NAS - Addition/Elimination

Introduction to NAS

In the preceding sections on Electrophilic aromatic substitution, we observed benzene behaving like a nucleophile in electrophilic aromatic substitution reactions.  However, some specially substituted benzenes undergo Nucleophilic aromatic substitution (NAS).  In such reactions, the aromatic ring behaves as an electrophile.

For an NAS to occur the following three conditions must be met. 

  1. There must be a strong electron-withdrawing group (EWG) on the benzene ring (e.g. -NO2, CF3, -CN).

    A strong EWG pulls electron density from the ring making it a better electrophile.  This is evident by the + charge in the ring in the resoance structure of nitrobenzene below.

  2. There must be a leaving group, usually a halogen (Cl, Br, F).

    The halogen is a good leaving group by virtue of them have a full octet of electrons in their anionic state.  In addition the highly electronegative halogens also pull electron density from the carbon its attached to making that carbon more electrophilic.

  3. The leaving group must be in a position ortho or para to the powerful electron-withdrawing group.
    Position ortho and para to the electron-withdrawing group, are deficient in electron density as seen in its resonance structures below.


The NAS reaction above proceeds as follows.  The aromatic ring is deficient in electrons because of the -NO2 group and is an electrophile.  The nucleophilic hydroxide ion (OH-) attacks at the carbon attached to the leaving group in an addition reaction.  This forms a cyclohexadienyl anion (Meisenheimer complex).  The Meisenheimer complex is not aromatic.  There are 4 resonance structure for this complex, I've drawn two of them,  can you draw A and B? The Meisenheimer complex then eliminates the Cl ion.


Real World Example

I once had to perform the following reaction for a pharmaceutical intermediate.  The compound on the left is chloropyrimidine and it undergoes an NAS reaction.  It is a bit more reactive than benzene, especially considering the Cl is attached to the carbon between the two nitrogens.