Nitrosation,

Nitrosation of pyrrole or alkylpyrroles may result in ring opening or oxidation of the ring and removal of the alkyl groups. This is illustrated by the formation of the maleimide (119) from 2,3,4-trimethylpyrrole. 

Reactivity of Five-membered Rings with One Heteroatom 

3-Nitroso derivatives (120) are obtained from indoles they exist largely in oximino forms (121) (80IJC(B)767). The N-nitrosation of 5-chloroindole is followed by a migration of the nitroso group from N to C-3, to give an indolenine-3-oxime (122) hydrolysis and recyclization leads to a indazole carbaldehyde (123) (86JA4115). 

Kinetic studies of nitrosation by aqueous nitrous acid have been carried out for reaction at nitrogen, carbon, oxygen, and sulphur. There are many similarities between the kinetic forms observed for reaction at the different centres it appears that nitrosation can involve the nitrosonium ion or a number of carriers of the nitrosonium ion depending on the acidity and the other species present. Some of the nitrosating agents that have been suggested are shown below in the expected order of reactivity  

The number of intermediates involved and the number of possible ratedetermining stages together make nitrosation a reaction of unusual kinetic complexity, but, for many nitrosation reactions, the contributions of the separate reaction paths have been clearly established and the corresponding rate-determining stages have been identified. 

The other main source of evidence on the mechanisms of nitrosation comes from the C-nitrosation of aromatic compounds but, for this reaction, the final proton loss from the J-complex is usually rate-determining (Challis and Higgins, 1972). Under these conditions, the overall rate and kinetic form of the reaction provide no evidence on the rate and mechanism of the nitrosation stage. Fortunately the work of Challis and his co-workers (Challis and Higgins, 1973 Challis and Higgins, 1975 Challis and Lawson, 1973) has shown that the C-nitrosation stage is rate-determining for the nitrosation of some reactive aromatic substrates (2-naphthol, azulene, 1,2-dimethylindole) in feebly acidic media and these are the reactions referred to below. 

The kinetics of aromatic nitrosation at ring carbon have received little attention. The first attempt to determine the nature of the electrophile was made by Ingold et a/.117, who measured the rates of the nitrous acid-catalysed nitration of 4-chloroanisole by nitric acid in acetic acid which proceeds via initial nitrosation of the aromatic ring. Assuming that the electrophiles are the nitrosonium ion and 

Since Goulden and Miiien showed102 that dinitrogen tetroxide is slightly ionised according to the equilibrium 

The constancy of the second-order rate coefficients (k2) in the presence of tetra-alkyl-ammonium nitrates (Table 26) indicates the validity of the assumptions. 

EFFECT OF ADDED NITRATES ON THE RATE OF NITRATION via NITROSATION OF 

From an analysis of the results, the values of k and k. were determined as 13 x 10-3 and 132 x 10-3 respectively, which implies, not unreasonably, that NO+ is a more reactive electrophile than N204 the nitrosation rate was also relatively independent of the water concentration. 

Primary and secondary nitroso compounds usually stabilize themselves, even under the conditions of their preparation, by passing irreversibly into their isomers, the oximes. In tertiary aliphatic nitroso compounds this transformation is accompanied by fission of the neighboring carbon-carbon bond by hydrolysis or decarboxylation. Aromatic nitroso compounds are more stable, and when oxime formation does occur this is usually reversible within the framework of a true tautomeric equilibrium for instance, the tautomeric pair -nitrosophenol/p-benzoquinone monooxime is obtained both by nitrosation of phenol and by oximation of / -benzoquinone. 

Nothing is known of the reactivities of the pyridazines, and triazines are cleaved before substitution by the usual sulfonating agents [63AG(E)309], 

A few examples of Mannich reactions exist in the series. Pyridazine N-oxides, substituted at the 3- or 5-position by hydroxy, are alkylated at either of the vacant ring positions, although activated methyl groups may react preferentially (68CPB939 73CPB1510 75CPB923). 

In pyrimidine, the most likely metallation site for lithiation is C-5 (cf. base-catalyzed hydrogen exchange, Section 2), but even two methoxy groups in the 4- and 6-positions failed to allow lithium-hydrogen exchange at -40°C in this system (65JCS6695). At lower temperature ( -70°C), however, 5-pyrimidinyllithium derivatives can be prepared by 

Both l-methyl-3,5-diphenyl-4-nitrosopyrazole and l,3-dimethyl-5-phenyl-4-nitrosopyrazole were prepared and used as spin traps the ESR spectra of the radicals formed in the trapping (CH20H and CHj radicals) were recorded 89ACS503 . 

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These systems nitrate aromatie eompounds by a proeess of electro-philie substitution, the eharacter of whieh is now understood in some detail ( 6.1). It should be noted, however, that some of them ean eause nitration and various other reactions by less well understood processes. Among sueh nitrations that of nitration via nitrosation is especially important when the aromatic substrate is a reactive one ( 4.3). In reaetion with lithium nitrate in aeetie anhydride, or with fuming nitrie aeid, quinoline gives a small yield of 3-nitroquinoline this untypieal orientation (ef. 10.4.2 ) may be a eonsequenee of nitration following nucleophilic addition. ... 

We are not concerned here with the mechanism of nitrosation, but with the anticatalytic effect of nitrous acid upon nitration, and with the way in which this is superseded with very reactive compounds by an indirect mechanism for nitration. The term nitrous acid indicates all the species in a solution which, after dilution with water, can be estimated as nitrous acid. 

The theory that the catalysed nitration proceeds through nitrosation was supported by the isolation of some />-nitrosophenol from the interrupted nitration of phenol, and from the observation that the ortho.-para ratio (9 91) of strongly catalysed nitration under aqueous conditions was very similar to the corresponding ratio of formation of nitrosophenols in the absence of nitric acid. ... 

The observation of nitration nitrosation for mesitylene is important, for it shows that this reaction depends on the reactivity of the aromatic nucleus rather than on any special properties of phenols or anilines. 

Nitration at the encounter rate and nitrosation As has been seen ( 3.3), the rate of nitration by solutions of nitric acid in nitromethane or sulpholan reaches a limit for activated compounds which is about 300 times the rate for benzene imder the same conditions. Under the conditions of first-order nitration (7-5 % aqueous sulpholan) mesitylene reacts at this limiting rate, and its nitration is not subject to catalysis by nitrous acid thus, mesitylene is nitrated by nitronium ions at the encounter rate, and under these conditions is not subject to nitration via nitrosation. The significance of nitration at the encounter rate for mechanistic studies has been discussed ( 2.5). 

Under the conditions mentioned, i-methylnaphthalene was nitrated appreciably faster than was mesitylene, and the nitration was strongly catalysed by nitrous acid. The mere fact of reaction at a rate greater than the encounter rate demonstrates the incursion of a new mechanism of nitration, and its characteristics identify it as nitration via nitrosation. 

Under the same conditions the even more reactive compounds 1,6-dimethylnaphthalene, phenol, and wt-cresol were nitrated very rapidly by an autocatalytic process [nitrous acid being generated in the way already discussed ( 4.3.3)]. However, by adding urea to the solutions the autocatalytic reaction could be suppressed, and 1,6-dimethyl-naphthalene and phenol were found to be nitrated about 700 times faster than benzene. Again, the barrier of the encounter rate of reaction with nitronium ions was broken, and the occurrence of nitration by the special mechanism, via nitrosation, demonstrated. 

The evidence outlined strongly suggests that nitration via nitrosation accompanies the general mechanism of nitration in these media in the reactions of very reactive compounds.i Proof that phenol, even in solutions prepared from pure nitric acid, underwent nitration by a special mechanism came from examining rates of reaction of phenol and mesi-tylene under zeroth-order conditions. The variation in the initial rates with the concentration of aromatic (fig. 5.2) shows that mesitylene (o-2-0 4 mol 1 ) reacts at the zeroth-order rate, whereas phenol is nitrated considerably faster by a process which is first order in the concentration of aromatic. It is noteworthy that in these solutions the concentration of nitrous acid was below the level of detection (< c. 5 X mol... 

Without further studies little weight can be given to these ideas. In particular there is the possibility that with acetanilide, as with anisole, nitrosation is of some importance, and further with nitrations in sulphuric acid the effect of protonation of the substrate needs quantitative evaluation. The possibility that the latter factor may be important has been recognised, and it may account for the difference between nitration in sulphuric acid and nitration with nitronium tetrafluoroborate. 

Phenol. The change in the orientation of substitution into phenol as a result of the superimposition of nitrosation on nitration is a well-established phenomenon. In aqueous sulphuric acid it leads to a change from the production of 73 % of o-nitrophenol under nitrating... 

Again the uncertainty about the proportion of an observed result which is due to nitration and the proportion which is due to nitrosation exists. Thus, in expt. 11 phenol was being nitrated above the encounter rate and the observed isomer distribution could arise from a combination of nitration by whatever is the usual electrophile with nitration by a new, less reactive electrophile, or with nitrosation, or all three processes could be at work. 

Thus, strong arguments against all of the obvious nitrating species acting alone can be found. However, as has been pointed out, the extent to which ions require solvation by nitric acid molecules in this medium is unknown, and such solvation would influence the apparent order with respect to the stoichiometric nitric acid. The possibility also exists that more than one mechanism of nitration, excluding nitrosation, is operative. 

Butler recently reviewed the diazotization of heterocyclic amines (317). Reactions with nitrous acid yield in most cases N-exocyclic compounds. Since tertiary amines are usually regarded as inen to nitrosation, this... 

Even when deactivated by nitro substitution on C-5, the 2-aminothiazoles still undergo diazotization (35, 338-340). As with carbonyl derivatives (Section III.2.B), competition may occur between N nucleophilic reactivity and nitrosation of the 5-position when it is unsubstituted (341-344). 

The reasons for this apparent polywalent activity toward nitrosation (N ring reaction, N exocyclic reaction, nitrosation on the 5-position) are not... 

Ambident reactivity of the same nucleophilic species toward different nitrosation electrophilic centers. 

Some recent general reviews deal with the mechanism of N-nitrosation in aqueous solution (345), the nitrosation of secondary amines (346). the effect of solvent acidity On diazotization (347) and the reactivity of diazonium salts (1691). Therefore, a complete rationalization of the reactivity of amino azaaromatics would be timelv. 

Nitrosation in the 5-position has been reported with compounds 185 and 186 (Scheme 118) (165, 241). which are then reducible to the 5-aminothiazoles by Zn dust in AcOH. An old report (164) describing the nitrosation product of 2-methylaminothiazole as 2-(N-methylimino)-3-nitroso-2,3-dihydrothiazole (187) (Scheme 118) has been recently corrected by Ref. 314. 

C-5, nitrosation yields 384 (Scheme 219). If alkylisocyanates replace alkylisothiocyanates, the corresponding thioureas (382b) (X = S) are obtained (482). Tertiary ureas 386 are prepared by reaction... 

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