Reactions in Side Chains of Aromatic Compounds

Nucleophilic substitution of haloarenes is difficult, and poor reactions are obtained unless the arene bears a group able to accept electrons by resonance. 

Substitution of haloarenes bearing strongly electron-accepting groups proceeds by an addition-elimination mechanism. The addition step is rate determining, and the effect of the electron-withdrawing groups is additive—more electron acceptors means a faster reaction. 

To be effective in delocalizing charge in the intermediate, the electron-withdrawing groups must by ortho or para to the group we wish to substitute. Conversely, electron donors at the ortho- or pora-positions retard reaction. Groups at the meto-position have little effect. 

2-Halopyridines and 4-halopyridines may also be readily substituted by nucleophiles by an addition-elimination mechanism. 

Halobenzenes and pyridines that are not specifically activated toward substitution by appropriately placed electron-accepting substituents may be substituted by an elimination-addition mechanism involving benzyne and related aryne intermediates a very strong base is required. 

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