INTRODUCTION The branch of chemistry dealing with synthesis, properties and application of heterocycles is called heterecyclic chemistry. A heterocycle compound is a cyclic compound which contain at least one atom other than carbon as part of the ring system. Nitrogen, oxygen and sulphur are the most common heteroatoms but heterocyclic rings containing other heteroatoms are known. A heterocyclic ring may comprise of three or more atoms which may be saturated or unsaturated. Also, the ring may contain more than one hetero atoms which may be similar or different. 2 Heterocyclic compounds occur widely in nature and in variety of non-naturally occurring compounds. A large number of them are essential to life. Various compounds such as alkaloids, coumarines, chromones, flavones, anthocyanins, antibiotics and a large number of synthetic drug and dyes contain heterocyclic ring systems.

A knowledge of heterocyclic chemistry is useful in biosynthesis and in drug metabolism as well.

3 CLASSIFICATIONS •Heterocyclic compounds may be classified into aliphatic and aromatic. The aliphatic heterocycles are the cyclic analogues of amines, ethers, thioethers, amides etc. the aromatics, in contrast contain heteroatoms in their rings and behave in a manner similar to benzene in some of their properties. (Huckel’s rule of (4n+2)π electron. • Single or fused ring • Saturated or unsaturated. 4 NOMENCLATURE

There is a special name for individual ring system and a trivial name for each compound which convey little or no structural information. The systematic name is designed so that one may deduce from it the structure of the compound. The IUPAC rule for naming are shown in the next slide:

5 TABLES

Elements Oxygen Nitrogen Sulphur Phosphorus Valence 2 3 2 3 Prefix oxa aza thio phospha

Ring Size Fully saturated compdpounds Fully unsaturated compounds With Nitrogen without Nitrogen With Nitrogen without Nitrogen 3 - iridine -irane -irine -Irene 4 - etidine -etane -ete -ete 5 - olidine -olane -ole -ole 6 - -ane -ine -in 7 - -pane -epine -epin 8 - ocin -ocane -ocine -

6 EXAMPLES

H i. N O ii. N iii. N iv. O v. vi. NH S aziridine oxetane thiirane azete 2,3-dihydroazete oxaziridine

vii. viii. S ix. S x. O S N O thietane 1,2-oxathiolane 1,2-thiazole tetrahydrofuran

7 EXAMPLES

H H xi. O xii. O O xiii. xiv. N xv. N

N N N 4H-1,3-oxazine azole azolidine H 2H-1,4-oxazine 4H-1,4-oxazine xvi. xvii. xviii. S xix. S N N N thiolane pyridine pyridazine thiole

8 3-MEMBERED RINGS

Three membered rings are more reactive because of ring strain. Those with one hetero atom are in general stable while those with 2 are more likely to occur a reactive intermediates. Examples are: O S

oxirane thiirene

9 PREPARATIONS OF 3-MEMBERED RINGS Epoxides are easily prepared by reactions of alkenes with peracids, usually with good stereospecificity. Because of their high angle strain, epoxides are

more reactive than unstrained ether. O i. CO 2OH O OH + H2C CH2 +

ii. HO O H O base HX X 2 + H2C CH2 + 2 X 10 REACTIONS OF 3-MEMBERED RINGS i. -SCN O S

H + ii. H N Cl- Cl N 3 2HCl

H3C H3C

11 FOUR-MEMBERED RINGS - PREPARATIONS The simple procedure of treating a 3-halo alcohol, thiol or amine with base is generally effective. S i. HS base

HO Cl HO

CH ii. 3 Br CH N 3 50% KOH

H C NH CH H3C 3 3 CH3

12 FOUR-MEMBERED RINGS - REACTIONS i. O (1) RMgBr R OH + (2) H3O ii. H N + - 2HCl Cl NH3 Cl

H3C 13 FIVE-MEMBERED RING - PREPARATION A general preparation of substituted furans, pyrroles and thiophenes from 1,4- dicarbonyl compounds is known as Paal-Knorr synthesis. R'''

H C H3C N 2 R R'' R'' R'''NH + 2 R

R' CH2 R'

14 FIVE-MEMBERED RING - REACTIONS

CHO i. DMF

POCl3 N N H H N N + ii. - N2 X + N N O N NO 2 H 2 H

15 SIX-MEMBERED RING Fully unsaturated six-membered nitrogen heterocycles, such as pyridine, pyrazine, pyrimidine and pyridazine have stable aromatic rings. The diazines are weaker bases than pyridine due to the inductive effect of the second nitrogen.

16 SIX-MEMBERED RING - REACTIONS i. Substitution

C2H5Br CH3COCl + + N - N N Br Cl- C2H5 H3C O N-ethylpyridinium bromide N-acetylpyridinium chloride

ii. Oxidation

COOH

KMnO4

N N COOH 17