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HETEROCYCLIC CHEMISTRY
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1. PYRAZOLE:
Pyrazole contains two nitrogen atoms at 1 and 2 positions in a five membered heterocycle. One of the nitrogen (1) is of pyrrole type and other (2) nitrogen is of pyridine type. It is1,2-diazole and a excessive heterocycle.

N
1N
2

H
PHYSICAL PROPERTY: It is a colorless solid and has pleasant odour. Its m.p is 70c and is soluble in water and organic solvents. Its b.p is 187c. it is amphoteric in nature. The molecular weight of pyrazole is normal in gas phase, but in non-polar solvents like benzene, it tends to associate through hydrogen bonding. The H-bonding formation is absent in pyrrole.(b.p 130c) and in pyridine (B.P.115c) and as a consequence these compounds have lower boiling points than pyrazole. The H-bonding association may be linear or cyclic.

H N N H linear H N N

N N N N H N cyclic H N

ACIDITY AND BASICITY: Pyrazole are weakly basic. It has a pKa value 2.53. it is less basic than imidazole. This is because of direct N-N bond linkage. As a result of which inductive effect predominates mesomeric effect and basicity is reduced.

Since, pyrazole has N-H group, it also behaves as acid, but behaves more as basic than acidic, so it is amphoteric in nature. AROMATICITY: Pyrazole exhibits aromatic character as there are six electron in the ring. The three C-atoms give 3 electrons (one from each Pz orbital), N at 2nd position gives 2 electrons and the hetero atom(N-1) gives remaining 1 electron to complete the aromatic sextet. Resonating structures:

1N

..
H

..
N
2

CH

CH
+

N H

N H

HC

N H

N H

(I)

(II)

(III)

(IV)

The mesomeric structure at C3 and C5 forms with highly unfavoured +vely charged azomethine nitrogen. Therefore, it makes them unstable. Out of four resonating structures, structure (I) is the most stable as there is no double bond between two N atoms. Hence, electrophilic substitution takes place at 4th position. Nucleophillic reactions are very few and causes ring opening. SYNTHESIS: 1. from di-arbonyl compounds

CH3 O H3C O H2N

-H2O

CH3 N N H

+
NH2

H3C

The method involves a reaction between 1,3-dicarbonyl compound and hydrazine or its derivative. For simple reaction acetyl acetone is used.
CH3 O H3C
acetyl acetone
-H2O

CH3 N N C6 H5

O HN

+
NH2 C6 H5
phenyl hydrazine

H3C

2. From ,-unsaturated carbonyl compounds: having LGat position It consist of a reaction between an ,-unsaturated carbonyl derivative and hydrazine or its derivative. The carbonyl compound must contain easily replaceable group at or position. O C6H5
C6H5NHNH2

H5C6 Cl

C6H 5

-H2O, -HCl

N H5C6 N C6H5 CH3

O
CH3NHNH2

H3C N NH

C6H5 N H5C6 CH3 N C6H5

H3C

C6H5

-H2O

3. From 1,3-dipolar cycloaddition of alkyne and diazomethane:

HC H2C
+

+ CH N N
-

Et2O 0 C

N N N H

4. From other ring system:

O
-

O N
+

+ H2C

CN

70 C

N N C6 H5

CO 2

HCN

H5 C6

Syndone and acrylonitrile result in pyrazole formation. The cyano pyrazoline formed as an intermediate is immediately converted to pyrazole

2. IMIDAZOLE

..
N 1 H

N3
2

..

STRUCTURE: Imidazole is an azapyrrole, the nitrogen atom being separated by one carbon atom. It is a 5membered heterocycle consisting of one pyrrole and one pyridine type of nitrogen atom in 1 and 3 positions respectively. It is 1,3-diazole and -excessive heterocycle. PHYSICAL PROPERTIES: Imidazole is a colourless liquid(B.P.256c) as compared to pyrazole and is high boiling than all the other 5membered heterocyclic compounds. However 1-methyl imidazole has B.P198c which shows that H-bonding exists in imidazole ring(linear) and may consist upto 20 molecules.
H N N H N N H N N

ACIDITY AND BASICITY: Imidazole is more basic(pKa=7.2) than pyrazole and even pyridine. This is because the two N-atoms being placed at 1 and 3 positions favours mesomeric effect predominates over inductive effect. The two nitrogens are far apart and can donate electrons more easily as no competition between two N-atoms. Imidazole shows amphoteric properties and behaves as an acid because it contains pyrrole type amino nitrogen in the ring and forms metallic salts with NaNH2 and RMgX which are extensively hydrolysed by water. The introduction of an alkyl group into ring increases the basicity. AROMATICITY: Imidazole is an aromatic compound and possess resonance energy of 14.2 Kcal/mole which is almost half of pyrazole. Each C atom and N-1 atom contribute one electron each while N-3 atom contribute one electron pair to form aromatic sextet. Resonating structures:
N N H N H N
+ -

N HC
-

N N H
+

CH N
-

N H (II)

CH

N H

(I)

(III)

(IV)

Because of high basicity and resonance, imidazole is more reactive than thiazole and oxazole. From resonance,it is clear that, nucleophillic attack takes place at C2 while electrophilic attack takes place at C4 or C5, this has been confirmed by electron density distribution. The large value of dipole moment (4.8D) indicates a considerable polarity in the imidazole ring, although the extent of polarization is much less than the required to yield an ionic structure. SYNTHESIS: 1. Radiszewski synthesis: ( dicarbonyl compound) It consists of corresponding a dicarbonyl compound such as glyoxal, -ketoaldehydes or -diketones with an aldehyde in presence of ammonia.
H5C6 O O H5C6 H2NH

+
H2NH

O H3C

C6H5

H5C6
-3H2O

N N

C6H5 H

H5C6 H5C6

N N H C6H5

H5C6

2. dehydrogenation of imidazole:

NH2 NH2
-

+
R

sulphur -NH3

N H3C N H
imidazoline

BaMnO4 dehydrogenation

1,2 ethane diamide

alkyl cyanide

N H
imidazole

3. from -haloketones: reaction involves interaction between amide and -ketone.

H3C H3C CH2

H2C

N CH3
-Br-H2O

+HC
3

H3C

N H

CH3

phenacyl bromide
4. From amidene and acyloin.

benzimidine

R R R
1

HN

N
-2H2O

+
OH H2N

N H

REACTIONS: 1. With acids: Imidazole is monoacidic base and forms crystalline salt with acids.

N N H

N
H+

H N

N
+

N H

It also possesses weakly acidic properties and is even more acidic than pyrrole and thus forms salts of the following type with Grignard reagents or metal ion:

N N H

MgCl
+

imidazole magnesium chloride

2. Alkylation: Alkylation of imidazole can be achieved by heating 1-carboethoxy imidazole obtained by reacting imidazole with ethyl chloroform
N R N H
1

O H3C O R

N R N COOR
1

, 170 C -CO2

N R N R
1

(C2H5)3N, CH 3CN -HCl

3. Electrophilic substitution: The resonating structures of imidazole contributes more no of charged structures than those of benzene. Hence, imidazole posses increased reactivity towards electrophilic attack. It is more susceptible to electrophilic attack than pyrazole or thiazole and also even furan and thiophene. Electrophilic substitution in imidazole takes place at 4 and 5 posotion

C4 position: N
E
+

E H HC
+

E N N H H N H N
+

N H C5 position: N N H

CH N H E N H

H E N H

N CH
+

E H N H

N
+

Bromination (Br 2/CHCl 3) yields 2,3,5 tribromo derivative N

Br2/ CHCl3

Br N Br N CH3 Br

N CH3

-10 C

4. Oxidation and reduction: Imidazole itself is stable to auto oxidation and to activation of chromic acid. Oxygen in presence of sensitizer(single oxygen) reacts to give an imidazole derivative. 5. With nucleophillic agents: Imidazole in general do not react by nucleophillic substitution unless electron withdrawing group is present. A halogen atom at 2nd position can be replaced by nucleophiles such as alkoxy, thiols or aminoalkyl. Often a nucleophillic attack results in ring fission.

3. OXAZOLE
STRUCTURE:

4 5

N3 2 O1

Oxazole is a 5-membered heterocyclic ring consisting of oxygen as in furan 1 st position and pyridine type nitrogen at 3rd position. It is 1,3-oxazole REACTIVITY: PHYSICAL PROPERTY: Oxazole is colourless liquid having B.P.69c and has an odour similar to that of pyridine. It is miscible with water and many organic solvents. It has dipole moment of 1.5D. ACIDITY AND BASICITY: Oxazole is weakly basic compound with pKa 0.7 to 0.8. this is because of inductive effect by oxygen atom. It is more basic than isoxazole. It is weaker base than corresponding pyridines.

AROMATICITY: Although it posses a sextet of -electrons, all its speactral properties indicate that delocalization is incomplete. Hence, it has but little aromatic character. Resonating structures:

N O

N
+

N O
+

N
-

CH

HC

Oxazole functions as diene rather than aromatic compound. Electrophilic substitution is rare and takes place in presence of substituent at 2 and 4. Electrophilic attack is at 5 th position. It undergoes ring cleavage very easily on oxidation and during nucleophillic attack. SYNTHESIS: 1. From ethyl -hydroxy keto succinate and formamide: It involves a reaction between ethyl -hyrdocy succinate and formamide to give a diethyl oxazole4,5-dicarboxylate which on hydrolysis and decarboxylation gives isoxazoe.

COOC 2H5 N O CHOH COOC 2H5

COOC 2H5
Ba(OH)2

COO N

quinoline

N O

HCONH

100 C

COOC 2H5 O

H2 O

COO O

-2CO2

2. Robinson-gabriel synthesis: This method involves an -acylamino ketone which undergoes cyclisation and dehydration in presence of phosphorus pentoxide or strong mineral acid.

R N R
1

H
H
+

R N R
1

R R
2 -H2O

N R O
2

O O
3. From isocyanide:
H5C6
+ n- BuLi -H
+

Li H5C6

+ -

O N
+

CH Cl N H5C6 H Cl
+ +

CH

H3C

CH3

H N N H5C6 O
-HCl

O CH3 Cl

H5C6 H

CH3

4. From -amino carbonyl compound:

H NH H5C6 OC 2H5
+

NH2 NH
-NH3

H2N O CH3

CH3COOH reflux

H5C6

HN CH3

H CH3

OC 2H5

H5C6

O OC 2H5

H N H5C6 H5C6 O CH3

-C2H5OH

N O NH2

H5C2O

5. From acylaziridines:
Ar
-

..
O H2N

t-Bu
210 C -

t-Bu C
-

t-Bu N Ph Ar
-

N Ph

N H

Ph H

Ar

O oxidation -t-buH

N Ar
-

Ph O (96%)

REACTIONS: 1. Addition to nitrogen(quarternization): Oxazole can be quarternised using methyl iodide or dimethyl sulfoxide. (a) Protonation:

N O
(b) Quarternization:

H+

N O

N O

N
CH3I or DMSO

CH3

2. Electrophilic substitution: Oxazole is more reactive towards electrophilic substitution than thiazole but less than imidazole. The preffered position for attack is 5.
H3C N P h O H3C
Br2

N P h O

Br

3. Diels-alder reaction:
O R R
2 1

N R O

COOCH

HN R
2

+
R COOCH
3

COOCH COOCH
3

-H2O

-RCN

COOCH R R
1

H3COOC
3 3

COOCH R
2

COOCH R
2

furan derivative

pyridine derivative

4. Nucleophillic substitutition: There is high tendency for the ring to be cleaved rather than simple nucleophillic displacement. Ph Ph H Ph N .. N N NH3 NH3 Ph CH3 CH3 Ph CH3 Ph 180 C O H2N H O H N O NH2 2

-H2O

Ph N Ph N H CH3 -NH 3

Ph N Ph H N NH2 2 CH3

5. Oxidation and reduction:

H3CO N Ph O CH3
O2, sensitizers MeOH, 2days, RT

H N CH3 O O

Ph

N Ph O
6. Metallation:

LAH

NH CH 2PH

Ph

THF

HOPhHC

N O

N
n -BuLi THF

Li

N O CH3

n -BuLi THF

N Li O CH3

4. ISOXAZOLE:
STRUCTURE:

4 5 1O

3 N2

In isoxazole the oxygen and nitrogen atoms are in 1,2 relationship. It is a 5-membered heterocycle. It contains furan type oxygen at 1st position and pyridine type nitrogen in 2nd position. REACTIVITY: PHYSICAL PROPERTIES:

Isoxazole is a liquid having B.P 95c and resembles pyridine in odour. It is not miscible in weak acids. ACIDITY AND BASICITY: It is a very weak base with pKa=1.3. AROMATICITY: Isoxazole nucleous is considerably less aromatic than other five membered heterocycles including oxazole and furan. Resonating structures:
CH N O O (I)
+ -

CH HC
-

N O

N O

(II)

(III)

(IV)

SYNTHESIS: 1. From diketones: It involves condensation-cyclisation of .-diketone with hydroxyl amine. 2 1 1 R

NH2OH

O O R
2

N O R

+
2
2

N O R

2. From ,-unsaturated ketoximes: (using PdCl2)

R N OH H
1

2 (Ph3P)2 PdCl2

R
3

R R
3

Pd (II) N O R H
3

NaOC6H5,reflux cyclisation

N OH Pd (II) H

N O

3. From nitrile oxide:

R NOH Cl
Base -HCl

H R O
-

N R

OH R
1

R N O
1

nitrile oxide

vinyl halide reacts w ith nitrile oxide R N

+

+
H2C

R Cl N O

NH2 Cl H
-HCl

R N O

REACTIONS: 1. Electrophilic substitution reaction: The electrophilic attack readily occurs at 4th position and fails is=f this position is occupied. Both the heteroatom influence the rate of electrophilic substitution because of electron withdrawing nature of N atom. Br i)
NBS

N O O

ii) H3C N O

O 2N
HNO3 H2SO4

H3C

N O

2. With nucleophiles: Isoxasole is very labile towards the action of nucleophiles. Strong bases on cleavage of isoxazole ring yield -ketonitriles.
H
C2H5O Na
+

N
H3O+

R O

R
C2H5OH, RT

R CH2 ketonitrile

3. Condensation involving methyl group

CH3
NaNH2

CH3 N O

H3C

N O

PhCHO

H2O

Ph

4. Photochemical reaction: Isoxazole isomerizes to oxazole. Ph

h

CH3 H3C O N Ph

N Ph O oxazole

Ph O

isoxazole 5. Reduction:

NH2 N O NH2
H2/Ni raney Ni

NH2 Ph O N Ph

NH2

5.THIAZOLE
STRUCTURE:

4 5 S 1

3 2

Thiazole is a five membered ring and it contains sulfur and nitrogen atom at 1 and 3 position. The numbering in thiazole starts from sulfur atom. REACTIVITY: PHYSICAL PROPERTY: Thiazole is a colorless liquid b.p. 177 c which is close to pyridine(115 c) than thiophene(84 c). it resembles pyridine in odour and is miscible with water. ACIDITY AND BASICITY:

It is weakly basic having pKa= 2.5 and behaves as tertiary base. The alkyl derivative of thiazole are more basic. SYNTHESIS: 1. From -carbonyl compounds: Inthis method an -haloketone is reacted with an appropriate thiamide. Or thiourea
H O CH 2Cl NH2 HS
-H2O -HCl

N S

O H NH2 P2S5 H

S NH2

2. From -thiocyanato ketones: -halo-carbonyl compounds and metal thiocyanate react to give -thiocyanato ketone which cyclizes on treatment with acid or alkali. H3C O N O H3C OH H3C N H+, H 2 O H2N

-NaCl

Cl

S Na

H3C

H3C N OH S S

H N O

3. The Gabriel synthesis: This synthesis involves the heating of acylamino compounds with phosphorus pentasulfide to give thiazole derivative.

H NH
P2S5

H N

H N H3C S

H3C

O O

CH3

H3C S O

CH3

CH3 OH H3C S

N CH3

CHEMICAL REACTIONS: 1. Reaction with acids 2. Electrophilic substitution:

N S

Br2 250 -400 C

N Br S

H N S O
PCl5

N Cl S

3. Reaction with nucleophillic reagent

CH3
OH-

N H3C S

CH3 N H3C S
-H+

CH3 N H3C CHO S

-

H OH

4. Reactin with oxidizing and reducing agents

H5C6 N S
H2, Ni CH3OH

H5C6

NH2 CH3

H2S

5. Photochemical reactions

6.Benzimidazole:
STRUCTURE:
4 5 6 7 9

N3 2

8 N 1 H

The benzoderivative of imidazole is known as benzimidazole. It belons to fused heterocycle system in which imidazole ring is fused with benzene ring in which two C atoms are common to both the ringc.

REACTIVITY: It is a colourless solid with M.P is 170.5 c. it is soluble in hot water, alcohol,ether, but insoluble in
benzene. It has dipole moment of 3.93 D.

ACIDITY AND BASICITY: They are less basic than imidazole because of delocalization of electron in benzene ring. Benzimidazole has pKa of about 5.68. it is more acidic than simpleimidazole. AROMATICITY: It shows aromatic character similar to that of imidazole but it is more aromatic than imidazole. Its resonance energy is 30.90Kcal/mol. Resonating structure:

N N H (I)

N N H (II)
+

N
-

N HC
-

..

CH

N (III)

N N H (VI) (V)

N N H
+

CH

N N (IV)
+

..

SUNTHESIS;

1. 1,2-diaminobenzene condenses with a carboxylic acid on heating in a acidic medium to give benzimidazole.

NH2

100 C

N R N H

+
NH2

R HO

-2H2O

2. The cyclisation of N-haloamidines with sodium ethoxide forms benzimidazole via nitrene intermediate.
N R NHBr C 6 H5
NaOC2H5

N R N
2-

C6 H5 R

N N H

REACTIONS:

7. BENZOXAZOLE:
STRUCTURE:

4 5 6 7 O 1

3 N 2

The benzoderivative of oxazole is known as benzoxazole. It belongs to fused heterocycle system in which two carbon atoms are common to both the rings. REACTIVITY: PHYSICAL PROPERTY: It is colourless crystalline solid having m.p. 31c. it is soluble in organic solvents. ACIDITY AND BASICITY: It is nearly two pKa units weaker base but some what stronger as an acid than oxazole. This is because of inductive effect of oxygen which is stronger than mesomeric electron release from it. AROMATICITY: It is little more aromatic than simple oxazole. Resonating structures:
N O (I) (II) C
-

CH N O
+

N HC
-

N O (IV)
+

O (III)

NH O (V)
+

SYNTHESIS: 1. From smino phenol:

i)

NH2

+
OH

HO R O
-2H2O

N R O

ii)

NH2

boric acid

NHCHO

N O

+
OH

reflux

OH

iii)

NH2 OH

H3CO

conc. HCl

N O

+
H3CO

OCH 3

-3CH3OH

2. Photochemical rearrangement of indoxazine:

N O

N O O
-

NH2

N O

N O

CH

3. By treatment of KNH2 in liq. NH3 with O-chloro phenyl acetamide:

Cl
KNH2

O NH CH3

N CH3 O

N H

CH3

liq. NH3

4. From O-amino phenol and cyanogens bromide:

H NH2 OH NH2 N N
-HBr +

H N
-

+ Br

N O

O
+

-H

H N NH2 O
HOH

N N O
-

REACTIONS: 1. Addition to nitrogen: (i) Protonation:

N O
H+

(ii)

Quarternization:
N O
CH3I

CH3

2. Electrophilic substitution reaction: Due to strong inductive effect of oxygen, the ring itself becomes electrophile. Hence, electrophilic substitution is rare and takes place at 2nd position.
N O
SOCl2

N Cl O

SO 2

HCl

3. Nucleophillic substitution reaction:

N O

N
piperazine,CHCl3 Et3N. 0 C

N O N H

8.BENZOTHIAZOLE
STRUCTURE:

4 5 6 7

3N 2 1S

It is a benzo derivative of thiazole in which thiazole ring is fused with benzene ring with two C-atom common to both the rings. SYNTHESIS: 1. From 2-amino thiophenols and carboxylic acid or anhydride:
O NH2 O NH OH
-H2O -H2O

H+

N S

+
SH

SH

2. Benz thiazole can also be obtained by the direct thiocyanation(KSCN/CuSO4) of substituted aniline.

NH2
KSCN/CuSO4

N NH2 S

R
diazotisation H3PO2

N S

H3C

H3C

H3C

3. Condensation of N-ethoxy carbonyl thiamides with o-amino thiophene yield 2-substituted benzothiazoles.

S R NHCOOC 2H5

NH2

N R S

+
SH

REACTIONS: 1. Benzothioles can be quarternised. They form stable crystalline salts with strong acids.
N S
H+

N S

CH3

2. Electrophilic substitution: It takes place at 6th position. Heterocyclic ring can not be substituted it requires drastic conditions.

N S
3. Oxidation:

HNO3 H2SO4

N S

O 2N

O N S
peracid

S benzothiazole -N -oxide