Heterocyclic chemistry - Fused ring systems
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Transcript of Heterocyclic chemistry - Fused ring systems
Heterocyclic ChemistryFused ring systems
Mr. C. Naresh BabuAssistant Professor
Email: [email protected]
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 2
Quinoline – Molecular Formula – C9H7N
• In quinoline all ring atoms (9 carbons and 1 nitrogen) are SP2 hybridized.• Two SP2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The third SP2 orbital on each carbon atom overlaps with an S orbital of hydrogen and forms C-H σ bonds.
Quinoline is a Fused aromatic ring system also known as benzo(b)pyridine.
•The third SP2 orbital of nitrogen is occupied by the nitrogen lone pair of electrons.• Each ring atom possess one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 3
• Overlap of these p – orbitals produces delocalized π – molecular orbital containing 10 electrons.• Quinoline shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).• The nitrogen lone pair is not released into the aromatic system because it is perpendicular to the system.•The nitrogen withdraws electrons by resonance, resulting in an electron-deficient ring system.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 4
Preparations1. Skraup Synthesis: Here a mixture of glycerol (propane- 1,2,3-triol), aniline
(phenylamine), sulfuric acid, nitrobenzene and ferrous [iron(II)] sulfate are heated together.
The reaction is exothermic and tends to become very violent. ferrous [iron(II)] sulfate is added to make the reaction less
violent. Nitrobenzene, or an alternative oxidant (iodine or chloroaniline
are often recommended), is required to convert the product, 1,2- dihydroquinoline into quinoline.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 5
Skraup Synthesis
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 6
2. Friedlander Synthesis: It involves condensation of o-amino benzaldehyde with acetaldehyde in the presence of an alkali.
O
NH2
o-amino benzaldehyde
CH3CHOacetaldehyde N
Quinoline
- 2 H2O
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 7
Basic Character:• Quinoline is slightly weaker base than pyridine. It reacts with acids
to yield salts which are sparingly soluble in water.
NQuinoline
HCl
N
H
ClQuinoline
Hydrogen chloride
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 8
Chemical reactions:1. Electrophilic substitution reactions: Takes at C5 & C8 positions.a) Nitration:
b) Sulphonation
NQuinoline
HNO3
N
H2SO4
N
NO2
NO2
8-nitroquinoline
5-nitroquinoline
NQuinoline
N
H2SO4
N
SO3H
SO3H
quinoline-8-sulfonic acid
quinoline-5-sulfonic acid
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 9
2. Nucleophilic substitution reactions:Reaction with sodamide: Substitution mostly happens at C-2 position, if any substitution present at C-2 position then reaction occur at C-4 position.
3. Reaction with KOH:
4. Reaction with n-butyl lithium
NQuinoline
N
NaNH2
Liq. NH3NH2
quinolin-2-amine
NQuinoline
N OH
KOH
quinolin-2-ol
NQuinoline
N CH2
C4H9Li
quinolin-2-ol
H2C
CH2
CH3- LiH
10
5. Reaction with per acetic acid:
6. Reaction with KMnO4:
7. Reduction:
NQuinoline
N
CH3
O
OHO
peracetic acid
O
Quinoline-N-oxide
NQuinoline
N
KMnO4
HOOC
HOOCpyridine-2,3-dicarboxylic acid
Quinolinic acid
NQuinoline
NH
NH
1,2,3,4-tetrahydroquinoline
decahydroquinoline
Sn / HCl
H2 / Pt
1400C
11
8. Reaction with alkyl halides:
NQuinoline
N
CH3I
CH3
I
N-methyl quinolium iodide
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 12
Isoquinoline – Molecular Formula – C9H7N
• In isoquinoline all ring atoms (9 carbons and 1 nitrogen) are SP2 hybridized.• Two SP2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The third SP2 orbital on each carbon atom overlaps with an S orbital of hydrogen and forms C-H σ bonds.
Isoquinoline is a Fused aromatic ring system also known as benzo(c)pyridine.
•The third SP2 orbital of nitrogen is occupied by the nitrogen lone pair of electrons.• Each ring atom possess one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 13
• Overlap of these p – orbitals produces delocalized π – molecular orbital containing 10 electrons.• Isoquinoline shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).• The nitrogen lone pair is not released into the aromatic system because it is perpendicular to the system.•The nitrogen withdraws electrons by resonance, resulting in an electron-deficient ring system.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 14
Preparations1. Bischler-Napieralski Synthesis: This method is very useful for the construction of 1-substituted
3,4- dihydroisoquinolines, which if necessary can be oxidized to isoquinolines.
β-phenylethylamine is reacted with an acyl chloride and a base to give the corresponding amide (R1 = H) and then this is cyclized to a 3,4-dihydroisoquinoline by treatment with either phosphorus pentoxide or phosphorus oxychloride. Finally, aromatization is accomplished by heating the 3,4-dihydroisoquinoline over palladium on charcoal.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 15
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 16
2. Pictet-Spengler Synthesis:β-phenylethylamine react with an aldehyde, the reaction intermediate is an imine which, provided the benzene ring contains electron donating groups, often ring closes under very mild acidic conditions. Indeed, cyclization can occur under physiological conditions, and in Nature this is an important step in the biosynthesis of many tetrahydroisoquinoline alkaloids. This tetrahydroisoquinoline can be dehydrogenated by palladium to form 1-substituted isoquinoline.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 17
NH2
2-phenylethanamine
RCHON
C
RH
H+
N
3,4-dihydro-1-substitutedisoquinoline
N
Pd
1-substituted isoquinolineRR
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 18
Basic Character:• Isoquinoline is slightly weaker base, It reacts with acids to yield
salts which are sparingly soluble in water.
NHCl
NH
Cl
isoquinoline Isoquinoline Hydro chloride
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 19
Chemical reactions:1. Electrophilic substitution reactions: It takes place at the
position 5.a) Nitration:
b) Sulphonation
N
HNO3N
NO2
isoquinoline 5-nitroisoquinoline
N N
H2SO4
SO3H
isoquinoline isoquinoline-5-sulfonic acid
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 20
c. Bromination:
2. Reduction:
N N
Br
isoquinoline
Br2
5-bromoisoquinoline
N
isoquinoline
Na-HgSncl2
Pt
H2H2
H2
NH NH
NH
1,2-dihydroisoquinoline 1,2,3,4-tetrahydroisoquinoline
decahydroisoquinoline
21
3. Oxidation / Reaction with KMnO4:
4. Reaction with alkyl halide:
5. Reaction with sodamide:
NN
KMnO4
(O)
COOH
COOH
pyridine-3,4-dicarboxylic acidisoquinoline
COOH
COOHphthalic acid
N N
CH3I
CH3
Cl
isoquinoline Isoquinalonium methyl iodide
N N
NaNH2
isoquinolineNH2
isoquinolin-1-amine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 22
Indole – Molecular Formula – C8H7N
• In indole all ring atoms (8 carbons and 1 nitrogen) are SP2 hybridized.• Two SP2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The third SP2 orbital on each ring atom overlaps with an S orbital of hydrogen and forms C-H and N-H σ bonds.
Indole is a Fused aromatic ring system also known as benzo(b)pyrrole.
•The un hybridized p – orbital of nitrogen is occupied by the nitrogen lone pair of electrons.• Each carbon atom in ring possess one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 23
• Overlap of these p – orbitals produces delocalized π – molecular orbital containing 10 electrons. (8 electrons from 8 carbons and lone pair of electrons from nitrogen)• Indole shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).• The nitrogen lone pair is released into the aromatic system.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 24
Preparations1. Lipp Synthesis: In this method o-amino chlorostyrene is heated with sodium
ethoxide at 160-1700C.
NH2
o-amino chloro styrene
HC
CH
Cl
NaOC2H5
NH
Indole
C2H5OH Nacl
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 25
NH
NH2Phenyl hydrazine
O
H3C O
OHPyruvic acid
NH
-H2ON
H3C COOH
ZnCl2
-NH3
NH
COOHDecarboxylation
NH
1H-indole
-CO2
2. Fisher indole synthesis: Pyruvic acid is first treated wit phenyl hydrazine to form the corresponding phenyl
hydrazine. Then the hydrazine is heated with anhydrous zinc chloride or poly phosphoric acid
to give indole-2-carboxylic acid, which upon decarboxylation yields indole.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 26
3. Madelung synthesis: O-toluidine is react with formic acid to form N-formyl o-toluidine. This undergoes
dehydration on heating with sodium ethoxide or potassium t-butoxide to tield indole.
CH3
NH2
o-toluidine
O
HO
H
formic acid
- H2OCH3
NH
H
O
C2H5ONaC4H9O-K+
- H2O
NH
1H-indole
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 27
4. From o-nitro phenyl acetaldehyde: This involves reduction of o-nitro phenyl acetaldehyde with iron powder and
sodium bisulphite to give o-amino phenyl acetaldehyde, which cyclizes spontaneously to yield indole.
o-nitro phenyl acetaldehyde
Na+
O-
S
O
HO
Sodium bisulphite
O
NH2
o-amino phenylacetaldehyde
O
NO2
- H2O
NH
1H-indole
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 28
Basic Character & Acidic character:• Indole is a weak base and also a weak acid as like pyrrole.• Indole is a weak base since the lone pair of electrons of nitrogen
atom contributes to the 4n+2 π electron cloud (aromatic sextet). Thus, the availability of these lone pair of electrons is decreased.
• Indole also exhibit weak acidic properties, the weak acidic property is because of its formation of potassium indole with KOH.
NH
1H-indole
KOH
N
K
- H2O
Potassium indole
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 29
Chemical reactions:Electrophilic Substitution reactions (C-3 versus C-2): Electrophiles attack indole at C-3, rather than at C-2. This is the opposite result to that observed for pyrroles, but can be explained if the
intermediates for each type of reaction are considered. For a reaction at C-3, the energy of activation of the intermediate is lowered
because it is possible to delocalize the positive charge through resonance involving the nitrogen lone pair of electrons.
This favourable situation is not possible in the corresponding intermediate for attack at C-2. Any attempt to delocalize the positive charge would now disrupt the 6π electrons system of the benzene ring.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 30
a) Nitration:
b) Sulphonation
c) Halogenation
NH
1H-indole
C2H5NO2
Ethyl nitrate
C2H5ONa
5o CNH
NO2
3-nitro-1H-indole
NH
1H-indole
SO3
Pyridine
110o CNH
SO3H
1H-indole-3-sulfonic acid
NH
1H-indole
SO2Cl2
Br - CH3OHNH
X
3-halo 1H-indole
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 31
d) Friedal-craft acylation
e) Formylation
f) Vilsmeyer reaction
NH
1H-indole
CH3COCl
Acetyl chloride
SnCl4
NH
COCH3
3-acetyl indole
NH
1H-indole
HCN - HCl
NH
CHO
3-formyl-1H-indole
NH
1H-indoleNH
CHO
3-formyl-1H-indole
N O
N-formyl dimethyl amine
POCl3
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 32
g) Reimer – tiemann reaction:
h) Alkylation
i) Mannich reaction:
NH
1H-indole
CHCl3
Chloroform
NaOH
NH
CHO
3-formyl indole
NH
1H-indole
DMF
NH
CH3
CH3I
3-methyl-1H-indole
NH
1H-indole
NH
CH2-N(CH3)2
HCHO
HN
CH3H3C
Dimethyl amine
- H2O
3-Dimethyl amino methyl-1H-indole
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 33
j) Reduction: Mild reduction by Zn & HCl.
But catalyst Ni / Pt reduces both rings and forms octa hydro indole.
k) Diazo coupling:
NH
1H-indole
NH
indoline or 2,3-dihydro-1H-indole
Zn / HCl
NH
1H-indole
NH
Ni / Pt
octahydro-1H-indole
NH
1H-indole
N+N
Cl-
Benzene diazonium chloride NH
NN
1-(1H-indol-3-yl)-2-phenyldiazene
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 34
Acridine – Molecular Formula – C13H9N
• In acridine all ring atoms (13 carbons and 1 nitrogen) are SP2 hybridized.• Two SP2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. The third SP2 orbital on each carbon atom overlaps with an S orbital of hydrogen and forms C-H σ bonds.
Acridine is a Fused aromatic ring system also known as Dibenzo[b,e]pyridine / 2,3-Benzoquinoline
•The third SP2 orbital of nitrogen is occupied by the lone pair of electron of nitrogen.• Each ring atom in ring possess one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 35
• Overlap of these p – orbitals produces delocalized π – molecular orbital containing 14 electrons. • Acridine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).• The nitrogen lone pair is not released into the aromatic system.• It is a planar molecule that is structurally related to anthracene with one of the central CH group is replaced by nitrogen.
36
Preparations1. From diphenyl amine-2-carboxylic acid:
O
HO
Cl
o-chloro benzoic acid
H2N
Aniline
Base
NH
COOH
Diphenylamine-2-carboxylic acid
H2SO4POCl3
NH
O
NH
Cl
9-chloro-9,10-dihydroacridine
acridin-9(10H)-one
Na / Amylalcohol
H2 / Ni
NH
9,10-dihydroacridine
Oxidation
NAcridine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 37
2. From o-amino diphenyl methane:Acridine is also prepared by passing o-amino diphenyl methane through a red hot tube.
Basic character:Acridine is a weak base but it forms soluble salts with mineral acids.
NH2
o-amino diphenyl methane
Red hot tube
NAcridine
NAcridine
HCl
N
H
Cl
Acridine hydrochloride
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 38
Chemical reactions:1. Electrophilic substitution reactions:Halogenation:
2. Reaction with nucleophilic reagents Acridine easily reacted with nucleophilic reagents. Nucleophilic attack takes place at 9-position, because the electron
density is decreased at this position when compare to 1,2,3 and 4th positions.
NAcridine
Br2
CH3COOHN
N
Br
BrBr
2,7-dibromoacridine
2-bromoacridine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 39
So, Acridine easily reacted with sodamide in liq. Ammonia, it gives 9-amino acridine.
3. Reaction with oxidizing agents:
NAcridine
NaNH2
Liq. NH3
N
NH2
9-Amino acridine
NAcridine
KMnO4
N
N
COOH
COOHquinoline-2,3-dicarboxylic acid
CH3
O
OHO
Peracetic acid
O Acridine-N-oxide
Acridine is very stable ring system towards oxidizing agents. But in the presence of per acids acridine easily converted to N-oxide.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 40
4. Reaction with reducing agents:
5. Reaction with alkyl halides: Acridine readily reacts with alkyl halides for example with methyl iodide it gives N-methyl acridinium iodide.
NAcridine
H2 / Ni
NH
9,10-dihydroacridine
NAcridine
CH3I
N
H3C
I
10-methyl Acridinium iodide
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 41
Benzimidazole – Molecular Formula – C7H6N2
• In Benzimidazole all ring atoms (7 carbons and 2 nitrogens) are SP2 hybridized.• Two SP2 orbitals on each atom overlap with each other to form the C-C and C-N σ bonds. •The third SP2 orbital on each carbon atom and one nitrogen atom overlaps with an S orbital of hydrogen and forms C-H and N-H σ bonds.
Benzimidazole is a Fused aromatic ring system fusion of benzene and imidazole.
•The third SP2 orbital of second nitrogen is occupied by the lone pair of electrons.• Each carbon atom in ring possess one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.
Benzo(d)imidazole
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 42
• One of the nitrogen in benzimidazole having lone pair of electrons are released into the aromatic system.• Overlap of these p – orbitals, lone pair of electrons from one nitrogen produces delocalized π – molecular orbital containing 10 electrons. • Benzimidazole shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).• benzimidazoles display annular tautomerism in solution, e.g.
43
Preparations1. From o-phenylenediamine / Phillips reaction:It is the most important method of preparing benzimidazole by refluxing o-phenylenediamine with a carboxylic acidnin 4N HCl.
NH2
NH2
o-phenylene diamine
OH
O
R
4N HCl, Reflux
N
NH
2-Substituted Benzimidazole
R
- 2 H2O
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 44
Basic Character & Acidic character:• Benzimidazole is a weak base and also a weak acid.• Benzimidazole is a weak base because due to the presence of
lone pair of electrons on one of the nitrogen atom.• Benzimidazole also exhibit weak acidic properties, the weak acidic
property is because of its formation of potassium phenothiazine with KOH.
N
NH
Benzimidazole
HClN
NH
H
Cl
Benzimidazole hydrochloride
N
NH
KOH
- H2O
N
N
K1H-benzo[d]imidazole
N-potassium benzimidazole
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 45
Chemical reactions:Electrophilic Substitution reactions: Electrophiles attack in benzimidazole take place preferentially at the 5- or 6-
position. However, the electrophile may also enter the 4- or 7-position if the 5- or 6-position is blocked.
Nitration:
Sulphonation:
N
NH
Benzimidazole
HNO3N
NH
O2N
5-nitro-1H-benzo[d]imidazole
N
NH
Benzimidazole
H2SO4N
NH
HO3S
1H-benzo[d]imidazole-5-sulfonic acid
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 46
By treatment with acid anhydrides: 1-benzimidazoylmagnesium bromide when treated with benzoyl chloride in ether solution gives mostly N,N’- dibenzoylbenzimidazole and the rupture of the imidazole ring has been postulated by hydrolysis.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 47
Halogenation: When 2,5 (or 2,6)-dimethylbenzimidazole in an aqueous acid solution is treated with a saturated solution of bleaching powder at 0 to 5°C, 1-chloro-2,5(or 2,6)-dimethylbenzimidazole is obtained.
Nucleophilic substitution reaction:Reaction with sodamide:
N
NH
Benzimidazole
NaNH2
N
NH
NH2
1H-benzo[d]imidazol-2-amine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 48
Reduction: Mild reduction by Zn & HCl.
But catalyst Ni / Pt reduces both rings and forms octa hydro indole.
NH
N
NH
HN
Zn / HCl
1H-benzo[d]imidazole 2,3-dihydro-1H-benzo[d]imidazole
NH
N
NH
HN
Ni / Pt
1H-benzo[d]imidazole octahydro-1H-benzo[d]imidazole
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 49
Phenothiazine – Molecular Formula – C12H9NS
• In phenothiazine all ring atoms (12 carbons and 1 nitrogen and 1 sulphur) are SP2 hybridized.• Two SP2 orbitals on each atom overlap with each other to form the C-C and C-N and C-S σ bonds. •The third SP2 orbital on each carbon atom and nitrogen atom overlaps with an S orbital of hydrogen and forms C-H and N-H σ bonds.
Phenothiazine is a Fused aromatic ring system also known as Dibenzothiazine
•The third SP2 orbital of sulphur is occupied by the lone pair of electrons.• Each carbon atom in ring possess one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 50
• Overlap of these p – orbitals, lone pair of electrons from Sulphur and nitrogen produces delocalized π – molecular orbital containing 14 electrons. • Phenothiazine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).• The nitrogen and Sulphur lone pair are released into the aromatic system.
51
Preparations1. From diphenyl amine:It is prepared by fusing diphenyl amine with Sulphur.
2. From o-amino thiophenol:It is prepared by heating o-amino thiophenol with catechol.
NH
Diphenyl amine
2 S- H2S
S
NH
Phenothiazine
NH2
SH
o-amino thiophenol
HO
HO
Catechol
- 2H2O
S
NH
Phenothiazine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 52
Basic Character & Acidic character: Phenothiazine is a weak base and also a weak acid.• Phenothiazine is a weak base since the lone pair of electrons of
nitrogen atom contributes to the 4n+2 π electron cloud. Thus, the availability of these lone pair of electrons is decreased.
• Indole also exhibit weak acidic properties, the weak acidic property is because of its formation of potassium phenothiazine with KOH.
S
NH
Phenothiazine
KOH
- H2O
S
N
KPotassium phenothiazine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 53
1. Electrophilic substitution reactions:Mostly the electrophilic substitution reactions happens at 2, 3, 7 and 8 th positions.
S
HN
Phenothiazine
NitrationSulphonation
Halogenation
S
HN
S
HN
S
HN
NO2O2N HO3S SO3H
ClCl
Cl Cl
2,8-dinitro-10H-phenothiazine 10H-phenothiazine-2,8-disulfonic acid
2,3,7,8-tetrachloro-10H-phenothiazine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 54
2. Reaction of phenothiazine and n-butyl lithium followed by the addition of solid carbon dioxide to the mixture and gives 1-carboxy phenothiazine.
3. Nucleophilic substitution reactions:Mostly happens at 1 or 9th positions.Reaction with sodamide:
S
HN
Phenothiazine
NaNH2
S
HN
NH2
10H-phenothiazin-1-amine