7 - Aromatic Substitution Approaches to Synthesis

Abstract

This chapter focuses on the aromatic substitution approaches. Substitution processes on the preformed rings usually lead to 1-, 2-, 4-, and 5-substitution in imidazole, and 1-, 2-, 5- and 6-substitution in benzimidazole. Nucleophilic substitution reactions in imidazoles are confined largely to displacements of halogen or suitable sulfo groups, but even these need to be activated by an electron-withdrawing group elsewhere in the molecule, or by quaternization. In imidazole and benzimidazole the 2-position is the most prone to nucleophilic attack; 2-halogenoimidazoles are almost as reactive as 2-halogenopyridines. A number of nucleophiles cause ring opening of the molecules, especially under vigorous conditions. Imidazoles and benzimidazoles are quite prone to electrophilic substitution reactions, and benzimidazoles undergo some nucleophilic substitutions quite readily. Nucleophilic and radical substitutions are less well known in these compounds, but there are exceptions which may be synthetically useful. Electrophilic substitution on carbon in imidazole is largely restricted to nitration, sulfonation, and halogenation. Acidic electrophiles tend to protonate the azole, producing the much less reactive imidazolium species. For this reason, Friedel–Crafts reactions are not known, and C-alkyl and C-acyl imidazoles must be made by alternative methods. Most electrophilic reactions in imidazole (except for diazo coupling, some acylations, and deuterium exchange) occur initially at the 4(or 5)-position.