Directing effects of substituents in monocyclic compounds

Large 1-alkyl substituents increase 3-substitution in the Vilsmeier formylation of pyrroles (70JCS(C)2573). A similar trend occurs in trifluoroacetylation of W-alkylpyrroles (80JCR(S)42). The trifluoroacetylation, formylation and bromination of 1-tritylpyrrole occur regioselectively at the 3-position in high yield (83JCS(P1)93). 

Electron donor 2-substituents orient substitution in furan, thiophene and selenophene into the 5-position. In pyrrole, although the ratio of a to (3 reactivity is much smaller than in the other five-membered rings, 5-substituted 2-alkylpyrroles still appear to be the major products. 

Electron donor 3-substituents supplement the a-directing effect of the heteroatom and direct the incoming substituent into the 2-position. However, steric effects can result in an increased proportion of 5-substitution. 

For pyrroles with electron acceptor substituents in the 1-position electrophilic substitution with soft electrophiles can be frontier orbital controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles can be charge controlled and occur at the 3-position. 

Nitration and Friedel-Crafts acylation of 1-benzenesulfonylpyrrole occur at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N+ = CH2), in formylation under Vilsmeier conditions (R2N+ = CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO4 =CHC1) effect substitution mainly in the 2-position (81TL4899, 81TL4901). 

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