Organic Chemistry-II

CHT1138

Heteroaromatic Compounds

Dr. Hitesh Pawar

Assistant Professor
DBT-ICT-CEB, Institute of Chemical Technology
Mumbai-400 019, India
[email protected]
Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019
 Sr. No Content
UNIT-4 IUPAC Nomenclature, Structure and common names, comparison with benzenoid compounds,
reactivity and synthesis-pyrroles, furans, thiophens and pyridines.
Topics and IUPAC Nomenclature: Hantzsch Widman Nomenclature of heterocyclic compounds
Subtopics I. Introduction: Electronic structure and aromaticity of furan, pyrrole, thiophene & pyridine.
II. Preparation: Paal-Knorr synthesis of furans, pyrroles and thiophenes &Hantzsch synthesis of
pyridine
III.Reactivity:
a) Pyrrole, Furan & Thiophene towards ESR
b) Pyridine towards ESR & NSR
IV. Basicity of nitrogen heterocycles
V. Reactions of 5 membered heterocycles: Halogenation, nitration, sulfonation, Vilsmeier Haack
reaction, Friedel crafts reaction; unusual reactions of furan: Diels Alder, ring opening reactions
Reactions of Pyridine: Sulfonation; reduction; Chichibabin reaction

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Heterocyclic Compounds
▪ Heterocyclic chemistry: Heterocyclic chemistry is the branch of organic chemistry dealing with the
synthesis, properties, and applications of these heterocycles.

▪ Heterocyclic compounds : Heterocyclic compounds are organic compounds in which one of the carbon
atom in a ring is replaced by heteroatom such as O, N, S etc.
- The most common heterocycles are those having five- or six-membered rings and containing heteroatoms
of nitrogen (N), oxygen (O), or sulfur (S).
- Heterocyclic compounds are normally classified according to the size of the heterocyclic ring and the
nature and number of the heteroatoms.

▪ Heterocyclic aromatic compounds: In heterocyclic aromatic compounds, at least one carbon atom is
replaced by one of the heteroatoms oxygen, nitrogen, or sulfur.
- Aromatic heterocyclic compounds found generally in biologically active synthetic and natural
compounds, agrochemicals, and medicines etc.
- Aromatic heterocyclic compounds are extensively utilized for the formation of dyes and polymeric materials etc.
Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019
 Comparison with Carbocyclic Compounds
▪ Carbocyclic Compounds: When the ends of the carbon chains are joined together into a ring, results
a cyclic compounds; such cyclic compound is referred as carbocyclic or alicyclic compounds.
- A typical carbocyclic compound is cyclopentane (C5H10), the molecular structure is indicated as,

- If one of the carbon atoms of cyclopentane is replaced with nitrogen (N), it results heterocyclic compound
- Heterocycles may be classified as saturated, unsaturated, or aromatic.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 - In general, synthetic methods and physical and chemical properties of the saturated and the partly
unsaturated heterocyclic compounds closely resemble those for their acyclic (noncyclic, or open-
chain) analogs.

- Pyrrolidine may be considered as a cyclic secondary amine and has much in common with the
corresponding acyclic amine, diethylamine.

pyrrolidine

- 4,5-dihydrofuran mirrors many of the properties of the corresponding unsaturated ether, ethyl vinyl ether

4,5-dihydrofuran ethoxyethane
Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019
 Nomenclature of Heterocyclic
Compounds

The IUPAC rules allow three nomenclatures.

I. The Hantzsch-Widman Nomenclature

II. Common Names

III.The Replacement Nomenclature

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 I. The Hantzsch-Widman Nomenclature

▪ The Hantzsch-Widman nomenclature is based on the type (Z) of the heteroatom; the ring

size (n) and nature of the ring, whether it is saturated or unsaturated.

▪ This system of nomenclature applies to monocyclic three-to-ten-membered ring

heterocycles.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 1. Types of Heteroatom: The types of heteroatoms present in a ring are indicated by prefixes; in particular,
oxa-, thia-, and aza- denote oxygen, sulfur, and nitrogen atoms, respectively.
- Heterocyclic compounds can contain N, S or O atom in a ring.

O N S
Atom Prefix Name No. of Suffix Name for H
Oxole Azole Thiole
O Oxa atoms in completely (Furan) (Pyrrole) (Thiophene)
the ring unsaturated system
N Aza
5 -ole
S Thia
6 -ine N
P Phospha Azine
(Pyridine)

▪ The numbers of heteroatoms of a particular kind are indicated by number prefixes joined to the heteroatom
prefixes, as dioxa- and triaza-.

▪ The presence of different kinds of heteroatoms is indicated by combining the above prefixes, using the
following order of preference: oxa- first, followed by thia- and then aza-.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 2. Ring Size (n): The ring size indicated by suffix as below;
- Some of the syllables are derived from Latin numerals, namely ir from tri, et from tetra, ep from hepta, oc
from octa, on from nona, ec from deca..

Table-I: Stems to indicate the ring size of heterocycles

Rig Size Suffix

3 -ir
4 -et
oxirane oxetane oxolane oxine
5 -ol
6 -in
7 -ep
8 -oc
9 -on oxepane oxocane oxonane oxecane
10 -ec

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 aziridine azetidine pyrrolidine thietane thiolane
thiirane
tetrahydrothiophene

piperidine azepane azocane thiane thiepane thiocane

tetrahydro-2H-thiopyran

azonane
azecane thionane thiecane

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 - The endings indicate the size and degree of unsaturation of the ring.

Table-II: Stems to indicate the ring size and degree of unsaturation of heterocycles

Ring Size Saturated Unsaturated Saturated with N

3 -irane -irine -iridine
4 -etane -ete -etidine
5 -olane -ole -olidine
6 -inane -ine
7 -epane -epine
8 -ocane -ocine
9 -onane -onine
10 -ecane -ecine

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 - According to this system heterocyles are named by combining appropriate prefix/prefixes with a stem
from Table II. The letter “a” in the prefix is omitted where necessary.

- Each suffix consists of a ring size root and an ending intended to designate the degree of
unsaturation in the ring.

- It is important to recognize that the saturated suffix applies only to completely saturated ring systems,
and the unsaturated suffix applies to rings incorporating the maximum number of non-cumulated
double bonds.

- Systems having a lesser degree of unsaturation require an appropriate prefix, such as "dihydro"or
"tetrahydro".

- Saturated 3, 4 & 5-membered nitrogen heterocycles should use respectively the traditional "iridine",
"etidine" & "olidine" suffix.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019
 - If substituents are present, the heteroatom is designated number 1, and the substituents around
the chain are numbered so as to have the lowest number for the substituents.

- The compound with the maximum number of noncumulative double bonds is regarded as the parent
compound of the monocyclic systems of a given ring size.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 - If compound is partially unsaturated use fully unsaturated name with dihydro, tetrahydro, etc.

- When numbering give priority to saturated atoms.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Type (Z)- Prefix
Size (n) – Suffix
Nature of ring – Endings

O - Oxa
N - Aza
S - Thia
P - Phospha

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Rings with More Than One Heteroatom
- Two or more similar atoms contained in a ring are indicated by the prefixes ‘di-’, ‘tri’, etc.

- If more than one hetero atom occur in the ring, then

the heterocycle is named by combining the
appropriate prefixes with the ending in Table I in
order of their preference, O > S > N.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 - Priority of heteroatoms for numbering purposes:

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 - The ring is numbered from the atom of preference in such a way so as to give the smallest possible
number to the other hetero atoms in the ring. As a result, the position of the substituent plays no
part in determining how the ring is numbered in such compounds.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 II. Common Names
- There are a large number of important ring systems which are named widely known with their
non-systematic or common names.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 III. Replacement Nomenclature
- In replacement nomenclature, the heterocycle's name is composed of the carbocycle's name and a
prefix that denotes the heteroatom.

- Thus, "aza", "oxa", and "thia" are prefixes for a nitrogen ring atom, an oxygen ring atom, and a sulfur
ring atom, respectively.

- Notice that heterocyclic rings are numbered so that the heteroatom has the lowest possible number.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Electronic Structure and Aromaticity

All the above structures are similar to each other, except for the fact that pyrrole has a lone pair and
one N-H bond instead of two lone pair of electrons (as in furan and thiophene). All the atoms in the
above structure are sp2 hybridized.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 The distribution of electrons in these structures is as follows

Atomic no of the
Heteroatom No. of Valence Electrons in sp2 Electron/s in unhybridized
hetero atom
electrons hybrid orbitals p- orbital

2 electrons forming σ
1 lone pair (2 electrons)
6 bonds with C atoms+ A
Furan Oxygen 8 involved in aromatic
(2+2+2) lone pair (2 electrons).
sextet.

2 electrons forming σ
6 bonds with C atoms+ A 1 lone pair (2 electrons)
Thiophene Sulphur 16
(2+2+2) lone pair (2 electrons). involved in aromatic
sextet.

2 electrons forming σ
bonds with C atoms 1 lone pair (2 electrons)
5
Pyrrole Nitrogen 7 +1 electron forms bond involved in aromatic
(2+1+2)
with hydrogen. sextet.

Electrons in sp2 hybridized orbitals ⇒ form σ bonds

Electrons in unhybridized p-orbitals- perpendicular to σ framework ⇒ involved in aromatic sextet.
Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019
 Furan ,Thiophene and Pyrrole are aromatic..?
1. All (Furan, Thiophen and Pyrrole) are cyclic and planer.

2. All atoms in these structures are sp2 hybridized. So , all the four carbon atoms and the heteroatom
are in the same plane. Thus, all the three structures are planar.

3. They all have an aromatic sextet i.e 6π(4n+2 π , where n=1) electrons. These electrons are in the
unhybridized p-orbital of each atom- perpendicular to the plane of the ring. The double bonds and
the lone pair involved in the sextet are in conjugation as shown below-

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Order of Aromaticity

More electronegativity of the hetero atom

less – is the aromaticity of the compound.

▪ Benzene is more aromatic than thiophene, pyrrole and furan because all the π electrons are totally
involved in forming the aromatic sextet.

▪ Whereas in other molecules, the heteroatoms being more electronegative than carbon, they pull the
electron cloud towards themselves. Thus, there is an uneven charge distribution.

▪ Oxygen is the most electronegative and so furan is least aromatic. Sulphur is less electronegative.

▪ The 3s and 3p electrons are the valence electrons in sulphur atom as opposed to 2s and 2p in
oxygen and nitrogen
Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019
 Resonance Structures

− −
etc. − −
X X X X
.. +

• Electron donation into the ring by resonance but inductive electron withdrawal

1.44 Å 1.43 Å 1.42 Å

1.35 Å 1.37 Å 1.37 Å
0.71 D 1.55 D 0.52 D
1.37 Å O 1.38 Å N 1.71 Å S
H

1.68 D 1.57 D 1.87 D

O N S
H

• O and S are more electronegative than N and so inductive effects dominate

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Paal-Knorr synthesis of Furans, Pyrroles and Thiophenes

NH3

 N
H

R - NH2

 N
R
H H H H
O O OH HO
P2O5

 O

P2 S5

 S

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 I. Paal-Knorr synthesis of Furan: The acid-catalyzed cyclization of 1,4-dicarbonyl compounds known
as the Paal-Knorr synthesis is one of the most important methods for the preparation of furans.
- The reaction is usually reversible and can be used to convert furans into 1,4-diketones
- A trace of acid is required – usually TsOH (p-MeC6H4SO3H)

R1 R2 R1 R2
R1 R2
O
O O O O
OH
H H H

H heat
H
H

R1 R2 R1 R2 R1 R2
O O O
OH2

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 II. Paal-Knorr synthesis of Thiophen: The condensation of 1,4-dicarbonyl compounds in presence of
excess of sulfur is known as the Paal-Knorr synthesis of thiophen is one of the most important methods
for the preparation of thiophen.
- The reaction might occur via the 1,4-bis-thioketone

Me Me
Me Ph

P4S10 S O
Me Ph
Me Me Ph
S
O O

Me Ph

O S

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 III. Paal-Knorr synthesis of Pyrrole: The condensation of 1,4-dicarbonyl compounds in presence of
excess of a primary amine or ammonia to give a pyrrole is known as the Paal-Knorr synthesis of
pyrrole is one of the most important methods for the preparation of thiophen.
- Ammonia or a primary amine can be used to give the pyrrole or N-alkyl pyrrole

Me Me Me Me Me Me

O O O HN O H2N

NH3, C6H6,
heat
H
H

Me Me R1 R2 R1 R2
N N N
H H OH H

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 IV: Hantzsch synthesis of pyridine: This reaction allows the preparation of dihydropyridine
derivatives by condensation of an aldehyde with two equivalents of a β-ketoester in the presence of
ammonia. Subsequent oxidation (or dehydrogenation) gives pyridine-3,5-dicarboxylates, which may
also be decarboxylated to yield the corresponding pyridines.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 - The reaction can be visualized as proceeding through a Knoevenagel Condensation product as a key
intermediate:

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

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Further condensation between these two fragments gives the dihydropyridine derivative:

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 Reactivity of furans, pyrroles and thiophenes

▪ Kinetic Aspect : Electron rich centers

- In Structures II and V, the charge separation is
across two bonds, making these canonical
structures less stable.

I II III - Hence structures III and IV which have separation

of charge only across one bond are more stable
and contribute more to the hybrid.

V IV - Positions 2 and 5 in pyrrole, thiophene and furan

are electron rich.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 ▪ Thermodynamic aspect : Stability of intermediate

▪ Electrophilic substitution normally occurs at a carbon atoms.

▪ Electrophilic substitution occurs preferentially at C-2 or C-5 (the position next to the heteroatom) rather

than at C-3 (if position 2- is occupied it occurs at position 3).

▪ The electrophilic attack at C-2 or C-5 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).

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Reactivity of Pyridine

- The lone pair of electrons on the Nitrogen are placed in a sp2

hybridized orbital perpendicular to the p-orbitals of the six
membered ring.

- Hence the lone pair cannot participate in the resonance

delocalization of p-pi electrons.

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 ▪ Consequences of the resonance forms of pyridine

- Not very reactive towards Electrophilic Substitution and orients the incoming electrophile to the 3
or 5 positions (electron availability through resonance forms).

- The lone pair gets protonated during electrophilic substitution and hence it further deactivates the
ring towards ESR

- Undergoes Nucleophilic substitution readily and orients the incoming nucleophile to 2, 4 or 6

positions and electrophilic substitution at 3 and 5 positions.

+
4
5 3

+ 6 2 +
N
1

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 Basicity of Pyridine and Pyrrole
Basicity of Pyridine:

STRUCTURE
N N N
H H

NAME Piperidine Pyridine Pyrrole

pKb 2.9 8.8 13.6

- Lone pair of electrons in pyridine is not a part of the aromatic sextet. Hence it is more basic than
pyrrole.
- However, the lone pair in pyridine is present in sp2 (% s = 33.33) hybridized orbital whereas in
piperidine it is present in sp3 (% s = 25) hybridized orbital.
- As the percentage s character increases, the electrons are held more tightly and basicity
decreases. Hence, piperidine is more basic.
Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019
 Basicity of pyrrole:

- Pyrrole is an extremely weak base for a secondary amine.

- Its pkb value is 13.6 as against 2.73 for pyrrolidine.

H+
−
N +
+
N
(1) Protonation leads to loss of aromaticity.
H H
H

(2)The lone pair of electrons in pyrrole are polarized into the ring as
against pyrrolidine which are polarized towards the nitrogen.
N N
H H
 = 1.57 D  = 1.8 D

Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019

 Reactions of Pyridine
Electrophilic Aromatic Substitution (Sulphonation):
SO3H
H2SO4, 24h

300 - 350 oC
N

N
20% oleum; HgSO4 SO3H
(Catalyst)

220 oC; 3.5h

N

Reduction of pyridine:

LiAlH4
N
H
Raney Ni

N N
LiAlH4 H

N
H
Organic Chemistry-II Heteroaromatic Compound Institute of Chemical Technology Mumbai-400 019
 REACTION FURAN PYRROLE

X X
SO 2Cl 2
Halogenation
Halogenation + Br 2 - C2H5OH
X X
N I 2 - aq. KI N
O H H

0o C
Nitration + CH3COONO 2 + CH3COONO 2
N NO 2
NO 2 N
O O H H

100 oC

Sulphonation + SO 3
SO 3H
+ SO 3
SO 3H
-
O N
+
SO 3 O N N
+
SO 3
- N
H H

BF3 - Ether 50 oC
Friedal Crafts + (CH3CO) 2O
+ (CH3CO) 2O
(No catalyst COCH3
Acylation O 0 C o
O
COCH3 N
H required)
N
H

O
O POCl3
POCl3 CH3
Vilsmeyer Haack CH3 + H N
+ H N
 CHO N  N
CHO
O O H H3C H
H3C

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 REACTION THIOPHENE
SO2Cl2

50 oC
Cl
S
Halogenation
S NBS

CHCl3; AcOH Br
S

(CH 3 CO) 2 O
Nitration + conc. HNO3 10 oC
S NO 2
S

95% H2SO4; 30 o C
Sulphonation OR Py - SO3; 100 oC
S SO 3H
S

CH3COCl SnCl4
CH3
Friedal Crafts Acylation + (CH3CO) 2O
50 o C
S S
O

DMF NaOH
Vilsmeyer Haack +
S POCl3 CH = N(CH3)2 CHO
S S

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 Miscellaneous reactions of Furan
Diels Alder Reactions:

- Furan has 2 conjugated double bonds and behaves as a diene as it is the least aromatic of the 5
membered heterocyles.

- They undergo Diels Alder reaction with very reactive dienophiles.

OH

Ether HBr
O + o
O
25 C
(Diene) (Dienophile) ( - Naphthol)

O O O

Ether Ether HBr

O + O O + O O O O

(Diene) (Dienophile) O O
O
(Diene) (Dienophile) (Phthalic Anhydride)

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 Ring opening reactions of furan:

- Furan adds molecular oxygen to give a peroxide which on hydrolysis gives 2-butenedial. This can be
reduced to succinaldehyde

O O H2O CHO H2 CHO

O + O
O O CHO Ni CHO

- In the presence of aqueous acid, it gives back 1,4-diketone or dialdehyde

H
+ H
O OH

H+ OH2 -H+ keto - enol CHO

+
O O H O H
CHO
OH

- In the presence of methanolic acid, the acetal or ketal is isolated

2CH3OH 2CH3OH OCH3 H2O

H3CO
HCl H3CO OCH3 HCl OHC CHO
O O
OCH3 OCH3
HCl

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 Nucleophilic Aromatic Substitution (Chichibabin Reaction):

NaNH2
liq. NH3
N N NH2

- -
HC CH
+ - H H H +
+ Na NH2
-
Na
N N NH2 N NH2 N NH2

- H
NH3 Na+NH2-
- +
- Na+NH2- N NH2 -NH 3 N NH Na
N+ NH2
-H2
Na

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