Synthesis of C-substituted imidazoles and benzimidazoles by electrophilic substitution

2 SYNTHESIS OF C-SUBSTITUTED IMIDAZOLES AND BENZIMIDAZOLES BY ELECTROPHILIC SUBSTITUTION 

Unsubstituted imidazole reacts with most electrophiles preferentially at C-4(5), but in neutral or basic media it is often difficult to prevent multiple substitution, e.g. halogenation. Deuterium exchange is unusual in that 2-exchange is more facile than 4- or 5-exchange, and diazo coupling occurs with about equal facility in both 2- and 4-positions. Acidic reagents almost always involve the protonated imidazole (imidazolium) as the reactive species. In this form the reactivity is greatly decreased, and 4(5)-substitution is observed, e.g. nitration and sulfonation. Friedel-Crafts reactions will not occur at all. Under severe conditions, disubstitution may be possible. 

When the imidazole or benzimidazole carries an iV-substituent, reactions which would have involved the conjugate base species either have to take an alternative pathway or may not take place, e.g. diazo coupling and halogenation. Preferential electrophilic attack now occurs at C-5. Exceptions to the usual orientation of substitution are observed in Regel acylations at C-2 (probably via initial A-acylation), and some hydroxymethylations. 

In benzimidazole, electrophiles preferentially substitute in the fused benzene ring in the 5(6)-position a powerful electron donor at C-5 will direct subsequent attack to C-4 electron-withdrawing groups lead to subsequent 4- or 6-substitution. Attack at C-2 is virtually unknown. 

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