Phenols nitrosation

Phenolic ethers, dealkylation of, 287 Phenols, nitrosation of, 394 Phenoxypropadiene, 11 3-Phenylamino-l-butyne, 97 Phenyl azide, 281-282 Phenylazoalkanes, 327 Phenylazodiphenylphosphine oxide, 328 Phenylazoethane, 308 Phenylazohydroperoxides, 331 2-Fhenylazo-l,3-indandione, 299 Phenylazo-l-naphthalene, 304, 311 PhenyIazo-2-naphthaIene, 304, 311 Phenylazonaphthalenes, 310... 

SCHEME 5 Proposed mechanism for phenol nitrosation by nitric oxide added in the presence of oxygen. 

J. P. C. thanks Dr. Larry K. Keefer of the National Cancer Institute for his translation of a German manuscript (Viebel and Mitteil, 1930) dealing with phenolic nitrosation. 

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. 

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... 

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. 

Inhibition of nitrosation is generally accompHshed by substances that compete effectively for the active nitrosating iatermediate. /V-Nitrosamine formation in vitro can be inhibited by ascorbic acid [50-81-7] (vitamin C) and a-tocopherol [59-02-9] (vitamin E) (61,62), as well as by several other classes of compounds including pyrroles, phenols, and a2iridines (63—65). Inhibition of iatragastric nitrosation ia humans by ascorbic acid and by foods such as fmit and vegetable juices or food extracts has been reported ia several instances (26,66,67). 

Dyes. Sodium nitrite is a convenient source of nitrous acid in the nitrosation and diatozation of aromatic amines. When primary aromatic amines react with nitrous acid, the intermediate diamine salts are produced which, on coupling to amines, phenols, naphthols, and other compounds, form the important azo dyes (qv). The color center of the dye or pigment is the -N=N- group and attached groups modify the color. Many dyes and pigments (qv) have been manufactured with shades of the entire color spectmm. 

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

The general discussion (Section 4.02.1.4.1) on reactivity and orientation in azoles should be consulted as some of the conclusions reported therein are germane to this discussion. Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol (diazo coupling, nitrosation, etc.). Pyrazole cations, formed in strong acidic media, show a pronounced deactivation (nitration, sulfonation, Friedel-Crafts reactions, etc.). For the same reasons quaternary pyrazolium salts normally do not react with electrophiles. 

Other typical electrophilic aromatic substitution reactions—nitration (second entr-y), sul-fonation (fourth entry), and Friedel-Crafts alkylation and acylation (fifth and sixth entries)—take place readily and are synthetically useful. Phenols also undergo electrophilic substitution reactions that are limited to only the most active aromatic compounds these include nitrosation (third entry) and coupling with diazonium salts (seventh entry). 

Recently it has been claimed (Ref 42) that PA may be prepd by nitrosating phenol with Na nitrate and Oxidizing the resulting nitrosophenols with nitric acid,... 

The kinetics of nitrosation of phenol in aqueous mineral acid have been studied in some detail. Suzawa et a/.118 showed that, with 0.01 M nitrous acid at 0° a second-order rate coefficient of 0.00148 was obtained and that this was increased to 0.00225 by the addition of hydrochloric acid to pH 1.3. Morrison and Turney119... 

The conclusions from the foregoing studies with phenol have been challenged by Challis and Lawson121, who find that rates of nitrosation (shown graphically) pass through a maximum at about 8 M perchloric acid, and also that the reaction shows a large primary kinetic isotope effect at 0.7 °C (Table 27). Hence loss of a... 

Ring nitrosation with nitrous acid is normally carried out only with active substrates such as amines and phenols. However, primary aromatic amines give diazonium ions (12-47) when treated with nitrous acid, " and secondary amines tend to give N-nitroso rather than C-nitroso compounds (12-49) hence this reaction is normally limited to phenols and tertiary aromatic amines. Nevertheless secondary aromatic amines can be C-nitrosated in two ways. The N-nitroso compound first obtained can be isomerized to a C-nitroso compound (11-32), or it can be treated with another mole of nitrous acid to give an N,C-dinitroso compound. Also, a successful nitrosation of anisole has been reported, where the solvent was CF3COOH—CH2CI2. " ... 

Recently nitrosamines have attracted attention because of their marked carcinogenic activity in a wide variety of animal species Q, ). Nitrosamines are likely to be carcinogens in man as well human exposure to these compounds is by ingestion, inhalation, dermal contact and vivo formation from nitrite and amines Nitrite and amines react most rapidly at an acidic pH A variety of factors, however, make nitrosation a potentially important reaction above pH 7 these include the presence of microorganisms, and the possibilities of catalysis by thiocyanate, metals and phenols, and of transnitrosation by other nitroso compounds. 

Smoking. The effects of smoking on the formation of N-nitros-amines in bacon has been investigated recently by Bharucha et al. ( ). They reported that unsmoked bacon samples generally tended to contain more N-nitrosamines, presumably because of their higher nitrite content at the time of frying. Sink and Hsu (55) showed a lowering of residual nitrite in a liquid smoke dip process for frankfurters when the pH also was lowered. The effects of smoke seem to be a combination of pH decrease and direct C-nitrosation of phenolic compounds to lower the residual nitrite in the product (56). This is an area which requires further study since certain C-nitrosophenols have been shown to catalytically transnitrosate amines in model systems (57). 

A further point of preparative significance still requires explanation, however. Highly reactive aromatic compounds, such as phenol, are found to undergo ready nitration even in dilute nitric acid, and at a far more rapid rate than can be explained on the basis of the concentration of N02 that is present in the mixture. This has been shown to be due to the presence of nitrous acid in the system which nitrosates the reactive nucleus via the nitrosonium ion, NO (or other species capable of effecting nitrosation, cf. p. 120) ... 

Aromatic nitrosation with nitrosonium (NO + ) cation - unlike electrophilic nitration with nitronium (NO ) cation - is restricted to very reactive (electron-rich) substrates such as phenols and anilines.241 Electrophilic nitrosation with NO+ is estimated to be about 14 orders of magnitude less effective than nitration with N02+. 242 Such an unusually low reactivity of NO+ toward aromatic donors (as compared to that of NO ) is not a result of the different electron-acceptor strengths of these cationic acceptors since their (reversible) electrochemical reduction potentials are comparable. In order to pinpoint the origin of such a reactivity difference, let us examine the nitrosation reaction in the light of the donor-acceptor association and the electron-transfer paradigm as follows. 

Phenols are rather common antimicrobial components of metalworking fluids however, their use in recent years has been declining (36). The inhibition of nitrosation by phenols has recently been reviewed (35). In general, phenolic compounds inhibit nitrosation by reacting with nitrite (phenol reacts with nitrite 10,0 0 0 times faster than with dimethylamine), but the intermediate nitrosophenolis unstable and enhances nitrosation. "The overall effect is dependent on the steady state concentration of the nitrosophenol and the relative degrees of retardation and enhancement exerted by the phenol and the nitrosophenol, respectively ( 35)". 

The nitration of phenols can result in anomalous and large differences in product isomer ratios, showing a high dependence on both nitrating agent and reaction medium. Here the situation is complicated by the intervention of an alternative nitration mechanism - that of nitrous acid catalyzed nitration, which proceeds via in situ nitrosation-oxidation (see Section 4.4). 

Nitrosation of phenolic substrates usually uses nitrous acid prepared in situ from a dilute mineral acid and an alkali metal nitrite. In general, for every phenolic group present in a substrate an equal number of nitroso groups can be introduced into the aromatic ring phenol, resorcinol and phloroglucinol react with nitrous acid to form 4-nitrosophenol, 2,4-dinitrosoresorcinol and 2,4,6-trinitrosophloroglucinol respectively. 

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