Nucleophilic Substitution Reactions via Meisenheimer Complexes

Nucleophilic substitution most readily occurs at the 2- and 4-position of the more electron-deficient heterocyclic ring of quinolines. However, SNAr reactions at the carbocyclic ring can occur, mainly at positions 5 and 7. 5,7-Dibromo-8-hydroxyquinoline, 5-bromo-8-hydroxyquinoline, and 7-bromo-8-hydroxy-5-methylquinoline undergo conversion to the corresponding chloroquinolines on treatment with neat pyridine hydrochloride at 220 °C in a process that is postulated to proceed via the formation of stabilized Meisenheimer complexes <1996TL6695> (Equations 20 and 21). 

The simplest example of an aromatic nucleophilic substitution is the SnAt reaction between l-chloro-2,4-dinitrobenzene and piperidine, the two-step mechanism of which, given in Eq. (5-26), is now fully established [501-503], It involves formation of a Meisenheimer-type zwitterionic intermediate via a dipolar activated complex, followed... 

The second example of a cine-substitution of a thiophene involves the reaction of arylthiolates with 3,4-dinitrothiophene (331) or 3-nitro-4-phenylsul-fonylthiophene (332) to give the 2,4-substituted products 333. Both an elimination-addition mechanism via the aryne (334) or an abnormal addition-elimination (AEa) mechanism (Section II.2.A.e) via the Meisenheimer complex (335) have been considered for these reactions. The former is unlikely for several reasons including the lack of precedence for aryne formation from aryl nitro compounds (Section II. 1) under these reaction conditions and the fact that addition of the nucleophile ArS" to the aryne (334) would have to proceed via the 3-thienyl anion (336) rather than via a more stable 2-thienyl anion such as 320 as would be expected. Contrariwise, cine-substitution by the AEa mechanism is favored by the ability of the complex (335) to stabilize the negative charge by delocalization to both the NO2 group and the a position of the thiophene ring." As in the pyrrole series (Section III.2.B) the actual mechanism appears to be more complex, however, involving several addition and elimination steps via 337, which was recently isolated from the reaction (X = NO2) and shown to go to the product 333 under the reaction conditions. It therefore appears that neither of the cine-substitutions of thiophene described in this Section proceeds via an aryne intermediate. 

---