CHEM 0320 Organic Chemistry 2 Lecture Notes

Lecture 7, January 23, 2019

Quick review of electrophilic aromatic substitution (EAS) (15.8)

H ẟ+ ẟ− H E
+ E X + HX
E

arenium ion (nonaromatic)

EAS is a stepwise reaction:

• Benzene reacts with strong electrophiles to form an unstable nonaromatic carbocation
intermediate (called arenium ion).
• This carbocation then undergoes deprotonation to form the substitution product.

In today's lecture, we are going to learn a number of EAS reactions.

A. Catalytic halogenation of benzene (15.9)

FeBr3 catalyst Br
+ Br2 + HBr

Mechanism:
• Activation of Br2 by the Lewis acid catalyst (e.g. FeBr3)

ẟ+
Br Br + FeBr3 Br Br FeBr3 Br Br FeBr3

Lewis acid more positively charged

catalyst more electrophilic

FeX3 and AlX3 are Lewis acid catalysts for the halogenation of benzene (X = Br or Cl).
The metal center (Fe and Al) is electron-deficient and can accept electron pairs into the
unoccupied d orbitals.

Effects of Lewis acid catalysts: It binds to a substrate and makes the substrate more
electron-deficient (i.e. more electrophilic).

• Electrophilic attack
Br Br FeBr3 H
H
Br + FeBr4−

nonaromatic cation
intermediate
Note: Br2−FeBr3 is a stronger electrophile than Br2.

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 • Deprotonation
H Br FeBr3 Br
Br + HBr + FeBr3

Note: Here, deprotonation is facilitated by a base (FeBr4−) to form the side product (HBr) and
regenerate the FeBr3 catalyst. Catalysts are not consumed in reactions.

Chlorination of benzene takes place via a similar mechanism (FeCl3 or AlCl3 is used as
catalyst).

Cl2, AlCl3 Cl
+ HCl

B. Nitration of benzene (15.10)

HNO3, H2SO4 NO2

Mechanism:
• Activation of HNO3 by H2SO4

O H O
HO N + H OSO3H O N + OSO3H
O H O

H O
O N O N O + H 2O
H O
nitronium
strong electrophile

HNO3 itself is not electrophilic enough to react with benzene. It needs to be acticated by H2SO4
to form nitronium ion (NO2+), which is a much stronger electrophile.

• Electrophilic attack
H
H O N O
NO2

• Deprotonation
H OSO3H
NO2
NO2
+ H2SO4

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C. Sulfonation of benzene (15.10)

SO3, H2SO4 SO3H

Note: H2SO4 itself is not electrophilic enough to react with benzene. A mixture of SO3 and
H2SO4 (called "fuming sulfuric acid") is used for aromatic sulfonation reactions.
Mechanism:
O HO
HO S O
H O S electrophilic attack proton transfer
O S O O
O

Aromatic sulfonation is reversible

Heating benzenesulfonic acid in dilute acid forms benzene and H2SO4.

HO
S O H2O, catalytic H2SO4 H
O + H2SO4
∆

The driving force of the reverse sulfonation is the exothermic reaction of SO3 and H2O to form
H2SO4.
HO
HO
S O H O
O S O + O S
O O

+ H 2O
H2SO4

Synthesis of sulfonyl chlorides

HO NaO Cl
S O NaOH S O PCl5 S O
O O O

sulfonic acid sulfonate sulfonyl chloride

D. Friedel-Crafts Alkylation (15.11)

AlCl3 catalyst R
+ R X + HX X = I, Br, Cl, or F

Other Lewis acids for Friedel-Crafts alkylations: AlBr3, BF3, SbCl5, FeCl3.

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Mechanisms:
R = primary alkyl R = secondary or tertiary alkyl

1. Haloalkane activation 1. Haloalkane activation

ẟ+ ẟ+ + − ẟ+ −
+
R X + AlCl 3 R X AlCl3 R X + AlCl 3 R + X AlCl3
no primary secondary/tertiary
carbocation carbocation
formed intermediate
2. Electrophilic attack 2. Electrophilic attack
ẟ+ + −
H + H
H R X AlCl3 H R
R R

3. Deprotonation

H X AlCl3 R
R + HX + AlCl3

Note #1: Haloalkanes are clearly not electrophilic enough to react with benzene. It needs to be
activated by a Lewis acid
Note #2: Primary carbocation cannot be formed in reactions with primary alkyl halides.
Reactions with secondary and tertiary alkyl halides form carbocation intermediates.

Using alcohols or alkenes in place of haloalkanes:

Alcohols and alkenes can also be used in Friedel-Crafts alkylations, under conditions in which
they are converted to carbocation intermediates.

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E. Limitations of Friedel-Crafts Alkylations (15.12)

Overalkylation
In the following reaction, both mono- and dialkylation products are formed. This is because the
monoalkylation product is more electron-rich than benzene (the alkyl substituent is electron-
donating). Therefore, the monoalkylation product reacts faster with electrophiles than benzene
itself.

FeBr3 catalyst FeBr3 catalyst

+ Br

more electron-rich Br
more reactive than
benzene in EAS
monoalkylation product dialkylation product

Note: The products of halogenation, nitration, sulfonylation, and acylation are more electron-
deficient than benzene. Therefore, there is no overfunctionalization in these reactions.

Carbocation rearrangement

AlCl3
+ Br

rearranged not observed

alkylation product

Here, the rearranged product is formed via a concerted 1,2-hydride shift (no primary
carbocation is formed) that gives a secondary carbocation.

Concerted 1,2-hydride shift

H
Br AlCl3 H

Note: Review chapter 9.3 for carbocation rearrangements.

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F. Friedel-Crafts Acylation (15.13)
O
O
AlCl3 R
+ R Cl + HCl

Mechanism:
• Activation of acyl halides to form acylium ions
sp hybridized
linear
O AlCl3 O − AlCl4− + O
+
O
+ − C C
R Cl R Cl AlCl3 R R

acylium ion
• Electrophilic attack
O + H
H C O
R
R

• Deprotonation
Cl AlCl3 O
H
O R
+ HCl + AlCl3
R

Scope:
O
O O
O
AlCl3 R
+ R O R +
HO R
carboxylic
anhydrides

Activation of anhydrides to form acylium ions

O
O O −
O O − Cl3Al
O R +
+ + O O
R O R R O R C C
−AlCl R R
AlCl3 3
acylium ion

There is no polysubstitution or carbocation rearrangement in Friedel-Crafts acylations.

• Acylated benzenes are less electron-rich. Therefore, the products react slower with
electrophiles.
• There is no carbocation intermediate involved in Friedel-Crafts acylations.

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 Summary of New Reactions in Lecture 7
• Electrophilic Aromatic Substitutions (EAS)
•
H ẟ+ ẟ− E
+ E X + HX

catalyst or
active
reactant activating product note
electrophile
reagent
Cl
FeCl3 or
chlorination Cl2 Cl−Cl+−Fe−Cl3
AlCl3
Br
FeBr3 or
bromination Br2 Br−Br+−Fe−Br3
AlBr3
NO2
O N O
nitration HNO3 H2SO4
nitronium ion
SO3H
Sulfonation is
sulfonation SO3, H2SO4 SO3
reversible.
R−X+−Al−Cl3
AlCl3 or R Limitations:
(R = primary) or
other polyalkylation/
R−X R+
Lewis carbocation
(R = secondary
acids rearrangement
or tertiary)
R
R R
alkylation OH BF3 R’
R’ R’

R HF H R
R

O
+ O O
R Cl or C
acylation AlCl3 R R
O O
acylium cation
R O R
Note: The following electrophiles cannot react with benzene before activation:
O O O

Cl2, Br2, HNO3, H2SO4, R−X, R Cl , R O R

• Synthesis of sulfonyl chlorides

HO NaO Cl
S O NaOH S O PCl5 S O
O O O

sulfonic acid sulfonate sulfonyl chloride