FIVE MEMBERED HETEROCYCLES CONTAINING ONE

HETEROATOM
 Resonance contributing forms of pyrrole:

+ - +
N N N

H - H H
-
+ +
N N
 
H H
 
N
H
 Resonance contributing forms of furan:

+ - +
O O O
-
-
+ +
O O
 

 
O
 Ring Synthesis
Paal-Knorr Synthesis

CH2 CH2 P2O5 HC CH

CHO CHO HC CH
O
NH3
P2S5
HC CH

HC CH
HC CH N
H
HC CH
S
Pyrrole (Azole)
4 3

5 1 2
N
H
 Commercial preparation:

Pyrrole is prepared commercially by

NH3 / H2O
Heat
O N

H
 Ring synthesis
Hantzsch pyrrole synthesis

EtOOC
EtOOC Cl
CH2 CH2
+
C C H3C N CH3
H3C O CH3
O H
NH3
Ethyl 2,5-dimethylpyrrole-3-carboxylate
 Basic properties
Although pyrrole is an amine, it is an extremely non
basic one because the nitrogen lone pair is involved in
the aromatic sextet and is therefore less available for
bonding to a proton. For pyrrole to accept a proton, a
highly endothermic reaction must occur because the
resonance energy of pyrrole is lost (aromaticity is lost).
H
H+
.. H + ..
N N N
H H H

H H
+ ..
H N
N H N
H H H

H H
H
+
H N N
N H H H H
H
Acidity of pyrrole
Pyrrole carries an acidic hydrogen.

+H
N N
-
H OH

The resulting pyrrole anion (after the loss of proton) exhibits

aromatic resonance stability resembling that of
cyclopentadienyl anion.
-

N -
- N N
-
-
N N

N
Some electrophilic substitution reactions in pyrrole.

- +
CH3COO NO2

N NO2
5 oC
H

SO3 / pyridine
N SO3H
90 oC
H

N
CH3COCl / 80 oC 150-220 oC
H
N N COCH3

COCH3 H

(CH3CO)2O/ 250 oC

N COCH3
without cat. (F.C.)
H
Halogenation

SO2Cl2

0 oC N Cl
N
H
H
 Other reactions

DMF/ POCl3

N CHO
Vilsmeier
H
N
HCHO/ Me2NH
H
Mannich N CH2NMe2

H
Reactions similar to phenol
KOH
Potassio pyrrole
N N

H K+
O=C=O
H
H
Kolb Schmidt
- -
N N N
C O
+
K H+
H O

COOH
N
Cl
H
CHCl3/ NaOH
CHO +
N N
Reimer Tiemann N
H H
a) Formation of pyrrole-2-carboxaldehyde

Mechanism of reaction of pyrrole with CHCl3/ NaOH

Cl Cl
NaOH -Cl-
H C Cl C Cl + :CCl2

Cl Cl

H H
:CCl2
+ -
- N CCl2
N N
Na+

NaOH OH -H2O
CHCl 2 CH
N
N N CHO
OH
H
H H
 b) Formation of 3-chloropyridine
Cl

cyclopropanation C
: CCl2 Cl
+
N N
-
H -
Cl - Cl

N
3-Chloropyridine

If the Riemeir Tiemann reaction is applied on 2,5-dimethylpyrrole

only the ring expansion reaction occurs as follows:

Cl
- Cl
C Cl
CHCl3/ NaOH
- Cl
H3C N CH3
CH3 N CH3 H3C N CH3
H
3-Chloro-2,6-dimethylpyridine
 Thiophene

Thiophene is prepared industrially by passing a mixture of

butane, butene or butadiene and sulfur through a reactor to
600oC.

CH2 CH2 S CH CH
S
CH3 CH3 CH2 CH2
o S
600 C
n-Butane 1,3-Butadiene Thiophene
 Electrophilic substitution reactions

+ +
E H H H 3-Canonical structures
+
S S S E S
E E
+
H H
+
E E E 2-Canonical structures

S S
+ S
..
+
1.Electrophilic substitutions
cold conc. H2SO4

S SO3H

fuming HNO3 and

(CH3CO)2O
S S NO2
(CH3COONO2)

SO2Cl2

S Cl
 HCHO /NH(CH3)2

Mannich S CH2N(CH3)2

HgCl2 / NaOAc

S HgCl
Thiophene-2-mercuric chloride

_
+
Bu Li CO2

S S Li S COOH

1- D. M. F. /POCl3

2- NaOAc solu. S CHO

Vilsmeier reaction
 2.Reactions of Thiophene-2-carboxaldehyde

Cannizzaro's reaction

conc. NaOH
2 +
CHO solution S COOH S CH2OH
S
Thiophene-2-carboxylic acid Thenyl alcohol

Thenoin Condensation (related to benzoin condensation)

alc. KCN OH O
2
S CHO CH C
S S
 3.Reduction of thiophene

H2 / Pd

Tetrahydrothiophene

Rany Ni
CH3 CH2 CH2 CH3 NiS
+

n - Butane
 Thiophene derivatives

2- Bromothiophene

CO2
Mg
+
S Br S MgBr S COOH

Thiophene-2-carboxylic acid
Furan (oxole)
4 3

5 2
O
1
 1) Feist Benary synthesis

EtOOC CH3 EtOOC CH3

CH2 O C Pyridine
+
C CH2 H 3C O
O Cl
H 3C
acetoacetic ester chloroacetone
3) Electrophilic substitution

- + H -CH3COOH
CH3COO NO2 H

CH3COO O NO2 O NO2

Nitration

SO3 / pyridine

O SO3H
O

RCOCl / SnCl4

Friedel Craft's O COR

acylation
 Thus the 2-halo furan derivatives can be obtained
indirectly from a less reactive derivative:

Using α-furoic acid

Cu/ quinoline/heat
Br2
COOH HBr + Br COOH Br
O O -CO2 O
4) Reactions comparable to phenolic compounds

1) HCN/ HCl/ SnCl2

2) H2O
CHO
Gattermann aldehyde synthesis O
+
Ph N N Cl
N N
O

+
O Ph N N Cl / NaOH

Gomberg Bachmann arylation O

2-Phenylfuran
5) Reduction

H2 / Raney Ni

O O
Tetrahydrofuran
 Reaction of certain Furan derivatives

Furfural

O CHO

Chemical reactions
1) Cannizzaro's reaction
2) Perkin

(CH3CO)2O/ NaOac
CHO CH CHCOOH
O O
Furyl acrylic acid
 Benzothiophene
Benzo[b]thiophene
4

5 3

6 2
S
7 1
Thianaphthene

Ring synthesis

HO O
C OH
ClCH2COOH P2O5
CH2
SH NaOH S S
Thiophenoxyacetic acid
Zn dust
+
E

S
 Benzofuran
Benzo[b]furan
4

5 3

6 2
O
7 1
Coumarone

Ring synthesis

HO O
C OH
ClCH2COOH 1) SOCl2
CH2
OH NaOH O 2) AlCl3 O
Phenoxyacetic acid
Zn dust

O +
E
 Indole

1H-Benzo[b]azole
1H-Benzo[b]pyrrole

4
5 3

6 2
7
N1
H
 Ring synthesis (Fischer indole synthesis)

+
CH3 H
N N C
H CH3
N CH3
H
CH3
N N C +
H H

N
H

CH3 ZnCl2 Heat

N N C
H COOH N COOH N
H H
Phenyl hydrazone
 Chemical properties

From the resonance hydrids it is noticed that there is a - ve charge

at position 3, so electrophilic substitution occur at the 3- position

H
+ H
E
.. E E
N N + +
N
H H
H

+ +
E
H
N
N E
H
H
If the 3-position is occupied then electrophylic substitution occurs at the 2-position.

If both 2, 3-positions are occupied then substitution occurs at the 6-position.

CH3 CH3
HNO3 / H2SO4

N CH3 O2N N CH3

H H
 Example of some indole reactions
I
I2

N
H

Br2 / H2O Br
N
H N
H

SO2Cl2 Cl

N
H
 NO2
Acetyl nitrate

N
H

N
H

CH2N(CH3)2
HCHO / NH(CH3)2

Mannich N
H
 D. M. F. / POCl3 CHO

Vilsmeier N
H

N
H
CHO Cl
CHCl3 / NaOH
+
Reimer Teimann N N
H
 Indole derivatives
Isatin
O

N O
H
Preparation of isatin
1) From aniline and oxalyl chloride

Cl CO Cl
+ Cl CO
CO
NH2 CO
N
H
F. C.
AlCl3
O

N O
H
 Structure of isatin

O O

N O N OH
H
Lactim form
Lactam form

This is an example of amide - imidol tautomeric system

O OH
R C NH2 R C NH
How to prove such tautomerism ?

a) Reactions to prove presence of N-H

O
CH3I

O N O
CH3

N O O
CH3COCl
H
N O
COCH3
b) Reactions to prove the presence of OH

O O
POCl3

N OH N Cl
Reactions to prove the 2 different carbonyl groups

There are 2 carbonyl groups

a) Carbonyl group at the 2-position, similar to an acid amide, and this can be proved
by the action of NaOH on isatin

O
O C COONa
NaOH

N O NH2
H Sod. isatinate
b) The C=O group at the 3-position is a proper ketonic carbonyl group
and this can be proved by oxime formation

O N OH
H2NOH

N O N O
H H
Isatin oxime
 FIVE MEMBERED HETEROCYCLES CONTAINING TWO
NITROGEN ATOMS (DIAZOLES)
PYRAZOLE (1,2-DIAZOLE)

Synthesis
Knorr synthesis

CH2 CHO
NH2 heat
CHO H2N N
+
N
Malondialdehyde
CH3 H CH3
NH2 CH3
CH2 C CH C HN heat
O O N
C C + N
-2H2O
O OH
Benzoylacetone enol

3-Methyl-1,5-diphenyl pyrazole
1) Pyrazole is a solid of m.p. 70oC, due to intermolecular hydrogen bonding that forms dimers.

H
N
N
N
N
H
2) Pyrazole occurs in tautomeric forms

4 3 4 5

5 N 3
2 NH 1
N1 N
2
H

By such tautomerism position 3 and 5 are equivalent

CH3 CH3
4 4
3 5
5 N 2 3 NH 1
N1 N
H 2

3-methylpyrazole 5-methylpyrazole

3(5)-methylpyrazole
If N-H is subst. eg. N-phenyl then no tautomerism occurs

So position 3 and 5 will be different

CH3

N
N H3C
N
N

3-Methyl-1-phenylpyrazole 5-Methyl-1-phenylpyrazole
Pyrazole has =N and NH i.e. it shows both the properties of
pyridine and pyrrole i.e. pyrazole has basic and acidic properties

N
N

The acidity is due to N-H group and it is more acidic than pyrrole
The basicity of pyrazole is due to the lone pair of electrons of =N
and it is less basic than pyridine
Examples of electrophilic substitution reactions

O2N
HNO3 / H2SO4
N
o
100 C N

H
HO3S
Oleum
N N
o
N 100 C N
H H

+
N N Cl

No Rx.
NaOH
 ClH 2C
CH2O / HCl
N N
N chloromethylation N
Ph Ph

ROC
RCOCl Heat
N
N
N
N
COR
H
N
N

H CH3I
N
N

CH3
 Imidazole (1,3-Diazole)

1) R
N
R C O
+ 2NH3 + RCHO + 3H2O
R C O R N R

Ph
2) Ph C O N
H2N
CH2 + C CH3 CH3
Br HN N

H
Phenacyl bromide Acetamidine
Properties
1) Imidazole is a solid m.p. 90 oC, this is due to the
intermolecular hydrogen bonding that results in polymeric
compound.

2) Imidazole occurs in two tautomeric forms

H3C
4 H3C 5 1
N 3 N H
5 2 4 2
N1 N
4(5)-Methylimidazole 3
H
As in case of pyrazole if the N-H is subst. there will be different 4 and 5-
positions
Imidazole has both acidic and basic properties due to NH and =N i.e.
similar to pyrrole and pyridine. Imidazole is more basic than pyridine
than pyrazole
This is because of the stability of the cation produced by protonation .

+
N NH NH
+
H
+
N N N

H H H
Imidazole is more acidic than pyrrole and pyrazole due to
a) -I and -R of =N
b) Stability of the anion , the -ve charge is distributed on 2N atoms.
N N

N N
 Thus imidazole anion can be easily generated
N
CO2
COOH
N
N
NaNH2 H
RX N
N
Na+
N
N
N R
RMgX RH
+
N
N
MgX
H
N
BuLi BuH
+
N
Li+
Electrophilic substitution occurs at the 4(5)-position
O2N
N
HNO3/H2SO4

heat N

H
HO3S
N
H2SO4/SO3
N
100 oC
N H
CH3
N N N
CH3I
H
N N

CH3

N
+ _
N N Cl
N N
N

NaOH H
• Synthesis of some 5-membered
heterocycles containing two different
hetero atoms
• Synthesis of oxazole derivatives:

O NH 2

C + C C N
O R
CH2Br CH C R
O
Phenacyl bromide Acid amide 2-Alkyl-4-phenyloxazole

OHC Cl NH2 N
-HCl
CH2 +
C
NH2
S NH2 -H2O S
Chloroacetaldehyde
Thiourea
2-aminothiazole
General method for the synthesis of imidazole, oxazole or thiazole
 From α-aminoketone and acid chloride followed by cyclization
Similar to Paal Knorr reaction.

R
R N
CH NH2 CH NH
RNH 2
R2COCl R 1
C C R 2
R1 N R2
1 C +
heat
R O
O O R
- +
P2O5 P 2S 5 CH3COONH4
heat heat heat

R
R R
N N N

R2 R2 R1 R2
1 N
R O R1 S
H
 Benzimidazole Benzoxazole Benzthiazole
Benzo[d]imidazole Benzo[d]oxazole benzo[d]thiazole

N N N

N O S
H

Ring synthesis

NH2 O N
heat
+ CH
-2H2O N
HO
NH2
H

NH2 O
heat N
CH
+
HO -2H2O O
OH

NH2 O heat N
CH
+ -2H2O S
HO
SH