Heterocyclic Compounds PDF

1/4/2013
HETEROCYCLIC COMPOUNDS
Under the guidance of
Dr.C.GOPINATH M.pharm.,Ph.D
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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
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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
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
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Unsaturated Homocyclics :Eg : Benzene & its derivatives. polynuclear aromatic compounds.
Benzene
Naphthalene
Anthracene
Phenanthrene
Pantacene
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).
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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
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.
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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.
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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.
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
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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.
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
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5)
O
Hetero atoms O Prefix - oxa. Ring size 7, compound saturated without N Suffix epane oxa + epane
oxepane.
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
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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)
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
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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
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Name
Structure
4 - membered Heterocyclic compounds :* Azetines

4 3
N1
* Oxetanes
4 3
4
O1
2
S1
* Thietanes
3
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
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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
+
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Name
Structure
6 membred Hetero cyclic having (Two) Hetero atoms :* Pyridazine

N N N N
Pyrimidine
* Pyrazine
N
FUSED HETERO CYCLICS :Benzo pyrazole :
N N
Benzo Imidazole :
H
N N
H
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Benzo isoxazole :
N O
Benzo oxazole :
N O
Benzo isothiazole : -
Benzo thiazole : -
N S
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Benzo furan : -
Benzo thiaphene :-
Quinoline : -
Iso Quinoline : -
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Phenothiazine :
S
Acridine :-
THIAZOLE
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Thiazole having an sulphur atom and

1,3 positions in five membered ring.
nitrogen atom at
N S
1
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
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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)
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
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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
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
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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
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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.
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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
2 - hydroxy thiazole
5 - bromo -2hydroxy thiazole
2) Chlorination :
N S
O
Pcl5
/
S
N CL
2 - Thiazolone
2 - Chlorothiazole
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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 .
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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
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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.
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
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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)
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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
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
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Physical properties :State Odour : Liquid : resembling that of pyridine very characteristic pungent odour.
Solubility : misible with H2O & many organic solvents. B.P : 69oC
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
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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.
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
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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
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
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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
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
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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
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
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REFERENCES:-
HETEROCYCLIC CHEMISTRY FOURTH EDITION
RAJ K.BANSAL
www.pharmainfo.net
www.wikipedia.org
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Heterocyclic Compounds PDF

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1/4/2013

INTRODUCTION , Defs NOMENCLATRUE CLASSIFICATION HETEROCYCLIC COMPOUNDS

Saturated Homocyclics:Eg: cycloalkanes

saturated Hetrocyclic compounds :Eg:

unsaturated Hetrocyclic compounds : 4 Eg: 4 3

NOMENCLATURE :The name of heterocyclic compound consists of two components

saturated ' N '

Common name endings / suffixes :

Suffixes for fully saturated

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

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

Suffix Ring size Nature of Ring.

O Tetra hydro furan

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

benzo, Naphtho etc. 4

CLASSIFICATION OF HETEROCYCLIC COMPOUNDS :

3 -- membered Heterocyclic compounds : 3

4 - membered Heterocyclic compounds :* Azetines

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

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

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

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

FUSED HETERO CYCLICS :Benzo pyrazole :

Thiazole having an sulphur atom and

The benzo derivative is known as BENZOTHIAZOLES.

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

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

Reaction between chloroacetaldehyde & Thiourea :O C H2C H S

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

Electrophillic substition reaction :4

5 - bromo -2hydroxy thiazole

2 - nitro thiazole www.pharmaaspirants.com

Thiazole - 5 - sulphonic acid

H3C - CH2 - CH2 - CH2 - Li

Thiazole - 2 - lithium www.pharmaaspirants.com

quarternary ammonium salts

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

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

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

The benzoderivative is known as BENZOXAZOLES .

Fully saturated system is called Oxazolidine

COOC2H5 C=O 100oC

formamide Diethyloxazole 4,5 dicarboxylate

alpha - hydroxy keto succinate

oxazole 4,5 dicarboxylic acid

alpha - acylamino ketone.

5 - bromo - 2 - phenyl oxazole

2,4,5 triphenyl oxazole

Na / amylalcohol 5 Birch Redn

IV) Photochemical reaction :In presence of UV light.

2- 4 diphenyl oxazole 2,5 diphenyl oxazole

Diels - Alder Reaction :Diene + Dienophile Adduct

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

Dimethyl pyridine 3,4 dicarboxlic acid

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

HETEROCYCLIC CHEMISTRY FOURTH EDITION

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