Stereochemistry of Heterocyclic compounds

1 Introduction
Stereochemistry: It is the branch of Chemistry that deals with the study
stereoisomers. (Stereo = Spatial or three dimensional) Stereoisomerism is a type
of isomerism in which compounds have same molecular structure but different
spatial arrangement of atoms or groups in the molecule such isomers are known
as stereoisomers. Stereoisomerism is mainly classified into: (i) Optical
isomerism, (ii) Geometrical isomerism.
(i) Optical Isomerism
It is a type of stereoisomerism in which compounds having same structural
formula, but different configuration & with equal and opposite character
towards plane polarized light. These compounds are called optical isomers or
enantiomers. Examples listed below:

Optical Activity
Substances which rotate the plane of polarized light are said to be optically
active and this property is known as optical activity. Substances which can
rotate the plane of polarized light to right are called dextro – rotatory and
indicated by sign 'd' or (+). But substances which can rotate the plane of
polarized light to left are called levo – rotatory and indicated by sign '1' or (-).
Example: (+) Lactic acid is an optically active compound.
a) Optical and specific rotation
When the plane polarised light (p-p light) is passed through certain substances
or solutions, the emerging light is found to be vibrate in a different plane. This
is called optical rotation. The measurement of optical activity is reported in
terms of specific rotation. This specific rotation is a constant for a particular
substance. For example specific rotation of

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i) Sucrose is + 66.5
ii) phenyl lactic aid is + 52.0

b) Condition for optical activity (Chiral molecule, Chirality)

A molecule that is not superimposable on its mirror image is said to be
dissymmetric or asymmetric molecule. This property is known as asymmetry or
chirality. Such molecules are also called as chiral molecules. Example : (+) and
(-) lactic acid. Chirality is the condition, criterion or the cause of optical
activity.

c) Achiral molecule
A molecule that is superimposable on its mirror image is known as achiral
molecule, Example : 2-propanol. It does not have chiral centre.

d. Chiral centre or asymmetric centre

A carbon atom surrounded by four different atoms or groups is known as chiral
centre or asymmetric centre atom. Example : Carbon atom (C*) in (+) lactic
acid.

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ii). Geometrical isomerism (Cis-trans isomerism)
Geometrical isomerism is a kind of stereoisomerism it which compounds
have same structural formula but different configurations around the double
bond. Such compounds and called geometrical isomers or cis-trans isomers.

Methods of distinguishing Geometrical isomers.

Configuration of geometrical isomers can be determined using the following
methods:

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 i) Dehydration:
Intramolecular reactions are possible only, when the reacting groups are
closer together in a molecule. In maleic acid both the COOH groups are nearer
to each other. Therefore on heating maleic acid undergoes dehydration and
gives cyclic anhydride readily. But fumaric acid does not form an anhydride of
its own. Thus maleic acid is the cis isomer and fumaric acid is the transisomer.

ii) Method of cyclization:

2-Bromo-5-nitroacetophenone oxime exists in two isomeric forms. The
-oxime of 2-bromo-5-nitroacetophenone is unaffected by NaOH, whereas the
-isomer undergoes ring closure to form 3-methyl-5-nitrobenziso-oxazole. Thus
the α-oxime is the syn-methloy1 isomer (A) and the –oxime the antimethyl
isomer (B).

iii) Dipole moment studies:

Dipole moment is a vector quantity. In the transisomer bond moments
cancel each other. Therefore in general cis-isomer always has higher dipole
moment than the trans-isomer. For example there are two isomeric 1,2dichloro
ethane. The isomer which has 'zero' dipole moment is 'trans' and the other one is
'cis'.

iv) Melting point:

The melting point or cis-isomer is lower than than of the trans-isomer.
Example:
i) Melting point of maleic acid (cis) is 130C◦.
ii) Melting point of fumaric acid (trans) is 287C◦.

2 Heterocyclic compounds
Heterocyclic compounds are stable cyclic compounds with the ring
containing carbon and Oxygen, Nitrogen and Sulphur. These are usually five or
six membered cyclic compounds exhibiting aromatic character. Heterocyclic
compounds are mainly classified into three classes: fully saturated, partially
saturated, and fully unsaturated. The saturated heterocycles, such
as pyrrolidine, piperidine, etc., behave like aliphatic amines. All the carbons and
heteroatoms in the saturated heterocycles are sp3 hybridized and the lone pair of
electrons present is in nonbonded hybrid orbital. in unsaturated heterocycles,
such as furan, pyrrole and thiophene, which will focus on in this report, all the
atoms are sp2 hybridized, and the lone pair of electrons of the heteroatom is
either in “p” orbital or sp2 hybridized orbital and contributes to an aromatic π
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electron sextet, responsible for their aromatic character. In the case of fully
unsaturated conjugated heterocycles, all the carbons are sp2 hybridized; the “p”
orbital is perpendicular to the hybrid orbital and participates in π-bond
formation. These heterocycles possess aromatic character because they fulfill
the criteria of (4n + 2) π electrons for aromaticity. In the case of partially
saturated heterocycles, all the carbons are sp3 hybridized except olefinic
carbons, which are sp2 hybridized. However, the sp3 state of hybridization of
heteroatoms remains unchanged. The presence of partial unsaturation reduces
the basicity of the molecule compared to fully saturated heterocycles because
the electronegativity of sp2 orbitals is higher compared to sp3 hybrid orbitals.
Heterocyclic compounds possess a cyclic structure with two or more
different kinds of atoms in the ring. This work is devoted to
organic heterocyclic compounds in which the ring contains at least one carbon
atom; all atoms other than carbon are considered as heteroatoms. Carbon is still
by far the most common ring atom in heterocyclic compounds, but the number
and variety of heteroatoms in the rings of known compounds has increased as
the years go by and thus there is a steady transition to include the expanding
domain of inorganic heterocyclic systems. Since rings can be of any size, from
three-membered upwards, and since the heteroatoms can be drawn in almost
any combination from a large number of the elements (though nitrogen, oxygen,
and sulfur are still by far the most common), the number of possible
heterocyclic systems is almost limitless. An enormous number of heterocyclic
compounds is known and this number continues to increase very rapidly. The
literature of the subject is correspondingly vast and of the three major divisions
of organic chemistry, aliphatic, carbocyclic, and heterocyclic, the last is by far
the largest. Over 31 million compounds are now recorded in Chemical
Abstracts and a very large proportion of these are heterocyclic. Below present
compound Furan, Pyrrole and Thiophene.

2.2 Furan
Furan is a class of five-membered heterocyclic organic compounds,
consisting of four carbon atoms and one oxygen atom with two double bonds in
the aromatic ring.
Furan, more than any other aromatic heterocycle, has found considerable
application as a distinct building block for alicyclic, heterocyclic and acyclic
substructures in high complexity targets. Furans are commonly found as

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synthons in natural product synthesis, medicinal chemistry and diversity-
oriented synthesis. Molecular formula: C4H4O.
2.2.1 Preparation
 Dry distillation of mucic acid gives furoic acid. This on heating gets
decarboxylated to give furan.
 Furan is manufactured by the catalytic decomposition of furfural in steam
in the presence of CaO Catalyst.
 Synthesis - Paul Knorr Synthesis: Derivatives of furan are obtained by
heating acetonyl acetone with P2O5.
2.2.2 Reactions of furan
 Reduction reaction: Furan is reduced with hydrogen in the presence of
RaneyNi to give Tetrahydrofuran.
 Oxidation: Furan on oxidation in oxygen to give succinaldehyde.
 Diel’s - Alder reaction: Furan undergoes Diel’s - Alder reaction with
maleic anhydride to form adduct.
 Substitution reaction:
i) Furan undergoes Nitration to give 2 Nitro furan.
ii)Sulphonation of furan gives furan-2-sulphonic acid.
iii) Acetylation of furan gives 2-Acetyl furan.

2.2.3Uses of furan:
i) It is used as a starting material for the preparation of dyes, plastics and
polymers.
ii) It is used in the manufacture of nylon.
iii) Tetrahydro furan is used as a solvent.

2.2.4 Pharmacology
Furan is a clear, colorless, flammable liquid cyclic ether with an ethereal
odor. Furan is used as an intermediate in the production
of tetrahydrofuran, pyrrole and thiophene. Inhalation exposure to this substance
causes eye and skin irritation and central nervous system depression. Furan is
mutagenic in animals and is reasonably anticipated to be a human carcinogen
based on evidence of carcinogenicity in experimental animals.
2.2.5 Human Metabolite Information
Furan is a colorless, flammable, highly volatile liquid with a boiling point
close to room temperature. It is soluble in common organic solvents, including

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alcohol, ether and acetone, but is insoluble in water. It is toxic and may be
carcinogenic. Furan is used as a starting point to other specialty chemicals.
Furan is a heterocyclic organic compound, consisting of a five-membered
aromatic ring with four carbon atoms and one oxygen. The class of compounds
containing such rings are also referred to as furans. Furan is aromatic because
one of the lone pairs of electrons on the oxygen atom is delocalized into the
ring, creating a 4n+2 aromatic system (see Huckel's rule) similar to benzene.
Because of the aromaticity, the molecule is flat and lacks discrete double bonds.
The other lone pair of electrons of the oxygen atom extends in the plane of the
flat ring system. The sp2 hybridization is to allow one of the lone pairs
of oxygen to reside in a p orbital and thus allow it to interact within the pi-
system. The Feist-Benary synthesis is a classic way to synthesize furans,
although many syntheses have been developed. One of the simplest synthesis
methods for furans is the reaction of 1, 4-diketones with phosphorus pentoxide
(P2O5) in the Paal-Knorr Synthesis. The thiophene formation reaction of 1, 4-
diketones with Lawesson's reagent also forms furans as side products. 2, 4-
Disubstituted furans can be synthesized by sulfone-mediated cyclization of 1, 3-
diketones.

2.3 Pyrrol
Pyrrole is an important heterocycle found in the structure of complex
macrocycles such as the porphyrins of heme, the bacteriochlorine, chlorophyll,
and porphyrinogens (00PCCP2145). Pyrrole is very much less basic than
secondary amines but by the same token it is much more acidic. Pyrrole is,
however, still a very weak acid (pKa 17.5). The nitrogen-bound proton can be
abstracted from pyrrole by the use of strong bases such as sodium amide in
liquid ammonia and n-butyllithium in hexane.
Pyrrole was first isolated in pure form in 1857 from bone oil, although it
had been observed in 1834 that coal tar and bone oil contained a substance
which imparted a red color to pine splinters moistened with mineral acid. The
structural formula was established in 1870. Pyrrole chemistry up to the early
1930s is reviewed in the comprehensive treatise of Fischer and Orth and two
modern (excellent) books by Gossauer, and Jones and Bean are available.
Molecular formula: C4H5N.
 Pyrrole belongs to the C2v symmetry point group and exhibits 24 normal
modes of vibration.
2.3.1 Preparation

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  Pyrrole is manufactured by passing a mixture of furgan, ammonia and
steam over heated alumina as catalyst.
 Pyrrole is synthesised by passing a mixture of acetylene and ammonia
through red-hot tube.
2.3.2 Reaction of Pyrrol
 Reduction reaction: It undergoes reduction in the presence of Ni catalyst
at 200C gives pyrrolidine.
 Oxidation: Pyrrole is oxidised by Cr2O3 in acetic acid to maleinimide.
 Substitution reaction: Substitution usually occurs at positions 2 or 5
unless there are suitably located blocking groups or electron-releasing
groups that direct substitution to other positions. These heterocycles are
so reactive towards electrophilic substitution that deactivating groups
(e.g. halogen, ester) do not preclude substitution. Benzo derivatives of
heterocycles (19) also participate in the Vilsmeier–Haack reaction.
Electrophilic substitution is often followed by
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intramolecular cyclization,  as exemplified by the reaction of 3-
cyanomethylthiophene with yielding the thienopyridine derivative via the
intermediate iminium salt.
2.3.3 Uses of pyrrole:
i) It is used as a solvent.
ii) It is used in pharmaceuticels.
2.4 Human Metabolite Information
Pyrrole is found in corn. Pyrrole is a flavouring ingredient Pyrrole has very
low basicity compared to conventional amines and some other aromatic
compounds like pyridine. This decreased basicity is attributed to the
delocalization of the lone pair of electrons of the nitrogen atom in the aromatic
ring. Pyrrole is a very weak base with a pKaH of about 4. Protonation results in
loss of aromaticity, and is, therefore, unfavorable. Pyrrole is a heterocyclic
aromatic organic compound, a five-membered ring with the formula C4H4NH.
Substituted derivatives are also called pyrroles. For example, C4H4NCH3 is N-
methylpyrrole. Porphobilinogen is a trisubstituted pyrrole, which is the
biosynthetic precursor to many natural products. The starting materials in the
Piloty-Robinson pyrrole synthesis are 2 equivalents of an aldehyde
and hydrazine. The product is a pyrrole with specific substituents in the 3 and 4
positions. The aldehyde reacts with the diamine to an intermediate di-imine (R

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C=N N=C R), which, with added hydrochloric acid, gives ring-closure and loss
of ammonia to the pyrrole.

2.5 Thiophene
Thiophene is a heterocyclic compound consisting of a planar five-membered
ring that improves the photovoltaic performance of dye-sensitized solar cells.
Thiophene has a molecule stable to elevated temperatures, and in conditions of
flash-vacuum pyrolysis even at 1100°C, intact thiophene is present. At a longer
heating time and elevated temperatures, thiophene generates benzene, hydrogen,
methane, and hydrogen sulfide as the main pyrolysis products and lower levels
of dithiophenes. In an additional study, ethylene and acetylene also were
reported as pyrolysis products. In other studies performed in various conditions,
C2H2 and elemental sulfur, or CS2, also were detected. In one study performed
in a wide range of temperatures (600–1000°C) in a continuous flow experiment
at atmospheric pressure under a current of argon with a residence time in the
heated zone of 20 s, a number of decomposition products were detected in the
pyrolyzate. Molecular formula: C4H4S or SCH=CHCH=CH.
2.4.1Preparation
 Paal - Knorr Synthesis: 2,5 - Dimethyl thiophene can be obtained by
heating acetonyl acetone with P2S5.
 It may be prepared by paring a mixture of acetylene and H2S over heated
alumina.
 Thiophene may be prepared by reaction between Furan and H2S in the
presence of Al2O3.

2.4.2 Reactions of Thiophene

 Addition reaction (or) Reduction (or) Birch reduction. Thiophene is
reduced with sodium in liquor NH3, it gives 2,3 dihydro thiophene and
2,5 - dihydro thiophenes.

 Substitution reaction:
i) Thiophene undergoes chlorination at 30C gives 2-chloro and 2,5 -
dichloro thiophene
ii) On nitration thiophene gives 2- Nitro thiophene.
iii) Thiophene undergoes Friedel - crafts reaction to give 2 - Acetyl
thiophene.
iv) Thiophene on sulphonation gives thiophene - 2 - sulphonic acid.

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2.4.3 Uses of Thiophene
i) Thiophene derivatives are used in rubber and resin industries
ii) It is used to prepare biotin which is a growth factor for yeast
iv) Thiophene derivatives are used in pharmaceuticals.

2.5 Comparison of aromatic character of Furan, Pyrrole and Thiophene.

The order of aromatic character of thiophene, pyrrole and furan can be given
as follows:

The variation in aromatic character among these three heterocyclic compounds

in due to the following facts:
a) Variation in the electronegative nature of hetero atoms.
In pyrrole the hetero atom is nitrogen. The members of the ring (Nitrogen and
carbon atoms) undergo sp2 hybridization to give a flat geometry to pyrrole; N
(7) = 1s22s22p3. The lone pair of electorn available in the 2pz orbital is involved
in aromatic sextet. In thiophene the hetero atom is sulphur. The members of the
rings (sulphur and carbon atoms) undergo sp2 hybridization to give a flat
geometry to thiophene; S(16) = 1s22s22p63s23p4. The lone pair of electron
available in 3pz orbital is involved in aromatic sextet. In furan the hetero atom
is oxygen. The members of the ring (oxygen and carbon atoms) undergo
sp2hybridization to give a flat geomentry to furan; O(8) 1s22s22p4.
The lone pair of electron available in 2pz orbital is involved in aromatic
sextet. Out of the nitrogen, oxygen and sulphur, oxygen is most electonegative.
Thus it attracts its lone pair and destabilises the aromatic sextet. Moreover the
lone pair involved in the aromatic sextet of thiophene is available in 3pz orbital.
Thus sulphur atom cannot destabilise the aromatic sextet of thiophene.
Therefore the variation in the aromatic character of thiophene pyrrole and furan
is due to the relative stability of their aromatic sextet.

b) Variation in their resonance energy.

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Resonance energy stabilises the aromatic compound. The resonance energy of
thiophene pyrrole and furan is given in the following table:
Compoun Resoance energy
d kJ/mole
Thiophene 117
Pyrrole 87.8
Furan 71.7

Since thiophene has more resonance energy it is more aromatic and furan has
the lowest resonance energy it is least aromatic.

b) The least aromatic nature of furan is proved by it’s adduct formation

with maleic anhydride (Diel’s-Alder reaction).

3 References

1. K.S. Tewari, N.K. Vishil, S.N. Methtra – A text book of org. chem – Ist
edition, Vikas Publishing House Pvt Ltd., 2001, New Delhi.
2. P.L. Soni, Text Book of Organic chemistry, Sultans chand, 1991, New Delhi.
3. Transition Metal Catalyzed Furans Synthesis, 2016.
4. Advances in Heterocyclic Chemistry, 2014.
5. Metal-Free Synthetic Organic Dyes, 2018.

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