Thesis--Wisconsin. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--Catholic University of America, 1930. / Biography. eContent provider-neutral record in process. Description based on print version record.

Thesis (Ph. D.)--Catholic University of America, 1931. / Vita.

The role of aryne intermediates in the reactions of acetylarylnitrosamines in solution has been investigated. Participation by 3-t-butylbenzyne in the decomposition of o-t-butyl-N-nitrosoacetanilide in benzene, leading to m-t-butylphenyl acetate, has been confirmed, although the major product, o-t-butylphenyl acetate, is formed predominantly from o-t-butylphenyl carbonium ions, 5-t-Butyl 1,4-dihydronaphthalene-1,4-endoxide has been isolated from the decomposition in the presence of furan. In common with the o-isomer, m- and p-t-butyl-N-nitroso-acetanilides yield 'aryne adducts' with 2,3,4,5-tetra- phenylcyclopentadienone in benzene. They do not, however, form t-butyl-l,4-dihydronaphthalene-l,4-endoxides with furan, and participation by a true aryne in their reactions and in those of unsubstituted N-nitrosoacetanilide, is discounted. The nature of the arynoid intermediato has not, in spite of the elimination of many possibilities, been conclusively established, but it is probably the dipolar conjugate base formed by removal of an o-proton from the arenediazonium cation. Anomalies similar to those observed in the decomposition of o-t-butyl-N-nitrosoacetanilide are exhibited by 2,5-di-t-butyl-N- nitrosoacetanilide, which affords aryne adducts with both furan and anthracene in greater yield than does the mono-substituted nitrosamide. Aryne participation was not evident in the highly complex decompositions in benzene of 1,4-di-t-butyl-2,5-di-(N-nitrosoacetamido) benzene, 2,5-di-t-butyl-2,5-di-(N-nitrosoacetamido)benzene, and 4-acetoxy-2,5-di-t-butyl-N-nitrosoacetanilide, Formation of 2,5-di-t-butylphenol, 2,5-di-t-butyl-2-benzoquinone, and acetic anhydride in the last-named reaction indicates deacetylation of the intermediate acetoxybenzenediazonium acetate, and suggests that complications in the reactions of the dinitrosamides arise from interaction between the N-nitrosoacetamido substituents. The decompositions of diphenyl[o-(N-nitrosoacetamido)phenyl] phosphine oxide and diethyl o-(N-nitrosoacetamido)phonyl]phosphonate have been studied, and evidence of aryne intermediacy obtained. The results are discussed in terms of currently acceptable mechanisms for the decomposition of N-nitroso- acetanilide and, where necessary, modifications to these are suggested.

As a synthetic procedure, the deoxygenation of aromatic nitro-compounds by tervalent organophosphorus compounds has been extended to include new routes to the anthranil and phenothiazine nuclei. Synthesis of anthranils from 2-nitrophenyl ketones has been exemplified by the preparation of 3-Phenylanthranil, 3-styrylanthranil and 5-chloro-3-methylanthranil from 2-nitro-benzophenone, 2 -nitrochalcone and 5-Chloro-2-nitroacetophenone respectively. The preparation of phenothiazines from 2-nitro-biaryl sulphides has been studied more extensively. It was found that when successful, this ring closure gave the cyclised product in about 55% yield. Rather more than half the sulphides used, however, gave no products or only a very low yield, and no rational means of predicting the success of a given ring closure could be found. Triethyl phosphite was the only phosphorus compound found to be capable of effecting this cyclisation. The use of several other phosphorus compounds was investigated, but although deoxygenation of the nitro-group undoubtedly took place, as evidenced by the large amounts of tar formed, no cyclised products could be isolated. Although a comprehensive investigation was not undertaken, the results of two experiments suggested that a considerable improvement in the yields of the phenothiazines could be achieved by carrying out the deoxygenations in a solvent (as opposed to pure phosphorus compound) and thus, reducing the extent of tar-forming side reactions. In addition, an unidentified product has been obtained from the reaction of 3-(o-nitrophenyl)coumarin with triethyl phosphate. Several unsuccessful attempts were made to synthesise a seven membered ring system. As part of an examination of the mechanism of the deoxygenation, the rate of reaction of a series of phosphorus compounds with 2-nitrobiphenyl was studied. It was found that phosphorus compounds with electron donating groups attached to the phosphorus atom reacted more rapidly, suggesting that the rate determining step involved a nucleophilic attack by phosphorus. No adequate explanation could be advanced for the finding that of all the phosphorus compounds studied, diethyl methylphosphonite reacted most rapidly. While the reactions of triethyl and triisopropyl phosphites were first order with respect to nitrobiphenyl, the reactions of hexaethyl phosphorous triamide and diethyl methylphosphonite appeared to be second order. A detailed kinetic study would be necessary to confirm this observation and investigate the fundamental change in mechanism which it implies. The possibility of the formation of nitroso-compounds as intermediates in the deoxygenation of the nitro-compounds has been discussed, and an unsuccessful attempt to trap such an intermediate has been made. Further attempts ought to be made in this direction and should be concentrated on finding a compound which will react more rapidly with the nitroso-compound than does triethyl phosphite. Such a trapping agent must also be capable of operating in the presence of an excess of nitro-compound. Much of the work in this thesis has been directed towards establishing whether an electron deficient nitrene intermediate is formed during the course of the deoxygenation of an aromatic nitro-compound. Although no one experiment could be regarded as conclusive, the overall weight of evidence argued convincingly in favour of this type of intermediate.

The reactions of tervalent phosphorus reagents with a number of aromatic nitro-compounds have been investigated. While it was expected that such reactions would give further examples of the deoxygenation and further reaction of the nitro-group, possibly via a reactive nitrene intermediates in fact, two, different, novel displacements of the nitro-group were found. In the first case, reaction of o-dinitrobenzene and related compounds with tervalent phosphorus reagents gave a series of phosphonates, phosphinates and phosphine oxides, in high yield, with the phosphorus atom bonded directly to the aromatic system, generally with an o-nitro-group still present in the final product. A mechanism involving nucleophilic aromatic substitution by the phosphorus reagent, with the displacement of the nitro-group as ethyl nitrite, was suggested. In the second case, reaction of p-nitrotoluene and p-ethylnitrobenzene, for example, with triethyl phosphite, gave low yields of diethyl p-tolyl- and p-ethylphenylphosphonate. As there is no activation of this nitro-group towards aromatic nucleophilic substitution, a mechanism involving attack on an oxygen of the nitro-group by the phosphorus reagent, with sub- sequent rearrangement through a four-membered intermediate was proposed. The other products of the reactions of o-alkyl-nitrosobenzenes and alkylnitrobenzenes with trialkyl phosphites were, in general, indicative of the participation, in the reaction, of a nitrene intermediate. The similarity of the products formed to those found in established examples of the reactions of nitrene intermediates, was noticed. The mechanism of this reaction was discussed in detail.

The decompositions of N-nitrosoacylarylamines in benzene and in carbon tetrachloride have been investigated. The reaction products of N-nitrosobenzanilldes parallel those of N-nitrosoacetanilides, carboxylic acids being the major products from almost all reactions carried out in both benzene and carbon tetrachloride. Carboxylic anhydrides, hitherto unreported products, have been isolated from reactions in carbon tetrachloride. The observed displacement of a bromo or uitro substituent in o- or p-positions in the amino moiety of the nitrosoamide by a chloride or benzoate ion during the formation of aryl halides and substituted phenyl benzoates is in contrast to Suschitsky's results. In general, the major part of the reaction appears to be abstraction by a carboxylate anion of hydrogen from the o-position in the amino moiety of the nitrosoamide to form the carboxylic acid. However, when both o-positions in the amino moiety of the nitrosoamide are substituted, the reaction proceeds primarily by nucleophilic displacement of a substituent by the carboxylate anion. The decomposition of N-nitrosoacetanilide in carbon tetrachloride gives a benzynoid-type adduct with 2,3,4,5-tetraphenylcyclopentadienone, with consequent suppression of the formation of chlorobenzene, which is a major product from a reaction carried out in the absence of the above diene. Appropriate benzynoid-type adducts are also formed in reactions of N-nitrosobenzanilides with 2,3,4,5 tetraphenylcyclopentadienone and with anthracene, but not with furan. By the use of substituted N-nitrosobenzanilides, it has been shown that, for appreciable adduct formation with 2,3,4,5-tetraphenylcyclopentadienone, a substituent must be in the m-position in the amino moiety, i.e. o- or p- to the hydrogen which is being removed in the formation of the carboxylic acid. The nature of the acyl moiety of the molecule has some influence on the formation of the adduct, but the nature of the solvent appears to have little influence on the yield of adduct formed. In reactions in which high yields of benzynoid-type adducts are obtained, the only other major product isolated is the appropriate carboxylic acid. True aryne intermediates are discounted, and it is suggested that the intermediate is dipolar in nature. A reaction scheme involving radicals, previously suggested by Riichardt et al. can be modified to account for the reaction in benzene. The reaction in carbon tetrachloride, however, appears to follow a different reaction path, and probably involves radicals to a slight extent only, the main reaction being ionic.

The E. S. R. spectra observed during the decomposition of acylarylnitrosamines in four series of solvents have been investigated, and the mechanisms of the reactions discussed in terms of the radicals involved. For aromatic hydrocarbons two signals were detected. The first was that due to the (N-phenylacetamido)phenyl-nitroxide pi-radical, as reported by Chalfont and Perkins), while the second was attributed to the phenyldiazotate o-radical. The structure of these radicals is discussed in the light of a study of the spectra resulting from variation of the acyl and aryl groups of the nitrosamide and of theoretical calculations using the McLachlan and CNDO methods. The mechanism originally proposed by Ruchardt and Freudenberg is preferred to that of Perkins, in view of the failure to detect the chain-carrier radical of the latter scheme in some of the solvents, the intensity of the phenyldiazotate signal remaining constant throughout. For ethers the two signals observed were assigned to (N-phenylacetamido) phenylnitroxide and (N-phenylacetamido)-1-alkoxyalkylnitroxide resulting from the addition of phenyl and 1-alkoxyalkyl radicals to the nitroso group of the nitrosamide. The mechanism proposed, which is also applicable to the reaction in alcohols, is based on that currently acceptable for the decomposition of diazonium salts in ethers. Whenever possible assignments have been made for the various other signals detected and the mode of formation of the radicals discussed.

The aim of this project was to investigate the cyclisation reactions of some o-nitroaryl derivatives of amino acids, with a view to the synthesis of potentially biologically active heterocyclic compounds. Chapter one is concerned with an overview of the synthesis of heterocyclic N-oxides, mainly via the cyclisations of ortho-substituted nitroaromatics. Firstly, the properties of heterocyclic N-oxides are considered, then both reductive and non-reductive methods of their synthesis by cyclisation reactions are explored. After a discussion of intramolecular condensations leading to cyclisation, the possibilities for alternative mechanisms for these reactions are deliberated. Chapter Two begins with an introduction to the specific cyclisation reactions of o-nitroaryl- and 2, 4-dinitrophenyl-amino acids. The preparation and cyclisation reactions of o-nitrophenyl derivatives of amino acid esters are then described with emphasis on the implications for the mechanism of these cyclisation reactions. Chapter Three discusses the related cyclisations of N-alkyl-o-nitroanilines which have no activating group (for example, an ester) on the N-alkyl chain. The mechanistic implications of this are explored, in the context of the cyclisations discussed in Chapter Two. In Chapter Four, the synthesis of benzimidazole and quinoxaline acyclic nucleoside analogues is briefly described. These have the potential to be biologically active compounds.

S-nitrosothiols are effective NO-donating drugs which can elicit vasodilation of vascular tissue and disaggregate or inhibit the aggregation of platelets in blood. The chemistries of two S-nitrosothiols, S-nitroso-N-acetyl-DL-penicillamine (SNAP) and S-nitrosoglutathione (GSNO) have been investigated in an attempt to identify the chemical and physiological mechanisms which underlie their biological actions as vasodilators and modulators of platelet behaviour. Although SNAP and GSNO have been found to be susceptible to decomposition by similar chemical mechanisms, such as by thermal and photochemical means, evidence is presented to suggest that they are both capable of NO transfer to other thiol containing compounds such as cysteine. This produces a very unstable S-nitrosothiol, S-nitrosocysteine, which readily produces NO. However, they can both be decomposed by different, distinctive mechanisms. Metal ion catalysis by copper is shown to greatly accelerate the decomposition of SNAP, but has little effect on GSNO. Instead, NO release from GSNO is effected by enzymatic cleavage of the glutamyl-cysteinyl peptide bond by the enzyme glutamyl transpeptidase (γ-GT). The resulting S-nitrosothiol, S-nitrosocysteinylglycine, would be expected to be more susceptible to release of NO by metal (copper) ion catalysis. It is concluded that transnitrosation (NO-transfer) between thiol groups, or enzymatic cleavage are obligatory steps in the mechanism of NO release from GSNO, whereas SNAP requires only the presence of trace amounts of metal ions like copper to effect this process. The different modes of NO production may go some way towards explaining the different physiological effectiveness of these S-nitrosothiols as vasodilators and inhibitors of platelet aggregation.