-dien-1-ol was very much faster than any other studied alcohol. The difference in this rate is thought to be due to the severe steric restraints that are present in this alcohol. The entropy of activation for this strained alcohol was shown. to be much less than for the other alcohols. / Ph. D.