(3,4,5 and 6-

membered ring of

O,N, S. Heterocyclic

compounds and di-

heteroatoms)

OS N

O N

CH3

N

N

CN

O

N

OH

CH3

N

NO

CHO

N N

SAc

N

OPh

NN

N

NO2

N N

NNEt

N

O Cl

NH

O S

O

O

N

N N

O O

S O

Introductory Heterocyclic Chemistry

Heterocycles

Ring compounds with elements other than carbon in the

ring. The most common hetero elements in heterocyclic

compounds are oxygen, nitrogen and sulfur.

The aliphatic heterocycles are similar to the open chain

analogues, ethers, amines and sulfides.

The aromatic heterocycles are similar to other aromatic

compounds.

• Heterocyclic compounds are frequently abundant in plants and

animal products; and they are one of the important constituent of

almost one half of the natural organic compounds known.

Alkaloids, natural dyes, drugs, proteins, enzymes etc. are the

some important class of natural heterocyclic compounds.

• Heterocyclic compounds can be easily classified based on

their electronic structure.

• Heterocyclic compounds are primarily classified as saturated

and unsaturated.

• The saturated heterocyclic compounds behave like the acyclic

derivatives with modified steric properties. Piperidine and

tetrehydrofuran are the conventional amines and ethers of this

category.

• However, unsaturated heterocyclic compounds of 5- and 6-

member rings have been studied extensively because of their

unstrained nature.

• The unstrained unsaturated heterocyclic compounds include

Pyridine, Thiophene, Pyrrole, Furan and their benzo fused

derivatives. Quinoline, Isoquinoline, Indole, Benzothiophene,

and Benzofuran are some important example of benzo fused

heterocycles.

• Heterocyclic compounds have a wide application in

pharmaceuticals, agrochemicals and veterinary products.

Many heterocyclic compounds are very useful and essential

for human life.

• Various compounds such as hormones, alkaloids antibiotic,

essential amino acids, hemoglobin, vitamins, dyestuffs and

pigments have heterocyclic structure.

Nomenclature of Heterocyclic

Compounds

The IUPAC rules for Heterocyclic compounds allow three

nomenclatures.

I. The Hantzsch-Widman Nomenclature.

II. Common Names or trivial Names

III. The Replacement Nomenclature

Heterocyclic Nomenclature

Replacement nomenclature (IUPAC recommended 1957)

Oxygen oxa

Sulfur thia

Nitrogen aza

Lowest number assigned to the hetero atom with the highest

precedence: O > S > N

S

thiacyclobutane

ONH

1-oxa-3-azacyclopentane

• In replacement nomenclature, the heterocycle's name is

composed of the carbocycle's name and a prefix that

denotes the heteroatom.

• Notice that heterocyclic rings are numbered so that the

heteroatom has the lowest possible number.

• The Hantzsch-Widman nomenclature is based on the

type (Z) of the heteroatom; the ring size (n) and

nature of the ring, whether it is saturated or

unsaturated.

• This system of nomenclature applies to monocyclic

three-to-ten-membered ring heterocycles.

Hantzsch-Widman

nomenclature

Hantzsch-Widman (1888)

Suffixes

ring with nitrogen ring without nitrogen

Ring members unsat’d sat’d unsat’d sat’d

3 -irine -iridine irene irine

4 ete etidine ete etane

5 ole olidine ole olane

6 ine perhydro__ine in ane

7 epine perhydro__epine epin epane

Some of the syllables are derived from Latin numerals,

namely ir from tri, et from tetra, ep from hepta, oc from octa,

on from nona, ec from deca.

The ring size is indicated by a suffix according to Table

below.

The endings indicate the size and degree of

unsaturation of the ring.

• According to this system heterocycles are named by

combining appropriate prefix/prefixes with a stem

from the table above. 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.

EXAMPLES

O S N

H

* oxiraneethylene oxideoxacyclopropane

* thiiraneethylene sulfidethiacyclopropane

* aziridineethylene imineazacyclopropane

N

N

N O

NH

diazirane 1-azirine oxaziridineoxazacyclopropane

You must know the * names

O S NH

N N

oxetaneoxacyclobutane

thietanethiacyclobutane

azetidineazacyclobutane

azeteazacyclobutadiene

1-azetine1-azacyclobutene

O

O NH

O

O S NH

* furanoxoleoxacyclopentandiene

* thiophenethiolethiacyclopentandiene

* pyrrole

1,3-dioxolane1,3-dioxacyclopentane

* tetrahydrofuran* pyrrolidineazacyclopentane

N

O

N

SON

NH

N

N

NH

N

NH

N

pyrazole imidazole 1,2,4-triazole

oxazole isooxazole thiazole

O O O

O

O

NH

NH

HN

O

O

4-hydropyran 2-pyrone 4-pyrone

* 1,4-dioxane * piperidine piperazine

N

N

NN

N

N

N NH

O

pyridazine pyrimidine pyrazine

* pyridine * morpholine

6

7

8

5

N1

2

34

6

7

8

5

1

N 2

34

NH

* quinoline * isoquinoline

* indole

• In case of substituents, the heteroatom is designated

number 1, and the substituents around the chain are

numbered so as to have the lowest number for the

substituents.

• Use fully unsaturated name with

dihydro, tetrahydro, etc

Rings With More Than One Heteroatom

If more than one hetero atom occur in the ring,

then the heterocycle is named by combining

the appropriate prefixes with the ending in the

table above in order of their preference, O > S

> N.

• Identical systems connected by a single bond

• Such compounds are defined by the prefixes bi-,

tert, quater-, etc., according to the number of

systems, and the bonding is indicated as follows:

• 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.

Naming Hetrocycles 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.

EXTRA HYDROGENS

Aliphatic heterocyclics, chemistry

Ethers

Amines

sulfides

O

conc. HBr

heatBrCH2CH2CH2CH2Br

HNCH3 C

Cl

O

+ CH3 C

N

O

2o amine

Three-membered rings undergo additions due to angle

strain, eg. epoxides

O

O

+ HBr

+ NH3

HOCH2CH2Br

HOCH2CH2NH2

Aromatic heterocycles

NH

O S

pyrrole furan thiophene

N

H

Aromatic! EAS very, very reactiveresonance stabilization energy ~ 22-28 Kcal/mole

sp2 6 pi electrons

no unshared pair on Nitrogen

very weak base

Kb = 10-14

NH

NH

strong acidspolymer!

CH3CO2-NO2

+

(CH3CO)2O, 5oC NH

NO2

SO3

pyridine, 90o

NH

SO3H

C6H5-N2

+Cl-

NH

N N

pyrrole

NH

NH

CH=O

NH

C

NH

Br

pyrrole

CHCl3, KOH

HCN, HClH2O

(CH3CO)2O

250o

CH3

O

Br2, EtOH

0o

BrBr

Br

O

furan

CH3CO2NO2

O NO2

pyridine:SO3

O SO3H

C6H5N2+

O NN

(CH3CO)2O, BF3

O CO

CH3

O

furan

O CH=O

O Br

O HgCl O I

1. HCN, HCl

2. H2O

Br2

dioxane

HgCl2

CH3CO2Na

I2

CH3COCl

O CO

CH3

S

less reactive, can use acids

H2SO4

S SO3H

CH3CO2NO2

(CH3CO)2O S NO2

Br2, benzene

S BrBr

I2, HgO

S I

N

H

N

H

N

H

N

H

N

H

YH

YH

Y

H

Y

H

Y

H

Why EAS 2-position?

2-

3-

NH

O

H2, Ni

250o

H2, Ni

50o

NH

O

Kb = 10-14 Kb = 10-3

2o amine

THF

Pyridine

N N N6 pi electrons,

sp2, flat

aromatic, resonance stabilization energy ~ 23 Kcal/mole

Kb = 2.3 X 10-9

3

2N

1

6

54

N

N

CH3

-picoline

Pyridine important solvent & base (~ 3o amine)

Reactions:

1) EAS (much less reactive than benzene ~ nitro)

N

KNO3, H2SO4, 370o

N

NO2

3% yield

H2SO4, SO3, HgSO4

220o, 24 hours

N

SO3

H

Br2, 300o

N N

Br Br Br

+

Friedel-Craftsno reaction

N

N

N

H Y

Y

H

Y

HN

Y

HN

Y

H

N

Y

H

N

Y

H

N

H Y

N

H Y

Deactivated to EAS due to electronegativity of NitrogenDirects beta due to destabilization of alpha and gamma

Pyridine, reactions

2) Nucleophilic aromatic substitution

N

NaNH2

N NH2

phenyl lithium H2O

NN

N

N

N

Br

Cl

Br

NH3, 200o

NH3, 200o

NH3, 200o

NR

N NH2

N

NH2

N

N

H Z

Z

H

activated to nucl. arom. subts.directs alpha & gamma

Pyridine, reactions

3) As base

Kb = 2.3 X 10-9

N

N

HBr

CH3I

N

H

Br

N

CH3

I

4o salt

Pyridine, reactions

4) reduction

N

H2, Pt

HCl, 25o, 3 atm. NH

piperidine

Kb = 2 X 10-3

aliphatic 2o amine

Polynuclear Heteroaromatics

6

7

8

5

N1

2

34

6

7

8

5

1

N 2

34

quinolineisoquinoline

EAS EAS

NAS

NAS

5

6

7

4

NH 1

2

3

indole

EAS

EAS -Electrophilic Aromatic Substitution

NAS – Nucleophilic aromatic Substitution