Aromaticity of heterocyclic compounds

Characteristics of aromatic compounds:

1.The structure must be cyclic with conjugated π bonds.

2.All atoms must be sp2 hybridized (i.e. double bond, cation or anion)

3.The compound must follow Hückel's Rule (4n + 2) π, where n = 0, 1,

2, 3, and so on).

4. Coplanar structure, with all the contributing atoms in the same

plane.

Antiaromatic compound: They are cyclic, conjugated, with

sp2 orbitals and follows 4n rule.

Nonaromatic compound: All atoms are not sp2 hybridized.

NNH

NNH

NH

N

Aromatic compounds

cyclic, conjugate

Sp2

6 pi electrons (4n+2 rule)

planar

cyclic, conjugate

Sp2

10 pi electrons (4n+2 rule)

planar

cyclic, conjugate

Sp2

2 pi electrons (4n+2 rule)

planar

cyclic, conjugate

Sp2

14 pi electrons (4n+2 rule)

planar

Antiaromatic compounds

cyclic, conjugate

Sp2

4 pi electrons (4n rule)

planar

Nonaromatic compounds

Have separate sp3 atoms

(i.e not all atoms are sp2)

cyclic, conjugate

Sp2

8 pi electrons (4n rule)

planar

HN

The π-excessive heterocyclic compoundsThey are Planar, fully conjugated, monocyclic systems with

6electrons [i.e. follow (4n + 2) electrons ,(n is an integer 0, 1, 2,

etc.)]

In benzene each carbon corner has one unit of pi-electron, but this system

(-excessive) has in each corner more than one -electron.

As a result of such a situation these molecules are generally more reactive

toward electrophiles than benzene itself and generally have reactivity similar

to that of electron rich benzene derivatives e.g. phenol or aniline.

O NH

S

16 21 29R.E.

In terms of valence bond theory these compounds are

resonance hybrids. However, resonance structures

have charge separation.

X X X X X

X = O, N, S

The π-difficient heterocyclic compounds

They are Fully unsaturated six membered heterocycles, the heteroatom lone

pair of electron does not contribute to this electronic configuration, in fact it is

out of plane.

As a result the reactivity pattern toward electrophiles similar to that of -

deficient benzene derivatives e.g. nitrobenzene.

Moreover, having p-deficient carbon these molecules are reactive towards

nucleophiles.

N N N N N

Kekulé forms

Reactivity of Five membered pi-Excessive Heterocyclic ring

Reactivity towards electrophilic substitution

Pyrrole, furan and thiophene are all much more reactive than benzene toward electrophilic substitution.

NH

OS

furan pyrrolethiophenebenzene

Thiophene is 100 times more reactive than benzene and pyrrole is the most reactive. Furan is less reactive than pyrrole because oxygen is more electronegative than nitrogen.

There are two position for electrophilic attack, C-2 and C-3.

Attack at C-2 is preferred because it yields a more stable

carbocation (3 resonance structures, while attack at C-3 gives

only 2 resonance structures(

E+ substitution occurs predominately at the 2-position (and if that

position is already substituted, substitution occurs at the C-5).

If 2- and 5-position are already occupied, electrophilic

substitution takes place at 3-position.

X

X = NH, O, S

attack at C-2

attack at C-3

X

X

X

E

H

E

H

E

H

XX X

E E

H

E

H

X E

-

H-

E

Resonance

energy 21 Kcal/mol 16 Kcal/mol 25 Kcal/mol

Reactivity sequence

N

H

O S

Although furan is the least aromatic (R.E. = 16 Kcal / mol), pyrrole (R.E.

= 21 Kcal / mol) is most reactive. Thiophene which is the most aromatic

with (R.E. = 29 Kcal / mol) is least reactive in electrophilic reactions.

This inverted reactivity pattern is due to the excessive participation of

nitrogen lone pair is stabilising reactive intermediate for substitution at C-2.

Energy needed to go from the more aromatic pyrrole to its reactive

intermediate is less than energy needed for a similar step with furan

N

H

O

E

E

N

H

E N

H

E

O E O E

Less energy demand

1- It was found that pyrrole reacts readily with some weak

electrophiles, while thiophene and furan did not react

NH

ClAr N N

Mannish reaction

ArCHO / R2NH

NH

N

NAr

NH

N

Ar

R

R

O

S

ClAr N N

Mannish reaction

No reaction

2- Halogenation. Just as is true for aniline, the pyrrole ring is

reactive toward bromine or chlorine, giving polysubstituted products

NH

Br2

NH

Br Br

BrBr

O

Br2

CS2, -5 oC OBr O

Br

Br

OBrBr

OBr

heat

- HBr

3- On the other hand, Due to the low aromaticity of furan, it reacts

differently towards bromine

4. Due to the sensitivity to acids nitration is conducted in

aprotic media.

NH

CH3CONO3

- 10 oC NH

NO2 NH

NO2

+

Major (50 %) Minor (13 %)

5- Only thiophene (least acid reactive can be nitrated by

mixed acid nitration.

S

HNO3

SNO2

S

NO2

+

Major Minor

H2SO4

6 : 1

6-Due to the low aromaticity of furan, its reactions in presence of a

nucleophile gives in many cases adducts in which intermediate

instead of undergoing proton loss reacts with nucleophile, e. g.

O

HNO3

Ac2O, -5 oCO

NO2

heat

ONO2 O

NO2AcO

AcO

ONO2

- AcOH

7. Acylation of -excessive molecules can be made either in complete

absence of a Lewis acid or in presence of ZnCl2. Pyrrole is acylated at N

and not at C-

NH

Ac2O

AcONaN

COCH3

N

Ac2O

H2O NH

MgBrO

CH3

Furan and thiophene undergo Friedel –Craft

reaction while pyrrole did not?

O

Ac2O

AcONa O

S

Ac2O

ZnCl2 S

O

CH3

O

CH3

O

Cl2 in CH2Cl2

O Cl

Br2 in Dioxan

-5oC O Br

HNO3 fuming

Ac2O / -5oC OAcO NO2 O NO2

SO3 / pyridine

O SO3H

O COCH3

(CH3CO)2O

BF3 / 0oC

Reactions of Furan

S

S I

S Br

S NO2 S

S SO3H

S COCH3

Ac2O / SnCl4

or ZnCl2

I2

NO O

Br

HNO3 / H2SO4+

NO2

6 : 1

H2SO4

room temp

(95%)

Reactions of Thiophene

NH

NH

X

NH

N=NPh

NH

NO2 NH

NH

SO3H

N

Ac2O

X2

+

NO2

50 % :13%

SO3 / pyridin

XX

X

CH3CONO3

- 10 oC

PhN2Cl+ -

COCH3

CH2O / R2NH

NH

CH2NR2

Reactions of Pyrrole

Unlike furan and thiophene, pyrrole is weakly acidic in nature.

Thus, on reaction with metallic potassium or potassium hydroxide it

forms a potassium salt, which is hydrolyzed back to pyrrole on

treatment with water.

NH

KOH

N

K

+ H2O

Acidic character of pyrrole

Pyrrole is a resonance hybrid of various structures carrying a positive charge on nitrogen.

The greater stability of pyrrole anion compared to

pyrrole.

The acidic character of pyrrole is due to

The higher stability of the anion is due to resonance.

N N NN

NH

N.. + H+

The acidic character is also reflected in the formation of pyrrolyl

magnesium halide when reacted with alkylmagnesium halide.

N

K

RX

N

R

N

H

R

N

MgBr

-

+

CO2

N

H

COOH

N

H

COR

RCOCl

The action of acids pyrrole, thiophene and furan

NH

HCl

NH

NH

NH

H

H

H

H

S

H3PO4

S S

S

O

H

OH

H2OOHC CHO

trimerization

trimerization

12

34

5

12

3 4

5

The mechanism of trimerization of

pyrrole in acid medium

NH

HCl

NH

H

H

NH

NH

NH

NH

NH

HCl

NH

NH

NH

H

H

H

H

H

H

We have seen that the reactivity of pyrrole, furan and thiophene towards electrophilic substitution is in the following order

NH O S

The reactivity of these rings towards nucleophilic substitution is

in the opposite order

NH O S

Nucleophilic Substitutions in

Pyrrole, Furan and Thiophene

Pyrroles: the pyrrole ring is the least reactive and both 2-

halo- and 3-halopyrroles behave like aryl halides in

nucleophilic displacement. Thus, 2-chloropyrrole does not

react with potassium tert-butoxide or with lithium aluminum

hydride

NH

Cl

KOC(CH3)3

LiAlH4

No reaction

No reaction

X Br

X = O, S

: Nu

X Br

NuX Nu

- Br

O Br

HN

200oC O N

Furans are more reactive towards nucleophilic displacement than pyrrole. 2-bromo- and 2-chloro react with piperidine at 200oC as follows:

The presence of electron-withdrawing groups on the furan

ring facilitates nucleophilic displacement. Thus, 2-bromo-5-

nitrofuran and methyl 2-bromo-5-carboxylate react readily

with nucleophiles

O BrO2N

HN

25oC O NO2N

O BrH3CO2C

HN

20oC

NaOCH3

CH3OH / 20oC

O NH3CO2C

O OCH3H3CO2C

•It is of considerable interest that in these reactions the

furans react about 10 times faster than the corresponding

benzene analogues. This strong behavior has also been

observed in theiophene series

Thiophenes

Nucleophilic substitution occurs much more readily within the

thiophene series than it does for the corresponding benzene

compounds. The thiophenes are at least 1000 times more

reactive than corresponding benzene analogues (This increased

reactivity has also been noticed in the electrophilic substitution of

thiophenes compared to the corresponding benzene analogues) .

The increased reactivity of thiophene ring nucleophilic

substitution can be explained by Wheland intermediates involved

in nucleophilic substitution of bromine in 2-bromo-5-

nitrothiophene.

It is suggested that the sulfur atom causes additional

stabilization by involvement of its d-orbitals "Structure III"

S BrO2N

Nu

S BrO2N

Nu

IS

N

O

O

Br

Nu

II

III

SN

O

O

Br

Nu

SN

O

O

Br

Nu

IV

It must be noted that the lone pair of the sulphur atom also enters into

resonance with the electrons. X-ray studies indicate that the valency

angle of C-S-C in thiophene is nearly 91o and not 105o as expected.

This can be explained by assuming that the 3d orbital of sulphur are

also used in resonance and following additional contributing structures

may be written.

..S S S S.... ..

Copper-meditated nucleophilic substitutions of halo thiophenes are also

of great synthetic utility. Examples of some transformation follow

S I

CuC CH

Pyridin / S H

S IH3C

Pyridin /

CuCN

8hrsS CNH3C

S Brquinolinde

S(Bu)

S SBu

Cu

Condensed Five-Membered

Heterocycles

Fusing benzene ring with 2,3-positions of furan, pyrrole and

thiophene leading to benzo[b]furan, indole and

benzo[b]thiophene, respectively.

O NH

S

benzo[b]furan indole benzo[b]thiophene

The molecular orbital description of benzofused heterocycles with one

heteroatom is very similar to that furan, pyrrole and thiophene, the only added

feature being distribution of - electrons. The reactivity of these fused

heterocycles is lower than that of the parent heterocycle but still higher than that

of benzene.

Position 3- is preferred position for electrophilic attack in indole, since it results in

two more stable resonance structures in the aromatic sixtet of the benzene ring

is preserved, which attack at position 2-yield one structure only in which the

aromatic sixtet is preserved.

NH

+ E

NH

E

H

NH

EH

NH

EH

Attack at position 2-

Attack at position 3-

NH

NH

N NPh

NH

SO3H

NH

NO2

NH

Br

NH

I

NH

CHO

N NHCH2NRR'

CH2NRR'

PhN2Cl

SO3 / pyridin

PhCONO3

N OOBr

H2O / KI3

POCl3 / DMF

Mannich

Electrophilic substitution in benzo[b]furan occurs

mainly at C-2.

O

O

O

O

CH3CONO3

POCl3 / DMF CHO

NO2

Ac2OCOCH3