REACTIONS OF FIVE

MEMBERED
HETEROCYCLES

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 Five-Membered Heterocycles
Structure

• The structures of five membered saturated heterocycles

adopt an envelope conformation similar to cyclopentane
to minimize torsional strain.
• The heteroatom occupies the out-of-plane position to
avoid gauche interactions.
• See the structure of pyrrolidine below.

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 Reactions of Five-Membered Heterocycles
Pyrrolidines as a Bases

• Among the saturated heterocycles only pyrrolidine has

significant basic character.

• Pyrrolidine is more basic than acyclic secondary amines

because the nitrogen lone pair is more exposed in the
structure. The pKa of pyrrolidine is 11.31 while the pKa
of diethylamine is 11.09
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 Basicity of Five-Membered Aromatic
Heterocycles
• The majority of five-membered heterocycles are
aromatic compounds with a planar structure.

• The lone pair of electrons on the heteroatom contributes

to the six-electrons of the p-system to fulfil the
aromaticity requirement.
• Due to this contribution to aromaticity, the lone pair of
electrons on nitrogen of pyrrole is not readily available
to engage in basicity. The pKa of pyrrole is −3.8. 4
 Structure of Five Membered Aromatic
Heterocycles
• Five-membered aromatic heterocycles have a p-electron
excess (six electrons on five atoms) relative to benzene
with an p-electron density of one on each ring atom.

• Although five membered heterocycles have an

electronegative heteroatom, they are more electron rich
compared to benzene, thus classified as p-excessive. 5
 Aromatic Heterocycles
Classification
• Generally, other aromatic heterocycles can also be
classified as either p-excessive or p-deficient.
AROMATIC HETEROCYCLES

p- EXCESSIVE p- DEFICIENT

• Thus relative to benzene, pyridine in p-deficient.

• There is a vast difference between the properties of the
two classes of aromatic heterocycles.
• A characteristic of p-deficient heterocyclic systems is
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their low reactivity with electrophilic agents.
 Reactions of Five Membered Heterocycles
Electrophilic Aromatic Substitution

• The substitution in the five membered heterocycles is

regioselective to the a position.
• However, when the a-positions are occupied, the b-
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position becomes the target for substitution.
 Reactions of Five Membered Heterocycles
Why the Regioselectivity

• An inspection of the resonance structures for a and b-

substitution shows that the +ve charge is better
resonance stabilized when the substitution is at the a-
position than at b-position.

• Whereas a more stable intermediate cation stabilized by

3 resonance structures is formed in a-substitution, in b-
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substitution only 2 resonance structures are formed.
 Halogenation of Five Membered
Heterocycles

• Halogenation occurs at the a-position. Bromination and

iodination are easy to control compared to the more
electrophilic chlorination, which requires low
temperatures to control the chlorination.
• For example, furan can be brominated and chlorinated
as illustrated below

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 Nitration of Five Membered Heterocycles

• The reagent AcONO2 is generated in situ from

concentrated HNO3 and Ac2O.
• The nitration with AcONO2 occurs by electrophilic
aromatic substitution.
• Furan, pyrrole and thiophene can readily be nitrated
using this combination of reagents.

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 Mechanism of Nitration of Five Membered
Heterocycles
• The nitration of furan follows the following steps:

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 Acylation of Five Membered Heterocycles

• The acylation of five membered heterocycles commonly

employs an acid anhydride in the presence of an acid
catalyst (e.g. phosphoric acid) or a Lewis acid (e.g. BF3,
ZnCl2 , SnCl4 and AlCl3 ).
• a-Acetylation of furan can be accomplished using acetic
anhydride in the presence of phosphoric acid.

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Mechanism of Acylation of Five Membered
Heterocycles
• The phosphoric acid catalyzed acetylation of furan with
acetic anhydride follows the following steps:

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 Reactions of Five Membered Heterocycles
Hydrogenation

• The five membered aromatic heterocycles undergo

hydrogenation in the presence of a metal catalyst to
provide the corresponding tetrahydro derivatives.
• Using different metal catalysts (Pd, Ni, Pt or PtO2),
diverse saturated heterocycles can be accessed.

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 Practice Questions
Reactions of Five Membered Heterocycles
Complete the following reactions by providing the principal
organic products:

Propose a reasonable and stepwise reaction mechanism for

the transformation below:

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 CAT 2

SYNTHESIS AND REACTIONS OF HETEROCYCLES

THURSDAY, 18TH APRIL 2019

10-11 AM
CHEMISTRY LAB

10:43 AM 17