Six membered aromatic heterocyclic pyridine

Heterocyclic Chemistry
N
O
S
Six-Membered
Aromatic Heterocyls:
Pyridine (Azine)
1

PYRIDINE- Structure and Aromaticity
 Pyridine is a six membered heterocyclic compound with
molecular formula of C6H5N and it is obtained from coal tar.
 It may be formally derived from the structure of benzene
through the exchange of one ring carbon for a sp2 hybridized
nitrogen.
 Pyridine is an aromatic compound, however, the nitrogen’s
lone pair of electrons is in an sp2 orbital orthogonal to the p
orbitals of the ring, therefore it is not involved in maintaining
aromaticity but it is available to react with protons thus
pyridine is basic
2

 Pyridine can be represented as a resonance hybrid
of the following structures.
PYRIDINE- Structure and Aromaticity
Due to the greater electronegativity of nitrogen (relative to
carbons) it tends to withdraw the electron density from
carbon atoms at positions 2, 4 and 6 which therefore
acquire partial positive charges while the N atom acquires
partial negative charge while the carbons at positions 3
and 5 remain neutral.
3

1- Common Strategy ‘’5 + 1’’
Synthesis of Pyridine
From 1,5-dicarbonyl compounds:
O O
N
H H
NH4OAc
4

2- Bönnemann cyclization:
3- Hantzsch Synthesis:
O
OEt
O O
H H
OEt
O
O
+
+
N
H
EtO
O
OEt
O
HNO3
[O]
NH3
Ethylacetoacetate
-dicarbonyl cpd
dihydropyridine drivative 1) KOH
2) CaO, 
N
O O
N
EtO
O
OEt
O

N
CH
CH
+ N
HC +
CH
CH
red hot tube
5

N
H
+ CHCl3
KOH
N
Cl
Pyrrole
C
N
+
N
CN CN - H2
N
CN
300 C
°
1,3-butadiene
4- From pyrrole:
5- By Diels Alder reaction
6

Basicity of pyridine
 Pyridine is a weak base; since lone pair is in an
sp2 hybrid orbital. Is the conjugate acid
aromatic?
 It undergoes many reactions typical of amines such as
reaction with Bronsted acids such as chromic acid and
hydrobromic acid.
N N
H
Br
Br2
N
H
Br3
+ HBr
Pyridinium salt
7

Compared to pyrrole, pyridine is much stronger base this is
due to the nitrogen lone pair is not involved in maintaining the
aromaticity thus it free for protonation, however, in pyrrole the
lone pair on the N atom is already involved in the aromatic
array of p electrons. Protonation of pyrrole on N atom results
in loss of aromaticity and is therefore unfavorable.
Compared to imidazole, pyridine is less basic this is due to the
on protonation the + ve charge can be delocalized over two
nitrogen atoms while in case of pyridine it is delocalized over
the ring which interrupt aromatcity.
8

Compared to analogous aliphatic amines, pyridine is less basic
this is due to the nitrogen atom in pyridine is sp2 hybridized
(more electronegative) and the lone pair of electrons occupies
an sp2 orbital thus it is held more tightly by the nucleus than
the lone pair of electron in aliphatic amines with sp3 hybrdized
N atom and the lone pair of electrons occupies an sp3 orbital
(less electronegative).
N
N
H
N
H
N
H
N
> > >
Decreasing order of basicity
9

Chemical properties:
1-Electrophilic substitution
 the negative pole in pyridine ring is at N while the positive
pole is at carbon skeleton which is opposite to what
happens in pyrrole.
 This is due to the greater electronegativity of nitrogen
(relative to carbons) it tends to withdraw the electron
density from carbon atoms at positions 2, 4 and 6 which
therefore acquire partial positive charges while the N atom
acquires partial negative charge and the carbons at
positions 3 and 5 (β-position) remain neutral therefore
these positions are the most preferred for elctrophilic
attack.
N


10

Chemical properties:
1-Electrophilic substitution
 Also as a consequence of electron deficiency on pyridine ring ,
pyridine is less reactive towards electrophiles than pyrrole and
benzene (it resembles highly deactivated benzene derivatives),
where it does not undergo Friedel-Craft’s alkylation or acylation or
coupling with diazonium salts.
 Moreover, electrophilic substitution reactions of pyridine require
very harsh conditions (e.g. v. high temp.) to take place and are
low yielding .
11

2-Pyridine as a nucleophile (reactions on N
atom)
 As a tertiary amine pyridine has nucleophilic properties thus it reacts
with electrophiles:
N
HCl N
H Cl
+
-
Pyridinium chloride
CH3I
N
CH3 I
+
-
N-methyl pyridinium iodide
CH3COOOH
r.t.
N
O
Pyridine-N-oxide
12

3-Nucleophilic substitution on carbon
Pyridine is very reactive towards nucleophiles than benzene it
resembles benzene having strong E.W.G due to the withdrawing
effect of the electronegative N atom .
 AS appeared from the canonical structures of pyridine
positions 2, 4 and 6 carry partial positive charges thus ncleophilic
substitution proceeds readily at the 2-position followed by 4-
position but not at the 3-position.
 Additionally, attack at positions 2, 4 or 6 results in resonance
structure in which the negative charge is delocalized at N thus it
is more preferred while attack at position 3 or 5 results in
resonance structures in which the negative charge is delocalized
over carbons only.
13

Orientation of nucleophilic
substitution in pyridine
N
+ Nu
N Nu
H
N Nu
H
N Nu
H
attack at C-2
more preferred
-ve charge on N
N
N
Nu
H
N
Nu
H
N
Nu
H
attack at C-4
more preferred
+ Nu
-ve charge on N
N N
attack at C-3
+ Nu
Nu
H
N
Nu
H
N
Nu
H
-ve charge on C only
14

3- Nucleophilic Substitution reactions
i) The Chichibabin reaction
R can be o-, m-, or p- substituent
ii) Reaction with organometallic compounds lithium
reagents
N
C4H9Li
N C4H9
+
Butyllithium
2-Butylpyridine 15

3-Nucleophilic substitution Reactions
iii) Reaction with potassium hydroxide
N
KOH / 320 C
N O N
H
O
H
2-Pyridone
2-Hydroxy pyridine
° keto-enol
tautomerism
16

4-Reduction Reactions
CH3CH2CH2CH2CH3 NH3
N
H
N
N
H
N
H
1) LiAlH 4
2) H
+ , H 2
O
Na/NH
3
Birch reduction
H
2 /Ni
H
I
,
3
0
0
o
C
+
1,4-Dihydropyridine
1,2-Dihydropyridine
piperidine
17

Derivative of pyridine:
N-oxide pyridine
 Pyridine can be oxidized easily to N-oxide pyridine by
peracids.
 On the basis of dipole moment studies, N-oxide pyridine is
considered as a resonance hybrid of the following structures
N N
O
AcOOH
r.t. N-oxide pyridine
N
O
N
O
N
O
N
O
N
O
N
O
The -ve. charges appear at positions 2, 4 thus active towards
E+
s.
The +ve. charges appear at positions 2, 4 thus active
towards nucleophiles
N
O
18

N-oxide pyridine
 As appears from the previous canonical forms , there are
positive and negative charges at positions 2 and 4 thus N-
oxide pyridine is more activated for electrophilic and
nucleophilic attack at these positions than pyridine itself.
 N-oxide pyridines are very important intermediates for
preparing pyridine derivatives that are difficult to prepare due
to the easiness of removal of oxygen atom by reduction.
 For instance, nitration of pyridine is very difficult and low
yielding reaction and it occurs at position 3, however using N-
oxide pyridine will direct the nitration to position 4 and then
the oxygen can be easily removed by reduction as shown in the
following scheme.
19

Reactions of N-oxide pyridine
N N
O
CH3CO OOH, r.t.
HNO3 / H2SO4
N
NO2
6 %
N
O
NO2
PCl3
N
NO2
H2 / Pd / H+
N
NH2
300 C°
HNO3
SOCl2
N
O
Cl
+
N
O
Cl
or H2O2
20

Six membered aromatic heterocyclic pyridine

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