Reactions of Pyridine

Pyridine shows the following types of reactions:

(1) Electrophilic substitution reactions
(2) Nucleophilic substitution reactions
(3) Oxidation
(4) Reduction
(1) Electrophilic substitution reactions:
Pyridine behaves as a highly deactivated aromatic nucleus towards electrophilic substitution
reactions and vigorous reaction conditions should be used for these reactions to take place. The
electrophilic substitution reaction occurs less readily in pyridine as compared to benzene. The
reactions are given below:
 Greater electronegativity of nitrogen atom decreases electron density (-I density) of the
ring thereby deactivating it.
 In acidic medium, it forms a pyridinium cation with a positive charge at the nitrogen
atom. Reacting electrophile itself (say E+) may also react with pyridine to form a
pyridinium ion and this decreases the electron density on nitrogen very much, thus,
deactivating the ring.

+ H+or E
+
+
N N
or E
H

It undergoes electrophilic substitution like halogenation, nitration and sulphonation only under
drastic conditions and does not undergo Friedel-Crafts reaction at all.
Why pyridine does not undergo Friedel-Crafts reaction?
Ans: Pyridine does not undergo Friedel-Crafts reaction. This is because lone pair present on the
nitrogen of pyridine forms salt with the alkyl group of alkylating agent or acyl group of acylating
agent in Friedel-Crafts reaction. Due to formation of salt, positive charge is present on nitrogen
and the ring is deactivated for reaction.

+
N –
I
CH3

Pyridine undergoes electrophilic substitution preferably at 3-position as it results in the

formation of a more resonance stabilized intermediate (3 resonating structures). The
intermediate formed by the attack of electrophiles at 2- and 4- positions are less stabilized,
since in the contributing structures, nitrogen carries a positive charge. The nitrogen is
electronegative in nature and a structure with +ve charge on electronegative atom is a high
energy structure and least contributing towards stabilization. Thus, the intermediate formed by
attack of electrophile at 2- and 4-positions have only two contributing structures.
Nitration:
Reactivity of pyridine is similar to nitrobenzene. Nitration of pyridine is difficult as that of
nitrobenzene because of electron withdrawing effect of nitrogen in pyridine and –NO2 group in
nitrobenzene that deactivates the ring. Pyridine is very difficult to nitrate on carbon, even
under extreme conditions only a small yield of 3-Nitropyridine is obtained.
NO2 NO2

+ NaNO 3 or KNO 3 +
+
N N N
-
SO 3
<5%

In this, salt is formed and yield of nitropyridine is very low. Salt is separated by adding base and
number of steps is increased. This is the disadvantage of the above reaction.
Why reagent (HNO3) used for the nitration of benzene is not used for the nitration of pyridine?
Reagent i.e. HNO3 used for the nitration of benzene cannot be used for the nitration of
pyridine. This is because HNO3 is acid which donates proton (H+). This proton forms salt with
pyridine acting as a base due to presence of lone pair of electrons on nitrogen of pyridine.
NO2
SO2
+ N2 O5
<50C
N N

This method is also not very good because %age yield is less. So, to increase the %age yield, a
donating group is introduced in pyridine.
NO2 O2 N
H2SO4
+ KNO 3 +
40°C
N OMe N OMe N OMe

Here, -OMe is electron donating group. But it can cause steric hindrance at ortho-position. As a
result, %age yield is low for ortho product. To avoid steric hindrance, a donating group like –OH
is introduced as it is small in size and does not cause steric hindrance. As a result, %age yield is
increased.
To get the –NO2 group at position-4 of pyridine, it is first converted into pyridine-N-oxide. This
gives 4-Nitropyridine in good yield.
NO2 NO2

CH3COOH Fuming H2SO4 PCl3

+
+ Fuming HNO3 + POCl3
H2O2 N 90°C +
N N N
-
O - 90%
O

Halogenation:
Pyridine reacts with chlorine, bromine and iodine to give the halogen substituted pyridine at
position-3 and position-5.
Chlorination:
Cl
2AlCl3
+ Cl 2
80-115°C
N N

Cl Cl Cl
HCl/ 2AlCl3
+ Cl 2 160-180°C +
+ +
N N - N -
Cl Cl
H H
Why two moles of aluminium chloride are required for chlorination of pyridine?
For the chlorination of pyridine, two moles of aluminium chloride are required. This is because
one mole is required to form a complex with the nitrogen atom of pyridine and the second
mole to activate the chlorine.
Bromination:
Br

66% Oleum
+ Br2
130°C +
N N N
-
SO 3

3-Bromopyridine is produced in good yield by the action of bromine in oleum. This substitution
is thought to proceed via pyridinium-1-sulphonate.
Br Br Br
573K
+ Br2 +
N N N

Bromination of pyridine at 573K gives 3-Bromopyridine and 3,5-Dibromopyridine.

3-Hydroxypyridine is brominated in aqueous NaOH to give 2-Bromo-3-hydroxypyridine. For
bromination, FeBr3 is not used because FeBr3 is Lewis acid and gives acid-base (pyridine)
reaction and salt is formed.
OH OH
aq. NaOH
Br2
+
N N Br

Iodination:
I I
Oleum
+ I2
+
N N N
-
SO 3

Sulphonation:
Pyridine is very resistant to sulphonation by conc.H2SO4 or oleum, only very low yields of
pyridine-3-sulphonic acid being produced after prolonged reaction periods at 320ᵒC.
SO 3 H

Conc.H2SO4

N
320°C N

Sulphonation of pyridine takes place with fuming sulphuric acid and a mercury (II) chloride
catalyst. The 3-sulphonic acid (75-80%) is obtained at 230ᵒC.
SO 3 H SO 3 H
HgCl2 neutralize
+ Fuming H2SO4
N
230°C + N
N
-
SO 3
Sulphonation may also take place in the presence of liquid SO2 at -10ᵒC
SO 3 H

Liquid SO2
+ SO3
N -10°C N
The introduction of bulky groups at position-2 and 6 avoids salt formation between –SO3 and
nitrogen of pyridine due to steric hindrance.
SO 3 H

Liquid SO2
+ SO 3
N
N -10°C

Acetoxy mercuration:
The salt formed by the interaction of pyridine and mercuric acetate at room temperature can
be rearranged to 3-Acetoxymercuric pyridine by heating to a relatively moderate temperature.
HgOAc
Hg(OAc)2 130°C
RT +
N N N
-
OAc
HgOAc

(2) Nucleophilic Substitution Reactions:

Pyridine is a highly deactivated system. Due to decrease of electron density on ring carbon
atoms, it becomes susceptible to nucleophilic attack. Since the positions-2 and 4 are very much
electron deficient than the position-3, hence nucleophilic substitution occurs readily at
position-2 and 4, the position-2 being more preferred. The pyridinium ion is still more reactive
than pyridine towards nucleophilic substitution because of the presence of full positive charge.
Chichibabin Reaction:
Direct amination of pyridine occurs on heating it with sodamide in toluene or xylene at 160ᵒC.
This is referred to as the Chichibabin reaction.

+Na NH2 + NaOH+ H2O

N N NH2

Substitution of alkyl group:

Pyridine reacts with organometallic compounds to form 2-alkyl and 2-aryl derivatives. The alkyl
group behaves as a nucleophile and attacks at2-position.

+ R Li
N R
N

C4H9Li 373K
+
N N C4 H9
 Li

+
N
N

Phenyl Lithium
2-Phenylpyridine

Formation of 2-Pyridone:
The reaction of pyridine with potassium hydroxide results in the formation of 2-
Hydroxypyridine which tautomerises to a more stable keto-form, that is 2-Pyridone.

i - KOH

N
ii - H3O+ N OH N OH
H

Pyridone can also be formed by the reaction of carboxylic acid with the halogen substituted
pyridine. Here the carboxylate ion acts as a Nu-.

RCOOH
O
..
N X
Et3N N N O
O C R
H

To increase the yield, salt of pyridine is formed. By salt formation, nitrogen becomes positively
charged and bond shifting is easy. The use of bromine instead of chlorine further increases the
yield.
Reaction with sodium bisulfite:
Pyridine reacts with sodium bisulfite by addition to give piperidine-2,4,6-trisulphonate. The first
step is very likely to be nucleophilic addition to pyridium cation.
-
SO3
H SO 3 H
H H
H H

SO 3 H
-
SO 3 SO 3 H
+ + -
N N N H N H N H
N -
O3 S H SO 3
H
H H H

What happens when Grignard reagent reacts with pyridine?

From the above reaction, it is expected that reaction of Grignard reagent with pyridine will
result in alkyl substituted pyridine. But it does not happen.
This does not happen because C-Mg bond has less electronegativity difference as compared to
C-Li bond. Magnesium has less metallic character than lithium. Even the reaction of Grignard
reagent with pyridine-N-oxide results in the formation of an open chain oxime. This can be
rationalized as the result of electrocyclic ring opening of the initial adduct.

Dry Ether N C6H5

+ C6H5MgBr HO
+ H+/H2O
N
-
O

Nucleophilic Substitution via Pyridine:

A hetaryne (e.g. Pyridine) is a reactive intermediate with a triple bond in the nucleus containing
the heteroatom. There are two hetarynes.
3,4-Pyridine:
3,4-Pyridine is obtained by the reaction of NaNH2 in Liq.NH3 with 3- or 4-Halopyridine. It takes
place in the presence of base like BuO-K+ ((CH3)3CO-K+). Here BuO-K+ acts as a base not as a
nucleophile. Because it has bulky groups which cause hindrance to the substitution reaction.
NH2
H
NH2
X
KNH2/Liq.NH3 NH2-
+
or BuO-K+ N N N
N

2,3-Pyridine:
2,3-Pyridine is not obtained from 2-Halopyridine because of amination reaction. It is obtained
from 3-Bromo-2-chloropyridine.
Br
BuLi
Et2O
N N
Cl -75°C

Diels-Alder Reaction:

O
O
+
N
3,4-Pyridine Diene N
(Dienophile)

+ O

N N
2,3-Pyridine Diene
(Dienophile)
(3) Oxidation Reaction:
Pyridine is easily oxidized with H2O2 or peracid to give Pyridine-N-oxide.

CH3COOH + H2O2
or +
N N
CH3COOOH -
O

(4) Reduction of pyridine:

Pyridine is reduced to different products by using different types of reducing agents. The
reactions are summarized as follows:
H2/Ni
Piperidine
N
H
HI/ 300°C
H3C CH3 + NH3
pentane
Na/NH3
1,4-Dihydropyridine
N N
H
LiAlH4

N
Li(Et)3BH H 1,2-Dihydropyridine

N Piperidine
H

Prepared By: Muhammad Umair Akram

Roll No: 03
Submitted To: Ma’am Sidra Ijaz