Unit 4 - Heterocyclic compounds-II.pptx.pptx

P
. Organic Chemistry-III
Unit-IV
Synthesis reactions & medicinal uses
of Important heterocycles

Unit-4: Syllabus
Part-1: Synthesis, reactions and medicinal uses of:
A] Five membered heterocyclic compounds containing two heteroatoms (Azoles):
Example: a) Pyrazole b) Imidazole c) Oxazole d) Thiazole
B] Six membered heterocyclic compounds containing one heteroatom:
Example: Pyridine and basicity of pyridine
C] Benzofused heterocyclic compounds containing one heteroatom:
Examples: a) Quinoline b) Isoquinoline c) Acridine d) Indole
Part-2: Synthesis and medicinal uses of:
D] Six membered ring containing more than one heteroatom:
Pyrimidine
E] Fused heterocyclic compound containing more than one heteroatom:
Purine
F] Seven membered heterocyclic compounds: Azepines

Six membered heterocyclic compounds containing one heteroatom
Pyridine
20

PYRIDINE
• Pyridine is a six membered heterocyclic ring containing nitrogen as a heteroatom.
• Other examples of six membered heterocyclic compounds containing one
heteroatom are:
alpha pyran (2H-Pyran),
gama pyran (4H-Pyran)
Piperidine.

PYRIDINE
• Source: Coal tar and bone oil. Now a days obtained synthetically.
• Physical Properties: Colourless, hygroscopic liquid,
B. P. 115°C, Freezing Point: -41.6°C
Odour: Fishy (Unpleasent),
Miscible with water and most
organic solvents.
Weakly basic and form with HCl
Derivatives:

PYRIDINE: Basicity
• Pyridine is more basic than Pyrrole and less basic than aliphatic amines (Aklylamines)
• Pyridine is basic in nature due to the presence of lone pair of electron on nitrogen
(pKa
= 5.21).
• The order of basicity is: Akylamines > Pyridine > Pyrrole
• Pyridine is less basic than pyrrole because in contrast to pyrrole, the lone pair of
electrons on pyridine nitrogen is not involved in delocalization (aromatic sextet) and
thus readily available for reaction with acids and haloalkanes. Hence pyridine is more
basic than pyrrole.

PYRIDINE: Basicity
• Pyridine is less basic than aliphatic amines: In both pyridine and alkylamines electron
pair is available for reaction but in case of alkylamines the nitrogen is sp3
hybridized
whereas in pyridine nitrogen is sp2
hybridized. We know that sp2
hybridized nitrogen is
more electronegative than sp3
hybridized nitrogen. So the lone pair of electrons is held
more tightly by the pyridine nitrogen and comparatively less available for reaction.

PYRIDINE: Synthesis
1. Hantzsch Pyridine Synthesis:
Statement: Involves condensation of β-Ketoester (2 molecules) and aldehyde in presence of ammonia.
(One molecule of β-Ketoester (Ethyl acetoacetate) reacts with ammonia and another molecule reacts with
aldehyde which leads to formation of dihydropyridine which on oxidation with nitric acid yields a pyridine
derivative)
• HNO act as a aromatizing or
oxidizing
3
agent
.
• If formaldehyde is used instead of
acetaldehyde, 2,6-dimethyl pyridine is
formed.

PYRIDINE: Synthesis
1. Hantzsch Synthesis: Mechanism is explained in 4 steps
Step-I: Enamine intermediate-I formation: 1 molecule of β-dicarbonyl compound (Here β-keto ester) reacts with 1
molecule of ammonia to yield β-amino crotonic ester (Ethyl 3-aminobut-2-enoate)
Step-II:
another
Aldol condensation:
mol of β-
dicarbonyl
compound reacts with aldehyde
to form Intermediate-II (Ethyl 2-
methylene-3-oxobutanoate)

PYRIDINE: Synthesis
Step-II:
another
Aldol condensation:
mol of β-
dicarbonyl
compound reacts with aldehyde
to form Intermediate-II (Ethyl 2-
methylene-3-oxobutanoate)

PYRIDINE: Synthesis
1. Hantzsch Synthesis:
SteStep-III (Michael addition): Intermediate I & II are added across double bond to form dihydropyridine
Step-IV (Oxidation of dihydropyridine): by HNO3 /H2SO4

PYRIDINE: Synthesis
2. Synthesis from acetylene: When a mixture of acetylene and HCN (Hydrogen cyanide) or ammonia
is passed through a red hot tube, pyridine Is formed.
3. Chichibabin synthesis: Special method to synthesize 5 ethyl-2-methyl pyridine in which
paraldehyde is heated with ammonium hydroxide under pressure.

PYRIDINE: Synthesis
4. Synthesis from Pyrrole: Pyrrole forms sodium salt when treated with sodium ethoxide which on
treatment with methylenediiodine at 200°C rearranges to pyridine

PYRIDINE: Reactions
Electrophilic substitution in pyridine preferentially takes place at 3 (or 5) position.
• 5 resonating structures can be drawn for Pyridine. The partial positive charges on the 2, 4, and 6 positions in
the resonance hybrid indicate electron density is less at these positions. So, pyridine will undergo
electrophilic substitution reactions less readily than benzene.
• The resonance hybrid of pyridine further tells us that 3-and 5-positions of pyridine are more electron dense
than 2,4, and 6-positions. Therefore, incoming electrophile will take 3 (or 5) position preferentially.
• This is also supported by the greater stability of the intermediate for the 3-attack than those of 2 and 4
attack.

Pyridine undergoes electrophilic aromatic substitution at
C-3

PYRIDINE: Reactions
1. Electrophilic substitution reactions:
a) Nitration
b) Sulphonation
c) Halogenation

PYRIDINE: Reactions
1. Electrophilic substitution reactions:
d) Mercuration
e)Friedel-crafts acetylation/alkylation: Since pyridine forms salt with lewis acid, cannot be alkylated by FC
method. It can be indirectly alkylated by Hofmann-Martius rearrangement
f)Hetaryne formation: Hetaryne is a reactive intermediate with a triple bond in the nucleus containing
heteroatom
2. Oxidation: Readily oxidized by perbenzoic acid, peracetic acid or H2
O2
to give Pyridine-1-oxide

PYRIDINE: Reactions
3. Reduction:

Pyridine undergoes nucleophilic aromatic substitution at
C-2 and C-4

PYRIDINE: Reactions
4. Nucleophilic substitution reactions:
Pyridine is deacitvated aromatic ring system. The electron deficient centers at 2 and 4 positions are
highly susceptible for attack of nucleophiles. The nucleophilic substitution in pyridine occurs at
2-position.
a) Metalation: Pyridine reacts with organometallic compounds to form 2-alkyl or 2-aryl derivatives. The
alkyl group behaves as a nucleophile and attacks at 2 position.

PYRIDINE: Reactions
4. Nucleophilic substitution reactions:
b) Hydroxylation: OH-
(Hydroxide ion) acts as a nucleophile in the formation of 2-Hydroxypyridine
which tautomerises to more stable keto form i.e. 2-Pyridone.
C) Chichibabin reaction: Pyridine and other nitrogen containing heterocyclic compounds are aminated
mainly at 2 (alpha) position with respect to nitrogen atom by alkali metal amides like sodamide
(NaNH2
) in liquid ammonia. It occurs at elevated temperature (100-200°C), where H atom gets
displaced by :NH2-
ion.

PYRIDINE: Medicinal uses
Pyridine and its derivatives (Corrosponding drugs) are used in medicine as-
1. Antibacterial: Sulphapyridine
2. Antihistaminic (Antiallergic): Mepyramine, Tripelennamine
3. Anti-tubercular: Isoniazid
4. Laxative: Bisacodyl
5. Vitamin-B supplement: Niacin, Pyridoxal
6. Antihypertensive: Amlodipine, Nifidipine
7. Antiinflammatory: Piroxicam
Sulphapyridine Isoniazid Piroxicam

Benzofused heterocyclic compounds containing one heteroatom
(a) Quinoline
20

QUINOLINE & ISOQUINOLINE (Benzopyridines)
• Benzopyridine is bicyclic heterocyclic ring system in which benzene nucleus is
fused to pyridine ring. Ex. Quinoline and Isoquinoline.
• When pyridine ring is fused with benzene at side “b”, the resulting structure is
known as Quionline. If the benzene is fused to pyridine at side “c”, the resulting
structure is known as Isoquinoline
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QUINOLINE
• Physical Properties:
✔ Colourless, Hygroscopic liquid, with characteristic smell resembling pyridine
✔ B. P. 237°C
✔ Miscible with organic solvents and water
✔ On exposure to air its color changes to yellow.
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QUINOLINE: Synthesis
1. Skraup synthesis: When aniline is heated with Conc. H2
SO4
, glycerol and mild dehydrogenating
agent (nitrobenzene), quinoline is formed. Reaction proceeds by following 4 steps:
Step-I: Dehydration of glycerol by the action of H2
SO4
to get acrolein
Step-II: Reaction of acrolein with aniline to form aniline propionaldehyde. (Michael addition reaction)
Step-III: Ring closure at ortho position of aromatic ring (formation of 1,2-dihydroquinoline
Step-IV: Dehydrogenation of 1,2-dihydroquinoline by nitrobenzene (formation of quinoline)
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QUINOLINE: Synthesis
2. Friedlander’s Synthesis: It involves condensation of o-aminobenzaldehyde and aldehyde (or
ketone ) having active methylene group in presence of alkali.
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QUINOLINE: Aromaticity and Basicity
Aromatic Character:
• Quinoline consist of 9 carbon and 1 nitrogen atom. All are SP2 hybridized and thus
the ring is planar.
• Quinoline have 10 pi electrons (9 from 9 carbons and 1 nitrogen atom) which is
the Huckels number (4n+2) thus it is aromatic ring.
Basic Character:
• Quinoline and isoquinoline are weak bases but slightly more basic than pyridine.
[and less basic than anilines since the nitrogen in quinoline and isoquinoline is more electronegative being sp2
hybridized compared to sp3
hybridized nitrogen of anilines]
• Basicity is measured analogouss to acidity. The smaller the pKb, the stronger the
base. The pkb values for quinoline & Pyridine are 5.06 and 8.77 respectively. So
quinoline is the comparatively stronger base than pyridine. That can be explained
by the conjugated (neighboring) aromatic system. The positive charge as a result
of protonation, is better delocalized because of the larger molecular orbitals that
such conjugated systems have. (Reference: Org.chem JM Khurana)
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25

Quinoline: Reactions
Quinolines and isoquinolines behave similar to pyridine. Both are weakly basic and undergo protonation of
nitrogen without affecting the aromaticity of the ring. Quaternary ammonium salts are formed on nitrogen by
alkylation.
1. Electrophilic aromatic substitution reactions:
Electrophilic substitution in quinoline and isoquinoline takes place on the benzene ring at C-5 or C-8
positions. Because nitrogen of the quinoline and isoquinoline has deactivating effect on the ring towards
electrophilic substitution as in case of pyridine (Pyridine ring is electron deficient as compared to benzene
ring. So in any benzofused heterocyclic ring electrophile attacks on benzene ring). However electrophilic
substitution of quinoline and isoquinoline requires less vigorous conditions than pyridine.
a) Nitration:
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b) Sulphonation:
b) Bromination:
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2. Nucleophilic aromatic substitution reactions:
Nucleophilic substitution in quinoline occurs on pyridine part at 2 position. If this position is already
occupied then it shifts to 4th
position.
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Chichibabin reaction

3. Oxidation: Quinoline and isoquinoline undergo oxidative cleavage with alk. potassium permangnate to give
pyridine-2,3-dicarboxylic acid and pyridine-3,4-dicarboxylic acid. However, pyridine-2,3-dicarboxylic acid
is not stable and undergoes decarboxylation to give nicotinic acid
[Quinoline and isoquinoline both form N-oxides when treated with hydrogen peroxide in acetic acid or with
organic peracids.]
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4. Reduction: Quinoline can be selectively reduced at 1,2-bond by reaction with lithium aluminium hydride
to give 1,2-dihydro quinoline. Catalytic reduction (hydrogenation) of quinoline by Pt/H2
or tin and
hydrochloric acid gives 1,2,3,4-tetrahydroquinoline.
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Quinoline: Medicinal uses
Quinoline and its derivatives (Corrosponding drugs) are used in medicine as-
1. Antimalarial: Chloroquin, Primaquin, Mefloquin, quinocide
2. Antibacterial : Ciprofloxacin (Fluoroquinoline derivative)
3. Anti-amoebics and treatment of skin infections: Cloquinol
4. In the clinical management of patients with COVID-19 infection: Chloroquin and
hydroxychloroquine. Reference:
https://www.elsevier.com/ data/assets/pdf_file/0007/988648/COVID-19-Drug-Therapy_Mar-2020.pdf
[At present there is no any single USFDA approved drug for the treatment of COVID-19 infection but
Chloroquin and hydroxychloroquine (quinoline derivatives) are used in the clinical management of corona
virus infected patients along with other antiviral agents (Lopinavir, Ritonavir and Remdesvir)
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Quinoline: Medicinal uses
Quinoline and its derivatives (Corrosponding drugs) are used in medicine as-
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a) Chloroquine b) Hydroxychloroquine

(b) Isoquinoline
32

ISOQUINOLINE: Synthesis
1. Bischler-Napieralski reaction:
Heating N-acetyl-2-phenylethylamine with phosphorous oxychloride results in intramolecular
cyclisation to form 3,4-dihydroisoquinoline, which on dehydrogenation over palladium gives
isoquinoline derivative.
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ISOQUINOLINE: Synthesis
2. Pictet-Spengler Synthesis:
Step-I: β-Arylethylamines reacts with aldehyde to give imine.
Step-II: Cyclisation of imine under acidic condition gives 1,2,3,4-tetrahydro isoquinoline.
Step-III: Dehydrogenation of 1,2,3,4-tetrahydro isoquinoline by palladium catalyst gives isoquinoline.
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ISOQUINOLINE: Reactions
Chemically isoquinoline behave similar to Quinoline in most of its reactions.
Electrophilic aromatic substitution reactions: Nitration and sulphonation occurs at position 5 & 8
whereas bromination occres at 4th
position.
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Chemically isoquinolines behave similar to Quinoline in most of its reactions.
Nucleophilic aromatic substitution reactions:
Nucleophilic aromatic substitution occurs at position 1 as it is more electropositive.
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3. Oxidation: Oxidation by KMnO leads to opening of isoquinoline ring.
4
4. Reduction: Depending upon the reducing agents and reaction conditions used, isoquinoline is
reduced at varying extent.
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ISOQUINOLINE: Medicinal Uses
Isoquinolline and its derivatives (Corrosponding drugs) are used in medicine as-
1. Antispasmodic and Vasodilator: Papaverine
2. Antidiabetic natural supplement: Berberine
3. Anasthetic: Dimethisoquin
4. Antihypertensive: Quinapril
5. Emetic: Emetine
6. Antiparasitic: Praziquantel
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ISOQUINOLINE: Medicinal Uses
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Papaverine Dimethisoquine

(c) Acridine
39

Acridine (Benzoquinoline/Dibenzpyridine)
• Properties:
13 9
• Acridine (C H N) is “aza” (N) derivative of pyridine. It is also known as benzoquinoline
or
Dibenzpyridine. It is made up of fusion of quinoline ring to benzene.
• First discovered by 1871 in the fraction of coal tar by German chemists Carl Grabe and
Heinrich Caro. They separated acridine from coal tar by extracting with dil. H2
SO4
,
precipitation of acridine bichromate by addition of potassium dichromate followed by
decomposition of potassium dichromate with ammonia.
• Name Acridine is due to its skin irritant nature and acidic nature. The numbering system
is exceptional i.e. it does not starts from heteroatom.
• P.P: Colourless, Crystalline solid, B. P. 100-106°C, Soluble in Chloroform, Alcohols, Diethyl
ether and Benzene
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Acridine (Benzoquinoline/Dibenzpyridine)
• Aromaticity and basicity:
• Molecular formula: C
H N
13 9
• Acridine consist of 13 carbons and one nitrogen, all are Sp2
hybridized. Two SP2
orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The
third SP2
orbital on each carbon atom overlaps with an S orbital of hydrogen and
forms C-H σ bonds. The third SP2
orbital of nitrogen is occupied by the lone pair of
electron. Thus acridine is a planar molecule which is structurally related to
anthracene. (Except presence of nitrogen)
• The total number of delocalized π electrons is 14 (13 from each carbons and 1 from
nitrogen) The nitrogen lone pair is not released into the aromatic system
• Thus it obeys Huckels rule (4n+2)π
electrons, and is aromatic.
• Acridine is slightly basic in nature.
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Acridine: Synthesis
1. Bernthsen Acridine synthesis: This method is used for the synthesis of 9-substituted
acridines aswell as unsubstituted acridine. It involves condensation of Diphenylamine
with Carboxylic acid in presence of zinc chloride at higher temperatures.
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Acridine: Synthesis
2. Ullmann Acridine synthesis:
3. Treatment of N-arylanthranilic acid with an acylating agent,
suchas
polyphosphoric acid (PPA), undergoes cyclisation reaction to 9-chloroacridine.
Acylating reagents used in this reaction are POCl3
(Phosphoryl chloride) or H2
SO4
or HCl or PPA.
PTO
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Acridine: Synthesis
2. Ullmann Acridine synthesis: Continued………
The chlorine in 9-chloroacridine molecule readily undergoes nucleophilic substitution
therefore it is widely used as an intermediate for the synthesis of 9-substituted acridines.δ
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Acridine: Synthesis
3. Friedlander’s Synthesis: When salt of anthranilic acid is treated with cyclohex-2-enone at
120°C, 9-methyl acridine is formed.
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Acridine: Reactions
a) Nitration: Nitration occurs at 2 and 7 positions.
a) Bromination: Bromination occurs at 2,4,5 and 7 positions.
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Acridine: Reactions
2. Nucleophilic aromatic substitution reactions:
Acridine shows variable regiochemistry (Preference for one orientation over another in the arrangement
of a reaction product) towards nucleophiles. Reaction with NaNH2
(Sodamide) gives 9-aminoacridine
while reaction with N,N-dimethylaniline in presence of sodamide gives 9,9-biacridynyl.
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Acridine: Reactions
3. Reduction:
Zn/HCl causes reduction of pyridine ring while Pt/HCl causes reduction of benzene rings in acridine.
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Acridine: Reactions
4. Oxidation:
Acridine gets oxidized by dichromate in acetic acid and gives acridone while It gets degraded by
permagnate in basic medium forming quinoline 2,3-dicarboxylic acid.
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Acridine: Reactions
5. Photoalkylation:
N-methylacridine when reacts with methanol in presence of UV light gives 10-methyl-9,10-
dihydroacridine-9-yl methanol
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Acridine: Medicinal Uses
Acridine and its derivatives (Corrosponding drugs) are used in medicine as-
1. Antiseptic and disinfectant: Acriflavin
2. Antibacterial: Proflavin
3. Antimalarial: Quinacrine, Mepacrine
4. Topical anasthetic: Bucricaine
5. Anticancer: Nitracrine (Damages DNA )
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Benzofused heterocyclic compounds cont. one heteroatom
d) Indole

Indole
• Indole (C H N) is a common name of a bicyclic heterocyclic system in which Six
8 7
membered benzene ring is fused with five membered pyrrole ring.
• The name indole is a combination of the words indigo and oleum, since
indole was first isolated by treatment of the indigo dye (Blue colored dye of
Indian origin) with oleum.

Indole
• Physical Properties:
• Source: Although the main source of indole is extraction from coal tar, It is also prepared
synthetically by many methods. First time it was prepared by Bayer in 1866 from zinc dust
distillation of oxindole
• Colour: White crystalline solid at room temperature,
• B.P & M. P: Melts at 52-54°C and boils at 254°C,
• Odour: Pure indole in low concentration smells flowery but its derivative 3-methyl indole
(Skatole) smells like feces. (Reference Joule and Mill)
• Solubility: Soluble in hot water and most organic solvents.
• Basicity:
• Indole is very weak base. As the lone pair of electrons on nitrogen is involved in delocalization
in the ring, it is not available for protonation. (However strong acids like HCl can protonate
indole at Carbon-3 rather than Nitrogen)

Indole
•Aromaticity:
• Indole consist of 8 carbons and one nitrogen, all are Sp2
hybridized.
• Thus Indole is a planar molecule.
• The total number of delocalized π electrons is 10 (8 from 8 carbons and two
from nitrogen)
• Thus it obeys Huckels rule (4n+2)π
electrons, and is aromatic.
•Resonance:
Its resonance energy is 47-49 kcal/mol. Because of the involvement of lone pair of
nitrogen, charge separated cannonical forms can be written as shown below:

Indole : Synthesis
1. Fischer Indole Synthesis: (1883): (Mostly used for synthesis of 2 or/and 3 substituted indoles.)
Statement:
Involves heating of aryl hydrazine with appropriate enolisable aldehyde or ketone to form a condensation
product arylhydrazone. Further this arylhydrazone undergoes lewis acid catalyzed sigmatropic rearrangement
with elimination of ammonia to yield substituted indole.
General reaction:
-The reaction was discovered by
Hermann Emil Fischer (Germany).
-Nobel Prize:1902

Indole : Synthesis
1. Fischer Indole Synthesis: (1883): (Mostly used for synthesis of 2 or/and 3 substituted indoles.)
Mechanism:

Indole : Synthesis
2. Reissert Indole Synthesis: (Reaction of o-Nitrotoluene with Diethyl oxalate)
The reaction of o-nitrotolune with diethyl oxalate in presence of the base gives o-nitrophenylpyruvate
which on reductive cyclisation, followed by dehydration leads to the formation of indole 2 carboxylate
and on further hydrolysis and decarboxylation gives indole.

Indole : Reactions
• Indole is a π electron excessive system where ring nitrogen is not basic. The lone pair of electrons on
nitrogen is involved in delocalization in the ring thus it is not available for protonation. (However strong
acids like HCl can protonate indole at Carbon-3 rather than Nitrogen).
• Indole undergoes following chemical reactions:
1. electrophilic substitution reactions
2. Nucleophilic substitution reactions
3. Reduction 4
Oxidation
5. Diels-
Alder
reaction
1. Electrophilic
substitution
reactions:
• Due to π electron excessive structure it is highly susceptible for electrophilic substitution reactions.
Electrophilic substitution in Indole preferentially takes place at 3 (β) position rather than 2(α) position.
Because the attack of electrophile at position 3 generates stable carbocation by using lone pair on Nitrogen
atom and do not disrupt the aromaticity of benzene ring. While the attack of electrophile at position 2
generates carbocation which disrupt the aromatic character by delocalizing the positive charge over
benzene ring. If the position 3 is already substituted then it takes place at 2 position and if 2 position is also
already occupied then electrophile attack on benzene ring.

Indole : Reactions
1. Electrophilic substitution reactions: Continued….

Indole : Reactions
a) Nitration: Nitration by nitric acid and acetic anhydride at reduced temperature gives 3-nitroindole
b) Sulphonation: Because of its acid sensitivity indole is sulphonated with mild sulphonating agents like
pyridine-sulphurtrioxide complex instead of H2
SO4.
Product of sulphonation is Indole-3-sulphonic acid.

Indole : Reactions
C) Halogenation:
2 and 3 haloindols are very unstable compounds
And needs to be freshly prepared when required.

Indole : Reactions
d) Friedel craft acylation: Indole with acetic anhydride in presence of acetic acid
produces 1-acetyl and 1,3- diacetyl Indoles
e) Mercuration: Reacts with mercuric acetate to yield 2,3-dimercuric acetate.

Indole : Reactions
2. Nucleophilic aromatic substitution reactions: π - electron excessive character makes indole inert towards
nucleophilic attack. Nucleophilic substitution do not occure in direct displacement of ring bound substituent.
However it is possible if indole is deprotonated by readily displacable nucleopholic reagent such as n-Butyl
Lithium. The nucleophile then attacks at C-2 position by displacing n-Butyl Lithium.
3. Reduction: Reduction product of Indole depends on reducing agent used. Indole can be reduced selectively
in benzene or pyrrole part of the ring. Ex- When reduced with Zn/HCl it is converted to Indoline and complete
reduction occurs when reduced with Ni/HCl to yield octahydroindole.

Indole : Reactions
4. Oxidation: In presence of air and light, indole undergoes auto-oxidation to form a resinous material.
Auto-oxidation by atmospheric oxygen converts indole to indigotin.

Indole : Medicinal uses
Indol is a core part of many drugs. These drugs are used in medicine as:
1. Antihypertensive/Anti-psychotic : Reserpine (Rauwalfia alkalloid)
2. Non-steroidal anti-inflammatory agent: Indomethacin
3. Oxytocic: Ergometrine (Ergot alkalloid)
4. B-adrenergic receptor blocker : Pindolol
5. Amino acid supplement: Tryptophan
6. In the treatment of migraine: Ergotamine
7. Anticancer: Vincristine and vinblastine (Vinca alkalloids)
8. Antiemetic: Ondasetron
9. Neurotransmitter: Serotonin

Synthesis & medicinal uses
of 1.
Pyrimidine

Pyrimidine
• Structure and numbering: Pyrimidine is a six membered diazine heterocycle. Other
examples of diazines are pyridazine and pyrazine.
Pyrimidine is a 1,3-diazine heterocycle containing two imine nitrogen atoms. These two
heteroatoms withdraw electron density from the ring carbons even more than that of
pyridine, so unsubstituted diazines (pyrimidine, pyridazine and pyrazine) are even more
resistant to electrophilic attack than pyridine.
• Aromaticity and basicity:
Pyrimidine consist of 4 carbon and two nitrogen atoms. All are SP2
hybridized. Hence
the ring is planar. Total number of delocalized π electrons is 6 (4 from 4 carbons and 2
from two nitrogens) Thus it follows Huckels rule [(4n+2)π
electrons] and is aromatic.
Pyrimidine is a weak base.

Pyrimidine
• Gabriel Synthesis (Synthesis from barbituric acid):
Statement: Involves three steps-
1. Cyclocondensation of malonic acid and urea to produces barbituric acid
(2,4,6-trihydroxypyrimidine).
2. Chlorination of barbituric acid by POCL to obtain trichloro
pyrimidine.
3
3. Dehalogenation (Dechlorination) of trichloro pyrimidine by zinc dust to yield
Pyrimidine.

Pyrimidine : Synthesis
2. Whittakar Method: (From 2,4-dichloropyrimidine)
3. Pyrimidine can be prepared just by catalytic reductive dechlorination of
2,4-dichloropyrimidine by palladium catalyst.

Medicinal Uses of
pyrimidine:
Pyrimidine and its derivatives are widely used in medicine as:-
1. Antineoplastic agents: 5-fluoro uracil, Azathiopurine, Mercaptopurine
2. Antiviral (Anti-HIV): Famiciclovir, Cidofovir
3. Antibiotic: Bacimethrin, Amicetin
4. Sulphonamide antibiotcs: Sulphadiazine, Sulphadoxine
5. Antifungal: Flucytosine
6. Anthelmintic: Pyrantel pamoate
7. Anti-TB: Capreomycin
8. Hypnotic and sedative: Pentobarbital, Hexobarbital, Allobarbital
9. Antihyperthyrodism: Thiouracil
10. Diuretics: Caffeine, Theophylline
11. Vasodilators: Pentifylline, Pentoxyfylline
12. NSAID: Bentiamine

of 2. Purine

Purine
•Structure and numbering:
Purine is a aromatic heterocyclic ring which consist of a pyrimidine ring fused to
imidazole ring.
Purine is an important component of nucleic acids (RNA and DNA). Out of five
bases required in the construction of nucleic acids two (Adenine and Guainine)
are the derivatives of Purine. It is also component of certain co-enzymes.

Purine:Synthesis
purines. The
1. Traube synthesis: (From 4,5-Diamino-pyrimidines)
4,5-Diamino-pyrimidines reacts with carboxylic acid to
give carbonyl carbon corresponds to carbon 8 in the purine ring.

Purine:Synthesis
2. From substituted imidazoles:
This method is useful for synthesis of purine derivatives
such as xanthine (Purine 2,6-dione).

Medicinal Uses of
purine:
Purine and its derivatives are widely used in medicine as:-
1. Antiviral (Anti-HIV): Acyclovir, Didanosine
2. Antifungal: O-alkyl guanine acts against against Candida tropicalis
3. C.N.S. Stimulant (Analeptic): Caffeine, Theophylline
4. Anti-gout: Allopurinol
5. Anticancer: 6-mercaptopurine
6. Anti-Leishmanial activity: Formycin-A, Formycin-B

of 3. Azepines

Azepines
•Structure and numbering:
□ Azepines are non-aromatic azacyclo heptatrienes. It means their structure is
made up of seven membered ring with three double bonds and nitrogen as a
heteroatom.
□ Theoretically four tautomeric forms of azepines can be drawn but out of them
only 3-H-azepine can be isolated practically.
□ The stability of azepine tautomers in decresing order is: 3H > 4H > 1H

Azepine:Synthesis
1. From Benzene: (Valence bond isomerization)
Valence bond isomerization means reorganization of the electrons and does not involve migration
of any group or atom.

Azepine:Synthesis
2. From nitrobenzene: The nitrobenzene is deoxygenated by using
tributylphosphine. The resulting arylnitrene undergoes ring expansion through
intramolrcular rearrangement in presence of primary/secondary alcohol to give 2-
alkoxy-3H-azepine.

Medicinal Uses of
azepines:
Azepine and its derivatives are used in medicine as:-
1. Anticonvulsants: Carbamazepine
2. Antidepressants: Imipramine
3. Anxiolytics/ Hypnotics : Diazepam
4. Antihypertensive/ACE inhibitor: Temocapril

Unit 4 - Heterocyclic compounds-II.pptx.pptx

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