FIVE MEMBERED HETEROCYCLES CONTAINING ONE
HETEROATOM
Ring Synthesis
Paal-Knorr Synthesis
CH2 CH2
P2O5
CHO CHO
HC
CH
HC
CH
O
NH3
P2S5
HC
CH
HC
CH
S
HC
CH
HC
CH
N
H
Pyrrole (Azole)
4
3
1
5
Commercial preparation:
N
H
NH3 / H2O
Heat
O
2
N
H
Ring synthesis
Hantzsch pyrrole synthesis
EtOOC
EtOOC
Cl
CH2
+
C
H3 C
CH2
O
O
NH3
H3 C
C
CH3
N
CH3
H
Ethyl 2,5-dimethylpyrrole-3-carboxylate
Basic properties
Although pyrrole is an amine, it is
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).
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.
N
-
-
N
N
N
N
N
Some electrophilic substitution reactions in pyrrole.
CH3COO
+
NO2
NO2
N
5o C
H
SO3 / pyridine
SO3H
N
o
90 C
H
N
CH3COCl / 80 oC
H
(CH3CO)2O/
150-220 oC
N
N
COCH3
H
250 oC
without cat. (F.C.)
N
H
COCH3
COCH 3
Halogenation
SO2 Cl 2
N
H
0 oC
N
H
Cl
Halogenation
SO2 Cl 2
0 oC
N
N
Cl
H
H
Other reactions
DMF/ POCl3
Vilsmeier
N
CHO
H
N
H
HCHO/ Me2NH
Mannich
N
H
CH2NMe2
Reactions similar to phenol
KOH
Potassio pyrrole
N
N
H
H
N
N
K+
O=C=O
H
Kolb Schmidt
-
-
N
K+
H+
N
C
H O
COOH
Cl
H
CHCl3/ NaOH
N
H
Reimer Tiemann
N
H
CHO
+
N
O
a) Formation of pyrrole-2-carboxaldehyde
Mechanism of reaction of pyrrole with CHCl3/ NaOH
Cl
H
C
Cl
Cl
NaOH
C
Cl
-Cl+
:CCl2
Cl
Cl
H
H
N
N
-
+
:CCl2
N
CCl2
Na+
NaOH
N
H
OH
CHCl2
-H2O
CH
N
H
OH
N
H
CHO
b) Formation of 3-chloropyridine
Cl
C
cyclopropanation
+
: 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
C
CHCl3/ NaOH
H3C
N
CH3
CH3
N
Cl
Cl
Cl
CH3
H3 C
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
CH3
CH3
n-Butane
CH
S
600
CH
S
oC
CH2
CH2
1,3-Butadiene
S
Thiophene
Electrophilic substitution reactions
E
+
+
H
H
H
+
S
S
S
E
S
E
3-Canonical structures
E
+
H
H
E
S
+
E
E
S
..
+
S
+
2-Canonical structures
1.Electrophilic substitutions
cold conc. H2SO4
S
SO3H
fuming HNO3 and
(CH3CO)2O
S
(CH3COONO2)
S
NO2
SO2Cl2
S
Cl
HCHO /NH(CH3)2
Mannich
S
CH2N(CH3)2
S
HgCl
HgCl2 / NaOAc
Thiophene-2-mercuric chloride
_
Bu
Li
+
S
CO2
S
Li
S
CHO
1- D. M. F. /POCl3
2- NaOAc solu.
Vilsmeier reaction
S
COOH
2.Reactions of Thiophene-2-carboxaldehyde
Cannizzaro's reaction
conc. NaOH
2
CHO
S
solution
COOH
S
Thiophene-2-carboxylic acid
+
S
CH2OH
Thenyl alcohol
Thenoin Condensation (related to benzoin condensation)
OH O
alc. KCN
2
S
CH C
CHO
S
S
3.Reduction of thiophene
H2 / Pd
S
Tetrahydrothiophene
S
Rany Ni
CH3
CH2
n - Butane
CH2
CH3
+
NiS
Thiophene derivatives
2- Bromothiophene
CO2
S
Br
+
Mg
S
MgBr
S
COOH
Thiophene-2-carboxylic acid
Furan (oxole)
3
4
5
2
O
1
1) Feist Benary synthesis
EtOOC
O
C
CH3
Pyridine
+
C
H3C
EtOOC
CH3
CH2
O
acetoacetic ester
CH2
Cl
chloroacetone
H3C
O
3) Electrophilic substitution
+
CH3COO NO2
Nitration
H
H
CH3COO
O
SO3 / pyridine
O
O
SO3H
O
COR
RCOCl / SnCl4
Friedel Craft's
acylation
NO2
-CH3COOH
O
NO2
Thus the 2-halo furan derivatives can be obtained indirectly
from a less reactive derivative:
Using α-furoic acid
COOH
O
Br2
Cu/ quinoline/heat
HBr
+
Br
COOH
O
-CO2
Br
O
4) Reactions comparable to phenolic compounds
1) HCN/ HCl/ SnCl2
2) H2O
CHO
Gattermann aldehyde synthesis
Ph
+
N
O
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
Chemical reactions
1) Cannizzaro's reaction
CHO
2) Perkin
(CH3CO)2O/ NaOac
CHO
O
CH CHCOOH
O
Furyl acrylic acid
Benzothiophene
Benzo[b]thiophene
4
5
3
6
2
S
7
1
Thianaphthene
Ring synthesis
HO
ClCH2COOH
SH
NaOH
S
O
C
OH
P 2 O5
CH2
S
Thiophenoxyacetic acid
Zn dust
E
S
+
Benzofuran
Benzo[b]furan
4
5
3
6
2
7
O
1
Coumarone
Ring synthesis
HO
ClCH2COOH
OH
NaOH
O
O
C
CH2
OH
1) SOCl2
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
N N C
H
COOH
ZnCl2
Heat
N
H
Phenyl hydrazone
COOH
N
H
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
E
H
+
E
..
N
H
+
E
H
N
H
+
N
+
+
N
H
H
N
H
H
E
E
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
N
H
CH3
CH3
HNO3 / H2SO4
O2N
N
H
CH3
Example of some indole reactions
I
I2
N
H
Br
Br2 / H2O
N
N
H
H
Cl
SO2Cl2
N
H
NO2
Acetyl nitrate
N
H
N
H
CH2N(CH3)2
HCHO / NH(CH 3) 2
Mannich
N
H
CHO
D. M. F. / POCl3
Vilsmeier
N
H
N
H
CHO
CHCl3 / NaOH
Reimer Teimann
N
H
Cl
+
N
Indole derivatives
Isatin
O
N
O
H
Preparation of isatin
1) From aniline and oxalyl chloride
+
NH2
Cl
CO
Cl
CO
Cl
CO
CO
N
H
F. C.
AlCl3
O
N
H
O
Structure of isatin
O
N
O
O
N
H
Lactim form
Lactam form
This is an example of amide - imidol tautomeric system
O
R C NH2
OH
R C NH
OH
How to prove such tautomerism ?
a) Reactions to prove presence of N-H
O
CH3I
N
O
O
CH3
N
H
O
O
CH3COCl
N
O
COCH3
b) Reactions to prove the presence of OH
O
N
OH
O
POCl3
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
N
H
O
NaOH
C COONa
NH2
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
H
O
N
H2NOH
N
O
H
Isatin oxime
OH
FIVE MEMBERED HETEROCYCLES CONTAINING TWO
NITROGEN ATOMS (DIAZOLES)
PYRAZOLE (1,2-DIAZOLE)
Synthesis
Knorr synthesis
CH2 CHO
NH2
CHO
+
heat
H 2N
N
N
Malondialdehyde
H
CH3
CH2 C
CH
O
C
Benzoylacetone
CH3
NH2
C
HN
heat
O
C
O
CH3
N
+
-2H2O
N
OH
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
4
3
5
N1
N2
3
By such tautomerism position 3 and 5 are equivalent
CH3
CH3
4
3
5
NH 1
N
2
H
4
5
N2
5
3
N1
NH 1
N
2
H
5-methylpyrazole
3-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
3-Methyl-1-phenylpyrazole
H3C
N
N
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
H
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
N
o
100 C
N
H
H
+
N
N Cl
No Rx.
NaOH
ClH2C
CH2O / HCl
N
N
N
chloromethylation
Ph
N
Ph
ROC
RCOCl
N
N
H
N
N
CH3I
N
N
COR
H
Heat
N
N
CH3
Imidazole (1,3-Diazole)
R
1)
R
R
C
O
C
O
2NH3
+
N
+
RCHO
R
N
H
2)
Ph
C
CH2
Ph
O
N
H2N
C
+
Br
Phenacyl bromide
CH3
HN
Acetamidine
CH3
N
H
R
+
3H2O
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
N 3
5
2
N1
H3C
1
N
5
4
H
2
N
3
4(5)-Methylimidazole
H
As in case of pyrazole if the N-H is subst. there will be different 4 and 5positions
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
N
+
NH
H+
NH
+
N
N
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
H
Thus imidazole anion can be easily generated
N
CO2
COOH
N
N
H
NaNH2
RX
N
N
Na+
N
N
N
RMgX
+
N
RH
N
MgX
H
N
BuLi
N
Li+
+
BuH
R
Electrophilic substitution occurs at the 4(5)-position
O2N
N
HNO3/H2SO4
N
heat
H
HO3S
N
H2SO4/SO3
N
100 oC
N
H
CH3
N
N
H
N
CH3I
N
N
CH3
N
N
+ _
N Cl
N
N
NaOH
H
N
• Synthesis of some 5-membered
containing two different hetero atoms
heterocycles
• Synthesis of oxazole derivatives:
NH2
O
+
C
Cl
OHC
CH2
N
CH
C
NH2
+
N
-HCl
C
Thiourea
R
O
2-Alkyl-4-phenyloxazole
Acid amide
S
Chloroacetaldehyde
C
R
O
CH2Br
Phenacyl bromide
C
NH2
-H2O
S
NH2
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
CH
1 C
R
CH NH
NH2
R2COCl
+
N
R1
O
C
C
O
- +
CH3COONH4
heat
N
N
R2
R1
R2
R
R2
O
N
R
R
N
R1
heat
R1
heat
heat
R
RNH 2
O
P2S5
P2O 5
R2
S
R1
N
H
R2
Benzimidazole
Benzoxazole
Benzo[d]imidazole
Benzthiazole
Benzo[d]oxazole
N
benzo[d]thiazole
N
N
N
S
O
H
Ring synthesis
NH2
O
N
heat
CH
+
HO
-2H2O
NH2
N
H
O
NH2
N
heat
CH
+
HO
-2H2O
O
heat
O
OH
NH2
N
CH
+
SH
HO
-2H2O
S