Heterocyclic compounds

(4)

By
Dr. Ghassan Qais Ali
There are some important questions that we need to know and answer before
you start studying the reactions of five-membered rings such as:

 Why five-membered heterocycles with one heteroatom undergo electrophilic

substitution reactions instead of electrophilic addition reactions?
 Why are electrophilic substitution on five-membered rings occurring on carbon
atoms rather than on heteroatoms?
 Why Five-membered heterocycles with one heteroatom undergo electrophilic
substitution reactions at C-2 and C-3 ?
 Why pyrrole more reactive than furan and thiophene?
 Why the five-membered heterocycles more reactivity than benzene toward
electrophiles?
 Why the aromaticity of Thiophene greater than furan and pyrrole?
Five-membered heterocycles with one heteroatom; pyrrole, furan and thiophene, are
and are characterized by their ability to undergo electrophilic
substitution reactions on the ring carbons rather than to undergo addition reactions.
The electrophilic attack on the heteroatom is rare in the neutral heterocycles due to
the mesomeric electron release from the heteroatom. The heteroatom bears
partial positive charge and hinders the attack of electrophile, while the
negatively charged carbons facilitate the attack of electrophiles to occur at the
ring carbon atoms
 Five-membered aromatic heterocycles with one heteroatom undergo electrophilic
substitutions preferentially at the -position (C-2 and C-5) rather than at the -
position (C-3 and C-4) because of greater resonance stabilization of intermediate.
 In our study of electrophilic aromatic substitution, we found that we could
account for orientation on the following basis: the controlling step is the
attachment of the electrophilic reagent to the aromatic ring, which takes place
in such a way as to yield the most stable intermediate carbonium ion.

 Let us apply this approach to the reactions of pyrrole.

 Attack at position 3 yields a carbonium ion that is a hybrid of structures I and II.
 Attack at position 2 yields a carbonium ion that is a hybrid not only of structures
III and IV (analogous to I and II) but also of structure V.
 The extra stabilization conferred by V makes this ion the more stable one.
Reactivity Order in Five-Membered Heterocycles
 The reactivity of five-membered heterocycles towards electrophiles depends on:
(1) The electron availability on the ring carbon atoms.
(2) Mesomerically electron release from the heteroatom.
(3) The greater stabilization of transition state.

 The order of reactivity in five-membered heterocycles is :

pyrrole > furan > thiophene > benzene (for comparison).

 The greater reactivity of pyrrole towards electrophiles is attributed to the greater

electron releasing ability of trivalent nitrogen (when linked by three bonds)
making ring carbon atoms electron rich and to the greater stabilization of transition
states involving positive charge on the tetravalent nitrogen atom
 Furan is also reactive (although less than pyrrole) towards electrophiles
(preferably at C-2) and the reason is the same as for pyrrole. Since oxygen is
more electronegative than nitrogen and withdraws electrons from the ring
carbon atoms, the positive charge is less readily accommodated by oxygen
atom than by nitrogen atom. The transition state with oxygen atom positively
charged resulting from the electrophilic attack on furan is, therefore, less stable
than that of pyrrole. Thus, furan is less reactive towards electrophiles than
pyrrole as phenol is less reactive than aniline.
 Thiophene is less reactive than even furan towards electrophiles. The sulfur
atom is less electronegative than the oxygen atom and therefore withdraws
electrons less readily from the ring carbon atoms. Moreover, +M effect of
sulfur (mesomeric electron release from sulfur) is smaller than that of oxygen
because of not effective overlapping of differently sized p-orbitals of carbon
and sulfur than in carbon and oxygen. The relative reactivity of thiophene and
furan can be shown by the following reaction in which nitration with mild
nitrating agent occurs only in furan nucleus at C-2

 The extra stabilization of thiophene is attributed to the expansion of valence

shell of sulfur by using d-orbitals in hybridization.
Reactivity Comparison with Benzene
The electrophilic substitution in thiophene is much easier than in benzene. Thiophene
is brominated 109 times more rapidly than benzene which, in tum, is 103-107 times
more reactive than pyridine. Thus, benzene is much less reactive than the five-
membered heterocycles towards electrophiles. The reactivity depends on:

(i) The stabilization energy.

(ii) The stability of transition state.

The lower reactivity of benzene towards electrophiles is attributed partly to the

greater resonance stabilization energy of benzene. The higher energy of the transition
state of benzene than the structurally related transition states of five-membered
heterocycles is also responsible for the lower reactivity of benzene . The stability
order of the transition states has been observed to be as follows
Effect of Aromaticity on Reactivity

Electrophilic addition in acyclic system

Electrophilic substitution in heterocyclic system

 Thus, in both the systems; acyclic and heterocyclic
 The first step is the same and involves an electrophilic attack.
 The second step acyclic conjugated system instead of losing a proton is attacked
by a nucleophile at the positively charged carbon atom providing addition
product.
summary
. Pyrrole, furan, and thiophene undergo electrophilic substitution, preferentially at C-2.
(Reactivity)

• The aromaticity order in these heterocycles depends on the electronegativity of

the heteroatom : O > N > S and, therefore, the aromaticity follows the order as :
Thiophene > Pyrrole > Furan.
• The extra stabilization of thiophene is attributed to the expansion of valence shell of
sulfur by using d-orbitals in hybridization.

General mechanism of electrophilic substitution in the five-membered heterocycles

Orientation:
Effect of electron-releasing substituents at C-2
 The effect of electron-releasing substituents at C-2 position is similar to that of
ortho-para directing substituents in benzene and tend to direct incoming electrophile
to C-5 position.
1) In the presence of weakly electron-releasing substituents(-Cl, -CH3) at C-2
position tend to direct incoming electrophile to C-5 position.
2) But with strongly activating substituents (-OCH3, -NHCOCH3) the substitution
may occur at C-3 due to the ortho-effect of electron-releasing substituents
Effect of electron-withdrawing substituents at C-2
The effect of electron-withdrawing substituents is similar to the meta-directing effect in benzene.
1) The presence of electron-withdrawing substituent at C-2 causes substitution at C-4 due to directing
influence of the substituent.
2) But the directing effect of substituent competes with the -directing effect of heteroatom which
causes substitution to occur at C-5. The formation of 2,5-disubstituted furan is rationalized by the
most powerful -directing effect of oxygen in furan than that of sulfur and nitrogen in thiophene, and
pyrrole respectively.
Effect of electron-releasing substituents at C-3
 The presence of electron-releasing substituents at C-3 will reinforce the -directing effect of ring
heteroatom with the substitution at C-2

 If the electron-releasing substituent is alkyl, the reactivity of -positions (C-2 and C-5) does not
differ appreciably and in case of the sterically hindered alkyl group or incoming electrophile, the
substitution at C-2 is restricted and occurs at C-5
Effect of electron-withdrawing substituents at C-3
 The effect of electron-withdrawing substituent at C-3 is similar to the meta
directing effect in benzene and is reinforced by the a-directing effect of ring
heteroatom. Thus, the combined effect of both the effects; meta-directing effect
of the substituent and directing effect of the heteroatom, causes substitution to
occur at C-5 most favourably
Effect of electron-releasing substituents at C-2
Weakly electron-releasing substituents (-Cl, -CH3) at C-2 position C-5 position

Strongly activating substituents (-OCH3, -NHCOCH3) at C-2 position C-3 position

Effect of electron-releasing substituents at C-3

The presence of electron-releasing substituents at C-3 position C-2 position

Sterically hindered alkyl group at C-3 position or incoming electrophile C-5 position

Effect of electron-withdrawing substituents at C-2

The presence of electron-withdrawing substituent at C-2 position C-4 and C-5 position

The directing effect of substituent at C-2 competes with the directing effect of furan C-5
position

Effect of electron-withdrawing substituents at C-3

The effect of electron-withdrawing substituent at C-3 position C-5 position
Electrophilic substitution in pyrrole, furan, and thiophene.

 Like other aromatic compounds, these five-membered heterocycles

undergo nitration, halogenation, sulfonation, and Friedel-Crafts
acylation. They are much more reactive than benzene and resemble
the most reactive benzene derivatives (amines and phenols) in
undergoing such reactions as the Reimer-Tiemann reaction,
nitrosation, and coupling with diazonium salts. The reaction takes
place predominantly at the 2-position. For example:
 In some of the examples, we notice modifications in the usual
electrophilic reagents.
 The high reactivity of these rings makes it possible to use milder
reagents in many cases, as, for example:
 The weak Lewis acid stannic chloride in the Friedel Crafts
acylation of thiophene.
 The sensitivity to protic acids of furan (which undergoes ring
opening) and pyrrole (which undergoes polymerization) makes it
necessary to modify the usual sulfonating agent
Reactions of Pyrroles:
1- Nitration:
1-(1H-pyrrol-2-yl)ethan-1-one
2- Sulfonation :
Pyrrole and its N- and C-alkylpyrroles cannot be sulfonated under ordinary conditions as these are
polymerized by concentrated sulfuric acid. These are, therefore, sulfonated by mild sulfonating agent
(pyridine-sulfur trioxide) of low acidity. The reaction of pyrrole with pyridine-sulfur trioxide complex at
100°C, a 90% yield of the corresponding pyrrole-2-sulfonic acid is obtained, after acidification.

Pyrroles substituted with electron- withdrawing substituents require vigorous reaction conditions (
chlorosulfonic acid, cone. sulfuric acid and oleum). If both the a-positions are blocked, the sulfonation
occurs at the
3- Halogenation :
The high reactivity of pyrrole ring system causes it to undergo halogenation at all the
strongly activating positions. The special reagents with mild conditions are, therefore,
required for the halogenation of pyrroles.

sulfuryl chloride

Note:
 Bromination of pyrrole with bromine in acetic acid gives 2,3,4,5-tetrabromopyrrole

 pyrrole substituted with electron-withdrawing substituent undergoes bromination providing

monobrominated pyrroles

ethyl 1H-pyrrole-2-carboxylate
 with bromine in carbon tetrachloride, 3-bromopyrrole is obtained by the isomerization of
thermodynamically less stable 2-bromopyrrole
4- Friedel-Crafts Acylation:
Typical electrophilic reactions, such as nitration, halogenation with a Lewis acid (as a ‘carrier’),
Friedel-Crafts C-alkylation and -acylation, that work well with benzene, cannot be applied to
pyrrole, because heating with strong acids, or a Lewis acid, destroys the heterocycle. However,
milder conditions can sometimes be used.

or pyrrole with acetic anhydride in the presence of sodium acetate provides N-acylpyrrole
 N-Acylpyrroles can be obtained by the reaction of alkali metal salt of pyrroles with
an acyl halide

5- Vilsmeier reaction :
The Vilsmeier reaction (reagents: POCl3, and N, N-dimethylformamide) gives 2-
formylpyrrole
6- Friedel-Crafts Alkylation:
Because of high reactivity of the pyrrole ring, Friedel-Crafts alkylation of pyrrole with alkyl halides and
highly reactive allyl- and benzyl halides results in polyalkylation under milder conditions. Therefore, it
is not possible to obtain monoalkylated product.
7) Hydroxymethylation (Mannich Reaction)
Pyrrole undergoes Mannich reaction with formaldehyde and primary or secondary amine in the presence
of an acid with the introduction of functionalized alkyl group at the -position. However, if both the a-
positions are substituted, the substitution then occurs at a free -position. The reaction is
considered to involve electrophilic attack of iminium electrophile which is produced in situ from the
reaction of formaldehyde with amine in the presence of an acid. The product of Mannich reaction
(Mannich base) is synthetically useful as it undergoes a number of transformations providing important
compounds.
Mechanism

R = CH3
8) Diazo Coupling
Pyrrole undergoes diazo coupling reactions very readily with benzenediazonium salts providing 2-
aza- or 2,5-bis(aza)- pyrroles depending on the reaction conditions. The rate of the reaction is faster
in an alkaline media as it involves pyrrolyl anion and results in the formation of 2,5-bis(aza)-
pyrrole

 If both the -positions are occupied, diazo coupling occurs at the B-position
9) Reimer-Tiemann reaction