Pharmaceutical Organic Chemistry-III (13PH0401) Unit-3 Topic: Heterocyclic Compounds

Pharmaceutical Organic Chemistry-III
(13PH0401)
Unit-3
Topic: HETEROCYCLIC
COMPOUNDS
Presented by - Ms.Chandni Padwani

Assistant professor
Faculty of pharmacy
TABLE OF CONTENTS
1. INTRODUCTION
2. CLASSIFICATION
3. NOMENCLATURE
4. SYNTHESIS
5. REACTIONS
6. MEDICINAL USES
INTRODUCTION
 Aromatic compounds which have rings composed of carbon atoms only

(carbocyclic).
 There are a large number of compounds in which the ring system includes
atoms other than carbon the commonest being 0, N and S.
 These are called Heterocyclic compounds.
 Heterocyclic compounds are frequently abundant in plants and animal

products; and they are one of the important constituent of almost one half of
the natural organic compounds known.
INTRODUCTION
 Alkaloids, natural dyes, drugs, proteins, enzymes etc. are the some
important class of natural heterocyclic compounds.
 Heterocyclic compounds can be easily classified based on their electronic

structure.
 Heterocyclic compounds have a wide application in pharmaceuticals,

agrochemicals and veterinary products.
 Various compounds such as hormones, alkaloids antibiotic, essential

amino acids, hemoglobin, vitamins, dyestuffs and pigments have
heterocyclic structure.
GENERAL CLASSIFICATION
CLASSIFICATION OF HETEROCYCLIC COMPOUNDS
Heterocycles
Nature/no.of Size of
Degree of
hetero-atom(s) heterocyclic
saturation
present compounds
No. of Atoms making

“N” present – AZOLES
AROMATIC/ NON-AROMATIC up the ring systems.
“S” PRESENT -
SATURATED/UNSATURATED SIMPLE / FUSED Ring
THIOPHENES
systems
CLASSIFICATION OF HETEROCYCLIC COMPOUNDS
NOMENCLATURE
 The systematic nomenclature gives important structural information.
 The most relevant system that is recommended by IUPAC for nomenclature

of heterocyclic compounds is the Hantzch-Widmann system of
nomenclature.
 This nomenclature system specifies the nature, position, ring size, number,
and types of heteroatoms present in any heterocyclic compounds.
 This systematic method generally derived the nomenclature using the

following syntax –
Name: Prefix + Stem + Suffix

Following are the important points to be remembered during the systematic
nomenclature of heterocyclic compounds.
1. In this nomenclature the nomenclature of heterocyclic compounds are assigned by

combining ‘prefix’ (that indicate the heteroatom present) with ‘stem’ (that indicate
the ring size as well as the saturation and unsaturation in the ring) and ‘suffixes’.
2. If there are two or more than two hetero atoms of same types are present in a
heterocyclic compound they are indicated by di-, tri- etc.
3. The position of saturated atom is numerically indicated with prefix ‘H-’ as a part
of the name of the ring system.
 The cyclic part (from Greek kyklos, meaning “circle”) of heterocyclic indicates that
at least one ring structure is present in such a compound.
 The prefix hetero- (from Greek heteros, meaning “other” or “different”) refers to
the noncarbon atoms, or heteroatoms, in the ring.
 In their general structure, heterocyclic compounds resemble cyclic organic

compounds that incorporate only carbon atoms in the rings for
example, cyclopropane (with a three-carbon-atom ring) or benzene (with a six-
carbon-atom ring) but the presence of the heteroatoms gives heterocyclic
compounds physical and chemical properties that are often quite distinct from those
of their all-carbon-ring analogs.
1. TYPE - The types of heteroatoms present in a ring are indicated by prefixes;
in particular, oxa-, thia-, and aza- denote oxygen, sulphur
and nitrogen atoms, respectively.
2. NUMBER of heteroatoms of a particular kind are indicated by number

prefixes joined to the heteroatom prefixes, as dioxa- and triaza-.
3. PRESENCE OF HETERO-ATOMS - 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-.
COMPOUNDS TO BE STUDIED FURTHER
PYRROLE – INTRODUCTION
 Pyrole is an important  e- rich

aromatic heterocycles, because,
this ring is present in
biomolecules like porphyrin :
i. porphin(HAEM),
ii. Chlorine (CHLOROPHYLL)
and
iii. Corrins (Vit. B12).
 Pyrrole was isolated in pure

form drom BONE OIL in 1857
and its structure was
established in 1870.
PYRROLE – STRUCTURE
 Pyrrole is a heterocyclic aromatic organic

compound/, a five-membered ring with
the formula C4H4N.
 Carbon atom is substituted by N group.
 Naming of pyrrole starts from N atom.

PYRROLE – SYNTHESIS
Following are the general methods of preparation of pyrrole:
i. FROM BONE OIL:
 Bone oil is rich of pyrrole.
 The basic and acidic impurities of Bone oil are removed by sequential treatment of it
with dilute acidic and dilute basic solutions.
 The treated Bone oil is then subjected for fractional distillation, the fraction obtained
between 373K and 423K is collected.
 The collected fraction is then purified with KOH to obtained POTASSIO-PYRROLE.
 Steam distillation of potassiopyrrole gives pure pyrrole.

2. From succinimide: Succinimide when is distilled with Zn dust it reduces the
succinimide to pyrrole.
REDUCTION
3. From Furan: Industrially pyrrole is prepared by passing a mixture of furan and
ammonia over alumina over 400° C.
4. Pall-Knorr synthesis: In this method, when a 1,4-diketone is heated with ammonia
or a primary amine it gives the corresponding pyrrole
derivatives.
PYRROLE – PHYSICAL PROPERTIES
 It is a colorless liquid with boiling point 131° C.
 It is highly sensitive to air, when pyrrole is exposed to air it turns brown and gradually
resinifies.
 It is slightly soluble in water but completely miscible in ether and ethanol.

PYRROLE – CHEMICAL PROPERTIES
 It is an aromatic compound and more reactive than benzene.
 In pyrrole there is a conjugated system of carbon atoms, linked directly to NH grouping.
 The NH group activates the ring so that pyrrole undergoes the usual substitution reactions of
the aromatic compounds readily.
 The aromatic part of the ring ‘in turn decreases the basic character of the NH group.
 Because of the aromatic nature pyrrole gives all characteristic reactions (electrophilic
substitution reactions) of aromatic compounds such as,
 halogenation,
 nitration,
 sulphonation,
 Friedel-Crafts reactions etc.
a. ACIDIC CHARACTER OF PYRROLE:
 The lone pair of nitrogen usually participates in resonance and thus makes the pyrrole aromatic.
 That is the reason, the lone pair of nitrogen could not be available free to react with a proton.
 However, pyrrole can behave as a weak acid.
 When pyrrole is heated with potassium in n-heptane as solvent, stable potassium pyrrolide is formed.
 Potassium pyrrolide when reacts with alkyl halide at 60° C to give N-alkyl pyrrole.
 The N-alkyl pyrrole can easily rearrange to C-alkyl pyrrole.

b) Electrophilic Substitution Reactions of Pyrrole: Pyrrole undergoes electrophilic substitution
reactions at position C-2.
i. Halogenation: Pyrrole reacts with halogens [X2 (X2 = Cl2, Br2 and I2)] to give
TETRAHALOPYRROLE.
 For example, Reaction of bromine with pyrrole gives tetrabromopyrrole.

ii. Nitration: Nitration of pyrrole is achieved by reacting it with HNO3 in acetic
anhydride.
 The reaction of HNO3 and acetic anhydride resulted acetyl nitrate in which –NO2
acts as an electrophile.
iii. Sulphonation: Sulphonation of pyrrole is achieved by reacting it with sulfur trioxide (SO3) –
pyridine mixture in ethylene chloride.
iv. Friedel-Crafts Acylation: Reaction of pyrrole with acetic anhydride under heating
condition gives 2-acetylpyrrole.
v. Diazotization: Pyrrole reacts with benzenediazonium chloride in acidic medium to give
2-phenylazopyrrole.
Reimer-Tiemann Reaction: Pyrrole reacts with Chloroform in presence of KOH to give 2-
Formylpyrrole.
 This reaction is known as Reimer-Tiemann reaction.
 It also takes place through electrophilic substitution reaction mechanism.

Reduction: Pyrrole can be reduced to pyrrolidine (tetrahydropyrrole) by H2 gas or Ni
at very high temperature (473K).
Oxidation: Pyrrole when oxidized with Chromium trioxide in H2SO4 it gives Malecimide.
PYRROLE – MEDICINAL USES
 These derivatives or molecules including a pyrrole nucleus, show interesting
 anti-microbial,
 anti-viral,
 anti-malarial,
 antitubercular,
 anti-inflammatory,
 enzyme inhibiting and
 anticancer properties
 In addition, compounds from the pyrrole ring are also precursors to certain drugs.
 For instance, pyrrole is a precursor of the drug tolmetin, and N-methylpyrrole is a

precursor to N-methylpyrrolecarboxylic acid.
 Pyrroles are also found in several drugs, including
 Atorvastatin,
 Ketorolac and
 Sunitinib
 Furthermore, hydrogenation of pyrrole and its derivatives is of fundamental importance in

chemical and pharmaceutical processes.

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Pharmaceutical Organic Chemistry-III

Presented by - Ms.Chandni Padwani

 Aromatic compounds which have rings composed of carbon atoms only

 These are called Heterocyclic compounds.

 Heterocyclic compounds are frequently abundant in plants and animal

 Heterocyclic compounds can be easily classified based on their electronic

 Heterocyclic compounds have a wide application in pharmaceuticals,

 Various compounds such as hormones, alkaloids antibiotic, essential

No. of Atoms making

 The systematic nomenclature gives important structural information.

 The most relevant system that is recommended by IUPAC for nomenclature

 This systematic method generally derived the nomenclature using the

Name: Prefix + Stem + Suffix

1. In this nomenclature the nomenclature of heterocyclic compounds are assigned by

 In their general structure, heterocyclic compounds resemble cyclic organic

2. NUMBER of heteroatoms of a particular kind are indicated by number

3. PRESENCE OF HETERO-ATOMS - presence of different kinds of

 Pyrole is an important  e- rich

 Pyrrole was isolated in pure

 Pyrrole is a heterocyclic aromatic organic

 Carbon atom is substituted by N group.

 Naming of pyrrole starts from N atom.

Following are the general methods of preparation of pyrrole:

i. FROM BONE OIL:

 Bone oil is rich of pyrrole.

 The collected fraction is then purified with KOH to obtained POTASSIO-PYRROLE.

 Steam distillation of potassiopyrrole gives pure pyrrole.

 It is a colorless liquid with boiling point 131° C.

 It is slightly soluble in water but completely miscible in ether and ethanol.

 It is an aromatic compound and more reactive than benzene.

 In pyrrole there is a conjugated system of carbon atoms, linked directly to NH grouping.

 However, pyrrole can behave as a weak acid.

 The N-alkyl pyrrole can easily rearrange to C-alkyl pyrrole.

 For example, Reaction of bromine with pyrrole gives tetrabromopyrrole.

 This reaction is known as Reimer-Tiemann reaction.

 It also takes place through electrophilic substitution reaction mechanism.

 These derivatives or molecules including a pyrrole nucleus, show interesting

 For instance, pyrrole is a precursor of the drug tolmetin, and N-methylpyrrole is a

 Furthermore, hydrogenation of pyrrole and its derivatives is of fundamental importance in

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