In 1933, benzo[a]pyrene, a hydrocarbon, which was and still is of very great importance for cancer research, was isolated from coal tar and also was synthesized. In recent years more than 450 synthetic compounds have been found to be carcinogenic, and more than 200 are polycyclic aromatic hydrocarbons, their derivatives and analogues. Recently a new polynuclear hydrocarbon, a seven ring compound naphtho[2,1-a]perylene was synthesized in This Laboratory Physiological tests have revealed this compound to be a potent carcinogen. This experience has prompted a new initiative to prepare a number of related compounds of this type in order to bring further insight to the relation between chemical structure and the mechanism of physiological activity. During the synthesis of the four new seven fused aromatic ring systems and a new eight fused aromatic ring system, several modifications and improvement of existing synthetic procedures were made. A recently published modification of the Rosenmund-von Braun method of nitrile synthesis was successfully applied to the preparation of 2-(2-naphthylmethyl)benzonitrile. It was found that 2-(2-naphthylmethyl)phenyl-1-naphthyl ketone and 2-(2-naphthylmethyl)phenyl-2-naphthyl ketone could be prepared by the reaction of a Grignard reagent with a nitrile as well as by the inverse addition of a Grignard reagent to the appropriate acid chlorides. The alumina cyclodehydrogenation procedure was confirmed to be the, only method of synthesis that yields 12-(1-naphthyl)-benz[a]anthracene from its precursor ketone. The yield of 12-(2-naphthyl)benz[a]anthracene was increased from 61% to 83% when anhydrous hydrogen fluoride was used in place of 48% hydrogen bromide and glacial acidic acid as the cyclodehydration media of the precursor ketone. A new cyclodehydrogenation procedure was developed. This procedure, which employs a mixture of aluminum chloride-stannic chloride and alumina, was used to prepare a new hydrocarbon, naphtho[l,2-a]-perylene. An aluminum chloride-sodium chloride melt permeated with carbon dioxide was successfully employed in the preparation of naphtho[2,2-1]benzo- (a]pyrene, naphtho(l,2-l]benzo[a]pyrene, and naphtho- (2,3-1]benzo[a]pyrene. It was shown that high temperature gas chromatography with ionization detectors can be used with success to analyze all of the above discussed ketones, benz[a]anthracenes as well as the new perylene and pyrenes. Additional support of the validity of the. structures of naphtho[1,2-a]perylene and naphtho- [2,1-1]benzo[a]pyrene was provided when the cyclodehydrogenation of these hydrocarbons yielded one and the same product, naphtho[l,7,8-efg]anthanthrene. It was observed that the correlation between color and structure of the newly prepared hydrocarbons follows the principles of annelation. When the ultraviolet and visible spectra peak frequencies were compared it was found that the values and positions of the peaks follow the principles of the annelation method. The examination of the infrared absorption spectra revealed that naphtho[l,2-a]perylene, naphtho[2,1l-1]benzo[a]pyrene, naphtho[1,2-1]benzo[a]-pyrene, and naphtho[2,3-1]benzo[a]pyrene exhibited Peaks at all four, "solo," "duo," "trio," and "quartet", carbon-hydrogen vibration regions, but as expected naphtho[1,7,8-efg]anthanthrene had the "quartet" carbon-hydrogen peak missing between 770 and 755 cm. which further substantiated the validity of the naphtho[1,7,8-efg]anthanthrene structure. The TNF molecular adducts of the five newly prepared compounds, naphtho[1,2-a]perylene, naphtho- [2,1-1]benzo[a]pyrene, naphtho1l,2-1]benzo[a]pyrene, naphtho[2,3-1]benzo[a]pyrene, and naphtho[1,7,8-efg]-anthanthrene were prepared and their melting points recorded. In order to ascertain the structures of the naphtho[1,2-a]perylene and the naphtho[1,2-l]benzo[a]-pyrene obtained from the cyclodehydrogenation of 12-(1-naphthyl)benz[a]anthracene and 12-(2-naphthyl)-benz[a]anthracene, respectively, other routes of synthesis were undertaken. The hydrocarbon, 11-(1-naphthyl)benz[a]anthracene, was prepared by the reaction of 1-naphthylmagnesium bromide with 11-keto-5,6,8,9,10,11-hexahydrobenz[a]- anthracene which on distillation under reduced pressure gave 11-(1-naphthyl)-5,6,8,9-tetrahydrobenz[a]anthracene and on aromatization yielded 11-(1-naphthyl)benz[a]-anthracene. When 1-naphthyl magnesium bromide was allowed to react with the 11-keto-8,9,10,11-tetrahydrobenz[a]anthracene, 11-(1-naphthyl)-8,9~dihydrobenz[a]anthracene was obtained when distilled under reduced pressure. This, likewise, gave 11-(1-naphthyl)- benz[a]anthracene on aromatization. Naphtho[1,2-a]perylene was synthesized unequivocally from 11-(1-naphthyl)benz[a]anthracene via a cyclodehydrogenation reaction. The hydrocarbon, 1-(1-naphthyl)-1,2,3,4-tetrahydrobenz[a]anthracene, was prepared by the reaction of 1-naphthylmagnesium bromide with 1-keto-1,2,3,4- tetrahydrobenz[a]anthracene. On distillation under reduced pressure 1-(1-naphthyl)-1,2,3,4-tetrahydrobenz[a]anthracene was obtained. Under the conditions of an aromatization procedure, naphtho[1,2-1]benzo[a]-pyrene was obtained. The hydrocarbons 11-(1l-naphthyl)-5,6,8,9-tetrahydrobenz[a]anthracene, 11-(1-naphthyl)-8,9-dihydrobenz[a]anthracene, 11-(1-naphthyl)benz[a]-anthracene, 1-(1-naphthyl)-1,2,3,4-tetrahydrobenz[a]anthracene are additional new compounds. / Ph. D.

The scope and limitations of aromatic diazines undergoing nucleophilic substitution reactions occurring via a radical-chain Sʀɴ1 mechanism were investigated. The study was conducted on a series of mono- and dihalogenated aromatic diazines interacting with various ketone enolates in ammonia. Results indicate that this previously unrecognized reaction pathway in these nitrogen heterocycles is easily obtained and should prove of great synthetic utility in preparation of substituted diazines. / Ph. D.

In the light of previous investigations of the cyclodehydration of o-benzylbenzophenones and analogous compounds to polycyclic aromatic hydrocarbons a study of 2'-substituted-2-benzylbenzophenones was undertaken. The previous work had been concerned with the rates of cyclization or 3'-substituted and 4'-substituted ketones in which no ortho effects were operating. The results of these investigations could be adequately interpreted according to the electronic theory of the English school. In the 2'-series ortho effects are superimposed upon the usual electronic effects. When the 2'-substituents were halogens a decrease in rate was observed with an increase in the size of the halogen atom. This indicates that one aspect of these ortho effects is steric. These reactions were carried out in a sealed tube in hydrobromic and acetic acids at 150°C rather than at 117.5°C which was the temperature used previously. This increase was necessary to get a reaction with all the ketones concerned. Even under these conditions the 2'-hydroxy-2- benzylbenzophenone cyclized very poorly. This was attributed to a second ortho effect due to intramolecular hydrogen-bonding between the hydroxy group and the keto group. Infrared spectroscopy demonstrated that this type of hydrogen-bonding is present. The 3'-hydroxy-2-benzylbenzophenone apparently cyclizes very readily since the 3'-methoxy compound is cyclized to 9-(3-hydroxyphenyl)anthracene quite readily. Thus, the two reactions in the 3'-series, ether cleavage and the cyclization reaction both proceed more rapidly than the cyclization of the 21-hydroxyketone. The 9-(2- methoxyphenyl)anthracene can be prepared in good yield by the use of phenyl acid phosphate or polyphosphoric acid as a cyclizing agent. This compound can be easily converted to 9-(2-hydroxyphenyl)anthracene by heating under reflux with a mixture of hydrobromic and acetic acids. The halogen substituted ketones are very viscous oils. In order to have solid derivatives for identification purposes these ketones and the methyl derivative were oxidized to the corresponding o-dibenzoylbenzenes which are all solids. Chromium trioxide in acetic acid was usually found to be the best reagent for this purpose. Two of the 9-phenylanthracenes were oxidized to the corresponding 9-phenyl-9-hydroxy-10-anthrones using sodium dichromate in acetic acid. This reaction is carried out very readily and in excellent yield. It may prove to be valuable in the identification of other aromatic polycyclic hydrocarbons. The reduction of 2'-fluoro-2-benzylbenzophenone to 2'-fluoro-2-benzylbenzhydrol was carried out using sodium borohydride in pyridine. The infrared spectrum showed no evidence of intramolecular hydrogen-bonding between the fluorine atom and the hydroxy group. A study of the use of solid surfaces in aromatic cyclodehydration was made using 4'-chloro-2-benzylbenzophenone as a model compound. Experiments with a large number of solids brought to light two factors which seem to contribute to the ability of a surface to catalyze the reaction. One is the acidity of the surface and the other is the ability of a surface to bind the ketone irreversibly. Surface acidity was measured in terms of the H₀ function by the use of Hammett indicators adsorbed on the surface. The color of the adsorbed indicators was used to obtain the H₀ values. The activity of each surface was measured in terms of the percent yield of the product. The solid of highest activity and highest acidity was a silica-alumina cracking catalyst containing 13% alumina. This catalyst gave a 94% yield with 4'-chloro-2-benzylbenzophenone compared to only about 25% on the commonly used Fisher activated alumina. 2'-Methyl-2-benzylbenzophenone was cyclized in 60% yield. This ketone gave a yield of only 20% when cyclized in the hydrobromic-acetic acid mixture at 180° for 9 hr. 2’,6’-Dimethyl-2-benzylbenzophenone has resisted all attempts to cyclize it including an attempt with the most active solid surface available, the silica-alumina cracking catalyst. / Ph. D.

Various nucleophiles were subjected to SRNl (nucleophilic substitution via a radical chain mechanism) conditions with representative carboaromatic and heteroaromatic substrates. Upon 5-25 min of near-UV irradiation, the carbanions of 2-benzyl-4,4-dimethyl-2-oxazoline, ethyl phenylacetate, t-butyl acetate, N,N-dimethylacetamide and dimethyl methylphosphonate underwent reactions with both 2-bromopyridine and iodobenzene in an S_R_N1 manner to give yields of good substitution products. The S_R_N1 reaction between N,N-dimethylacetamide enolate ion and 2-chloroquinoline occurred even without photostimulation. Due to incomplete ionization and the lack of homogeneity of the reaction mixture, potassio-2,4,4-trimethyl-2-oxazoline reacted with 2-bromopyridine to give low yield of the substitution product through a photostimulated S_R_N1 pathway. However, the reaction of this carbanion with iodobenzene afforded moderate yield of the substitution product, which was found to be formed via both S_R_N1 and AE mechanisms. The dimethyl phosphite anion reacted slowly with 2-bromopyridine and failed to react with 2-chloroquinoline and chloropyrazine under the influence of near-UV light. This unusual trend of reactivity was attributed to the inability of the product radical anion to restore an electron to the aromatic substrate, a necessary step in the propagation of the S_R_N1 cycle. Treatment of t-butyl α-trimethylsilylacetate with KNH₂ caused cleavage of the C-Si bond. t-butyl acetate and hexamethyldisiloxane were obtained upon quenching. Methylene triphenylphosphorane, sulfur and selenium stabilized carbanions of 1,3-dithiane, 2-phenyl-1,3-dithiane, dimethyl sulfone, t-butyl α-phenylthioacetate, bisphenylthiomethane and t-butyl α-phenylselenoacetate, failed to react with 2-bromopyridine and iodobenzene. The carbanion of dimethyl sulfone remained unreactive towards iodobenzene even upon attempted entrainment by a catalytic amount of acetone enolate. The dianion of phenylacetic acid reacted with iodobenzene to give biphenylacetic acid and benzene upon irradiation. Similar results were obtained with p-bromotoluene as substrate where substitution occurred only at the para position of the dianion. A non-chain mechanism was proposed to described both of these reactions. The dianion of phenylacetic acid also reacted with 2-bromopyridine to give a complex mixture under photostimulated conditions. 2-Benzylpyridine, bis(2-pyridyl)phenylmethane, p-(2-pyridyl)phenylacetic acid, potassio α-bis(2-pyridyl)phenylacetate, and 2-aminopyridine were found as products. Based on experiments performed with several probable intermediates of this reaction, and S_R_N1 mechanism can account for formation of all products. Preliminary results showed that the reaction of phenylacetamide dianion with iodobenzene also gave rise to the para substituted product. The dianion of 1,3-phenylacetone was found to react with iodobenzene to give 1,1,3-triphenylacetone via a mechanism other than an S_R_N1 pathway. / Ph. D.

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

Yes / Condensation of a pyridyl-2-carbaldehyde derivative with 2-(bromoethyl)amine hydrobromide gave tetracyclic pyrido[1,2-a]pyrido[1’,2’:3,4]imidazo-[2,1-c]-6,7-dihydropyrazinium dications in excellent yields. Crystal structures and NOE data demonstrated the helical character of the dications, the dihedral angles between the two pyrido groups ranging from 28–458. An intermediate in the synthesis was also characterized. A much brighter emission compared to literature helicenes has been found, with quantum yields as high as 60% in the range of l=460– 600 nm. Preliminary cytotoxicity studies against HT-29 cancer cells demonstrated moderate-to-good activity, with IC50 values 12–30x that of cisplatin.

m-Bromotrifluorotoluene, 1, was subjected to microbial oxidation by Pp 39/D. The products from the reaction were isolated and identified by various spectral techniques. The absolute stereochemistry of the major metabolite has been determined as cis-ααα-trifluoromethyl 2R, 3S-dihydroxy-5-bromo-4,6-cyclohexadiene 2. The absolute stereochemistry was discovered by comparison of the products from the convergent synthetic pathway of 2 and the known diol metabolite from α,α,α-trifluorotoluene, 4. / Master of Science

Ceratocystis moniliformis grows well in a semi-synthetic liquid medium containing 30:1 glucose:yeast extract, vitamins, and minerals. At 25°C and 100 rpm on a rotary shaker, the culture grows and produces many pleasing and potentially useful fruity aroma-bearing compounds. A sensory evaluation panel described the aromas "banana," "citrus," "fruity," "peach," and "floral" in samples of this culture. However, yields of the compounds that cause these aroma perceptions are low, as their production is limited due to toxicity, or perhaps a feedback inhibition mechanism. Seventeen volatile aroma compounds were tentatively identified by Gas Chromatography - Mass Spectrometry (GC- MS), and of these, the production of isoamyl acetate, B -myrcene, acetophenone, i1-octanol, and geraniol was studied using GC analysis. In an attempt to increase the production of these compounds relative to the production level of aroma-bearing compounds obtained by traditional incubation methods, mineral oil was added to the growth medium as a thin (2 mm) layer. Difficulties in analyzing oil-free cultures made it impossible to directly compare yields in oil-free versus oil-containing cultures. However, the mineral oil acted as a trapping agent, and production of aroma compounds continued in the presence of mineral oil for up to 8 days, yielding from 246 to 2071 ug/100 ml culture of the aroma compounds. The above-mentioned compounds are similar to natural and synthetic essential oil components that are currently used as food flavorants. Thus, aroma-bearing compounds that are produced by Ceratocystis moniliformis may prove to be valuable alternative sources for food flavoring. / Master of Science

Hydrocarbon solvents are widely used in the production of paints, adhesives, dyes, polymers, plastics, textiles, printing inks, agricultural products and pharmaceuticals. While the neuropathic potential of aliphatic solvents was shown in the 1970s, little is known about the neuropathic potential of aromatic solvents. The present study examines such solvents, 1,2-diethylbenzene (DEB) and its metabolite 1,2-diacetylbenzene (DAB), to determine (a) the neuropathological evidence for peripheral neuropathy in rodents treated with 1,2-DAB, (b) the neurochemical basis for the neurotoxic properties of this compound, and (c) the structural requirements for nerve fiber damage. The properties of 1,2-DAB and 2,5- hexanedione (HD) are also compared. A key finding of this thesis is that 1,2-DAB induces a 2,5-HD-like pattern of nerve damage of motor and sensory axons with focal swellings containing neurofilaments. Whereas nerve damage begins distally in 2,5-HD intoxication, with 1,2-DAB treatment axonal swellings begin intraspinally and in the proximal ventral roots of motor nerve fibers. A second key finding is the reactivity of 1,2-DAB with amino acids, notably lysine, a property that is shared with 2,5-HD. 1,2-DAB and 2,5-HD react with amino acids and proteins to form blue and yellow chromophores, respectively. Relative to 2,5-HD, 1,2-DAB is three orders of magnitude more reactive in forming high-molecular-weight species. 1,2-DAB treatment of spinal cord slices in vitro and intact sciatic nerve in vivo showed that neurofilament proteins react more readily than beta-tubulin. The heavy and medium subunits of neurofilament protein were more reactive than the light subunit. The reactivity of these four axonal proteins was in proportion to their lysine content. These data are consistent with selective accumulation of neurofilaments in giant axonal swellings. In summary, these studies have shown a relationship between the chromogenic and neuropathic properties of two gamma-diketones, one aliphatic (2,5-HD) the other aromatic (1,2-DAB). These studies are relevant to occupational and public health for at least two reasons. First, urinary chromogens generated by neuropathic aliphatic and aromatic hydrocarbons could serve as biological markers of exposure to solvents with neuropathic potential, and second, other chromogenic solvents (such as tetralin) should be considered for neuropathic potential. / Graduation date: 2002

TOL plasmids of Pseudomonas putida encode enzymes for the degradation of toluene and related aromatics. These genes are organized into two operons regulated by the Xy1R and Xy1S transcriptional activators. Previous analysis of the TOL pDK1 catechol-2,3-dioxygenase gene (xy1E) and a comparison of this gene to xy1E from the related TOL plasmid pWW0, revealed the existance of a substantial level of sequence homology (82%).