Orientation and Reactivity of Nucleophilic Substitution in Pyridine, Nucleophilic Substitution Reactions of Pyridine at C-2 position

1. 1
B.Sc. Final year
MEB Students
for
Today’s
Chemistry Lecture
by
Dr Pramod R Padole

2. 2

4. LOGO
A) Heterocyclic Compounds:

5. LOGO
b) 6-membered Heterocyclic compounds
(ii) Pyridine or AZABENZENE:
Molecular Formula of Pyridine is C5H5N
..
N
Pyridine

7. Electrophilic Substitution Reactions of Pyridine
at C-3 position:
Reaction with
Con.HNO3
or Con.KNO3
in presence
of Con.H2SO4:
Chemical Reactions
(ii) Sulphonation:
(i) Nitration:
Reaction with
fuming
Sulphuric acid (H2SO4):

8. (i) Nitration:
Reaction with Con.HNO3
or Con.KNO3
in presence of Con.H2SO4:

9. companyname
(i) Nitration:
Con.HNO3
in presence
of
Con.H2SO4
Reaction
with
Con.KNO3
in presence
of
Con.H2SO4
Q.1) How does pyridine reacts with nitrating mixture? (W-15, 2 Mark)
Q.2) How will you convert pyridine to 3-nitro-pyridine? (S-19, 2 Mark)

10. companyname
(i) Nitration:
Reaction with Con.HNO3 or Con.KNO3
in presence of Con.H2SO4:
 When pyridine is heated with concentrated nitric acid
(con. HNO3) or potassium nitrate (con.KNO3) in the
presence of concentrated sulphuric acid (con.H2SO4)
at 300oC (573K), undergoes nitration; to form
3-nitro-pyridine in poor (less) yield.
3
N
Conc. H2SO4
0
N
NO2
573KHO-NO2
HNO3
or
+ KO-NO2
or KNO3
300 C or
(- H2O)
Conc. H2SO4
0
573K300 C or
(- KOH)
Pyridine 3-nitro-pyridine
H
3 + H2O
+ KOH

11. Fuming sulfuric acid is a mixture of pyrosulphuric
acid, H 2 S 2 O 7, and other condensed acids, made by
dissolving sulphur trioxide in concentrated sulphuric acid.
Also called: oleum, Nordhausen acid
Q.1) What is the difference between
sulfuric acid and fuming sulfuric acid?
 The key difference between oleum
and sulfuric acid is that the oleum is sulfur
trioxide in sulfuric acid whereas the sulfuric
acid is an inorganic acid having the chemical
formula H2SO4. We call oleum as “fuming
sulfuric acid” as well. ...
 Sulfuric acid, on the other hand, is a syrupy
liquid, which is highly water soluble.

12. (ii) Sulphonation:
Reaction with fuming Sulphuric acid (H2SO4):
 When pyridine is heated with fuming sulphuric acid (H2SO4) in the
presence of mercuric sulphate (HgSO4) as a catalyst at 230oC (503K);
to form pyridine-3- sulphonic acid.
pramodpadole@gmail.com By Dr Pramod R Padole
Q.1) Complete the following reaction. (W-18, 2 Mark)
Q.2) How will you convert pyridine to Pyridine 3-sulphonic acid
(S-19, 2 Mark)
?
N
Fuming H2SO4
33
N Fuming H2SO4
N
SO3H
HgSO4HO - SO3H
or at 230 o
C
Pyridine Pyridine-3-sulphonic acid
H
+ H2O

13. LOGO
Orientation of Nucleophilic
Substitution in Pyridine:
In pyridine, nucleophilic substitution occurs mainly
C-2 position or C-4 position rather than C-3 position.

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Orientation and Reactivity of
Nucleophilic Substitution in
Pyridine:
Q.1) At what positions pyridine undergoes nucleophilic
substitution? Explain with resonating structures.
(W-12, 5 Mark)
Q.2) On the basis of resonance theory discuss the orientation of
nucleophilic substitution in pyridine. (W-12, 5 Mark)
Q.3) Discuss the orientation of nucleophilic substitution in
Pyridine. (S-13, S-14, W-16, S-17 & S-19, 4-5 Mark)
Q.4) Why pyridine is more reactive to nucleophilic substitution?
Q.5) Explain in pyridine, nucleophilic substitution take place at
2- or 4-postion rather than 3-position.
Q.6) Explain the orientation of nucleophilic substitution in
pyridine on the basis of resonating structures. (W-15, 4 Mark)

15. Resonance Structures of Pyridine:
 According to resonance theory, pyridine is the resonance
hybrid of the following resonating structure-
N N N N
Pyridine I II III
.. .. .. .. N

 
..
Resonance hybridResonating structures of Pyridine
1 1 1 1
1
2 2
3 3
4
44
3
2
5 5
6 6
6
6
5
4
4
3
2
2
.. .. ..
Pyridine is more reactive to Nucleophilic Substitution:

16. Resonance Structures of Pyridine:
 In the resonating structures,
N-atom attracts π-bond (π-electron pair) from adjacent
2-position, so nitrogen atom gets negative charge with
additional lone pair.
The 2-position gets positive charge.
N
Pyridine
.. 1
2 / 6
3 / 5
4 / 4
5 / 3
6 / 2
N
I
.. 1
2
3
4
..
Resonating structures
of Pyridine

17. Resonance Structures of Pyridine:
The positive charge delocalizes at alternate position (i.e.,
4th position of ring carbon) with shifting of double bond.
N
I
.. 1
2
3
4
..
N
II
..
Resonating structures of Pyridine
1
4
3
2
5
6..

18. Resonance Structures of Pyridine:
 The positive charge delocalizes at alternate position (i.e.,
6th position of ring carbon) with shifting of double bond.
N
II
.. 1
4
3
2
5
6..
N
III
..
Resonating structures of Pyridine
1
6
5
4
3
2 ..

19. Pyridine is more reactive
to Nucleophilic Substitution:
 According to resonance theory, pyridine is the resonance
hybrid of the following resonating structure –
 Thus, the overall pyridine ring is electron deficient and
positively charged carbons as shown in resonance hybrid.
 Since, nitrogen (more EN) accepts the electrons, so
positively charged on the ring increases and deactivates
the pyridine ring towards electrophilic substitution
reaction.
 Hence, pyridine is more reactive to
nucleophilic substitution reaction.
N N N N
Pyridine I II III
.. .. .. .. N

 
..
Resonance hybridResonating structures of Pyridine
1 1 1 1
1
2 2
3 3
4
44
3
2
5 5
6 6
6
6
5
4
4
3
2
2

20. ..
N
Pyridine
N
..
Pyridine
N
..
Pyridine
1
2 / 6
3 / 5
4 / 4
6 / 2
5 / 3

21. N
..
Pyridine
1
2 / 6
3 / 5
4 / 4
6 / 2
5 / 3
Attack of Nu- at ?

22. pramodpadole@gmail.com By Dr Pramod R Padole
Orientation of Nucleophilic Substitution in Pyridine:
Attack of Nu- at 2-position (at C-2):1
Attack of Nu- at 3-position (at C-3):2
Attack of Nu- at 4-position (at C-4):3
Unlike benzene and pyrrole, pyridine undergoes nucleophilic
substitution reactions.
In pyridine, nucleophilic substitution occurs mainly
C-2 position or C-4 position rather than C-3 position.
N
..
Pyridine
1
2 / 6
3 / 5
4 / 4
6 / 2
5 / 3

23. Orientation of Nucleophilic Substitution in Pyridine:
By Dr Pramod R Padole
Attack of Nu- at 2-position (at C-2):1
N
Nu
N N N
H H
Nu
H
NuNu
2 - Substituted PyridineA
M O R E S T A B L E
- H
H
C-2
I II III
Three resonating structures
More stable structures as N contains negative charge
Pyridine
attack
at
1
2
3
4
5
6
1 1 1
3 5
N.. Nu
2
1
Most favourable
product
It is seen from the intermediate ions that nucleophilic attack of C-2
position in pyridine; to form intermediate ion (A) in which negative
charge appeared on more electronegative nitrogen as well as on
carbons.
This (A) further increases the stability with substitution at C-2 position
predominantly.

24. www.themegallery.com
By Dr Pramod R Padole
Orientation of Nucleophilic Substitution in Pyridine:
Attack of Nu- at 4-position (at C-4):2
-H
attack
at
1
2
3
4
5
6
1
N..
4
1N
Nu
NNN
H NuH NuH Nu
B
M O R E S T A B L E
4 - Substituted Pyridine
H
C-4
I II III
Three resonating structures
More stable structures as N contain negative charge
Nu
3
4
5
1 1
2
3
6
Favourable
product
It is seen from the intermediate ions that nucleophilic attack of C-4
position in pyridine; to form intermediate ion (B) in which negative
charge appeared on more electronegative nitrogen as well as
on carbons.
This (B) further increases the stability with substitution at C-4
position predominantly.

25. www.themegallery.com
By Dr Pramod R Padole
Orientation of Nucleophilic Substitution in Pyridine:
Attack of Nu- at 3-position (at C-3):3
-H
attack
at
1
2
3
4
5
6
1 N..1
3 - Substituted Pyridine
I II
III
N
Nu
N N
N
H
Nu
H
Nu
H
Nu
L E S S S T A B L E
H
C-3
structures as N does not contain negative charge
1
1
2
6
3 3
3
Nu
3
4
6
5
4 4
5
So, nucleophilic attack at C-2 position & C-4 position are most stable
than C-3 position.

26. Orientation of Nucleophilic Substitution in Pyridine:
By Dr Pramod R Padole
N
Nu
N N N
H H
Nu
H
NuNu
2 - Substituted PyridineA
M O R E S T A B L E
- H
H
C-2
I II III
Three resonating structures
More stable structures as N contains negative charge
Pyridine
attack
at
1
2
3
4
5
6
1 1 1
3 5
N.. Nu
2
1
Most favourable
product
-H
attack
at
1
2
3
4
5
6
1
N..
4
1N
Nu
NNN
H NuH NuH Nu
B
M O R E S T A B L E
4 - Substituted Pyridine
H
C-4
I II III
Three resonating structures
More stable structures as N contain negative charge
Nu
3
4
5
1 1
2
3
6
Favourable
product
-H
attack
at
1
2
3
4
5
6
1 N..1
3 - Substituted Pyridine
I II
III
N
Nu
N N
N
H
Nu
H
Nu
H
Nu
L E S S S T A B L E
H
C-3
structures as N does not contain negative charge
1
1
2
6
3 3
3
Nu
3
4
6
5
4 4
5

27. N
Nu
N N N
H H
Nu
H
NuNu
2 - Substituted PyridineA
M O R E S T A B L E
- H
H
C-2
I II III
Three resonating structures
More stable structures as N contains negative charge
Pyridine
attack
at
1
2
3
4
5
6
1 1 1
3 5
N.. Nu
2
1
Most favourable
product
Orientation of Nucleophilic Substitution in Pyridine:
By Dr Pramod R Padole
Attack of Nu- at 2-position (at C-2):1
So, nucleophilic attack at C-2 position & C-4 position are most stable
than C-3 position.
Nucleophilic attack at C-2 position is most stable because C-2 position (or
C-6 position) is nearest to electron withdrawing N-atom (more EN).
So C-2 position is more electrons deficient. Hence in pyridine
nucleophilic substitution takes place more prefentially at C-2 position
(than C-4 position).

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29. Nucleophilic Substitution Reactions of
Pyridine at C-2 position:
Reaction
with
Sodamide (NaNH2):
Reaction
with
Phenyl lithium:
NSR of Pyridine at C-2:
Reaction with
solid
Potassium hydroxide
(KOH):

30. (i) Reaction with Sodamide (NaNH2):
or Chichibabin Reaction:
Or Preparation of 2-amino pyridine from Pyridine:

31. companyname
(i) Reaction with Sodamide (NaNH2):
or Chichibabin Reaction:
Or Preparation of 2-amino pyridine from Pyridine:
Q.1) Complete the following reaction. (W-09, 2 Mark)
Q.2) What happens when Pyridine is treated/heated with sodium amide in liquid
ammonia? (S-10, 2 Mark)
Q.3) Complete the following reaction. (W-13, S-15, W-17 & S-18, 2 Mark)
Q.4) How does pyridine reacts with sodamide in liquid ammonia (NH3)? (W-15, 2 Mark)
Q.5) How will you convert: Pyridine to 2-amino pyridine? (S-16 & W-19, 2 Mark)
Q.6) What happens when Pyridine is heated with sodium amide in liquid NH3 at 373K
followed by acidification with HCl? (W-16, 2 Mark)
Q.7) How will you prepare: 2-amino pyridine from Pyridine? (W-17, 2 Mark)
Q.8) What is Chinchibabin reaction? (S-19,1 Mark)
N
?
N NH2
?
Liquid NH3/373 K
N
NaNH2
i) Liquid NH3/373 K
ii) Acidification
with HCl
? + ?

32. companyname
(i) Reaction with Sodamide (NaNH2):
or Chichibabin Reaction:
Or Preparation of 2-amino pyridine from Pyridine:
 When pyridine is heated or treated with sodamide
(Na-NH2) in liquid ammonia at about 100oC (373K)
followed by acidification with HCl; to form 2- amino
pyridine.
 This reaction is known as Chichibabin reaction.
N
Na-NH2
N NH2
NaCl
i) Liquid NH3 at 100o
C
(373 K)
ii) Acidification
with HCl
Pyridine 2-amino pyridine
H sodamide
22
Knoevenagel Condensation

33. pramodpadole@gmail.com By Dr Pramod R Padole
(ii) Reaction with solid Potassium hydroxide
(KOH):
Or Preparation of 2-pyridone form Pyridine:
 When pyridine is heated with solid KOH or NaOH at
300oC (573K) in presence of oxygen or air; to form
2-hydroxy pyridine (Pyridol) gives less yield,
which is isomerizes into 2-pyridone.
Q.1) What happens when Pyridine reacts with solid KOH at 573K? (S-11, 2 Mark)
N N O H
K-OH
N
H
O
2-hydroxy-pyridine
or Pyridol 2- Pyridone
at 300o
C (573K)
Pyridine
solid
in presence of O2
or air
(- KH)
H
Isomerization
(Enol form)
(Keto form)
(Less yield)
(More yield)
.. ..
..

34. Last Reaction of Pyridine:

35. By Dr Pramod R. Padole
3) Reaction with Phenyl lithium:
Or Preparation of 2-phenyl pyridine
from Pyridine:
 When pyridine is reacted or heated with phenyl
lithium at 100oC (373K); to form 2-phenyl
pyridine.
Q.1) Complete the following reaction. (W-16, 2 Mark)
N
C6H5 Li LiH373K ?
N N C6H5
C6H5 Li LiH
2-Phenyl pyridine
373K
Pyridine
Phenyl lithium
or 100o
CH

38. 38
MCQ on Pyridine

39. D. Six membered heterocyclic compound
C. Five membered heterocyclic compound
B. Four membered heterocyclic compound
Pyridine is a which type of heterocyclic
compound from the following options?
A. Seven membered heterocyclic compound

40. Which element is present as
hetero atom in pyridine?
A. Sulphur
B. Nitrogen
D. Sulphur and nitrogen
C. Oxygen

41. D. sp2-orbital
C. sp –orbital
B. sp3-orbital
The electron of Nitrogen participating in the
resonance in pyridine is present in which
orbital?
A. p-orbital

42. 42
B. False
A. True
Pyridine is a not a planner
compound?

43. D. None of above
C. less
B. average
A. more
Pyrrole ____ is basic than Pyridine.

44. D. Ficus religiose
C. Azadirachta indica
B. Atropa belladonna
A. Ocimum tenuiflorum
Which of the following plant is
the natural source of pyridine?
Explanation: Pyridine is not abundant in nature,
it is present in the leaves and roots of
belladonna (Atropa belladonna).

45. 45
D. Claisen condensation
B. Aldol condensation
A. Knoevenagel Condensation
In the synthesis of pyridine by Chichibabin
synthesis, synthesis of acrolein is done which
method?
C. Dieckmann condensation
Explanation: Acrolein is formed in a Knoevenagel
condensation from the acetaldehyde and
formaldehyde. It is then condensed with acetaldehyde
and ammonia into dihydropyridine.

46. D. Hantzsch pyridine synthesis
B. Dealkylation of alkylpyridines
A. Chichibabin synthesis
What is the name reaction of the following reaction?
C. Bönnemann cyclization
Explanation: The trimerization of a part of a hydrogen
cyanide molecule and two parts of acetylene into
pyridine is called Bönnemann cyclization.
C
C
C
C
N
C
H
H
H
Red hot tube
N
H
H
Acetylene
Acetylene
(H-CN, Hydrogen cyanide)
Pyridine

47. D. sp3d
C. sp2
B. sp3
A. sp
In pyridine, nitrogen atom is in a
state of ____ hybridisation.

48. D. NaNH4
C. NaNH3
B. KNH2
A. NaNH2
Sodamide means ___

50. LOGO

51. LOGO
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Heterocyclic Compounds by Dr Pramod R. Padole
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