Heterocyclic Compounds SS - Final

ANJAC CHEMISTRY CSIR / GATE / SET 15-10-2023
COACHING PROGRAMME
CHEMISTRY OF HETERCYCLIC COMPOUNDS
Synthesis and reactivity of common

1 Five membered Aromatic heterocycles heterocyclic compounds containing one
or two heteroatoms (O, N, S)
2 Fused five membered Aromatic heterocycles

SYNOPSIS
3 Six membered Aromatic heterocycles
4 Fused six membered Aromatic heterocycles
5 Non-aromatic heterocycles
6 Questions
Dr. S. SARAVANAN, Associate Professor of Chemistry, Ayya Nadar Janaki Ammal College, Sivakasi
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COACHING PROGRAMME
Introduction
 Cyclic organic compounds containing one or more heteroatom in the ring structure.
 Nitrogen, Oxygen and Sulphur are the most common heteroatoms.
 Heterocyclic compounds have many biological properties.
Antibiotic Sedative Sweetener
 Many heterocycles have the same chemistry as their open chain counterparts. For example, Lactone and acyclic esters
behave similarly, lactams and acyclic amides behave similarly and cyclic and acyclic ethers behave similarly.
 However, in certain cases, particularly when the ring is unsaturated, heterocycles have unique and interesting properties.
Classification
 Aromatic (Unsaturated)  3 membered heterocyclic compounds  Heterocyclic compounds with

 4 membered heterocyclic compounds one hetero atom
 Heterocyclic compounds with
 Aliphatic (saturated)  5 membered heterocyclic compounds
more than one hetero atom
 6 membered heterocyclic compounds
 Fused or condensed heterocyclic  7 membered heterocyclic compounds
compounds
 8 membered heterocyclic compounds
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COACHING PROGRAMME
Five membered Aromatic heterocyclic compounds with one heteroatom

Fused Heterocyclic compounds with one hetero atom
Simple Heterocyclic compounds

with one hetero atom
Six membered Aromatic heterocyclic compounds

Fused Heterocyclic compounds with two hetero atoms
Simple Heterocyclic compounds

with two hetero atom
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COACHING PROGRAMME
RETROSYNTHETIC ANALYSIS
 Typical disconnections for the synthesis of five- and six-membered aromatic heterocycles.
1,4-dicarbonyl compounds with N / S / O nucleophiles 1,5-dicarbonyl compounds with N / S / O nucleophiles
enol / enolate with C-C-X enamine with 1,3-dicarbonyl compounds
1,3-dipolar cycloaddition
SYNTHESIS OF FIVE MEMBERED HETEROCYCLES

Cyclization of 1,4-dicarbonyl compounds with N / S / O nucleophiles gives aromatic heterocycles.
Pall-Knorr synthesis:
In this method, a 1,4-diketone is heated with ammonia or a primary amine to gives the corresponding pyrrole
derivatives
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COACHING PROGRAMME

Cyclization of 1,4-dicarbonyl compounds with N / S / O nucleophiles gives aromatic heterocycles.
• Pall-Knorr synthesis:

 Synthesis from enol / enolate and C-C-X compound.
R4 must be an acidifying group

Ketone, ester, nitrile or nitro group Knorr Synthesis From a - Aminocarbonyl - Compounds and Activated Ketones
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COACHING PROGRAMME

General combinations to produce five-membered heterocycles via 1,3-dipolar cycloadditions.
Diploar addition of mesoionic

compounds to alkene / alkyne
leads to pyrroles.
Cycloreversion
– preparation of furan from oxazole
SYNTHESIS OF FIVE MEMBERED HETEROCYCLES (TWO HETEROATOMS)

From Furan: Industrially pyrrole is prepared by passing a mixture of furan and ammonia over alumina over 400° C.
 Interaction of thioglycolates with 1,3 - dicarbonyl - compounds
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COACHING PROGRAMME
STRUCTURE OF FIVE MEMBERED HETEROCYCLES
REACTIVITY OF FIVE MEMBERED HETEROCYCLES

Protonation of Pyrroles
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COACHING PROGRAMME

Reactions of Protonated Pyrroles
The 2 H - and 3 H - pyrrolium cations are electrophilic: they play the key role in polymerisation and reduction
of pyrroles in acid
The reaction of pyrroles with hydroxylamine hydrochloride produces ring - opened 1,4 - dioximes,

Aromatic Electrophilic Substitution Reactions
 Pyrrole, furan and thiophene undergo aromatic electrophilic substitution reactions preferentially at C-2 position.
 Reaction at C-2 position leads to a more stable carbocation intermediate having three resonance forms
 Reaction at C-3 position gives a less stable carbocation with only two resonance forms and hence the reaction at C-
3 proceeds more slowly.
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COACHING PROGRAMME

 Aromatic Electrophilic Substitution Reactions

 The relative reactivities are reflected in the Lewis acid required to catalyze a Friedel-Craft’s acylation reaction.
 Benzene requires a relatively strong Lewis acid.
 Thiophene can undergo a Friedel-Crafts reaction using SnCl4, a relatively weaker Lewis acid.
 An even weaker Lewis acid, BF3, can be used when the substrate is furan.
 Pyrrole is so reactive that an anhydride is used instead of a more reactive acyl chloride and no catalyst is necessary.
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COACHING PROGRAMME
The reaction of HNO3 and acetic anhydride resulted acetyl nitrate in which –NO2 acts as an electrophile.
Effect of substituent on Regioselectivity
2-Methylpyrrole
2-acetylpyrrole
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COACHING PROGRAMME

Sulphonation
sulfur trioxide (SO3) – pyridine mixture in ethylene chloride
Sulfenylation of pyrrole 20 and thiocyanation of pyrrole or of 1 - phenylsulfonylpyrrole also provide means for the
electrophilic introduction of sulfur groups, at lower oxidation levels

Halogenation
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COACHING PROGRAMME
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COACHING PROGRAMME

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

Reaction with nucleophilic agents
Pyrrole and its derivatives react with nucleophilic reagents when the leaving group is ortho or para to an electron - withdrawing
group.
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COACHING PROGRAMME

Oxidation
Simple pyrroles are generally easily attacked by strong oxidising agents Reduction
Side chain Oxidation

Pyrroles which have a ketone or ester substituent are more resistant to ring degradation and high – yielding side - chain
oxidation can be achieved using cerium(IV) ammonium nitrate, with selectivity for an α - alkyl.

Condensation with aldehydes and ketones
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COACHING PROGRAMME

Condensation with aldehydes and ketones

Reactions with Bases Pyrrole N - hydrogen is much more acidic (p K a 17.5) than that of a comparable saturated
amine, say pyrrolidine (p K a 44), or aniline (p K a 30.7), and of the same order as that of
2,4 - dinitroaniline
Lithium, Sodium, Potassium and Magnesium Derivatives
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COACHING PROGRAMME

C - Metallation and Reactions of C - Metallated Pyrroles
Metal – Halogen Exchange

Reactions with Carbenes and Carbenoids
The reaction of pyrrole with dichlorocarbene proceeds in part via a dichlorocyclopropane intermediate, ring
expansion of which leads to 3 - chloropyridine
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COACHING PROGRAMME

 The relative resonance energies are in the order:
 It is the order of aromaticity.
Thiophene with the least electronegative heteroatom
 Hence, Furan undergoes Diels-Alder reaction readily.
has the greatest resonance energy
 It gives the thermodynamic product (exo adduct) since the reaction is reversible (Secondary orbital interaction Stabilizes).
 Pyrrole undergoes Diels-Alder reaction to give endo adduct.

 Aromaticity prevents thiophene to take park in Diels-Alder reaction. But oxidation to sulphone destroys the aromaticity,
because both lone pairs are involved in bonding to oxygen atom.
 The sulphones is unstable and reacts with itself but will also undergo Diel’s-Alder reaction. If the dieneophile is an alkyne,
loss of SO2 gives a substituted benzene derivative.
 Similar reactions occur with a-pyrones. They are also unstable and react with alkynes by Diels-Alder reactions followed by
reverse Diels-Alder reaction to give benzene derivative with the loss of CO2.
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COACHING PROGRAMME

 Typical reactions of pyrrole, furan and thiophene
18

Heterocyclic Compounds SS - Final

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ANJAC CHEMISTRY CSIR / GATE / SET 15-10-2023

CHEMISTRY OF HETERCYCLIC COMPOUNDS

Synthesis and reactivity of common

2 Fused five membered Aromatic heterocycles

3 Six membered Aromatic heterocycles

4 Fused six membered Aromatic heterocycles

CHEMISTRY OF HETERCYCLIC COMPOUNDS

Antibiotic Sedative Sweetener

CHEMISTRY OF HETERCYCLIC COMPOUNDS

 Aromatic (Unsaturated)  3 membered heterocyclic compounds  Heterocyclic compounds with

CHEMISTRY OF HETERCYCLIC COMPOUNDS

Five membered Aromatic heterocyclic compounds with one heteroatom

Simple Heterocyclic compounds

CHEMISTRY OF HETERCYCLIC COMPOUNDS

Six membered Aromatic heterocyclic compounds

Simple Heterocyclic compounds

CHEMISTRY OF HETERCYCLIC COMPOUNDS

1,4-dicarbonyl compounds with N / S / O nucleophiles 1,5-dicarbonyl compounds with N / S / O nucleophiles

enol / enolate with C-C-X enamine with 1,3-dicarbonyl compounds

CHEMISTRY OF HETERCYCLIC COMPOUNDS

SYNTHESIS OF FIVE MEMBERED HETEROCYCLES

CHEMISTRY OF HETERCYCLIC COMPOUNDS

SYNTHESIS OF FIVE MEMBERED HETEROCYCLES

CHEMISTRY OF HETERCYCLIC COMPOUNDS

SYNTHESIS OF FIVE MEMBERED HETEROCYCLES

R4 must be an acidifying group

CHEMISTRY OF HETERCYCLIC COMPOUNDS

SYNTHESIS OF FIVE MEMBERED HETEROCYCLES

Diploar addition of mesoionic

CHEMISTRY OF HETERCYCLIC COMPOUNDS

SYNTHESIS OF FIVE MEMBERED HETEROCYCLES (TWO HETEROATOMS)

 Interaction of thioglycolates with 1,3 - dicarbonyl - compounds

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REACTIVITY OF FIVE MEMBERED HETEROCYCLES

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