Heterocyclic compound

Introduction:
The IUPAC Gold Book describes heterocyclic compounds as:
‘Cyclic compounds having as ring members atoms of at least two
different elements, e.g. quinoline, 1,2-thiazole
IUPAC (2009) IUPAC Compendium of Chemical Terminology - the Gold Book heterocyclic compounds:
http://goldbook.iupac.org/H02798.html

‘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.
Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José
Barluenga, 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co.
KGaA
Heterocyclic compounds include many of the biochemical material essential to
life. For example, nucleic acids, the chemical substances that carry the genetic
information controlling inheritance, consist of long chains of heterocyclic units
held together. Many naturally occurring pigments, vitamins, and antibiotics are
heterocyclic compounds.

Ergot, a fungal disease of cereal grasses, is caused by the fungus1

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Claviceps purpurea, which produces indole alkaloids
Heterocyclic derivatives and classification
Heterocyclic derivatives as a group, can be divided into two broad areas:
aromatic and non-aromatic. (note : aromatic system must have 4n+2 π-electron)

1) the 1, five-membered rings are shown below, the derivative furan 1 is aromatic,
while tetrahydrofuran (2), dihydrofuran-2-one (3) are not aromatic, Why?.

2) The six-membered rings below, pyridine is aromatic (5), while piperidine (6),
piperidin-2-one (7) are not aromatic, why?
 Most heterocycles have the same chemistry as their open-chain counterparts
particularly when the ring is unsaturated.

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In general :
heterocyclic is the largest and most varied family of organic compounds, heterocyclic system
can be 3, 4, 5, 6, 7 membered rings

in addition to a fused rings (two rings joined at two adjacent atoms)

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 Heterocyclic analogues of cyclopentadiene with one heteroatom
or
Five membered monoheterocyclic*
*Organic chem. Solomons, p 655-
Cyclic compounds that include an element other than carbon are called heterocyclic
compound

N O S
Cyclopentadiene Cyclopentadiene
anion Furan Thiophene
H
Pyrrole

 Pyrrole, furan and thiophene are a five-membered heterocyclic compound, We

might expect each of these compounds to have properties of conjugated diene of
an amine , an ether or sulphide respectively.

 On this basis pyrrole , furan and thiophene must be considered to be aromatic, this is
proved by NMR spectrum

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 these heterocyclic compounds in general undergo electrophilic substitution reaction for
example; nitration ,sulphonation, halogenation ,Friedel-craft Acylation and coupling with
diazonium salts

 The Heat of combustion indicate resonance stabilization to the extent 22-28

kcal/mole less than the resonance energy of benzene (36kcal/mol)but much greater
than of most conjugated diene (about 3 kcal/mol).

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 Pyrrole

The delocalization of the lone pair of Pyrrole pushes electrons from the
nitrogen atom into the ring and we expect the ring to be electron-rich and
become more nucleophile.
Thus, decreased basicity of the nitrogen atom and increased acidity of the
NH group as a whole

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 Pyrrole is assumed to be an aromatic molecule. While Its protonated form is not
aromatic
Using orbital pictures, explain why?

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Class exercise
1) In each of the following, encircle the stronger base :

2) If the proton was removed from Pyrrole to give the structure shown below, would it still be
considered aromatic? Why or why not? Use pictures in your explanation.

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 Synthesis of heterocyclic
1. from 1,4-diketones: the Paal-Knorr synthesis

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 Paal-Knorr synthesis: pyrroles and thiophenes

-H2O

• Class exercise
• Write the Paal-Knorr synthesis of 2-ethyl-4-methyl Furan?
• Write the Paal-Knorr synthesis of 2-phenyl-5-methyl pyrrole starting from 1-phenyl-2,5-
dipentanon? 13
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2. Knorr pyrrole synthesis

α-

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Examples of pyrroles syntheses by Knorr method:

 Write the reaction mechanism for each reaction

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 Electrophilic substitution
The aromatic five-membered heterocycles pyrrole , furan and thiophene all undergo
electrophilic substitution, with a general reactivity order:
pyrrole >furan > thiophene > benzene.
This Due to the higher electron density at the carbons as shown by the resonance hybrids of
pyrrole as an example .

Write the resonance hybrids of furan and thiophene

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Electrophilic attack on aromatic five-membered heterocycles pyrrole , furan and
thiophene

Major isomer

Write the general electrophilic attack on furan and thiophene

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All these aromatic heterocycles react vigorously with chlorine and bromine, often
forming polyhalogenated products reaction 3. while reagent N-bromosuxcinamide (NBS)
give monosubstituted bromine

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Activity 1
in the following slid a top 200 pharmaceutical products by US prescription in 2012
http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster
open the link, choose one product, find the kinds of hetero rings system and write a
short note on its used (2-5 lines only) see the example bellow

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