Five-membered Heterocycles Pyrrole, Furan and Thiophene

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Pyrrole has a relatively high boiling point as compared to furan and ... Paal-Knorr Pyrrole Synthesis. Generally Substituted pyrrole may be synthesized through ...

Five-membered Heterocycles Pyrrole, Furan and Thiophene Assist.Prof.Dr. Mohammed Hassan Lecture 2

General Characteristics  Pyrrole, furan and thiophene are colorless liquids of boiling points 126o, 32o, and 84o respectively.

 Pyrrole has a relatively high boiling point as compared to furan and thiophene, this is due to the presence of intermolecular hydrogen bonding in pyrrole.

Structure and Aromaticity Pyrrole furan and thiophene are aromatic because: 1) they fulfill the criteria for aromaticity, the extent of delocalization of the nonbonding electron pair is decisive for the aromaticity, thus the grading of aromaticity is in the

order of: furan< pyrrole < thiophene< benzene this order is consistent with the order of electronegativity values for oxygen (3.44), nitrogen (3.04) and thiophene (2.56).

2)

They tend to react by electrophilic substitution due appearance of –ve charge on carbon atoms due to delocalization of electron as shown in the following resonance structures

O

O

O

O

O

S

S

S

S

S

N H

N H

N H

N H

N H

Evidences of aromatic character in pyrrole 1) All ring bonds are intermediates between single and double bonds. 2) It tends to react by electrophilic substitution 3) Its exceptional lack of basicity and acidity as a secondary

amine compared to the aliphatic analog (pyrrolidine). This can be explained on the basis of participation of N lone pair in aromatic sextet thus the dipole moment of pyrrole compared with pyrolidine is reverted and thus protonation occurs at carbons not at N

Pyrrole Synthesis Paal-Knorr Pyrrole Synthesis Generally Substituted pyrrole may be synthesized through the cyclization of 1,4-diketones in combination with ammonia (NH3) or amines, The ring-closure is proceeded by dehydration (condensation), which then yields the two double bonds and thus the aromatic π system. The formation of the energetically favored aromatic system is one of the driving forces of the reaction. Paal-Knorr Synthesis

R2

R1 O O

1,4-Dicarbony compound

R2



R1 + RNH2 OH OH R=H or Alkyl or Aryl

R2

+ 2H2O

N R

R1

The Hantzsch pyrrole synthesis Is the chemical reaction of β-ketoesters (1) with ammonia (or primary amines) and α-haloketones (2) to give substituted pyrroles (3). Note: direct reaction of β-ketoesters (1) with αhaloketones (2) gives furan [Fiest-Benary furan synthesis], and this can be a troublesome side reaction.

EtO2C

EtO2C

+ H3C

O

Cl

RNH2 H3C

NH R

EtO2C

+ O

CH3

H3C

N

CH3

R

Note: by this method we can prepare different pyrrole derivatives as:1,2,5 substituted pyrrole or 2,5 substituted pyrrole or 1,2,3,5 substituted pyrrole or 2,3,5 substituted pyrrole

Knorr Synthesis The Knorr pyrrole synthesis is a widely used chemical reaction that synthesizes substituted pyrroles (3) The method involves the reaction of an α-aminoketone (1) and a compound containing a methylene group α- to a carbonyl group (2) The original Knorr synthesis employed two equivalents of ethyl acetoacetate, one of which was converted to ethyl 2oximinoacetoacetate by dissolving it in glacial acetic acid, and slowly adding one equivalent of saturated aqueous sodium nitrite, under external cooling. Zinc dust was then stirred in, reducing the oxime group to the amine. This reduction consumes two equivalents of zinc and four equivalents of acetic acid.

H3C

O

H3C

O

EtO2C

N

NaNO2 AcOH

EtO2C

H3C

Zn AcOH

EtO2C

O NH2

OH

H3C

O

CO2Et

+ EtO2C

NH2

O

CH3

H3C EtO2C

CO2Et

N

CH3

Note: by this method we can prepare different pyrrole derivatives as: 2,4 substituted pyrrole or 2,3,4,5 substituted pyrrole

Pyrrole is obtained by distillation of succinimide over zinc dust O

N H

O

Zn, heat

N H

Succinimide

By heating a mixture of furan, ammonia and steam over alumina catalyst +

O

NH3

steam, Al2O3

N H

By passing a mixture of acetylene and ammonia over red hot tube.