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Unit 4 (Heterocyclic Comp 2)

Pyrazole is an aromatic heterocyclic compound with the formula C3H4N2, characterized by a ring of three carbon and two nitrogen atoms. It can be synthesized through various methods, including the Paal-Knorr synthesis and reactions involving hydrazine and carbonyl compounds. Medicinally, pyrazole derivatives are used in analgesics and anti-inflammatory agents, while related compounds like imidazole, oxazole, and thiazole have distinct properties and applications in pharmaceuticals.

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0% found this document useful (0 votes)
188 views31 pages

Unit 4 (Heterocyclic Comp 2)

Pyrazole is an aromatic heterocyclic compound with the formula C3H4N2, characterized by a ring of three carbon and two nitrogen atoms. It can be synthesized through various methods, including the Paal-Knorr synthesis and reactions involving hydrazine and carbonyl compounds. Medicinally, pyrazole derivatives are used in analgesics and anti-inflammatory agents, while related compounds like imidazole, oxazole, and thiazole have distinct properties and applications in pharmaceuticals.

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Pyrazole

Pyrazole is a aromatic heterocyclic organic compound characterized by a ring structure


composed of three carbon atoms and two nitrogen atoms in adjacent positions, with the
molecular formula C3H4N2. These are the derivatives of a five-membered heterocyclic ring
system called pyrrole. It consists of two nitrogen atoms at the 1 and 2 positions of the cyclic
system.
The sp2 hybridization of the nitrogen atom makes pyrazole a Lewis base, which means it can
coordinate with Lewis acids.
Properties
Pyrazole is a colorless solid and possesses a pleasant smell.
Pyrazole is soluble in water.
Pyrazole exhibits tautomerism.

Synthesis
Paal knorr synthesis (From 1,3-dicarbonyl compounds): 1,3-dicarbonyl compounds react
with hydrazine or hydroxylamine and give pyrazoles.

In the reaction between hydrazine and propargyl aldehyde, pyrazole is formed

Synthesis of substituted pyrazoles is caused by reaction of hydrazine salts with


aldehydes/ketones that are α, β-unsaturated.

With hydrazine, a substituted pyrazole can be easily formed from a derivative of α, β-


ethylene carbonyl.

1
From 1,3-di polar compounds: Pyrazole derivatives can also be prepared by adding a diazo
compound to an acetylenic derivative.

By reacting diarylhydrazones with vicinal diols, 1, 3-substituted pyrazoles are formed

Knorr pyrazole synthesis: The Knorr pyrazole synthesis uses a catalytic acid to convert a
hydrazine and 1,3-dicarbonyl compound to pyrazoles. The dicarbonyl deprotonates the acid
and is subsequently attacked by the hydrazine to produce an imine. The second nitrogen of the
hydrazine then attacks the second carbonyl group to form a second imine. The diamine then is
deprotonated to recreate the catalyst, resulting in the final pyrazole products. There can be two
different pyrazole formations depending on which carbonyl group of the dicarbonyl is attacked
first.

Chemical Properties:
1. Oxidation: Pyrazole is resistant to oxidizing agents but the side chain may be oxidized to
carboxylic acid group in presence of potassium permanganate.

2
2.Reduction: Pyrazole ring system can be reduced with molecular hydrogen and heavy metal
catalyst. Pyrazoline and pyrazolidine are formed which are stronger bases than Pyrazole.

3.Electrophilic aromatic substitutions:


It readily undergoes electrophilic substitution at position 4 through the intermediate formation
of arenium ion. The electrophilic substitution is favoured in neutral or basic medium but not in
acidic medium.
Pyrazole is an electron-rich heterocyclic system with two electrophilic positions (C3 and C5)
and three nucleophilic positions (N1, N2, and C4). The C4 position is more vulnerable to
electrophilic attack because the electronegative nitrogen atoms in the pyrazole ring reduce the
electron density of the C3- and C5-positions. In the presence of a strong base, the C3
electrophilic position may undergo deprotonation, leading to ring opening. In strong acid,
protonation of pyrazole leads to pyrazolium cations, which undergo electrophilic substitution
preferentially at C3.

4. Ring Opening reaction of Pyrazole

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The C3 electrophilic position may undergo deprotonation in the presence of a strong base,
leading to ring opening.

5. Alkylation and acetylation of Pyrazole

Medicinal compounds: Analgin is a pyrazoline derivative. It is an analgesic agent. It is also


used as antipyretic. Phenazone is 2,3-dimethyl-1-phenyl-3-pyrazolin-5-one. It is used orally as
an analgesic, antipyretic, anti-inflammatory as well as anticancer agents. Ex-Phenazone,
Celecoxib Phenylbutazone, Oxyphenbutazone.
Imidazole
Imidazoles are the derivatives of imidazole. Imidazole is a five-membered heterocyclic
compound possessing of two nitrogen atoms at 1 and 3 positions. Imidazole is isomeric with
Pyrazole and occurs in purine nucleus and in histidine.
Physical Properties:
1. Imidazole is a colourless solid.
2. It exhibits amphoteric properties. It is more basic than Pyrazole and pyridine. It also contains
pyrrole type of amino nitrogen in the ring structure and shows acidic properties.
Synthesis
1. From dicarbonyl compounds: Imidazoles can be prepared by condensing a dicarbonyl
compound with an aldehyde in the presence of ammonia.

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2.Debus method : According to the Debus Method published in 1858, glyoxal, formaldehyde,
and ammonia produce imidazole (glyoxaline). 2- and 3-mono- and 4,3-disubstituted imidazoles
are available in this product.

3. Radiszewski synthesis - By combining glyoxal with an aldehyde (e.g., benzaldehyde),


benzaldehyde is formed. Formamide can replace ammonia.

4.Maquenne synthesis

5.From aminonitrile and aldehyde

6. An imidazole derivative is formed by a reaction between alkenes, carbon monoxide,


and ammonia.

Chemical Reaction:
1. Basicity: Imidazole is a weak base forms salts with acids. It is more basic than Pyrazole,
pyrrole and pyridine. Imidazole also has acidic properties the hydrogen atom of -NH can be
displaced by metal. It is more acidic than pyrrole and pyridine.

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2. Electrophilic substitution reaction
Imidazole is more susceptible to electrophilic attack than pyrazole. Electrophilic aromatic
substitution of Imidazole involves through the intermediate formation of arenium ion.
Electrophilic substitution at the 4 or 5 position in Imidazole is favored due to the formation of
a highly stable resonance hybrid.

The attack at 2-position involves a canonical form with highly unfavoured nitrogen at 3-
position. In case, positions 4 & 5 are blocked, substitution takes place in position-2.

a) Nitration: Imidazole undergoes nitration with nitric acid in sulphuric acid

b) Sulphonation: Sulphonated with disulfuric acid at 100°C

c) Halogenation:
Brominated with bromine in chloroform

Imidazole is iodinated with iodine in alkaline condition

3. Alkylation The imino hydrogen atom of Imidazole can be replaced by alkyl groups on reaction
with alkyl halide. N-alkyl imidazoles isomerize on passing through red-hot tube to 2-alkyl
imidazole.

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4.Coupling reaction: Coupling of Imidazole with diazonium salts takes place in the 2-position.

5. Ring opening reaction: Benzoyl chloride in the presence of sodium hydroxide opens the
Imidazole ring.

5. Oxidation and Reduction: Imidazole is extremely stable to oxidising and reducing agents, but
hydrogen peroxide opens the nucleus to form oxamide. Imidazole is resistant to auto-oxidation,
chromic acid, and hydrogen peroxide, but is attacked by perbenzoic acid.

Medicinal Uses
Metronidazole is used in the treatment of bacterial infections and parasitic infections. Tolazoline is
a non-selective competitive α-adrenergic receptor antagonist. It is a vasodilator that is used to treat
spasms of peripheral blood vessels. Methimazole is used to treat hyperthyroidism, a condition that
occurs when the thyroid gland produces too much thyroid hormone. Clotrimazole is a topical broad-
spectrum antifungal agent used for the treatment of a wide variety of dermatophyte infections and
candidiasis. Miconazole is an azole antifungal with broad-spectrum activity used to treat fungal
infections affecting the vagina, mouth and skin, including candidiasis.

OXAZOLE
1,3-oxazole is a five-membered monocyclic heteroarene that is an analogue of cyclopentadiene with
O in place of CH2 at position 1 and N in place of CH at position 3. It is a mancude organic
heteromonocyclic parent, a monocyclic heteroarene and a member of 1,3-oxazoles. Oxazole is a
weakly basic heterocyclic compound, which is the parent compound for a number of other
heterocyclic compounds called azoles, which are five-membered heterocycles having a carbon
between the heterocyclic oxygen and nitrogen atom.
Oxazoles are aromatic compounds but less so than the thiazoles. Oxazole is a weak base and follows
the huckle rule (4n+2πe) because it has 6πe. Show sp2 hybridization and cyclic planer structure.

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Physical properties
It is a liquid, Chemical formula - C3H3NO
Molar mass: 69.06 g/mol. Boiling point: 69 to 70 °C. Pyridine like odour.
Miscible with water and some other organic solvents.
Weakly basic (But slightly more than iso-oxazole).

Synthesis:
1. Robinson gabriel synthesis (From α-acylamino carbonyl compound):- Oxazole is prepared
by refluxing α- acylamino carbonyl compound with acid or phosphorous pentaoxide. This is the
most common method to prepare oxazoles which involve cyclization and dehydration in
presence of phosphorous pentaoxide or strong mineral acid.

2.By heating ethyl α-hydroxy ketosuccinate with formamide followed by hydrolysis and
decarboxylation.

3.By the interaction of acid imides and α-halogenoketones

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Chemical reaction
1. Electrophilic Substitution:-
The oxazole ring does not undergo electrophilic substitutions easily unless the ring is substituted
with an electron-releasing substituent. The oxazole ring does not undergo electrophilic substitutions
easily unless the ring is substituted with an electron-releasing substituent. The preferred attack is at
position 5. These reactions occur more readily when the oxazole ring is activated by the electron-
donating group. Oxazole is more reactive with electrophiles than thiazole but less than imidazole.
The order of reactivity of positions in the oxazole ring is C4 > C5 > C2. Nitration, sulfonation, and
chloro sulfonation do not occur in unsubstituted oxazole rings due to highly electron-deficient
oxazoline cation. When the electron-releasing substituents are present in the ring, electrophiles
easily attack.

Another example of electrophilic substitution is the Mercuration of oxazole with mercuric acetate
in acetic acid

Vilsmeier-Haack Formylation Reaction

Nucleophilic substitution reactions: Oxazole with unsubstituted 2-position gets easily


deprotonated at C2-position by a strong base. Otherwise, oxazole rarely undergoes nucleophilic
substitution reactions. Electron withdrawing substituent at C4 facilitates nucleophilic attack at most
electron-deficient C2-position. For example, the halogen atom at C2 of the oxazole ring is easily
replaced by a nucleophile.

In most cases, nucleophile attacks on the oxazole ring rather result in the cleavage of the oxazole
ring than actual nucleophilic substitution reactions. For example, oxazoles get transformed into
imidazoles via ring cleavage when treated with ammonia /formamide (nucleophile).

Metallation: Lithium preferentially attacks the most electron-deficient C2-atom. The resulting 2-
lithia-oxazoles are unstable and get cleaved to the open-chain isocyanides.

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Oxidation: The oxazole ring is opened by the action of oxidizing agents such as cold potassium
permanganate, chromic acid, and ozone. Oxazole is normally stable to the action of hydrogen
peroxide. 2 – substituted oxazoles can be converted to N-oxides.

Reduction: Oxazoles are relatively easily reduced. Reduction of the oxazole ring to oxazolidines
can be effectively done with sodium in ethanol. Other reducing agents cause reduction and cleavage
of the ring to give open-chain products.

Cycloaddition reactions: Oxazoles easily undergo cycloaddition across 2, 5-positions. The


presence of electron-donating substituents on the oxazole ring facilitates the reactions with
dienophiles. The adducts so obtained serve as important precursors for substituted pyridine or furan
derivatives. Cycloadditions have been reported with alkene, alkyne, and benzyne dienophiles.

10
Medicinal Uses: Oxazole's wide range of biological activity has been found to make it effective at
combating bacteria, fungal infections, viral infections, tuberculosis, cancer, and inflammation.

Thiazole
Thiazole, a five-member ring, has molecular formula C3H3NS, indicating the presence of sulfur
and nitrogen atoms amidst the ring. hiazole rings are planar and aromatic. Thiazoles are
characterized by larger pi-electron delocalization than the corresponding oxazoles and have,
therefore, greater aromaticity. This aromaticity is evidenced by the chemical shift of the ring protons
in proton NMR spectroscopy (between 7.27 and 8.77 ppm), clearly indicating a strong diamagnetic
ring current. The calculated pi-electron density marks C5 as the primary site for electrophilic
substitution, and C2 as the site for nucleophilic substitution.
Resonance hybrid in the thiazole ring is considered in the following ways by resonating structure.
However, various resonating structures are also possible with the attachment of the d-orbital of
sulfur, as described in the figure. The molecular orbital methods calculated the p-bond order that
indicates aromatic thiazole molecule having a little diene character. Localization energies of the
electrophilic reactivity have been predicted in decreasing order as 5 > 2 > 4, and the nucleophilic
reactivities are arranged in the following order, 2 > 5 > 4. In the thiazole ring, the decreasing order
of acidity of hydrogen atoms is predicted to be as H2 >> H5 > H4.

Physical properties:
Thiazole compound have a clear to pale yellow liquid.
Odor similar to pyridine and its boiling point is 116 -118C.
Sparingly soluble in water and soluble in alcohol and ether.

Synthesis
1. Condensation of α-chlorocarbonyl compounds with thioamides:- Thiazole are synthesized
by condensing α-chlorocarbonyl compounds with thioamides.

2. Condensation of α-chloroketones with ammonium dithiocarbonate:- Thiazoles may also be


prepared by the condensation of α-chloroketones with ammonium dithiocarbonate.

11
3.By the interaction of thioamides and α-halo-carbonyl compounds.

4.By the interaction of chloroacetaldehyde and thioformamide.

5. By the interaction of thiourea and α-halo-carbonyl compounds.

6. 2-Mercaptothiazoles can be prepared from ammonium dithiocarbamate and α-halo-


carbonyl compounds.

Chemical Properties:-
a. Electrophilic substitution reactions:- Thiazole undergoes electrophilic substitution reactions.
The reactivity of thiazole is intermediate to pyridine and thiophene. The 4.5-position of the 4,5-
double bond can be electrophilically substituted depending on which sustituent occupies the 2-
position. Whenever, sulphur is in close proximity to a carbon atom, it behaves as electron donar.

All electrophile prefer C5 position to attack the thiazole ring. Electrophile do not attack other
position in C5 if it is already substituted. Even under mild condition, electron donating substituents
at C2 position facilitate the attack of electrophiles at C5.

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b. Diazo coupling: Coloured dyes are produced by combing thiazole with diazonium salts.

c. Condensation with benzaldehyde 2-methylthiazole condenses readily with benzaldehyde in


the presence of alkali.

d. Reaction with Nucleophiles: Thiazole is susceptible for nucleophilic attack at position-2.


Reaction of potassium amide in liquid ammonia with thiazole affords 2-aminothiazole.

e. Reaction with n-alkyllithium: With n-butyllithium thiazole is metalated at position-2.

f. Oxidation and Reduction: Thiazole ring is resistant to oxidation by nitric acid but the ring is
opened by potassium permanganate. Thiazole ring is also resistant to the action of many reducing
agents, although Raney nickel can be used for desulfurization reactions.

Medicinal Uses:- Thiazoles include mainly dyes and fungicides. Another widely used thiazole
derivative is the non-steroidal anti-inflammatory. Example: Troglitazone, Rosiglitazone,
Pioglitazone, Famotidine , Sulfathiazole, Phthalylsulfathiazole, Meloxicam, Thiabendazole.

Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is
structurally related to benzene, with one methine group (=CH−) replaced by a nitrogen atom. It is
a highly flammable, weakly alkaline, water-miscible liquid with a distinctive, unpleasant fishlike
smell. Pyridine is colorless, but older or impure samples can appear yellow. The pyridine ring occurs
in many important compounds, including agrochemicals, pharmaceuticals, and vitamins.
Historically, pyridine was produced from coal tar.
Pyridine have 5 Carbon and 1 Nitrogen, all are sp2 hybridised, sp2 hybridization is planar, it makes a planar
pyridine ring structure. Each ring atoms containes one electron in unhybridized p orbital that is perpendicular
to the plane of sigma bonds (plane of ring). p orbitals are parallel to each other, thus overlapping between p
orbital is possible. The total numbers of non bonding electrons are 6 (5 of five carbons, and 1 from N). The
resonance of 6 electrons follows the Huckel rule which makes pyridine an aromatic system.
Pyridine is more basic than pyrrole because in Pyridine the non bonding electrons on N atom is in
the same plane of pyridine hybridized orbitals plane, so it is not participating in resonance
phenomenon, due to this the lone pair of electrons on Nitrogen are readily available for acid-base
reaction.

13
Synthesis
1. By passing a mixture of acetylene and hydrogen cyanide through a red hot tube.

2. From Glutaconaldehyde and ammonia.

3. From Pentamethylenediamine hydrochloride.

4. Oxidation of 3-methyl pyridine (β-picoline)

4. Hantzsch synthesis

Chemical reaction
Electrophilic substitution reaction
Pyridine is much lesser reactive than benzene towards electrophilic reagents. Because, the
electronegativity of nitrogen lowers the electron density around the ring carbons & the usual
electrophiles can coordinate with the lone pair of electrons on nitrogen to form resonance stabilized
pyridinium ion. The formation of pyridinium ion deactivates the ring and thus further substitution
occurs with difficulty and at position

14
Electrophilic attack at position-2

Electrophilic attack at position-4

Resonance forms A & B which result from attack at position 2 & 4 respectively are energetically
unfavourable and may be ignored. Because, the nitrogen atom in these forms has only six electrons.
The intermediates arising from attack at position 2 & 4 have two resonance forms each.
So, the product with a substituent at position-3 predominates.

Electrophilic attack at position-3

[If position-3 is already blocked, substitution will occur at the other available β-position, i.e., at
position-5] Pyridine may be substituted by electrophilic reagents only under vigorous conditions.

15
Friedel-Crafts Acylation and Alkylation Pyridine doesn’t undergo Friedel-Crafts reaction. Because Lewis acid
which are used as catalysts in these reactions coordinate with the lone pair of electrons on nitrogen.

Nucleophilic substitution Reactions: The electron deficient nature of the 2 and 4 positions of
pyridine makes these positions very reactive towards nucleophilic reagents.

Oxidation
Due to low electron-density about its carbon atoms, pyridine is more resistant than benzene to most
of the oxidizing agents, such as boiling nitric acid or chromic acid. It is evident by the oxidation of
2-phenylpyridine to pyridine-2-carboxylic acid.

16
However, pyridine is oxidised by perbenzoic acid, peracetic acid or hydrogen peroxide in acetic
acid to pyridine-1-oxide.

Reduction
Due to lower electron density about the carbon atoms the pyridine ring is more easily reduced than
benzene. Raney nickel reduces pyridine to piperidine even at atmospheric pressure. If reduction is
effected by means of hydriodic acid at 300°C, the piperidine ring also reduced with the opening of
the ring.

Quinoline
Quinoline or 1-aza-naphthalene or benzo[b]pyridine is a nitrogen-containing heterocyclic aromatic
compound. It has a molecular formula of C9H7N and its molecular weight is 129.16. The log P
value is 2.04 and has an acidic pKb of 4.85 and a basic pKa of 9.5. Quinoline is a weak tertiary
base. It can form salt with acids and displays reactions similar to those of pyridine and benzene. It
is nontoxic to humans on oral absorption and inhalation.
All ring atoms in Quinoline are SP2 hybridize. The nitrogen lone pair electrons reside in an SP2
orbital and not involved in the formation of the delocalized π molecular orbital. It shows aromatic
properties because its π orbital contains ten electrons & satisfied the Huckel’s rule (n = 2 is 4n+2).

Physical properties
Quinoline is a colorless liquid, Boiling Point is 237°C. It turns yellow on standing, and has pyridine-
like smell. Quinoline is miscible with most organic solvents, and dissolves in water to about 0-7 %
at room temperature

Synthesis
1. By Skraup Synthesis: (Commercial method) In this reaction, a mixture of aniline and glycerol
is heated in the presence of sulphuric acid and a mild oxidizing agent, usually nitrobenzene or
arsenic pentoxide. The reaction is exothermic and tends to become very violent. Ferrous
sulphate or boric acid is generally added to make the reaction less violent.

17
2. By the Friedlander Synthesis: This involves the condensation of o-aminobenzaldehyde with
acetaldehyde in the presence of an alkali.

3. The Doebner–Miller reaction: It is the organic reaction of an aniline with α,β-unsaturated


carbonyl compounds to form quinolines

4. Combes synthesis: It involves the condensation of unsubstituted anilines (1) with β-diketones
(2) to form substituted quinolines (4) after an acid-catalyzed ring closure of an intermediate
Schiff base.

Chemical reactions
1. Electrophilic substitution reaction : In quinoline, electrophilic substitution reactions
primarily occur at positions C5 and C8 because the nitrogen atom in the pyridine ring
deactivates that ring towards electrophilic attack, making the benzene ring, particularly at
positions 5 and 8, the most electron-rich sites for substitution due to better resonance
stabilization of the resulting carbocation intermediates; essentially, the electron density is
higher at these positions, making them more susceptible to electrophilic attack.

18
However, nitration can take place at pyridine ring using nitric acid and acetic anhydride at
position 3 in case of quinoline.

2. Nucleophilic substitution reaction


Quinoline undergoes Chichibabin reaction to give 2-amino- quinoline

3. Reduction
The pyridine ring is more easily reduced. Quinoline can be selectively reduced at 1,2-bond by
reaction with lithium aluminium hydride but the 1,2-dihydro quinolines are unstable and
disproportionate easily to give quinoline and 1,2,3,4-tetrahydroquinoline. Quinoline can be
converted to 1,2,3,4-tetrahydroquinoline by catalytic hydrogenation or with tin and
hydrochloric acid

4. Oxidation
Quinoline undergo oxidative cleavage with alkalian potassium permangnate to give
pyridine-2,3-dicarboxylic acid. However, pyridine-2,3-dicarboxylic acid is not stable and
undergoes decarboxylation to give nicotinic acid. Quinoline form N-oxides when treated
with hydrogen peroxide in acetic acid or with organic peracids.

Medicinal uses:
Several anti-malarial drugs contain quinoline substituents. These include quinine, chloroquine,
amodiaquine, and primaquine.

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Isoquinoline
Isoquinoline is an ortho-fused heteroarene that is a benzopyridine in which the N atom not
directly attached to the benzene ring. It is a mancude organic heterobicyclic parent, an azaarene,
an ortho-fused heteroarene and a member of isoquinolines.

Physical properties
Isoquinoline is a colorless solid • (mp 26°C; bp 243°C) • Smell like that of benzaldehyde
(Almond like). • It is sparingly soluble in water, and is soluble in many organic solvents. • It
turns yellow on normal storage.

Synthesis
1. Bischler-Napieralski Synthesis
Acyl derivatives of β- phenylethylamine are cyclized by treatment with acids after (P2O5) to
yield dihydro isoquinoline, which can then be aromatized.

or

2-aryl-ethanamine reacts with a acyl chloride or anhydride to form an amide. Amide can be
cyclized, with loss of water, to a 3,4-dihydro isoquinoline, by treatment with either phosphorus
pentoxide or phosphorus oxychloride. Reduction of dihydro compound to isoquinoline.
2. Pictet-Gams Synthesis
It is the modification of the Bischler-Napieralski method. Synthesis of isoquinoline done using
a hydroxy-substituted reagent.

3. Pomeranz-Fritsch Synthesis
The method includes acid-promoted synthesis of isoquinoline from benzaldehyde & 2,2-
dialkoxyethylamine.
20
Chemical reaction
Electrophilic substitution reaction
ESR occurs at the benzene ring at positions 5 and 8. However, nitration can take place at the
pyridine ring using nitric acid and acetic anhydride at position 4.

Reduction: Isoquinoline can be reduced to 1,2-dihydro or 1,2,3,4-tetrahydroisoquinoline with


diethyl aluminum hydride and sodium-ethanol.

Oxidation: Isoquinoline undergo oxidative cleavage with alkalian potassium permangnate to


give pyridine-3,4-dicarboxylic acid.

21
Nucleophilic substitution reaction: Isoquinoline undergoes chichibabin reaction in
presence of sodamide

Medicinal Uses:
Neuromuscular blocking agents, Antitussive , Antispasmodic
Acridine
Carl Grabe and Heinrich Caro first isolated acridine in 1870 from coal tar. It is an aza derivative
of anthracene. The nitrogen atom is assigned position 10. Acridine and its derivatives have
applications as chemotherapeutic drugs and dye stuffs.
Acridine is an organic compound and a nitrogen heterocycle with the formula C13H9N.
Acridines are substituted derivatives of the parent ring. It is a planar molecule that is structurally
related to anthracene with one of the central CH groups replaced by nitrogen.
Physical properties
Pale yellow crystalline solid. Melting Point: 114 C Acridines and its derivatives gives
fluorescent solution. Acridine and its homologues are weakly basic. Acridine has a pKa of 5.1
similar to that of pyridine.

Synthesis:
Bernthsen acridine synthesis is the chemical reaction of a diarylamine heated with a
carboxylic acid (or acid anhydride) and zinc chloride to form a 9-substituted
acridine

Friedlander synthesis: In this synthesis the salt of anthranilic acid is treated with cyclohex-
2-enone at 120 C to obtain 9-methylacridine

From C-acylated diphenylamines: In this reaction diphenylamine is heated in the presence


of iodine to obtain 9-phenylacridine.

22
Chemical reactions
1.Electrophilic substitution of acridine: It occurs at 2 and 7 postion of acridine.

2. Reaction with nucleophiles: Acridine shows variable regiochemistry towards nucleophiles.


Reaction with NaNH2 in liquid ammonia leads to 9-aminoacridine whereas in N.N-
dimethylaniline the main product is 9,9-biacridanyl

3.Reduction:

4.Oxidation:
Acridine is oxidised by dichromate in acetic acid giving acridone whereas it get degraded by
permanganate in alkaline medium forming quinoline 2,3-dicarboylic acid.

5.Photoalkylation:
In presence of uv light, N-methylacridine hydrochloride reacts with methanol to give 10-
methyl-9,10-dihydroacridine-9-yl-methanol

23
5.Reductive alkylation: Acridine on reaction with n-pentanoic acid in the presence of uv
light, gives 9-n-butylacridine.

Medicinal uses
Cholinesterase inhibitors, used for treatment of Alzheimer, used in antiseptic and disinfectant,
antimalarial and anesthesia.

Indole
Indole is a ten pi electron aromatic system achieved from the delocalization of the lone pair of
electrons on the nitrogen atom. Indole is a benzo[b]pyrrole formed by the fusion of benzene ring
to the 2,3 positions of pyrrole nucleus. The word “Indole” is derived from the word India, as the
heterocycle was first isolated from a blue dye “Indigo” produced in India during sixteenth
century. In 1886, Adolf Baeyer isolated Indole by the pyrolysis of oxindole with Zn dust.
Commercially indole is produced from coal tar

Physical properties:
Weak basic compound, Conjugate acid of indole is strong acid (pKa = –2.4). White solid at room
temperature. Boiling point (253-254 *C). Melting point (52-54 *C). Slightly soluble in water,
readily soluble in organic solvents, e.g. Ethanol,ether and benzene. Solid at room temperature
Corresponding substituent is called indolyl. Chemical formula is C8H7N.

Synthesis:
1.Fischer Indole Synthesis: This reaction was discovered in 1983 by Emil Fischer and so far
remained the most extensively used method of preparation of indoles. The synthesis involves
cyclization of arylhydrazones under heating conditions in presence of protic acid or lewis
acids such as ZnCl2, PCl3, FeCl3, TsOH, HCl, H2SO4, PPA etc. The starting material

24
arylhydrazoles can be obtained from aldehydes, ketones, keto acids, keto esters and diketones
etc. Reaction produces 2,3-disubtituted products. Unsymmetrical ketones can give a mixture
of indoles.

2. Madelung Synthesis:
Base catalyzed cyclization of 2-(acylamino)-toluenes under very harsh conditions (typically
sodium amide or potassium t-butoxide at 250-300oC). Limited to the synthesis of simple indoles
such as 2-methyl indoles without having any sensitive groups.

3. Bartoli Indole Synthesis


Efficient and extremely practical approach for indole synthesis. Ortho-substituted nitrobenzenes
react with three mole equivalents of vinyl magnesium bromide (Grignard reagent) to give 7-
substituted indoles.

Chemical reactions
Electrophilic Substitution Reactions: The pyrrole ring in indole is very electron rich, in
comparison to the benzene ring, therefore, electrophile’s attack always takes place in the five-
membered ring, except in special circumstances.

The preferred site of electrophilic substitution is C-3, because the cation formed by the C-3 attack
of electrophile is more stable than that of the C-2 attack. In case of C-3 attack, transition
intermediate formed has positive charge adjacent to N atom that can be stabilized by the
delocalization of lone pair of electrons of nitrogen. Whereas, the positive charge of transition
intermediate formed by the C-2 attack, cannot be stabilized without disturbing aromaticity of
benzene ring. If C-3 position is occupied, then electrophilic substitution takes place at C-2 and
if both of them are occupied then electrophile attacks at C-6 position.

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Nitration:

Sulphonation: Sulfonation of indole, at C-3, is performed using the pyridine–sulfur trioxide


complex in hot pyridine.

Halogenation: 3-Halo- and 2-halo-indoles are unstable therefore, must be utilised immediately
after their preparation.

Alkylation: Indoles do not react with alkyl halides at room temperature. Indole itself begins to
react with methyliodide in dimethylformamide at about 80°C, to give main product 3-methyl
indole (skatole). As the temperature is increased, further methylation takes place resulting in
1,2,3,3tetramethyl-3H-indolium iodide.

Oxidation Reaction of Indole: C2-C3 double bond of indole is oxidatively cleaved by the use
of reagents such as ozone, sodium periodate, potassium superoxide or CuCl2 in O2 atmosphere.

Reduction Reaction of Indole: The indole ring can be reduced selectively in carbocyclic or the
heterocyclic ring. Nucleophilic reducing agents such as LiAlH4 or NaBH4 does not affect indole
nucleus. However, lithium/liquid ammonia reduces the benzene ring to 4,7-dihydroindole as
major product. The heterocyclic ring can be reduced in acidic reagents such as Zn/HCl or
NaCNBH3/CH3COOH to give indoline.

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Medicinal uses:
Some naturally occurring indole alkaloids have gained FDA approval, including vincristine,
vinblastine, vinorelbine and vindesine for anti-tumor activity; ajmaline for anti-arrhythmic
activity and physostigmine for glaucoma and Alzheimer's disease. Taking inspiration from these
natural compounds several synthetic drugs were synthesized that have reached the patient's
bedside, such as indomethacin (NSAID), ondansetron (chemotherapy induced nausea and
vomiting), fluvastatin (hypercholesterolemia), zafirlukast (leukotriene receptor antagonist).

Pyrimidine
Pyrimidine (C4H4N2) is an aromatic, heterocyclic, organic compound similar to pyridine. One
of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has
nitrogen atoms at positions 1 and 3 in the ring. The other diazines are pyrazine (nitrogen atoms
at the 1 and 4 positions) and pyridazine (nitrogen atoms at the 1 and 2 positions).

Synonyms: 1,3-diazine, Metadiazine, 1,3-diazabenzene

Physical properties
Pyrimidine is colourless compound. It is crystalline in nature having melting point 22C which
dissolve in water to give neutral solution. It reacts with mineral acids to form salts.

Pyrimidine derivatives
The nucleic acid bases are pyrimidine derivatives: Cytosine, thymine and uracil.

Synthesis:
1. Pinner pyrimidine synthesis: Acid or base catalysed condensation reaction of 1,3-
dicarbonyl compounds with amidines or guanidines yields pyrimidine derivatives and the
reaction is known as Pinner pyrimidine synthesis.

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2. Base Facilitated trimerization of alkane nitriles with free methylene group adjacent to
cyano group results in pyrimidine-4-amine derivatives.

3. Condensation of malonic acid ester


The condensation reaction of malonic ester with urea in the presence of base yields barbituric
acid which tautomerizes to trihydroxy form. Finally reaction with POCl3 followed by refluxing
with hot water and Zn dust yield pyrimidine.

Uses:
Pyrimidines serve as building block of DNA and RNA. Used in the synthesis of anti-malerial
drugs, anti-tubercular, anticancer, anti-viral. Ex-Sulfamerazine, 5-flurouracil, Phenobarbitone.

Purine:
Purine is a heterocyclic aromatic organic compound composed of a pyrimidine ring fused with
imidazole ring. It consists of two hydrogen-carbon rings and four nitrogen atoms. Purine is both
a very weak acid and an even weaker base. It is water-soluble. It comprises adenine and guanine
as nucleobases. The melting point of purine is 214 °c. Catabolism results in the production of
uric acid.

Purine derivatives

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Synthesis:
1. 1. Uric acid was reacted with PCl5 to give 2,6,8-trichloropurine which was converted with HI and PH4I
to give 2,6- diiodopurine. The product was reduced to purine using zinc dust.

2. Laboratory synthesis: Purine is obtained in good yield when formamide is heated in an open
vessel at 170 °C for 28 hours.

Medicinal Uses:
Anticancer, antiviral, antifungal, Immunosuppressant and CNS stimulant.
Caffeine, adenine, xanthine.

Azepines
Azepine is planar and cyclic with 8π electrons and obey 4nπ electron system. Therefore, azepine
is an anti-aromatic compound. Replacement of the sp3 hybridized carbon atom in
cycloheptatriene by nitrogen leads to an Azacyclohepatriene known as Azepines. These are
classes of nitrogen-containing seven-membered heterocycles with molecular formula C6H7N.

Azepine exhibits valence tautomerism and four tautomeric forms are possible (1) 1H-azepine
(2) 2H-azepine (3) 3H-azepine (4) 4H-azepine.

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Synthesis:
1. Insertion of nitrene:
The most frequently used synthetic method for azepine is the insertion of a stabilized singlet
nitrene into benzene ring by a concerted cycloaddition mechanism gives 1- azanorcaradiene
which changes to azepine.

2. Tributylphosphine is used to deoxygenate nitrobenzene. When 2-alkoxy-3-H-azepine are


rearranged intramolecularly with primary/secondary alcohol, the aryl nitrene undergoes ring
expansion.

3. From phenylazide: Phenylazide undergoes thermal or photolytic decomposition to yield


nitrene. This nitrene react with arenes to afford azanorcaradiene which rearrange to give
stable azepines.

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Medicinal uses: Antipsychotic (Carbamazepine), Antihistamine(azatadine), anticonvulsant,
antidepressant, ACE inhibitors (Temocapril)

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