Heterocyclic Chemistry

Heterocyclic Chemistry Part II
Dr. Santosh L. Gaonkar, Associate Professor,
Dept of Chemistry, MIT, Manipal

Structure and Aromaticity Pyrrole furan and thiophene are
aromatic because:
1) they fulfill the criteria for aromaticity,
the extent of delocalization of the
nonbonding electron pair is decisive
for the aromaticity, thus the grading of
aromaticity is in the order of:
Furan < Pyrrole < Thiophene < Benzene
this order is consistent with the order of
electronegativity values for oxygen (3.44),
nitrogen (3.04) and thiophene (2.56).
Hetero-Monocyclic Compounds
A. Five-membered Rings with one Heteroatom
The order of aromaticity
Benzene > Thiophene > Pyrrole > Furan 2

2) They tend to react by electrophilic substitution due appearance of –ve charge
on carbon atoms due to delocalization as shown in the following resonance
structures
O O O O O
S S S S S
N N N N N
H H H H H
Structure and Aromaticity
3

X
X = NH Pyrrole
= O Furan
= S Thiophene
3) Electrons not available for protonation—hence not basic
4- 6  electrons over 5 ring atoms ….. Electron rich… so more
reactive than benzene towards electrophilic substitution.
The order of reactivity is:
Pyrrole > Furan > Thiophene > Benzene
4

5) The pattern of reactivity with Electrophilic reagents.
Aromatic compounds ……. By substitution
addition followed by proton loss onium intermediate ]
Order of reactivity : Pyrrole > Furan > Thiophene > Benzene
X
X X X
X X X
X
+ E+
H
E
H
E
H
E
E- H+
H
E
H
E E
- H+
C2-attack
C3-attack
5

6) The order of aromaticity
Benzene > Thiophene > Pyrrole > Furan
In case of Thiophene [S] donate & accept
electrons…… so delocalization is complete as
benzene
S
In case of Furan [O] electronegativity more ….
Diene-like character CH2=CH-CH=CH2
O
In case of Pyrrole [N] -Diene-like
character CH2=CH-CH=CH2
6

Evidences of aromatic character in pyrrole
N
H
NNNN
-H+
Pyrrole anion
( Conjugated base)
It tends to react by electrophilic substitution
7

N
H
N
H
PyrrolidinePyrrole
Dipole monent of
pyrrole and its saturated analog
N
H
Pyrrole
aroamtic 2 amine
N
H
Pyrrolidin
Aliphatic 2 amine
<
Basicity of pyrrole and its saturated analog
°°
thus the dipole moment of pyrrole compared with pyrolidine is reverted and
thus protonation occurs at carbons not at N
N
H
N+
N N
CH3
H2
K+
Cl-
+ KICH3I
HCl
KOH
H2O +
3) Its exceptional lack of basicity and strong acidity as a secondary amine
compared to the aliphatic analog (pyrrolidine). This can be explained on the
basis of participation of N lone pair in aromatic sextet (see the resonance
structures)
N
H
N
-Na
+ NaNH2
Liq NH3
strong baseweak acid salt
N
H
NNNN
-H+
Pyrrole anion
( Conjugated base)
So Its weak acid
not basic as the
secondary amines
Lone pair of N is
involved in  cloud
and not available
for sharing with
acids
8

Sources & Synthesis
Pyrrole & Thiophene …. Coal Tar
Pyrrole ring ….
Porphyrin system…..
Chlorophyll &
Hemoglobin
Furan ….. Decarbonylation of
Furfuraldehyde …….
Oat hulls, corn cobs or rice hulls
Oat hulls corn cobs rice hulls
A) Sources
9

X
N
X
N
X = S ,O ,or N
1,3-Azoles 1,2-Azoles
Thiazole [ 1,3-thiazole]
Oxazole [ 1,3-oxazole]
Imidazole [ 1,3-diazole]
Isothiazole [ 1,2-thiazole]
Isoxazole [ 1,2-oxazole]
Pyrazole [ 1,2-diazole]
Five Membered Heteroaromatic Rings Containing 2X , at least one
Nitrogen
Five membered heterocycles with 2 hetero atoms -Azoles
10

Numbering order of preference Oxygen, Sulfur, Nitrogen,
13

N
H
N
Imidazole
Aromaticity & Basicity
Nitrogen
N
N
H
Pyridine like nitrogen
( basic character )
Pyrrole like nitrogen
( involved in aromaticity)
Each carbon contributes one Pz electron, nitrogen gives 4th electron
and second heteroatom gives 2 electrons to make aromatic sextet.
Pyrazoles and Imidazoles
14

N
H
N
Imidazole
Basicity
Nitrogen atom with pair of electrons-Azoles behave as bases as well as
nucleophiles 1,2-azoles are less reactive than 1,3-azoles
N
H
N
2ry amine
3ry amine
N
H
N H
N
N H
H
3ry amine ismore basic than 2ry amine
Nitrogen
N
N
H
Pyridine like nitrogen
( basic character )
Pyrrole like nitrogen
( involved in aromaticity)
15

Diazoles
N
N
H
N
N
H
ImidazolePyrazole
Imidazole is more basic than pyridine, but more acidic than pyrrole
N
N
H
H
N
N
H
H
N
N
N
N
+
_
_
Imidazole + H+
Imidazole - H+
NaOH
Properties: Very stable cation and anion of imidazole is formed
pKa = 14.5
(imidazole)
pKa = 16.5
(pyrrole)
- H2O
Five Membered Heteroaromatic Rings Containing 2X , at least one Nitrogen
16

Pyrazoles and benzopyrazole
Diverse biological properties act as drugs and dyes
Dihydropyrazoles -pyrazolines
17

Rapid tautomerism, involving switching of hydrogen from
one nitrogen to the other,
Two forms are identical, thus 2 nitrogen are
indistinguishable
18

Synthesis
•From 1,3-dicarbonyl compounds
From 1,3-dicarbonyl compounds
 1,3-Dipolar cycloadditions of nitrile Imines
1,2 - Azoles: Pyrazoles, Isoxazoles and Isothiazoles
19

Synthesis
•From 1,3-dicarbonyl compounds
•Dipolar Cycloadditions of Nitrile Oxides and Nitrile Imines
20

Chemical reactions
• Pyrazoles stable and innert, exhibit aromaticity resemble
pyrrole and pyridine
• Form complex with metal ions, because of acid
character of hydrogen on nitrogen, ligands co-ordinate
with metal ions
• Alkylation gives N-alkylated products
21

Electrophilic substitution
Pyrazole, isothiazole and isoxazole undergo straightforward nitration, at C - 4.
With acetyl nitrate or dinitrogen tetraoxide/ozone, 1 - nitropyrazole is formed,
but this can be rearranged to 4 - nitropyrazole in acid at low temperature
Methylation and formylation
Acylation and formylation
23

Pyrazoles are inert to nucleophiles. With sodamide ring opening takes place
24

Oxidation:
 Stable to oxidizing agents
 However side chain oxidation possible
Reduction:
 Ring reduction takes place
25

Photochemical reactions:
 Imidazoles are formed via azirine intermediates
 Benzopyrazoles give benzonitrile intermediates
26

Oxy- and Amino - 1,2 - azoles
• Only 4 - hydroxy - 1,2 - azoles can be regarded as being phenol - like.
• 3 -and 5 -hydroxy - 1,2 - azoles exist mainly in carbonyl tautomeric
forms, encouraged by resonance involving donation from a ring
heteroatom, and are therefore known as pyrazolones,
isothiazolones and isoxazolones
27

Orisul (Antibacterial) Antipyrine (Antipyretic)
Butazolidine (Anti-inflammatory) Pyrazofurin (Antiviral)
Bioactive pyrazoles
28

General method 1,2-azole synthesis
Examples
32

Isoxazoles and benzisoxazoles
Isoxazoles
Tautomemrism
34

Synthesis
Condensation –cyclization of α, β-diketones with hydroxylamines
Cycloaddition of nitrile oxides with alkynes
35

Electrophilic substitution:
• 1,2-azoles are much less reactive than 1,3-azoles.
• Isoxazoles are more reactive than isothiazoles
• Electrophilic attack occurs at C-4
• No reactivity in F-C reaction and Vilsmeier Hack reaction
• With nucleophiles and bases ring opening takes place
36

• Reduction leads to N-O bond cleavage
• In contrast, Isoxazole ring is stable to oxidizing agents though
not in alkali
• Isoxazoles are converted to oxazoles via azirine intermediates
37

• Isoxazoles act as dienophiles in the D-A reaction
in contrast to oxazoles which act as a diene
39

ISOTHIAZOLES AND BENZOISOTHIAZOLES:
1,2-thiazole or Isothiazole is the sulfur analog of isoxazole.
Saccharin is example of isothiazole compounds of importance
Synthesis
From Oxazoles
From Acylacetylenes:
Acyl acetylenes are treated with sodium thiosulfate followed by
cyclization in the presence of ammonia
40

Benzoisothiazole synthesis:
Cyclization of o-mercaptobenzaldoximes
Quarternization: Form salt with strong acids
Electrophilic substitution :
Least reactive compared to pyrazole and isoxazole Electrophillic attack
at C-4
41

Alkyl and phenylisothiazoles on irradiation yield the corresponding
thiazoles via zwitterionic intermediates
Isothiazole ring is stable to range of oxidizing and reducing
agents
Biologically active Thaizoles
42

• Imidazole, thiazole and oxazole, stable compounds do
not autoxidise. Oxazole and thiazole are water - miscible
liquids with pyridine - like odours. Imidazole, which is a
solid
• Imidazole, stronger base than thiazole and oxazole, also
stronger than pyridine due to the amidine - like
resonance that allows both nitrogens to participate
equally in carrying the charge.
• Low basicity of oxazole due to combination of inductive
withdrawal by the oxygen and weaker mesomeric
electron release from it.
1,3 - Azoles: Imidazoles, Thiazoles and Oxazoles:
50

Hydrogen Bonding in Imidazoles
• Imidazole, is amphoteric - both a good donor and acceptor of
hydrogen bonds; the imine nitrogen donates an electron pair
and the N - hydrogen, being appreciably acidic is an acceptor.
• This property is central to the mode of action of several
enzymes that utilize the imidazole ring of a histidine one of the
20 amino acids found in proteins.
51

Imidazoles with a ring N - hydrogen are subject to tautomerism,
which becomes evident in unsymmetrically substituted compounds
such tautomeric pairs are inseparable and the convention used to
represent this phenomenon is to write 4(5) – methylimidazole
52

Imidazole synthesis
Radiszewski synthesis
Dehydrogenation of imidazolines prepared from ethylenediamine Alkyl nitriles
53

Benzimidazole synthesis
Condensation of 1,2-diamine benzene with carboxylic acid
Cyclization of N-haloamidines with Base via nitrene intermediates
54

Electrophilic substitution
• Contribution of charged structures are more than benzene so more
reactive than pyrazole, thiazole, furan and thiophene.
• Substitution takes place at 4(5) position
Highly unfavoured
+ve N at C3
55

Reaction with Nucleophilic reagents
• Less reactive, EWG activates. Nucleophilic attack results ring cleavage
56

Reactions with Bases
Deprotonation of Imidazole N - Hydrogen and Reactions of Imidazolyl anions
React with bases and forms salts of imidazoles can be alkylated or acylated
on nitrogen.
57

Losartan
1-Histidine
Priscol
Carnosine
Biologically active Imidazole derivatives
59

Oxazole is a 1,3-azole having oxygen and pyridine type
nitrogen. Do not occur in nature.
Partially reduced oxazoles are called oxazolines
Oxazole Benzoxazole
4-oxazoline
• Although oxazole possess a sextet of pi-electrons,
delocalization is incomplete, shows little aromatic character.
• Chemically functions as diene in the Diels-Alder reaction
and electrophilic substitution is rare
60

From ethyl α-hydroxyl keto succinate
61

Robinson-Gabriel synthesis:
Αcylamino ketone undergoes cyclization and dehydration in the
presence of P2O5 or strong mineral acids
Benzoxazole synthesis:
Dehydration of 2-N-Acylamino phenols
62

Oxazoles are more reactive towards electrophilic
substitution than thiazoles but less than imidazoles.
Prepered attack at C-5.
Act as diene in D-A reaction to give cycloadducts which
further rearranges to pyridine and furan derivatives
63

Nucleophillic substitution is uncommon. Nucleophiles cleave
the oxazole ring to give intermediate which undergoes
cyclization to new ring.
64

Not stable to oxidative conditions and ring opening
takes place
Oxazoles are stable towards variety of reducing agents
LAH reduction causes reductive ring cleavage
65

Biologically active Oxazoles
66

Thiazole structurally related to thiophene and pyridine
and resembles pyridine in properties. Thiazole ring is part
of Vitamin B and penicillins.
Partially reduced thiazoles are called thiazolines
Thiazole Benzothiazole
67

From α-halocarbonyl compounds:
α-haloketones are treated with appropriate thiamide are thiourea
From Thioamides:
Reaction of thioamide with substituted 2-chlorooxiranes
68

Acylamino compounds are heated with P2S5
Benzothiazole synthesis:
Obtained from 2-aminothiophenols and carboxylic acid or
anhydride
69

N-Carboethoxythiacetamide reacts with o-
aminothiophenol to give substituted benzothiazoles
Benzothiazole synthesis:
Chemical reactions:
Thiazole and benzothiazoles can be quaternized
Reaction with acids:
The lone pair of electrons on the azomethine nitrogen
are not involved in aromatic sextet thus available for
protonation.
Form stable salts with strong acids
70

• Reactivity is intermediate between pyridine and
thiophene, less reactive than imidazole
• Attack takes place at C-5
Reaction with Nucleophilic reagents
• Contrast to imidazoles reaction with potassium amide in
liq.NH3 with thiazole affords 2-aminothiazole
• C-2 is the susceptible position for nucleophilic attack
shows thiazole resembles to pyridine
• Quarternization takes place at 3-position and thiazolium
salts are preferentially susceptible to nucleophilic attak
and results in ring opening
71

Thiazoles resist to oxidation by nitric acid but ring is
opened by KMnO4
Thiazoles resist to many reducing agents. However
Raney nickel is used to desulfurization
72

• Like oxazoles isomerization and interconversion are
predominant
• Benzoisothiazoles undergo isomerization to
benzothiazoles photochemically and thermally
73

Five Membered Rings with three nitrogen atoms
76

Prepared by the cycloaddition of an alkyne with an azide,
which can be promoted thermally or by metal catalysis.
From amines via Azides generated insitu
77

1,2,3 - Triazole is fairly resistant to N - alkylation under neutral
conditions, however both acylations and alkylations invole anion
occours readily
1,2,3 - Triazole forms a 4,5 - dibromo derivative
1 - Methyl - 1,2,3 - triazole can be mono - brominated at C - 4,
Nitration of 2 - phenyl - 1,2,3 - triazole proceeds fi rst
on the benzene ring
78

The ring system is relatively resistant to both oxidation and
reduction, as exemplified below.
N - Substituted 1,2,3 - triazoles can be lithiated directly at carbon,
but low temperatures must be maintained to avoid ring cleavage.
79

1,2,4 – Triazoles synthesis
Cyclodehydration reactions of N,N - diacyl hydrazines with amines
Condensations of aminoguanidine with esters
From triazines
80

N - Alkylations and - acylations generally occur at N - 1, shows the
higher nucleophilicity of N – N systems
Bromination occurs readily in alkaline solution giving 3,5 - dibromo -
1,2,4 - triazole
C - Lithiations can be easily effected on N - 1 - protected 1,2,4 -
triazoles, the resulting 5 - lithio derivatives being much more stable
than C - lithiated 1,2,3 - triazoles
81

3 - Amino - 1,2,4 - triazole can be diazotized normally
82

Oxadiazoles and Thiadiazoles
Named with the non - nitrogen atom numbered as 1, and the positions
of the nitrogen atoms shown with reference to the divalent atom
• 1,2,4 - Oxadiazoles, 1,3,4 - oxadiazoles and 1,2,5 - oxadiazoles are
well known,
• 1,2,3-oxadiazoles are unstable and undergo ring opening
• Part of number pharmaceuticals
Aromaticity, based on bonds lengths and NMR data
83

• Oxa - and thiadiazoles are very weak bases due to the inductive
effects of the extra heteroatoms, electrophilic substitutions on
carbon difficult
• Susceptible to nucleophilic attack, undergo ring cleavage with
aqueous acid or base unless both carbon positions are
substituted
Direct lithiations at carbon are generally easy. Lithiated
intermediates find number of applications
84

Hydrogens on side - chain alkyl groups are acidified by delocalisation
85

Ring Synthesis of Oxadiazoles and Thiadiazoles
1,2,4 – Oxadiazoles:
1,2,4 - Oxadiazoles can be prepared by reaction of amidoximes with activated
acids, acid chlorides or anhydrides, esters or Beta- keto - esters.
From amides via acylamidines, or via the cycloaddition of nitrile
oxides with nitriles
86

1,3,4 – Oxadiazoles
Symmetrical and plannar, show aromaticity, weak base. Resonance
energy is low due to presence of two nitrogens
Synthesis:
1,3,4 - Oxadiazoles are prepared by cyclodehydration of N,N”- diacyl -
hydrazine or their equivalent
Oxidative cyclisation of N - acyl - hydrazones
Reaction of a hydrazide with a trialkyl orthoalkanoate produces 1,3,4 -
oxadiazoles-
87

1,2,5 - Oxadiazoles
1,2,5 - Oxadiazoles result from the dehydration of 1,2 - bisoximes.
1,2,3 - Thiadiazoles
Prepared by reaction of a hydrazone, containing an acidic methylene
group, with thionyl chloride.
carrying identical groups at the 3 - and 5 - positions are obtained by
the oxidation of thioamides;
5 - chloro - 1,2,4 - thiadiazoles result from the reaction of amidines with
perchloromethyl mercaptan.
88

General routes including cyclisation of N,N1-diacyl - hydrazines, or 1,3,4 -
oxadiazoles, with phosphorus sulfides.
2-Amino-1,3,4-thiadiazoles are prepared via acylation of
thiosemicarbazides
1,3,4 - thiadiazole is easily obtained from hydrogen sulfide and
dimethylformamide azine.
89

Prepared by the oxidative cyclisation of 1,2 - diamines or
aminocarboxamides.
Condensation of sulfamide with 1,2 - diketones gives 1,2,5
- thiadiazole 1,1 - dioxides.
90

Biologically active Oxadiazole
91

Heterocyclic Chemistry

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