Heterocyclic Chemistry

Heterocyclic ChemistryDr. Ayad

Dr.ayad Dr.ayad

N

OS

Five-memberedHeterocycles

Pyrrole, Furan and ThiopheneElectrophilic Substitution Reactions

1

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

2) They tend to react by electrophilic substitution due appearance of –ve charge oncarbon atoms (2 & 3) due to delocalization as shown in the following resonance structures

O O O O O

S S S S S

N N N N NH H H H H

Orientation of Electrophilic Substitution inPyrrole, Furne & Thiophene

Electrophilic substitution normally occurs at a carbon atomsinstead of at the nitrogen as explained before.

Also it occurs preferentially at C-2 (the position next to theheteroatom) rather than at C-3 (if position 2- is occupied itoccurs at position 3).

This is due to attack at C-2 gives more stable intermediate (itis stabilized by three resonance structure) than theintermediate resulted from C-3 attack (it is stabilized by tworesonance structure) .

- H+

- H+

attack at C-2

attack at C-3

three resonance structures more stable

two resonance structuresless satble

Not formed

3

X = NH, O, S

1) All ring bonds are intermediates between single and doublebonds.

2) It tends to react by electrophilic substitution3) 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 ofparticipation of N lone pair in aromatic sextet (see theprevious resonance structures) thus the dipole moment of

Pyrrole :Evidences of aromatic character in pyrrole

pyrrole compared with pyrolidine

NH

NH

PyrrolidinePyrrole

Dipole monent ofpyrrole and its saturated analog

NH

Pyrrolearoamtic 2 amine

NH

PyrrolidinAliphatic 2 amine

<

Basicity of pyrrole and its saturated analog

°° 4

Acidic properties of pyrroleDue to participation of N lone pair in aromaticity), pyrrole has exceptionallystrong acidic properties for a secondary amine for instance it can react withstrong bases or Grignard reagent in inert solvents, and with sodium hydride,to give salt-like compounds which an be used to alkylate or acylate thenitrogen atom as shown below:

Pyrrole is sensitive to strong acids, protonation occurs at carbons not at NThis is due to protonation occurs at C-3 and the resulting protonated moleculewill add to another unprotonated pyrrole molecule this continues to give pyrroletrimer.This reaction is considered as electrophilic addition to pyrrole

K O HN

KD M S O

R X

NR

R M g X / E t 2 O

NM g X

- R H

NH

R = C H 3 o r C 2 H 5o r C H 2 P h

P h N = C = O

NC O N H P h

A c y l a t i o n

A l k y l a t i o n

N a H

NN a

+ H 2

5NH

NH

NH

NH

H+

pyrrole trimer

HH

Electrophilic substitution in pyrrole

As expected for aromatic compound, pyrrole can react by electrophilicsubstitution.

In comparison to benzene pyrrole is more reactive thus thesubstitution is easier and milder reagents can be used.

The increased reactivity is a result of resonance which pushes theelectrons from the N-atom into the ring making the c-atoms of pyrrolering more electron rich than in case of benzene. In fact pyrroleresembles most reactive benzene derivatives (phenols and amines) (seeslide 5 for resonance structures of pyrrole).

Consequently, there are some modifications in usual electrophilicreagents, for instance, sulphonating and nitrating reagents have beenmodified to avoid the use of strong acids (induce polymerization). Alsoreaction with halogens requires no Lewis acid.

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NH

Reactivity in electrophilic substitution

Electrophilic Substitution Reactions ofPyrrole

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NH

NH

X

NH

N

NH

N O 2

NH

S O 3 H

X 2

P h - N 2+ C l -

H N O 3

2 0 o C

S O 3 / P y r i d i n e

+NH

N O 2

XX

X

NP h

E r l i c h r e a c t i o n

8 0 % 2 0 %

/ A c 2 O

I 2 / a q . K Io r B r 2 / A c O H

N B S

NH

XS O C l 2 / e t h e r

N ( C H 3 ) 2O

H

H C l / E t O H NH

N ( C H 3 ) 2

E t O H / A c O N a

NH

C O C H 3

( C H 3 C O ) 2 O

2 0 0 - 2 5 0 C °

H C H O

M e 2 N HNH

NMe 2

M a n n i c h r e a c t i o n

Heterocyclic Chemistry

Reaction of pyrrole with aldehyes andketones

Aldehydes and ketones condense with unsubstituted pyrrole atα-position in acidic medium to give dipyrryl methane. Thecondensation may continue to give tetramer (4 pyrrole ringsconnected by methine bridge). The tetramers are known asporphyrinogens, they are stable, planar structures that canaccommodate a wide range of metal ions.

NH

+

R 1 R 2

O

R 1 a n d R 2 = H o r C H 3

H C l / 1 0 0 C°

NH

N H

R 1 R 2

NH

H NN H

HN

R 1

R 2

R 1

R 2R 2

R 1

D ip y rry l m e th a n e

R 1

R 28

Oxidation-Reduction of Pyrrole

Lithiation of Pyrrole and N alkyl pyrrole

NBuLi

NLi

R 1X

N

RRR

NH

B uLiN

Li

R X

N

R

R 1

9

NH

H2 / Ni

NH

NH

Cr2O3

AcOH NH

OO

Second electrophilic substitution

NH

EWGNH

EWG

E

NH

ED

E

E+

E+

(incoming E +directedtom-position i.e. position4)

(incoming E +directedto por o-positions i.e. position3or 5)

NH

NO2

AC2O

NH

NO2

H3COC

Less reactive thanpyrrole

a) Monosubstitutedpyrrole withelectronwithdrawinggroup

e.g.

b) Monosubstitutedpyrrole withelectrondonatinggroup

More reactive thanpyrrole

NH

ED

+NH

EDE

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Furan and thiopheneIntroduction

N OS > >

Furan is not very aromatic therefore if there is a possibility of forming stable bondssuch as C-O bonds by addition, this may be preferred to substitution i.e. tendency togive addition products rather than substitution products increses as aromaticitydecreases.

In comparison to benzene the order of reactivity in electrophilic substitution is asfollows: Pyrrole > Furan > Thiophene > Benzene

Regioselectivity: The 2 & 5 ( ) positions are more reactive than 3 & 4 ( ) PositionsAs in pyrrole the intermediate results from electrophilic attack at C2 can bestabillized by three resonance structure while the intermaediate results from theattack C3 is only satbilized by two resonance structures. Thus the former is morepreferred

>

Eelectrophilic substitution on furan requires very mild non acidic conditions (acidsmay induce polymerization or ring opening), however, for thiophene the acidity isless critical since it is stable to aqueous minral acids but not to 100 % strong acids orLewis acids such as AlCl3.

Order of aromaticity

H

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1- Addition Reactions

Reduction

On the other hand thiophene can not be reduced under the sameconditions due to sulfur poison the catalyst and desulphurizationoccurs with ring opening. However, partial reduction can take place by metals in acidicmedium.

Raney Ni / H2

O O

2-Methyltetrahydrofuran

S

Raney Ni / H2 + NiS

Zn / HCl

SS CH2CH3 CH2CH3

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2- Electrophilic Aromatic substitution Reactions

1) Nitration

2) Sulphonation

O

CH3COONO2

S

CH3COONO2

O NO2

S NO2

Pyridine

AcOH / Ac2O

O

S

O SO3H

S SO3H

SO3 / Pyridine complex

95 % H2SO4

NSO3

HO3S

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Electrophilic Aromatic substitution Reactions

3) Halogenation

OX 2 / r . t

O

X

X

X

X

C l 2 / C H 2 C l 2

- 4 0 C °O C l

x = C l o r B r

B r 2 / D i o x a n e

0 C ° O B r

I n d i r e c t i n s e r t i o n o f i o d i n e i n f u r a n r i n g

O C O O H

I 2 / K I

O IK O H

S

N B S

S B r

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S S COCH3

O O COCH3

Ac2O / SnCl4

(CH3CO)2O /

H3PO4

4) Acylation

Electrophilic Aromatic substitution Reactions

5) AlkylationIt is very low yielding reaction due to formation of polyalkylated products orpolymers.

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4) Lithiation

X LiXX = O, S

BuLi RXX R

5) Diazocoupling:Furan and thiophene can not couple with diazonium salts which shows that theyare less reactive than pyrrole.

O

S

A r N =N +C l-N o R eaction

Second Electrophilic Substitution in Furanand Thiophene

(incoming E + is directed to m-position i.e. position 4)S CN S CN

O2N

a) Monosubstituted furan & thiophene with electron withdrawing groups such asCOOH, CHO, CN, COR, SO3H are less reactive than unsubstitutted compounds

CH3COONO

2

Pyridine

(incoming E +is directed to position 5 mainly and to position 4as well )

Less reactive than furan

O CHO O CHOO2N

Less reactive than thiopene

HNO3

O CHO+

O2N

X

E+EWG

i) EWG at position 2

ii) EWG at position 3

X

EWG

E(incoming E +is directed to position 5)

O COOH

Br2 / DioxaneO COOHBr O COOH

+

Br

3 : 1

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Second Electrophilic Substitution in Furanand Thiophene

X E

EDG

E+

(incoming E +directed to 2 mainly or 5 due to steric effects )

b) Monosubstituted furan & thiophene with electron donating group such as CH3, OH, NH2,OCH3

More reactive than unsubstitutedcompound

orXE

i) EDG at position 2

X EDGX EDGE

(incoming E +is directed to position 5)

X

EDG

E+

O COCH3

CH3Ac2O / r.t.

25 % H3PO4O

CH3

+

OH3COC

EDG

CH3

ii) EDG at position 3

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