Transcript Indoles

Thiophene
1 – 1,4 – dicarbonyl compound with a source of sulphur
'R
O
'R
O
SH
R
OH
P2S5
R
'R
S
O
R
-H2O
R
lec5
S
R'
1
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
-2H2O
+
EtO2CCH2
CH3-C
EtO2C -C
CH2CO2Et
C - CH3
S
C - O2C-Et
S
CH3
CH3
Cu
300 c0
EtO2C
S
lec5
2
Chemical Reaction
Reaction with electrophilic reagent take place at position 2 & 3 but at 2
take place much faster yield a stable product .
Nitration
NO2
HNO3
S
+
AC2O/ACOH
0 0C
Sulphonation
NO2
S
S
10%
60%
Use of the pyridine – sulfur trioxide complex is probably the best method
+
N
SO3
S
Ba(OH)2
-
SO3
S
CH2Cl2
Ba2+
2
86%
lec5
3
Halogenation
Halogenation of thiophene occurs very readily at room temperatures
and is rapid even at – 30 cº in the dark.
Br2/Et2O
I2
S
I
aq.HNO3
90 0C
Br
48%HBr
90 %
+10 0C
-10
S
Br
S
Br2/Et2O
70 %
48%HBr
-25
-5 0C
S
Br
84 %
lec5
4
Acylation
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
MeCOCl
S
SnCl 4
S
lec5
C
||
O
CH3
% 80
5
Reactivity of indoles, benzo[b]thiophenes, benzo[b]furans.
isoindoles, benzo[c]thiophenes and isobenzofurans
X
X
Iso indole
Indole X = NH
Isobenzofuran
Benzofuran X = O
Benzo thiophene X = S Isobenzothiophenes
lec5
N
Indolizine
6
Indoles
Indoles 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
O
N
H
Zn
dust
(Red)
N
H
Oxidndole
Indole
lec5
7
Indoles are widely distributed in nature Tryptophen is an essential amino acid
COOH
NH2
N
H
tryptophan
The formula of indole was proposed by Baeyer in 1869 and was based on the
synthesis outlined
CH2COOH
Fe , NaOH
NO2
red
fuse
Sn , HCl
N
H
Zn dust , disti
CH2COOH
-H2O
N
H
NH2
lec5
O
8
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)
lec5
9
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 ,
H2ONHCOHNHCOH
The nitrogen containing ring of many substituted indoles can be
opened by the action of peroxy acid and ozone .
R
COR
PhCO 2OH
N
H
R'
O3 , H2O
NHCOR'
COH
PhCO2 OH
N
H
O3 , H2O
NHCOH
lec5
10
2 – Addition reaction
Indole , like pyrrole is very weak base and it is polymerized by
acid giving crystalline dimmer
Acid
N
H
N
H
N
H
indole dimer
3 – Reaction
Zn
N
H
N
H
sever
2,3-dihdroindole
condition
N
H
lec5
octa hydroindole
11
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
CHO
N
H
N
H
2,3-dihdro indole
N
CHO
Some
MeMgI
HCOOEt
N
MgI
lec5
12
Electrophilic subistitution
E
..
N
H
+
N
H
E
N
H
attack is more stable at position 3
SO3
SO3
N
H
Pyridine
N
H
SOCl2
Cl
N
H
lec5
13
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
..
N
H
H
E
..
N
H
H
E
E
N
H
H
H
more stable
aromatic sextet preserved
attack at position 2
lec5
14
This orientation agreement with the calculated change destant for
indole
1.065
N
H
1.059
Gattermen reaction
CHO
N
H
+ HCN
HCl
N
H
lec5
15
Mechanism
a-
+ -
H-C
+
N + HCl
HC = NH
|
Cl
-
H
b–
N
H
CH = NH
O
H2
-HCl
+ HC = NH
|
Cl
N
H
CHO
H2 O
H+
-NH3
N
H
lec5
16
Mannich reaction
Indol undergo Mannich reaction with formaldehyde and dimethyl
amine to give 3 – dimethylamine indole
H
O
CH3
CH3
+ H-C- H + HN
N
H
CH3
CH2 - N
HCl
CH3
- H2O
N
H
3 - dimethylamino methylindole
lec5
17