Electrophilic aromatic substitution arylation

Arylamines contain two functional groups the amine group and the aromatic ring they are difunctional compounds The reactivity of the amine group is affected by its aryl substituent and the reactivity of the ring is affected by its amine substituent The same electron delocalization that reduces the basicity and the nucleophilicity of an arylamme nitrogen increases the electron density in the aromatic ring and makes arylamines extremely reactive toward electrophilic aromatic substitution... 

Although It IS possible to prepare aryl chlorides and aryl bromides by electrophilic aromatic substitution it is often necessary to prepare these compounds from an aromatic amine The amine is converted to the corresponding diazonmm salt and then treated with copper(I) chloride or copper(I) bromide as appropriate... 

Tertiary alkylamines illustrate no useful chemistry on nitrosation Tertiary aryl-amines undergo nitrosation of the ring by electrophilic aromatic substitution... 

The two mam methods for the preparation of aryl halides halogenation of arenes by electrophilic aromatic substitution and preparation by way of aryl diazomum salts were described earlier and are reviewed m Table 23 2 A number of aryl halides occur natu rally some of which are shown m Figure 23 1... 

Resonance effects are the primary influence on orientation and reactivity in electrophilic substitution. The common activating groups in electrophilic aromatic substitution, in approximate order of decreasing effectiveness, are —NR2, —NHR, —NH2, —OH, —OR, —NO, —NHCOR, —OCOR, alkyls, —F, —Cl, —Br, —1, aryls, —CH2COOH, and —CH=CH—COOH. Activating groups are ortho- and para-directing. Mixtures of ortho- and para-isomers are frequently produced the exact proportions are usually a function of steric effects and reaction conditions. 

Aryl chlorides and bromides are conveniently prepared by electrophilic aromatic substitution. The reaction is limited to chlorination and bromination. Fluorination is difficult to control iodi-nation is too slow to be useful. 

A more practical solution to this problem was reported by Larson, in which the amide substrate 20 was treated with oxalyl chloride to afford a 2-chlorooxazolidine-4,5-dione 23. Reaction of this substrate with FeCL affords a reactive A-acyl iminium ion intermediate 24, which undergoes an intramolecular electrophilic aromatic substitution reaction to provide 25. Deprotection of 25 with acidic methanol affords the desired dihydroisoquinoline products 22. This strategy avoids the problematic nitrilium ion intermediate, and provides generally good yields of 3-aryl dihydroisoquinolines. 

Mechanistically there is ample evidence that the Balz-Schiemann reaction is heterolytic. This is shown by arylation trapping experiments. The added arene substrates are found to be arylated in isomer ratios which are typical for an electrophilic aromatic substitution by the aryl cation and not for a homolytic substitution by the aryl radical (Makarova et al., 1958). Swain and Rogers (1975) showed that the reaction takes place in the ion pair with the tetrafluoroborate, and not, as one might imagine, with a fluoride ion originating from the dissociation of the tetrafluoroborate into boron trifluoride and fluoride ions. This is demonstrated by the insensitivity of the ratio of products ArF/ArCl in methylene chloride solution at 25 °C to excess BF3 concentration. 

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. 

In general, if condensation polymers are prepared with methylated aryl repeat units, free radical halogenatlon can be used to introduce halomethyl active sites and the limitations of electrophilic aromatic substitution can be avoided. The halogenatlon technique recently described by Ford11, involving the use of a mixture of hypohalite and phase transfer catalyst to chlorinate poly(vinyl toluene) can be applied to suitably substituted condensation polymers. 

Careful studies by C. Eabom have shown that electrophilic aromatic substitution of silicon is faster than substitution of hydrogen. Thus a silicon in an aromatic ring directs substitution with hardly any rearrangement. This technique is particularly useful for preparation of specifically deuterated arenes as protolysis (deuterolysis) or aryl silanes is rapid. 

Other metals capable of electrophilic substitution of C-H bonds are salts of palladium and, environmentally unattractive, mercury. Methane conversion to methanol esters have been reported for both of them [29], Electrophilic attack at arenes followed by C-H activation is more facile, for all three metals. The method for making mercury-aryl involves reaction of mercury diacetate and arenes at high temperatures and long reaction times to give aryl-mercury(II) acetate as the product it was described as an electrophilic aromatic substitution rather than a C-H activation [30],... 

A nucleophilic attack of an N-tethered phenethyl substituent is shown in Scheme 50. The protonated thiazine ring brings about an intramolecular electrophilic aromatic substitution on the aryl substituent, whether this is a phenyl <1992CHE832> or a veratryl ring <1980JHC449>. 

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