heterocyclic chemistry
TRANSCRIPT
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Heterocyclic chemistry:Heterocyclic chemistry: Furan, Thiophene, Pyrrole, Imidazole, Indole
Dr. Taj Khan Dept. of Pharmaceutical Chemistry, Oriental college of pharmacy Sanpada, New Mumbai.
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Furan
O
OxoleOxacyclopentandiene
1
2
34
5α
β
α'
β’
Drugs:Furosemide, Nitrofurantoin, Nitrofurazone, Prazocin, Ranitidine
Scheele 1780
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Less stable than pyrrole & thiopheneless reactive than pyrrole towards E+
Aromatic as lone pair of e participate in Pi cloud, follow Huckel’s rule of aromaticity 4n + 2πO and 4 C SP2 hybridised & lie in same plane
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Synthesis of Furan: 1) From carbohydrate:
COH
C
C
C
OH
H
OH
H
HO
H
Pentose
CH2OH
H+
COH
C
C
C
OH
H
OH
H
HO
H
CH2OH
COH
C
CH
C
OH
OHH
CH2OH
-H2O
COH
C
C
C
O
OHH
CH2OH
H H-H2OC C
CHO
OH2C
O
H
H HH+
O
H
H
OH
CHO
H+
-H2O
O CHO
~100%
200 0C/Pd/C-CO
O
Polysaccharide (Oat)
Acidhydrolysis
Furfuraldehyde
2-furoic acid
Decarboxylation
Furan
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2) Synthesis of furan from Oxazole
N
O
Ph
+ HC C COOCH3
DA rxn
Diene DienophileN
OH3COOC
Ph
O
COOCH3
+PhCN
Methyl-3-furoate
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3) Synthesis of 3-substituted furan from DA adduct
O+ C C
DA rxn
Diene Dienophile
O
CF3
+
CF3F3C OCF3
CF3
OCF3
CF3
F3C
H2C CH2
3,4 trifluoromethyl furan
400 0C
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4) Synthesis of furan by Paal –Knorr method: Ring closure mtd. Subst. open chain compd (1,4 diketone) cyclize by acid to give furan
O
Ph
Ph
OH Ph
O
OHPhH
O
Ph
Ph
H +
-H2O
H +
150 0C
Mechanism via mono enol formation. Sterically hindered diketone do not cyclize to furan
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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 can occur.
O O
H
H
H2OOHC CHO
Succinaldehyde
F with EWD more stabile to acids
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Chemical reactions of furan:1)Reaction with Base:
O O Li O R
BuLi RX
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Chemical reactions of furan: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
O
Cl2/ DCM
1.6 moles eq O-40 0C
Cl O ClCl+O ClCl
+Gradual addition:
Cl 2/
DC
ME
xces
s
O ClClCl Cl
Cl Cl
2-chloromajor
2,5 dichloro
Cl
2,3,5 trichloro
% of 2 subst product can be increased by using less amt of Cl2
2- Bromo can be obtd by Br2 in dioxane
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Chemical reactions of furan:2)Electrophilic aromatic substitution:
B) Nitration: Mild nitrating agents used acetyl nitrate (acetic anhydride + HNO3
O
furan
CH3CO2NO2
O NO2
Further Nitration
O NO2O2N
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Chemical reactions of furan:2)Electrophilic aromatic substitution:
C) Sulfonation: Mild sulfonating agents used Pyridine- SO3 complex If H2SO4 used, it gives resin
OFuran
pyridine:SO3
O SO3H
pyridine:SO3Excess5 hr
35-40 0C
O SO3HHO3S
2-Furan sulfonic acid
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Chemical reactions of furan:2)Electrophilic aromatic substitution:
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.
OFuran O C
O
CH3
(CH3CO)2O
ZnCl2
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Chemical reactions of furan:3) Carbene and nitrene: Cabene add across 2,3 C db.There is not much report of reactions of nitrene with furan
OFuran
O
O
COOCH3
HO
H
COOCH3
Carbene adduct
160 0C
CIs-transmuconaldehydetautomerization
CH2N2
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Chemical reactions of furan:4) Reaction with reducing agents: dependent on catalyst, solvent & temp
OFuran
O
Raney Ni125 0C
100atm
Pt/CH3COOH
OH
Pt/Al
Or Cu/Al150 0C
O O
Selective reduction
THF
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Chemical reactions of furan:5) Reaction with oxidizing agents: F is O2/air sensitive, 1,4 addition to diene system
OFuran
Air
O
O O
Transannular peroxide
OHC CHOSuccinaldehyde
Further Rxn
CH3OH
OO OH
4-Hydroxy-2-butenolide(Lactone)
Air
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Chemical reactions of furan: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.
Ether/25 0C
O
H
H
Endo 59%
+O
H H
Exo 60%more stable
O
Furan
+
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Extra
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O
furan
CH3CO2NO2
O NO2
pyridine:SO3
O SO3H
C6H5N2+
O NN
(CH3CO)2O, BF3
O CO
CH3
2 Position reactiveExtra
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O
furan
O CH=O
O Br
O HgCl O I
1. HCN, HCl
2. H2O
Br2
dioxane
HgCl2
CH3CO2Na
I2
CH3COCl
O CO
CH3
Extra
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Thipohene
S1
2
34
alfa
Beta
alfa'
Beta'
5
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
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Synthesis of Thiophene:1)Using Na-SuccinateClassical mtd Phos. trisulfide ( Red P +S)
SCOONaNaOOC
P2S3 180 0C
S
S
Industrial mtd use hydrocarbon (butane/butene/1,3-butadiene and elemental S
600 0C
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Synthesis of Thiophene:2) Ring closure Mtd A) From unsaturated compds/ Fiesselmann mtd:
S
COOH
COOH S
COOCH3
COOCH3 S
COOCH3
COOCH3
H2N
S
COOCH3
COOCH3
HON
S
COOCH3
COOCH3
OHC
COOCH3
HCCOOCH3
CH2C
S
OH3CO
NaOCH3
CH3OH-OCH3
-
NH2OH
HCl
Reduction
1) NANO2, HCl
2)H3PO2, H2O
1) KOH, H2O, Heat
2) H+
Methyl thioglycolate Dimethyl
fumarate
H
H
H
H
Condensation Rxn
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Synthesis of Thiophene:2) Ring closure MtdB) Paal Knor mtd: General mtd
S R1
R
S R1R
HO
H
OS R1ROO R1R
P2S5
95 0C
-H2O
H
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Synthesis of Thiophene: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
PhPh
O Ot-BuOK
rt
PhPh
HC
SOEt
O
OEtOOC OEtOOC S COOEt
Base
-OEt
Ph Ph
CS
O
O
EtOOCO
H
C CO
PhPh
CS
EtOOCCHCOOK
Base
Base
S
Ph PhOCOOK
HEtOOC
-H2O
S
PhPh
EtOOC COOK
H+
S
PhPh
EtOOC COOH
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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.
S
Orthophosphoric acid
SS S
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Chemical reactions of Thiophen:1)Reaction with Base:
S S Li S R
BuLi RX
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Chemical reactions of Thiophene:2)Electrophilic aromatic substitution: more reactive than benzene.Pyrrole>furan>Thiophene>Benzene 2 position more reactive. A) Halogenation: Rxn with NBS gives 2- bromo T
S Cl S ClCl+
36% 14%
S Br S BrBr+
78% 13%
S I S II+
70% Minor
Br Br
S
0 0C
30 0C
Br2, CH3COOH
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SO HNO3
O
SO
O
O2N
S S NO2 SNO2
+O2N
Major
HNO3/AC2O
Chemical reactions of Thiophene:2)Electrophilic aromatic substitution: more reactive than benzene.Pyrrole>furan>Thiophene>Benzene 2 position more reactive. B) Nitration:
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Chemical reactions of furan:2)Electrophilic aromatic substitution:
C) Sulfonation: 95% H2SO4 used at rt readily occurs
SThiophene
H2SO4 95%
S SO3H
2-thiophene sulfonic acid
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Chemical reactions of furan:2)Electrophilic aromatic substitution: D) Friedel Crafts reaction: wide variety of choices available
SThiophene
Actyl chloride
S COCH3
2-Acetyl thiophene
SnCl4
SThiophene
RefluxS
2,2' thienoylbenzoic acid
AlCl3
O COOH
O
O
O
+
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Chemical reactions of furan: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+
SThiophene
+ CHCOOEtS
COOEtH
S
COOEt
S
COOEtH
HHCl, EtOH
S
COOEt
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S N3COOEt NS COOEt-S
NCOOEt
Ethyxycarbonylnitrene reacts with T to give 1,4-adduct which loses S to form N-carboethoxypyrrole
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Chemical reactions of furan:4) Reaction with Nu: Every positional combination of Nitro and Halo T actiavate system towards SN rxn
S
Br CuCl, pyridineDMSO
S
Cl
Seems like normal displacement Rxn
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Chemical reactions of furan:5) Reaction with free radicals/ Gomberg Bachmann rxn:1 of the best & simple mtd for synthesis of aryl thiophenes
S+ (PhCOO)2
S
HH
OCOPh
DimerizationS
HH
PhOCO2
-PhCOOH
S S
benzoyl peroxide
2,2'-bithienyl
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Chemical reactions of furan: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
SS O
O O
Thiophene 1,1’ dioxide/ Thiolane can form it’s also reactive but isolable
SO O
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Chemical reactions of furan:7) Reaction with reducing agents:
S
Na, CH3OH
NH3 -40 0C S S+ + Butenethiol
S
Pd/C
SH2
70%
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Chemical reactions of furan:8) Diels-Alder reaction: Acetylenic dienophiles. Chelotropic expulsion of S from unstable intermediate, which gives benzene derivative
S +
CNCCCN
SCN
CN
CN
CN-S
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Pyrrole
NH1
2
34
5 α
β
α'
β’
Ketorelac, atorvastatinHb, Chlorophyl, Vit B12, bile pigment
Runge 1837
Greek: Red
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Synthesis methods:1) From Furan
O NH
NH3
Steam/400 0C
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O NR
Al2O3RNH2 +
2)From Primary amine:
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The Knorr Synthesis:Imp & widely used mtdCondensation of Alfa amino ketone with another dicarbonyl compound with active methylene grp in presence of acetic acid
NH
H3CCOOEt
EtOOC CH3N
H
CH3COOEt
EtOOC CH3
O
N
CH3COOEt
EtOOC CH3
OH
NH2
CH3 COOEt
EtOOCCH3
O
H
O
CH3COOH
-H2O
-H2O
Alfa amino acetoacetic ester
NH
H3CCOOEt
EtOOC CH3
OH H
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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.
NH
EtOOC
H3C CH3
H3C
NH3 Ether
-H2OO
EtOOC
H3C NH2
EtOOC CH3O
CH2Cl
NH
EtOOC
H3C CH3
Cl
OH
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The Paal Knorr Synthesis of Pyrrole:General mtdCondensation of 1,4 diketone with NH3 or primary amine.
NH
H3C CH3
-2H2O
O OCH3
H3C
NH3
(NH4)2SO4
OCH3
H3C
HO NH2 N
H
HO OH
H H
H3C CH3
H
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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
R1 R1
R2R2
NH
R1 R1
R2R2
N NH H
CCR1 R1
R2R2
N N
H H
CCR1 R1
R2R2
N N
Pyridine
Benzene
H+
Xylene, 140 0C
-NH3
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Chemical reactions of Pyrrole:1) Reaction with acid:H attached at N undergoes rapid exchange in acid & alkaliSimilar exchange also possible for H at C under more acidic conditionExchange rate of α proton is double than that of β proton
NH
AcidPolymer(Pyrrole -red)
Isolation of trimer of pyrrole could be achieved by controlled addition of acid
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Chemical reactions of Pyrrole: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 saltAcidity of P can be increased by putting EWG at position 3 which stabilizes anion by resonance
NH
NH
N Netc
Base
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Resonance structures of furan Thiphene and Pyrrole
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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.
Chemical reactions of Pyrrole:3) Alkylation:
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Chemical reactions of Pyrrole: 3) Electrophilic Aromatic substitution: π e density is more as compared to benzene.ES Rxn occurs similar to benzenoid systemOccurs at 2 position if blocked to other positionMax resonance max stability/probability
NH
NH N
HNH
NH N
H
E
H
E
H
E
H
E
H
E
H
2 positionFollowed by 3
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Chemical reactions of Pyrrole:3) Electrophilic Aromatic substitution:A)Halogenation: Extremely reactiveChlorination (SO2Cl2)Bromination (Br2 CH3COOH)Iodination (I2/KI3)All these gives tetra halo derivativesHard to get mono halo derivative
Halo-pyrroles are v. unstable, decompose in air & light
NH
Ether, 0 0C
SO2Cl2
NH
Cl Cl
ClCl
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Chemical reactions of Pyrrole:3) Electrophilic Aromatic substitution:B) Nitration: Extremely reactive
HNO3
NH
NH
NO2 NH
+
Major
HNO3/AC2O
NH
H2SO4Tar
-10 0C
NO2
Very Minor
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Chemical reactions of Pyrrole:2)Electrophilic aromatic substitution:C) Sulfonation: If H2SO4 used at rt forms polymerSo mild sulfonating agent (Pyridine sulfur trioxide complex) used
NH
Pyrrole
NH
SO3H
2-Pyrrole sulfonic acid
N SO3-
90%
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Chemical reactions of Pyrrole:4) Reaction with oxidising agents: EasyAutoxidation 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
O3
NH
50 0CNH
O
H3C Et
CH3Or H2O2
H3C Et
CH3
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Chemical reactions of Pyrrole:5) Reaction with reducing agents: P won’t respond to rxn with LAH, Na/Liq NH3
But reduction is possible in acidic mediaSpecies under attack protonated
Zn, CH3COOH
N rt NRR
HH
NR
NR
NR
NR
NR
Pyrrolidine deri
3 Pyrroline
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Chemical reactions of Pyrrole:6) Diels Alder reaction:
N
+
NCH3CH3
NH
+
NH
Azanorbornadiene derivative
DA adduct
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Chemical reactions of Pyrrole:7) Reaction with carbene & nitrene:
NH
CCl2
CCl2
NH
N
Cl-HCl
CHCl3
NaOH
Cl
Cl
NH
Cl
Cl
H NH
CHCl2
H2O -2HCl
NH
CHO
2-pyrrolecarbaldehyde
NH
Halocyclopropyl int
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NH
N N CHCOOEt+Cu
100 0CNH
CH2COOEt
Ethyl pyrrole acetate
Diazoester
Rx with carbene
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N
NCH2COOEt
NHH
HN
H
N CH2COOEt-N2
N3COOEt
N NH2
CH2COOEt
Rx with Nitrene:Gives homoazopyrrole which rearranges to give final prdt
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5 Membered Heterocyclic ring containing 2 hetero atoms
N
NH
NNH
Imidazole Pyrazole
Imidazole
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N
NH
Imidazole1
2
34
5
Aka IminazolineAzopyrrole2 N atom separated by C
Histamine, Histidine,Pilocarpine & allantoinBenzimidazole in Vit B12
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Resonance structure of Imidazole:
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N
NH
N- like pyridine deactivate its vicinal positions
most strongly activated position1
2
34
5
Attack at 5If blocked then on 4
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1) Synthesis from imidazoline: Dehydrogenation of imidazoline in +ce of SAnother variation is use of Barium mangnate
N
NH
R
N
NH
R
BaMnO4-NH3
H2CH2C NH2
NH2+
NC
REthanediamine
Alkylnitrile
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2)Synthesis from α Haloketone: 2,4 disubs Imidazole from Benzimidine & α Haloketone
CH2BrC
PhO +
HNC
H2NPh
-Br-
-H2ON
NH Ph
Ph
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3)Radiszewski method: Imp mtdCondensation of diketone with aldehyde in +ce of NH3
-3H2O N
NH Ph
PhCC
O
O
Ph
Ph
+
H2NH
H2NH
+ CH
PhO
PhN
N
H
Ph
Ph
Ph
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Reaction of imidazole with acid & baseBase and form crystalline salt with acid. More acidic than pyrroles and thus forms salts of the following type with Grignard reagent or metal ions.
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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
NH
NH
NH
O2 / MeOH
O
MeO
MeO
Oxygen in the presence of a sensitizer (single oxygen) reaction gives an imidazolidine derivative
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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
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Reactions of imidazole -Nitration:
Bromination
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Reactions of imidazole - Sulfonation:
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NN
CH3
BuLi RXN
N R
N
Nph
N
Nph
Li
ph
R
BuLiN
N
CH3
R
Li
N
NH
N
N
NNH
NN
Ac2O
COCH3
CH2N2
CO2CH3
H3CCH3
H3C
CO2CH3
Acylation
Alkylation
Lithiation
Reactions of imidazole -
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Catalysis role of imidazole - Ester Hydrolysis.Inspired by evidence that the imidazole ring of histidine residues present in varioushydrolytic 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.
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Indole:
Indole
NH1
2
345
6
7
abundant in naturetryptophan, indole-3-acetic acid,serotonin, natural products, drugs Isolated industrially from coal tarBiosynthesis of tryptophan
Isoelectronic with naphthalene Very weakly basic: pKa of protonated indole: 2.4Protonation occurs at C–3 preferentiallyEasily oxidized (atmospheric oxygen) very e richElectrophilic attack occurs at C–3 (site of most electron density)
N–1 is the most nucleophilic site
C–2 is the second most reactive site
C–3 is more reactive to electrophilic attack than benzene
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Resonance structure of indole:
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Intramolecular cyclization of N-phenylamides using strong base at high temperature.
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The Fischer indole synthesis :best methods for preparing indoles. converts arylhydrazones into indoles in the presence of an acid catalyst.
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Reactions of indole:Protonation
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Bischler indole synthesis:2-aryl-indole from α-bromo-acetophenone and excess aniline
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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
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Reactions of indole:
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Reactions of indole:
Indoles – Electrophilic Substitution
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Reactions of indole:
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Reactions of indole:
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Reactions of indole:
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Reactions of indole:
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Oxidative cleavage of 2,3 db
Reactions of indole: