Electrophilic aromatic substitution of phenols

Oxygen is more electronegative than carbon. It is thus reasonable to expect the oxygen substituent on the aromatic ring to be (inductively) electron withdrawing. However, the experimentally observed acceleration of electrophilic substitution 

Sulfonation to produce disulfonic acids can also be carried out if fuming sulfuric acid (sulfuric acid [H2SO4] containing sulfur trioxide [SO3]) is used. The second sulfonic acid group is introduced into the unfilled ortho- or para-position. 

Halogen substitution for hydrogen in phenols can also be effected. Halogens (Cl, Br, and I) enter ortho and para with respect to the phenol hydroxyl (-OH). Chlorination with excess chlorine (CI2) in the presence of iron(III) chloride (ferric chloride, FeCla) at 70-75°C produces 2,3,4,6-tetrachlorophenol (Equation 8.27). 

In aqueous solution, bromine (Br2) reacts with phenol to provide 2,4,6-tribromophenol and isolation of intermediate 2- and 4-bromophenols cannot be effected. However, in nonpolar solvents, where proton transfer to the solvent is inhibited, substitution occurs less readily and both 2- and 4-bromophenols can be obtained and separated from each other (Equation 8.28). 

Problem 8.8. How would you account for the observation concerning the effect of solvent as noted in Equation 8.28  

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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.

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. 

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 ... 

The synthesis of 3-aryltetrahydroisoquinolines was accomplished by electrophilic aromatic substitution of polysubstituted phenols and phenyl ethers with Lewis acid-generated tosyliminium ions of 2-tosyl-3-methoxytetrahydroisoquinoline derivatives <00SL801>. In addition isoquinoline was reported to react with N-tosylated (R)- or (S)-amino acid fluorides to afford optically active dihydroimidazoisoquinolinones. The reaction proceeds via acylation followed by attack of the tosylamino group at Cl of the intermediate 2-tosylaminoacylisoquinolinium salt <00TL5479>. 

The Pechmann reaction is thought to proceed through electrophilic aromatic substitution of the phenol. The resulting /3-hydroxy ester then cyclizes and dehydrates to the coumarin, although of course dehydration may occur earlier in the sequence (Scheme 113). Indeed, the observation that 2-hydroxycinnamic acids readily yield coumarins in sulfuric acid (32JCS1681) renders these compounds or their esters plausible intermediates in the reaction. 

Coumarins are readily accessed via the Pechmann condensation of phenols and 1,3-dicarbonyl compounds, which proceeds via electrophilic aromatic substitution of the phenol followed by dehydration and lactonization <1984CHEC, 1996CHEC-II>. In this manner, the amino acid bearing coumarins 676 are formed by a Pechmann condensation of phenols and 2-amino-6-ethoxy-4,6-dioxohexanoic acid 677 (Scheme 161) <2004AGE3432>. The popularity of this approach results from the wide range of readily available substrates (phenols and 1,3-dicarbonyl compounds). However, a major drawback is that electron withdrawing groups on the phenolic component dramatically reduces the yield of a Pechmann reaction. 

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. ... 

An alternative broadly accepted mechanism based on all of these data has also been proposed. This mechanism suggests protection of the ester as its enol 28, then attack of phenol la on the P20s-activated ketone, providing 29. Dehydration provides 16 followed by electrophilic aromatic substitution of the activated ester to provide intermediate 30. Re-aromatization and loss of EtOH completes the formation of chromone 23a. 

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. 

The resulting compound bears an OF group coimected to a benzylic position. This OH can be protonated under acidic conditions, followed by loss of a leaving group to give a resonance-stabilized, benzylic carbocation. This carbocation can then 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... 

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

The hydroxyl group of a phenol is a strongly activating substituent and electrophilic aromatic substitution occurs readily m phenol and its deriv atives Typical examples were presented m Table 24 4... 

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. 

Pyrrole, furan, and thiophene, on the other hand, have electron-rich aromatic rings and are extremely reactive toward electrophilic aromatic substitution— rnore like phenol and aniline than benzene. Like benzene they have six tt electrons, but these tt electrons are delocalized over five atoms, not six, and ar e not held as strongly as those of benzene. Even when the ring atom is as electronegative as oxygen, substitution takes place readily. 

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 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 ... 

The mechanism for that step is closely related to that of the Friedel-Crafts acylation. Upon subsequent hydrolysis the o-substituted Lewis acid-coordinated phenolate 7 is converted to the free o-acylphenol 2. By an analogous route, involving an electrophilic aromatic substitution para to the phenolate oxygen, the corresponding para-acylphenol is formed. 

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. 

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. 

Resole syntheses entail substitution of formaldehyde (or formaldehyde derivatives) on phenolic ortho and para positions followed by methylol condensation reactions which form dimers and oligomers. Under basic conditions, pheno-late rings are the reactive species for electrophilic aromatic substitution reactions. A simplified mechanism is generally used to depict the formaldehyde substitution on the phenol rings (Fig. 7.21). It should be noted that this mechanism does not account for pH effects, the type of catalyst, or the formation of hemiformals. Mixtures of mono-, di-, and trihydroxymethyl-substituted phenols are produced. 

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. 

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