Electrophilic aromatic substitution comparison pyrrole/thiophene/furan

Electrophilic substitution in the azoles is intermediate in facility between pyridine on the one hand and pyrroles, thiophenes and furans on the other the presence of the electron-withdrawing imine unit has an effect on the flve-membered aromatic heterocycles just as it does when incorporated into a six-membered aromatic framework, i.e. the comparison is like that between benzene and pyridine (Chapter 7). The order of reactivity - pyrrole > furan > thiophene - is echoed in the azoles, though the presence of the basic nitrogen complicates such comparisons. The regiochemistry of electrophilic attack can be rationalised nicely by comparing the character of the various ring positions - those that are activated in being flve-membered in character and those that are deactivated by their similarity to a- and y- positions in pyridine. 

Thiophene is far more reactive than benzene in electrophilic substitution reactions. Reaction with bromine in acetic acid has been calculated to be 1.76 x 109 times faster than with benzene (72IJS(C)(7)6l). This comparison should, of course, be treated with circumspection in view of the fact that the experimental conditions are not really comparable. Benzene in the absence of catalysts is scarcely attacked by bromine in acetic acid. More pertinent is the reactivity sequence for this bromination among five-membered aromatic heterocycles, the relative rates being in the order 1 (thiophene) and 120 (furan) or, for trifluoroacetylation, 1 (thiophene), 140 (furan), 5.3 xlO7 (pyrrole) (B-72MI31300, 72IJS(C)(7)6l). Among the five-membered heteroaromatics, thiophene is definitely the least reactive. 

Electrophilic reactions on the electron-rich, aromatic thiophene nucleus continue to provide a powerful route to substituted derivatives. Comparison of positional selectivity of the heteroarenium ions derived from furan. pyrrole or thiophene suggest that ease of P-substitution correlates with the relative stabilities <94H2029>. Freidel-Crafts reaction of 2,5-... 

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