Heterocyclic Compounds

A heterocyclic compound is one that contains a ring made up of more than one
kind of atom.
In heterocyclic compounds, the ring (or rings) contain, in addition to carbon,
other kinds of atoms, most commonly nitrogen, oxygen, or sulfur. For example:
Structure of pyrrole, furan, and thiophene

We might expect each of these compounds to have the properties of a conjugated

diene and of an
amine, an ether, or a sulfide (thioether).

However, except for a certain tendency to undergo addition reactions, these

heterocycles do not have the expected properties: thiophene does not undergo the
oxidation typical of a sulfide, or
pyrrole does not possess the basic properties typical of amines.

These heterocycles and their derivatives most commonly undergo electrophilic

substitution: nitration, sulfonation, halogenation, Friedel-Crafts acylation, even the
Reimer-Tieman reaction
and coupling with diazonium salts.

Heats of combustion indicate resonance stabilization to the extent of 22-28 kcal/

mol; somewhat less than the resonance energy of benzene (36 kcal/mol), but much
greater than that of most
conjugated dienes (~ 3 kcal/mol).

Thus, pyrrole, furan and thiophene must be considered aromatic. Therefore, these
In pyrrole, each atom of the ring, whether carbon or nitrogen, is held by a σ bond
to three other atoms.

Each atoms use three sp2 orbitals, which lie in a plane and are 1200 apart.

After contributing one electron to each σ bond, each carbon atom of the ring has
left one electron and nitrogen atom has left two electrons; these electrons occupy
the p orbitals.

Overlap of the p orbitals gives rise to π clouds, one above and one below the plane
of the ring; the π clouds contain a total of six electrons, the aromatic sextet.
Delocalization of the π electrons stabilize the ring. As a result, pyrrole has an
abnormally low heat of combustion; it tends to undergo substitution so that its
stabilized ring is retained.

Nitrogen’s extra pair of electrons, which is responsible for the usual basicity of
nitrogen compounds, is involved in the π cloud, and is not available for sharing
with acids. Therefore, in contrast to most amines, pyrrole is an extremely weak
base (K b ~ 2.5 X 10-14).

On the other hand, the high electron density in the ring causes pyrrole to be
extremely reactive toward electrophilic substitution: it undergoes reactions like
nitrosation and coupling with diazonium salts which are characteristic of only the
most reactive benzene derivatives: phenols and amines.

Thus, pyrrole is better represented as following in which the circle represents the
aromatic sextet:

This structure can be considered a hybrid of the following structures:

Furan and thiophene are structurally quite similar to pyrrole.

The oxygen atom in furan and the sulfur atom in thiophene are sp2 -hybridized. In
both compounds the p orbital of the heteroatom donates two electrons to the π
system.

The oxygen and sulfur atoms of furan thiophene carry an unshared pair of
electrons in an sp2 orbital that is orthogonal to the π system.

Thus, furan and thiophene also behave like extremely reactive benzene
derivatives.

thiophen
e
Source of pyrrole, furan, and thiophene

Pyrrole and thiophene are found in small amounts in coal tar.

During the fractional distillation of coal tar, thiophene (b.p. 840 C) is collected along
with benzene (b.p. 800 C); as a result ordinary benzene contains about 0.5% of
thiophene, and must be specially treated if thiophene-free benzene is desired.

Thiophene can be synthesized on an industrial scale by the high-temperature

reaction between
n-butane and sulfur.

Pyrrole can be synthesized in a number of ways:

Furan is most readily prepared by decarbonylation (elimination of carbon
monoxide) of furfural (furfuraldehyde), which in turn is made by the treatment
of oat hulls, corncobs, or rice hulls with hot hydrochloric acid.

In the latter reaction pentosans (polypentosides) are hydrolyzed to pentoses,

which then undergo dehydration and cyclization to form furfural.

Most substituted pyrroles, furans, and thiophenes are prepared from open-chain
compounds by ring closure:
Electrophilic substitution in pyrrole, furan, and thiophene. Reactivity and
Orientation

These five membered heterocycles show more reactivity than benzene in

undergoing electrophilic substitution reactions like nitration, halogenation,
sulfonation, and Friedel-Crafts acylation.

They resemble the most reactive benzene derivatives (amines and phenols) in
undergoing reactions like the Reimer-Tieman reaction, nitrosation, and coupling
with diazonium salts.

Reactions take place predominantly at the 2-position. For example:

In some examples, we notice modifications in the usual electrophilic reagents.

The high reactivity of these rings makes it possible to use milder electrophilic
reagents. For example, we used a 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.
We can account for the orientation of the electrophilic substitution 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 carbocation.
Attack at position 3 yields a carbocation that is a hybrid of structures I and II.
Attack at position 2 yields a carbocation 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.
Viewed differently, attack at position 2 is faster because the developing positive
charge is accommodated by three atoms of the ring instead of only two.
Pyrrole is highly reactive, compared with benzene, because of contribution form
the relatively stable structure III. In III every atom has an octet of electrons;
nitrogen accommodates the positive charge simply by sharing four pairs of
electrons.
Thus pyrrole resembles aniline in reactivity: both owe their high reactivity to
the ability of nitrogen to share four pairs of electrons.
Orientation of substitution in furan and thiophene, as well as their high
reactivity, can be accounted for in a similar way.

Saturated five-membered heterocycles

Catalytic hydrogenation converts pyrrole and furan into the corresponding

saturated heterocycles, pyrrolidine and tetrahydrofuran.

Thiophene poisons most catalysts, thus tetrahydrothiophene is synthesized instead

from open-chain compounds.
aromatic properties. Thus pyrrolidine, tetrahydrothiophene and tetrahydrofuran
has the properties of a secondary amine, an aliphatic ether, or an aliphatic sulfide
respectively.

Pyrrole could not behave as a base as the lone pair of electrons on nitrogen was
part of the aromatic sextet and hence not available for donation (Kb ~ 10 -14). But in
pyrrolidine, that lone pair of electrons on nitrogen becomes available for sharing
with acids, leading to it having the normal basicity of an aliphatic amine(Kb ~ 10 -3 ).
Thus, hydrogenation of pyrrole increases the base strength by a factor of 10 11
(100 billion).

Figure: Electronic configuration and molecular shape: (a) and (b) pyrrole, aromatic; (c)
pyrrolidine, aliphatic.
Here, pyrrole has the characteristic aromatic shape: flat, like benzene – or, more precisely, like
the
cyclopentadienyl anion, with which it is isoelectronic.
Pyrrolidine, on the other hand, is clearly aliphatic, and closely resembles cyclopentane, with
an unshared pair of
Tetrahydrofuran is an important organic solvent. For example, it is used in: (a)
Reductions with lithium aluminium hydride (LiAlH4 ), (b) The preparation of
arylmagnesium chlorides (ArMgCl), and (c) Hydroborations.
Oxidation of tetrahydrothiophene yields tetramethylene sulfone (or sulfolane),
also used as an aprotic solvent.

Problem 1. An older process for the synthesis of both the adipic acid and the
hexamethylenediamine used in the manufacture of nylon-6,6 started with
tetrahydrofuran. Using
only familiar chemical reactions, suggest possible steps in their synthesis.

Solution:
Six Membered Ring

Structure of Pyridine

Pyridine is classified as aromatic because: (a) It is flat, with bond angles of 1200 ;
(b) The four carbon-carbon and two carbon-nitrogen bonds are of the same length;
(c) It resists addition and undergoes electrophilic substitution, (d) Its heat of
combustion indicates a resonance energy of 23 kcal/mol.

Pyridine can be considered a hybrid of the Kekulé structures I and II. It is

represented as structure III, in which the circle represents the aromatic sextet.

In pyridine the nitrogen atom, like each of the carbon atoms, is bonded to other
members of the ring by the use of sp 2 orbitals, and donates one bonding electron
to the π system.

This electron, together with one from each of the five carbon atoms, gives pyridine
a sextet of electrons like benzene.

The third sp2 orbital of each carbon atom is used to form a bond to hydrogen; the
third sp2 orbital of nitrogen simply contains a pair of electrons.
Source of pyridine compounds

Pyridine is found in coal tar along with a number of methyl-pyridines, the most
important of which are the picolines or the monomethyl pyridines.

Oxidation of picolines yields the pyridinecarboxylic acids.

The 3-isomer (nicotinic acid or niacin) is known as vitamin B3 . The 4-isomer

(isonicotinic acid) has been used (in the form of its hydrazide) in the treatment of
tuberculosis.
The increasing demand for certain pyridine derivatives has led to the
development of syntheses involving ring closure. For example:

Reactions of Pyridine

The ring of pyridine undergoes the substitution, both electrophilic and

nucleophilic, which is typical of aromatic rings; with the nitrogen atom affecting
the reactivity and orientation of these
reactions.

Pyridine also acts as a base or nucleophile; these reactions involve nitrogen

directly and are due to
its unshared pair of electrons.
Electrophilic Substitution in Pyridine

Toward electrophilic substitution pyridine resembles a highly deactivated

benzene derivative. It undergoes nitration, sulfonation, and halogenation only
under very vigorous conditions, and does not undergo the Friedel-Crafts reaction
at all.

Substitution occurs chiefly at the 3- (or β-) position.

Attack at the 4-position yields a carbocation that is a hybrid of structures I, II, and
III.

Attack at the 3-position yields an ion that is a hybrid of structures IV, V, and VI.

(Attack at the 2-position resembles attack at the 4-position just as ortho attack
resembles para attack in the benzene series.)
All these structures are less stable than the corresponding ones for attack on
benzene, because of electron withdrawal by the nitrogen atom. As a result,
pyridine undergoes substitution more slowly than benzene.

Of these structures, III is especially unstable, since in it the electronegative

nitrogen atom has only a sextet of electrons. As a result, attack at the 4-position
(or 2-position) is especially slow, and substitution occurs predominantly at
the 3-position.

It is important to see the difference between substitution in pyridine and

substitution in pyrrole. In the case of pyrrole, a structure in which nitrogen
bears a positive charge (IIIa) is especially stable since every atom has an
octet of electrons; nitrogen accommodates the positive charge simply by
sharing four pairs of electrons.

In the case of pyridine, a structure in which nitrogen bears a positive charge

(IIIb) is especially unstable since nitrogen has only a sextet of electrons;
nitrogen shares electron readily, but as an electronegative atom it resists the
removal of electrons.
Nucleophilic Substitution in Pyridine

Toward nucleophilic substitution, the pyridine ring resembles a benzene ring that
contains strongly electron-withdrawing groups.

Nucleophilic substitution takes place readily, particularly at the 2- and 4-

position.
The reactivity of pyridine toward nucleophilic substitution is so great that even
the powerfully basic hydride ion, :H- , can be displaced. Two important examples
of this reaction are amination by sodium amide (Chichibabin reaction), and
alkylation or arylation by organolithium compounds.

Tschitschibabin (Chichibabin) reaction, 1914

When heated with sodamide in toluene solution, pyridine forms 2-aminopyridine;

excess of sodamide produces 2,6-diaminopyridine. Actually, the sodium salts are
formed, but on treatment
with water, are hydrolyzed to the amine.

Mechanism
1930)

Similarly,

+ Li:H

In nucleophilic aromatic substitution, reaction proceeds by two steps; the rate of

the first step, formation of a charged particle, determines the rate of the overall
reaction.

In nucleophilic substitution, the intermediate charged particle is negatively

charged.

The ability of the ring to accommodate the charge determines the stability of the
intermediate and
the transition state leading to it, and hence determines the rate of the reaction.
Nucleophilic attack at the 4-position yields a carbanion that is a hybrid of
structures I, II, and III:

Attack at the 3-position yields a carbanion that is a hybrid of structures IV, V, and
VI:

(As before, attack at the 2-position resembles attack at the 4-position.

All these structures are more stable than the corresponding ones for attack on a
benzene derivative, because of electron withdrawal by the nitrogen atom.

Structure III is especially stable, since the negative charge is located on the atom
that can best accommodate it, the electronegative nitrogen atom.

Therefore, nucleophilic substitution occurs more rapidly on the pyridine ring

than on the benzene ring, and more rapidly at the 2- and 4-positions than at
the 3-position.

The same electronegativity of nitrogen that makes pyridine unreactive toward

electrophilic substitution makes pyridine highly reactive toward nucleophilic
substitution.

Basicity of Pyridine

Pyridine is a base with Kb = 2.3 X 10-9 . It is thus much stronger than pyrrole (Kb ~
2.5 X 10-14) but much weaker than aliphatic amines (Kb ~ 10 -4 ) and pyrrolidine (Kb ~
10-3 ).

Pyridine has a pair of electrons in an sp2 orbital that is available for sharing with
acids; pyrrole has not, and can accept an acid only at the expense of the aromatic
character of the ring. This explains the superior basicity of pyridine over pyrrole.

The fact that pyridine is a weaker base than aliphatic amines is more difficult
to explain. It is tried to be accounted for in the next slides.
Benzene is a stronger acid than an alkane, as shown by its ability to displace an
alkane from its salts. Conversely, phenyl anion, C6 H5 - , is a weaker base than an
alkyl anion, R - .

(Stronger acid liberates the weaker acid, here benzene, being the stronger acid,
liberates the weaker acid alkane from its salt.

Conversely, stronger base liberates the weaker base, here the sodium salt of
alkane, being the stronger base, liberates the weaker base, the phenyl salt of
sodium.)

Similarly, acetylene is a stronger acid than benzene, and the acetylide ion is a
weaker base than the phenyl anion.

Therefore,
In the alkyl, phenyl, and acetylide anions, the unshared pair of electrons occupies
respectively an sp 3 , an sp2 , and an sp orbital.

As we proceed along the series sp3 , sp2 , and sp, the p character of the orbital
decreases and the s character increases.

An electron in a p orbital is at some distance from the nucleus and is held

relatively loosely.
An electron is an s orbital is close to the nucleus and is held more tightly.

The alkyl anion is the strongest base since its pair of electrons is held most
loosely, in an sp 3 orbital. The acetylide ion is the weakest base since its pair of
electrons is held most tightly, in an sp orbital.

(If the electron pair in an anion is held weakly, it can donate that pair more easily,
hence it acts as a stronger base. )

The pair of electrons that gives pyridine its basicity occupies an sp2 orbital; it is
held more tightly and is less available for sharing with acids than the pair of
electrons in an aliphatic amine, which occupies an sp 3 orbital.

Pyridine is widely used in organic chemistry as a water soluble base.

Like amines, pyridine shows nucleophilicity in its reaction with alkyl halides to
form quaternary ammonium salts.

Reduction of pyridine

Catalytic hydrogenation of pyridine yields the aliphatic heterocyclic compound

piperidine, C 5 H11N.
Piperidine has the usual basicity of a secondary aliphatic amine, a million time
greater than that of
pyridine. Like pyridine, piperidine is often used as a basic catalyst in such
reactions as the
Knoevenagel reaction or Michael addition.

(a) (b) (c)

Figure: Electronic configuration and molecular shape: (a) and (b) pyridine,
aromatic; (c) piperidine, aliphatic

Pyridine has the shape of benzene, with an unshared pair of electrons taking the
place of one hydrogen. Piperidine has the familiar shape of chair cyclohexane
with an unshared pair occupying
an equatorial – or, in another conformation, an axial- position.