Chemistry of Natural Products

Unit 8- Heterocyclic Compounds

By
Dr K.M.Noorulla, M.Pharm., Ph.D.,
Associate Professor (Medicinal Chemistry),
College of Health Sciences,
Arsi University,
Asella, Ethiopia.
Unit 8 - Heterocyclic Part 1
(Introduction, Classification and
Nomenclature)
What’s Heterocyclic Compound?

A heterocyclic compound is one that

contain rings made up, in addition to
carbon, one or more heteroatoms like
0,N,S,P…. etc.
Heterocyclic compounds can be
classified into

1) Aliphatic heterocycles:
Examples
Heterocyclic compounds can be
classified into

2) Aromatic heterocycles:
Examples
Nomenclature of Heterocycles

a- Trivial names:

b- Generic names, and Trade names:

c- IUPAC (or systemic or chemical name):

A -Nomenclature of non Fused
Heterocycles

Prefix + Stem + Suffix

1- The Prefix
It indicates the type of the heteroatom, their
numbers and their positions. (Table I):
When two or more heteroatom of same type are
present, the prefix di, tri,...etc. is used.
If the heteroatoms are different, their order of
citation start with the heteroatomof as high a
group in the periodic table and as low an atomic
number in that group. Thus the order of naming
will be: O > S > Se >N > P > Si > B > Hg
etc. (see table I):
2-The stem
It determines the ring-size from 3
membered ring to 10 membered ring.
3- The Suffix

It determines the state of

saturation or unsaturation which depends
upon
(i) the presence or absence of N, and
(ii) the ring size.
saturation or unsaturation state
 Table III (cont): a: The complete saturation is
indicated by prefixing "perhydro " added
before
the total name of the unsaturated state.

b: no suffix

c: no stem

N.B: If the ring size is more than 10, use the

carbocyclic monocyclic name and the
heteroatom is indicated by prefixes: Oxa,
thia, aza
Example
Manner of numbering of the
monocycles
Rule 1

Monocyles containing one heteroatom,

re numbered beginning at the
heteroatom and the substituents takes
he least possible number:
Rule 2

Cycles containing more than one different

heteroatoms the numbering begins at the
atoms of the higher order of priority
(shown in table I) and proceeds round the
ring in order to give other heteroatoms
the least possible numbers without
regards to the substituents;
Rule 2
Nomenclature of Partially
Saturated Ring
Rule 1

If the number of double bonds is less

than the maximum, prefix dihydro
tetrahydro,…. etc are added to the
same name of unsaturated state. The
saturated positions are given the least
numbers after the hetero atom:
Rule 1
Rule 2

Obligatory saturation of a single

position is indicated by a symbol 1H, 2H,
3H... etc. according to the position of the
saturated atom
Rule 2
Rule 3

In case of 4 & 5 membered rings with

partial saturation (i.e) contain only one
double bond. The suffix will be (ine) when
N is present and (ene) when N is absent,
and indicate the position of the double
bond over Δ symbol.
Rule 3
The following are the IUPAC and trivial
names of most monocycles
The following are the IUPAC and trivial
names of most monocycles
The following are the IUPAC and trivial
names of most monocycles
The following are the IUPAC and trivial
names of most monocycles
B-Nomenclature of Fused
Heterocycles
B-Nomenclature of Fused Heterocycles

(B I) Carbocycle fused with heterocyclic

system.

(B II) Heterocycle fused with another

heterocyclic system
I-Nomenclature of Carbocycle fused
with Heterocycles IUPAC name:

1. The Parent name (written at the end) is

the name of the heterocyclic ring.

2. The fused name (written at first) is the

name of the fused benzene called
(Benzo).
I-Nomenclature of Carbocycle fused
with Heterocycles IUPAC name:

3. The Side of fusion of the parent ring

with the fused benzene ring is indicated
by alphabetical numbering and put such
letter (a, b, c, ... etc) between square
brackets in between the prefix and parent
name. In this case the parent ring is
numbered as usual and the sides
1,2, take letter (a), side 2,3 takes
letter (b), side 3, 4 takes letter (c), ... etc
I-Nomenclature of Carbocycle fused
with Heterocycles IUPAC name:
I-Nomenclature of Carbocycle fused
with Heterocycles IUPAC name:

4- The total numbering of the complete

fused system in done to determine the
positions of saturations or substitutions
according to the following rules:
a- The fused system is oriented so that:
The greatest number of ring is in a
horizontal row, and the remaining
rings above the right of this horizontal
row.
I-Nomenclature of Carbocycle fused
with Heterocycles IUPAC name:

b- The numbering starts from the atom

next to the fusion giving the hetero atom
the least possible numbering and
continue numbering in clockwise
direction (whenever possible) and the
fused carbons are given the same
previous number adding to it letters (a, b, c, etc).
c- In case of poly cycles, the parent name is
given to the largest heterocycles
containing many rings (provided it has a
famous trivial name).
The following are the agreed trivial and
IUPAC names of the some of the famous
carbocycles fused with hetero cycl :
The following are the agreed trivial and
IUPAC names of the some of the famous
carbocycles fused with hetero cycl :
The following are the agreed trivial and
IUPAC names of the some of the famous
carbocycles fused with hetero cycl :
(II) Nomenclature of Heterocycle fused
with another Heterocycles

The IUPAC rules for naming such systems

are also composed of 4 points:
The Parent name given to the more prior
heterocycle(s), is used as suffix.
The fussed ring (s) name is the less prior
rings and is used as prefix.
The side of fusion for both rings.
The numbering of the total system.
1. The selection of the parent ring(s) (as
suffix) should be according to the following
order of preferences

i- The Nitrogen containing ring must be taken

as a parent ring:
ii- If no Nitrogen, the ring contain the more
prior heteratom (according to table l), is
considered as a parent ring:
iii) The largest ring size is taken as a parent
ring if the two rings contain N or does not
contain N.
iv) The largest number of rings with famous
trivial name is always used as parent name:
v) The ring containing the greatest
number of hetero atoms or
varieties of heteroatoms is
ring:
vi) A component ring having the more
prior heteroatom(according table I) is the
parent ring:
vii) The parent ring is the ring containing
a more number of carbon atoms adjacent
to the fusion:
2- The naming of the prefix of fused(less
prior) heterocycles is given as such:

Furan = furo
Thiophene = thieno
Pyridine = pyrido
Pyrrole = pyrrolo
Imidazole = imidazo
Quinoline = quino
3- Determination of the sides of fusion
for both sides of the two fused
heterocycles as such:
a- The side of fusion with the parent ring is
numbered alphabetically and the letter of fusion
is placed between square brackets at its end.

b- The side of fusion of the prefix ring is

indicated by two numbers denoting the two
positions of fusion with the parent ring, these
twonumbers are also placed at first in the square
brackets. The order of writing these two numbers
conforms the direction of lettering of the parent
ring.
3- Determination of the sides of fusion
for both sides of the two fused
heterocycles as such:
Unit 8 - Heterocyclic Part 2
(Physical and Chemical Properties,
Significance of Some Heterocyclic
Compounds in Pharmacy)
 Heterocyclic Chemistry

N Five-membered Heterocycles

S
Pyrrole, Furan and Thiophene
O
 Hetero-Monocyclic Compounds
Five-membered Rings with one Heteroatom
➢ Pyrrole is present in the structure of haem; the blood respiratory
pigment, and the chlorophyll; the green photosynthetic pigment of
plants.

➢ Thiophene and its derivatives occurs in petroleum.

➢ Furan occurs widely in secondary plant metabolites, especially in
terpenoids.
➢ Unsubstituted pyrrole, furan, and thiophene are usually obtained
from petroleum.

X = NH Pyrrole
N S O
= O Furan
X H Thiophene Furan
=S Thiophene Pyrrole
 Hetero-Monocyclic Compounds
Five-membered Rings with one Heteroatom

➢ Pyrrole, furan and thiophene are colorless liquids of boiling

points 126o, 32o, and 84o respectively.
➢ Pyrrole has a relatively high boiling point as compared to furan
and thiophene, this is due to the presence of intermolecular
hydrogen bonding in pyrrole.

N N N N N
H H H H H
 Five-membered Rings with one Heteroatom
Hetero-Monocyclic Compounds

Structure and Aromaticity

❖ Pyrrole, furan and thiophene are

aromatic because:
1) they fulfill the criteria for
aromaticity, the extent of
delocalization of the nonbonding
electron pair is decisive for the The order of aromaticity
aromaticity, thus the grading of Benzene > Thiophene > Pyrrole > Furan
aromaticity is in the order of:

Furan < Pyrrole < Thiophene < Benzene

 Five-membered Rings with one Heteroatom
Structure and Aromaticity

2) They tend to react by electrophilic substitution due appearance of –

ve charge on carbon atoms due to delocalization as shown in the
following resonance structures.

O O O O O

S S S S S

N N N N N
H H H H H
 Five-membered Rings with one Heteroatom
Structure and Aromaticity

3) Electrons not available for protonation—hence not basic.

4) 6  electrons over 5 ring atoms ….. Electron rich… so more reactive
than benzene towards electrophilic substitution.
The order of reactivity is:
Pyrrole > Furan > Thiophene > Benzene

X = NH Pyrrole

=O Furan
X
=S Thiophene
 Five-membered Rings with one Heteroatom
Structure and Aromaticity

5) The pattern of reactivity with Electrophilic reagents.

Aromatic compounds ……. By substitution, addition followed by
proton loss.
Order of reactivity : Pyrrole > Furan > Thiophene > Benzene

H H H - H+ E
E E E
C2-attack X X X X

+ E+
X
H H E
E E +
C3-attack -H
X X X
 Five-membered Rings with one Heteroatom

Sources
Pyrrole & Thiophene …. Coal Tar

Pyrrole ring ….
Porphyrin system…..
Chlorophyll &
Hemoglobin

Furan ….. Decarbonylation of

Furfuraldehyde …….
Oat hulls, corn cobs or rice hulls
Oat hulls corn cobs rice hulls
 Reactions of pyrrole

1- D
MF O
2- H /PO
Cl H3C C
OHC 2O + 3
O
N Na
H 2 CO Ac 2O COCH3
3 N H3C C
pyrrole-2-carboxaldehyde H O
2-acetylpyrrole
acetic anhydride
N H
H 2 \pt
Ac Acetylation
Vilsmier Rex SO 3ridine OH
py HNO3 CH3COO NO2 \20
0
+Ac2o
HO3S N
-

N H
H
+

2-pyrrole sulfonic acid pyrrolidine

NO2 Reduction
Sulfonation N
H

2-nitropyrrole

Nitration
 Reactions of Furan

Acetylation
1-
DM
OHC F/P
O 2- OC
H
2O
l3 Ac 2O COCH3
+N O
furfulaldehyde aC
furfural
2 O
BF 3
3 2-acetyl furae
Vilsmier Rex
O di
lN
CH HO
1, 00 3C
OO
3
SO 3 idine H,
r
py [0
]
NO2
HO3S O
O

2-furan sulfonic acid 2-nitrofuran

Sulfonation Nitration
 Reactions of Thiophene

Sulfonation
Acetylation
OCl COCH3
SO CH3C S
L4
HO3S
S
pyr 3 , 100
idin SOC
e
2-thiophene-2- sulfonic acid S di
l
NH
CH O3
3C
Br 2 OO Nitration
H,
OH [0
Ac Cl2 ]
NO2
Br 50 S HNO3 O2N NO
2
S
Br
S Br S
major minor Cl Cl

Cl Cl Cl
S Cl S Cl S

Halogenation
 THE IMPORTANCE OF HETEROCYCLES IN
MEDICINE
✓ 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.

✓ Heterocycles have dominated medicinal chemistry from the

beginning. Consistent with their importance, many U.S. patents by
pharmaceutical companies involve heterocyclic compounds.

✓ All the major pharmaceutical companies have significant research

efforts involving heterocycles.
 Furans
Furans gained importance in pharmaceutical chemistry
when it was discovered that nitrofurans constituted a class
with highly active and useful antibacterial activity.

Nitrofurazone Nidroxyzone

Ranitidine (H2 receptor antagonist)

 Thiophenes
The synthesis of the anti-inflammatory agent Prifelone is
an example of the application of the basic chemistry of
the thiophene system in the construction of valuable
pharmaceutical agents.

Prifelone
 Pyrrole
The pyrrole ring appears in some pharmaceuticals, but
multicyclic compounds, especially based on indole, are of
more common occurrence. Pyrrolidines also are of
importance.

Clopirac (NSAIDs) Prinomide (NSAIDs)

 Heterocyclic Chemistry

Five-membered with two

N heteroatoms
S
O Imidazole and Pyrazole
 Introduction
➢ Replacing a CH group in the pyrrole ring with a nitrogen atom can
give rise to two compounds : pyrazole and imdazole.

➢ Only one nitrogen atom can contribute two electrons to the

aromatic sextet. It is the nitrogen with the hydrogen (black in color)
and it is described as pyrrole-like nitrogen. While the second
nitrogen which has no hydrogen (green) is described as pyridine-
like.
 Physical Properties of Imidazole and Pyrazole
➢ Imidazole and pyrazole are water soluble solids and insoluble in aprotic
solvent.
➢ They have very much higher boiling point: 256 and 187°C respectively, this
difference is due to imidazole has an extensive hydrogen bonding than
pyrazole thus imidazole molecules can exist as oligommers, consequently
more energy is required to break these bonds to bring the molecules from
one phase to another.
➢ On the other hand pyrazole molecules can form dimers only thus lesser
energy is required to break these molecules.

imidazole molecules as a polymer pyrazole molecules as a dimer

N H N N H
N
N
N
N
H N
N
H N
 Physical Properties of Imidazole and Pyrazole

➢ N-subsituted imidazole and pyrazole have lower boiling and melting points than
the unsubstituted compounds due to inability to form H-bonds.

Basicity

➢ Imidazole is a stronger base than pyrazole or pyridine and of

course pyrrole.
➢ Basicity order: Imidazole > Pyrazole > Pyridine > pyrrole
 Effect of substitution on basicity
➢ Generally E.D.G groups on the ring increase the basicity while E.W.G.
decrease it.

➢ N-methyl imidazole is more basic than imidazole itself.

➢ However, N-methylpyrazole is less basic than pyrazole which can be

attributed to steric hindrance effect which cause difficulty in accessing the
lone pair of electron by the proton.

N N
Basicity > N < N
N N N N
H H

CH3 CH3
 Electrophilic Aromatic Substitution

➢ Diazoles are less reactive than 5-membered heterocycles with one

heteroatom (pyrrole and its analogs) in electrophilic aromatic
substitution due to the inductive electron-withdrawing effect of the
second heteroatom.
➢ The orientation in pyrazole, is at the 4-position due to the
deactivation effect of the pyridine-like nitrogen.

E+ E

N
N
N
H N
H
Pyrazole 4-substituted
 Electrophilic Aromatic Substitution

❖ The orientation in imidazole, is at 5-position, due to the additional

N-atom deactivates its vicinal positions

N-like pyridine deactivate its vicinal positions

4 N3
5 2
N1
H
most strongly activated position

❖ However, if the position 5 is occupied the electrophiles will be

directed to 4-position.
Electrophilic Aromatic Substitution

HO3S
H2SO4 / SO3
N
N 100 C° N
H N
H

N HNO3 / H2SO4 N
N 160 C° O2N
H N
H
Br
Br2 / CHCl3
N N
N N
H H
 Imidazole
Simple nitro derivatives of imidazole are effective as antibacterial agents. They
also are useful in treating infections caused by protozoans, such as
Trichomonas.

1,2dimethyl-5-nitroimidazole (trichomonal infections in veterinary medicine)

Phenytoin (treating epilepsy) Fadrozole (treating neoplasms)

 Pyrazole

Tepoxalin (anti-inflammatory drug)

 Heterocyclic Chemistry

Six-Membered Aromatic
N Heterocycle's
S
O Pyridine (Azine)
 PYRIDINE- Structure and Aromaticity

➢ Pyridine is a six membered heterocyclic compound with molecular

formula of C6H5N and it is obtained from coal tar.
➢ It may be formally derived from the structure of benzene through the
exchange of one ring carbon for a nitrogen.
➢ Pyridine is an aromatic compound, however, the nitrogen’s lone pair of
electrons is not involved in maintaining aromaticity but it is available to
react with protons thus pyridine is basic.
 PYRIDINE- Structure and Aromaticity

➢ Pyridine can be represented as a resonance hybrid of the

following structures.

➢ Due to the greater electronegativity of nitrogen (relative to carbons) it

tends to withdraw the electron density from carbon atoms at positions
2, 4 and 6 which therefore acquire partial positive charges while the
N atom acquires partial negative charge while the carbons at
positions 3 and 5 remain neutral.
 Basicity of pyridine
➢ Pyridine is a weak base.

Pyridinium salt

➢ Compared to pyrrole, pyridine is much stronger base this is due to the

nitrogen lone pair is not involved in maintaining the aromaticity thus it free
for protonation.
➢ However, in pyrrole the lone pair on the N atom is already involved in the
aromatic array of p electrons. Protonation of pyrrole on N atom results in
loss of aromaticity and is therefore unfavorable.
 Chemical Properties:
Electrophilic Substitution
➢ The negative pole in pyridine ring is at N while the positive pole is at carbon
skeleton which is opposite to what happens in pyrrole.

➢ Positions 2, 4 and 6 acquire partial positive charges while the N atom

acquires partial negative charge and the carbons at positions 3 and 5 (β-
position) remain neutral, therefore these positions are the most preferred
for electrophilic attack.


N


 Chemical Properties:
Electrophilic Substitution
➢ Also as a consequence of electron deficiency on pyridine ring,
pyridine is less reactive towards electrophiles than pyrrole and
benzene (it resembles highly deactivated benzene derivatives), where
it does not undergo Friedel-Craft’s alkylation or acylation or coupling
with diazonium salts.
➢ Moreover, electrophilic substitution reactions of pyridine require very
harsh conditions (e.g. v. high temp.) to take place and are low
yielding.
 Nucleophilic Substitution on Carbon
➢ Pyridine is very reactive towards nucleophiles than benzene it
resembles benzene having strong E.W.G due to the withdrawing
effect of the electronegative N atom .
➢ As appeared from the canonical structures of pyridine positions
2, 4 and 6 carry partial positive charges thus nucleophilic
substitution proceeds readily at the 2-position followed by 4-
position but not at the 3-position.
➢ Additionally, attack at positions 2, 4 or 6 results in resonance
structure in which the negative charge is delocalized at N thus it is
more preferred while attack at position 3 or 5 results in resonance
structures in which the negative charge is delocalized over
carbons only.
 Orientation of Nucleophilic Substitution in
Pyridine

H H H
+ Nu
N N Nu N Nu N Nu
attack at C-2
more preferred
-ve charge on N

H Nu H Nu H Nu

+ Nu
attack at C-4
N
more preferred N N N

-ve charge on N

H H
H Nu
Nu Nu

+ Nu
attack at C-3 N
N N
N
-ve charge on C only
 Nucleophilic Substitution reactions
i) The Chichibabin reaction

R can be o-, m-, or p- substituent

ii) Reaction with organometallic compounds lithium

reagents

+ C4H9Li

N Butyllithium N C4H9

2-Butylpyridine
 Nucleophilic Substitution reactions

iii) Reaction with potassium hydroxide

KOH / 320°C keto-enol

N N O H tautomerism N O
H
2-Hydroxy pyridine
2-Pyridone
 Reduction Reactions

lH 4
L iA O
2
1) + , H N
H H
H 2)
N 2 /N 1,2-Dihydropyridine
i
H
piperidine
Na
N Bir /N
H
C
0o

ch
red 3
30

uc
I,

tio
H

n
CH3CH2CH2CH2CH3+ NH3 N
H
1,4-Dihydropyridine
 Pyridine

Nifedipine (used to relieve the chest pain) Ofornine (Antihypertensive)

Ethionamide (Antitubercular) Acrivastine (Antihistamines)

 Heterocyclic Chemistry

Six-Membered rings with

N two heteroatoms
S
O Diazines
 Introduction
➢ Replacing a CH group in the pyridine ring with a nitrogen
atom can give rise to three compounds having the
molecular formula C4H4N2 known as diazines.

Pyridazine
1,2-Diazine

Pyrimidine
1,3-Diazine

Pyrazine
1,4-Diazine
 Introduction

➢ The main biological importance of diazines is that

they are main components of nucleic acids
ribonucleic aid (RNA) and deoxyribonucleic acid
(DNA) the molecules that carry the genetic
information in the cells.
 Basic nucleotide structure

➢ Nucleotides are phosphoric esters of nucleosides

➢ Thus hydrolysis of a nucleotide yields: a diazine unit (nitrogen base) – a

pentose unit (ribose in RNA) and (2-deoxyribose in (DNA) and a
phosphate group.
 Bioactive diazines: (a) Pyrimidines
➢ Pyrimidines that present in DNA are:
cytosine and thymine
➢ Pyrimidines that present in RNA are:
cytosine and uracil
NH2
O O
N
HN HN
O N
O N O N H
H H

Uracil Thymine Cytosine

 Bioactive diazines: (b) Purines

➢ Adenine and guanine are the principle purines of DNA and

RNA.

NH2 O

N N
N NH

N N N N NH2
H H

Adenine Guanine
Nucleosides of DNA
Nucleosides of RNA
 Pyrimidine

(Hypnotic)
Minoxidil (Antihypertensive)
 Heterocyclic Chemistry

Five-Membered rings with

N two heteroatoms
S
O Oxazole and Isoxazole
 Oxazole and Isoxazole:
Oxazole is a five membered heterocycle containing
oxygen and nitrogen at first and third positions
respectively.
N

Isoxazole is a five membered heterocycle containing

oxygen and nitrogen at 1, 2 positions respectively.

N
O
 Oxazole and Isoxazole

Sulfisoxazole (antibacterial) Isocarboxazid(CNS

stimulant)

antibiotic Dicloxacillin (antibiotic)

 Heterocyclic Chemistry

Six-Membered rings with

N two heteroatoms fused
S with carbocycles
O
Phenothiazine
 Phenothiazine
Phenothiazine, is an organic compound that has the formula S(C6H4)2NH
and is related to the thiazine-class of heterocyclic compounds. Derivatives of
phenothiazine are highly bioactive and have widespread use.
 Phenothiazine
The phenothiazine structure is found in a number of Pharmaceuticals
used as antihistamines, antipsychotics, sedatives and antiemetics.

Chlorpromazin (neuroleptic) Promethazine (sedative)