Kwame Nkrumah University of

Science & Technology, Kumasi, Ghana

CHEM 253:
Heterocyclic Chemistry
L. S. Borquaye
 Our Focus

n = 1,2,3, ……
n

Z is a heteroatom (a different atom

from carbon)
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Aliphatic Heterocycles

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Aromatic Heterocycles

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 Why heterocyclic chemistry?
❑About 2 out of every 3 organic compounds are
heterocyclic in nature. Heterocyclic compounds, and
therefore their chemistries are very important in the
life of humans.

❑Most pharmaceuticals are based on heterocycles. An

inspection of the structures of the top-selling brand-
name drugs in 2007 reveals that 8 of the top 10 and
71 of the top 100 drugs contain heterocycles.

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 Some Important Heterocyclic
Drugs

As early as 16th century,

Antipyrine is the first synthetic
quinine was used as an
drug used for fever reduction
antimalarial agent.
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 Some Important Heterocyclic
Drugs

Sulphapyridine: The first Viagra : approved for the

effective antibiotic introduced treatment of male impotence
in 1938. in 1997.
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Nomenclature of Heterocyclic
Compounds
IUPAC rules permit 3 systems:

1. The Hantzsch-Widman Nomenclature

2. Common Names
3. The Replacement Nomenclature

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Hantzsch-Widman Nomenclature

❑ Nomenclature is based on the type (Z) of the

heteroatom; the ring size (n) and nature of the ring
(saturated or unsaturated).
❑ This system of nomenclature applies to monocyclic
three-to-ten-membered ring heterocycles.
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 Type of the Heteroatom
The type of heteroatom is indicated by a prefix
as shown below for common heteroatoms:

Heteroatom Prefix
O Oxa
N Aza
S Thia
P Phospha

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 Ring Size
❑ The ring size is indicated by a suffix as shown in the
table below.
❑ Some of the syllables are derived from Latin
numerals; ir from tri, et from tetra, ep from hepta, oc
from octa, on from nona, ec from deca.
Ring size Suffix Ring size Suffix

3 ir 7 ep
4 et 8 oc
5 ol 9 on
6 in 10 ec
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 Ring Size + Nature of Ring
❑ The endings indicate the size and degree of
unsaturation of the heterocyclic ring.

Ring size Saturated Unsaturated Saturated (With Nitrogen)

3 -irane -irine -iridine
4 -etane -ete -etidine
5 -olane -ole -olidine
6 -inane -ine
7 -epane -epine
8 -ocane -ocine
9 -onane -onine
10 -ecane -ecine
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Hantzsch-Widman Nomenclature
❑ Heterocycles are named by combining appropriate
prefix/prefixes with a stem from earlier tables. The letter “a” in
the prefix is omitted where necessary.
❑ Each suffix consists of a ring size, root and an ending intended
to designate the degree of unsaturation in the ring.
❑ It is important to recognize that the saturated suffix applies
only to completely saturated ring systems, and the
unsaturated suffix applies to rings incorporating the maximum
number of non-cumulated double bonds.
❑ Systems having a lesser degree of unsaturation require an
appropriate prefix, such as "dihydro“ or "tetrahydro".
❑ Saturated 3, 4 & 5-membered nitrogen heterocycles should use
respectively the traditional "iridine", "etidine" & "olidine"
suffix.
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 Examples

Oxa+irane= Oxirane Thia+irane= Thiirane Aza+iridine= Aziridine

Oxa+etane=Oxetane Thia+etane=Thietane Aza+etidine=Azetidine

Oxa+olane= Oxolane Thia+olane= Thiolane Aza+olidine= Azolidine

 Examples

Azinane Azine (Pyridine) Oxirine Azirine

Azepine Azocine
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Hantzsch-Widman Nomenclature
❑ When substituents are present, the heteroatom is designated
number 1, and the substituents around the chain are numbered
so as to have the lowest number for the substituents.

2-Bromo-3-methylaziridine

2-Propyloxirane
2-Bromo-4-ethylthiolane

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Hantzsch-Widman Nomenclature
Partial Saturation
❑ Use fully unsaturated name with dihydro, tetrahydro, etc

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Hantzsch-Widman Nomenclature
Partial Saturation
❑ When numbering give priority to saturated atoms

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Hantzsch-Widman Nomenclature
Rings With More Than One Heteroatom
❑ Two or more similar atoms contained in a ring are indicated
by the prefixes ‘di-’, ‘tri’, etc.

1,3,5-Triazine 1,2,4-Triazole

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Hantzsch-Widman Nomenclature
Rings With More Than One Heteroatom
❑ If more than one heteroatom is present, then the heterocycle
is named by combining the appropriate prefixes with the
ending in Table I in order of their preference, O > S > N.

Oxaziridine 1,3-Thiazole 1,4-Oxazine

(Thiazole)
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Hantzsch-Widman Nomenclature
Rings With More Than One Heteroatom
❑ If more than one heteroatom is present, then the heterocycle
is named by combining the appropriate prefixes with the
ending in Table I in order of their preference, O > S > N.

1,4,2-Dithiazine 3-Chloro-5-methyl-1,2,4-Oxadiazole

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Hantzsch-Widman Nomenclature
Rings With More Than One Heteroatom
❑ The ring is numbered from the atom of preference
(O > S > N > P > C) in a manner that gives the smallest
possible number to the other heteroatoms in the ring. As a
result, the position of the substituent(s) plays no part in
determining how the ring is numbered in such compounds.

4-Methyl-1,3-Thiazole

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 Common Names
❑ A number of heterocyclic compounds are widely known with
their non-systematic or common names.

Furan Thiophene Pyrrole Pyridine

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 Common Names
❑ A number of heterocyclic compounds are widely known with
their non-systematic or common names.

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 Common Names
❑ A number of heterocyclic compounds are widely known with
their non-systematic or common names.

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 Common Names
Identical systems connected by a single bond
❑ Such compounds are defined by the prefixes bi-, ter-, quarter,
etc., according to the number of systems, and the bonding is
indicated as follows:

2,2’-Bipyridine 2,2’:4’,3’’-Terthiophene

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 Common Names
Naming Heterocycles with fused rings
When naming such compounds, the side of the heterocyclic ring
is labeled by the letters a, b, c, etc., starting from the atom
numbered 1. Therefore side ‘a’ being between atoms 1 and 2,
side ‘b’ between atoms 2 and 3, and so on as shown below for
pyridine.

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 Common Names
Naming Heterocycles with fused rings
The name of the heterocyclic ring is chosen as the parent
compound and the name of the fused ring is attached as a prefix.
The prefix in such names has the ending ‘o’, i.e., benzo, naphtho
and so on.

Benzo [b] furan Benzo [b] pyridine Benzo [c] thiophene

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 Common Names
❑ In a heterocyclic ring, other things being equal, numbering
preferably commences at a saturated, rather than at an
unsaturated heteroatom.

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The Replacement Nomenclature
❑ In this system, the heterocycle's name is composed
of the carbocycle's name and a prefix that denotes
the heteroatom.

❑ Thus, "aza", "oxa", and "thia" are prefixes for a

nitrogen ring atom, an oxygen ring atom, and a
sulfur ring atom, respectively.

❑ Note that heterocyclic rings are numbered so that

the heteroatom has the lowest possible number.

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The Replacement Nomenclature

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The Replacement Nomenclature

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 Properties of Aromatic
Heterocycles
Six Membered Aromatic Heterocycles
❑ Pyridine is aromatic, with 6 delocalized
electrons in the ring

❑ In general, 6-membered heterocycles are more

closely related to benzene as they are
aromatic on the basis of their π-electron
systems without the need for delocalization of
heteroatom lone pairs. The empirical
resonance energy for pyridine is about 28
kcal/mol, only slightly lower than that for
benzene (36 kcal/mol).
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 Properties of Aromatic
Heterocycles
Pyridine Structural Analysis

❑ Pyridine has a divalent, negatively charged N, which is a stable

condition for N. The positive charge is dispersed to carbons
around the ring, specifically to C-2 and C-4.
❑ The net effect is to reduce the π-electron density in the ring
relative to benzene, and as result pyridine is electron deficient
compared to benzene.

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 Properties of Aromatic
Heterocycles
Pyridine Structural Analysis
Pyridine, unlike benzene, is a polar molecule due to the
presence of the electronegative nitrogen

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 Properties of Aromatic
Heterocycles
Six Membered Aromatic Heterocycles
❑6-membered heterocycles with an
electronegative heteroatom are generally
electron deficient compared to benzene.
Such compounds are classified as π-
deficient.
❑Electron-withdrawing heteroatoms
decrease the π-electron density at the
carbon atoms and are thus π-deficient
relative to benzene.
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 Properties of Aromatic
Heterocycles
Five-Membered Aromatic Heterocycles

❑ The 5-membered aromatic heterocycle ring has a π-

electron excess (6 electrons on 5 atoms), while in
benzene, the π-electron density is one on each ring
atom.
❑ 5-membered heterocycles with an electronegative
heteroatom are generally electron rich compared to
benzene (6 electrons for 5 carbons). Such
compounds are classified as π-excessive.
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 Properties of Aromatic
Heterocycles
Five-Membered Aromatic Heterocycles
❑ The degree of aromatic character in a 5-
membered ring is determined by the ease with
which the lone pair may be released into the
delocalized system.

❑ The ease with which the lone pair of electron is

released is directly related to the
electronegativity of the heteroatom. Thus the
lower the electronegativity of the heteroatom,
the higher the aromaticity
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 Properties of Aromatic
Heterocycles

❑There is a vast difference between the properties of

the two types of aromatic compounds.
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 Properties of Aromatic
Heterocycles
Reactions of π-deficient heterocyclic aromatic
compounds
❑π-deficient heterocyclic systems have low reactivity
with electrophilic agents, slower than benzene.

❑For example, pyridine is less reactive than benzene

by a factor of 106 when subjected to conditions of
nitration. The reactivity is on the order of that of
nitrobenzene, which is well known to require much
more drastic conditions than those for benzene itself.
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 Properties of Aromatic
Heterocycles
Reactions of π-excessive heterocyclic aromatic
compounds

❑ A significant feature of the π-excessive ring systems is that

they undergo electrophilic aromatic reactions faster than
benzene.

❑ The reactivity is greater than that of benzene and is in roughly

the same range as found for benzenes bearing electron
releasing groups such as in aniline. The greater electron
density in these rings accounts for this higher reactivity.

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 Properties of Aromatic
Heterocycles
Reactions of π-excessive heterocyclic aromatic
compounds
❑ These π-excessive heterocycles undergo electrophilic aromatic
substitution reactions much faster than benzene under similar
conditions. The reasons for this are:

➢ The resonance energy of the heterocycles is less than that

of benzene, i.e. less aromatic than benzene.

➢ The five-membered aromatic heterocycle ring has a π-

electron excess (6 electrons on 5 atoms), while in
benzene, the p-electron density is one on each ring atom.
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