Aryl halides 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... 

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. 

Nucleophilic aromatic substitution is much more restrictive in its applications than electrophilic aromatic substitution. In nucleophilic aromatic substitution, a strong nucleophile replaces a leaving group such as a halide. The mechanism cannot be the Sn2 mechanism because aryl halides cannot achieve the correct geometry for backside displacement. The aromatic ring blocks approach of the nucleophile to the back of the carbon bearing the halogen. 

The facility of arene reductive elimination underpins numerous C-C, C-O and C-N bond-forming reactions, which may be catalysed by late transition metals, in particular palladium (Figure 4.10). Although there are many variants, the general reaction scheme involves introduction of the aryl in electrophilic form via oxidative addition of an aryl halide (or sulfonate), substitution of the palladium halide by a nucleophile (which may also be carbon based) followed by reductive elimination. It is noteworthy that nucleophilic aromatic substitution in the absence of such catalysts can be difficult. 

The electrophilic aromatic substitution of aryl halides takes place less readily than with benzene (electron-withdrawing effect), but occurs at the ortho and para positions (the lone pairs on the halogen assist in delocalizing the positive charge in the intermediate). Further chlorination of chlorobenzene, in the presence of aluminium or iron trichlorides, gives 1,4-dichlorobenzene and some 1,2-dichlorobenzene. Nitration normally occurs to give the 2- and 4-nitro- and 2,4-dinitrochlorobenzenes (Scheme 4.13). 

We have seen that the aryl halides are characterized by very low reactivity toward the nucleophilic reagents like OH , OR, NH3, and CN" that play such an important part in the chemistry of the alkyl halides. Consequently, nucleophilic aromatic substitution is much less important in synthesis than either nucleophilic aliphatic substitution or electrophilic aromatic substitution. 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

The inductive effect of halogens. The halogens are more electronegative than carbon and have an electron-withdravdng inductive effect. Aryl halides, therefore, react more slowly in electrophilic aromatic substitution than benzene does. 

As in the above chemistry with alkynes, the palladium-bound products of this cydoisomerization (e.g., 15, Scheme 6.23) can also be trapped with the addition of external reagents prior to the elimination step. This typically involves the oxidative addition of R—X substrates (e.g., aryl or vinyl halides, allylic substrates, etc.) to a palladium(O) catalyst to create the palladium( 11) complex needed for cydoisomerization, followed by reductive elimination of the substituted furan product. As illustrated with the example in Scheme 6.25, this provides a route to selectively install substituents into the 3-furan position a derivatization difficult via more traditional electrophilic aromatic substitution routes [35]. 

The methods described above for alkyl halides (on sp hybridized carbons) cannot be applied to the synthesis of aryl halides (on sp hybridized carbons). The introduction of a halogen to benzene (or a benzene derivative) can be accomplished either by an electrophilic aromatic substitution reaction (Cy FeCls or Br2/FeBr3) or by treatment of a diazonium salt (ArNaO with a halide nucleophile (Cul, CuBr, HBF4, or KI). 

Since electrophilic aromatic substitution begins with benzene (or a benzene derivative), the retrosynthesis of an aryl chloride or bromide simply involves the replacement of the halide with a hydrogen atom. Another possible retro-synthesis that can be applied to any aryl halide is an FGI that replaces the halide with a nitro group, since the nitro group can be converted to any halide via the diazonium salt. 

Bromine Water. Since the aromatic ring is electron rich, aromatic ethers can undergo electrophilic aromatic substitution with bromine to yield the corresponding aryl ether-halide (s). Therefore, if elemental tests indicate that an aromatic group is present in an ether, treatment with the bromine water reagent may substantiate the presence of an aryl ether. 

Electrophilic aromatic substitution can be effected on aryl halides. In contrast to nucleophilic substitution vide supra), electrophihc substitution does not generally result in substitution of the electrophihc reagent for the halogen. Instead, the incoming electrophile is substituted for a proton on the aromatic ring and, as shown in Table 7.6 for the nitration of halobenzenes, the substitution occurs largely ortho and para to the halogen. 

Early work performed by Lenz et al. in the 1960s demonstrated this approach by using electrophilic aromatic substitution to produce poly(phenylene sulfide) [91] (Scheme 1.10). In this case, an aryl halide is the electrophile, which is substituted by the metal thiophenoxide nucleophile. In the monomer, the metal sulfide is a strong electron-donating group, which deactivates the para position where electrophilic substitution must take place. Conversely, the polymer chain end is only weakly deactivated by the sulfide bond, rendering the polymeric aryl halide more reactive than the monomeric aryl halide. Unfortunately, Lenz was unable to characterize molecular weight distribution due to the insolubility of the resultant polymers. 

---