Heterocycles

Heterocyclic Compounds Heterocycles

• Definition: Heterocyclic compounds are organic • Cyclic organic compounds are carbocycles or
compounds that contain a ring structure containing heterocycles
– Carbocycle rings contain only carbon atoms
atoms in addition to carbon, such as sulfur, oxygen or – Heterocycle rings atoms in addition to carbon (N,S,O are
nitrogen, as the heteroatom. The ring may be aromatic common)
or non-aromatic • Heterocycles include many important natural materials as
well as pharmaceuticals

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Five-Membered Heterocycles Five-Membered Heterocycles

• Pyrrole, furan, and thiophene are common five- • The main reason for the study of pyrrole came from the work
on the structure of haem; the blood respiratory pigment, and
membered unsaturated heterocycles the chlorophyll; the green photosynthetic pigment of plants.
• Thiophene does occur in plants in association with
• Each has two double bonds and N, O, or S polyacetylenes with which they are biogenetically closely
linked.
• Furan occurs widely in secondary plant metabolites,
especially in terpenoids.
• Unsubstituted pyrrole, furan, and thiophene are usually
obtained from petroleum

N S O
H Thiophene Furan
Pyrrole

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Aromatic Heterocycles Aromatic Heterocycles

• Aromatic heteroyclic compounds are • Erich Hückel, a German physical chemist

those have a hetroatom in a ring and recognized in the early 1930s through MO
calculations that cyclic planar molecules
behave in a manner similar to benzene with a closed loop of 2,6,10,14,18,22…… π
in some of their properties (i.e. react -electrons in a fully conjugated system
by electrophilic aromatic substitution) . should be aromatic.
• This finding is called the (4n+2) π -electron
• Further more, these compounds rule. Conversely, monocyclic planar
comply with the general rule proposed molecules with 4n π-electrons are said to be
by Huckel. antiaromatic.

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Heterocycles

Structures of Pyrrole, Furan, and

Aromaticity
Thiophene
• For a molecule to be aromatic it must: • Pyrrole, furan, and thiophene are aromatic
• Be cyclic
(Six π electrons in a cyclic conjugated
• Have a p-orbital on every atom in ring
• Be planar system of overlapping p orbitals)
• Posses 4n+2 p electrons (n = any integer)
Erich Hückel
• In pyrrole π electrons come from C atoms
and lone pair on sp2-N
benzene naphthalene

[14]-Annulene
cyclopropenyl cation

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Structure and Aromaticity Structure and Aromaticity

• Pyrrole furan and thiophene are aromatic 2) They tend to react by electrophilic substitution due
appearance of –ve charge on carbon atoms due to
because: delocalization as shown in the following resonance
• 1) they fulfill the criteria for aromaticity, the extent of delocalization of
the nonbonding electron pair is decisive for the aromaticity,
structures
– thus the grading of aromaticity is in the order of: furan< pyrrole <
thiophene< benzene O O O O O
• this order is consistent with the order of electronegativity values
for oxygen (3.44), nitrogen (3.04) and thiophene (2.56).

S S S S S

N N N N N
H H H H H

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Structures of Pyrrole, Furan, Structures of Pyrrole, Furan,

and Thiophene and Thiophene
• However, the extent of aromaticity (as determined by • As O is more electronegative than N and S , it provides
resonance energies, see below) for these compounds is the two electron necessary for the aromatic sextet less
different from that of benzene (which undergoes easly, and in consequence furan is less aromatic than
electrophilic substitution reactions) . pyrrole and thiophene
– Resonance Energies (experimental and theoretical values):
• Furan 88 KJmol-1 • Element O N S
• Pyrrole 100 KJmol-1 • Electron negativity 3.44 3.04 2.58
• Thiophene 130 KJmol-1
• Benzene 151 KJmol-1 • For the same reason pyrrole is less aromatic than
• Thus the order of aromatic character of these three thiophene which resonance energy is higher than that of
heterocycles is as follows: furan and pyrrole and about the same as in benzene.
Thiophene > pyrrole > Furan • Therefore thiophene resemble benzene rather than furan
• This order is consistent with the order of the or pyrrole in many o f its reactions but it is more reactive
electronegativity values and less stable.

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Heterocycles

Pyrrole General Characteristics

• Commercially from coal tar or by treatment • Pyrrole, furan and thiophene are colorless liquids of
boiling points 126o, 32o, and 84o respectively.
of furan with ammonia over an alumina • Pyrrole has a relatively high boiling point as compared to
catalyst at 400°C. furan and thiophene, this is due to the presence of
intermolecular hydrogen bonding in pyrrole.

N N N N N
H H H H H

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Synthesis of Pyrrole Synthesis of Pyrrole

1) From 1,4-dicarbonyl compounds (Paal-Knorr Synthesis) 2) Pyrrole is obtained by distillation of succinimide over
Generally Substituted pyrrole may be synthesized through the zinc dust.
cyclization of 1,4-diketones in combination with ammonia (NH3) or
amines, The ring-closure is proceeded by dehydration (condensation),
which then yields the two double bonds and thus the aromatic π
system. The formation of the energetically favored aromatic system is
one of the driving forces of the reaction. Zn, heat
Paal-Knorr Synthesis O N O N
R2 R1
R2 R1 +
RNH2
Δ + 2H2O H H
OH OH R2 N R1
O O R=H or Alkyl or Aryl Succinimide
R
1,4-Dicarbony compound

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Synthesis of Pyrrole Synthesis of Pyrrole

3) By heating a mixture of furan, ammonia and steam 4) By passing a mixture of acetylene and ammonia over
over alumina catalyst red hot tube.
CH CH
steam, Al2O3 + NH3 +
red hot tube
+ NH3
CH CH
O N N
H
H

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Heterocycles

Synthesis of Pyrrole Acidic Properties of Pyrrole

5) Knorr-pyrrole synthesis: • Due to participation of N lone pair in aromaticity, pyrrole has

exceptionally strong acidic properties for a secondary amine for
This involves the condensation of α-amino ketones with instance it can react with strong bases or Grignard reagent or
a β-diketone or a β-ketoester to give a substituted potassium metal in inert solvents, and with sodium amide in liquid
ammonia, to give salt-like compounds which an be used to alkylate
pyrrole. or acylate the nitrogen atom as shown below:
R' H3C R'
H3C O
+ + H2 N
N CONHPh
R NH2 O CH3 R N CH3 Na
H PhN=C=O
Acylation
R' = -COR; β− diketone NaH
KOH
RX
N R= CH3 or C2H 5 N
DMSO K
= -COOC2H5; β− diester
or CH2Ph
Alkylation R
N
H RMgX/ Et2O

-RH N
MgX

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Sensitivity of Pyrrole to acids Electrophilic Substitutions

• Pyrrole is sensitive to strong acids. • As expected for aromatic compound, pyrrole can react by electrophilic
substitution.
• This is due to protonation occurs at one of C-3 and the resulting
• In comparison to benzene pyrrole is more reactive thus the substitution is
protonated molecule will add to another unprotonated pyrrole easier and milder reagents can be used.
molecule this continues to give pyrrole trimer. • The increased reactivity is a result of resonance which pushes the electrons
• This reaction is considered as electrophilic addition to pyrrole from the N-atom into the ring making the c-atoms of pyrrole ring more
electron rich than in case of benzene. In fact pyrrole resembles most
H reactive benzene derivatives (phenols and amines)
H
• Consequently, there are some modifications in usual electrophilic reagents,
H+ for instance, sulphonating and nitrating reagents have been modified to
avoid the use of strong acids (induce polymerization). Also reaction with
N N N N
H H H H halogens requires no Lewis acid.
Reactivity in electrophilic substitution
pyrrole trimer

N
> >
H N

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Electrophilic Substitution Electrophilic Substitutions

• Orientation
– Electrophilic substitution normally occurs at a carbon atoms instead of at
the nitrogen as explained before.
– Also it occurs preferentially at C-2 (the position next to the heteroatom)
rather than at C-3 (if position 2- is occupied it occurs at position 3).
– This is due to attack at C-2 gives more stable intermediate (it is stabilized
by three resonance structure) than the intermediate resulted from C-3
attack (it is stabilized by two resonance structure) .

- H+
attack at C-2

three resonance structures more stable

- H+
attack at C-3
Not formed
two resonance structures
less satble

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Heterocycles

Electrophilic Substitution Reactions

Electrophilic Substitutions
NO2
of Pyrrole
AcONO2, AcOH/ -10 C (CH3CO)2O
+ 200- 250 C° N
COCH3
NO2 H
N N N
H H H NBS
SOCl2 / ether
Normal acidic nitration causes polymerization51% 13% N
H
X

X2 X X
Vilsmeier Reaction I2/ aq. KI
1. POCl3
or Br2 / AcOH X
O 2. Na2CO3, H2O X
+ H
N
H

N H NMe2 Ph-N2+Cl-
N
N N N N
H O H EtOH / AcONa H Ph
H NO2
59% HNO3 / Ac2O
o
20 C
+
O O N NO2 N
H H
Me Me 80 % 20 %
Ac2O, AlCl3 NaOH (aq) SO3/Pyridine
rt N SO3H
N N N O H
N(CH3)2
N(CH3)2
SO2Ph SO2Ph 82% H
H
HCl / EtOH N Erlich reaction
H
Electron-withdrawing group allows substitution at the 3-position
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Other Five Membered Heterocycles Furan

N
H
S
Thiophene
O
Furan
• Made commercially by extrusion of CO
Pyrrole from furfural, which is produced from
Least reactive The least aromatic: sugars
The O atom is too electronegative

More aromatic than Furan

Less reactive than pyrrole,

but substitution always at
Electrophilic Substitution, not addition 2-position

Can give addition, as well as substitution products when

reacted with E+
Thiophene has similar reactivity to benzene

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Synthesis of Furan Synthesis of Furan

• Paal Knorr Synthesis

– The acid catalyzed furan synthesis proceeds by
protonation of one carbonyl which is attacked by the
forming enol of the other carbonyl. Dehydration of the
hemiacetal gives the resultant furan.

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Heterocycles

Synthesis of Furan Synthesis of Furan

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Reactions of Furan Reactions of Furan

O
ZnCl2, 100 C
+ MeO OMe H+, H2O
S S
O O O
83% O O
Furan is more reactive than thiophene O H H
O
ZnCl2, 0 C H H
+ cis-butenediol
O O
O O (too unstable to isolate)
O
95% acetal acetal

Br Br O H O R1
- H2O 1 1
+ R O O R
Br2, CCl4 Br2, MeOH MeO 1
OMe R H O R
H R H
Br O Br O
O H H aldehyde + 2 x alcohol acetal
not a clean reaction
Wittig reaction Addition product acid-catalysed
H+, H2O
OHC CHO
Ph3P OHC
_
+ O CHO
H+, H2O
Hydrolysis of acetal Furan is easily cleaved to dicarbonyls O O
OHC R O R
CHO R R
Furan is a source of 1,4-dicarbonyls in Organic Synthesis

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Reactions of Furan Reactions of Furan

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Heterocycles

Diels Alder Reaction Diels Alder Reaction

O
H
O O H CO2Me
+
OMe The configuration of the
100 C H
OMe
CO2Me dienophile is retained
H
+ O O O
benzene Always reacts via the cis-diene
O
Diene H
H CO2Me
4π system O 100% O + MeO
dienophile H
OMe
CO2Me
H
2π system 4+2π cycloaddition Otto Diels O

Electron rich
O H O
Electron poor 25 C
+ O O
O O 100%
H O
O
30 C
H H
+
H
100% Kurt Alder H endo product
O (100%)
Noble Prize in 1950 O O
Under kinetic control
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Diels Alder Reaction Reactions of Furan

CH3CO2NO2
Furan readily undergoes the Diels-Alder reaction with maleic anhydride
O O NO2
O
Thermodynamic furan
exo-product forms as
endo-product O
the temperature is
pyridine:SO3
O

O
raised
O SO3H
More stable due to less steric reasons

Aromaticity prevents thiophene from taking part in the Diels-Alder reaction

C6H5N2+
O
N
S O O N
O - SO2
S +
O X
X
X (CH3CO)2O, BF3
O
O C
This sulfone is not aromatic & very reactive CH3

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Reactions of Furan Thiophene

1. HCN, HCl
O O CH=O
2. H2O • From coal tar or by cyclization of butane or
furan
butadiene with sulfur at 600°C
Br2
O Br
dioxane

HgCl2 I2
HgCl O I
O
CH3CO2Na

CH3COCl

O
O C
CH3

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Heterocycles

Synthesis of Thiophene Synthesis of Thiophene

• Paal Knorr Synthesis

– Thiophene synthesis is achieved via a mechanism
very similar to the furan synthesis. The initial
diketone is converted to a thioketone with a
sulfurizing agent, which then undergoes the same
mechanism as the furan synthesis.

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Electrophilic Substitutions Reactions of Thiophene

Avoid concentrated mineral acids or strong Lewis acids, e.g. AlCl3

HNO3, AcOH, Ac2O / -10 C

NO2
S S
85%
1. POCl3
O 2. Na2CO3, H2O
+ H
S H NMe2
S
68% O

Cl
SO2Cl2, heat
Cl Cl
S S S
43% 10%
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Reactions of Thiophene
less reactive, can use acids

S H2SO4
S SO3H

CH3CO2NO2

(CH3CO)2O S NO2

Br2, benzene
Br S Br

I2, HgO

S I
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