Heterocyclic chemistry-six membered ring systems

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.


• 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



• 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.


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


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


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


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.


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.


• 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


The pyridine nitrogen is a meta director:

HgSO4

N

BrBr

3,5-Dibromo pyridine


• 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


Pyridine is reactive toward nucleophilic aromatic substitution because of the presence of the electronegative nitrogen:

Nucleophilic substitution Reactions:


Pyridine undergoes nucleophilic aromatic substitution atC-2, C-4 and C-6:


If the leaving groups at C-2 and C-4 are different, the incoming nucleophile will preferentially substitute for the weaker base:


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


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


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


Diazotization of Aminopyridine


• 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.


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.


•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.


• Pyrazine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).



N

N

N1

N

N

N

N

N

N

N

N

N4

N

N

N

N

N

N


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


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


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


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


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)


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


• 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.



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.




• Pyrimidine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).




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


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


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


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.


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


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


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


• 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.



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.




• Pyridazine shows aromatic properties because the resulting molecular orbital satisfies the Huckle’s rule (4n+2 rule).



NN

N1

NN

NN

NN

N2

NN

NN

NN

NN


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


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


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


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


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


6. Rearrangement:• Substituted Pyridazine under UV irradiation rearrangement takes place.

NN

N

N

UV irradiation

R

R1 R

R1

Education

Heterocyclic chemistry-six membered ring systems