Tutorial 3

PC304
 Conversions
• Butanedial to pyrrole-2-carbaldehyde.
• Butanedial to 3-chloropyridine.
• Butanedial to N-acetylpyrrole.
• Butanedial to pyrrole-2 carboxylic acid.
• Butanedial to pyrrole-2 sulphonic acid.
• Btanedial to 2-nitropyrrole.
 CH2 CH2

Kolb Schmidt - +
CHO CHO
CO2/KOH CH3COOH NO2
COOH N NO2
N
NH3 5oC
H H

SO3 / pyridine
N CHO N SO3H
Reimer Tiemann 90 oC
H CHCl3/ NaOH H
+
Cl N
CH3COCl / 80 oC
H
N
N
COCH3
150-220 oC
SO2Cl2
(CH3CO)2O/ 250 oC
N Cl
0 oC without cat. (F.C.)
H N COCH3

Complete…..???
 cold conc. H2SO4
• Similarly……….. S SO3H

fuming HNO3 and

(CH3CO)2O
S NO2
(CH3COONO2)

P2S5 SO2Cl2
OHC CHO
CH2CH2 S O S Cl

N Br

O S Br

Br2 / benzene

Br S Br
 - +
CH3COO NO2

Nitration
O NO2

SO3 / pyridine

O SO3H

P2O5 RCOCl / SnCl4

H H
O O O Friedel Craft's O COR
acylation

O
O
O

O O O

O
OH

H+
O
 Mention one good application for the
following reagents
• Ethyl acetoacetate.
• Aminoacetone.
• Butanedial.
• N-Bromosuccinamide.
• Maleic anhydride.
• Thiophenoxyacetic acid / thiophenol.
• Malondialdehyde.
• Hydrazine
 O CH3 Heat with
OH CH2 acid or base H3C
CH3 C + C enolisation CH3 C catalyst
+ C
CH2 CH3 - 2 H2O
O CH CH3
HO N CH3
NH2
ketone NH2
Amino ketone H

EtOOC
EtOOC Cl
CH2 CH2
+
C C H3 C N CH3
H3C O CH3
O H
NH3
Ethyl 2,5-dimethylpyrrole-3-carboxylate

EtOOC CH3 EtOOC CH 3

CH2 O C Pyridine
+
C CH2 H 3C O
O Cl
H3C
acetoacetic ester chloroacetone
 4

5 3

6 2
S
7 1
Thianaphthene

Ring synthesis

HO O
C OH
ClCH2COOH P2O5
CH2
SH NaOH S S
Thiophenoxyacetic acid
Zn dust
+
E

Conversions ??? From thiophenol to …..,

Complete….
 O2N
HNO3 / H2SO4
N
o
100 C N

H
H
HO3S
Heat Oleum
O
N N
H N o
100 C N
O NH2
H2N H H

+
N N Cl

No Rx.
NaOH

Conversions ??? From malondialdehyde to …..,

Complete….
 I
CH3 I2
H
N N C
COOH
N

ZnCl2
Br
Br2 / H2O

Heat N

H
N COOH N
H H Cl
SO2Cl2

NO2
Acetyl nitrate

Conversions ??? From pyruvic N

acid or from phenylhydrazine H

to ….., Complete…. CH2N(CH3)2

HCHO / NH(CH3)2

Mannich N

H
 Electrophilic substitution occurs at the 4(5)-position

O2N
N
HNO3/H2SO4

heat N

H
HO3S
N
N
COOH H2SO4/SO3
N
CO2 N
100 oC
H N N
NaNH2 H
CH3

N RX N N N N
CH3I
Na+ H
N N N

R CH3

N
+ _
N N Cl
N N
N

NaOH H
 Benzimidazole Benzoxazole Benzthiazole
Benzo[d]imidazole Benzo[d]oxazole benzo[d]thiazole

N N N

N O S
H
Ring synthesis
o-phenylenediamine NH2 O N
heat
+ CH
-2H2O N
HO
NH2
H
2-aminophenol
NH2 O
heat N
CH
+
HO -2H2O O
OH
2-aminothiophenol
NH2 O heat N
CH
+ -2H2O S
HO
SH
 Conversions
• Pyridine to 3- …….pyridine.
• Pyridine to piperidine.
• Pyridine to pyridinium methiodide.
 Br2 2
NO2
KNO /H SO4
3 2
NO2
KNOKNO
200-300 o3C/H2 SO
/H SO 4
+
N 3 2 4
370oC N +
370oC
370oC ++
N N N
N
Br2 H H
H
NO2 3+
SO H SO3 H
SOSO
3 /H2 SO /HgSO
oC24 SO
/H 44/HgSO
500 4 SO3 H OCH3
SO3 /H SO
3
2KNO 4 /HgSO
4
3 2 SO4
/H N Br Br N Br OCH3
220oC /o24 hrs. - OCH
+ - OCH3
220oC220 24oC
/370 C / 24 hrs.
hrs. ++
NN + 3 NaOCH3 /CH3 OH
OCH
- +3
OCH
oC
N -radical NaOCH
N induced
thermallyH substitution
150
3 /CH3 OH N
OCH3
N
HH NO OCH3
+ N
Br
2 HH Br
Br o
150 CBr pyridyne
KNO32/H2 SO4 SO
Br3 H Br Br N N
SO3 /H2Br
SO2 4 /HgSO4 Cl H Cl Br Br intermediate
Br N
370o
Cl200-300 oBr + + pyridyne
2 AlCl 3C
/ 2 C2
N (or 3,4-dehydropyridine)
N o
200-300
220 C / 24o C hrs. + Cl intermediate
N o H +N +N NH2
N 200-300 C NN SO3 HN N (or 3,4-dehydropyridine)
- NH2
SO3 /H2 SO4 /HgSO4 N N NH3 /H2 O/CuSO4
Br2 H
N NH2 NH2
oC / 24 hrs. N+ oC - +NH2
Br-
220Br + NH150
3 /H2 O/CuSO4
2 o
500
Br C + HBrN Br Br Br NH2
500 C Br2
o2
H N Br+ Br + oCBr
N 150
N N
+ N
N
Br2oC o
N Br Br
Br + Br N+ N Br
Br N
200-300 500 C - N N
N +
thermally
HBr
N induced
+ N
radical substitution
H Br
200-300oC BrN Br +bromine
pyridinium N Br
N N thermally induced radical -substitution
N
Br-
N N
+ HBr+ HBr Br
Br + +Cl - H
N N+ HBr Cl2Br / 22AlCl3
2 thermally
N S
N 2induced
Br
N radical
pyridinium substitution
bromine-
ooCC + CH I + + Cl + I
N Cl 500
/ 2500
AlCl 3 H
N H
 NBr + Br
2 3
pyridiniumN H Nbromine
Br Br
.. CH I + pyridinium bromine
Br Br N
N N S N2 Cl N -
pyridinium
Cl 2 /32AlCl 3N bromine
I
CHinduced
thermally radical substitution I
S 2 3
- +3 CH
+ CH3 +I CH IN N thermally
SN2 induced
I radical substitution
-
..
- pyridinium methiodide
IN
SN2
Cl2 /2 AlCl3 +
3 Cl
N
.. N
+ CH 3
I N +NI CH3
(crystalline salt)
.. + ClN
pyridinium methiodide
N
.. Cl2 / 2AlCl 3 CH
N N3 CH3
H2/Ptpyridinium methiodide (crystalline salt)
 pyridinium
CH 3 methiodide
(crystalline
pyridinium salt)
piperidine
methiodide
N (crystalline
RT salt)
N
(crystalline salt)
H
 Conversions
• Pyridine to 2- …….pyridine.
• Pyridine to 2-pyridone.
• Pyridine to pyridinium methiodide.
 -
O -
O
OH HNO2 OH

N OH N OH

O-
-
O -O
O -
OH
CN OH
CN

N OH
CN CN
N NN OH N O
H
N Cl -
O N Cl O -O
-O -
NH2 - NH
CN
O OH 2
CN
NNN CN
NHOH
+ - N NH2 CN
2
NaNH2 1. diaz. N
N Cl O-
Chichibabin
2. Sandmayer
EtOHN Cl O -2
- NH
O
EtOH
N N NH2 N Cl NH2CN
Cu2Cl2/HCl/ OEt
NH
OEt NN CN
2
N N N NH2

N Cl O-
EtOH
EtOH NH2

NN OEt
NH
N N OEt NH22

Nu- EtOH
H - H+
+
N +
N Nu N Nu N OEt
CH3 CH3 CH3
 Conversions
• Pyridine to 2- phenylpyridine.
• Pyridine to 4…….pyridine.
• Pyridine to 4-pyridone.
• Pyridine to 2,4-dichloropyridine.
 C6H5Li

SN2Ar + NO2 NO2

N C6 H5
O- PCl3/CHCl3
RCOOOH
HNO3/H2SO4 to remove + POCl3
N + + the oxide N
N N
O O
-
H2/pd

Cl O
NH2 NH2 OH
POCl 3
H2/pd HNO2

N Cl + N
N N N
H
O-
NH2 Cl

1. diaz.

2. Sandmayer
N N
From aniline or quinoline or isoquinoline to pyridine-3-
carboxylic acid

CH2 OH
1. H2SO4
+ CHOH
As2O5
NH2 CH2 OH
FeSO4 N

COOH COOH
KMnO4 Heat

N N COOH N

HOOC
COOH COOH
KMnO4 Heat
N
N N
Conversion and complete

1. NaNH2

N 2. H2O N NH2

KOH

N N OH

EtMgBr
N N
H2O
C2H5
 Synthesis of Pyridazine

Pyridazine is prepared by the action of hydrazine hydrate

on unsaturated1,4-dicarbonyl compound.

R R
R
OH
N
O R NH R N
R O N
HO H
NH2
H2N
 Synthesis of Pyrimidine
X
R R
H2N NH2
O N
Urea or
R O thiourea R N X
H
Malonic acid or ethyl malonate
 Synthesis of pyrazine
R O H N
2 R N R N
- H2O oxidation
+
R O H2N R N R N
 BENZODIAZINES

Synthesis of phthalazine
benzo[d]pyridazine H
C O
H2 N N

+
O H2 N N
o-phthalaldehyde C
H
Synthesis of quinazoline
benzo[d]pyrimidine
From acetyl o-aminoacetophenone
O CH3
C CH3
EtOH N
+ NH3
heat in
NH C CH3 sealed tube N CH3
O 2,4-dimethyl-
Synthesis of quinoxaline quinazoline

From o-phenylenediamine and glyoxal.

NH2 N
O = CH 
O = CH
NH2 N
Nucleophilic substitution

N
N
N
N N N

3,6-positions 2,4,6-positions 2-position

if blocked ; 4,5-positions

Electrophilic substitution

Electrophilic substitution is very difficult and occurs only if we have an activating

group (electron donor group).
*Similarly, Electrophilic and nucleophilic substitutions of all
heterocycles.

Arrange :

* Acidity.
* Basicity.
* The reactivity towards reactions with electrophiles (example) or
nucleophiles (example).
 Order of electronegativity:
O>N>S
(large bonding radius)

Order of aromaticity:
Thiophene > pyrrole > furan

Order of acidity:
Imidazole > pyrazole > pyrrole
(-I,-R) (-I)

Order of basicity:
Imidazole > pyridine > pyrazole
Due to stability of cation formed by protonation.