Chapter 16

Introduction
Electrophilic aromatic substitution is the most
common reaction of aromatic compounds
It replaces a proton (H+) on an aromatic ring with
another electrophile (E+)
It leads to the retention of the aromatic core

Some electrophilic aromatic substitution reactions

1.

Bromination of Aromatic Rings

Benzene is a site of electron density

Its 6 electrons are in a cyclic conjugated system
Its 6 electrons are sterically accessible to other
reactants because they are located above or below
the plane

 Benzene acts as an electron donor (a Lewis

base or nucleophile)
It reacts with electron acceptors (Lewis acids or
electrophiles)
Benzenes electrons participate as a Lewis
base in reactions with Lewis acids

Bromination of benzene occurs in two steps:

Step 1: The electrons act as a nucleophile toward

Br2 (in a complex with FeBr3) to form a nonaromatic
carbocation intermediate

Step 2: The resonance-stabilized carbocation

intermediate loses H+ to regenerate the aromatic ring

Electrophilic Alkene Addition

Electrophilic Aromatic Bromination

Aromatic rings are less reactive toward electrophiles

than alkenes
Unlike alkenes, benzene does not react rapidly with
Br2 in CH2Cl2
For bromination, benzene requires FeBr3 as a
catalyst to polarize the bromine reagent and make it
more electrophilic

 Step 1: The electrons act as a nucleophile and

attack the polarized Br2 (in a complex with FeBr3)
to form a nonaromatic carbocation intermediate
It is a slow,
slow rate-limiting step (high G)
The carbocation is doubly allylic (nonaromatic)
nonaromatic
and has three resonance forms

 The carbocation intermediate is not aromatic and

is high in energy (less stable than benzene)

 Step 1 is endergonic,
endergonic has a high G and is a slow
reaction

 Step 2: The resonance-stabilized carbocation

intermediate loses H+ to regenerate the aromatic
ring and yield a substitution product in which H+ is
replaced by Br+
It is similar to the 2nd step of an E1 reaction
The carbocation intermediate transfers a H+ to
FeBr4- (from Br- and FeBr3)
This restores aromaticity (in contrast with
addition in alkenes)

 Step 2 is exergonic,
exergonic has a low G and is a fast
reaction

Electrophilic Aromatic Bromination: Mechanism

Why is there electrophilic aromatic substitution rather

than addition?
Substitution reaction retains the stability of the
aromatic ring and is exergonic

Addition
Loss of aromaticity
Endergonic

Substitution
Retention of aromaticity
Exergonic

Practice Problem: Monobromination of toluene gives a mixture of

three bromotoluene products. Draw and name
them.

2.

Other Aromatic Substitutions

The reaction with bromine involves a mechanism

that is similar to many other reactions of benzene
with electrophiles
The cationic intermediate was first proposed by
G. W. Wheland and is often called the Wheland
intermediate

Electrophilic Aromatic Substitution

An electrophilic aromatic substitution reaction

involves two steps:
reaction of an electrophile E+ with an aromatic ring
loss of H+ from the resonance-stabilized carbocation
intermediate to regenerate the aromatic ring

 The same general mechanism is used by

other aromatic substitutions including:
Chlorination
Iodination
Nitration
Sulfonation
F is too reactive for monofluorination

Aromatic Chlorination

Benzene ring reacts with Cl2 in the presence of FeCl3 catalyst to yield
chlorobenzene
It requires FeCl3 to polarize Cl2 (make it more electrophilic)

Aromatic Iodination

Benzene ring reacts with I2 in the presence of an oxidizing agent (H2O2 or CuCl2) to
yield iodobenzene
Iodine must be oxidized to form a more powerful electrophilic I + species (with Cu2+ or
peroxide)

Aromatic Nitration

Benzene ring reacts with a mixture of concentrated nitric and sulfuric acids (HNO3 and
H2SO4) to yield nitrobenzene
The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion), an
electrophile

 The electrophile NO2+ is produced when HNO3 is

protonated by H2SO4 and loses H2O

 NO2+ reacts with benzene to give a carbocation

intermediate which loses H+ to yield nitrobenzene

 Aromatic nitration is useful in the pharmaceutical

industry because the nitro-substituted product can
be reduced by Fe or SnCl2 to yield arylamine

Aromatic Sulfonation

Benzene ring reacts with fuming sulfuric acid (a mixture of H2SO4 and SO3) to yield
benzenesulfonic acid
The reactive electrophile is either HSO3+ or neutral SO3 depending on reaction
conditions

 The reactive electrophile is either sulfur trioxide SO3

or its conjugate acid HSO3+

 The reaction occurs via the Wheland intermediate

(carbocation)

 The reaction is reversible (Sulfonation is favored in

strong acid; desulfonation, in hot, dilute aqueous
acid)

 Aromatic sulfonic acids are useful as intermediates

in the synthesis of dyes and pharmaceuticals.

Example:
Example Sulfadrugs

A sulfadrug

 Aromatic sulfonic acids undergo alkali fusion reaction

Heating with NaOH at 300 C followed by neutralization with acid replaces the SO 3H group with an
OH

Example:
Example Synthesis of p-cresol

Practice Problem: How many products might be formed on

chlorination of o-xylene (o-dimethylbenzene),
m-xylene, and p-xylene?

Practice Problem: When benzene reacts with D2SO4, deuterium

slowly replaces all six hydrogens in the
aromatic ring. Explain.

3.

Alkylation of Aromatic Rings: The

Friedel-Crafts Reaction

Benzene ring reacts with an alkyl chloride in the

presence of AlCl3 catalyst to yield an arene
Alkylation was first reported by Charles Friedel
and James Crafts in 1877

 Friedel-Crafts alkylation is an electrophilic

aromatic substitution in which the electrophile is
a carbocation, R+.
AlCl3 catalyst promotes the formation of the
alkyl carbocation, R+, from the alkyl halide, RX
The Wheland (carbocation) intermediate forms
Alkylation is the attachment of an alkyl group to
benzene; R+ substitutes for H+

Friedel-Crafts Alkylation Reaction: Mechanism

Limitations of the Friedel-Crafts Alkylation

1. Only alkyl halides can be used (F, Cl, Br, I)
Aryl halides and vinylic halides do not react (their
carbocations are too high in energy to form)

2. No reaction occurs if the aromatic ring has an amino

group or a strongly electron-withdrawing group
substituent
Amino groups react with AlCl3 catalyst in an acid-base
reaction

3. It is difficult to control the reaction. Multiple alkylations

can occur because the first alkylation is activating
Polyalkylation is often observed

4. Carbocation rearrangements occur during alkylation,

particularly when a 1o alkyl halide is used
Catalyst, temperature and solvent affect the amount
of rearrangement

Rearranged

Unrearranged

Carbocation rearrangements of Friedel-Crafts alkylation

are similar to those that occur during electrophilic
additions to alkenes
can involve hydride (H:-) or alkyl shifts

More Stable

Limitations of the Friedel-Crafts Alkylation

1.

Only alkyl halides can be used (F, Cl, Br, I)

2.

No reaction occurs if the aromatic ring has an amino

group or a strongly electron-withdrawing group
substituent

3.

It is difficult to control the reaction. Multiple alkylations

can occur because the first alkylation is activating

4.

Carbocation rearrangements occur during alkylation,

particularly when a 1o alkyl halide is used

Practice Problem: The Friedel-Crafts reaction of benzene with 2chloro-3-methylbutane in the presence of AlCl3
occurs with carbocation rearrangement. What
is the structure of the product?

Practice Problem: Which of the following alkyl halides undergo

Friedel-Crafts reaction without
rearrangement?
Explain.
a. CH3CH2Cl
b. CH3CH2CH(Cl)CH3
c. CH3CH2CH2Cl
d. (CH3)3CCH2Cl
e. Chlorocyclohexane

Practice Problem: What is the major monosubstitution product

from Friedel-Crafts reaction of benzene with 1chloro-2-methylpropane in the presence of
AlCl3?

4.

Acylation of Aromatic Rings: The

Friedel-Crafts Reaction

Benzene ring reacts with a carboxylic acid chloride,

RCOCl, in the presence of AlCl3 catalyst to yield an
acylbenzene
Acylation is the attachment of an acyl group,-COR,
to benzene; RCO+ substitutes for H+

 Friedel-Crafts acylation is an electrophilic aromatic

substitution in which the reactive electrophile is a
resonance-stabilized acyl cation, RCO+.
AlCl3 catalyst promotes the formation of the acyl
cation, RCO+, from the acyl chloride, RCOCl
The acyl cation, RCO+, does not rearrange; it is
resonance-stabilized
The Wheland (carbocation) intermediate forms

Friedel-Crafts Acylation Reaction: Mechanism

The mechanism of Friedel-Crafts acylation is
similar to Friedel-Crafts alkylation

 In Friedel-Crafts acylation, there is no carbocation

rearrangement nor multiple substitution
No carbocation rearrangement: The acyl cation, RCO+, does not
rearrange because it is resonance-stabilized by interaction of the
vacant orbital on C with lone pair of electrons on O

No multiple substitution: Acylated benzene is less reactive than

nonacylated benzene

Practice Problem: Identify the carboxylic acid chloride that might

be used in a Friedel-Crafts acylation reaction
to prepare each of the following acylbenzenes

5.

Substituent Effects in Substituted

Aromatic Rings

A substituent present on an aromatic ring affects:

the reactivity of the aromatic ring

the orientation of the reaction

Substituents affect the reactivity of the aromatic ring

Substituents may

activate the ring, make it (much) more reactive than

benzene or

deactivate the ring, make it (much) less reactive

than benzene

Substituents affect the orientation of the reaction

Substituents present on the ring determine the
position of the 2nd substitution: ortho,
ortho meta,
meta and para

Classification of Substituent Effect

Substituents can be classified as:

ortho- and para-directing activators,

ortho- and para-directing deactivators, and
meta-directing deactivators

The directing effects of the groups correlate with their

reactivities:

All meta-directing groups are strongly deactivating

Most ortho- and para-directing groups are activating
Halogens are unique being ortho- and para-directing but
weakly deactivating

Origins of Substituent Effects

Reactivity and orientation in electrophilic aromatic substitutions are
controlled by an interplay of inductive effects and resonance effects:
effects
Inductive effect - withdrawal or donation of electrons through a
bond
Resonance effect - withdrawal or donation of electrons through a
bond

Inductive Effects
Inductive effects - withdrawal or donation of electrons through a bond
due to electronegativity and polarity of bonds in functional groups

Halogens, C=O, CN, and NO2 groups inductively withdraw electrons

through bond connected to ring

Alkyl groups inductively donate electrons

Halogens, C=O, CN, and NO2 inductively withdraw

electrons through bond connected to ring

Alkyl groups inductively donate electrons

Resonance Effects
Resonance effect - withdrawal or donation of electrons
through a bond due to the overlap of a p orbital on
the substituent with a p orbital on the aromatic ring

C=O, CN, and NO2 groups withdraw electrons from

the aromatic ring by resonance

Halogen, OH, alkoxyl (OR), and amino substituents

donate electrons to the aromatic ring by resonance

C=O, CN, and NO2 groups withdraw electrons from the aromatic ring by
resonance
electrons flow from the ring to the substituents, placing a positive charge in the ring

C=O, CN, and NO2 groups withdraw electrons from the aromatic ring by resonance
placing a positive charge in the ring
Effect is greatest at ortho and para

Z is more electronegative than Y

Halogen, OH, alkoxyl (OR), and amino substituents donate electrons to the aromatic
ring by resonance
electrons flow from the substituents to the rings placing a negative charge in the ring

Halogen, OH, alkoxyl (OR), and amino substituents donate electrons to the
aromatic ring by resonance placing a negative charge in the ring
Effect is greatest at ortho and para

Y has a lone pair of electrons

Contrasting Effects: Inductive vs Resonance

When the two effects act in opposite direction, the

strongest effects dominate.

Halogens have electron-withdrawing inductive effects due

to electronegativity

Halogens have electron-donating resonance effects due

to lone-pair electrons

Resonance interactions are generally weaker, affecting

orientation. Thus, halogens deactivate the ring

Practice Problem: Predict the major product of the monosulfonation

of toluene.

Practice Problem: Write resonance structures for nitrobenzene to

show the electron-withdrawing resonance
effect of the nitro group.

Practice Problem: Write resonance structures for chlorobenzene

to show the electron-donating resonance
effect of the chloro group.

Practice Problem: Predict the major products of the following

reactions

a. Mononitration of bromobenzene
b. Monobromination of nitrobenzene
c. Monochlorination of phenol
d. Monobromination of aniline

6.

An Explanation of Substituent
Effects

Activating groups donate electrons to the ring,

stabilizing the Wheland intermediate (carbocation)
OH, OR, NH2 and R

Deactivating groups withdraw electrons from the

ring, destabilizing the Wheland intermediate
CN, C=O, NO2 and X

An electron-withdrawing group makes the ring more electron-poor (eg. CN and Cl)

An electron-donating group makes the ring more electron-rich (eg. CH3 and NH2)

Practice Problem: Rank the compounds in each group in order of

their reactivity to electrophilic substitution

a. Nitrobenzene, phenol, toluene, benzene

b. Phenol, benzene, chlorobenzene, benzoic acid
c. Benzene, bromobenzene, benzaldehyde, aniline

Practice Problem: Explain why Friedel-Crafts alkylations often

give polysubstitution but Friedel-Crafts
acylations do not

Practice Problem: Would you expect trifluoromethylbenzene to be

more reactive or less reactive than toluene
toward electrophilic substitution? Explain.

Ortho- and Para-Directing Activators: Alkyl Groups

Alkyl groups are activating

They have an electron-donating inductive effect

Alkyl groups are ortho and para directors

The ortho and para intermediates are the most stabilized (lower in energy)
The positive charge is directly on the alkyl-substituted carbon (3
3o carbon)
carbon and is stabilized by the inductive electron-donating effect of the alkyl group

The positive charge is directly on the alkyl-substituted

carbon (3o carbon)
carbon and is stabilized by the inductive
electron-donating effect of the alkyl group

Ortho- and Para-Directing Activators: OH and NH2

OH, OR and NH2 groups are activating

They have a strong electron-donating resonance and a weak electron-withdrawing inductive effect

OH, OR and NH2 groups are ortho and para directors

The ortho and para intermediates are the most stabilized (lower in energy)
The positive charge is stabilized by resonance donation of an electron pair from O or N

The ortho and para intermediates are more stable because

of resonance donation of an electron pair from O or N

Practice Problem: Acetanilide is less reactive than aniline toward

electrophilic substitution. Explain.

Ortho- and Para-Directing Deactivators: Halogens

Halogens are deactivating

They have a strong electron-withdrawing inductive and a weak electron-donating resonance effect

Halogens are ortho and para directors

The ortho and para intermediates are the most stabilized (lower in energy)
Halogens stabilize the positive charge by resonance donation of a lone pair of electrons

The ortho and para intermediates are more stable because

of resonance donation of an electron pair from X

Meta-Directing Deactivators

All meta-directing groups are strongly deactivating

They have electron-withdrawing inductive and
resonance effects that reinforce each other
The ortho and para intermediates are destabilized
The positive charge of the carbocation intermediate
in ortho and para attack is directly on the carbon
that bears the deactivating group and resonance
cannot produce stabilization

The meta intermediate is more stable because resonance does not place
the positive charge directly on the carbon that bears the deactivating group

Summary of Substituent Effects in Aromatic Substitution

Practice Problem: Draw resonance structures for the intermediates

from reaction of an electrophile at the ortho, meta,
and para positions of nitrobenzene. Which
intermediates are most stable?

7.

Trisubstituted Benzenes: Additivity

of Effects

Three rules for the additive effects of two different groups:

1. If the directing effects of the two groups are the
same, the result is additive
2. If the directing effects of two groups oppose each
other, the more powerful activating group
determines the principal outcome
3. The position between the two groups in metadisubstituted compounds is unreactive

1.

If the directing effects of the two groups are the same, the result is additive

It gives a single product

2.

If the directing effects of two groups oppose each other, the more powerful
activating group determines the principal outcome

It usually gives mixtures of products

3.

The position between the two groups in meta-disubstituted compounds is unreactive

The reaction site is too hindered

To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound

Practice Problem: What product would you expect from bromination

of p-methylbenzoic acid?

Practice Problem: At what positions would you expect electrophilic

substitution to occur in the following substances?

Practice Problem: Show the major product(s) from reaction of the

following substances with (i) CH3CH2Cl, AlCl3
and (ii) HNO3, H2SO4

8.

Nucleophilic Aromatic Substitution

Nucleophilic aromatic substitution is a reaction that

aryl halides with electron-withdrawing substituents
undergo
It replaces a halide ion (X-) on an aromatic ring with
another nucleophile (Nu-)

Nucleophilic Aromatic Substitution

A nucleophilic aromatic substitution reaction occurs in two steps

by the addition/elimination mechanism:
Step 1: Addition of the nucleophile (Nu-) to the electron-deficient
aryl halide, forming a resonance stabilized carbanion
intermediate (Meisenheimer complex)
Step 2: Elimination of a halide ion (X-) from the carbanion
intermediate to regenerate the aromatic ring

Nucleophilic Aromatic Substitution: Mechanism

Nucleophilic aromatic substitution occurs ONLY if the aryl

halide has an electron-withdrawing substituent in ortho
and/or para position
The more such substituents, the faster the reaction
Only ortho and para electron-withdrawing substituents
can stabilize the anion intermediate through resonance

Only ortho and para intermediate carbanions (Meisenheimer

complex) are resonance stabilized by electron-withdrawal

A nucleophilic aromatic substitution reaction is neither an Sn 1 nor an Sn2

reaction:

Not Sn1: Aryl cations are unstable for dissociation to occur

Not Sn2: Backside displacement is sterically blocked

Electrophilic vs Nucleophilic Aromatic Substitution

Electrophilic Aromatic
Substitution

Nucleophilic Aromatic
Substitution

is favored by electrondonating groups

is favored by electronwithdrawing groups

involves a carbocation
intermediate

involves a carbanion
intermediate

replaces a H with an
electrophile

replaces a leaving group

with a nucleophile

 Electron-donating
groups

Electron-withdrawing
groups

favor electrophilic
aromatic substitution

favor nucleophilic
aromatic substitution

stabilize carbocation
intermediate

stabilize carbanion
intermediate

are ortho-para
directors in
electrophilic reaction

are ortho-para directors

in nucleophilic reaction
but meta-directors in
electrophilic substitution

Practice Problem: Propose a mechanism for the reaction of 1chloroanthraquinone with methoxide ion to give
the substitution product 1-methoxyanthraquinone.
Use curved arrows to show the electron flow in
each step.

9.

Benzyne

Aryl halides without electron-withdrawing substituents

undergo substitution with a benzyne intermediate
Phenol is prepared on an industrial scale by
treatment of chlorobenzene with dilute aqueous
NaOH at 340C under high pressure

The synthesis of phenol occurs in two steps by the

elimination/addition mechanism rather than addition/elimination:
Step 1: Elimination of a HX from halobenzene in an E2
reaction catalyzed by a strong base, forming a highly reactive
benzyne intermediate
Step 2: Addition of a nucleophile (Nu-) to the benzyne
intemediate

Evidence for Benzyne as an Intermediate

Bromobenzene with 14C only at C1 gives substitution
product with label scrambled between C1 and C2
The reaction proceeds through a symmetrical
intermediate in which C1 and C2 are equivalent
The intermediate must be benzyne

 Trapping experiments further demonstrate that

benzyne was the intermediate
Benzyne is too reactive to be isolated and thus can be
intercepted in a Diels-Alder reaction

Structure of Benzyne
Benzyne is a highly distorted alkyne
The triple bond uses sp2-hybridized carbons, not the
usual sp
The triple bond has one bond formed by pp
overlap and one bond formed by weak sp2sp2
overlap

Practice Problem: Treatment of p-bromotoluene with NaOH at 300 oC

yields a mixture of two products, but treatment of
m-bromotoluene with NaOH yields a mixture of
three products. Explain

10. Oxidation of Aromatic Compounds

There are two reactions of alkylbenzene side chains:
Oxidation of Alkylbenzene Side Chains
Bromination of Alkylbenzene Side Chains

Aromatic ring activates neighboring benzylic (C-H)

position toward oxidation

Oxidation of Alkylbenzene Side Chains

Alkyl side chains can be oxidized to carboxyl groups,

-CO2H, by strong oxidizing agents such as KMnO 4 and
Na2Cr2O7
The alkyl side chains must have a C-H next to the ring
This converts an alkylbenzene into a benzoic acid, ArR Ar-CO2H

The mechanism of side-chain oxidation involves

reaction of C-H next to the ring to form intermediate
benzylic radicals

t-butylbenzene is inert (no benzylic Hs)

Practice Problem: What aromatic products would you obtain from

the
KMnO4 oxidation of the following substances?

Bromination of Alkylbenzene Side Chains

Reaction of an alkylbenzene with N-bromo-succinimide

(NBS) and benzoyl peroxide (radical initiator)
introduces Br into the side chain
Bromination occurs exclusively in the benzylic
position

Mechanism of NBS (Radical) Reaction

Abstraction of a benzylic hydrogen atom generates

an intermediate benzylic radical

This reacts with Br2 to yield product and Br

Br radical cycles back into reaction to carry on chain
Br2 is produced from reaction of HBr with NBS

Bromination occurs exclusively in the benzylic

position because the benzylic radical intermediate is
resonance-stabilized

The benzylic radical is stabilized by overlap of its p orbital

with the ring p electron system

Practice Problem: Refer to Table 5.3 for a quantitative idea of the

stability of a benzyl radical. How much stable (in
kJ/mol) is the benzyl radical than a primary alkyl
radical? How does a benzyl radical compare in
stability to an allyl radical

Practice Problem: Styrene, the simplest alkenylbenzene, is prepared

commercially for use in plastics manufacture by
catalytic dehydrogenation of ethylbenzene. How
might you prepare styrene from benzene?

11. Reduction of Aromatic Compounds

There are two reduction reactions:
Catalytic hydrogenation of Aromatic Rings
Reduction of Aryl Alkyl Ketones

Catalytic hydrogenation of Aromatic Rings

Reduction of an aromatic ring requires more powerful

reducing conditions (H2/Pt at high pressure or
rhodium catalysts)

Aromatic rings are inert to catalytic hydrogenation

under conditions that reduce alkene double bonds

It is possible to selectively reduce an alkene double

bond in the presence of an aromatic ring

Reduction of Aryl Alkyl Ketones

Aromatic ring activates neighboring carbonyl group toward reduction

Aryl alkyl ketone is converted into an alkylbenzene by catalytic

hydrogenation over Pd catalyst

Conversion of a carbonyl group to a methylene group

by catalytic hydrogenation (C=O CH2)
is limited to aryl alkyl ketones
is not compatible with the presence of a nitro group

Practice Problem: Show how you would prepare diphenylmethane

(Ph)2CH2, from benzene and an appropriate acid
chloride

12. Synthesis of Trisubstituted Benzenes

These syntheses require planning and consideration of alternative routes

1. Compare the target and the starting material
1. Consider reactions that efficiently produce the outcome.
1. Look at the product and think of what can lead to it

A synthesis combines a series of proposed steps to go from a defined set of

reactants to a specified product

Synthesis as a Tool for Learning Organic Chemistry

In order to propose a synthesis, one must be familiar with
reactions:

What they begin with

What they lead to
How they are accomplished
What the limitations are

The order in which reactions are carried is critical in the

synthesis of substituted aromatic rings
The introduction of a new substituent is strongly affected by the
directing effects of other substituents

Practice Problem: Synthesize p-bromobenzoic acid from benzene

Br Bromination using Br2/FeBr3

CO2H Friedel-Crafts alkylation or acylation followed by oxidation

Practice Problem: Propose a synthesis of 4-chloro-1-nitro-2propylbenzene from benzene

Cl Chlorination using Cl2/FeCl3

NO2 Nitration using HNO3/H2SO4
CH2CH2CH3 Friedel-Crafts acylation followed by reduction

Practice Problem: Propose syntheses of the following substances

from benzene:

a. m-Chloronitrobenzene
b. m-Chloroethylbenzene
c. p-Chloropropylbenzene

Practice Problem: In planning a synthesis, it is important to know

what NOT to do as to know what do. As written,
the following reaction schemes have flaws in
them. What is wrong with each?

Chapter 16