topic for first year Pharm. D students

1. Electrophilic Aromatic SubstitutionElectrophilic Aromatic Substitution
Dr. R B KotnalDr. R B Kotnal
BLDEA’s SSM College of Pharmacy and
Research Centre, Vijayapur
BLDEA’s SSM College of Pharmacy and
Research Centre, Vijayapur

2. Electrophilic Aromatic Substitution (Aromatic compounds)
Ar-H = aromatic compound
1. Nitration
Ar-H + HNO3, H2SO4  Ar-NO2 + H2O
2. Sulfonation
Ar-H + H2SO4, SO3  Ar-SO3H + H2O
3. Halogenation
Ar-H + X2, Fe  Ar-X + HX
4. Friedel-Crafts alkylation
Ar-H + R-X, AlCl3  Ar-R + HX

3. Friedel-Crafts alkylation (variations)
a) Ar-H + R-X, AlCl3  Ar-R + HX
b) Ar-H + R-OH, H+
 Ar-R + H2O
c) Ar-H + Alkene, H+
 Ar-R

4. NO2
SO3H
Br
CH2CH3
HNO3
H2SO4
SO3
H2SO4
Br2, Fe
CH3CH2-Br
AlCl3

5. toluene
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Br
Br
NO2
NO2
SO3H
SO3H
HNO3
H2SO4
SO3
H2SO4
Br2, Fe
+
+
+
faster than the same
reactions with
benzene

6. nitrobenzene
NO2
NO2
NO2
NO2
NO2
NO2
NO2
SO3H
Cl
HNO3
H2SO4
H2SO4
SO3
Cl2, Fe
slower than the same
reactions with
benzene

7. Substituent groups on a benzene ring affect electrophilic
aromatic substitution reactions in two ways:
1) reactivity
activate (faster than benzene)
or deactivate (slower than benzene)
2) orientation
ortho- + para- direction
or meta- direction

8. -CH3
activates the benzene ring towards EAS
directs substitution to the ortho- & para- positions
-NO2
deactivates the benzene ring towards EAS
directs substitution to the meta- position

9. Common substituent groups and their effect on EAS:
-NH2, -NHR, -NR2
-OH
-OR
-NHCOCH3
-C6H5
-R
-H
-X
-CHO, -COR
-SO3H
-COOH, -COOR
-CN
-NR3
+
-NO2
increasingreactivity
ortho/para directors
meta directors

10. OCH3
CHO
Br
Br2, Fe
HNO3, H2SO4
H2SO4, SO3
OCH3
Br
OCH3
Br
+ faster than benzene
CHO
NO2
slower than benzene
+
Br Br
SO3H
SO3H
slower than benzene

11. If there is more than one group on the benzene
ring:
1. The group that is more activating (higher
on “the list”) will direct the next
substitution.
2. You will get little or no substitution
between groups that are meta- to each
other.

12. CH3
OH
NHCOCH3
CH3
CHO
OCH3
Br2, Fe
HNO3, H2SO4
Cl2, Fe
CH3
OH
Br
NHCOCH3
CH3
NO2
CHO
OCH3
Cl
CHO
OCH3
Cl
+

13. Orientation and synthesis. Order is important!
synthesis of m-bromonitrobenzene from benzene:
NO2
Br
NO2
HNO3
H2SO4
Br2, Fe
synthesis of p-bromonitrobenzene from benzene:
Br Br Br
NO2
NO2
+
Br2, Fe HNO3
H2SO4
You may assume that you can separate a pure para-
isomer from an ortho-/para- mixture.

14. note: the assumption that you can separate a pure para
isomer from an ortho/para mixture does not apply to any
other mixtures.
Br Br
Br
Br
Br
NO2 NO2
Br
NO2
Br
Br
NO2
Br
Br
Br
Br
NO2
+
+
Br2, Fe Br2, Fe
Br2, Fe Br2, FeHNO3
H2SO4
HNO3
H2SO4
synthesis of 1,4-dibromo-2-nitrobenzene from benzene
separate pure para isomer from ortho/para mixture
cannot assume that these can be separated!

15. CH3
CH3
CH3
COOH
COOH COOH
CH3 COOH
NO2
NO2 NO2
+ ortho-
CH3Br
AlCl3
CH3Br
CH3Br
AlCl3
AlCl3
KMnO4
KMnO4
KMnO4
heat
heat
heat
HNO3
H2SO4
HNO3
H2SO4
synthesis of benzoic acids by oxidation of –CH3

16. +
HO-NO2 + H2SO4  H2O-NO2 + HSO4
-
+ +
H2O-NO2  H2O + NO2
H2SO4 + H2O  HSO4
-
+ H3O+
HNO3 + 2 H2SO4  H3O+
+ 2 HSO4
-
+ NO2
+
nitration

17. nitration:
1) HONO2 + 2 H2SO4 H3O+
+ 2 HSO4
-
+ NO2
+
2) + NO2
+ RDS
electrophile

18. H
NO2
H
NO2
H
NO2
H
NO2
resonance

19. Mechanism for nitration:
1) HONO2 + 2 H2SO4 H3O+
+ 2 HSO4
-
+ NO2
+
2) + NO2
+
H
NO2
3)
RDS
NO2 + H+
H
NO2

20. Mechanism for sulfonation:
1) 2 H2SO4 H3O+ + HSO4
- + SO3
2) + SO3
RDS
H
SO3
-
3)
H
SO3
-
SO3
-
+ H+
4) SO3
-
SO3H+ H3O+ + H2O

21. Mechanism for halogenation:
1) Cl2 + AlCl3 Cl-Cl-AlCl3
2) + Cl-Cl-AlCl3
RDS
H
Cl
+ AlCl4
-
3)
H
Cl
+ AlCl4
-
Cl + HCl + AlCl3

22. Mechanism for Friedel-Crafts alkylation:
1) R-X + FeX3 R + FeX4
-
2) + R
RDS
3)
H
R
H
R
+ FeX4
-
R + HX + FeX3

23. 1) R-OH + H+
ROH2
+
3) + R
RDS
4)
H
R
H
R
R
2) ROH2
+ R + H2O
+ H+
Mechanism for Friedel-Crafts with an alcohol & acid

24. 2)
+ R
RDS
3)
H
R
H
R
R
1) C C + H+
R
+ H+
Mechanism for Friedel-Crafts with alkene &
acid:
electrophile in Friedel-Crafts alkylation = carbocation

25. “Generic” Electrophilic Aromatic Substitution mechanism:
1) + Y+Z-
RDS
H
Y
+ Z-
2)
H
Y
+ Z-
Y + HZ

26. Why do substituent groups on a benzene ring affect the
reactivity and orientation in the way they do?
 electronic effects, “pushing” or “pulling” electrons by
the substituent.
Electrons can be donated (“pushed”) or withdrawn
(“pulled”) by atoms or groups of atoms via:
Induction – due to differences in electronegativities
Resonance – delocalization via resonance

27. N
H
H
unshared pair of electrons on the nitrogen
resonance donating groups
(weaker inductive withdrawal)
N
R
R
N
R
H
NR
R
R strong inductive withdrawal
(no unshared pair of electrons on the
nitrogen & no resonance possible

28. H3C C
O
N
H
resonance donation
(weaker inductive withdrawal)
H
O
resonance donation
(weaker inductive withdrawal)
R
O
resonance donation
(weaker inductive withdrawal)

29. resonance donation
H3C
inductive donation
sp3 sp2 ring carbon
inductive withdrawalX—

30. H
C
O
HO
C
O
RO
C
O
R
C
O
resoance withdrawal and
inductive withdrawal

31. N
O
O
resonance and
inductive withdrawal
resonance and
inductive withdrawal
CN

32. Common substituent groups and their effect on reactivity in EAS:
-NH2, -NHR, -NR2
-OH
-OR
-NHCOCH3 electron donating
-C6H5
-R
-H
-X
-CHO, -COR
-SO3H
-COOH, -COOR electron withdrawing
-CN
-NR3
+
-NO2
increasingreactivity

33. Electron donating groups activate the benzene ring to
electrophilic aromatic substitution.
1. electron donating groups increase the electron density
in the ring and make it more reactive with
electrophiles.
2. electron donation stabilizes the intermediate
carbocation, lowers the Eact and increases the rate.
H Y
CH3

34. H Y
NO2
Electron withdrawing groups deactivate the benzene ring to
electrophilic aromatic substitution.
1. electron withdrawing groups decrease the electron density
in the ring and make it less reactive with electrophiles.
2. electron withdrawal destabilizes the intermediate
carbocation, raising the Eact and slowing the rate.

35. CF3
PH2
PO3H
electron withdrawing = deactivating & meta-director
electron withdrawing = deactivating & meta-director
electron donating = activating & ortho-/para-director

36. Br2, Fe
Br + ortho-
NO2
Br2, Fe
NO2Br + ortho-
O
O
Br2, Fe
O
O
Br
+ ortho-

37. How to draw resonance structures for EAS
Y
H
Y
H
Y
H
Y

38. G G G
G G G
G G
H H H
Y Y Y
H
Y
H
Y
H
Y
H Y H Y
G
H Y
ortho-attack
meta-attack
para-attack

39. G
H
Y
G
H Y
If G is an electron donating group, these structures are
especially stable.

40. G G G
G G G
G G
H H H
Y Y Y
H
Y
H
Y
H
Y
H Y H Y
G
H Y
ortho-attack
meta-attack
para-attack

41. Electron donating groups stabilize the intermediate
carbocations for ortho- and para- in EAS more than for
meta-. The Eact’s for ortho-/para- are lower and the
rates are faster.
Electron donating groups direct ortho-/para- in EAS

42. G
H
Y
G
H Y
If G is an electron withdrawing group, these structures
are especially unstable.

43. G G G
G G G
G G
H H H
Y Y Y
H
Y
H
Y
H
Y
H Y H Y
G
H Y
ortho-attack
meta-attack
para-attack

44. Electron withdrawing groups destabilize the intermediate
carbocations for ortho- and para- in EAS more than for
meta-. The Eact’s for ortho-/para- are higher and the
rates are slower.
Electron withdrawing groups direct meta- in EAS

45. Halogens are electron withdrawing but are ortho/para
directing in EAS.
The halogen atom is unusual in that it is highly
electronegative but also has unshared pairs of electrons
that can be resonance donated to the carbocation.

46. X X X
X X X
X X
H H H
Y Y Y
H
Y
H
Y
H
Y
H Y H Y
X
H Y
X
H Y
X
H
Y
ortho-
meta-
para-
halogens are deactivating in EAS but direct ortho and para

47. Common substituent groups and their effect on EAS:
-NH2, -NHR, -NR2
-OH
-OR
-NHCOCH3
-C6H5
-R
-H
-X
-CHO, -COR
-SO3H
-COOH, -COOR
-CN
-NR3
+
-NO2
increasingreactivity
ortho/para directors
meta directors

48. Thank youThank you