REACTIONS OF FIVE MEMBERED

HETEROCYCLES

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Five-Membered HeterocyclesStructure

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• 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.

Reactions of Five-Membered HeterocyclesPyrrolidines as a Bases

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• 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

Basicity of Five-Membered Aromatic Heterocycles

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• 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.

Structure of Five Membered Aromatic Heterocycles

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• 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.

Aromatic HeterocyclesClassification

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• 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

their low reactivity with electrophilic agents.

Reactions of Five Membered HeterocyclesElectrophilic Aromatic Substitution

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• The substitution in the five membered heterocycles is

regioselective to the a position.

• However, when the a-positions are occupied, the b-

position becomes the target for substitution.

Reactions of Five Membered HeterocyclesWhy the Regioselectivity

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• 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-

substitution only 2 resonance structures are formed.

Halogenation of Five Membered Heterocycles

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• 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

Nitration of Five Membered Heterocycles

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• 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.

Mechanism of Nitration of Five Membered Heterocycles

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• The nitration of furan follows the following steps:

Acylation of Five Membered Heterocycles

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• 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.

Mechanism of Acylation of Five Membered Heterocycles

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• The phosphoric acid catalyzed acetylation of furan with

acetic anhydride follows the following steps:

Reactions of Five Membered HeterocyclesHydrogenation

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• 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.

Practice QuestionsReactions of Five Membered Heterocycles

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Complete the following reactions by providing the principal

organic products:

Propose a reasonable and stepwise reaction mechanism for

the transformation below:

CAT 2

SYNTHESIS AND REACTIONS OF HETEROCYCLES

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THURSDAY, 18TH APRIL 2019

10-11 AM

CHEMISTRY LAB

10:43 AM