Aromatic Chemistry

Electrophilic and Nucleophilic

Aromatic Substitution

1
 Electrophilic Substitution
We have previously seen electrophilic addition, in which an electrophile
adds across a bond

This chapter is concerned with electrophilic substitution

2
Section 13.1

REPRESENTATIVE ELECTROPHILIC
AROMATIC SUBSTITUTION
REACTIONS OF BENZENE
 Electrophilic Aromatic Substitution
CH 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

4
Note the use of Brnsted acids as electrophiles.
 Electrophilic Aromatic Substitution
CH 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.
5
 Electrophilic Aromatic Substitution
CH 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

6
Section 13.2

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

8
 Mechanism of EAS
Electrophilic aromatic substitution has the same first step and
carbocation intermediate

arenium cation

9
 Mechanism of EAS
The second step of electrophilic addition involves nucleophilic
Y attacking the carbocation

10
 Mechanism of EAS
In step 2 of electrophilic aromatic substitution, Y
deprotonates the cation in an E1-style elimination step

aromaticity restored

11
Reaction Coordinate Diagram
Kinetically feasible reactions require
very reactive electrophiles.

Understanding the nature of the

electrophile is very important!

Step 1 is rate determining. 12

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+)

14
 Generation of the Electrophile

Step 1: H2SO4, the stronger acid, protonates HNO3

Step 2: H2O is eliminated from protonated nitric acid

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 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

16
 Mechanism of Substitution

Step 2: water (or solvent base) deprotonates the

arenium cation at the -position, restoring
aromaticity; the proton is lost from the carbon where
the new substituent added

17
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
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 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

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 Mechanism of Substitution

Step 2: proton transfer from H2SO4 to the sulfonate

group occurs, forming the sulfonic acid product

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Section 13.5

HALOGENATION OF BENZENE
 Halogenation of Benzene

X2 reacts only very slowly with benzenea catalyst is

required
Metallic iron can be used together with Br2 or Cl2

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 Halogenation of Benzene

X2 reacts only very slowly with benzenea catalyst is

required
The active catalyst is FeX3, a good Lewis acid

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 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

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 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
good leaving group

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 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

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 Mechanism of Substitution

Step 2: tetrabromoferrate deprotonates the arenium

cation at the -position, restoring aromaticity
The proton is lost from the carbon where the new
substituent added

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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

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 Friedel-Crafts Alkylation

The reaction of carbocations with arenes is called

Friedel-Crafts alkylation

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 Rearrangements

The carbocation intermediates of Friedel-Crafts

alkylation are susceptible to rearrangements

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 Rearrangements

Even primary alkyl halides, which do alkylate benzene

with AlX3, undergo rearrangements

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 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

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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

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 Friedel-Crafts Acylation

The active electrophile is acylium ion, an acyl halide

without the halide!

Acylium ions do not engage

in rearrangements.

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 Mechanism of Acylation

Analogous to other electrophilic aromatic substitution

mechanisms, with acylium as the active electrophile

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 Mechanism of Acylation

Analogous to other electrophilic aromatic substitution

mechanisms, with acylium as the active electrophile

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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
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 41
 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 42

 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 43
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 45
 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

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 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

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 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

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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:

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

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 Methyl-substituted Arenium Cations
The more stable areniums from ortho or para
substitution have one resonance form with a tertiary
carbocation!

52
 Methyl-substituted Arenium Cations
The more stable areniums from ortho or para
substitution have one resonance form with a tertiary
carbocation!

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

Methyl is an electron-releasing substituent. 54

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 56
 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

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 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

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 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. 59