Electrophilic aromatic substitution reactions hydroxylations

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. 

Stack and co-workers recently reported a related jx-rf / -peroxodi-copper(II) complex 28 with a bulky bidentate amine ligand capable of hydroxylating phenolates at - 80 °C. At - 120 °C, a bis(yu,-oxo)dicopper(III) phenolate complex 29 with a fully cleaved 0-0 bond was spectroscopically detected (Scheme 13) [190]. These observations imply an alternative mechanism for the catalytic hydroxylation of phenols, as carried out by the tyrosinase metalloenzyme, in which 0-0 bond scission precedes C - 0 bond formation. Hence, the hydroxylation of 2,4-di-tert-butylphenolate would proceed via an electrophilic aromatic substitution reaction. 

SAMPLE SOLUTION (a) The ring that bears the hydroxyl group is much more reactive than the other ring. In electrophilic aromatic substitution reactions of rings that bear several substituents, it is the most activating substituent that controls the orientation. Bromination occurs para to the hydroxyl group. 

Now we have an excellent electrophile for the electrophilic aromatic substitution reaction. The hydroxyl lone pair is a much better electron-releasing group than the methyl, so the electrophile adds ortho to the best electron-releasing group, hydroxyl (the para position is already occupied by methyl). The Dg step removes the proton from the carbon that the electrophile attacked to rearomatize the ring. 

In looking at vancomycin and teicoplanin, the hydroxyls are but one choice for functionalization reactions. Each natural product also possesses electron-rich arenes, which may be platforms for electrophilic aromatic substitution reactions. In parallel studies of enantioselective and atropisomer-selective bromination reactions [161-164], we were gaining experience with catalyst-controlled bromina-tions, and we wondered whether these might be extended to site-selective reactions. We speculated that an appropriately positioned Lewis base, such as a dimethyl amide unit, could assist in the delivery of electrophilic bromine... 

Electrophilic aromatic substitution reactions are common with phenols and in these processes, the hydroxyl group is retained. However, as pointed out above, preparation of suitable derivatives can induce loss of that hydroxyl group too. 

The chemistry of aromatic compounds is dominated hy electrophilic aromatic substitution reactions, both in the laboratory and in biological pathways. Many variations of the reaction can be carried out, including halogenation, nitration, sulfonation, and hydroxylation. Friedel-Crafts alkylation and acylation, which involve reaction of an aromatic ring with carho-cation electrophiles, are particularly useful. 

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. 

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 ... 

In accordance with a typical electrophilic aromatic substitution, this reaction is successfully accomplished by simply treating aromatic compounds activated by electron-donating groups, such as alkoxy, phenoxy, hydroxyl and thiophenoxy moieties, with tellurium tetrachloride in reflnxing chloroform, carbon tetrachloride or tolnene. ° ... 

Perdenteration of the methylene hnker affords a relatively kinetically stable complex, which allows for the monitoring of exogenons snbstrate oxidations. When (7) is exposed to cold (-95 °C) acetone solntions of the lithium salts of para-substituted phenolates, clean conversion to the corresponding o-catechols is observed. Deuterium kinetic isotope effects (KIEs) for these hydroxylation reactions of 1.0 are observed, which is consistent with an electrophilic attack of the peroxo ligand on the arene ring. An electrophilic aromatic substitution is also consistent with the observation that lithium jo-methoxy-phenolate reacts substantially faster with (7) than lithium / -chloro-phenolate. Furthermore, a plot of observed reaction rates vs. / -chloro-phenolate concentration demonstrated that substrate coordination to the metal center is occurring prior to hydroxylation, and thus may be an important feature in these phenolate o-hydroxylation reactions. 

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