Electrophilic Aromatic Substitution

Activating and Directing effects of substituents already on the ring

Products of Nitration

CH3 CH3

NO2

CH3

NO2

CH3

O2N

+ +HNO3

H2SO4

ortho meta para

63% 3% 34%

CN CN

NO2

CN

NO2

CN

O2N

+ +HNO3

H2SO4

17% 81% 2%

OH OH

NO2

OH

NO2

OH

O2N

+ +HNO3

H2SO4

50% 0% 50%

1 hr

48 hr

0.0003 hr

Mechanism of Electrophilic Aromatic Substitution

E

H

E

H

E

H

E+

E

H

GE

H

GE

H

GE

+G

With a substituent group G

Depending on the nature of the substituent, the substituent G may stabilize the carbocation intermediate and therefore speed the reaction, or it may raise the energy of the carbocation and slow the reaction. Substituents that make the ring react faster (than benzene) with electrophiles are called activators; those that make the ring react slower (than benzene) are called deactivators.

Substituent effects

All activators also direct incoming electrophiles to the ortho- and the para-positions.

Most deactivators direct incoming electrophiles to the meta position. The exceptions are the halogens, which are weakly deactivating yet ortho-para directing.

Classification of Substituents

H

F

Cl

Br

I

Benzene

o,p-directingdeactivators

o,p-directingactivators

Ar

R

NHCOCH3

OR NH2

OH

CHOCO2H

COR

O

CR

O

CN

SO3HNO2

NR3+

m-directingdeactivators

more activatingmore deactivating

Product Distribution in Nitration (Percent %) (Percent %)

X ortho meta para X ortho meta para

(meta-directing Deactivators) (ortho- and para-directing Deactivators)

-N(CH3)3 2 89 11 -F 13 1 86

-NO2 7 91 2 -Cl 35 1 64

-CO2H 22 77 2 -Br 43 1 56

-CN 17 81 2 -I 45 1 54

-CO2CH2CH3 28 72 2 (ortho- and para-directing Activators)

-COCH3 26 72 2 -CH3 63 3 34

-CHO 19 72 9 -OH 50 0 50

-NHCOCH3 19 2 79

o,p-Activators (alkyl & aryl groups)

3º, especially stable

3º, especially stable

p

m

o

E

E

E

CH3

CH3

HE

CH3

H

H

E

CH3

H

HE

CH3

H

E

CH3

HE

CH3

H

H

E

CH3

H

H

E

CH3H

E

CH3

H

H

E

CH3

H

CH3

OH

H

E

OH

H

H

E

OH

H

H

E

OHH

E

OH

HE

OH

HHE HE

OH

HE

OH

H

OH

OH

E

E

EHE

OH

H

E

OH

H

H

E

OH

H

E

OH

H

o,p-Activators with a lp of electrons

4 resonance forms

4 resonance forms

o-

m-

p-

o,p-Deactivators (Halogens)Cl

H

E

ClH

E

ClH

E

ClH

E

H

E

Cl

HE

Cl

H

E

Cl

HE HE

Cl

HE

Cl

Cl

Cl

E

E

EHE

Cl

Cl

Cl

H

E

4 resonance forms

4 resonance forms

o-

m-

p-

meta-directing DeactivatorsCN

H

E

CNH

E

CNH

E

CN

H

E

CN

HE

CN

H

E

CN

HE

CN

HE

H

E

CN

HE

CN

CN

CN

E

E

E

Especially UNSTABLE**

Especially UNSTABLE**

o-

m-

p-

Explanation of meta- deactivators

Meta directors slow the reaction by raising the energy of the carbocation intermediate because they have (in one resonance form, shown below) a positively charged atom attached to the ring. Two positively charged atoms so close together is very high in energy (especially unstable).

NO O

E

H

SO OH

E

H

O

CO CH3

E

H

E

H

N

C

nitro group sulfonic acid ketone nitrile

Summary of Substituent Effects

When the substituent is R (alkyl) or Ar (aryl), the resonance hybrid cation intermediate has three resonance forms. For attack of the electrophile at the ortho or para positions, one of these is a 3º carbocation, which is especially stable. This lowers the energy of the intermediate, thus facilitates (speeds) the substitution reaction at the o- and p- positions.

When the substituent has a lone pair of electrons, such as the halogens, oxygen or nitrogen, the resonance hybrid for attack of the electrophile at the ortho and para positions has four resonance forms. This lowers the energy of the those intermediates, thus facilitates (speeds) the substitution reaction at the o- and p- positions.

Summary of Substituent Effects…

When the substituent has a multiple bond conjugated with the ring, and the second atom from the ring is more electronegative than the first, the substituent deactivates the ring and directs incoming electrophiles meta. It does this by raising the energy of the carbocation intermediates from ortho and para attack by an electrophile even more than it raises the energy of the intermediate resulting from meta attack.

Summary

-H (unsubstituted)

-R or -Ar, ortho- and para- -R or -Ar, meta-

-NH2 or -OH, meta-

-NH2 or -OH, ortho- and para-

-Cl or -Br, ortho- and para-

-Cl or -Br, meta-

-NO2 or -CO2H, meta-

-NO2 or -CO2H, ortho- and para-

Deactivators

Activators

Reactants

[CarbocationIntermediate]

Reaction Progress

Energy

Additivity of substituent effects in disubstituted aromatic rings

Rule 1: If the directing effects of two substituents reinforce each other, the predicted product predominates.

CH3

CO2H

CH3

CO2H

NO2HNO3

H2SO4

(o,p)

(m)

Additivity of substituent effects…

Rule 2: If the directing effects of two substituents oppose each other, the more activating group dominates, but mixtures often result.

NH2

CH3

NH2

CH3

BrBr2

(FeBr3 catnot needed)

(o,p; STRONG activator)

(o,p; weak activator)

Additivity of substituent effects…

Rule 3: Substitution almost never occurs between two substituents meta to each other.

CH3

Cl

CH3

SO3H

Cl

SO3

H2SO4

CH3

Cl

HO3S

CH3

Cl

SO3H

+

but not:

(o,p)

(o,p)

X (too crowded)

Additivity of substituent effects…

Rule 4: With a bulky o,p- director and/or a bulky electrophile, para substitution predominates.

OCCH3

O

SO3H

OCCH3

O

SO3

H2SO4

(o,p; BULKY)

(HSO3+ is a

BULKY electrophile)