17.4: Electrophilic Aromatic Substitution
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The first reaction in this sequence is an electrophilic aromatic substitution (EAS). This reaction is used to place the second group (SO2Cl) on the benzene ring. This is not intended to be a full discussion of EAS mechanisms. For a comprehensive treatment please consult your organic chemistry textbook.
The most important steps in the mechanism are presented below.
1. GENERATION OF THE ELECTROPHILE
2. POSSIBLE SITES FOR ELECTROPHILIC ATTACK ON THE BENZENE RING
3. FORMATION OF THE “ACTIVATED σ-COMPLEX,” A RESONANCE-STABILIZED REACTION INTERMEDIATE (structures I-IV).
4. REGENERATION OF THE AROMATIC BENZENE RING
5. REACTION OF SULFONYL CHLORIDE GROUP WITH A NUCLEOPHILE (AMMONIA).
6. HYDROLYSIS OF THE AMIDE GROUP
7. PROTECTING GROUP STRATEGY - Acetanilide is used as the starting material in these reactions, but at the end the amide group gets hydrolyzed into an amine group. Why not start the reaction sequence with aniline (below) rather than acetanilide, and save the last step? The answer is that the amino group in aniline is too reactive and it can react at several stages in the course of the reaction sequence.
For example, the amine can react in step 5 (reaction of the sulfonyl chloride group with ammonia), just like ammonia does, since they are both nucleophiles of similar structure. At the beginning of the reaction, the free amino group would get protonated by the strong acid (chlorosulfonic acid) to become a meta-directing group, rather than a paradirecting group.
By using the amide, instead of the free amine, the nucleophilic properties of the nitrogen get reduced by resonance stabilization of the lone pair of electrons. In addition, the bulk of the amide group in acetanilide favors para-substitution over ortho-substitution due to steric hindrance.
the free amine is a strong nucleophile
resonance delocalization of the lone electron pair reduces the nucleophilic ability of nitrogen in the amide