heterocyclic.docx

7/27/2019 heterocyclic.docx

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HETEROCYCLICCHEMISTRY[Type the document subtitle]


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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.

NN

H

12

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.

NN

H

NN

HN

N

H

linear

NN

H

NN

H

cyclic

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.


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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 3electrons (one from each Pz orbital), N at 2

ndposition gives 2 electrons and the hetero atom(N-1)

gives remaining 1 electron to complete the aromatic sextet.

Resonating structures:

NN

H

12

....

NH

+

CH-

NNH

+N

-

NH

+CH

-N

NH

+

(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

CH3O

O

CH3

-H2O

+NH2 NH2

NH

N

CH3

CH3

The method involves a reaction between 1,3-dicarbonyl compound and hydrazine or its

derivative. For simple reaction acetyl acetone is used.

CH3O

O

CH3

-H2O

+NH NH2

C6H5

NN

CH3

CH3

C6H5

phenyl hydrazine

acetyl acetone


4/27

2. From ,-unsaturated carbonyl compounds: having LGat positionIt 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.

H5C6

O

C6H5

Cl

C6H5NHNH2

-H2O, -HCl NN

H5C6

C6H5

C6H5

CH3 C6H5

O

CH3NHNH2

-H2O

CH3

N

C6H5

NH CH3

N

N

H5C6

CH3

C6H5

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

CH2+

N N-

- +Et2O

0 CN

NN

H

N

4. From other ring system:

N+

N

O

O-

H5C6

+ CH2 CN70 C

NN

C6H5

+ CO2 HCN+

Syndone and acrylonitrile result in pyrazole formation. The cyano pyrazoline formed as an

intermediate is immediately converted to pyrazole


5/27

2. IMIDAZOLE

NH

N

1

2

3

..

..

STRUCTURE:

Imidazole is an azapyrrole, the nitrogen atom being separated by one carbon atom. It is a 5-

membered 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 5-

membered 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.

N NH N NH N NH


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.


NH

N

NH

+

N-

NH

+CH

-

N

NH

+CH

-

N

NH

+

CH-N

(I) (II) (III) (IV)


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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

H5C6

O

O C6H5

CH3

O

+ +

H2NH

H2NH

-3H2ON

N

C6H5

H

H5C6

H5C6

NH

NH5C6

H5C6C6H5

2. dehydrogenation of imidazole:

NH2

NH2

+N

R

sulphur

-NH3 NH

CH3 RBaMnO4

dehydrogenation NH

N

R

1,2-ethane

-diamide alkyl cyanide

imidazoline imidazole

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

CH3

CH3

CH2+

CH2

CH3

CH3 -Br-

-H2ONH

N

CH3CH3

phenacyl bromidebenzimidine

4. From amidene and acyloin.O

OH

R

R1

+NH

NH2 NH

N

R

R1

-2H2O


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REACTIONS:

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

NH

NH

+

N

N+

H

H

N+

N H

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:

NH

NMgCl

+

-

imidazole magnesium chloride 2. Alkylation:

Alkylation of imidazole can be achieved by heating 1-carboethoxy imidazole obtained by reacting

imidazole with ethyl chloroform

N

N

R1

H

(C2

H5

)3

N, CH3

CN

-HCl

CH3 O

O

R

N

N

R1

COOR

N

N

R1

R

, 170 C

-CO2

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


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NH

NE+

NH

CH+

N

E

H

NH

+

N

E

H

C4 position:

C5 position:

NH

N

NH

CH+N

H

E

H

NH

CH+

N

E

E

NH

+

N

H

N

N

CH3

Br2/ CHCl3

-10 C

N

N

CH3

Br

Br Br

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

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:

O

N

1

2

34

5


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Oxazole is a 5-membered heterocyclic ring consisting of oxygen as in furan 1st

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.


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.


O

N

O+

N

O+

CH-

N

O+

CH-

N-

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 5th

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 oxazole-4,5-dicarboxylate which on hydrolysis and decarboxylation gives isoxazoe.


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COOC 2H5

CHOH

O

COOC 2H5

+ HCONH 2 100 CO

NCOOC 2H5

COOC 2H5

Ba(OH)2

H2OO

N

COO-

COO-

O

Nquinoline

-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.

O

N

O

H

R2

R

R1

H+

O

NR

R1

H

R2

-H2O

O

N

R2

R

R1

3. From isocyanide:

ON

H5C6

H

CH3Cl

N+

C-

H5C6 n- BuLi

-H+

C-

N+

CH-

H5C6

Li+

CH3

O

Cl

CH

N+

O-

CH3

ClH

H5C6

H+

-HCl

ON

H5C6 CH3

H

4. From -amino carbonyl compound:

H5C6

NH

OC2H5

+NH2

OCH

3

CH3COOH

reflux

H5C6

OC2H5

NH

NH2

O CH3

-NH3

NH+

H5C6 OC2H5

H

CH3

O

O

NH5C6

H5C2ONH2

H

-C2H5OHO

N

H5C6 CH3

H+


11/27

5. From acylaziridines:NAr

-

O

t-Bu

NH2 Ph

..210 C C

-N

+

O H

t-BuH

Ar-

Ph O

NPh

t-B

Ar-

oxidation

-t-buH

O

N

PhAr-

(96%)

REACTIONS:

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

(a) Protonation:

O

N

O

N+

HH+

(b)Quarternization:

O

N

O

N+ CH3

CH3I

or DMSO

2. Electrophilic substitution:Oxazole is more reactive towards electrophilic substitution than thiazole but less than imidazole.

The preffered position for attack is 5.

O

N

Ph

CH3Br2

O

N

Ph

CH3

Br


12/27

3. Diels-alder reaction:

O

N

R

R1

R2

+

COOCH 3

COOCH 3

NH

OR

1

COOCH 3

COOCH 3

R2

R

N R2

COOCH 3

COOCH 3

R1

R

O

COOCH 3H3COOC

R1

R2

furan derivative

pyridine derivative

-RCN-H2O

4. Nucleophillic substitutition:There is high tendency for the ring to be cleaved rather than simple nucleophillic displacement.

O

NCH3

Ph

PhO

N

CH3

Ph

PhNH2

NH3

180 C

..NH3

OH

N

CH3

Ph

Ph

H

NH2NH2

N

CH3

Ph

Ph

NH2NH2NH

N

CH3

Ph

Ph

-H2O

-NH3


13/27

5. Oxidation and reduction:

O

NCH3Ph

O2, sensitizers

MeOH, 2days, RTO

N

O

CH3Ph

H3COH

O

N

PhPh

LAH

THF

NH

HOPhHC CH2PH

6. Metallation:

O

Nn -BuLi

THF O

N

Li

O

N

CH3

n -BuLi

THFO

N

CH3Li

4. ISOXAZOLE:

STRUCTURE:

O N1

2

34

5

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:


14/27

Isoxazole is a liquid having B.P 95c and resembles pyridine in odour. It is not miscible in weak acids.


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.


ON

O+

N

CH-

O+

CH-

N

O+

N-

O+

CH-

NO

(I)(II) (III) (IV)

SYNTHESIS:

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

OO

R2

R1

NH2OH

ON

R1

R2

+O

N

R2

R1

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

OH

NH

R1

R2

R3

(Ph3P)2 PdCl2

NaOC6H5,reflux

cyclisationOH

NH

R1

R2

R3

Pd (II)

ON R

3

Pd (II)

R2

R1

H ON

R1

R2

3. From nitrile oxide:


15/27

R

Cl

NOHBase

-HCl

RN

+

O-

R

NOH

R1

O

N

RH

R1

R N+

O-+

CH2

ClR

O

N

NH2

Cl

H

R

O

N-HCl

vinyl halide reacts w ith nitrile oxide

nitrile oxide

REACTIONS:

1. Electrophilic substitution reaction:The electrophilic attack readily occurs at 4

thposition 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.

ON

NBS

ONCH3

ON

CH3

O2N

Br

ON

HNO3

H2SO4

i)

ii)

2. With nucleophiles:Isoxasole is very labile towards the action of nucleophiles. Strong bases on cleavage of isoxazole ring

yield -ketonitriles.

H

ONR

C2

H5

O-Na

+

C2H5OH, RT O-

NR

H3O+

CH2

N

R

ketonitrile

3. Condensation involving methyl group


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ON

CH3

CH3 + PhCHOO

N

CH3

Ph

O

NaNH2

H2O

4. Photochemical reaction:Isoxazole isomerizes to oxazole.

ON

Ph

Ph

h

O N

CH3

CH3 O

N

Ph Ph

oxazoleisoxazole 5. Reduction:

O

N

NH2

H2/Ni

raney Ni

NH2

NH2

Ph

O N

NH2

5.THIAZOLE

STRUCTURE:

S

N

12

34

5

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.



17/27

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

CH2Cl

O

+SH

NH2-H2O

-HClS

N

H

O

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.

CH3 O

Cl

+

N

S-Na

+

-NaCl

CH3 O

S

NH+, H2O

CH3 OH

NH2

O

S

N

HCH3

O

S

NCH3

OH

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

thiazole derivative.


18/27

CH3 O

NH

O CH3

P2S5

CH3

S

N

O

CH3

HH

S

N

H

CH3

OHCH3 CH3 S

N

CH3

CHEMICAL REACTIONS:

1. Reaction with acids2. Electrophilic substitution:

S

N

S

N

Br

S

N

H

O S

N

Cl

Br2

250 -400 C

PCl5

3. Reaction with nucleophillic reagent

S

N+

CH3

CH3

OH-

S

N

CH3

CH3

OH

H-H+

S-CH3

N

CH3

CHO

4. Reactin with oxidizing and reducing agents

S

NH5C6

H2, Ni

CH3OH

H5C6 NH2

CH3+ SH2

5. Photochemical reactions


19/27

6.Benzimidazole:

STRUCTURE:

N

NH

1

23

45

6

78

9

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.


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:


20/27

N

N

H

N

CH-

N+

H

C-

N

N+

H

CH-

N

N+

H

CH-

N

N+

H

N-

N+

H

N

N

H

..

..

(I)(II)

(III)

(IV)(V)

(VI)

SUNTHESIS;

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

NH2

NH2

+

O

OH

R

100 C

-2H2O

N

N

H

R

2. The cyclisation of N-haloamidines with sodium ethoxide forms benzimidazole via nitreneintermediate.

R

N C6H5

NHBr

NaOC2H5R

N C6H5

N2-

N

NH

R

REACTIONS:

7. BENZOXAZOLE:

STRUCTURE:


21/27

N

O1

2

34

5

6

7

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.


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.


N

O C-

N

O+ CH

-

N

O+

CH-

(I)(II)

(III)(IV)

(V)

SYNTHESIS:

1. From smino phenol:


22/27

NH2

OH

+OH

O

R -2H2O

N

O

R

)

NH2

OH

+ HO

X

boric acid

reflux

NHCHO

OH

N

O

ii)

NH2

OH

R

+

H3CO

H3CO

OCH 3

conc. HCl

-3CH3OH

N

O

Riii)

2. Photochemical rearrangement of indoxazine:


23/27

N

O

hN

O

NH2

+

O-

N

O

N+

CN

O

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

N

H

OCH3

KNH2

liq. NH3

NH CH3

ON

O

CH3

4. From O-amino phenol and cyanogens bromide:


24/27

NH2

OH

+N

Br

-HBr

NH2

O

N

N+

O

HH

N-

-H+

N

O

H

HOHN

O

NH2

REACTIONS:

1. Addition to nitrogen:(i) Protonation:

N

O

H+

N+

O

H

(ii) Quarternization:N

O

N+

O

CH3CH3I

2. Electrophilic substitution reaction:Due to strong inductive effect of oxygen, the ring itself becomes electrophile. Hence, electrophilicsubstitution is rare and takes place at 2

ndposition.

N

O

N

O

ClSOCl2

+ +SO2 HCl


25/27

3. Nucleophillic substitution reaction:N

O

N

O

N

N H

piperazine,CHCl3

Et3

N. 0 C

8.BENZOTHIAZOLE

STRUCTURE:

N

S1

2

34

5

6

7 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:

NH2

SH+ H OH

O-H2O

SH

NH H

O

H+

-H2O

N

S

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

CH3

NH2

KSCN/CuSO4

N

S

NH2

CH3

Rdiazotisation

H3PO2

N

SCH3

R

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


26/27

R

S

NHCOOC 2H5+

NH2

SH

N

S

R

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

HNO3

H2SO4

N

SO2N 3. Oxidation:

N

S

peracidN

+

S

O-

benzothiazole -N -oxide


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