Substitution reactions of phenols

The phenolic group is activating and ortho-para directing. The electrophilic substitution reactions in the nucleus in (a) nitrosation and nitration (b) halogenation and (c) acylation and alkylation, are therefore particularly facile, and various experimental procedures need to be adopted to control the extent of substitution (cf. substitution reactions of aromatic amines and their acylated derivatives, Sections 6.6.1 and 6.6.2, pp. 906 and 916 respectively). 

Phenol may be converted into a mixture of o- and p-nitrophenols (Expt 6.102) by reaction with dilute nitric acid the yield of p-nitrophenol is increased if a mixture of sodium nitrate and dilute sulphuric acid is employed. Upon steam distillation of the mixture of nitrophenols, the ortho isomer passes over in a substantially pure form the para isomer remains in the distillation flask, and can be readily isolated by extraction with hot 2 per cent hydrochloric acid. The mechanism of the substitution probably involves an electrophilic attack (cf. Section 6.2.1, p. 851) by a nitrosonium ion at a position either ortho or para to the activating hydroxyl group, to yield a mixture of o- and p-nitrosophenols, which are then oxidised by the nitric acid to the corresponding nitrophenols. The reaction depends upon the presence in the nitric acid of traces of nitrous acid which serve as the source of the nitrosonium ion. 

If the phenol is allowed to react with nitrous acid (generated in an acidified solution of sodium nitrite), the nitrosophenol may be obtained in good yield. An example is provided by the nitrosation of 2-naphthol which yields l-nitroso-2-naphthol (Expt 6.103). 

When treated with bromine water an aqueous solution of phenol gives an immediate precipitate of 2,4,6-tribromophenol (Section 9.6.6, p. 1251), owing to the powerfully activating influence of the negatively charged oxygen in the phenoxide ion. 

The monobromination of phenol can, however, be achieved by using solutions of bromine in non-polar solvents such as carbon disulphide and carbon tetrachloride at low temperature (0-5 °C). The product is almost exclusively the para isomer (Expt 6.105). 

---

Electrophilic Aromatic Substitution Reactions of Phenols (Continued)... 

Table 5—Summary of Electrophilic Substitution Reactions of Phenol, Diphenyl Ether, and Anisole... 

The available rate data for the substitution reactions of phenol, diphenyl ether, and anisole are summarized in Table 5. The elucidation of the reactivity of phenol is hindered by its partial conversion in basic media into the more reactive phenoxide anion. Because of the high reaction velocity of phenol and the even greater reactivity of phenoxide ion the relative rates are difficult to evaluate. Study of the bromination of substituted phenols (Bell and Spencer, 1959 Bell and Rawlinson, 1961) by electrochemical techniques suitable for fast reactions indicates the significance of both reaction paths even under acidic conditions. 

Intramolecular nucleophilic substitution reactions of phenol ether derivatives induced by activated iodine(III) reagents such as PIFA-TMSOTf and PIFA-BF3 Et20 [Eq. (7) - (11)] have been applied to total or formal synthesis of various types of bioactive natural products. 

There are a number of substitution reactions of phenols in which the hydrogen (for which substitution is being made) is replaced by carbon. The Friedel-Crafts alkylation already mentioned (Scheme 8.40 above) has an acylation counterpart, which, in some cases, is complicated by an initial acylation of the phenol on oxygen ( O-acylation ) and a subsequent rearrangement to the ring substitution products. Indeed, in practice, initial preparation, isolation, and purification of the phenol ester (Chapter 9) resulting from O-acylation, followed by treatment of the ester with a Lewis acid such as aluminum trichloride (AICI3), often provides a cleaner overall... 

Problem 8.2L Electrophilic aromatic substitution reactions of phenol generally produce ortho- and para-products. Write a pathway using curved arrows to account for the bromination of phenol as shown in Equation 8.28. 

---