Nitrosation of phenol

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... 

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). 

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. 

The nitrosation of phenols proceeds in a manner similar to that of tertiary amines. For example, l-nitroso-2-naphthol has been prepared from the sodium salt of /9-naphthol by treatment with sodium nitrite and sulfuric acid near 0°C [29], This general procedure, suitably modified, has been used to prepare other nitrosophenols such as p-nitrosophenol (m.p. 135°-136°C) [30]. 

The nitrosation of phenol and cresols in buffer solutions involves a diffusion-controlled C-nitrosation followed by rate-limiting proton loss. /r-Crcsol is much less reactive than the other substrates.79 Nitrosation in trifluoroacetic acid or in acetic-sulfuric acid mixtures is regioselective (e.g. 4-nitroso-m-xylene is fonned from m-xylene) and possible non-selective nitrous acid-catalysed nitration can be eliminated by purging reaction solutions with nitric oxide.80... 

In addition to the nitration of phenols by substitution of sulpho groups (p. 130) the method of nitrosation of phenols, followed by oxidation of the nitroso to the nitro group has some practical application ... 

Pure p- nitrophenol may also be prepared by nitrosation of phenol, followed by oxidation of p- nitrosophenol with dilute nitric acid. The m- isomer is usually prepared by diazotization of m- nitroaniline. 

An additional pathway for nitrophenol formation upon nitrite photolysis is linked with the nitrosation of phenol to yield 4-nitrosophenol, followed by the oxidation of 4-nitrosophenol to 4-nitrophenol [44]. A similar pathway involving phenol, 2-nitrosophenol and 2-nitrophenol might tentatively be postulated [65,66]. The nitroso derivative pathway is likely to be a secondary one in neutral to acidic solution [44,55], but it is a major source of 4-nitrophenol upon nitrite photolysis under basic conditions [59]. 

Until relatively recently no kinetic studies on the nitrosation of alcohols had been reported, presumably since the reactions are very rapid and require special techniques. Some kinetic measurements on the reverse reaction, the hydrolysis of alkyl nitrites have been reported here conventional kinetic methods were used. Early workers examined the reactions of the series methyl, ethyl, i-propyl and t-butyl nitrites in an acetic acid-acetate buffer and found a small increase in rate constant along the series (Skrabal et a ., 1939). Later Allen measured the rate constants for the hydrolysis of a number of alkyl nitrites in aqueous dioxan solvent for both acid- and base-catalysed reactions (Allen, 1954). The rate constants for the O-nitrosation of alcohols were determined indirectly by measurement of the overall equilibrium constant for the process, by noting the change in the rate constant for the nitrosation of phenol in the presence of added alcohols. These, combined with the known data for the reverse hydrolysis reaction, enabled the rate constants for the forward reaction to be obtained (Schmid and Riedl, 1967). The reactivity sequence MeOH > EtOH > i-PrOH > t-BuOH was deduced, and attributed to a steric effect. 

Aromatic tertiary amines and phenolic compounds undergo nuclear nitro sation, as illustrated by the synthesis of p>nitrosodimethyl aniline (89%)i nitrosophenol (80%), and l-nitroso-2-naphthol (99%) In the reaction of a-naphthol, an isomeric mixture of the nitrosonaphthols is obtained. The nitrosation of phenols with nitrous acid usually produces p nitroso compounds however, o-nitiosophenols can be prepared by nitrosating phenols in the presence of cupric sulfate. ... 

Uses of the reagent listed below do not include diazotization, nitrosation of phenols and tertiary aromatic amines, and simple N-nitrosation of amines. 

One synthesis of the analgesic paracetamol (acetaminophen, 12) involves the nitrosation of phenol followed by reduction of the 4-nitrosophenol. Subsequent selective acetylation of the more reactive amino group completes the process ... 

Table 1. Nitrosation of phenol in aqueous media with NaNCh (2 equivalents) / H2SO4 system...

Table 2. Nitrosation of phenol in acetonitrile media with NOBF4...

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. 

Scheme 8.37. Representation of a pathway that accounts for the para-nitrosation of phenol.

Scheme 10.11. The nitrosation of phenol (QH5OH) with nitrosyl chloride, NOCl (see Chapter 8, Section IV (b) D) to produce p-nitrosophenol (P-HOC6H4NO) and its subsequent reduction by thiophenol to the corresponding p-hydroxyphenylnitrosyl radical (p-HOCeH4NHO ). The oxidation product is the corresponding diphenyldithio ether (CeHsSSCeHs).

The exact nature of the nitrosating agent in these strongly acidic solutions is also not clear either the nitrous acidium ion or the nitros-onium ion (or even both) may be involved. In this connection, it is interesting to note that the nitrous acid deamination of benzamide in concentrated sulphuric acid has been interpreted as a reaction of the nitrosonium ion although precisely the opposite conclusion has been reached for the nitrosation of phenol in concentrated perchloric acid... 

Nitrosation.—Copper(ii) is claimed to retard the nitrosation of phenol by HNO2 and the subsequent oxidation of >-nitrosophenol to the nitro-compound by HNO3 through formation of complexes with HNO2 and the nitroso-phenol. The nitrosation of iV-methylindole (a reaction studied almost a century ago by Fischer) has been re-examined and the products have finally been characterized. With equimolar amounts of substrate and HNO2, a di-indole (48) (40%) and very little of the di-indole oxide (49) are formed, whereas with excess of HNO2 the... 

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