Heterocyclic ChemistrySix membered ring systems
NPyridine
N
NPyrazine
N
N
Pyrimidine
NN
Pyridazine1,4-Diazine 1,3-Diazine 1,2-Diazine
Mr. C. Naresh BabuAssistant Professor
Email: [email protected]
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 2
Pyridine – Molecular Formula – C5H5N
In pyridine all ring atoms (5 carbons and 1 nitrogen) are SP2 hybridized.
Pyridine is a six membered aromatic with one hetero atom, Nitrogen.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 3
• 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.
• The third SP2 orbital of nitrogen is occupied by the nitrogen lone pair of electrons.
• All σ bonds in pyridine lie in one plane and all bond angles are approximately equal to 1200.
• Each ring atom possesses one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.
• Overlap of these p – orbitals produces delocalized π – molecular orbital containing 6 electrons.
Structure & Aromaticity
NPyridine
H
H
H
H
H
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 4
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 5
• Pyridine 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 6
Preparations1. By passing a mixture of acetylene and hydrogen cyanide
through a red hot tube.
2. By dehydrogenation of Piperidine with concentrated H2SO4 at 3000C or with nitrobenzene at 2600C.
NH
Piperidine
Conc. H2SO4 at 3000C
NPyridine
3H2
HC
CH
Acetylene & Hydrogen cyanide
CH
HC
N CH
NPyridine
H
H
HH
H
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 7
3. By heating pyrrole with dichloro methane in the presence of sodium ethoxide.
NH
Pyrrole
H2C
ClClDichloro methane
Na+H2C
CH3-O
Sodium ethoxide
Heat
NPyridine
2 NaCl 2 C2H5OH
4. By heating tetrahydro furfuryl alcohol with ammonia in the presence of aluminium oxide at 5000C.
ON
Pyridine
2 H2O 2 H2OH
(tetrahydrofuran-2-yl)methanol
NH3
Ammonia
Al2O3
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 8
Basic Character:• Pyridine behaves as a base, it reacts with acid to form stable salts.
• Basic character of pyridine is due to the lone pair of electrons in SP2 orbital (Not involved in delocalized π – molecular orbital).
• So lone pair of electrons readily makes a bond with a proton and forms N-H bond.
• Pyridine is more basic than pyrrole because in pyrrole lone pair of electrons involved in delocalized π – molecular orbital and forms a part of aromatic sextet.
NPyridine
HCl
N
H Cl
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 9
Pyridine is less basic than aliphatic amines:
• In both Pyridine & aliphatic amines the lone pair of electrons on N are available for reaction.
• In case of aliphatic amines, the nitrogen is SP3 hybridized where as in pyridine, nitrogen is SP2 hybridized.
• The SP2 hybridized nitrogen is more electronegative than SP3 hybridized nitrogen. The lone pair of electrons held more towards electronegative SP2 hybridized nitrogen and is relatively less available for reaction.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 10
Characteristic reactionsElectrophilic aromatic substitution at C-3 or C-5:
6-position
5-position
In pyridine Electrophilic substitution reactions takes place extremely at vigorous conditions in C-3 or C-5 positions. At this points more stable 3 resonance structures were possible. At C-2, 4 & 6th positions give only 2 stable resonance structures.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 11
• Pyridine is less reactive than benzene towards electrophilic substitution. Pyridine contains nitrogen atom it is more electronegative, so it lowers the electron density around the ring carbons.
• The usual electrophiles can co-ordinate with the lone pair of electrons on nitrogen to form resonance stabilized pyridinium salts.
>
NPyridineBenzene
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 12
The pyridine nitrogen is a meta director:
HgSO4
N
BrBr
3,5-Dibromo pyridine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 13
• Aluminium chloride and other lewis acid catalysts co-ordinate with the pair of electrons of nitrogen, friedel – craft reaction i.e., alkylation and acylation fails with the pyridine.
NPyridine
Al
Cl
Cl Cl
N
Al
Cl
Cl Cl
Aluminium Chloride
Pyridine Aluminium chloride
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 14
Pyridine is reactive toward nucleophilic aromatic substitution because of the presence of the electronegative nitrogen:
Nucleophilic substitution Reactions:
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 15
Pyridine undergoes nucleophilic aromatic substitution atC-2, C-4 and C-6:
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 16
If the leaving groups at C-2 and C-4 are different, the incoming nucleophile will preferentially substitute for the weaker base:
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 17
Reaction with sodamide (Chichibabin reaction):Pyridine reacts with sodamide at C-2 and gives 2-amino pyridine and sodium hydride. Sodium hydride formed is removed by reaction with liq. Ammonia to give back sodamide.
NPyridine
N
NaNH2
Liq. NH3
1000CNH2
NaH
2 - Amino pyridine
NaH + NH3 NaNH2 + H2
Reaction with sodium hydroxidePyridine reacts with sodium hydroxide at C-2 and gives 2-hydroxy pyridine and upon keto-enol tautomerism it forms keto form of 2-pyridone.
NPyridine
N
NaOH3000C
OH2 - Hydroxy pyridine
NH
O
pyridin-2(1H)-one
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 18
Reaction with n-butyl lithium:Pyridine reacts with n-butyl lithium at C-2 and gives 2-(n-butyl) pyridine.
OxidationLike benzene pyridine is stable towards mild oxidizing agents. It does not react with chromic acid and nitric acid. However it may be oxidized by peracetic acid to give pyridine-N-oxide. 2-alkyl pyridine easily oxidized.
NPyridine
N
Lin-butyl lithium
2-butylpyridine
-LiH
N2-Methyl pyridine
N
[O]
Pyridine-2-carboxylic acidCH3COOH
NPyridine
N
[O]
O
Pyridine-N-oxide
CH3
O
OHO
Peracetic acid
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 19
ReductionPyridine undergoes reduction with lithium aluminium hydroxide or hydrogen in the presence of nickel catalyst to form piperidine.
Reaction with alkyl halidesPyridine reacts with alkyl halides to form N-alkyl pyridinium halide. Pyridine with methyl bromide yields crystalline N-methyl pyridinium bromide.
NPyridine
3 H2Ni
2000CNH
NPyridine
CH3-Br
N
CH3
Br
N-methyl pyridinium bromide
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 20
Diazotization of Aminopyridine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 21
• Pyrazine all ring atoms (4 carbons & 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 overlaps with an S orbital of hydrogen and forms C-H σ bonds.
• The third SP2 orbital of two nitrogens is occupied by the nitrogen lone pair of electrons.
• All σ bonds in pyridine lie in one plane and all bond angles are approximately equal to 1200.
Pyrazine - Structure & Aromaticity - Molecular Formula – C4H4N2
Pyrazine is a six membered aromatic ring system with two hetero atoms of Nitrogen at 1st and 4th positions.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 22
•Each ring atom possesses one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.• Overlap of these p – orbitals produces delocalized π – molecular orbital containing 6 electrons.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 23
• Pyrazine 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.
N
N
N1
N
N
N
N
N
N
N
N
N4
N
N
N
N
N
N
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 24
Preparations1. From amino carbonyl compounds: Condensation of two
molecules of α-amino carbonyl compounds followed by oxidation.
CH
CR O
NH2R
C
CHH2N R
RO2 H2O
BaseN
N
R
R R
R
N
N
R
R R
R
OxidationHgCl2
Pyrazine derivative
alpha-amino carbonyl compounds
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 25
2. From diamines: Pyrazine prepared by condensation of ethylene diamine and ethylene oxide followed by dehydrogenation.
H2C
H2C
NH2
NH2
ethane-1,2-diamineH2C CH2
O
oxiraneEthylene oxide
NH2
HN
OH
Al2O3/Ni
NH
N
Dehydrogenation
N
N
Pyrazine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 26
Basic Character:• Pyrazine is a weak mono basic compound, since the available
electrons of one nitrogen atom are shared with the other nitrogen atom. It gets protonated at N, Diprotonation is possible only in presence of strong acid.
• Basic character of pyrazine is due to the lone pair of electrons in SP2 orbital (Not involved in delocalized π – molecular orbital).
• So lone pair of electrons readily makes a bond with a proton and forms N-H bond.
N
NPyrazine
N
N
N
N
H+ H+
H H
H
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 27
Characteristic reactions1. Electrophilic substitution reactions:• Pyrazine is less reactive with electrophiles because of presence of two nitrogens,
these atoms deactivate the ring.• However presence of electron donating group at C-2 position, electrophilic
substitution is possible.N
N CH3
Cl2CCl4
N
N CH3
Cl
2-chloro-3-methylpyrazine2-methylpyrazine
2. Reaction of pyrazine with nucleophiles:• Pyrazine undergoes reaction with nucleophilic reagent.
N
N
Liq. NH3
N
N NH2
NaNH2
pyrazine pyrazin-2-amine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 28
3. Reaction with oxidizing agents:• Pyrazine is stable towards oxidizing agents, but presence of alkyl group at C-2
position it gets oxidized to carboxyl group.
4. Reduction:• In the presence of Na/C2H5OH, pyrazine can be used to hexahydro pyrazine
N
N CH3
N
N COOH
2-methylpyrazine
Oxidation
pyrazine-2-carboxylic acid
N
N
HN
NH
Reduction
Pyrazine
Na / C2H5OH
Piperazine(Hexa hydro pyrazine)
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 29
5. Isomerization of Pyrazine:• Pyrazine under photolytic conditions it gets isomerized to other diazine.
N
N
CH3H3C
2,6-dimethylpyrazine
Isomerization N
N
H3C
CH3
2,5-dimethylpyrimidine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 30
• Pyrimidine all ring atoms (4 carbons & 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 overlaps with an S orbital of hydrogen and forms 4 C-H σ bonds.
• The third SP2 orbital of two nitrogens is occupied by the nitrogen lone pair of electrons.
• All σ bonds in pyridine lie in one plane and all bond angles are approximately equal to 1200.
Pyrimidine - Structure & Aromaticity - Molecular Formula – C4H4N2
Pyrimidine is a six membered aromatic ring system with two hetero atoms of Nitrogen at 1st and 3rd positions.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 31
•Each ring atom possesses one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.• Overlap of these p – orbitals produces delocalized π – molecular orbital containing 6 electrons.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 32
• Pyrimidine 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 33
Preparations1. From alkyl pyrimidines: Alkyl pyrimidines on oxidation followed
by decarboxylation gives pyrimidine.
N
N
CH3
4-methylpyrimidineN
N
COOH
N
N
pyrimidinepyrimidine-4-carboxylic acid
Oxidation Decarboxylation
2. From chloro pyrimidines: Catalytic reductive dechlorination of 2,4-dichloro pyrimidine gives pyrimidine.
N
N
N
N
pyrimidine
Cl
Cl
H2
Pd
4,6-dichloropyrimidine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 34
3. From barbituric acid: Pyrimidine is synthesized from barbituric acid by the following steps.
NH
ONH
O
O
Barbituric acid
N
OHNHO
OH
POCl3
pyrimidine-2,4,6-triol
N
ClNCl
Cl
2,4,6-trichloropyrimidine
Zn dustHot water
N
N
Pyrimidine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 35
Basic Character:• Pyrimidine is a weaker base than pyridine, because of electron
withdrawing effect of the second nitrogen atom present in pyrimidine.
• Pyrimidine gets protonated in acidic medium.• Presence of electron donating groups like alkyl, alkoxy enhance
the basicity.• Under normal conditions only one nitrogen of pyrimidine is
protonated. But under strong acidic conditions both nitrogens are protonated to form deprotonated pyrimidine.
N
N
N
N
N
N
H+ H+
HH
H
Strong acidic conditions
pyrimidine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 36
Characteristic reactions1. Electrophilic substitution reactions:
• Pyrimidine is less reactive than pyridine due to two electron withdrawing groups towards electrophilic substitution.
• However presence of electron donating groups on ring, electrophilic substitution is possible at 5th position (the least electron-deficient).
• Nitration, Sulphonation, Bromination, Formylation and azo coupling have been observed with substituted pyrimidines.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 37
N
N
CH3
2-methylpyrimidine
N
N
CH3 N
N
CH3
N
N
CH3
N
N
CH3
N
N
CH3
Nitration
Sulphonation
Bromination
FormylationHCN - HCl
Azo coupling
O2N HO3S
Br
OHC
N
Benzene diazoniumchloride
N Br2, Nitrobenzene
2-methyl-5-nitropyrimidine 2-methylpyrimidine-5-sulfonic acid
5-bromo-2-methylpyrimidine
2-methylpyrimidine-5-carbaldehyde
1-(2-methylpyrimidin-5-yl)-2-phenyldiazene
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 38
2. Nucleophilic Substitution reactions:• Pyrimidine easily undergoes nucleophilic substitution.• Nucleophilic attack takes place at 2,4 or 6th positions.• The amino group at C-2 or C-4 positions may conveniently replaced by hydroxyl
group on heating with water.
N
NH2N
4-Amino Pyrimidine
H2O
N
NHO
4-Hydroxy Pyrimidine
3. Nucleophilic Addition reactions:• Pyrimidine undergo reaction with nucleophiles to form nucleophilic addition
products.
N
NAq. NaOH
HN
NHO
pyrimidine 3,4-dihydropyrimidin-4-ol
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 39
4. Reaction with oxidizing agents:• Pyrimidine is oxidized slowly while alkyl substituted pyrimidines are oxidized
readily to N-oxide with peroxy acids.
N
NCH3COOOH
H3C N
N
H3C O
4-methylpyrimidine 4-Methyl pyrimidine- N-oxide
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 40
• Pyridazine all ring atoms (4 carbons & 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 overlaps with an S orbital of hydrogen and forms 4 C-H σ bonds.
• The third SP2 orbital of two nitrogens is occupied by the nitrogen lone pair of electrons.
• All σ bonds in pyridine lie in one plane and all bond angles are approximately equal to 1200.
Pyridazine - Structure & Aromaticity - Molecular Formula – C4H4N2
Pyridazine is a six membered aromatic ring system with two hetero atoms of Nitrogen at 1st and 2nd positions.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 41
•Each ring atom possesses one un hybridized p – orbital containing one electron and those are perpendicular to the plane containing the σ bonds.• Overlap of these p – orbitals produces delocalized π – molecular orbital containing 6 electrons.
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 42
• Pyridazine 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.
NN
N1
NN
NN
NN
N2
NN
NN
NN
NN
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 43
Preparations1. From 1,4-diketones: Pyridazines are prepared by reacting
hydrazine hydrate with unsaturated 1,4-diketones.
2. From maleic dialdehyde: Pyridazines are also prepared by reacting hydrazine hydrate with maleic dialdehyde.
RC
O
CH
HC
C
O
RNH2-NH2
NNR
R
OHC
HC CH
CHO
NH2-NH2N
N
H2O
pyridazinemalealdehyde
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 44
Basic Character:• Pyridazine is a weak base it reacts with strong acids to yield salts.
The second nitrogen can not be protonated because it needs high energy to develop positive charge on the adjacent nitrogen atoms.
NN
H+
NN
Hpyridazine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 45
Characteristic reactions1. Electrophilic substitution reactions:
• Pyridazine undergoes electrophilic substitution reactions only under drastic conditions because of electron withdrawing nature of nitrogen atoms.
• Hence, when activating groups are present in pyridazine ring then electrophilic substitution reactions are possible
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 46
2. Reaction with Nucleophilic reagents:• The two nitrogen atoms present in pyridazine make all other carbon atoms (3,4,5
and 6) electron deficient.• So, pyridazine is easily reacts with nucleophilic reagents.
3. Reduction:• Pyridazine upon reduction it gives hexahydro pyridazine
NN
ClCl
3,6-dichloro pyridazineH2N OH
3-Amino phenol
C6H5NO2
AlCl3N
NCl
HN
HO6-Chloro-3-(p-hydroxy anlino)pyridazine
NN
Pyridazine
Reduction
NHNH
Hexahydro pyridazine
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 47
4. Reaction with oxidizing agents:• Pyridazine has been resistant towards oxidizing agents because of electron
deficiency in the ring system.• However peroxy benzoic acid is able to convert pyridazine to pyridazine oxide.
NN
Pyridazine
NN
C6H5COOOH
O5. Hofmann’s reaction:• Pyridazine undergoes reaction with one mole of methyl iodide to yield quarternary
ammonium halide.
NN
Pyridazine
NN
CH3I
CH3
I
Pyridazine quarternary ammonium iodide
Mr. C. Naresh Babu, Asst. Professor, RIPER, ATP 48
6. Rearrangement:• Substituted Pyridazine under UV irradiation rearrangement takes place.
NN
N
N
UV irradiation
R
R1 R
R1