Six Membered Heterocycles:
N N
H
pyridine piperidine
Pyridine replaces the CH of benzene by a N atom (and a pair of electrons).
Hybridization = sp2 with similar resonance stabilization energy.
Lone pair of electrons not involved in aromaticity.
1H NMR: d
H 7.5
Pyridine is a weak base
H H 7.1
Pyridine is -electron deficient
H N H 8.5
Electrophilic aromatic substitution is difficult
Nucleophilic
pyridine aromatic substitution is easy
Chemical Synthesis
1. Pyridine is synthesized by reacting acetaldehyde with formaldehyde and
ammonia.
2. Hantzsch synthesis: It is a condensation reaction between an aldehyde, two equivalents
of 1, 3-dicarbonyl compound and ammonia.
3. Guareschi Thorpe Synthesis: Two molecules of aldehydes condense with the
keto ester to give substituted pyridine.
4. Krohnke pyridine synthesis: The α-pyridinium methyl ketone salts react with α, β-
unsaturated carbonyl compounds to give 2, 4, 6-trisubstituted pyridines.
5. Bonnemann Cyclization: It involves trimerization of one part of a nitrile
molecule and two parts of acetylene either by heat or by light.
6. Gattermann – Skita synthesis:
Chemical Reactions
The electronegative nitrogen in the pyridine ring makes the pyridine molecule
relatively electron deficient.
Hence unlike benzene.
(i) Pyridine does not undergo electrophilic aromatic substitution readily.
(ii) Pyridine is more prone to nucleophilic substitution at positions 2 and 4 and
metalation of the ring by strong organometallic bases, and
(iii) Like tertiary amine, pyridine undergoes N – protonation and undergoes
oxidation to form N-oxide.
Electrophilic attack at C-3 position
• The electrophilic substitution takes place at C-3 in
pyridine.
• The electrophilic attack at C-3 gives a carbocation which
is hybrid of three resonance structures in which the
positive charge is on the carbon atoms only.
Attack at C-2 position
Attack at C-4 position
Y H Y H Y H
N N N N
• The electrophilic attacks at C-4 or C-2 also give an ion that is a
hybrid of three resonance structures but one of the resonance
structures in each contains positively charged nitrogen which is a
sextet and so unstable and hence does not contribute significantly
to the resonance hybrid.
• Thus, the resonance hybrid resulting from electrophilic attack at
C-3 is more stable and the preferred site of the electrophilic attack.
Attempted Electrophilic Aromatic
Substitution
i
i NO2
N+ N N
H i, HNO3, H2SO4
Unreactive, Stable
O
ii
ii R
N+ N N
_ ii, AlCl3, RCOCl
AlCl3
Unreactive, Stable
How can we do nitration of pyridine?
NO2
H2O2, AcOH HNO3, H2SO4
N N+ N+
_ _
O O
Pyridine N-oxide
85%
_
O N O O
+ +
Mechanism O N H
N+ N+
_
O O
NO2 NO2
PPh3
+ O PPh3
N+ N
_
O 75%
Nucleophilic Substitution at 2- and 4-positions of
pyridine is most favoured
_
Nu
Nu
N Cl N
_ Cl N Nu
E.g. PhSH, NEt3
N Cl N SPh
93%
Br NH2
Br Br
NH3 (aq)
N N
65%
Skraup Synthesis
• Exothermic reaction
• To control the violent nature FeSO4 is used, which slows
down the reaction
• I2 is used to convert 1,2dihydroquinoline to Quinoline
Mechanism
Friedlander Synthesis
Knorr Quinoline Synthesis
DOEBNER-MILLER SYNTHESIS
Properties
Basic Character
Slightly weaker base than Pyridine
Reactions at heteroatom
Electrophilic Substitution reaction on carbon
It requires strong sulfuric acid and occurs fastest at C
- 8, then at C - 5 and C – 6
Nitration
50% 50%
Sulphonation
Halogenation
In concentrated sulfuric acid, quinoline gives a mixture
of 5 - and 8 - bromo derivatives
Nucleophilic substitution Reactions
Reaction with Sodamide
Reaction with KOH
Oxidation with KMnO4
Reduction
Isoquinoline Synthesis
Bischler–Napieralski Reaction
Pictet Splengler Synthesis
Pomeranz–Fritsch reaction
Mechanism
Properties
Basic Character
Slightly weaker base than Pyridine
Reaction at Heteroatom
Electrophilic Substitution reaction on carbon
It requires strong sulfuric acid and occurs fastest at C-
C-5
90%
10%
Sulphonation
Halogenation
In concentrated sulfuric acid, quinoline gives a mixture
of 5 - and 8 - bromo derivatives
Nucleophilic substitution Reactions
Reaction with Sodamide
Reaction with KOH
Oxidation
Reduction
Medicinal Property of Quinoline
UD FDA approved Isoquinoline based drug molecules
ACE inhibitor
Acridine
Synthesis of Acridine
Bernthsen acridine synthesis
From 2-chlorobenzoic acid
Friedlander synthesis
From C – acylated diphenylamine
Reactions of Acridine
Acridine acts as a weak base
Electrophilic Substitution Reactions on Carbon
Electrophiles will attack on 2nd and 10th carbon
Oxidation
Reduction
Medicinal Importance
Indole
Fischer – indole synthesis
Japp−Klingemann Reaction
Synthesis
Synthesis of Indole Using Ethylene glycol
Bartoli Synthesis
From N- or O-benzyl benzaldehydes using dimethyl sulfoxide as a carbon
source
Reactivity of Indole
Electrophilic Substitution Reactions
The pyrrole ring in indole is highly electron-rich compared to the benzene
ring. Therefore, electrophiles will attack the five-membered ring, except in
special circumstances
The preferred site of electrophilic substitution is C-3
Nitration
➢ Common nitrating reagent, mixture of acids (H2SO4 + HNO3)
leads to acid-catalysed polymerisation of indole.
➢ Therefore, nitration of indole is carried out using non-acidic
nitrating agent such as benzoyl nitrate and ethyl nitrate
Sulfonation
Halogenation
Vilsmeier Haack reaction
Mannich reaction (reaction with iminium ions)
Oxidation Reaction of Indole
Reduction Reaction of Indole
Medicinal Importance of Indole
Azines
The heterocyclic compounds having two nitrogen atoms in the ring are known as
diazines, which are classified into three types based on the position of the nitrogen
atoms, namely pyridazine(1, 2-diazine), pyrimidine (1, 3-diazine), and pyrazine(1, 4-
diazine)
Pyrimidine ring in nature
1. From Acetophenone
2. From ketones, NH4OAc, and N,N-dimethylformamide dimethyl acetal
3. From the cyclocondensation of β-keto esters and amidines
4. From Aldehyde and acetophenone
Medicinal Uses: Pyrimidine is an important structural component of
cytosine, uracil and thymine (RNA and DNA), vitamin B1 (thiamine),
barbiturates (sedative/hypnotics), sulfadiazine (antibacterial), amicetin
(antibiotic), lamivudine (anti-AIDS), flucytosine (antifungal), etc.
cytosine
thymine
Purine
It is a heterocyclic aromatic compound that consists of a pyrimidine
ring fused to an imidazole ring. Together with certain pyrimidine
bases, purines are constituents of DNA and RNA. Purines also act
as hormones and neurotransmitters and are present in some
coenzymes.
Synthesis
1. From Uric Acid
2. Traube Synthesis:
Synthesis from uracil derivative
Medicinal Uses: Purine analogs are having antibacterial,
antifungal, antitumor, antiviral and anti HIV activity. Important
drugs from purine category include caffline (CNS stimulant), 6-
mercaptopurine (anti-cancer), aristeromycin. Drugs having
isoster of purine include sildenafil (erectile dysfunction),
allopurinol (anti-gout), tubercidin (anti-cancer).
Azepines
Azepines are poly-unsaturated non-aromatic seven membered
heterocyclic ring, with a nitrogen replacing a carbon. The increase in
ring size constrains these compounds to be non-polar in order to
lessen the ring strain. This explains their non-aromatic nature. These
heterocylics follow reactivity pattern of cyclic polyenes. The chemistry
of azepines is dominated by their polyene character.
Synthesis:
Carbamazepine synthesis
anticonvulsant
• Discuss Skraup synthesis of quinoline with reaction mechanism.
• Write down any four chemical properties of indole with reaction.
• Give any two methods of preparation and two chemical reactions of
pyridine.
• Give any two methods of preparation and chemical reactions of
imidazole.
• Draw the structure of imidazole and indole.
• Give any three reactions of indole.
• Why is pyridine more reactive towards nucleophiles than benzene?
• Draw structures of imidazole, 1,3 oxazole and isoquinoline with
numbering.
• Write examples of pharmaceutical drugs containing pyridine skeleton.