Electrophilic aromatic substitution in phenols

Phenol and anisole are among the commonly encountered benzene derivatives listed in Table 11.1. Electrophilic aromatic substitution in phenol is discussed in more detail in Section 24.8. 

A hydroxyl group is a very powerful activating substituent, and electrophilic aromatic substitution in phenols occurs far- faster, and under milder conditions, than in benzene. The first entry in Table 24.4, for exfflnple, shows the monobromination of phenol in high yield at low temperature and in the absence of any catalyst. In this case, the reaction was carried out in the nonpolar- solvent 1,2-dichloroethane. In polar- solvents such as water it is difficult to limit the bromination of phenols to monosubstitution. In the following exfflnple, all three positions that are ortho or para to the hydroxyl undergo rapid substitution ... 

Many of the properties of phenols reflect the polarization implied by the contributing structures. The hydroxyl oxygen is less basic, and the hydroxyl proton more acidic, in phenols than in alcohols. Electrophilic aromatic substitution in phenols is much faster than in benzene, indicating that the ring, especially at the positions ortho and para to the hydroxyl group, is relatively electron-rich. ... 

The Lewis acid complex 4 can cleave into an ion-pair that is held together by the solvent cage, and that consists of an acylium ion and a Lewis acid-bound phenolate. A fr-complex 6 is then formed, which further reacts via electrophilic aromatic substitution in the ortho- or para-position ... 

Diazonium coupling reactions are typical electrophilic aromatic substitutions in which the positively charged diazonium ion is the electrophile that reacts with the electron-rich, ring of a phenol or arylamine. Reaction usually occurs at the para position, although ortho reaction can take place if the para position is blocked. 

We shall return to reactions of phenols and phenyl ethers when we consider directing effects in electrophilic aromatic substitution in other reactions and in Friedel-Crafts reactions in particular. 

The reaction of phenol with FITS reagents led to a mixture of ortho-, meta- and para-perfluoroalkylphenols, formed by electrophilic aromatic substitution. In the case of the relatively hindered electron-rich phenols, a different outcome was observed 0-perfluoroalkylation was observed together with the C-perfluoroalkylation products. At high temperature, the amount of the 0-substituted product became predominant. ... 

Scheme 8.42. Electrophilic aromatic substitution of phenol with an acyl group. The acylation of phenol with acetyl chloride (CH3COCI) in the presence of aluminum trichloride (AICI3) can apparently occur via a direct addition of the aluminum trichloride complexed acetyl chloride (in competition with O-acylation) or by a subsequent rearrangement of O-acylated phenol. The former is presented in the upper portion of the scheme, while the latter is shown in the lower portion.

Kolbe Reaction The phenoxide ion is even more susceptible to electrophilic aromatic substitution than phenol itself. (Why ) Use is made of the high reactivity of the phenoxide ring in a reaction called the Kolbe reaction. In the Kolbe reaction carbon dioxide acts as the electrophile. 

Aspirin, prepared industrially by selective electrophilic aromatic substitution of phenol, is arguably the blockbuster drug of all times. Its active metabolite, 2-hydroxybenzoic acid (salicylic acid), obtained from the bark of the white willow tree, has been used for four millennia for the treatment of inflammation and to relieve pain or discomfort caused by arthritis, soft-tissue injuries, and fever. Aspirin was discovered by the German company Bayer in the late 19th century and ironically marketed together with another drug, heroin, whose addictive side effects were not recognized then. 

Formaldehyde is protonated to give a resonance-stabilized cation that can serve as an electrophile in an electrophilic aromatic substitution reaction. Phenol functions as the nucleophile and attacks the electrophile, giving a resonance-stabilized intermediate (sigma complex). Water can then serve as a base and remove a proton from the sigma complex, thereby restoring aromaticity ... 

In general, the reaction between a phenol and an aldehyde is classified as an electrophilic aromatic substitution, though some researchers have classed it as a nucleophilic substitution (Sn2) on aldehyde [84]. These mechanisms are probably indistinguishable on the basis of kinetics, though the charge-dispersed sp carbon structure of phenate does not fit our normal concept of a good nucleophile. In phenol-formaldehyde resins, the observed hydroxymethylation kinetics are second-order, first-order in phenol and first-order in formaldehyde. 

In most of their- reactions phenols behave as nucleophiles, and the reagents that act on them are electrophiles. Either the hydroxyl oxygen or the aromatic ring may be the site of nucleophilic reactivity in a phenol. Reactions that take place on the ring lead to electrophilic aromatic substitution Table 24.4 summarizes the behavior of phenols in reactions of this type. 

The hydroxyl group of a phenol is a strongly activating substituent, and electrophilic aromatic substitution occurs readily in phenol and its derivatives. Typical examples were presented in Table 24.4. 

The optimal pH-value for the coupling reaction depends on the reactant. Phenols are predominantly coupled in slightly alkaline solution, in order to first convert an otherwise unreactive phenol into the reactive phenoxide anion. The reaction mechanism can be formulated as electrophilic aromatic substitution taking place at the electron-rich aromatic substrate, with the arenediazonium ion being the electrophile ... 

The hydroxyl group is a strongly activating, ortho- and para-directing substituent in electrophilic aromatic substitution reactions (Section 16.4). As a result, phenols are highly reactive substrates for electrophilic halogenation, nitration, sulfonation, and lTiedel-Crafts reactions. 

Novolacs are prepared with an excess of phenol over formaldehyde under acidic conditions (Fig. 7.6). A methylene glycol is protonated by an acid from the reaction medium, which then releases water to form a hydroxymethylene cation (step 1 in Fig. 7.6). This ion hydroxyalkylates a phenol via electrophilic aromatic substitution. The rate-determining step of the sequence occurs in step 2 where a pair of electrons from the phenol ring attacks the electrophile forming a car-bocation intermediate. The methylol group of the hydroxymethylated phenol is unstable in the presence of acid and loses water readily to form a benzylic carbo-nium ion (step 3). This ion then reacts with another phenol to form a methylene bridge in another electrophilic aromatic substitution. This major process repeats until the formaldehyde is exhausted. 

Mercuration of aromatic compounds can be accomplished with mercuric salts, most often Hg(OAc)2 ° to give ArHgOAc. This is ordinary electrophilic aromatic substitution and takes place by the arenium ion mechanism (p. 675). ° Aromatic compounds can also be converted to arylthallium bis(trifluoroacetates), ArTl(OOCCF3)2, by treatment with thallium(III) trifluoroacetate in trifluoroace-tic acid. ° These arylthallium compounds can be converted to phenols, aryl iodides or fluorides (12-28), aryl cyanides (12-31), aryl nitro compounds, or aryl esters (12-30). The mechanism of thallation appears to be complex, with electrophilic and electron-transfer mechanisms both taking place. 

A second group of aromatic substitution reactions involves aryl diazonium ions. As for electrophilic aromatic substitution, many of the reactions of aromatic diazonium ions date to the nineteenth century. There have continued to be methodological developments for substitution reactions of diazonium intermediates. These reactions provide routes to aryl halides, cyanides, and azides, phenols, and in some cases to alkenyl derivatives. 

---