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)

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

3º, especially stable

3º, especially stable

o,p-Activators with a lp of electrons

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

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-

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)

Mechanism

Halogenation of Benzene

Requires a Lewis acid catalyst

Reactivity: F2 >> Cl2 > Br2 >> I2

Catalyst

Mechanism (Cont’d)

Nitration of Benzene

Electrophile = NO2

⊕ (nitronium ion)

Mechanism

Sulfonation

r.d.s

repeat next slide

repeat

Sulfonation & Desulfonation-useful!

(heat)

Friedel–Crafts Alkylation

Electrophile = R⊕ (not vinyl or aryl)

R = 2o or 3o

Friedel–Crafts Acylation

Acyl group:

Electrophile is R–C≡O⊕ (acylium ion)

RX and Mechanism

Ch. 15 - 33

Acid chlorides (or acyl chlorides)

Prep

Ch. 15 - 35

(not formed)

Limitations of Friedel–Crafts Reactions

carbocations rearrangement

Ch. 15 - 36

1o cation (not stable)

Reason

3o cation

Ch. 15 - 3

Questions?

Problems: Friedel–Crafts alkylations, acylations, etc. with withdrawing groups & amines (basic)

generally give poor yieldsdeactivating gps

Basic amino groups (–NH2,–NHR, & –NR2) form

strong electron withdrawing gps with acids

Not Friedel-Crafts reactive

Another problem: polyalkylations can occur

More common with activated aromatic rings

Substituents effect reactivity & regiochemistry of substitution

Y = EDG (electron-donating group) or EWG (electron-withdrawing group)

possibilities

metam

parap

Ch. 15 - 50

Ring is electron poor; Ring reacts slower than benzene with E+

Ring is electron rich; Ring reacts faster than benzene with E+

relative to benzene

Reactivity towards electrophilic aromatic substitution

Ch. 15 - 57

Regiochemistry: directing effect

General aspects Either o-, p- directing or m-directing

Rate-determining-step: aromatic ring -electrons attacking the E

Ch. 15 - 59