Heterocyclic Chemistry

2010
 Syllabus of Heterocyclic Chemistry
Aims:
The aims of this course are to provide non-aromatic and aromatic
heterocycles by examining their properties and reactivity patterns
and by important methods for their synthesis.

Importance of Heterocyclic chemistry:

Heterocycles constitute the vast majority of all known compounds
and are key components of pharmaceuticals, agrochemicals, electro-
active polymers, flavouring ets. They are also found widely in
biologically important natural products (e.g.vitamins, haemoglobin,
dyes, antibiotics, hormones) etc.
 Learning outcomes
After completion of this course you will able to:
1. Appreciate the importance of heterocyclic compound
to mankaind
2. Understand the factors whih influence the reactivity
of functional groups in ring structures
3. Have a clear understanding of the differences
betweeen acyclic and heterocylic compounds
4. Recognise and describe reactions for heterocycles
synthesis
5. Discuss the concept of aromaticity in heteroaromatics
 Recommended Reading

1. Heterocyclic Chemistry – J.A. Joule, K. Mills and G.F. Smith

2. Heterocyclic Chemistry – T. Gilchrist
3. B.K Banik, Editor, “B-Lactams : Synthesis, Stereochemistry
and Biological Evaluation”, Current Medicinal Chemistry (USA)
2004, 11, Volume 14, pages 1813-1964
Introduction of Heterocyclic Chemistry

Week 1
Classification of heterocyclic compounds,
Replacement and systematic nomenclature (Hantzsch
Widman system) for monocyclic, fused and bridged
heterocycles, numbering of bicyclic system with
accepted numbering trivial name.
Definition: Heterocyclic compounds are organic
compounds that contain a ring structure containing atoms in
addition to carbon, such as sulfur, oxygen or nitrogen, as the
heteroatom. The ring may be aromatic or non-aromatic
(aliphatic)

Aliphatic heterocyclic – cyclic analogues of amines, ethers, thioethe r,

amide, etc. Their properties are particularly influenced by the presence of strain in
the ring. Small membered-ring : 3- and 4-membered and normal (5 to 7
membered ring).

Aromatic heterocyclic – heteroatom in the ring and behave in a

manner similar to benzene in some of their properties. These compounds also
comply with the general rule proposed by Huckel.
 Heterocylic ring may contain more than one
heteroatom which may be similar or dissimilar. Also
the ring may comprise of three or more atoms which
may be saturated or unsaturated.

Significance – Two thirds of all organic compounds are aromatic

heterocycles. Most pharmaceuticals are heterocycles.

Examples
Pfizer: Viagra

Quinine
Erectile dysfunction
Treatment of malaria for 400 years (Peru)
 H
N NHMe
N
N
Me NC
N
H Treating stomach & intestinal ulcers

Camptothecin Analogues

Pfizer - Irinotecan GSK - Topotecan

Ovarian & lung cancer

More soluble & less side-effects
 Structure of β-Lactam Antibiotics

Cephalosporin
Cephalosporin are related to the penicillins in both structure and mode of action.
They are widely used to treat gonorrhea, meningitis, pneumococcal, and streptococcal
infections. The cephalosporin class of antibiotics is usually divided into generations by
their antimicrobial properties.
Three generations of cephalosporins are recognized and the fourth has been grouped.
Also, the third-generation cephalosporins can penetrate into tissues well, and thus
antibiotic levels are good in various body fluids.
.
Recent in vitro examinations
strenghten the antiproliferative
effects of prenylated naringenin
(Humulus lupulus L., hops) on
prostate tumour cell line
culture.
(Phytomedicine. 13 (9-10), 732-4.
2006.)
• Oxygen of pyrane ring is quaterner.
• Oxoniumbases with acids form salines.
20 dkg soybean contains ca.
300 mg izoflavones.
Saturated and unsaturated
Heterocycles
 Aromatic Heterocycles
Carbocycles
Aromatic Heterocycles
 Nomenclature

 Hetero-atom is to be counted as 1 or as low as possible

 When there is more than one hetero-atom, preference is
given to O, then S, then N, then C. Also N-H presides over –
N=. Mnemonic: Old Soldiers Never Cry
 When there is more than one hetero-atom, numbering should
be as direct as possible from one to the other
 Substituents are numbered as low as possible
 Acceptable prefixes include O=Oxa; S=Thia; N=Aza
 Common suffixes for N- and non-N-heterocycles. For partially
unsaturated systems, H is(are) are used to indicate the
location of saturation
 Hantzsch-Widman System of systematic name of heterocyclic
compounds
Hantzsch – Widman Nomenclature
(adopted by IUPAC)

Hetero atom Valence Prefix

O 2 Oxa

N 3 Aza

S 2 Thia

Se 2 Selena

P 3 Phospha

Si 4 Sila
 Hantzsch – Widman Nomenclature (adopted by IUPAC)

Ring Saturated Partly Saturated Unsaturated

Size
3 -irane - -irene
4 -etane (dihydro) -ete
5 -olane (dihydro) -ole
6 -inane (di or tetrahydro) -ine
7 -epane (di or tetrahydro) -epine
8 -ocane (di, tetra, or -ocine
hexahydro)

O
Common name : ethylene oxide
Systematic name : Oxa + irane …. Oxirane

O Common name : furan

Systematic name : Oxa + ole …. Oxole
 Common name : pyrrole
NH
Systematic name : H at 1 position + Aza + ole …. 1H-Azole

H
N

Common name : piperidine

Systematic name : Aza + inane …. 1H-Azinane

N Common name : pyrimidine

Systematic name : two aza at 1, 3 positions + ine ….
……………………………………………….[1,3]-diazine
N
 H O
N O
S

NH NH

Azocane [1,3]-Oxazocane [1,3,7]-Oxathiazocane

Ph Ph

O O O

S S

N N

CH3 CH 3
4,5-dihydro-2H,8H-
[1,3,7]-oxathiazocine 6-Methyl-2-phenyl- 6-Methyl-2-phenyl-
2H,8H-[1,3,7]-oxathiazocine 2H,3H,8H-oxocine
 Exercise
1. Draw structures for the following :
a. 2H-1,2-benzoxazine
b. thieno[3,4-b]furan
c. furo[3,2-d]pyrimidine
2. Name each of the following by Hantzsch-Widman system: