SNAr reaction

Reaction, Reagents
& Mechanism

Reaction & Reagents info

  • Normally, electrophilic aromatic substitutions are common with benzene derivative.
  • Aryl halides do not undergo nucleophilic substitution reactions, as the ring is already electron rich
  • Chlorobenzene does not react with NaOH (only under extreme conditions, this reaction occurs). However, 2,4-dinitrochlorobenzene undergoes reaction with NaOH to result in corresponding Phenol derivative

  • Aryl halides do undergo nucleophilic substitution (SNAr) reactions, provided that there are strong electron withdrawing groups are present on the ring

    • The reactivity of halogen depends on its electronegativity and ability to act as a leaving group
    • The reactivity order in SNAr reactions: F > Cl > Br > I

    Useful Links on Reagent & Reaction:

    Mechanism

    Additional details

    Scheme & Procedure

    EWG = Electron withdrawing groups such as -NO2, -CN, -SO2R

    General Procedure-1 (when Nu=amines, thiols and phenols) :

    A mixture of Ar-F derivative (1 eq.), Nucleophile (1 eq.), K2CO3 or Cs2CO3 (2 eq.) in acetonitrile or DMF or NMP (10 Vol) is stirred under nitrogen atmosphere at 80 oC for 3 to 4 h. The reaction is monitored by TLC. The reaction mixture is diluted with water (20 Vol) and extracted with DCM or ethyl acetate two times. , The combined organic layer is then successively washed with water (10 Vol) and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to get the desired compound. The crude product is purified by column chromatography.

    If required, acid-base work-up procedure shall be included for the better isolation

    General Procedure-1 (when Nu=aliphatic alcohols) :

    To a suspension of NaH (60% dispersion in oil, 1.2 eq.) in THF (10 Vol) at 0 oC is added a solution of Ar-F derivative (1 eq.) in THF dropwise and stirred at room temperature for 6 to 8 h. The reaction is monitored by TLC. The reaction mixture is cooled to 0 oC and quenched by adding isopropanol or methanol or saturated NH4Cl brine solution (to quench excess sodium hydride). Further, the mixture is diluted with water (10 Vol) and extracted with DCM and EtOAc (10 Vol x 2). The combined organic layer is then successively washed with water (10 Vol) and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure to get the desired compound. The crude product is purified by column chromatography.

    Note:

    • Appropriate safety protocols are to be followed while handling NaH

    Typical Procedure:

    WO2010038081, page No. 284

    WO2007084786, page No. 132

    WO2010045258, page No. 341

    WO2012013716, page No. 100

    Scale-up &
    Green Chem

    SNAr reactions are commonly carried out on manufacturing scale

    Scale-Up Typical Procedure:

    Green Chemistry Aspects:

    Reaction Tree

    References

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