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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
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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
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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
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:
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.
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:
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+
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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
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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
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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:
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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:
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:
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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.
ACIDITY AND BASICITY:
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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.
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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
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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.
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:
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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:
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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.
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 C-
N
O+ CH
-
N
O+
CH-
(I)(II)
(III)(IV)
(V)
SYNTHESIS:
1. From smino phenol:
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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:
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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:
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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
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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.
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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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