Chapter 12

Reactions of Arenes: Electrophilic Aromatic Substitution

Need to make benzene (and other aromatic compounds) derivatives - biologically and
commercially useful
CH 3
CH 3
CH 3
HO
CH 3
HO
CH 3
N
N
NH 2
NHCH 3
H
H

OH
OH
adrenaline
(epinephrine)
O

ephedrine

amphetamine

CO 2H

Cl

methamphetamine
("speed")
OH

CO 2H

C(CH 3 )3

(CH 3 )3C

Cl

Cl
Cl

CH 3

Cl

2,4-dichlorophenoxyacetic acid
(2,4-D)
2,4,5-trichlorophenoxyacetic acid
(2,4,5-T)

butylated hydroxytoluene
(BHT)
food antioxidant

agent orange
So how do you make these? Typically by electrophilic aromatic substitution.
E
H
H

E+

H
This is different than alkene chemistry! WHY?

H
+

H
H

H+

H
HCl

Cl

H
2 carbocation

syn and anti addition

across double bond

and

BrBr

Br

Br
H

H
bromonium ion
H
Br
H

antiaddition

free 2 carbocation
is not as stable as the
cyclic bromonium ion

In both cases, a C=C bond and an XY bond is converted to C-X and C-Y bonds
cf. Table 5.4. Bond Dissociation Energies (p. 163),
C=C bond

kcal/mol

Br-Br

kcal/mol

C-Br

kcal/mol

overall rxn is exothermic (and favorable)

So for alkene addition, we had 3 steps:
1) get or make an electrophile (something that wants electrons) such as H+ or Br+
- does not need to be a free floating species so it could be a complex
2) electron rich double bond attacks electrophile to make a carbocation
3) nucleophile attacks carbocation center to make a stable product

#3 is VERY IMPORTANT: HCl and Br2 add across the double bond because the
product of XY addition is stable (it is an exothermic/exoergic process)

E ner gy

transition
state

transition
state

intermediate
H

activation
energy

Br
H
H
+ Br2

Hrxn

H
Reaction Coordinate
How does electrophilic aromatic substitution compare?
BENZENE: electrophilic aromatic substitution
1) First step:
Br 2

(a)

no reaction

(b) Add FeBr3 (a Lewis Acid) to activate the Br2 to react.

Br

Br2
FeBr 3

polarized bromine

Br-Br

+
Br

FeBr3

"Br + "

Br

FeBr

BrFeBr 3

At the end of step 1, we have an ....

2) Second step: electron rich double bond attacks electrophile

Br+

BrFeBr 3

H
Br

Br

Br

resonance stabilized carbocation

(not necessary to have a bromonium
ion for stability)

3) Third step:
H

H
Br

Br

RESULT
Br

IF
H

H
Br

Br

Br

Br

IF
H
transition
state

E ner gy

H
H
Br

activation
energy

Br
Br
Hrxn

+ Br2
+ FeBr3

Hrxn

Reaction Coordinate
a) first addition is

b) re-forming the benzene ring is

Similarity to anything you have seen before?

Br

A tri-substituted double bond is more stable than a mono-substituted double bond

and you can isomerize a less substituted double bond to a more stable double bond -and the driving force is making a more stable product!
H

H
H-O-SO 3H

E ner gy

H 3C
H 3C

CH 2

H 3C
H 3C

CH 3 H O
2

H 3C

CH 3

H 3C

Hrxn

H 3C
H 3C

H 3C

CH 3

H 3C
Reaction Coordinate

So electrophilic aromatic substitution is composed of 3 steps:

(1) make electrophile (E+)
(2) electrons from benzene ring attack electrophile to make a
resonance stabilized carbocation
(3) make the most stable product (that is, re-form benzene ring
and regain aromaticity)

Halogenation:
Br

Br2
FeBr3

Cl

Cl2
FeCl3

I2
CuCl2
or
H 2O 2

Nitration: need electrophile NO2+; use nitric acid with sulfuric acid
O
+ HSO4
+ H2SO4
HO N
O

H 2O +

N+2

N+2

NO2+ is isoelectronic with CO2

H
NO2+

NO2 H O
2

Can also use pure sources of NO2+ such as NO2+ BF4 salt

NO2
+ H3 O +

Once again, 3 steps:

1) make electrophile E+: NO2+
2) electrons attack electrophile to make stabilized carbocation
3) reform aromatic ring and re-generate aromatic stability
Nitro compounds can be converted to amines very readily
NO2

NH 2

Sulfonation: need electrophile: H2SO4 + SO3 (fuming sulfuric acid)

H
O

S +2
O
O

S +2
O
O

H2SO4

etc....

SO3H+

etc....
H
SO H

SO3H+

SO3H

Base

Important difference from nitration or bromination is that sulfonation is reversible

(a) sulfonation favored in strong acid (fuming sulfuric acid)
(b) de-sulfonation is favored in hot, dilute aqueous acid
SO3H can also be replaced by nucleophiles (but conditions to put the SO3H on in
the first place are vigorous)
CH
CH
3

SO3H

OH

Friedel Crafts Acylation: need good electrophile (E+): acylium ions

O
R

AlCl3

+ AlCl4

Cl
acylium ion (good E+)

C
R

Cl

AlCl 3
AlCl

O
product trapped as a
complex so unreactive
to further acylation

3 steps: (1) make good E+; (2) electrophilic addition; (3) most stable product formed
Friedel- Crafts Alkylation: need good electrophile (E+): carbocations
CH 3
Cl

AlCl 3

+
H 3C

CH 3

CH 3
H

Cl
H 3C

+ HCl

CH 3

AlCl 3

H 3C

CH 3
E+

+ AlCl4

Same mechanism as before; need to make a carbocation as the E+:

(1) alkyl halides are fine but

do not react

(2) alkylation reactions need electron rich double bond on aromatic ring so FriedelCrafts alkylation will not work when the ring has
(3)
R = alkyl

R
R

RCl

RCl

AlCl 3

AlCl 3

more reactive
than benzene
(4) carbocation as E+, so

CH 3
CH 3-CH 2-CH 2-Cl

CH 3

AlCl 3
H

+
Cl

CH
H 3C

AlCl

CH 2

H 3C

CH 3

+ AlCl4

more stable
2 carbocation

hydride shift
Can make carbocation many ways:
(a)
+

(CH
3)3CCl

AlCl 3
FeCl 3

C(CH 3 )3

same product

(b)
C(CH3)3

CH3
+ H 2C
CH3

CH3

electrophile (E+)

CH 2
CH3
BF4
(c)
(CH ) C
3 3

BF 3

OH

(CH 3)3C +
E+

To avoid over-alkylation or rearrangements, use acylation and reduction steps.

O
O
AlCl3
C
(CH ) CH
+
C
2 4
3
Cl
(CH ) CH
2 4

1) H2NNH2
2) KOH,
H H
C

(CH ) CH
2 4

Zn/Hg
HCl
H H
C

(CH ) CH
2 4

Advantage: acylation can only happen once and no rearrangement is possible

Disadvantage: acylation cannot occur on a deactivated ring

Activating / Deactivating Substituents

(1) electron rich () double bond has to attack E+
(2) the more electron rich the double bond, the easier it is to attack an E+
(3) relative rate of attack is compared to benzene
Activating Substituents: more reactive than benzene
X
H

>
O
where X = NH 2, OH, OCH 3, CH 3, NHCCH 3
Lone pair on X can donate electron density into ring OR can stabilize the
carbocation formed as the first intermediate.
Deactivating Substituents: less reactive than benzene
H
Z

>
O

where Z = F, Cl, Br, C-H, C-OH, SOH, NO2, CN

O

O
C

O
H

Two important aspects of substituent effects:

(a)
to ring

effect - electronegativity differences and the polarity of bonds attached

(b)
effects - conjugation of substituents to the ring to increase electron
density for bonds and to stabilize carbocation intermediates

OCH 3

OCH 3

OCH 3

OCH 3

"more negative charge on the ring": more reactive to an electrophile (E+)

O
N

O
N

O
N

"more positive charge on ring": less reactive to an electrophile (E + )

So what about the direction of E+ attack when a substituent is already present?

X

X
E+

E
or

or
E
E

Hammonds postulate - for an endothermic reaction, the transition state will

resemble the product; what stabilizes the first intermediate (decreases its energy) will also
stabilize the first transition state that generates the intermediate

+
transition
state

E ne r g y

intermediate

activation
energy
Hint (> 0)

+ E+

Hrxn

Reaction Coordinate

Let us consider substituent preferences for the intermediate carbocation and then try
to infer whether the substituent will help (or hurt) the transition state

OCH3

OCH 3

OCH3
H
E

E+

OCH3
H
E

H
E

ortho

OCH3

OCH3

OCH3

E+
H

meta

OCH3

E+

H
E

OCH 3

OCH3

para
H

For ortho and para: -OCH3 substituent can help to stabilize the carbocation
intermediate; meta is not in the right spot to conjugate (interact) via resonance
structures with the electron donating substituent
What does that mean?
(a) ortho and para direction of E+ attack because the intermediate carbocation is
stabilized by the substituent on the ring and (via Hammonds postulate) the transition
state that formed the intermediate is lower in energy => lower activation barrier =>
faster formation of the ortho and para products
(b) meta direction of attack is even not as good as benzene as the oxygen is
inductively electron withdrawing too; meta attack can NOT compete with ortho and
para attack
methoxy (-OCH3) substituent is ortho-para directing and activating


Gm

E ner gy

GH

Go,p

Reaction Coordinate

activating (A) substituents are ortho-para directors

E ner gy

Go,p

Gm

GH

Reaction Coordinate
MOST (but not all) deactivating (D) substituents are meta directors

Meta directors: deactivating substituents are meta directing for incoming E+

N
+
C

N
+
C

+
C

+
C
H

E+

H
E

ortho

N
+
C

+
C

+
C

E+
para
H

+
C

+
C

+
C

E+
meta

H
E

H
E

H
E

meta is NOT good but instead meta avoids the positive-positive interaction that
ortho and para have; so meta is less poor compared to the other choices
Most (but not all) deactivating substituents are meta directing.

Halogens: F, Cl, and Br are deactivating substituents but ortho-para directing. Why?
(a) deactivating substituents from an inductive sense halogens are more
electronegative than carbon; the aromatic rings double bonds are less electron rich
(b) ortho-para directing because halogen substituent also have lone pairs to donate in
order to stabilize the carbocation intermediate

Cl

Cl

Cl
H
E

E+

Cl
H
E

Cl
H
E

H
E

ortho

Cl

Cl

Cl

E+
H

meta
E

para would be stabilized just like ortho as we saw before draw them!

H
E

Alkyl substituted benzene reactions:

CH3 is activating at all positions (slight electron donating/polarizableeffect)

GH

Gm

E ner gy

Go,p

Reaction Coordinate
But meta cannot stabilize the intermediate carbocation from the addition of E+ as well
as ortho-para; therefore, alkyl groups are ortho-para directors and slightly activating
(but not by much)
CH 3

CH 3

CH 3

H
E

H
E

E+

CH 3
H
E

ortho

CH 3

CH 3

CH 3

E+
H

meta
E

H
E

H
E

Summary:
(a) donating substituents direct new substituents (electrophiles) into the ortho and para
positions; these positions react faster than benzene would
(b) withdrawing substituents direct new substituents (electrophiles) into the meta
position; all positions react slower than benzene, but meta is just better than ortho and
para
Making tri-substituted benzenes: how do two groups direct the third substituent?
(1) If both groups reinforce each other:
OCH3
OCH3
E+
E+

NO2

NO2

CO2H

CO2H

O 2N

O 2N

E+
(2) If competition between directing effects, then donating groups will dominate
OCH3
OCH3
E+
E+

O 2N

O 2N
HNO3
H2SO4
OCH3

E+
OCH3
NO2

+
O 2N

O 2N
NO2

(3) If two donating or two withdrawing groups are competing, it is hard to predict
(probably will get a mixture)
CH 3
CH 3

HNO 3
H2SO 4

mixture (mess)
O

O
HN

HN

CH 3
OCH 3

CH 3
OCH 3

HNO 3
H2SO 4
NO 2

Besides electrophilic aromatic substitution, are there other kinds of mechanisms that
occur with aromatic rings?

(1) Nucleophilic Aromatic Substitution:

Cl

OH
NO 2

O 2N

O 2N

1) HO
2) H3O +

NO 2

NO 2

NO 2

NOT SN1 (phenyl cation is not a good carbocation)

NOT SN2 (no backside attack is possible)
where one gets nucleophilic attack on the ring and
electron withdrawing substituents can stabilize the negative charge in the intermediate
Cl
O 2N

Cl
NO 2

HO

OH
NO 2

O 2N

NO 2

NO 2

and other
resonance
forms

Meisenheimer
complex

OH
NO 2

O 2N

Cl

NO 2
first step is an addition; second step is an elimination to make the product
(a) many resonance forms with NO2 group which can help to stabilize the negative
charge
(b) if the ring did not have good electron withdrawing substituents to stabilize the
negative charge, this mechanism could not occur
(c) electron withdrawing substituents must be in the ortho and para positions relative
to leaving group in order to stabilize the negative charge (draw the resonance forms)

(2) Benzyne: need a very strong base; an

X

elimination

+
addition

H-B

benzyne

Base (B):
(1) could be HO (very high temperature) in H2O or
(2) NH2 in liquid NH3 (-33C)

Br

NH2
NH3 (liq)

NH 2
+

Br

benzyne can be trapped by other compounds too it is a very reactive intermediate