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Thiophene

1 – 1,4 – dicarbonyl compound with a source of sulphur

OO R'RP2S5

OS R'R

R'R SH OH-H2O

SR'R

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2 – The Hinsberg Synthesis The consecutive aldol condensation between α 1,2 – dicarbonyl compound and diethylthiodiacetate give thiophenes .The immediate product is an ester – acid produced by a stobbe – type mechanism , but the reaction are often worked up via hydrolysis to offord an isolated diacid

CH3 - C - C - CH3 || || O O

+EtO2CCH2

SCH2CO2Et

EtO2C -C S

CH3-C C - CH3

C - O2C-Et

Cu

300 c0

EtO2C S

CH3CH3

-2H2O

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Chemical Reaction Reaction with electrophilic reagent take place at position 2 & 3 but at 2 take place much faster yield a stable product .

Nitration

S

HNO3

AC2O/ACOH 0 0C

S NO2

+

S

NO2

60% 10%Sulphonation

S

SO3-

N+

CH2Cl2

Ba(OH)2

S SO3

-

Ba2+2

86%

Use of the pyridine – sulfur trioxide complex is probably the best method

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Halogenation

S I

70 %

I2

aq.HNO3S

S BrBr

S Br

90 %

84 %

Br2/Et2O

48%HBr

-10 +10 0C

Br2/Et2O

48%HBr

-25 -5 0C

90 0C

Halogenation of thiophene occurs very readily at room temperatures and is rapid even at – 30 cº in the dark.

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Acylation

S S C || O

CH3

80%

MeCOCl

SnCl4

The Friedel – crafts acyalation of thiophene is much – used reaction and produced generally to give good yield under controlled condition , adding catalyst to thiophene and acylatting agent avoid reaction of aluminium chloride with thiophene to generate tars

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N

Indolizine

X

Iso indole Isobenzofuran

Isobenzothiophenes

X

Indole X = NHBenzofuran X = O

Benzo thiophene X = S

Reactivity of indoles, benzo[b]thiophenes, benzo[b]furans.isoindoles, benzo[c]thiophenes and isobenzofurans

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IndolesIndoles are colourless crystalline solids .Many simple indoles are available commercially and all of these are produced by synthesis .Most indoles are stable in air with exception of those which carry simple alkyl group at c – 2 autoxidises easily even in dark brown bottle.

The word indoles derived from the word India blue dye. chemical degradation of the dye give rise oxygenated indoles .which named indoxyl and oxindole ; indol as first prepared in 1866 by zinc dust distillation of oxindole

NH

O

Zndust

(Red)NH

Oxidndole Indole

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Indoles are widely distributed in nature Tryptophen is an essential amino acid

NH

COOH

NH2

tryptophan

The formula of indole was proposed by Baeyer in 1869 and was based on the synthesis outlined

CH2COOH

NO2

Fe , NaOH

fuse NH

CH2COOH

NH2

-H2O

NH O

red Sn , HCl Zn dust , disti

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The resonance energy of indole calculated from its heat of combustion is )47 – 49 ( kcal / mol the increase in resonance energy over pyrrole )23 – 27 ( is almost identical to the difference between the resonance energies of naphthalene )61( and benzene )36(

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Chemical properties The chemical properties of indole are quite similar of these of pyrrole

1 – The direct oxidation of indole .PhC2 O OH O3 , H2ONHRR'CORNHCOR'PhCO2OHO3 , H2ONHCOHNHCOHThe nitrogen containing ring of many substituted indoles can be

opened by the action of peroxy acid and ozone.

PhC 2 O OH

O3 , H 2ONH

R

R'

COR

NHCOR'

PhCO2OH

O3 , H 2ONH

COH

NHCOH

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2 – Addition reaction Indole , like pyrrole is very weak base and it is polymerized by acid giving crystalline dimmer

NH N

H

NH

indole dimer

Acid

3 – Reaction

NH N

H

2,3-dihdroindole

Zn

octa hydroindole

NH

sever

condition

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4 – Subistitution reactions the hydrogen at position 1 of indole is acidic and can be displaced by metallic sodium or pot . hydroxide at 125 – 130 c° or by Grignard reagent

NH

MeMgI

NMgI

HCOOEt

NH

CHO

2,3-dihdro indole

NCHO

Some

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Electrophilic subistitution

NH

..

NH

NH

+

E

E

NH

NH

SO3SO3

Pyridine

NH

Cl SOCl2

attack is more stable at position 3

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Electrophilic subistitution reaction NHEHH..NHEH..NHEHmore stablearomatic sextet preserved attack at position 2

The pyrrole ring in the indoles readily undergo subistitution reactions .The general Pattern of reaction is similar to that observed with Pyrrole itself except that many of reaction with indole introduce 3 – Subistituents , lead to 3-subistituted indoles .This orientation can be accounted as follows

NH

E

H

H

..NH

E

H

..NH

E

H

more stablearomatic sextet preserved

attack at position 2

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This orientation agreement with the calculated change destant for indole

NH

1.065

1.059

Gattermen reaction

NH

+HCN HCl N

H

CHO

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H - C N + HCl + -

+ -HC = NH | Cl

NH

H

+ HC = NH | Cl

NH

CH = NHO H2

NH

CHOH2O

H+-NH3

-HCl

Mechanism

a -

b –

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Mannich reaction Indol undergo Mannich reaction with formaldehyde and dimethyl amine to give 3 – dimethylamine indole

O HCl

NH

H

+ H-C- H + HN N

H

CH2 - N

CH3

CH3 H2OCH3

CH3

3 - dimethylamino methylindole

-