Hetrocyclic Chemistry

Course Title: Carbohydrates, Hetrocyclic Compounds,
Organometallic Reagents and Synthetic Methods

MSCHE3001C04
Heterocyclic compounds: Brief introduction of hetrocyclic compounds. Nomenclature of heterocyclic compounds.

Structure, reactivity, synthesis and reactions of pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine,
purine and indole.
Benzo-fused heterocycles: Synthesis and reactions of benzofurans, benzothiophenes, benzoxazoles, benzothiazoles and
benzimidazoles. Six-membered heterocycles with two or more heteroatoms: Synthesis of Diazines and triazines.
Heterocyclic compound
Any of a class of organic compounds whose molecules contain one or more rings of atoms
with at least one atom (the heteroatom) being an element other than carbon, most frequently
oxygen, nitrogen, or sulfur.
Heterocyclic compounds include many of the biochemical material essential to life.
Our Previous Knowledge
• Introduction of heterocyclic compounds

• General classification of heterocyclic compounds
• Structural and electronic features of heterocyclic compounds
• Degree of aromaticity among heterocyclic compounds
• Synthesis of heterocyclic compounds
• Reactivity pattern of heterocyclic compounds
• Reactions of different heterocyclic compounds
• Spectroscopic Properties of Aromatic Heterocycles
Recommended Books
• Heterocyclic Chemistry: John A. Joule, Keith Mills

• I. L. Finar, Volume 1 and 2
pyrazole, imidazole,
oxazole, isoxazole,
thiazole, isothiazole,
pyrimidine, purine and
indole.
benzofurans, benzothiophenes,
benzoxazoles, benzothiazoles
and benzimidazoles
Diazines and triazines

1,2 - and 1,3 - azoles
1,2 - and 1,3 - azoles
Structure of Pyrrole
• Resonance leads, to the establishment of partial negative charges on the carbons and a partial positive charge on the
nitrogen. Of course the inductive effect of the nitrogen is, as usual, towards the heteroatom and away from carbon, so that
the electronic distribution in pyrrole is a balance of two opposing effects,
• the mesomeric effect is probably the more significant, and this results in a dipole moment directed away from the nitrogen.
• It is because of this electronic drift away from nitrogen and towards the ring carbons that five – membered heterocycles of
the pyrrole type are referred to as ‘ electron - rich.
Structure of Pyridine
Reaction of Pyrrole Ring
• Undergoes electrophilic substitution reaction but with a preference for attack adjacent to the heteroatom – at their a - positions.
Structures of Imidazoles
Imidazoles
• Aphoteric nature, susceptible to

electrophilic and nucleophilic
attack.
Tautomerism
Hydrogen Bonding in Pyrazole and Imidazoles
Imidazole, like water, is both a good donor

and a good acceptor of hydrogen bonds
Imidazoles have high melting and boiling points when compared to pyrrole, oxazole and thiazole because
the imidazole molecule is a donor as well as an acceptor of hydrogen bonds, and only intermolecular
hydrogen bridges can be formed
mp 90°C, bp 256°C,
Imidazole containing drugs
• It is used for the treatment of

metastatic malignant melanoma
benzodiazepine antagonist that is

used for the complete or partial
reversal of the sedative effects
caused by benzodiazepines
Cimetidine is used to treat ulcers;

gastroesophageal reflux disease
Synthesis of Imidazole
Synthesis of Imidazole
Debus Synthesis
Glyoxal
Mechanism
Radiszewski Synthesis
Mechanism
Reactions with Electrophilic Reagents
Protonation Acid-base reactions
• Imidazoles are moderately strong bases. The pKa value of the

conjugate acid of imidazole is 7.00. They form salts with many
acids, e.g. chlorides, nitrates, oxalates and picrates:
• Imidazoles unsubstiruted in the 1-position are weak acids. The

pKa value of imidazole is 14.52. Hence its acidity is greater
than that of pyrrole and of ethanol. The sodium salt of
imidazole is formed with sodium ethoxide in ethanol
Reactions with electrophilic reagents
Alkylation, acylation, sulfonation and silylation occur on the N-atoms of imidazoles
The quaternary salts that are formed initially usually undergo rapid deprotonation to 1-alkylimidazoles. These can
react with a second mole of haloalkane to give 1,3-dialkylimidazolium salts
However, in the presence of strong bases, the imidazolyl anion reacts with the haloalkane
Because of the ambident character of the imidazolyl anion, 4- or

5-substituted imidazoles
yield mixtures of 1,4- and 1,5-disubstituted imidazoles
• When imidazole undergoes halogenation and azo-coupling in electrophilic substitution reactions at carbon
• nitration and sulfonation proceed very slowly because the reactions take place in an acidic medium with formation
of imidazolyl cations, for instance in the nitration with nitric acid:
Reactions with nucleophilic reagents
• Reactions of imidazoles with nucleophiles occur slowly and demand vigorous conditions. Attack of the nucleophile
occurs in the 2-position. For instance, l-methyl-4,5-diphenylimidazole reacts with potassium hydroxide at 300°C to give
imidazol-2(3//)-one
• The nucleophilic substitution reactions of 2-haloimidazoles are only possible under drastic conditions,
e.g.:
Synthetic Application
• The use of 1-acylimidazoles as acylating agents is of great importance.
• Acylimidazoles are much more reactive like acid anhydrides or acid chlorides, are able to transfer the acyl group to
water, alcohols, phenols and amines:
l,1’-carbonyldiimidazole
Prepared from phosgene and imidazole, is particularly reactive.

Even at room temperature, it reacts vigorously with water to give imidazole and carbon dioxide.
With carboxylic acids in aprotic solvents, 1-acyloxycarbonylimidazole is formed, which is capable of an intermolecular
trans acylation:
Pyrazole
Acid— base reactions
• Pyrazoles are much weaker bases than imidazoles
• The conjugate acid of pyrazole has a pKa value of 2.52. The difference is due to the fact that the positive charge in the
pyrazolium ion is less delocalized than in the imidazolium ion
• The pKa value of pyrazole is 14.21 and equals that of imidazole. Pyrazole reacts with sodium to give the sodium salt.
Pyrazole containing drugs
Synthesis of Pyrazole
• Hydrazine, and alkyl- or arylhydrazines undergo
Knorr Pyrazole Synthesis cyclocondensation with 1,3-dicarbonyl compounds
to give pyrazoles
Pechmann Pyrazole Synthesis

• The 1,3-dipolar cycloaddition of diazoalkanes to alkynes
leads to pyrazoles, e.g.:
mp 70°C, bp 188°C, is soluble in water. Pyrazole exists in the
Hydrogen Bonding solid state and in concentrated solution as a dimer with two
intermolecular hydrogen bonds. For this reason, the melting
point and boiling point of pyrazole are higher than those of
pyrrole and pyridine, but lower than those of imidazole.
Reactions with electrophilic reagents
• The best procedure for methylation of pyrazole is via the sodium salt which reacts with iodomethane or dimethyl sulfate:
• Benzylation, acetylation, benzoylation, methylsulfonation, methoxycarbonylation and trimethylsilylation of pyrazole are

effected by analogous methods
• Mixtures of 1,3- and 1,5-disubstituted pyrazoles are

formed from 3- and 5-substituted pyrazoles because
of the ambident nature of the pyrazolyl anion, e.g.:
Michael additions
C4 Electrophilic Substitution
Reactions with nucleophilic reagents
• Pyrazoles either do not react with nucleophiles, or react with them only very slowly.
For instance, pyrazoles unsubstituted in the 3 -position undergo ring opening on heating with alkali hydroxides. Nucleophilic
substitution of a halogen in halopyrazoles is also difficult.
Oxazole
Construction of the Oxazole Ring
It is the cyclodehydration
of 2-acylamidoketones,
Fisher oxazole synthesis
The condensation of an aromatic aldehyde with an aldehyde cyanohydrin under anhydrous acidic conditions provides
oxazoles.
Isoxazole

Hetrocyclic Chemistry

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Course Title: Carbohydrates, Hetrocyclic Compounds,

Organometallic Reagents and Synthetic Methods

Heterocyclic compounds: Brief introduction of hetrocyclic compounds. Nomenclature of heterocyclic compounds.

• Introduction of heterocyclic compounds

• Heterocyclic Chemistry: John A. Joule, Keith Mills

Diazines and triazines

• Aphoteric nature, susceptible to

Imidazole, like water, is both a good donor

• It is used for the treatment of

benzodiazepine antagonist that is

Cimetidine is used to treat ulcers;

Protonation Acid-base reactions

• Imidazoles are moderately strong bases. The pKa value of the

• Imidazoles unsubstiruted in the 1-position are weak acids. The

Alkylation, acylation, sulfonation and silylation occur on the N-atoms of imidazoles

Because of the ambident character of the imidazolyl anion, 4- or

• The use of 1-acylimidazoles as acylating agents is of great importance.

Prepared from phosgene and imidazole, is particularly reactive.

Pechmann Pyrazole Synthesis

Reactions with electrophilic reagents

• Benzylation, acetylation, benzoylation, methylsulfonation, methoxycarbonylation and trimethylsilylation of pyrazole are

• Mixtures of 1,3- and 1,5-disubstituted pyrazoles are

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