1

Pyrroles, thiophenes and furans

Introduction :

Pyrrole 3.1, thiophene 3.2, and furan 3.3 are five-membered

ring heteroaromatic compounds containing one heteroatom, they are
derived from 1,3-cyclopentadienide anion 3.4 by replacing the CH of
3.4 by hetroatom, NH for pyrrole, S for thiophene, and O furan. Since
the lone pair of electrons of the heteroatom is busy with,

N S O
H
3.1 3.2 3.3 3.4

conjugation, so it is not available for production and alkylation, and

these heterocycles are not truly lewis bases.

These heterocycles are 6 aromatic compounds, obeying

Hckel rule, where n=1. The resonance energy is dependent on the
heteroatom electronegativity, as electronegativity decreases, O>N>S,
the resonance energy increases, furan (16.2 Kcal/mole) < pyrrole (21.6
Kcal/mole) < thiophene (29.1 Kcal/mole), furan is the least aromatic
of the trio, because oxygen have the highest electronegativity. They
are called electron-rich or -excessive heteromatics, since 6 electrons
are distributed over five atoms, unlike benzene 6 electrons are
distributed over six carbon atoms. The lone pair of electrons of the
heteroatom is extensively delocalized over the 4 carbon atoms, as
shown below,
 2

X X X X X
+

This variation in aromaticity affects the reactivities of these

heterocycles towards electrophiles, so while pyrrole resembles aniline
and phenol, where it undergoes electrophilic aromatic substitution
easily. On the other hand, furan has very low resonance energy, so its
chemistry is much closer to nucleophilic dienes rather than benzene.
Thiophene is aromatic compound, and undergoes electrophilic
aromatic substitution, but at slower rate than pyrrole.
The following facts have to be considered in the discussion of
pyrrole chemistry :-

1. Pyrrole as secondary amine fails to form adduct with methyl

iodide.
2. Reaction of pyrrole with Ac2O fails to give the corresponding
amide 1-acylpyrrole.

These facts can be explained in terms of corresponding

intermediates products, electrophilic attack of X+ on nitrogen

produces intermediate A with localized positive charge on nitrogen

and it is antiaromatic, while elecrophilic attack of X + on carbon

produces intermediate , in which positive charge is delocalized over
three atoms,
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+
X A
N+
R X
N
+ H H
R X H
on C N+ X N X N X
R B R R

as consequence of this instability of intermediate A, the transition state

leading to it have high activation energy in comparision with
intermediate B.

Relative reactivities of - and - position :

Electrophilic attack occurs more readily at -position than that

at the -positions, this can be understood in terms of resonance
stabilization of positively charged intermediates.
+
Y H H H
+ - attack
X X Y X Y X Y

H H
Y Y
+
Y - attack
X X X

as shown above, note that cation produces from -attack is

delocalized over three atoms, where cation produced from -attack is
delocalized over two atoms only, also note that C4-C5 double bond do
not contribute is resonance stabilization. This defference between -
 4

and - positions reactivities is least observed for pyrrole, while this

difference is obvious in thiophene.
A comparative study of some electrophilic substitution reactions
on pyrrole, furan, tellurophene, selenophene, and thiophene has
established that these ring systems are decreasingly reactive in the
order shown

N
H
> O
> Te
> Se
> S
>
The following table shows the relative rate constants for
trifluoroacetylation of different five-membered heteroaromatics.

N O Te Se S
H

3.8x1015 1 3.3x10-1 5.2x10-3 7.1x10-3

This greater reactivity of pyrrole can be demonstrated by the

rapid reaction of pyrrole with weak elecrophilic like phenyldiazonium

cation Ph2+ , while furan and thiophene do not react with Ph2+.

+ N2 N N
N N
H H

The relative rates of these reactions reflect more than

 5

aromaticity, the ground-state electronic distribution for C and C, the

electronegativity of heteroatom is important, the electronegative
heteroatoms faciliate these reactions more than those heteroatoms for
which d-orbital participation is possible (S, Se, Te).
The rate differences between heterocycles vary with reagent, for
example
+ +3
D2O / H
relative rate = 1x10
S S D

+
D2O / H
D relative rate = 1

While

Br2 / HOAC relative rate = 1x10+9

S S Br

Br2 / HOAC
Br relative rate = 1

Like, the rate differences between heterocycles vary with reagent, also
the rate differences between reaction at an - or - position vary with
reagent, for example nitration of thiophene gives 6:1 mixture of 2-
nitrothiophene and 3-nitrothiophene, respectively, whereas
chloronation gives 2-chlorothiophene only.
NO2
H2SO4
NO2 +
S HNO3 S S
6 1

Cl2
S AlCl3 S Cl

Pyrroles : Synthesis and reactions

 6

Pyrrole in Greek means red. Pyrrole is colorless liquid, b.p

1290C and darken upon exposure to air and oxygen. It is a polar
molecule with dipole moment directed from nitrogen to carbon. It is
manufactured commerically by alumina-catalyzed gas-phase
interaction of furan and ammonia.

Al2O3 + H2O
+ NH3
O N
H

Simple pyrroles occur naturally, like 3.5 and 3.6

Cl

O
NO2 O
Cl HO ON O
N
N
H
3.5 3.6
Pyrrole unit is very important in the structure of haemin, the blood
respiratory pigment, and chlorophylla

N
N
N Fe N CH3
C20H34O N Mg N
N
CO2H N
O
Me C
MeO
CO 2H
O
Haem Chlorophyll -a

which crucial for all form of life on earth, in which CO 2 is converted

to carbohydrate, known as photosynthesis.
 7

These pigments are synthesized in the living cell from

porphobilinogen, which is also fundemental for metabolism.
CO2H
HO2C

N
H2N H

Synthesis of pyrroles:
a. Paal-knorr synthesis :
Reaction of 1,4-dicarbonyl compounds with ammonia or primary
amine.
example :

NH3
90% yield
PhH / N
OO -2 H2O
H

2,5-alkyl-bridged pyrroles and fused pyrrole can be prepared using

this synthesis.

O O
CH3
-2 H2O
+ CH3NH2
O N
O
CH3

OO N
+ NH3
H

Dry distillation of alkyl ammonium salt of mucic acid affords alkyl

pyrrole in 25%.
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OH OH
_H O
OH OH _ 2
+ CO2
HO2C CO2NH3R N
But
b. Knorr synthesis :
Reaction of -aminoketones with activated -methylene
compounds.
example:
O H
H CO2Et CO2Et
_
+ H2O
H NH2
O N
H

Since free -aminocarbonyl compounds dimerize easily, they are

NH2
O CH2Ph CH2Ph
- H2O
+
PhCH2 O H2N PhCH2 N

-2H

N CH2Ph

PhCH2 N

stored as hydrochloride salt and liberated for reaction in situ.

CO2Et
O CO2Et
aq. KOH
+
R.T CO2H
NH3 CO2Me N
- O
Cl H

/ 1day KOH

Me CO2H
CH3

N
N
H
H
 9

The yield for Knorr synthesis is good if active methylene group

compounds were used, otherwise self condensation of -
aminocarbonyl competes.
Alternative way to avoid this problem of -aminocarbonyl
dimerization is the preparation of -aminocarbonyl compound in
situ by reducing the oxime moitey in the presence of acetoacetic
ester.

CO2Et
CH3 O CO2Et
+ Sodium
dithionite
H NOH N
O
H

CO2Et O CO2Et
1 mole of
HNO2 +
EtO2C NOH O
O

Zn / HOAc

CO2Et CO2Et
O

+
EtO2C N EtO2C NH2 O
H

C. Hantzch Synthesis :
Reaction of a-halocarbonyl compound with keto-ester compound
in the presence of ammonia.
 10

Cl CO2Et Cl CO2Et
+ NH3
+
O O Me O H2N

CO2Et

N
H

Synthesis of Prophobilinogen :

O CH3 O O O CO2Et
EtO C C OEt
N EtOK N O
NO2 NO2

H2 / Pd
N
O
O CH2
Me2NH + CH2O
N
N HCl N CO2Et
N CO2Et
H
H
O

OMe / CH3OH
+
Na OMe

O
O OCH3 O CO2Et
CH3
OCH3 HCl
N N
N CO2Et O N CO2Et
H H
0
HBr / 150C

HO2C CO2Et O CO2Et

1) H2 / Pd - C
2) H2O /
3) aq.KOH / R.T N
N H N CO2Et
H2N H H
 11

Chemical reactions of pyrroles

1) Protonation
Pyrrole is a weak acid with Pka value of 17.5

+
+ H PKa = 17.5
N N
H

Pyrrole itself is an extermly weak base with Pka vlaue of -3.8 for
proton exchange at C2 and C3. While proton exchange on nitrogen
is the fastest.
H
H
H - H+
+H+ PKa = -3.8
N H - H+ N +H+ N
H H H

This basicity increses with increasing alkyl substitution for

example, 2, 3, 4, 5-tetramethylpyrrole has a Pka value of +3.7.

H+ H PKa = 3.7
N N
H H

The 2H- and 3H- pyrrolium above are essentially immonium ions
and are truly electrophilic, so the reaction of pyrrole with
hydroxylamine. HCl gives succindialdehyde dioxime.
H H

NH2OH / HCl NH2OH H

/ C2H5OH + HON NOH
N N N NHOH HH
H H H

2) Nitration :
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H2SO4 + HNO3 mixture causes complete polymerization of

pyrrole, while fuming HNO3 and acetic anhydride affords 2-nitro
pyrrole and 3-nitro pyrrole is 4:1 ratio respectively.

NO2
HNO 3
AC 2O +
N o
N NO2 N
- 10 C
H H H

3) Sulphonation :
_
N SO3
HCl
N 100o C N SO3H
H H

Pyridine-SO3 complex converts pyrrole into pyrrole-3-sulfonic

acid after work-up in good yield.

4) Halogenation :

SO2Cl2
o
N Et 2O / 0 C
N CL
H H

NBS
N N Br
H H
I I
KI / AcOH
EtOH/H2O2 I I
N N
H H

5) Acylation and formylation :

 13

AC2O
N 150o C - 200
o C
N COCH3
H H

_ O
CH3CN / HCl (gas) OH
Et2O / 0oC C CH3
N N
H H

POCl3 Na2CO3
DMF / RT aq
N N CHO
H H
83%

Condensation with aldehydes and Ketones :-

CH3
Me2CO - H 2O
HCl OH +
N N N
CH3
H H H

pyrrole

N
H
N H H N
H N
N HH N
2 Me2CO
HCl

88%

EtO2C
EtO2C CO2Et
CH3CHO
N EtOH / HCl
N N
H H H
dipyrromethane

Aromatic aldehydes with electron-releasing substituent the

cationic intermediate can be isolated.