Synthesis, reactivity, aromatic character and importance of 6-membered heterocycle containing one heteroatom - Pyridine

1. Synthesis, reactivity, aromatic
character and importance of Pyridine
N



1
2
3
4
5
6'
'
Prepared by
Dr. Krishna swamy
Faculty
DOS & R in Organic Chemistry
Tumkur University

2. Pyridine is the simplest heterocycle of the azine type.
It is derived from benzene by replacement of a CH group by a N-atom.
From heat of combustion measurements, the aromatic stabilization energy of pyridine
is 21 kcal/mole.
N



1
2
3
4
5
6'
'

3. Nomenclature of heterocyclic rings will be done by three ways
(1) Common names
Pyridine
(2) Replacemnet nomenclature
N
Benzene Azabenzene
Replace CH by N
N

4. (3) Hantzsch-Wideman nomenclature
Prefix + Ring + Suffix
Type of heteroatom
Size of the ring
Degree of unsaturation of ring
Nitrogen 6-membered Aromatic
Aza in e Azine
N

5. Electron donating substituents will increase the basicity of a pyridine, and that
substituents on the 2 and 4-positions will influence this basicity more than an
equivalent 3-substituent.
N
2
4
6
EDG
EDGEDG N
35 EDG EDG
N
Pyridine and its derivatives are weak bases (pKa=5.2), reflecting the
sp2 hybridization of the nitrogen. Pyridine is aromatic with unshared electron pair is
not part of the aromatic sextet.

6. Synthesis
Hantzsch pyridine synthesis
Condensation approaches
From other heterocyclic ring systems

7. Hantzsch pyridine synthesis
It is a four component reaction between 2 equivalents of keto esters, 1 equivalent of
aldehyde and ammonia results in reduced pyridines which upon oxidation (or)
dehydrogenation gives the corresponding pyridines.
R H
O
O
EtO2C
O
CO2Et
NH3
pH - 8.5 N
H
R
EtO2C CO2Et
Oxidation
(or)
dehydrogenation
N
R
EtO2C CO2Et
Dihydropyridine
(Reduced pyridine) Pyridine

8. Hantzsch pyridine synthesis involves the following mechanisms
Aldol condensation of aldehyde with β-keto ester
R
O
H
O
CO2Et CO2Et
O
R
O
H
CO2Et
O
R
OH
H
CO2Et
OR
H

9. Michael addition of β-keto ester with enone
O
CO2Et
EtO2C
R
H
O
EtO2C
R
CO2Et
O O
EtO2C
R
CO2Et
O O
Addition of ammonia to form imine or enamine followed by cyclization
EtO2C
R
CO2Et
O O
NH3
EtO2C
R
CO2Et
O HN
EtO2C
R
CO2E
t
O H2N
EtO2C
R
CO2Et
H
N
-H2O
-H2O

10. EtO2C
R
CO2Et
H
N
H
O
O
CN
CN
Cl
Cl
EtO2C
R
CO2Et
H
N
EtO2C
R
CO2Et
N
-H
DDQ
Dehydrogenation of dihydropyridine gives the corresponding pyridines

11. Dihydropyridine intermediates prepared from aromatic aldehydes are calcium blocking
agents and therefore valuables drugs for heart disease.
H
O
O
EtO2C
O
CO2Et
NH3
pH - 8.5 N
H
EtO2C CO2Et
Dihydropyridine
(Reduced pyridine)
R
R

12. Condensation approaches to prepare pyridines
O O
NH3
N
H
air / HNO3 /
CAN / MnO2
N
Condensation of 1,5 diones followed by oxidation
Condensation of 1,5 diones with hydroxylamine instead ammonia avoids oxidation step
O O
NH2OH
N N
-H2O
OH
H H
HCl

13. Synthesis from 1,3 dicarbonyls and 3-aminoenones
N
O
O
O
H2N
O
From other heterocyclic ring systems
Ciamician-Dennstedt Rearrangement
N
X
N
H
CHX3
Strong base

14. Reactions of pyridines
Pyridine undergoes reaction at Nitrogen as well as at Carbon
Reaction at C is usually difficult and slow than at N
N
Reaction at Nitrogen
N
Reaction at Carbon

15. Reactions at Nitrogen
Electrophilic addition at Nitrogen
Lone pair of electrons on the ring nitrogen undergoes electrophilic addition reaction
with electrophiles such as protonation, nitration, alkylation and acylation.
N NE
E
Pyridine reacts as a base or a nucleophile and forms a pyridinium cation in which the
aromatic sextet is retained and the nitrogen acquires a formal positive charge.
BOTH ARE AROMATIC

16. Protonation at Nitrogen
Pyridine nitrogen form salt with most protic acids.
N N
H
H
Acid chlorides react rapidly with pyridines generating 1-acyl-pyridinium salts in
solution.
Acylation at Nitrogen
N N
PhCOCl
Ph O
Cl

17. Alkyl halides react readily with pyridines giving quaternary pyridinium salts.
Alkylation at Nitrogen
N N
R
RX
X
Reaction of pyridines with nitronium salts such as nitronium tetrafluoroborate leads
to nitration at nitrogen. Protic nitrating agents such as HNO3 leads to N-protonation.
Nitration at Nitrogen
N N
NO2
NO2BF4
BF4

18. Electrophilic substitution of pyridines at a carbon is very difficult. Two factors seem
to be responsible for this unreactivity:
Pyridine ring is less nucleophilic than the benzene ring because nitrogen atom is
more electronegative than carbon atoms and therefore it pulls electrons away from
the carbon atoms inductively leaving a partial positive charge on the carbon atoms.
When pyridine compound is exposed to an acidic medium, it forms pyridinium salt.
This increases resistance to electrophilic attack since the reaction will lead to doubly
positive charged species.
Hence pyridine is bad at electrophilic aromatic substitution but under drastic
condition pyridine ring reacts with electrophile only at 3rd position.
Reactions at Carbon

19. The positive charge residing
on an electronegative
element with sextet
configuration is unfavoured.
The positive charge residing
on an electronegative
element with sextet
configuration is unfavoured.
In pyridine, β
substitution is favoured
but the reaction is
slower than that of
benzene
Electrophilic aromatic substitution at carbon

20. Nitration of Pyridine
Sulfonation of Pyridine
Electrophilic aromatic substitution at carbon

21. Nucleophilic substitution is easy with pyridines
Nitrogen atom makes pyridines more reactive towards nucleophilic substitution,
particularly at the 2- and 4-positions.
Nitrogen acts as electron sink hence favoured
Nitrogen acts as electron sink hence favoured

22. Nucleophilic substituents favoured by electron-withdrawing substituents that are
also good leaving groups.
The position of the leaving group influences reaction rate i.e.
 >  >> 
Nucleophilic aromatic substitution

23. Nucleophilic substitution also occurs through Pyridyne intermediate similar to
benzyne and are very reactive not isolable.
Pyridyne
Pyridyne formation

24. Halogenopyridines can undergo metal-halogen exchange when treated with
butyllithium.
Metal-halogen exchange
The lithium derivatives then behave in a similar manner to arylithiums and Grignard
reagents and react with electrophiles such as aldehydes, ketones and nitriles.
Lithium derivative of pyridine reaction with ketones

25. Lithium derivative of pyridine reaction with nitriles

26. Deprotonation of alkyl pyridines
Deprotonation of alkyl pyridines occurs in presence of strong base and
deprotonation occurs only with alkyl groups at α and γ position not with β
position.
N
H
H
H
Acidic hydrogen
PhLi
N
H
H
N
H
H
Resonance stabilization
N
HH
H
N
HH
N
HH
PhLi

27. N
H
H
H
Acidic hydrogen
PhLi
N
H
H
N
H
H
R
O
H
OCO R Br
N
OH
R N
O
OH N
R
H3O+
H3O+
Resonance stabilization

28. If the pyridine ring attached to alkene then conjugate addition occurs.

29. Pyridine undergoes nucleophilic reaction with hydrides and the reaction with
Li/NaNH2 is referred to as the Chichibabin reaction.
N
LiNH2
N H
NH2
Li
N NH2
NH3
NH2H
-H2
Chichibabin reaction

30. Nicotine is pharmacologically
active constituent of tobacco –
toxic and addictive
Isoniazide has been an important
agent to treat tuberculosis
Bioactive Pyridines