Chapter 13

Electrophilic and Nucleophilic

Aromatic Substitution
 Electrophilic Substitution
• We have previously seen electrophilic addition, in which
an electrophile adds across a π bond

• This chapter is concerned with electrophilic substitution

Section 13.1

REPRESENTATIVE
ELECTROPHILIC AROMATIC
SUBSTITUTION REACTIONS OF
BENZENE
 Electrophilic Aromatic Substitution
• C–H groups in arenes can be substituted by electrophilic
reagents; this reaction is called electrophilic aromatic
substitution
• Many different types of electrophiles can be employed in
this reaction

Note the use of Brønsted acids as electrophiles.

 Electrophilic Aromatic Substitution
• C–H groups in arenes can be substituted by electrophilic
reagents; this reaction is called electrophilic aromatic
substitution
• Many different types of electrophiles can be employed in
this reaction

Elemental halogens are not electrophilic enough on their own,

but can be used together with a Lewis-acidic catalyst.
 Electrophilic Aromatic Substitution
• C–H groups in arenes can be substituted by electrophilic
reagents; this reaction is called electrophilic aromatic
substitution
• Many different types of electrophiles can be employed in
this reaction
Section 13.2

MECHANISTIC PRINCIPLES OF
ELECTROPHILIC AROMATIC
SUBSTITUTION
 Mechanism of EAS
• The first step of electrophilic addition involves the π bond acting
as nucleophile

• Electrophilic aromatic substitution has the same first step and

carbocation intermediate
arenium cation
 Mechanism of EAS
• The second step of electrophilic addition involves nucleophilic Y–
attacking the carbocation

• In step 2 of electrophilic aromatic substitution, Y– deprotonates

the cation in an E1-style elimination step
aromaticity broken aromaticity restored

cyclohexadienyl cation, arenium

ion, or σ-complex
 Reaction Coordinate Diagram

The high activation energy of the 1st

step requires very reactive
electrophiles.

Understanding the nature of the

electrophile is very important!

Step 1 is rate determining.

Section 13.3

NITRATION OF BENZENE
 Nitration of Benzene
• Benzene reacts with nitric and sulfuric acids at moderate
temperatures to form nitrobenzene

• The active electrophile is the nitronium cation (NO2+)

 Generation of the Electrophile
• Step 1: H2SO4, the stronger acid, protonates HNO3
• Step 2: H2O is eliminated from protonated nitric acid
 Mechanism of Substitution
• Step 1 (RDS): benzene attacks NO2+, forming an
arenium cation
• This is the slow step that determines the rate of the
reaction
 Mechanism of Substitution
• Step 2: water (or solvent base) deprotonates the
arenium cation at the β-position, restoring aromaticity
• The proton is lost from the carbon where the new
substituent added
Section 13.4

SULFONATION OF BENZENE
 Sulfonation of Benzene
• Sulfonation with H2SO4 alone is reversible, but driven
forward if SO3 is included

• The active electrophile is SO3, generated

via elimination of H2O from H2SO4
 Mechanism of Substitution
• Step 1 (RDS): benzene attacks SO3, forming an arenium
cation
• This is the slow step that determines the rate of the
reaction
 Mechanism of Substitution
• Step 2: hydrogen sulfate deprotonates the arenium
cation at the β-position, restoring aromaticity
• The proton is lost from the carbon where the new
substituent added
 Mechanism of Substitution
• Step 3: proton transfer from H2SO4 to the sulfonate
group occurs, forming the sulfonic acid product
Section 13.5

HALOGENATION OF BENZENE
 Halogenation of Benzene
• X2 reacts only very slowly with benzene—a catalyst is
required
• Metallic iron can be used together with Br2 or Cl2

• The active catalyst is FeX3, a good Lewis acid

 Active Electrophile
• The active electrophile is a complex of Br2 with FeBr3
• A Lewis-basic Br attacks the Lewis-acidic Fe atom,
rendering the other Br electrophilic

electrophilic
Br atom
 Mechanism of Substitution
• Step 1 (RDS): benzene attacks the active electrophile,
forming an arenium ion
• This is the slow step that determines the rate of the
reaction
 Mechanism of Substitution
• Step 2: tetrabromoferrate deprotonates the arenium
cation at the β-position, restoring aromaticity
• The proton is lost from the carbon where the new
substituent added
Section 13.6

FRIEDEL-CRAFTS
ALKYLATION OF BENZENE
 Friedel-Crafts Alkylation
• In the presence of AlX3, alkyl halides RX form carbocations R+
which can serve as electrophiles in EAS reactions

• The reaction of carbocations with arenes is called Friedel-Crafts

alkylation
 Rearrangements
• The carbocation intermediates of Friedel-Crafts alkylation are
susceptible to rearrangements

• Primary alkyl halides, which do alkylate benzene with AlX3,

undergo rearrangements
 Other Carbocation Precursors
• Many different routes to carbocations can be used for Friedel-
Crafts alkylation
– Protonation of alcohols followed by dissociation of H2O
– Protonation of alkenes
Section 13.7

FRIEDEL-CRAFTS ACYLATION
OF BENZENE
 Friedel-Crafts Acylation
• Acyl halides contain a carbonyl group bound to a halogen X
• Friedel-Crafts acylation: acyl halides participate in electrophilic
aromatic substitution in the presence of AlX3

• The active electrophile is acylium ion, an acyl halide without the

halide!

Acylium ions do not engage

in rearrangements.
 Cl + AlCl3 Cl AlCl3

O O

+ AlCl4-
O
 Mechanism of Acylation
• Analogous to other electrophilic aromatic substitution
mechanisms, with acylium as the active electrophile
Preparation and Alternative Acyl Chloride
Section 13.8

SYNTHESIS OF ALKYLBENZENES
BY ACYLATION-REDUCTION
 Strategic Synthesis of Alkylbenzenes
• Friedel-Crafts acylation avoids rearrangements, but the products
are aryl ketones rather than alkylbenzenes
 Strategic Synthesis of Alkylbenzenes
• Friedel-Crafts acylation avoids rearrangements, but the products
are aryl ketones rather than alkylbenzenes
• A subsequent reduction step converts the C=O group to a CH2
group (aryl ketone to alkylbenzene)

• There are two common methods for carbonyl reduction; one uses
acidic conditions and the other basic conditions
 Clemmensen Reduction
• Clemmensen reduction: Zn(Hg) amalgam in
hydrochloric acid reduces C=O to CH2
• Zn is the active reducing agent (source of electrons),
with HCl as a source of protons

• Useful for substrates that can withstand strong acid

 Wolff-Kishner Reduction
• Wolff-Kishner reduction: H2NNH2 in KOH at high
temperatures reduces C=O to CH2

• Useful for substrates that can withstand strong base

• Both methods leave other reducible groups untouched
Will a direct F/C alkylation work?
AlCl3
+ Cl
Section 13.9

RATE AND REGIOSELECTIVITY IN

ELECTROPHILIC AROMATIC
SUBSTITUTION
 Rate of Electrophilic Substitution
• Substituents on the ring affect the rate of
electrophilic aromatic substitution

• Electron-withdrawing substituents (–CF3) slow down substitution;

electron-donating substituents (–CH3) speed it up (it is
ELECTROPHILIC reaction, the electrophile reacts with the π
electrons, the higher π electron density on the ring, the faster the
reaction.)
 Rate of Electrophilic Substitution
• Electron-withdrawing substituents (–CF3) slow down substitution;
electron-donating substituents (–CH3) speed it up
• Electrostatic potential maps illustrate how substituents affect
electron density in the ring

Least reactive Most reactive

Least electron Most electron
density in ring density in ring
 Methyl Group

Toluene undergoes nitration

CH3 20-25 times faster than
benzene.
A methyl group is an
activating substituent.

44
 Trifluoromethyl Group

(Trifluoromethyl)benzene
CF3 undergoes nitration 40,000
times more slowly than benzene .
A trifluoromethyl group is a
deactivating substituent.

45
 Regioselectivity of Substitution
• For substrates with one substituent already, where does the
new substituent appear in the product?
• Depends on the donating or withdrawing nature of the
substituent
• The electron-donating methyl substituent directs substitution
to the ortho and para positions

–CH3 is an ortho, para director.

 Regioselectivity of Substitution
• For substrates with one substituent already, where does the
new substituent appear in the product?
• Depends on the donating or withdrawing nature of the
substituent
• The electron-withdrawing –CF3 substituent directs substitution
to the meta position

–CF3 is a meta director.

Section 13.10

RATE AND REGIOSELECTIVITY IN

THE NITRATION OF TOLUENE
 Structure and Stability of Arenium
• Substituents profoundly affect the stability of the possible
arenium cations that can arise from substitution at different
positions (and thereby the relative rates of substitution)
• Resonance structures involving the substituent explain why a
particular arenium cation is formed preferentially
• Consider the nitration of toluene:

• Can we explain why this is the case?

Methyl-substituted Arenium Cations
• The arenium from meta substitution has resonance forms with
secondary carbocations

• The more stable areniums from ortho or para substitution have

one resonance form with a tertiary carbocation!
Methyl-substituted Arenium Cations
• The arenium from meta substitution has resonance forms with
secondary carbocations

• The more stable areniums from ortho or para substitution have

one resonance form with a tertiary carbocation!
 Nitration of Toluene: Interpretation

• The rate-determining intermediates for ortho and para

nitration each have a resonance form that is a tertiary
carbocation. All of the resonance forms for the rate-
determining intermediate in meta nitration are
secondary carbocations.
• Tertiary carbocations, being more stable, are formed
faster than secondary ones. Therefore, the
intermediates for attack at the ortho and para
positions are formed faster than the intermediate for
attack at the meta position. This explains why the
major products are o- and p-nitrotoluene.

52
 Relative Activation Energies
Substitution at the ortho position is slighly
disfavored relative to para due to steric factors.

Methyl is an electron-releasing substituent. All sites in toluene are more

reactive than that in benzene!
 Nitration of Toluene: Partial Rate Factors

• The experimentally determined reaction rate can be

combined with the ortho/meta/para distribution to give
partial rate factors for substitution at the various ring
positions.
• Expressed as a numerical value, a partial rate factor
tells you by how much the rate of substitution at a
particular position is faster (or slower) than at a single
position of benzene.

54
Nitration of Toluene: Partial Rate Factors

CH3
1
1 1 42 42
1 1 2.5 2.5
1 58

All of the available ring positions in toluene are more

reactive than a single position of benzene (b/c?).
A methyl group activates all of the ring positions, but
the effect is greatest at the ortho and para positons.
Steric hindrance by the methyl group makes each
ortho position slightly less reactive than para.
55
 Nitration of Toluene vs. tert-Butylbenzene

CH3

CH3 H3C C CH3

42 42 4.5 4.5
2.5 2.5 3 3
58 75

tert-Butyl is activating and ortho-para directing

tert-Butyl crowds the ortho positions and decreases
the rate of attack at those positions.

56
Section 13.11

RATE AND REGIOSELECTIVITY IN

THE NITRATION OF
(TRIFLUOROMETHYL)BENZENE
 The Trifluoromethyl Group
• The trifluoromethyl (–CF3) group is electron
withdrawing: it pulls electron density from the ring
• –CF3 strongly destabilizes an adjacent carbocation

• Arenium cations with C+ adjacent to the –CF3 group are

destabilized relative to those with C+ farther away
 –CF3-substituted Arenium Cations
• Substitution ortho or para to –CF3 produces a cation with
positive charge next to the substituent
• These cations are strongly destabilized
 –CF3-substituted Arenium Cations
• Substitution ortho or para to –CF3 produces a cation with
positive charge next to the substituent
• These cations are strongly destabilized
 –CF3-substituted Arenium Cations
• Substitution meta to –CF3 produces a cation with
positive charge relatively far from the substituent
• These cations are not quite as destabilized, so meta
substitution occurs preferentially

No resonance form has C+ directly attached to –CF3.

 Relative Activation Energies

Trifluoromethyl is an electron- All sites in trifluoromethylbenzene are

withdrawing substituent. less reactive than that in benzene!
 Nitration of (Trifluoromethyl)benzene:
Partial Rate Factors

CF3

4.5 x 10-6 4.5 x 10-6

67 x 10-6 67 x 10-6
4.5 x 10-6
All of the available ring positions in
(trifluoromethyl)benzene are much less reactive than
a single position of benzene.
A CF3 group deactivates all of the ring positions but
the degree of deactivation is greatest at the ortho and
para positons. 63
Section 13.12

SUBSTITUENT EFFECTS IN
ELECTROPHILIC AROMATIC
SUBSTITUTION: ACTIVATING
SUBSTITUENTS
 General Rules for Substituent Effects

• There are three general rules for substituent effects in

electrophilic aromatic substitution
1. All activating substituents are ortho, para directors
2. Halogen substituents are slightly deactivating but are ortho,
para directors
3. Strongly deactivating substituents are meta directors
Activating Substituents
 Strongly Activating Substituents
• Strongly activating substituents contain O or N with a lone pair
directly attached to the ring
• Oxygen-containing activators include hydroxy, alkoxy, and
acyloxy groups

• Nitrogen-containing activators include amino and acylamino

groups
 Ortho, para Directors
• Attachment of the electrophile to the meta position gives the
standard three resonance forms for the arenium cation

• Attachment of the electrophile to the ortho or para position leads

to an additional resonance form!

The ortho and para arenium cations are more stable than the meta arenium cation.
 Ortho, para Directors
• Attachment of the electrophile to the meta position gives the
standard three resonance forms for the arenium cation

• Attachment of the electrophile to the ortho or para position leads

to an additional resonance form!

The ortho and para arenium cations are more stable than the meta arenium cation.
Section 13.13

SUBSTITUENT EFFECTS IN
ELECTROPHILIC AROMATIC
SUBSTITUTION: STRONGLY
DEACTIVATING SUBSTITUENTS
Deactivating Substituents
 Strongly Deactivating Substituents
• Strong deactivators contain a polarized –X=Y group in
which Y is more electronegative than X: –C=O, –N=O,
etc.

• Strong deactivators are meta directors and slow the rate

of electrophilic aromatic substitution
• These groups withdraw electron density from the ring,
making it a worse nucleophile
 Meta Directors
• Attachment of the electrophile at the meta position
avoids a positive charge close to the partially positive
substituent
 The Nitro Group
• The nitrogen of the nitro group is formally positive—nitro
is a very strong electron-withdrawing group

• Nitro is a highly selective meta director and strongly

deactivates the ring towards electrophilic substitution
Section 13.14

SUBSTITUENT EFFECTS IN
ELECTROPHILIC AROMATIC
SUBSTITUTION: HALOGENS
 Deactivating ortho, para Directors
• Halogens are deactivating, but are ortho, para directors
• Deactivating effect: the halogen pulls electron density
from the ring via an inductive effect
 Deactivating ortho, para Directors
• Halogens are deactivating, but are ortho, para directors
• Directing effect: halogen lone pairs stabilize arenium
cations from ortho and para substitution
Partial rate factors: completion between
lone pair and inductive effect
Section 13.15

MULTIPLE SUBSTITUENT
EFFECTS
 Equivalent Sites
• In the simplest case, multiple substituents direct to
equivalent sites
• For example, all four C–H groups in p-xylene are
equivalent
 Reinforcing Effects
• In some cases, both substituents direct to the same
site(s)

• Steric hindrance dictates the site of substitution when

multiple sites are activated
 Distinctly Activated Sites
• The stronger activating group dictates the major site of
substitution in cases when sites are activated by two
different groups
 Distinctly Activated Sites
• Steric hindrance is important in reactions of
dialkylbenzenes

• Reaction occurs preferentially at the less hindered

activated site(s)
Section 13.16

RETROSYNTHETIC ANALYSIS
AND THE SYNTHESIS OF
SUBSTITUTED BENZENES
 Retrosynthesis of Substituted Arenes

• Substituents already on the ring dictate regioselectivity

• Thus, we must think carefully about the order in which
groups are added to a benzene ring
– Don’t add a meta director if you need to add a substituent
para next!
– Don’t add an ortho, para director if you need to add a
substituent meta next!
• For example…
 Retrosynthesis of Substituted Arenes

• Substituents already on the ring dictate regioselectivity

• Thus, we must think carefully about the order in which
groups are added to a benzene ring
– Don’t add a meta director if you need to add a substituent
para next!
– Don’t add an ortho, para director if you need to add a
substituent meta next!
• For example…

meta director ortho, para

director
 Retrosynthesis of Substituted Arenes

• Substituents already on the ring dictate regioselectivity

• Thus, we must think carefully about the order in which
groups are added to a benzene ring
– Don’t add a meta director if you need to add a substituent
para next!
– Don’t add an ortho, para director if you need to add a
substituent meta next! Acylation would give
the para product!
• For example…

meta director ortho, para

Only route a is feasible in practice. director
 Consider Deactivation
• Substituted benzenes more deactivated than
monohalobenzenes do not participate in Friedel-Crafts
reactions at synthetically useful rates

• Route b is impractical because nitrobenzene reacts

extremely slowly in Friedel-Crafts acylation
 Functional-group Manipulations
• Functional-group transformations can be used:
– To convert a meta director to an ortho, para director or vice
versa
– To unveil a functional group that cannot be installed via
electrophilic substitution (such as –CO2H)

The final oxidation step is the key to installing the benzoic acid group.
 Functional-group Manipulations
• Functional-group transformations can be used:
– To convert a meta director to an ortho, para director or vice
versa
– To unveil a functional group that cannot be installed via
electrophilic substitution (such as –CO2H)

The final oxidation step is the key to installing the benzoic acid group.
Section 13.17

SUBSTITUTION IN
NAPHTHALENE
 Substitution in Naphthalene
• Naphthalene has two distinct sites for electrophilic
substitution (all others are equivalent to these two)
• Substitution occurs preferentially at C-1
 Substitution in Naphthalene
• Substitution occurs preferentially at C-1 because the
arenium cation formed via C-1 substitution is more stable
than the C-2 alternative
Section 13.18

SUBSTITUTION IN
HETEROCYCLIC AROMATIC
COMPOUNDS
 Substitution of Pyridine
• Pyridine contains a strongly deactivating “internal
withdrawing group”—the C=N bond
• Pyridine is much less reactive that benzene in
electrophilic substitutions
– The ring is deactivated
– Lewis acids coordinate to nitrogen, deactivating the ring
further
• Substitution occurs only at very high temperatures and
at C-3 selectively
 Pyrrole, Furan, and Thiophene

•• •• ••
N O S
•• ••
H
Have 1 less ring atom than benzene or
pyridine to hold same number of π electrons
(6).
π electrons are held less strongly.
These compounds are relatively reactive
toward EAS.
96
 Example: Furan

O O O
BF3
+ CH3COCCH3 CCH3
O
O
75-92%

undergoes EAS readily

C-2 is most reactive position

97