Electrophilic aromatic substitution blocking groups

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 product formed when the nitrogen of a tertiary amine shares its lone pair with a nitrosonium ion caimot be stabilized by loss of a proton. A tertiary aryl amine, therefore, can undergo an electrophilic aromatic substitution reaction with a nitrosonium ion. The product of the reaction is primarily the para isomer because the bulky dialkyl-amino group blocks approach of the nitrosonium ion to the ortho position. 

Now we can remove the "blocking group" - SO3H and next form the final product 2,4-D. To do this we treat 2-hydroxy 3,5-dichloropbenzenesulfonic acid with steam at 120°C with a trace of acid catalyst. This is essentially the reverse of sulfonation, or "desulfonation." We note that sulfonation is the only one of the common electrophilic aromatic substitutions that is reversible and the question arises why this is so. This calls for an analysis of the general mechanism of electrophilic aromatic substitution. The idealized energy profile for such a reaction (chlorination) is ... 

The nitrogen atoms are retained in the product. This electrophilic aromatic substitution reaction is called diazo coupling, because in the product, two aromatic rings are coupled by the azo, or —N=N—, group. Para coupling is preferred, as in eq. 11.34, but if the para position is blocked by another substituent, ortho coupling can occur. All azo compounds are colored, and many are used commercially as dyes for cloth and in (film-based) color photography ... 

USING BLOCKING GROUPS TO CONTROL THE REGIOCHEMICAL OUTCOME OF AN ELECTROPHILIC AROMATIC SUBSTITUTION REACTION... 

A blocking group can be used to control the regiochemical outcome of an electrophilic aromatic substitution. 

Using Blocking Groups to Control the Regiochemical Outcome of an Electrophilic Aromatic Substitution Reaction... 

Electrophilic substitution of aromatic nuclei in tyrosine and tryptophan side chains has frequently been reported in connection with acidolytic removal of blocking groups. C-Benzylation and tert.butylation of the tyrosine side chain and N-alkylation of the indole nucleus in tryptophan are often attributed to the alkyl cations generated in the reaction. This common side reaction is caused, however, mainly by the alkylating agents formed in the process, such as benzyl bromide or tert.butyl trifluoroacetate. The same is true for the S-alkylation of the methionine side chain. Conversion of the thioether to a sulfonium salt can... 

The reversibility of sulfonation may be used to control further aromatic substitution processes. The ring carbon containing the substituent is blocked from attack, and electrophiles are directed to other positions. Thus, the sulfonic acid group can be introduced to serve as a directing blocking group and then removed by reverse sulfonation. Synthetic applications of this strategy will be discussed in Section 16-5. 

Electronegative groups in the aromatic are necessary for reaction the polyhalo groups deactivate the aromatic for electrophilic substitution by SO 3, increase the thermal stability and also block potential sites of substitution. 

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