Heterocyclic Rings

Pyrrole

Importance of Pyrroles

Porphyrin

Haem (iron (II) complex)

Chlorophyll

Bilrubin: (formerly referred to as haematoidin) is the yellow breakdown product of normal heme catabolism, caused by the body's clearance of aged

red blood cells which contain hemoglobin.

Vitamin B12, vitamin B12 or vitamin B-12, also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood.

4: insect pheromone5: amino acid proline6: nicotine

Synthesis of pyrrole, Knorr Synthesis

L. Knorr, Ber. 17, 1635 (1884); Ann. 236, 290 (1886); L. Knorr, H. Lange, Ber. 35, 2998 (1902).

The original Knorr synthesis employed two equivalents of ethyl acetoacetate, one of which was converted to ethyl 2-oximinoacetoacetate 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.

CH3 O

EtO2C

CH3 O

NEtO2C

OH

CH3 O

NH2EtO2CAcOH

CH3 O

NH2EtO2C CH3O

CO2Et

N

CH3

CH3

CO2Et

EtO2C

NaNO2 Zn

AcOH

+

Nitrosation of aliphatic carbon atoms

The nitrosation reaction consists in the replacement of a hydrogen atom by the nitroso group with the formation of a nitroso or oximo derivative. With a few exceptions, the replacement of hydrogen on an aliphatic carbon atom requires the presence of an electron-attracting groups adjacent to the carbon to be nitrosated. Acyl, aroyl, carbonyl, carboxy, carbalkoxyl, nitrogen, cyano, imino, and aryl groups may serve as activators. Monoketones are readily converted into alpha-oximino ketones, whereas monoesters containing no other activating groups do not undergo the reaction. Victor Meyer discovered the reaction in 1873–1874.

ON

O OHN

O ON

O

H

H

N O

CH3 O

EtO2C

CH3 OH

EtO2C

CH3 O

EtO2C NO

CH3 O

EtO2C NOH

Na+ - HOAc H+ +

- H2O

+

+ OAc-

+ HOAc

+ NaOAc

OAc-

Paal-Knorr Pyrrole Synthesis

The Hantzsch pyrrole synthesis• The Hantzsch pyrrole synthesis, named for

Arthur Rudolf Hantzsch, 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 α-haloketones (2) gives furan [Fiest-Benary furan synthesis], and this can be a troublesome side reaction.

The Hantzsch pyrrole synthesis

CH3 O

EtO2C

RNH2CH3 NH

EtO2C

R

CH3O

Cl

N CH3CH3

EtO2C

R

CH3 NH

EtO2C

R

+

+

Reactions of Pyrrole

Substitution at nitrogen, A) Metallation of Pyrrole

N -

N

MgBr

NH

NH

N

LiNH

NaNH2, or KNH2, NH3 liq

Na+ (K+)or Na, or K

EtMgBr / ether

RLi

ionic

covalent

covalent

B) Formation of N-substituted pyrrole

N

K+

-

N

MgBr

N

Me

N

Me

MeI/ NH3 Liq

MeI/ HMPA

hexamethylphosphorousamide

95%

98%

N

K+

-

N

MgBr

N

O Ph

N

Ac

NH

Ac

CH3COCl

PhCOCl

toluene / 110 oC

+

Electrophilic Substitution (position 2 and 5)

The aromatic five-membered heterocycles all undergo electrophilic substitution, with a general reactivity order:

pyrrole >> furan > thiophene > benzene

The Vilsmeier Haack reaction

Cycloaddition Reactions with dichlorocarbeneReimer-Tieman Reaction

N

KN CHO

N

ClCHCl3

ether +

Reimer-Tieman Reaction

Ring Expansion

Diels-Alder Reactions of pyrrolePyrroles normally do not undergo DA reactions, Exception

N

O

OEt

CO2Me

CO2MeN

CO2Et

CO2Me

CO2Me

+

N-Ethoxycarbonylpyrrole Dimethyl acetylenedicarboxylate

[2 +2] Cycloaddition