Reactions of Benzene

OH Cl NH 2
NaOH NH 3
High pressure High pressure
High temperature High temperature

Phenol Aniline

How will you classify these reactions ?

Nucleophilic Aromatic Substitution (SNAr)

Nucleophilic Aromatic Substitution
What could be the mechanism(s) for such a reaction ?

SN1 or SN2 ?

1. Addition-Elimination Mechanism

2. Elimination-Addition Mechanism
Addition-Elimination Mechanism
Addition-Elimination Mechanism
Addition-Elimination: Kinetics
In protic solvents typically 2nd order Kinetics is observed
• 1st order in Nucleophile
• 1st order in Aromatic substrate
X
SNAr

NO2 X = F, Cl, Br or I
addition
slow step
elimination
fast step
Rate: F > Cl > Br > I

“Stronger bond dipoles associated

with more electronegative atom
favor the addition step lowering
activation energy of the
nucleophile addition step”
Addition-Elimination Mechanism

Proof for the addition elimination mechanism

Ø Jakob Meisenheimer was successful in isolating the negatively charged intermediate

OMe MeO OEt

O2N NO2 O2N NO2
EtOK
K

NO2 NO2

Meisenheimer complex
Applications
Determination of N-terminal of Proteins - Sanger’s Method
Proteins – polymers made up of amino acids

O
R
OH α−Amino acid Frederick Sanger
NH2

Sanger used this method to determine the structure of

insulin which won him his first Nobel Prize.
Applications

Sanger’s Reagent
Applications

Antidepressant agent
Nucleophilic Aromatic Substitution…contd

CH3 CH3 CH3

NaOH +
H2O, 350 °C
OH
Cl OH

Mixture of regioisomers observed !!!

How do we explain?

Elimination-Addition mechanism
Elimination-Addition Mechanism
CH3 CH3 CH3

NaOH +
H2O, 350 °C
OH
Cl OH
Direct substitution Cine substitution Benzyne