© E.V. Blackburn, 2011 Electrophilic aromatic substitution.

© E.V. Blackburn, 2011

Electrophilic aromatic substitution


Substitution?

The characteristic reactions of benzene involve substitution in which the resonance stabilized ring system is maintained:

NO2

HNO3/H2SO4


Reactivity

- an electron source, benzene reacts with electron deficient reagents - electrophilic reagents.


1. Nitration

ArH + HNO3/H2SO4 ArNO2 + H2O

2. Sulfonation

ArH + H2SO4/SO3 ArSO3H + H2O

3. Halogenation

ArH + X2/FeX3 ArX + HX

Electrophilic aromatic substitution


4. Friedel - Crafts alkylation

ArH + RCl/AlCl3 ArR + HCl

5. Friedel - Crafts acylation

ArH + RCOCl/AlCl3 ArCOR + HCl

Friedel - Crafts reactions

Ar R

O


Substituent effects

Toluene is more reactive than benzene.....

CH3

HNO3

H2SO4

CH3

NO225C

+

CH3NO2

+

CH3

NO2

34% 63% 3%


Reactivity

• Compare the time required for reactions to occur under identical conditions.

• Compare the severity of reaction conditions.

• Make a quantitative comparison under identical reaction conditions.

How is “reactivity” determined in the lab?


Substituent effects

It also directs the attacking reagent to the ortho and para positions on the ring.

In some way, the methyl group makes the ring more reactive than that of the unsubstituted benzene molecule.


Substituent effects

Nitrobenzene undergoes substitution at a slower rate than does benzene. It yields mainly the meta isomer.

NO2

HNO3

H2SO4

NO2

NO225C

+

NO2NO2

+

NO2

NO2

2% 7% 91%


Substituent effects

A group which makes the ring less reactive than benzene is called a deactivating group.

A group which makes the ring more reactive than that of benzene is called an activating group.

A group which leads to the predominant formation of ortho and para isomers is called an “ortho - para directing group.”

A group which leads to the predominant formation of the meta isomer is called a “meta directing group.”


Activating, o,p directors

-OH -NH2 -NHR -NR2

moderately activating

-OR -NHCOR

weakly activating

-aryl -alkyl

strongly activatingA

All activating groups are o,p directors.


Deactivating, m directors

-NO2 -SO3H -CO2H -CO2R

-CONH2 -CHO -COR -CN

+ +-NH3 -NR3

A

All m directors are deactivating.

O or N


Deactivating, o, p directors

-F, -Cl, -Br, -I


Orientation in disubstituted benzenes

Here the two directing effects are additive.

CH3

NO2

H2SO4

HNO3

CH3

NO2

NO2



When two substituants exert opposing directional effects, it is not always easy to predict the products which will form. However, certain generalizations can be made....



• Strongly activating groups exercise a far greater influence than weakly activating and all deactivating groups.

OH

CH3

HNO3/H2SO4

OHNO2

CH3


• If there is not a great difference between the directive power of the two groups, a mixture results:

CH3

Cl Cl

NO2

CH3 CH3

NO2

Cl

+HNO3

H2SO4

58% 42%



• Usually no substitution occurs between two meta substituents due to steric hindrance:

Cl

Br

1%

62%

37%

......nitration



Synthesis of m-bromonitrobenzene

In order to plan a synthesis, we must consider the order in which the substituents are introduced.......

If, however, we brominate and then nitrate, the o and p isomers will be formed.

NO2

HNO3

H2SO4

Br2/FeBr3NO2

Br


Orientation and synthesis

Let’s look at converting a methyl group into a carboxylic acid:

Now let’s see how we can make the three nitrobenzoic acids:

If a synthesis involves the conversion of a substituants into another, we must decide exactly when to do the conversion.

H

H or R

H or R

1. KMnO4, OH-,

2. H3O+

CO2H


The nitrobenzoic acids

m-nitrobenzoic acid

CH3

KMnO4

HNO3

H2SO4

CO2HHNO3

H2SO4

CO2H

NO2

CH3 CH3NO2

NO2

+

bp 225oC bp 238oC


The nitrobenzoic acids

o-nitrobenzoic acid p-nitrobenzoic acid

CH3 CH3NO2

NO2

+

K2Cr2O7

CO2HNO2

K2Cr2O7

CO2H

NO2


Nitration

HONO2 + 2H2SO4 H3O+ + 2HSO4- + NO2

+

nitronium ion - a Lewis acid

NO2+ H

NO2

+

HNO2

+ HSO4-

NO2H2SO4 +


The structure of the intermediate carbocation

O2N H

+

The positive charge is not localized on any one carbon atom.

It is delocalized over the ring but is particularly strong on the carbons ortho and para to the nitro bearing carbon.

HNO2

+ HNO2

+

HNO2

+


Sulfonation

2H2SO4 H3O+ + HSO4- + SO3

S OO

OSO3

-+

H

SO3-+

H

HSO4-

H2SO4 +SO3

-


Halogenation

Br Br FeBr3 Br Br FeBr3

+ -Br Br FeBr3

+ -

Br Br FeBr3+ - Br

+

H + FeBr4-

Br+

HBr FeBr3

- + HBr + FeBr3

Br


Friedel - Crafts alkylation

R X AlX3 R+ + AlX4-

R+R

+

H

R+

HX AlX3

- + AlX3

R


An electrophilic carbocation?

(CH3)3COH + H+ (CH3)3COH2

+

(CH3)3COH2

+H2O + (CH3)3C+

(CH3)3COH/H+ C(CH3)3



(CH3)2C=CH2 + H+ (CH3)3C+

(CH3)2C=CH2/H+ C(CH3)3



+

CH2CH2CH3

CH3CH2CH2Cl

AlCl3

CH(CH3)2

~33% ~67%



When RX is primary, a simple carbocation does not form. The electrophile is a complex:

H3C Cl AlCl3

-


Limitations

• A polysubstitution is possible - the reaction introduces an activating group!

• Aromatic compounds bearing -NH2, -NHR or -NR2 do not undergo Friedel - Crafts substitution. Why?

• Aromatic rings less reactive than the halobenzenes do not undergo Friedel - Crafts reactions.


Friedel - Crafts acylation - the reaction

AlCl3

Cl O

+

O

+ HCl


Friedel - Crafts acylation

acylium ion

RC O+

+ AlX3

O

R X + AlX4-

RC O+

RC O+

+

HR

O

+

HX AlX3

-R

O

+ HX + AlX3R

O


NO2

+

Cl O

AlCl3 ?

Limitations


The mechanism

slow, rate determining step

fast

Evidence - there is no significant deuterium isotope effect.

+ E+

E H

+

E H

+ Nu:+

E


Isotope effects

A difference in rate due to a difference in the isotope present in the reaction system is called an isotope effect.


Isotope effectsIf an atom is less strongly bonded in the transition state than in the starting material, the reaction involving the heavier isotope will proceed more slowly.

C H + ZkH

C H Z C + HZ

The isotopes of hydrogen have the greatest mass differences. Deuterium has twice and tritium three times the mass of protium. Therefore deuterium and tritium isotope effects are the largest and easiest to determine.


Primary isotope effectsThese effects are due to breaking the bond to the isotope.

C H + ZkH

C H Z C + HZ

C D + ZkD

C D Z C + DZ

kH

kD = 5 - 8

Thus the reaction with protium is 5 to 8 times faster than the reaction with deuterium.


CH3CHCH3

Br NaOEt

kH

CH3CH=CH2

CD3CHCD3

Br NaOEt

kD

CD3CH=CD2

kH/kD = 7

Evidence for the E2 mechanism - a large isotope

effect


The mechanism

slow, rate determining step

fast

Evidence - there is no significant deuterium isotope effect.

+ E+

E H

+

E H

+ Nu:+

E


The reactivity of aromatic rings

The transition state for therate determining step:

Factors which stabilize carbocations by dispersal of the positive charge will stabilize the transition state which resembles a carbocation; it is a nascent carbocation.

HE

+

+


Carbocation stability

electron donation stabilizes the carbocation

electron withdrawal destabilizes the carbocation

HE

+

HE

+

CH3

HE

+

NO2


Orientation

A deactivating group deactivates all positions on the ring but deactivates the ortho and para positions more than the meta position.

Why? Examine the transition state for the rate determining step for ortho, meta and para attack.

An activating group activates all positions on the ring but directs the attacking reagent to the ortho and para positions because it makes these positions more reactive than the meta position.


CH3 - an o/p director

para attack

ortho attack

meta attack

E H

+CH3

E HE H+

+

CH3 CH3

E H+

CH3

E HE H+

+CH3 CH3

E H+

CH3

E HE H+

CH3 CH3

+

3°

3°


NO2 - a m director

para

ortho

meta

E H E HE H

++

+

NO2 NO2 NO2

E H E HE H+ +

+NO2 NO2 NO2

E H E HE H+ +

NO2 NO2 NO2

+


NO2 - a m director

para

E H E HE H+ +

NO2 NO2 NO2

+

E H

CH3C O

+

E H

NO O

++

-


NH2 - an o/p director??E H E HE H

++

+

NH2 NH2 NH2

E H E HE H+ +

+NH2 NH2 NH2

E H E HE H+ +

NH2 NH2 NH2

+

E H

+NH2 :

E H +NH2


Deactivation results from electron withdrawal:

Halogen - a deactivating group

HE

+

HE

+

Cl


Halogen - an o/p directing group

o/p directors are electron donating. How can a halogen substituent donate electrons?


Halogen - an o/p directing group

E H E HE H+ +

Cl Cl Cl

+

E H E HE H

++

+

Cl Cl Cl

E H E HE H+ +

+Cl Cl Cl

E H +Cl

E H

Cl+


SO3H

SO3,H2SO4

H2O, ,dil. H2SO4

R1. KMnO4, OH-,

2. H3O+

CO2H

HNO3, H2SO4

NO2

R

O

© E.V. Blackburn, 2011 Electrophilic aromatic substitution.

Documents

methyl group

directing effects

deactivating groups

sulfonation arh h

disubstituted benzenes

substituent effects

directional effects

ortho para