Synthesis of pyridine
1 – By heating the hydrochloride of pentamethylene diamine and
oxidizing the product piperidine with concentrated sulphuric acid at 300 cº.
CH2 - CH2 - NH2 .HCl
CH2
CH2 - CH2 - NH2 .HCl
CH2 - CH2
-NH4Cl
-HCl
H2SO4
NH
CH2
300 co
CH2 - CH2
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N
1
2 – from 1,5 – dicarbonyl compounds and ammonia : Ammonia react with 1,5 – dicarbonyl compounds to give 1,4
dihydropyridine which are easily dehydrogenated to pyridines .The
reaction proceed via loss of two molecules of water .
H
H
H
H
H
+
O
O
N-H
H
-2H2O
Oxidation
N
H
1,4 - dihydropyridine
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N
Pyridine
2
3- From ethyl acetoacetate two mole with dichloromethane in presences
of ammonia .
EtOOC
CH2
|
C=O
CH3
EtOOC
CH2
|
O=C
CH3
NaOEt
CH2Cl2
EtOOC H
- EtOOC
||
C
CH3
OH
CH2
EtOOC - C
HC-COOEt
||
C
CH3
OH
CH3
EtOOC - C
C-COOEt
-H2O
CH3
Oxide
NH2 HO
CH3
HO
CH3
NH3
-H2O
H
EtOOC - C
CH3
EtOOC - C
CH3
HO
H
CH2
C-COOEt
C-COOEt
N
H
CH3
C-COOEt
N
CH3
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3
4 – From 1,3 – dicarbonyl compound and cyanoacetamide
CH3
C=O
|
CH2
O=C
|
CH3
CH3
CN
+
H
H
C
CH2
C
H
C=O
CH3
CN
C=O
C =O
H2N
H2N
acetylacetone
OH
C
cyanoacetamide
H
CH
CH
H
C - CN
CH3 -C
OH
C
C
CN
-2H2O
C=O
CH3
N
H
H
C
C
C =O
OH H2N
CH
CH
C - CN
CH3 -C
C - OH
N
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4
Chemical reactions
Basicity of pyridine
Pyridine behaves as abase , It react with acids to from fairly stable salt . The
reason for the basic character of pyridine is that the nitrogen lone pair being in
sp2 hybrid orbital is not involve in the delocalized π molecular orbital .It is readily
available for the formation of a new p N – H bond with proton .
Pyridine is a stronger base than pyrrole in which the basicity is reduced by
delocalization of the nitrogen lone pair
Pyrrole < Pyridine < aliphatic amine
N
H
RNH2
N
Basicity increase
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5
Addition and ring – opening reaction
The acid derivatives combine with the pyridine to give a quaternary salt (e.g 2)
.Which have been isolated as acidchlorides .This salt react with hydroxyl group
yielding the Acyl derivative ; the liberated acid is taken up as the pyridine salt (3)
.Quaternary salts as (2) are immediately decomposed by water to pyridine
hydrochloride and the organic acid but with etheylcyanoacetate the ring open
yielding (4)
PhCoCl
+
N
CoPh
(2)
N
EtCOOCH2CN
+
Cl- R /OH
PhCOOR +
+
N
H
(3)
Cl-
H2O
+
C(CN)CO2Et
N
NH
|
Ph - C = C(CN)CO2Et
(4)
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Cl-
PhCOOH
6
The ring is comparatively easily opened by nucleophilic reagent 2,4 –
Dinitrophenylpyridinum chloride (5) is a colourless crystalline solid which is
formed from pyridine and 2,4 – dinitrochlorobenzene at 100 cº this reaction is
reversed at 200 cº with water at 150 cº yield pyridine hydrochloride and 2,4 –
dinitrophenol , but with cold aqueous alkali a deep red compound (6) is formed
which on successive treatment with dilute aniline and acid yields 2,4 –
dinitroaniline and glutaconic aldehyde dianil (7) .
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7
NO2
100 c0
+
N
Cl
200 c0
NO2
Cl-
N
NO2
2.4 - dinitrophenylpyridinum
chlorid
cold aquKOH
NO2
H
C
(5)
CH
CH
HO - CH
CH
PhNH2
N
PhNH2
NO2
+
N
H
+ KCl
NO2
(6)
150 c0
H 2O
+
OH
H
C
OH
NO2
CH
+
Ph - NH - CH
Pridinium
Chloride
NO2
aniline Acid
CH
Cl-
NO2
2.4 - dinitrophenol
CH = NPh
(7)
glutaconic aldehydedianil
NO2
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8
Reduction
Pyridine is easily reduce to hexahydropyridin or piperidine by a variety
of method including hydrogen over Raney nickel , rubidium at 60 ºc
palladium charcoal with acetic acid .1,4 – dihydropyridine has however
been obtained by the reduction of pyridine with trimethylsilane .
N
+ Me3Si H
Pd catalyst
N
SiMe3
0.1% KOH
MeOH
N
H
The pyridine is cleaved by ultrasonic waves giving acetylene and hydrogen
cyanide .
N
ultra
sound
2 CH
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CH + HCN
9
Electrophilic subistitution reactions .
Toward electrophilic subistitution pyridine resembles a deactivated
benzene derivative it is often compared to nitrobenzene in reactivity
(+)
N
(+)
N
(+)
N
N
(+)
N = O
O
(+) (+)
N
N
O
O
O
O
(-)
(-)
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N
O
O
(-)
10
when the reaction take place the attack at β position can be understood in term of
the resonance forms shown above in which ( α ) and ( γ ) position have a positive
charge , this orientation can be understood also by comparison of the
intermediate resulting from attack at various position
H
H
H
E
N
..
H
..N
E
H
..N
E
H
Attack at β position
H
E
N
..
H
H
H
E
H
..N
E
N
..
Attack at γ position
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11
three resonance can be written for each intermediate but one of these
in the case of attack at the γ ( or α ) leaves positive charge on
nitrogen this must be regarded as an unfavorable structure as
compared to one in which carbon has a positive charge for nitrogen
more electronegative than carbon .
NO2
KNO3
H2SO4
N
3 - nitropyridine
370 c0
N
SO3H
HgSO4
H2SO4
N
Br2
300 c0
3 - pyridinesulphonicacid
Br
N
Rx or RCox
AlCl3
3 - bromo pyridine
No reaction
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12
Nucleophilic subistitution in pyridine
The reactivity of pyridine toward nucleophilic subistitution is so great even the
powerfully basic hydride ion , H- , can be displaced .Two important example of this
reaction are amination by sodium amide and Alkylation by organolithium
compounds .
+
-
+ NaNH2
heat
N
H
N
+
NH3
NH2
N
Na
-
+ NaNH2
NH2
+ NH3
NHNa
Sod salt of 2 - amino pyriine
N
+
-
+ C6H5Li
heat
N
H
N
Ph
+ LiH
N
Li
Ph
2 - phenylpyridine
KOH
N
320
N
OH
N
H
O
The attack take place at α – position because the positive charge arises in α – position
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13
Pyrylium salt and pyrans
Very few simple derivatives of the aromatic pyrylium cation (1) are known ,
although benzopyrylium are widely distributed as flower petal colouring matters
.The potentially very reactive 4-pyran (3) has been obtained recently and the
pyranes ( 4 and 5 ) are well known .2,3 – Dihydro – 4 – pyran (6) has received
some attention now it is easily available , and tetrahydropyran ( 7 ) is used as a
synthetic intermediate .The sulphur analogues of these compounds have
received little attention until very recently
O
4
5
6
4
3
+
O
3
2
O
1
O
O
2
O
O
1
1
2
Pyriliumcation
5
O
5
6
3
4
5
6
O
7
2pyrone 4 pyrone
4
3
6
+
7
8
O
2
1
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14
Pyrylium salts
The sodium salt of glutaconic aldehyde with perchloric acid at – 20 cº
gives ared oxonium salt , which on standing at o cº cyclizes to the
colourless pyrylium perchlorate (8) .This perchlorate has received little
attention ,but with ammonia it yields 2,4,6 – triphenylpyrylium
ferrichloride ( 9 ) can be prepared easily . It is stable in acid solution and
nitrates . with ammonia it yields 2,4,6 – triphenylpyridine while with alkali
the ring is opened , yielding (II) through the intermediate (10 )
- +
CH
CH
CH
CH = O
Na O CH
CH
H ClO 4
O2-
HO
6
4
O
CH
+
CH = OH
CH
c0 0
-H2O
-
ClO4
sod . salt of glutaconic aldehyde
Oxonium salt
5
CH
3
2
-
ClO4
1
)8(
Pyrylium perchlorate
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15
+
CH
Ph
CH
H
CH2
CH2
FeCl3
O = C-Ph
Ph -C = O
Ph
CH
CH2
C= O
Ph
C=O
Ph
phenyl 1 - phenyl 2 - benzoyl ethylene methyl ketone
Ph
Ph
-
FeCl4
+
Ph
O
Ph
NH3
(A)
Ph
N
Ph
2,4,6 - triphenyl
Pyrylium ferricchloride
NaHCO3
aq
NaOAC orr
(B)
Ph
CH
Ph
CH
Ph
O
Ph
OH
CH2
C = O OC
Ph
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Ph
16
Mechanism
Ph
CH
Ph
CH
H
+
- CH +
- CH2
Ph -C = O
O = C-Ph
CH2
FeCl 3
Ph
C=O
CH2
C= O
Ph
keto form
Ph
H
C
HC
CH
Ph
C
-H2O
Ph
enol form
Ph
CH
Ph
CH
HC
Ph
CH
+
CH
C - OH
Ph
HO -C
Ph
C
O
C
CH
Ph
CH
C - Ph
FeCl4-
)A (
HC
NH 3
C
O
Ph
H
NH
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CH
+
C - Ph
O
2
-
17
Ph
CH
HC
Ph
CH
CH
HC
Ph
CH
+
Ph
C
C - Ph
HO
N:
H2
C
Ph
H
+
N
-H2O
C - Ph
OH
Ph
H
+
N
H
Ph
Ph
Ph
Ph
N
Ph
Ph
Ph
B
NaOaC
Ph NaHCO3
aq
+
O
Ph
H+/ OH -
+
Ph
O
Ph
Ph
FeCl4-
Ph
O
Ph
OH
Ph
Ph
Ph
Ph
O
- +
Ph
OH
Ph
O
Ph
OH
enol form
OO
Ph
keto form
1,3,5 - triphenyl
glutaconicdialdehyde
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18
Reaction of pyrylium cation
A–Reaction with electrophilic reagent 2,4,6 –Triphenylpyrylium undergoes exchange at 3 – and 5 – position in hot deuteroacetic acid
Ph
Ph
Ph
ACDO
+
Ph
O
Ph
-)
( + ACO
OAC
Ph
O
Ph
D +
Ph
5
+
O
D
H
OAC
Ph
B – No nitration of pyrylium are known
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19
Synthesis of α – pyrones
6 – hydroxyl – α – pyron can be prepared by heating a glutaconic acid with
acetic anhydride .
CH
H2C
O=C
CH
C=O
OH OH
- H 2O
( CH3CO) 2O
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HO
O
O
20
Synthesis of γ – Pyrones
1- γ – pyrone may be prepared by heating chelidonic acid just above
its melting point .chelidonic acid may be prepared from acetone and
ethyl oxalate
CH3
+ 2 (COOEt )2
O=C
CH3
C2H5ONa
CH2CO . COOEt
O=C
-2(EtOH)
CH2CO . COOEt
OH
CH = C- COOEt
CH = C- COOEt
heat
O=C
O=C
CH = C - OH
COOEt
O
CH = C
COOEt
chelidonic acid
O
heat
O
γ - Pyrone
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21
2 – The dimethyl γ – pyrone may be prepared from the copper salt of
ethylacetoacetate as follows
CH3 -CO - CH - COOEt
Cu
CH3 -CO - CH - COOEt
CoCl2
C=O
CH3 -CO - CH - COOEt
CH3 -CO - CH - COOEt
CH3 -CO - CH2
hyd
heat
CH3 -C = CH
OH
C=O
OH
CH3 -C = CH
CH3 -CO - CH2
CH3
heat
-H2 O
C
C=O
CH
O
C=O
C
CH
CH3
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22
Reaction of α and γ – Pyrone .
1-
NaOH
O
HCl
COONa
ONa
O
COOH
OH
α - pyrone
O
2-
3-
O
O
NaOH
H+
O
O
O
+ NH2NH2
OH
OH
O
O
-H2O
O
OH O
OH NH
NH
|
|
NH2
NH
2
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N O
|
NH2
1 - amino pyridone
23
O
O
O
NH3
5-
O
CH3
CH3
-H2O
CH3 OH
CH3
CH3
NH2
R
N
H
CH3
2,6 - di methyl - 4 - pyrone
R
R
6-
CH3
+ CH3MgBr
O
O
R
O
OH
O
HO
7CH3
O
+ CH3MgBr
CH3
CH3
..
O
CH3
CH3
CH3
HClO4
-H2O
+
O
CH3
CH3
ClO4-
pyrylium salt
O
OCH3
CH3I
8CH3
O
..
CH3
+
CH3
O
OCH3
I-
HClO4
+
CH3
-H I
CH3
O
CH3
ClO4lec8
24
R
R
P2S5
9R
O
O
R
O
O
S
S
P2S5
10 O
R
R
R
O
R
R
R
Br
Br2 / ACOH
11 R
O
O
R
O
O
3 -bromo - 2 - pyrone
O
O
Br
12 CH3
Br 2 / ACOH
O
CH3
CH3
O
CH3
3 -bromo - 4 - pyrone
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25
R
R
NO2
HNO3 / ACOH
13 R
O
O
R
O
O
O
NO2
14 CH3
O
HNO3 / ACOH
O
CH3
CH3
O
CH3
3 -bromo - 4 - pyrone
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26
Sulphur – containing analogues
4 H – Thiopyran ( 1 ) has been obtained in asimilar way to its oxygen
analogue and has b.p 30 cº at 12 mm it is readily oxidized by chlorine to
thiapyrylium (2) chloride , and an alternative way of making this class of
compound is outlined 2,4,6 triphenylthia pyrylium perchlorate (3) with
phenyllithum gives the deep purple 1,2,4,6 – tetraphenylthia (IV) benzene
(4) . On standing it isomerizes to colurless 4H - thiapyran (5)
PhNMe2
Cl
S
Cl
Cl2
40
S
+
S
(1)
(2)
Ph
Ph
+
S
(3)
Ph
ClO4- PhLi
Ph
Ph
isomerize
Ph
S Ph
Ph
(4)
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Ph
S
Ph
(5)
27
1- methyl – 3,5 – diphenylthia(IV)benzene 1- oxide (6) has been obtained
as indicated below .It has m.p 148º and can be sublimed at near this
temperature at 0 – 0.5 mm pressure .The compound is therefore very
much more stable than (IV) benzene such as (4)
Ph
-
Ph
O
+
S
Me
(6)
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28