Anda di halaman 1dari 32

1/4/2013

HETEROCYCLIC COMPOUNDS
Under the guidance of
Dr.C.GOPINATH M.pharm.,Ph.D

www.pharmaaspirants.com

Vishnu seedrala Y10Mph267 1st M.PHARMACY Pharmaceutical chemistry Hindu College of Pharmacy

INTRODUCTION , Defs NOMENCLATRUE CLASSIFICATION HETEROCYCLIC COMPOUNDS

THIAZOLE
I) INTRODUCTION II) SYNTHESIS III) CHEMICAL REACTIONS IV) MEDICINAL COMPOUNDS CONTAIN THIAZOLE RING * THIABENDAZOLE * SULFATHIAZOLE * THIAMINE

OXAZOLE
I) INTRODUCTION II) SYNTHESIS III) CHEMICAL REACTIONS IV) MEDICINAL COMPOUNDS CONTAIN OXAZOLE RING * PIMPRININE * CALCINOMYCIN

www.pharmaaspirants.com

1/4/2013

INTRODUCTION
Organic compounds [ carbon containing ] based on the presence/absence of ring structure classified in to two categories.

Classification :

Organic compounds
Cyclic compounds

Acyclic compounds

Homocyclic compounds

Heterocyclic compounds

www.pharmaaspirants.com

Homocyclic Compounds:
Def: These are the cyclic compounds, the ring structure is exclusive made up of carbon atoms. These are also known as carbocyclic compounds. These may be saturated (or) unsaturated.

Saturated Homocyclics:Eg: cycloalkanes


cyclohexane

cyclopropane

www.pharmaaspirants.com

1/4/2013

Unsaturated Homocyclics :Eg : Benzene & its derivatives. polynuclear aromatic compounds.

Benzene

Naphthalene

Anthracene

Phenanthrene

Pantacene

www.pharmaaspirants.com

HETEROCYCLIC COMPOUNDS :
Def: Heterocyclic compounds are the cyclic compounds which contain one (or) more other elements along with carbon atoms are called Heterocyclic compounds.

The heteroatoms are Nitrogen(N) Oxygen (O) Sulphur (S) Phosphorous (P) silicon (Si).

www.pharmaaspirants.com

1/4/2013

saturated Hetrocyclic compounds :Eg:


4 3 2
5 6 4 3 2

O
1

N H
1

Tetrahydro furan

Piperidine

unsaturated Hetrocyclic compounds : 4 Eg: 4 3


5 3 2

O
1

N
1

Furan

www.pharmaaspirants.com

Pyridine

NOMENCLATURE :The name of heterocyclic compound consists of two components

prefix +suffix.
Prefix -------->> Tells about the nature of the hetero atom. Suffix ------- >> gives information about (i) Ring size. (ii)Presence/Absence of unsaturation. Note :-Prefix gives information about the position of the hetero atom.

www.pharmaaspirants.com

1/4/2013

RULES :1) If heterocyclic compounds consists of only one hetero atom, the numbering should start from that particular hetero atom.
4

Eg :

5 6

3 2

N
1

Pyridine
2) If heterocyclic compound consisting of more than one heteroatoms the priorities to hetro atoms is in the following order O>S>N>P>Si.

3) The prefix corresponding to various hetero atoms are Hetero atom O S N P Si prefix Oxa Thia Aza Phospha Sila.

4) If more than one hetero atom present in the hetero cyclic compound then the numbering of hetero atom is given according to lowest sum Rule
3 4 4

N O
1
2

1+3=4 1+4=5

25

5
1

oxazole
of these minimal is 4 so numbering is given ois 1 &n is 3.

1/4/2013

5) If Heterocyclic compounds consists of two simillar hetero atoms if which one is saturated & other is un saturated than the numbering should be started from saturated hetero atom.
4

N
5

unsaturated 'N'

saturated ' N '

H Imidazole
6) The suffixes in heterocyclic compounds represents the ring size & the presence /absence of unsaturation.

www.pharmaaspirants.com

Common name endings / suffixes :


Ring size Suffixes for fully unsaturated
With N With out N -Irene -ete -Ole -In -epin -

Suffixes for fully saturated


With N With out N - Irane

3 4 5 6 7 8

- irine -Ete -Ole - ine -Epine - ocine

-Iridine

-Etidine - Etane -Olidine - Olane - ocin -ane - Epane - ocane

www.pharmaaspirants.com

1/4/2013

Eg : 1)
O

Prefix heteroatom

Suffix Ring size Nature of Ring.

Prefix : Oxygen present ------> oxa Suffix : 3 Ring size + saturated ------> irane oxa + irane ------> oxirane 2)

Prefix------> Nitrogen -------> Aza. Suffix------> 4 ring+unsaturation ----> ete Aza+ete -----> Azete.

www.pharmaaspirants.com

3)

N O

Hetero atoms are oxygen &Nitrogen. Prefixes -----> oxa & Aza. Priority O>S>N>P>Si. Ring size ---- 5 , compound is unsaturated with N atom Suffix --- ole. oxa + Aza+ole 4)
S N

oxazole.

Hetero atoms are S & N Prefixes Thia &Aza Priority O>S>N>P>Si. Ring size ---- 5 , compound unsaturated N Suffix --- ole. Compound name Thia +Aza + ole. Thiazole

www.pharmaaspirants.com

1/4/2013

5)

O
Hetero atoms O Prefix - oxa. Ring size 7, compound saturated without N Suffix epane oxa + epane

oxepane.

www.pharmaaspirants.com

7) If Hetero cyclic compound consists of saturated atoms [ partially / completely saturated ]presence of that saturation is represented using pre-prefixes like Dihydro , Tetrahydro etc.
4 5 3 2

O
1

O Tetra hydro furan

Furan

Dihydro furan

www.pharmaaspirants.com

1/4/2013

Note : The presence of double bond in the heterocyclic compound is represented by symbol .

The superscript of the symbol x represents position of the double bond(s).

Eg: 2 3(5)

double bond b/w C2 & C3 carbon atoms. double bond b/w C3 & C5 (for bridged C atom)

www.pharmaaspirants.com

8) when two ( or ) more same hetero atoms present the prefix will by di &Tri etc used.

Eg:
5

N N
1

3 2

1,3,5 Triazine

1/4/2013

9) In fused rings, the name of heterocyclic ring is chosen as parent compound name of fused ring is attached as the prefix in such names has ending O .

benzo, Naphtho etc. 4


5 3 2 7

Eg:

benzo furan

CLASSIFICATION OF HETEROCYCLIC COMPOUNDS :


Name Structure

3 -- membered Heterocyclic compounds : 3

* Aziridine

N1 H

*oxirane

O1

* Thiiranes

S1

www.pharmaaspirants.com

10

1/4/2013

Name

Structure

4 - membered Heterocyclic compounds :* Azetines


4 3
N1

* Oxetanes

4 3
4

O1

2
S1

* Thietanes
3

www.pharmaaspirants.com

Name

Structure

5 - membered Hetero cyclic compound with (one) Hetero atoms :4 3 2

* Pyrrole

N1
H

3 2

* Furans

O1

3 2

* Thiophene

S1

www.pharmaaspirants.com

11

1/4/2013

Name

Structure

5 membered Hetero cyclic compounds contain (Two) Hetero atoms : -

Pyrazole

N N
H

* Isoxazole
O

* IsoThiazole
S

N
N

* Imidazole

N
H

* oxazole
O

* Thiazole
S

Name

Structure

6 membred Hetero cyclic having (One) Hetero atoms :-

* Pyridines
N

* Pyrylium salt
O

* Thiopyrylium salt
+

www.pharmaaspirants.com

12

1/4/2013

Name

Structure

6 membred Hetero cyclic having (Two) Hetero atoms :* Pyridazine


N N N N

Pyrimidine

* Pyrazine
N

www.pharmaaspirants.com

FUSED HETERO CYCLICS :Benzo pyrazole :

N N

Benzo Imidazole :
H

N N
H

www.pharmaaspirants.com

13

1/4/2013

Benzo isoxazole :

N O
Benzo oxazole :

N O

www.pharmaaspirants.com

Benzo isothiazole : -

Benzo thiazole : -

N S

www.pharmaaspirants.com

14

1/4/2013

Benzo furan : -

Benzo thiaphene :-

www.pharmaaspirants.com

Quinoline : -

Iso Quinoline : -

www.pharmaaspirants.com

15

1/4/2013

Phenothiazine :
S

Acridine :-

www.pharmaaspirants.com

THIAZOLE

www.pharmaaspirants.com

16

1/4/2013

Thiazole having an sulphur atom and


1,3 positions in five membered ring.

nitrogen atom at

N S
1

www.pharmaaspirants.com

The benzo derivative is known as BENZOTHIAZOLES.

N S
Partially reduced Thiazoles are called THIAZOLINES. And three types of possible depending on the position of double bond. These are

www.pharmaaspirants.com

17

1/4/2013

N
5

N
2

S
1

S
1

S
1

2-THIAZOLINE

3-THIAZOLINE

4-THIAZOLINE

PHYSICAL PROPERTIES:
State : colour : odour : Solubility : Boiling point : Liquid colourless It has a very characteristic pungent odour Miscible with water. 177o c It is weakly basic with(pka2.5)

www.pharmaaspirants.com

Method of Preparation : I. From - Halocarbonyl compounds :H

O
C

+
C H 2c l Haloke tone H C - NH
2

N
- H2 O

Thiamide

-H c l

www.pharmaaspirants.com

18

1/4/2013

Mechanism : H H OH C C-H H-CH


H - CH

O
C

NH2

+
S

- H2O

N-H C-H

cl

cl
N

S
H N H - HCL C H S H

+
Hcl

cl

www.pharmaaspirants.com

Reaction between chloroacetaldehyde & Thiourea :O C H2C H S

C NH2

NH2

NH 2

cl
N S Thiazole
-N2 C2H5OH

2 amino thiazole
NaNO2+Hcl

N S N2cl

Diazonium salt

www.pharmaaspirants.com

19

1/4/2013

GABRIEL SYNTHESIS :CH2 H3C C O NH C O CH3 P2S5 H CH H3C C


S

H N C O H3C CH3

H C C S N H C CH3 OH

acylamino compound

-H2O

N S
CH3

H3C

2,5-Dimethyl Thiazole

www.pharmaaspirants.com www.pharmaaspirants.com

REACTIVITY AND CHMICAL REACTIONS :Thiazole is an aromatic compound & Aromatic sextet in thiazole comprises of 4e- of two double bonds in one lone pair of electrons on sulphur. Like Benzene its derivatives thiazole will undergo electrophilic aromatic substitution. Presence of an electron releasing group preferably at 2nd position catalytes electrophilic aromatic substitution.

www.pharmaaspirants.com

20

1/4/2013

Electrophillic substition reaction :4

N3
2

Br 2 400 - 600 C
o

N S Br

I.

Bromination :-

S1

Thiazole
NBS

2 Bromothiazole

N3
2 5

Br

S1

5 bromothiazole
4 3

N
2

Bromination OH Br S

N OH

www.pharmaaspirants.com

2 - hydroxy thiazole

5 - bromo -2hydroxy thiazole

2) Chlorination :

N S
O

Pcl5

/
S

N CL

2 - Thiazolone

2 - Chlorothiazole

www.pharmaaspirants.com

21

1/4/2013

3) Nitration :
Thiazole generally resists the nitration even under vigorous experimental conditions. So Nitration is done by Indirect method .
N S
NaNH2 NH3

N S
NH 2

2 - amino thiazole
Diazothistation NaNO2+Hcl

N S

N2 cl
NaNO2 - N2

- Nacl N S NO2

2 - nitro thiazole www.pharmaaspirants.com

4) sulphonation :N
H2SO4 HgSO4

HO 3S

Thiazole

Thiazole - 5 - sulphonic acid

II)Nucleophillic Aromatic substitution reaction :Thiazole consists of the highly electronegative sulphur & Nitrogen atoms which pulls electrons & decreases the electron density of aromatic ring, making it a strong electrophile & made to readily be attacked by a Nucleophile .

www.pharmaaspirants.com

22

1/4/2013

N S Thiazole

NaNH2 NH3

N S

NH2

2 amino thiazole

H3C - CH2 - CH2 - CH2 - Li

n - butyl lithium N S Li

Thiazole - 2 - lithium www.pharmaaspirants.com

III) Reaction

with Acids : -

Thiazole consists of N atom it acts as a weak base ( 3o amine ) react with mineral acids to form stable crystalline salts.
4 5

N3
2

NHcl

Hcl S

S1

quarternary ammonium salts

www.pharmaaspirants.com

23

1/4/2013

Medicinal compounds contains thiazole moiety : Thiabendazole :S N N N

2 - (4 - thiazolyl ) - 1 - benzimidazole
Uses :- It is broad spectrum anthelmentic
It is effective in most of worm infections.

www.pharmaaspirants.com

Sulfathiazole :NH2

N SO2 NH S

4 - amino - N - (thiazol - 2 - yl) benzene sulphonamide

Uses :- It is used for skin infections It is used as a topical treatment of vaginal infections
www.pharmaaspirants.com

24

1/4/2013

Thiamine :NH 2 N
H3C

CH2 N

N S

CH3 CH2CH2OH

2,5 - Dimethyl - 6 - aminopyrimidine + 4 methyl,5 - hydroxyethyl thiazole

Uses :- used for the treatment of beri-beri used in the treatment of polyneuritis ( disfunction of nervous system)

www.pharmaaspirants.com

www.pharmaaspirants.com

25

1/4/2013

INTRODUCTION
Oxazole having an oxygen atom and nitrogen at 1,3 positions in a fire membered ring .

4 5

N3
2

The benzoderivative is known as BENZOXAZOLES .

O1

N O

www.pharmaaspirants.com

Oxazole does not occurs in nature. Partially reduced oxazoles are called oxazolines and three types are possible depending on the position of the double bond. These are 2 oxazoline 3 oxazoline 4 oxazoline
4 5 (2)
(3)

N3
2

4 5

N3
2

4 5

N3
2

O1

O1

O1

Fully saturated system is called Oxazolidine

N O

www.pharmaaspirants.com

26

1/4/2013

Physical properties :State Odour : Liquid : resembling that of pyridine very characteristic pungent odour.

Solubility : misible with H2O & many organic solvents. B.P : 69oC

www.pharmaaspirants.com

SYNTHETIC METHODS :
1) From Ethyl Hydroxy keto succinate :COOC2H5
O

COOC2H5 C=O 100oC

N O
COOC 2H5

NH2

CHOH

formamide Diethyloxazole 4,5 dicarboxylate

COOC2H5

alpha - hydroxy keto succinate

Ba(OH2)H2O

COOH
3 2 4

Quinoline (Cu)
-2CO2

3N 2 1

O 1 oxazole

COOH

oxazole 4,5 dicarboxylic acid

27

1/4/2013

Robinson Gabriel Synthesis :It is the most common method for preparation of oxazoles.

R N R1 C
O O

H
H+
1

R N R
- H2O

N O R2

C R2

Ho

R2

R1

alpha - acylamino ketone.

www.pharmaaspirants.com

Reactivity & Chemical reactions :Oxazole is an aromatic compound which obeys the Huckels rule of aromaticity. The aromatic sextet of oxazole comprises of four e- s of two double bonds & one lone pair of e- of oxygen. as oxazole is an aromatic compound, it will undergo electrophillic aromatic substitution reactions. I) Bromination :
4 5

N3 O
2 1

Bromination
NBS

4 5

N3 O
2 1

ph

Br

ph

2 phenyl oxazole

5 - bromo - 2 - phenyl oxazole

www.pharmaaspirants.com www.pharmaaspirants.com

28

1/4/2013

To participate in electrophillic aromatic substitution oxazole should consist of an e- releasing substituent at 2nd position.

ii) OXIDATION :oxazole resists the oxidation process with mild agents. In presence of strong oxidising agents, substituted oxazoles will undergo degradation to give the products.
O

C
4

OH

N3 O1
2

Kmnoy (O)

2,4,5 triphenyl oxazole

Benzoic acid

www.pharmaaspirants.com

iii)Reduction :4 5

N3
2

Na / amylalcohol 5 Birch Redn


2

N3
2

O1

O1 oxazoline

Na/amylalcohol

4 5

3 2

O1 oxazolidine

www.pharmaaspirants.com

29

1/4/2013

IV) Photochemical reaction :In presence of UV light.

COOH 4 5

N3 O1
2

UV light

N O

+
Benzoic acid

2- 4 diphenyl oxazole 2,5 diphenyl oxazole

www.pharmaaspirants.com

Diels - Alder Reaction :Diene + Dienophile Adduct


COOCH3

COOCH3

R N R1 O R2

C C -H2O

R
5

4 3

COOCH3

R1

N1

R2

COOCH3

oxazole (Diene)

Methyl - 1,2 dicarbox;y - acetylene (Dienophile)

Dimethyl pyridine 3,4 dicarboxlic acid

www.pharmaaspirants.com

30

1/4/2013

Medicinal compound contain oxazole moiety : oxazole in nature is rare. naturally occuring oxazole include the alkaloid PIMPRININE It is isolated from streptomyces pimprina

O N

PIMPRININE

www.pharmaaspirants.com

It is a oxazole derivative. it posses antibiotic activity it is used in mixed infections.

O O N NHCH 3 COOH

N O H CALCINOMYCIN

www.pharmaaspirants.com

31

1/4/2013

REFERENCES:-

HETEROCYCLIC CHEMISTRY FOURTH EDITION

RAJ K.BANSAL

www.pharmainfo.net
www.wikipedia.org

www.pharmaaspirants.com

www.pharmaaspirants.com

32