Pharmaceuticals Organic chemistry 3 BP401T_Thiophene.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 thiophene
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Thiophene
• Five membered heterocyclic compound with
• Thiophene derivatives are found in natural sources
• Thiophene occurs in coal tar and also as
• Thiophene occurs in coal tar and also as
Physical properties
• Colorless liquid with boiling point 80 0C
• Miscible in most organic solvents but immiscible
Thiophene
Five membered heterocyclic compound with sulphur
derivatives are found in natural sources – Plants and animals
also as an impurity in commercial benzene
also as an impurity in commercial benzene
C
immiscible with water
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Structure of Thiophene
• In thiophene, the sp2 hybrid orbitals overlap
of four hydrogen atoms forming C-C, C-S
• Each carbon atom and the sulphur atom
• The p orbitals on carbons contain one
contains an unshared pair of electrons
• The lateral overlap of these p orbitals produces
six electrons
Thiophene
overlap with each other and with s orbitals
S and C-H σ bonds
possesses an unhybridized p orbital
electron each and p orbitals on sulphur
produces a π molecular orbital containing
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Resonance structures of
• Sulfur atom is less electronegative than
• Thiophene releases electrons readily
aromaticity
aromaticity
• Thiophene is therefore more aromatic than
Resonance structures of Thiophene
oxygen and nitrogen
into the ring to form a π-sextet for
than pyrrole and furan
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Synthesis of
• From sodium succinate: By heating a mixture
trisulfide
Synthesis of Thiophene
mixture of sodium succinate and phosphorus
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Synthesis of
From unsaturated compounds:
• Involves the use of methyl thioglycolate
fumarate in the presence of a base
fumarate in the presence of a base
thioglycolate and its condensation with dimethyl
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Synthesis of
Paal Knorr Synthesis:
• By condensation of 1,4 diketone in the presence
• P2S5 acts as both sulphuration and dehydration
• P2S5 acts as both sulphuration and dehydration
presence of phosphorus pentasulphide
dehydration reagent
dehydration reagent
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Reactions of
With Acids:
• Thiophene is stable to action of acids,
oligomerization
oligomerization
• Orthophosphoric acid (H3PO4) under milder
trimer
Reactions of Thiophene
acids, very strong acids may bring about
milder conditions has been found to give
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Reactions of
Electrophilic substitution Reactions:
• Electrophilic substitution occurs preferably
furan
preferably at the 2nd position like pyrrole and
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Reactions of
Halogenation:
• Thiophene reacts vigorously with chlorine
polyhalogenated products
• Much milder conditions have to be used
• Much milder conditions have to be used
derivatives ( less than 0°C)
chlorine and bromine at room temperature to give
used to obtain monochloro or monobromo
used to obtain monochloro or monobromo
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Reactions of
Nitration:
• Thiophene can be nitrated with nitric
nitro thiophene
acid in acetic anhydride (-10 °C) to form 2-
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Reactions of
Sulphonation:
• Sulphonated with 95% sulphuric acid at
sulphonic acid
at room temperature to yield thiophene-2-
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Reactions of
Friedel Crafts acylation:
• Thiophene can be acetylated with acetic
acetyl chloride in the presence of SnCl4 to
acetyl chloride in the presence of SnCl4 to
acetic ahydride in the presence of H3PO4 or
to yield 2-acetylthiophene
to yield 2-acetylthiophene
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Importance of
Medicinal compounds
• Tiaprofenic acid, a NSAID
• Tieinilic acid, a diuretic for hypertension
• Tieinilic acid, a diuretic for hypertension
Importance of Thiophene
hypertension
hypertension
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Summary
• Thiophene contains sp2 hybridized carbons,
one electron remaining in pz orbital and
to the aromatic sextet
to the aromatic sextet
• Thiophene is more aromatic than pyrrole
• Synthesized from succinic acid, fumarate
• Very reactive with strong acids and forms
• Thiophene undergoes electrophilic
• Thiophene undergoes electrophilic
position.
• Medicinal compounds like tiaprofenic
thiophene
Summary
carbons, planar pentagon, each ring atom has
and heteroatom contributes two p-electrons
pyrrole and furan
fumarate and 1,4 diketones
forms trimer
substitution reactions preferably at 2nd
substitution reactions preferably at 2
acid and tieinilic acid are synthesized form
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Pharmaceuticals Organic chemistry 3 BP401T_Thiophene.pdf

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