Pharmaceuticals Organic chemistry BP401T_Pyrrole.pdf

Learning Objectives
By the end of this session, students will be able
 Discuss chemistry, method of synthesis, reactions
LastBenchPharmacist.blogspot.com
Learning Objectives
able to:
reactions and importance of pyrrole
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Pyrrole
• Simplest of five membered heterocyclic compound
• Occurs naturally from coal tar, bone oil, products derived from proteins
Physical properties
• Colourless liquid with boiling point of 130
• Odour resembling that of chloroform
• Slightly soluble in water but freely soluble in organic solvents
Pyrrole
Simplest of five membered heterocyclic compound
Occurs naturally from coal tar, bone oil, products derived from proteins
liquid with boiling point of 130 0C
Slightly soluble in water but freely soluble in organic solvents
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Chemistry of
Molecular properties
• Contains sp2 hybridized carbons, each ring carbon atom has one electron
remaining in p orbital and heteroatom contributes two p
remaining in pz orbital and heteroatom contributes two p
aromaticity (4n+2) π electrons
Chemistry of Pyrrole
hybridized carbons, each ring carbon atom has one electron
orbital and heteroatom contributes two p-electrons to the
orbital and heteroatom contributes two p-electrons to the
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Resonance structures of pyrrole
•
•
•
Resonance structures of pyrrole
• Pyrrole is extremely weak base among
amines
amines
• Because of partial delocalization of
electrons in pyrrole, nitrogen atom cannot
donate electrons like amines
• High electron density in the ring makes
pyrrole extremely reactive towards
pyrrole extremely reactive towards
electrophilic substitution reactions
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Synthesis of
Commercially obtained from fractional distillation
From Furan: By passing it over ammonia or
From Furan: By passing it over ammonia or
the presence of aluminium oxide as catalyst
Synthesis of Pyrrole
distillation of coal tar or bone oil
or amine and steam and heated to 4000C in
or amine and steam and heated to 400 C in
catalyst
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Synthesis of
From ammonium mucate: On heating ammonium
dehydrates followed by decarboxylation and
compound
ammonium mucate dissociates into free acid,
and cyclization in ammonia yields parent
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Synthesis of
Paal Knorr Synthesis:
• By condensation of 1,4 diketone with ammonia
• Most widely used method for preparation
• Most widely used method for preparation
ammonia or primary amine
preparation of substituted pyrroles
preparation of substituted pyrroles
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Reactions of
• With Acids and Bases: Proton attached
acids and bases
• Pyrrole forms a mixture of polymers with
• Pyrrole forms a mixture of polymers with
Reactions of Pyrrole
attached to nitrogen undergoes rapid exchange in
with acids
with acids
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Reactions of
• With Bases: Liberates hydrogen with strong
salt
strong base (KOH) and forms corresponding
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Reactions of
Electrophilic substitution Reactions:
• Electrophilic substitution occurs preferably
• Three resonance forms for substitution
substitution at 3rd position
substitution at 3rd position
preferably at the 2nd position
substitution at 2nd position and two forms for
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Reactions of
Halogenation:
• Pyrrole is extremely reactive towards halogens
(Br2/AcOH), Iodination (I2/KI3) at 0° C, yields
• Monohalogenation occurs in the presence
pyrrole ring
pyrrole ring
halogens- chlorination (SO2Cl2), bromination
yields corresponding tetrahalo derivatives
presence of electron withdrawing groups on the
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Reactions of
Nitration:
• Nitration carried out with acyl nitrate at lower
lower temperature (Ac2O, HNO3, -10° C)
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Reactions of
Sulphonation:
• Sulphonated with Sulphur trioxide in pyridine
sulphonic acid
pyridine at about 100°C to yield pyrrole-2-
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Reactions of
Friedel Crafts acylation:
• C-Acylation of pyrroles is carried out by
of catalyst or acetic anhydride to give 2-Acetyl
of catalyst or acetic anhydride to give 2-Acetyl
reaction with acid chlorides in the absence
Acetyl pyrrole
Acetyl pyrrole
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Reactions of
Friedel Crafts alkylation *:
• Alkylation with usual Lewis acid is not possible
• Alkylation with nitro alkene carried out using
• Alkylation with nitro alkene carried out using
* Tetrahedron 2015, 71 (19), 2882-2890
possible
using Bisphenol A as catalyst
using Bisphenol A as catalyst
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Reactions of
Alkylation:
• Potassium and sodium salts of pyrrole reacts
N-alkyl pyrroles
N-alkyl pyrroles
• Alkyl and benzyl substituents in N-substituted
in pyrrole ring at higher temperature
reacts with alkyl halides to give good yields of
substituted pyrroles migrate to 2nd and 3rd position
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Reactions of
Intermolecular hydrogen bonding:
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Importance of
• Amino acid proline has pyrrole ring
• Various compounds like haemoglobin, bile
contain porphyrin ring which consists of pyrrole
Importance of Pyrrole
bile pigments, vitamin B12 and chlorophylls
pyrrole nucleus
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Importance of
• Medicinal compounds clopirac and tolemetin
compounds, NSAIDs) are obtained from pyrrole
Importance of Pyrrole
tolemetin (Non-steroidal anti-inflammatory
pyrrole
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Summary
• Pyrrole contains sp2 hybridized carbons,
electron remaining in pz orbital and heteroatom
aromatic sextet
• Pyrrole is extremely weak base among amines
• Synthesized from furan, mucate and 1,4
• Very reactive and behaves as both acid
• Pyrrole undergoes electrophilic
intermolecular hydrogen bonding
intermolecular hydrogen bonding
• Pyrrole is present in various natural compounds
• Medicinal compounds are synthesized form
Summary
carbons, planar pentagon, each ring atom has one
heteroatom contributes two p-electrons to the
amines
4 diketones
and base
substitution reactions. Pyrrole forms
compounds.
form pyrrole
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Pharmaceuticals Organic chemistry BP401T_Pyrrole.pdf

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Pharmaceuticals Organic chemistry BP401T_Pyrrole.pdf