vdocuments.net_heterocyclic-chemistry-58bb82e5b406c.ppt

Heterocyclic chemistry:
Furan,
Thiophene,
Pyrrole,
Imidazole,
Indole

• Unsaturation is often introduced by elimination e.g. dehydration, dehydrohalogenation
General Strategies for Heterocycle Synthesis
Manipulation of Oxidation State
X
X
X, Y = O, S, NR
conjugate addition
+ +
+
Ring Construction
• Cyclisation – 5- and 6-membered rings are the easiest to form
• CX bond formation requires a heteroatom nucleophile to react with a C electrophile
Y  Y 
X
hexahydro
[O]
H2 H2
[O]
X
X X
tetrahydro dihydro
H2
[O]
X
aromatic
or

14
General Strategies for Heterocycle Synthesis
O O
NH3
N
H
NH3
N
N
H
O O
N
H
2H2O 2H2O
X X
Common Strategies
“4+1” Strategy
X X
• Strategy can be adapted to incorporate more than one heteroatom
“5+1” Strategy
• 1,5-Dicarbonyl compounds can be prepared by Michael addition of enones
O O
NH3
H
N N
H
H2
[O]
2H2O

Furan
α
β
α'
β’
Drugs:
Furosemide, Nitrofurantoin,
Nitrofurazone, Prazocin, Ranitidine

Less stable than pyrrole & thiophene
less reactive than pyrrole towards E+
Aromatic as lone pair of e participate in Pi cloud, follow Huckel’s rule of
aromaticity 4n + 2π
O and 4 C SP2 hybridised & lie in same plane

Synthesis of Furan: 1) From carbohydrate:
Polysaccharide (Oat)
Acid
hydrolysis
Furfuraldehyde
2-furoic acid
Decarboxylation
Furan

2) Synthesis of furan from Oxazole

3) Synthesis of 3-substituted furan from DA adduct

4) Synthesis of furan by Paal –Knorr method: Ring closure mtd. Subst. open
chain compd (1,4 diketone) cyclize by acid to give furan
Mechanism via mono enol formation.
Sterically hindered diketone do not cyclize to furan

Chemical reactions of furan:
1) Reaction with acid: F can be hydrolysed easily by acid to give aldehyde. Mild
conditions shd be used otherwise protonated F undergoes polymerization.
F with EWD more stabile to acids

1) Reaction with Base:

2) Electrophilic aromatic substitution: more reactive than benzene.
2 position more reactive. Conditions need to be controlled.
A) Halogenation: proceeds quickly to give mix of either mono and poly subs or
resin
% of 2 subst product can be increased by using less amt of Cl2
2- Bromo can be obtd by Br2 in dioxane

2) Electrophilic aromatic substitution:
B) Nitration: Mild nitrating agents used acetyl nitrate (acetic anhydride
+ HNO3

C) Sulfonation: Mild sulfonating agents used Pyridine- SO3 complex
If H2SO4 used, it gives resin

D) Friedel Crafts reaction: Anhydride and acyl halide need Lewis catalyst.
But reactive anhydride like (CF3CO)2O work without catalyst.
Alkylation not successful, polymerization.
F containing EWD can be alkylated.

3) Carbene and nitrene: Cabene add across 2,3 C db.
There is not much report of reactions of nitrene with furan

4) Reaction with reducing agents: dependent on catalyst, solvent & temp

5) Reaction with oxidizing agents: F is O2/air sensitive, 1,4 addition to diene system

6) DA Reaction : Furan as a diene reacts with dienophiles to give DA adduct.
But due to aromatic character and ring strain in cycloadduct it is thermolabile,
revert to SM.

O
furan
O CH=O
O Br
O HgCl O I
1. HCN, HCl
2. H2O
Br2
dioxane
HgCl2
CH3CO2Na
I2
CH3COCl
O C
O
CH3
Extra

Thipohene
Have two pairs of nonbonding e
but only 1 pair is in the
unhybridized p orbital and is able
to overlap with the C of the ring.
Mayer 1882
Coal tar, pt and animal metabolite

Synthesis of Thiophene:
1) Using Na-Succinate
Classical mtd Phos. trisulfide ( Red P +S)
Industrial mtd use hydrocarbon (butane/butene/1,3-butadiene and elemental S
600 0C

2) Ring closure Mtd
A) From unsaturated compds/ Fiesselmann mtd:
Condensation Rxn

2) Ring closure Mtd
B) Paal Knor mtd: General mtd

2) Ring closure Mtd
C) Hinsberg Mtd: 1,2 dicarbonyl compound diethylthiodiacetate in
presence of st base
involved 2 aldol condensation betn reactant and forms half ester

Chemical reactions of thiophene:
1) Reaction with acid: T stable to acid.
V. st acid can cause polymerization. Orthophosphoric acid under mild condition
gives trimer.

Chemical reactions of Thiophen:
1) Reaction with Base:

Chemical reactions of Thiophene:
Pyrrole>furan>Thiophene>Benzene
2 position more reactive.
A) Halogenation: Rxn with NBS gives 2- bromo T

Pyrrole>furan>Thiophene>Benzene
2 position more reactive.
B) Nitration:

C) Sulfonation: 95% H2SO4 used at rt readily occurs

D) Friedel Crafts reaction: wide variety of choices available

•Chemical reactions of Thiophene:
3) Reaction with carbene & Nitrene: caboethoxy carbene adds to C2-C3 bond to
give cyclopropane compd, which can be opened with acid to give thiophene Beta-
acetic ester
R=C:
R–N: acts as E+

Ethyxycarbonylnitrene reacts with T to give 1,4-adduct which loses S to
form N-carboethoxypyrrole

4) Reaction with Nu: Every positional combination of Nitro and Halo T actiavate
system towards SN rxn
Seems like normal displacement Rxn

5) Reaction with free radicals/ Gomberg Bachmann rxn:
1 of the best & simple mtd for synthesis of aryl thiophenes

6) Reaction with oxidising agents:
Resistant to mild oxidising agents.
HNO3 breaks ring to maleic acid and oxalic acid.
Peracid (perbenzoic acid attacks S atom)
Initial sulfoxide ca not be isolated due to dimerization &
further oxidation to
Thiophene 1,1’ dioxide/ Thiolane can form it’s also reactive but isolable

•Chemical reactions of
Thiophene:
7) Reaction with reducing agents:

8) Diels-Alder reaction: Acetylenic dienophiles. Chelotropic expulsion
of S from unstable intermediate, which gives benzene derivative

Pyrrole
α
β
α'
β’
Ketorelac, atorvastatin
Hb, Chlorophyl, Vit B12, bile pigment
Runge 1837
Greek: Red

Synthesis methods:
1) From Furan

The Knorr Synthesis:
Imp & widely used mtd
Condensation of Alfa amino ketone with another dicarbonyl compound
with active methylene grp in presence of acetic acid

Hantzch synthesis of pyrrole:
Alfa halo ketone/aldehyde react with beta keto ester (Beta chloro ketone)
In presence of N containing base (NH3 or amine) which acts as base as well as solvent.
Yield moderate to good.

The Paal Knorr Synthesis of Pyrrole:
General mtd
Condensation of 1,4 diketone with NH3 or primary amine.

The Piloty Robinsons Synthesis:
Monocyclic version of Fischer indole synthesis.
Ketazine with st acid to give pyrrole through [3,3] sigmatropic rearrangement
of tautomeric divinyl hydrazine

Chemical reactions of Pyrrole:
1) Reaction with acid:
H attached at N undergoes rapid exchange in acid & alkali
Similar exchange also possible for H at C under more acidic condition
Exchange rate of α proton is double than that of β proton
Isolation of trimer of pyrrole could be achieved by controlled addition of acid

2) Reaction with base:
pKa 17.5 which is larger than imidazole so pyrrole is wk acid than imidazole.
Weaker than phenol but equal to EtOH
It reacts with K to liberate H2 and form salt
Acidity of P can be increased by putting EWG at position 3 which stabilizes
anion by resonance

Resonance structures of furan Thiphene and Pyrrole

Mono-C-alkylation of pyrroles cannot be achieved by direct reaction
with simple alkyl halides, either alone or with a Lewis-acid catalyst,
e.g. pyrrole does not react with methyl iodide even above about 150
°C, gives further heating leads to a complex mixture made up
mostly of polymeric material together with some poly-methylated
pyrroles.
The more reactive allyl bromide reacts with pyrrole at room
temperature, but mixtures of mono- to tetra-allyl-pyrroles together
with oligomers and polymers are obtained.
3) Alkylation:

3) Electrophilic Aromatic substitution: π e density is more as
compared to benzene.
ES Rxn occurs similar to benzenoid system
Occurs at 2 position
if blocked to other position
Max resonance max stability/probability
2 position
Followed by 3

3) Electrophilic Aromatic substitution:
A) Halogenation: Extremely reactive
Chlorination (SO2Cl2)
Bromination (Br2 CH3COOH)
Iodination (I2/KI3)
All these gives tetra halo derivatives
Hard to get mono halo derivative
Halo-pyrroles are v. unstable, decompose in air & light

3) Electrophilic Aromatic substitution:
B) Nitration: Extremely reactive

C) Sulfonation: If H2SO4 used at rt forms polymer
So mild sulfonating agent (Pyridine sulfur trioxide complex) used

4) Reaction with oxidising agents:
Easy
Autoxidation by air, light red brown colour.
Ozonolysis at low temp breakdown of ring.
If ring does survive it forms maleinimide
deri.
With H2O2 also it gives similar prodt

5) Reaction with reducing agents:
P won’t respond to rxn with LAH, Na/Liq NH3
But reduction is possible in acidic media
Species under attack protonated

6) Diels Alder reaction:
DA adduct

7) Reaction with carbene & nitrene:
Halocyclopropyl int

Rx with Nitrene:
Gives homoazopyrrole which rearranges to give final prdt

vdocuments.net_heterocyclic-chemistry-58bb82e5b406c.ppt

5 Membered Heterocyclic ring containing 2 hetero atoms
Imidazole

Aka Iminazoline
Azopyrrole
2 N atom separated by C
Histamine, Histidine,
Pilocarpine & allantoin
Benzimidazole in Vit B12

Resonance structure of Imidazole:

Attack at 5
If blocked then on 4

1) Synthesis from imidazoline:
Dehydrogenation of imidazoline in +ce of S
Another variation is use of Barium mangnate

2)Synthesis from α Haloketone:
2,4 disubs Imidazole from Benzimidine & α Haloketone

3)Radiszewski method:
Imp mtd
Condensation of diketone with aldehyde in +ce of NH3

Reaction of imidazole with acid & base
Base and form crystalline salt with acid.
More acidic than pyrroles and thus forms salts of the following type with Grignard
reagent or metal ions.

Reaction of imidazole with oxidising agents:
stable to auto oxidation and to the action of chromic acid
Can be oxidised by KmnO4 .
H2O2 Readily opens the ring to form oxamide
N
N
H
NH
N
H
O2 / MeOH
O
MeO
MeO
Oxygen in the presence of a sensitizer (single oxygen) reaction gives an
imidazolidine derivative

Reactions of imidazole -Electrophilic substitution Rxn:
E + would attack the unshared electron pair on N-3, but not that on the
‘pyrrole’ nitrogen since it is the part of the aromatic sextet.
It is more susceptible to E + attack than thiazole, furan and thiophene.
Attack takes place at the 4th and 5th position

Reactions of imidazole -Nitration:
Bromination

Reactions of imidazole - Sulfonation:

N
N
CH3
BuLi RX
N
N R
N
N
ph
N
N
ph
Li
ph
R
BuLi
N
N
CH3
R
Li
N
N
H
N
N
N
N
H
N
N
Ac2O
COCH3
CH2N2
CO2CH3
H3C
CH3
H3C
CO2CH3
Acylation
Alkylation
Lithiation
Reactions of imidazole -

Catalysis role of imidazole - Ester Hydrolysis.
Inspired by evidence that the imidazole ring of histidine residues present in various
hydrolytic enzymes is responsible for their proteolytic activities,
imidazole itself has been shown to be an excellent catalyst of ester hydrolysis
In intramolecular transesterifications and hydrolyses of 2-hydroxymethylbenzoic acid derivatives,
the accelerating role of imidazole is due to its ability to act as a proton transfer catalyst rather
than as a nucleophile.

Indole:
abundant in nature
tryptophan, indole-3-acetic acid,
serotonin, natural products, drugs
Isolated industrially from coal tar
Biosynthesis of tryptophan
Isoelectronic with naphthalene
Very weakly basic: pKa of protonated indole: 2.4
Protonation occurs at C–3 preferentially
Easily oxidized (atmospheric oxygen) very e rich
Electrophilic attack occurs at C–3 (site of most
electron density)
C–3 is more reactive to electrophilic attack than benzene

Resonance structure of indole:

Intramolecular cyclization of N-phenylamides using strong base
at high temperature.

The Fischer indole synthesis :
best methods for preparing indoles. converts arylhydrazones
into indoles in the presence of an acid catalyst.

Reactions of indole:
Protonation

Bischler indole synthesis:
2-aryl-indole from α-bromo-acetophenone and excess aniline

Reissert indole synthesis:
Basic condensation of o-nitrotoluene with oxalic ester to o-
nitrophenylpyruvic ester, reduction of the nitro group to an amino group,
cyclization to indole-2-carboxylic acid and final decarboxylation

Indoles – Electrophilic Substitution

Oxidative cleavage of 2,3 db

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