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.

A structure for the selenium analogue of the Roussin's black anion, [Fe4S3(NO)7]− had been proposed, on the basis of 15N.N.M.R. spectroscopy results, as being similar to that of the sulphur molecule. X-Ray crystallography was carried out on a crystal of Ph4AS Fe4Se 3(NO)7]− to determine whether this conclusion was correct. The crystal, Mr=1053.67, was triclinic of space group p1̅ with a=13.122 (9), b=13.936 (9), c=9.908 (8)A, α =99.30 (6), β =97.04 (6), γ=71.94 (5)° and Z=2. This structure was refined from diffractometer data to an R value of 0.047 and was found to consist of isolated Ph4As+ cations and [Fe4Se3(NO)7]− anions which exhibit approximate C3v symmetry, and agrees with that deduced from earlier work. It was also found that the capping influences the size of the Fe4 cage. Nitrosation studies of amines by iron sulphur nitrosyl clusters had reached a variety of conflicting conclusions; i.e. that no anaerobic nitrosation occurred and that the formation of solvocomplexes may or may not have been important in the nitrosation mechanism. An investigation was undertaken using tetranuclear, dinuclear and mononuclear iron sulphur nitrosyl complexes in a variety of atmospheres and solvents with amines of different basicities. It was found that tetranuclear clusters do not nitrosate amines readily and that solvocomplex formation is not important in nitrosation by tetranuclear clusters. The cluster does require to be oxidised however. Only morpholine and pyrrolidine, both of which were capable of forming mononuclear solvocomplexes themselves, were nitrosated by dinuclear clusters and it is thought that the formation of solvocomplexes is important to nitrosation by di-iron species, which was found to occur as readily in an atmosphere of nitrogen as in air. These amines were also nitrosated by mononuclear iron complexes and it was found that the dinitrito species [Fe(N0)2(N2)2]- did not nitrosate amines more readily than other monoiron sulphur nitrosyl complexes. Fragmentation and reassembly is thought to be the likely mechanism of conversion of the Roussin's black salt anion, [Fe4S3(NO)7]-, to the cubane-type cluster, although mixed cluster experiments were found to be invalid for these studies because the black salt anion spontaneously converts to the cubane-type cluster on refluxing it in toluene. Experiments done to investigate the likely mechanism of the methylation of [Fe(SH)2(NO)2]- found that reactions with bromopentane, which would cause the sulphur atom to be methylated, and pentanethiol, which would attack the metal atom, both gave the same product. Chapter One summaries the history and development of iron sulphur nitrosyl chemistry and provides an introduction to the biological aspects of this field of work. Chapter Two describes the crystal structure determination of tetraphenylarsonium heptanitrosyl-tri-μ3-seleno tetraferrate (1-). Chapter Three provides an account of a study of the nitrosation of amines by iron sulphur nitrosyl complexes of various nuclearities and suggests mechanisms for and limitations on their nistrosating ability. In Chapter Four is to be found a description of two other lines of research which were undertaken; a study of the mechanism of the conversion of [Fe4S3(NO)7]− to [Fe4s4(no)4] and an investigation of the methylation of [Fe(SH)2(NO)2]−. Chapter Five contains a description of all preparations used during the work.

S-Nitrosothiols (RSNO) are an important class of NO-donor drugs. They have been used clinically and occur naturally where they may have a role in several biological and physiological processes in the human body. The medical importance of S-nitrosothiols has been highlighted recently by several reports which describe the clinical use of GSNO (13) to inhibit platelet aggregation during coronary angioplasty and also to treat a form of preeclampsia, a high blood pressure condition suffered by some pregnant women. We set out to extend the range of compounds of this type by synthesising a novel series of biologically active S-nitrosothiols (1-13) and to look for a correlation between structure, chemical stability, and physiological activity. The situation has been complicated by the recent discovery that the main route for the release of NO from S-nitrosothiols is a copper- catalysed process. A detailed kinetic study of copper ions, and thiols on the stability of the compounds we synthesised has shown that the dominant pathway for the decomposition of S-nitrosothiols in most circumstances is one catalysed by Cu+ ions. We suggest that Cu+ ions are formed by the reaction of Cu2+ ions with thiol, present in the S-nitrosothiols as an impurity. The implications of this discovery for an understanding of the biological action of S-nitrosothiols is suggested. All the new S-nitrosated dipeptides (2-12) examined show less susceptibility to copper (I)- catalysed release of NO than SNAP (1) but are more reactive than GSNO (13). We found that S-nitrosated dipeptides are potent vasodilators and suitable inhibitors of platelet aggregation but are chemically very stable in the absence of copper ions. All thirteen compounds combine the favoured property of chemical stability with a high level of biological activity. We found that copper(I)-chelation induced reduction of the biological activity of S- nitrosothiols in smooth muscle relaxation. The results show that responses to both SNAP and GSNO are reversibly inhibited by neocuproine. We conclude that relaxation of vasodilator smooth muscle by SNAP and GSNO is caused in part by NO released into solution via a Cu+-dependent catalytic reaction, and provide evidence that endogenous Cu+ ions may also contribute to the maintenance of vasodilator 'store' in vivo by catalysing the decomposition of naturally-occurring S-nitrosothiols. A particularly interesting finding recently by Gordge et al. (1995) shows that the inhibition of platelet aggregation activity shown by GSNO is much reduced in the presence of neocuproine and the closely related bathocuproine, both specific Cu+-chelating agent. However, it was shown very recently (Schrammel et al, 1996) that copper ions inhibit basal and NO-stimulated recombinant soluble guanylate cyclase activity and that Cu+ is more effective than Cu2+ in this regard. L-Ascorbic acid (vitamin C) could play a role in the in vivo release of NO from naturally occurring and exogenous S-nitrosothiols and so play a part in smooth muscle relaxation and in inhibition of platelet aggregation. All thirteen compounds examined show the ability to release NO in vitro. The inhibitory effect of Hb, a recognised NO scavenger, was investigated. In smooth muscle, responses to intermediate doses of S-nitrosothiols were significantly inhibited by Hb, though not abolished entirely. In platelet, we found that the inhibitory activity of these S-nitrosothiols was reversed by haemoglobin, indicating the involvement of NO in the process. We found that the solution stability of the S-nitrosothiols did not correlate with relaxation of vascular smooth muscle or inhibition of platelet aggregation, again suggesting that the tissue specificity is a function of the R- group. We conclude that the biological activity of S-nitrosothiols depends upon the release of NO in a process catalysed by Cu(I), and that the decomposition may occur inside or outside the cell, depending upon the structure of RSNO.

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