Pyridines

Pyridine is the simplest heterocycle of the

azine type. It is derived from benzene by
replacement of a CH group by a N-atom.

88
The structure of pyridine is completely analogous to that of
benzene, being related by replacement of CH by N.
The key differences are:

I. The departure from perfectly regular hexagonal

geometry caused by the presence of the hetero atom, in
particular the shorter carbon-nitrogen bonds,

II. The replacement of a hydrogen in the plane of the ring

with an unshaired electron pair, likewise in the plane of
the ring, located in an sp2 hybrid orbital, and not at all
involved in the aromatic p-electron sextet; it is this
nitrogen lone pair which is responsible for the basic
properties of pyridines, and
89
III.A strong permanent dipole, traceable to the
greater electronegativity of the nitrogen
compared with carbon.

90
The following reactions can be predicted for
pyridines on the basis of their electronic structure:
I. The heteroatom make pyridines very unreactive
to normal electrophilic aromatic substitution
reactions. Conversely pyridines are susceptible to
nucleophilic attack. Pyridines undergo
electrophilic substitution reactions (SEAr) more
reluctantly but nucleophilic substitution (SNAr)
more readily than benzene.
II. Electrophilic reagents attack preferably at the N-
atom and at the b-C-atoms, while nucleophilic
reagents prefer the a- and c-C-atoms.
91
Reactions of Pyridine
Electrophilic Addition at Nitrogen
In reactions which involve bond formation using the
lone pair of electrons on the ring nitrogen, such as
protonation and quaternisation, pyridines behave just
like tertiary aliphatic or aromatic amines.
When a pyridine reacts as a
base or a nucleophile it
forms a pyridinium cation in
which the aromatic sextet is
retained and the nitrogen
acquires a formal positive
charge.
92
Protonation at Nitrogen
Pyridines form crystalline,
frequently hygroscopic,
salts with most protic acids.

Nitration at Nitrogen
This occurs readily by
reaction of pyridines
with nitronium salts,
such as nitronium
tetrafluoroborate.
Protic nitrating agents such as nitric acid of course
lead exclusively to N-protonation.
93
Acylation at nitrogen
Acid chlorides and arylsulfonic acids react rapidly
with pyridines generating 1-acyl- and 1-
arylsulfonylpyridinium salts in solution.

94
Alkylation at nitrogen
Alkyl halides and sulfates react readily with pyridines
giving quaternary pyridinium salts.

95
Electrophilic substitution at Carbon
atoms of the pyridine ring
Electrophilic substitution of pyridines at a carbon is
very difficult. Two factors seem to be responsible for
this unreactivity:
I. Pyridine ring is less nucleophilic than the benzene
ring; nitrogen ring atom is more electronegative
than carbon atoms and therefore it pulls electrons
away from the carbon atoms inductively leaving a
partial plus on the carbon atoms.

96
II. 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.

Less reactive than pyridine

97
When an electrophile attacks the pyridine ring, only
position 3 is attacked.

Why?

Hint: draw resonance structures that result from

electrophilic attack at various positions. The positive
charge residing on an electronegative element with
sextet configuration is unfavoured.

98
For example, 3-bromopyridine is formed when
pyridine is reacted with bromine in the presence of
oleum (sulfur trioxide in conc. sulfuric acid) at 130C.

99
 Br

Br

N H

SO3

Mechanism
of bromination of pyridine

100
Pyridine can be activated to electrophilic
substitution by conversion to pyridine-N-oxides.

A series of preparatively interesting reactions on

pyridine can be carried out by means of pyridine N-
oxides such as the introduction of certain functions
into the ring and side-chain which cannot be
achieved in the parent system by direct methods.
101
The activating oxygen atom can be removed by
reacting the pyridine N-oxide with
phosphorous trichloride.

102
In such reactions there is a balance between electron
withdrawal, caused by the inductive effect of the oxygen
atom, and electron release through resonance from the
same atom in the opposite direction. Here, the resonance
effect is more important, and electrophiles react at C-2(6)
and C-4.

4
3

2
N

103
Thionyl chloride, for example, gives a mixture of 2-
and 4-chloropyridine N-oxides in which the 4-isomer
is predominant.

PCl3
Cl

+
N Cl N
104
However, pyridine N-oxide reacts with acetic
anhydride first to give 1-acetoxypyridinium acetate
and then, on heating, to yield 2-acetoxypyridine
through an addition-elimination process.
4
3

2
N
O O

O O

N O

105
When a similar reaction is carried out upon the 2,3-
dimethyl analogue, the acetoxy group rearranges
from N-1 to the C-2 methyl group, at 1800C, to form
2-acetoxymethyl-3-methylpyridine.

N
O O

O O

106
H2 Pd/EtOH

NH2

107
Anion Chemistry of Pyridine

H
N

H The negative charge

generated on the
carbon goes to the
electronegative
H
N nitrogen, which can
H better accommodate
Resonance stabilized it.

Works for 2(6)- and 4-alkylpyridines not for 3(5)-alkyl

pyridines, why?
108
109
 R Br

R
N

110
Another approach to electrophilic substitution
involves the chemistry of 2-pyridone and 4-
Pyridones which are obtained from the diazotization
of the corresponding 2-aminopyridine and 4-
aminopyridines, respectively.

111
Both pyridones can react with electrophiles at positions
ortho and para to the activating oxygen atom. Reaction with
phosphorous oxychloride gives chloropyridines.

112
Nucleophilic substituition of pyridine

a) X=H
b) X=Good leaving group
X=H, Substitution with hydride transfer
Nu: NaNH2 - amination
Nu: BuLi, PhLi etc - alkylation / arylation
Nu: NaOH - hydroxylation

113
At high temperature the intermediate anion can
aromatize by loss of a hydride ion, eventhough, it is a
poor leaving group.
114
b) X=LG, The nucleophilic substitution is much more
facile when good leaving group such as X:
Halogen (F>>Cl,>Br,>I), -OSO2R, -NO2, -OR, are
employed.

115
116
 Cl

SLOW

Nu N

-H: is a bad leaving group

117
N OMe N SPh

N X

Ph
N N
N NH2
Me
118
Halogenopyridines can undergo metal-halogen
exchange when treated with butyllithium. The
lithium derivatives then behave in a similar manner
to arylithiums and Grignard reagents and react with
electrophiles such as aldehydes, ketones and nitriles.

119
 O
O
N OMe

NaOMe
MeOH N

- NO2

OMe

120
121
 SCH 402

Synthesis of Heterocycles Compounds

:Nu

(CH2)n
(CH2)n

Nu
Nu 122
Dr. Solomon Derese
 SCH 402

Synthesis of Furan,
Pyrrole
and
Thiophene

Dr. Solomon Derese 123

 SCH 402

Furans, pyrroles and thiophenes from 1,4-dicarbonyl

compounds: Paal Knorr synthesis

:Nu
R1 R2
d+ d+
O O
(CH2)2
:Nu = RNH2, H2S

Dr. Solomon Derese Nu 124

 SCH 402

RNH2 H

Dr. Solomon Derese 125

 SCH 402

Dr. Solomon Derese 126

 SCH 402
Furans, pyrroles and thiophenes from
1,3-dicarbonyl (b-ketocarbonyl) compounds
O O
Base
R1 R2

acidic hydrogens enolate React

with
electrophiles

Dr. Solomon Derese 127

 SCH 402
FeistBenary synthesis of furans
The Feist-Benary synthesis is an organic
reaction between a-haloketones and b-
dicarbonyl compounds to give substituted furans in
the presence of base.
O
O
R1 O R1
OEt Na2CO3 OEt
+
X O R2
R2
O
a-haloketones
X = Cl, Br, I
Dr. Solomon Derese 128
 SCH 402

O
HO
R1 OEt

O R2

Dr. Solomon Derese 129

130
 SCH 402
Knorr-pyrrole synthesis
This involves the condensation of a-amino ketones
with a b-diketone or a b-ketoester to give a
substituted pyrrole in the presence of a base like
pyridine.

a-amino ketones

Dr. Solomon Derese 131

 SCH 402

O
HO
R1 OEt

H
N R3
R2 H

Dr. Solomon Derese 132

 SCH 402
Fiesselmann synthesis
1,3-Dicarbonyl compounds or b-chlorovinyl
aldehydes react with thioglycolates or other thiols
possessing a reactive methylene group to give
thiophenes in the presence of pyridine.

Dr. Solomon Derese 133

 SCH 402

Dr. Solomon Derese 134

 SCH 402

Synthesis of Pyridine

O R1 R2 O

1,5-Dicarbonyl compound

:Nu = RNH2

Dr. Solomon Derese 135

I. Reaction between a 1,5-diketone and ammonia
Ammonia reacts with 1,5-diketones to give unstable
1,4-dihydropyridine, which can be easily
dehydrogenated (using nitrobenzene or nitric acid)
to give pyridine.

1,4-dihydropyridine
136
II. The Guareschi synthesis
Unsymmetrical pyridines can be synthesised from a
reaction between a b-dicarbonyl compound and a b-
enaminocarbonyl compound or nitrile.

137
 O O

OH N

138
139
III. The Hantzsch synthesis
Symmetrical 1,4-dihydropyridines, which can be
easily dehydrogenated (to form pyridines), are
produced from the condensation of an aldehyde,
ammonia, and two equivalents of a 1,3-dicarbonyl
compounds (commonly a -ketoester) which must
have a central methylene.
The product from the classical Hantzsch synthesis is
necessarily a symmetrically substituted 1,4-
dihydropyridine. Subsequent oxidation (or
dehydrogenation) gives a symmetrical pyridine
compound.
140
STEP I
The reaction is believed to proceed via Knoevenagel
Condensation.

STEP II
A second key intermediate is an ester enamine,
which is produced by condensation of the second
equivalent of the -ketoester with ammonia:

141
STEP III
Further condensation between these two fragments
gives the dihydropyridine derivative:

142
143
 MECHANISM
Ph
O O Ph O
H
O NH3 O O OH
H H O H H
O O O

- H2O

Ph
O

O O O O
I
H - H2O
O O O

NH3 O H NH2 OH NH2

II

144
145
Nifedipine
is in a group of drugs
called calcium channel
blockers. It works by NO2
relaxing the muscles of MeO2C CO2Me
your heart and blood
vessels. Nifedipine is used
to treat hypertension (high Me N Me
H
blood pressure) and
Nifedipine
angina (chest pain).

146
 CO2Me

NH3
O Me

NO2

MeO2C CO2Me

Me Me
O O 147
OXAZOLE

148
IMIDAZOLES

THIAZOLES

149
Diazepam (Valium)
O
used for the treatment of N
anxiety disorders. Diazepam
also is used for the
treatment of Cl N
agitation, tremors, delirium,
seizures, and hallucinations
resulting from alcohol
withdrawal. It is used for the
treatment of seizures and
relief of muscle spasms in Diazepam
some neurological diseases
150
 NaOH (Aq)

O
N NH

NH3 O
Cl N Cl

Diazepam
151
Antifungal drug

152
 N

NaNO2, HCl

0oC N

153
 F

H
N
HN

154
Clopirac
Nonsteroidal Antiinflammatory Drug)
O

HO

H3C CH3
N

Cl 155
 H3C I

N
HO

H3C CH3
KOH H3C CH3
N N

C C

Cl Cl 156