Heterocyclic - PSAU · Pyrrole, furan and thiophene are colorless liquids of boiling points 126o, 32 o, and 84 respectively. Pyrrole has a relatively high boiling point as compared

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Heterocyclic

Chemistry

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Heterocyclic Chemistry

N

O

SFive-membered Heterocycles

Pyrrole, Furan and Thiophene

1-To identify Types of five member of Heterocyclic

compounds

2- To Know Sources of five member of Heterocyclic

compounds

3- To Know syntheses of five member of

Heterocyclic compounds

4-To understand methods of reaction five member of

Heterocyclic compounds

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Hetero-Monocyclic Compounds

The main reason for the study of pyrrole came from the work on

the structure of haem; the blood respiratory pigment, and the

chlorophyll; the green photosynthetic pigment of plants.

Thiophen does occur in plants in association with polyacetylenes

with which they are biogenetically closely linked.

Furan occurs widely in secondary plant metabolites, especially in

terpenoids.

Unsubstituted pyrrole, furan, and thiophene are usually obtained

from petroleum

N

H

S O

Pyrrole

Thiophene Furan

A. Five-membered Rings with one Heteroatom

X

X = NH Pyrrole

= O Furan

= S Thiophene

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.

N N N

H H H

N

H

N

H



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 as shown in the following resonance

structures

O O O O O

S S S S S

N N N N N

H H H H H


A. Five-membered Rings with one HeteroatomStructure and Aromaticity



X

X = NH Pyrrole

= O Furan

= S Thiophene

3-Their protons show the same sort of chemical shift in NMR

as the protons of benzene with δ = 6.5 ppm-8 ppm

2- Electrons not available for

protonation—hence not basic

3- 6 electrons over 5 ring atoms …..

Electron rich… so more reactive than

benzene towered electrophilic

substitution

Pyrrole > Furan >Thiophene>benzene







2- Electrons not available for

protonation—hence not basic

3- 6 electrons over 5 ring atoms …..

Electron rich… so more reactive than

benzene towered electrophilic

substitution

Pyrrole > Furan >Thiophene>benzene





4- The pattern of reactivity with Electrophilic reagents. Cycloalkanes

…… by addition reaction

Aromatic compounds ……. By substitution

addition followed by proton loss

[ onium intermediate

Order of reactivity :Pyrrole > Furan >Thiophene>benzene

X

X X X

X X X

X

+ E+

H

E

HE

H

EE

- H+

HE

HE

E

- H+

C2-attack

C3-attack



5-The order of aromaticity

Thiophene > Pyrrole > Furan

ne

In case of Thiophene [S] donate & accept

electrons…… so

delocalization as complete as benzeneS

In case of Furan [O] electronegativity more …. Diene-like

character CH2=CH-CH=CH2 O

In case of Pyrrole [N] -Diene-like character

CH2=CH-CH=CH2

Evidences of aromatic character in pyrrole



NH

NNNN

-H+

Pyrrole anion( Conjugated base)

1) All ring bonds are intermediates between

single and double bonds.

2) It tends to react by electrophilic substitution

NH

NH

PyrrolidinePyrrole

Dipole monent of

pyrrole and its saturated analog

NH

Pyrrole

aroamtic 2 amine

NH

Pyrrolidin

Aliphatic 2 amine

<

Basicity of pyrrole and its saturated analog

°°



thus the dipole moment of pyrrole compared with pyrolidine is reverted and thus

protonation occurs at carbons not at N

NH

N+

N N

CH3

H2

K+

Cl-

+ KICH3I

HCl

KOH

H2O +

3) Its exceptional lack of basicity and strong 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 (see the resonance structures)

NH

N-Na

+ NaNH2Liq NH3

strong baseweak acid salt

NH

NNNN

-H+

Pyrrole anion( Conjugated base)

So Its weak acid

not basic as the

secondary amines

Lone pair of N is

involved in cloud

and not

Available for

sharing with acids



Sources & Synthesis

Pyrrole & Thiophene …. Coal Tar

Pyrrole ring ….

Prophyrin system…..

Chlorophyll &

Hemoglobin

Furan ….. Decarbonylation of

Furfuraldehyde …….

Oat hulls, corn cobs or rice hullsOat hulls corn cobs rice hulls

A) Sources

http://www.nadyapeche.com/wp-content/uploads/chlorophyll-hemoglobin.jpg


A. Five-membered Rings with one HeteroatomB) Synthesis

ThiopheneCH3-CH2-CH2-CH3 + 4 S

S

560+ 3 H2S

n- butane

Pyrrole

HC CH + 2 HCHOCu2C2 HOH2CC CCH2OH

NH

NH3

pressure

1,2-butyldiolFormaldehydeEthyne

Furan ( C5H8O4 )nH2O,H+

CHO

(CHOH)3

CH2OH

Pentose

OCHO

OFurfural Furan

-3H2O400

Pentosan

Reactions of pyrrole

NH

NH

NH

NH

NH

NH

OHCCOCH3

CO

C

O

O

H3C

H3CAc2

O

1- DMF/POCl3

2- H2 O + Na

2 CO3

CH

3 CO

O-N

O2 +

NO2

H2 \pt

AcOH\200

SO 3

pyridine

HO3S

2-nitropyrrole

pyrrolidine2-pyrrole sulfonic acid

2-acetylpyrrole

pyrrole-2-carboxaldehyde

acetic anhydride

Acetylation

Vilsmier Rex

Nitration

ReductionSulfonation



HNO3

+Ac2o

NH

:CCl2

HCCl3 / NaOH NH

CCl

Cl

ring openning

enlargementN

Cl

3-chloropyridine

with carbine

Halogenation

X

Br2

Dioxane

SOCl2

pyridine

X

X

Br

Cl

2-bromo.....

2-chloro.....

Reactions of pyrrole A. Five-membered Rings with one Heteroatom


O

O

OO

O

OHCCOCH3Ac2

O

1- DMF/POCl

3

2- H2 O + Na

2 CO3

dil NH

O3

CH3C

OO

H,[0]

NO2

SO 3 ,100

pyridine

HO3S

2-nitrofuran2-furan sulfonic acid

2-acetyl furae

furfulaldehyde furfural BF3

NitrationSulfonation

Acetylation

Vilsmier Rex


A. Five-membered Rings with one HeteroatomReactions of Furan

Rex of furfural

O

OCOOH

OO

CH3CH2OH

+

NaOH

30 c

CO

H

N2 H

2base2-methyl furan

+ Furfu

ral

KCN

OC

O

CH

OH

O

furoin

[O]

OC

O

C

O

O

furil

O CHO COOH

O

furfulic acid

NaOH

Cannizaro RexWolff-Kishner

reduction

Benzoin-

condensation



Reaction of Thiophene

S

S

S

SCOCH3CH3COCl

dil NHO

3C

H3C

OO

H,[0]

NO2

SO3 , 100pyridine

HO3S

2-thiophene-2- sulfonic acid

SOCL4

SNO2O2NHNO3

SS

S S S

BrBr

Br

Cl ClCl

Cl

Cl Cl

Cl

Br 2

AcOHCl2

50

major minor

Nitration

Sulfonation

Acetylation

Halogenation



Five Membered Heteroaromatic Rings

Containing 2X , at least one nitrogen

X

N

X

N

X = S ,O ,or N

1,3-Azoles 1,2-Azoles

Thiazole [ 1,3-thiazole]

Oxazole [ 1,3-oxazole]

Imidazole [ 1,3-diazole]

Isothiazole [ 1,2-thiazole]

Isoxazole [ 1,2-oxazole]

Pyrazole [ 1,2-diazole]



NH

N

Imidazole

Aromaticity & Bascisity

Strong base, due to the greater electron releasing capacity of the two nitrogen's

NH

N

2ry amine

3ry amine

NH

N H

N

N H

H

3ry amine ismore basic than 2ry amine



Five Membered Heteroaromatic Rings

Containing 2X , at least one nitrogen

N

N

H

Pyridine like nitrogen( basic character )

Pyrrole like nitrogen( involved in aromaticity)

Importance of the ring

Building blockes as Histidine and Histamine

It exist in two tautomeric forms …..

As base & weak acid

NH

N

N

NH

50 % 50 %

Fused Five Membered

Heteroaromatic Rings With one X

NH

NH

benzo[b]pyrroleIndole

benzo[c]pyrroleIsoindole

Found in coal tar & orange blossoms, humane feces

In amino acids as Tryptophan, alkaloid * pigments

NH

CH2CH

COOH

NH2

Tryptophan

NH

Carbazole



Fischer Synthesis NHNH2

+C

O

CH3

Ph

Phenylhydrazine acetophenon

NHN

CH3

Ph

NH

Ph

2-phenyl indole

AcO

H

or ZnC

l 2

- H2O



Indole

Fused Five Membered

Heteroaromatic Rings With one X

Basicity of Indole

Not basic because lone pair is delocalized

and contributed to the Aromatic system

It undrego Electrophilic

Subistitution at Position 3

NH

+ E+

NH

NH

NH

NH

H

E

HE

H

E

H

E

Not favoureddestroy aromatic str.of benzene

C-3attack

C-2attack


A. Five-membered Rings with one HeteroatomFused Five Membered

Heteroaromatic Rings With one X Indole

- H+

- H+

attack at C-2

attack at C-3

three resonance structures more stable

two resonance structures less satble

Not formed

Rex with carbene

Vilsmier Rex

NH

DMF / POCl3

tolueneNH

CHO

Indole-3-carboxylaldehyde

NH

:CCl 2

(HCCl 3

/NaOH)

:CHCl(H2 CCl

2 /NaOH)

N

Cl

Cl

HN

Cl

N

Cl

H

HN

3-chloroquinoline

quinoline



Fused Five Membered Hetero aromatic Rings

With tow X

NH

N

Benzimidazole

In nature as N-ribosyl-dimethyl

benzimidazole …

In Vit B12 :Commercially as an parasisticide



Documents

Heterocyclic - PSAU · Pyrrole, furan and thiophene are colorless liquids of boiling points 126o, 32 o, and 84 respectively. Pyrrole has a relatively high boiling point as compared