Reactions of Phenols Electrophilic Aromatic Substitution

Many plant pigments are tricyclic phenols called flavanoids, which among their other properties are antioxidants. A fiavanoid in green tea and red wine, (-l-)-catechin may play a role in the low incidence of atherosclerosis in Japan and France. 

Spotted knapweed produces a phenolic compound that kills other plants. 

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 22.3 summarizes the behavior of phenols in reactions of this type. 

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 22.3, for exanple, shows the monobromination of phenol in high yield at low temperature and in the absence of any catalyst. In polar solvents such as water it is difficult to limit the bromination of phenols to monosubstitution. In the following example, all three positions that are ortho or para to the hydroxyl undergo rapid substitution  

Other typical electrophilic aromatic substitution reactions— nitration (second entry), sulfonation (fourth entry), and Friedel-Crafts alkylation and acylation (fifth and sixth entries)—take place readily and are synthetically useful. Phenols also undergo electrophihc 

PROBLEM 24.6 Each of the following reactions has been reported in the chemical literature and gives a single organic product in high yield. Identify the product in each case. 

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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. 

Probably the best modem method for introduction of OF by electrophilic aromatic substitution is lithiation, reaction with a boronate ester, and oxidation.4 These are the same boron compounds that are used in Suzuki coupling (chapter 18) and are made the same way. In this example, selective mono-lithiation by Br/Li exchange on available tribromoanisole 39 (easily prepared by bromination of anisole or phenol) occurs ortho to the MeO group and reaction of aryl-lithium 39 with trimethyl borate gives the boronic ester 40. Peroxyacids such as peracetic acid are usually used for the final oxidation. 

Intramolecular Pd-catalyzed aryl-aryl coupling reactions under dehydrohalogenation are assumed to proceed via palladacycles as illustrated by the example in Scheme 47.[33]-P7] Several mechanistic pathways may explain the cyclopalladation step including the C,H-activation however, a reaction of an electrophilic arylpalladium bromide with the electron-rich phenolate in the sense of an electrophilic aromatic substitution is certainly a plausible explanation. C—C bond formation finally takes place by reductive elimination. 

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

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. 

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. 

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. 

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>. 

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