Chapter 12 Reactions of Arenes: Electrophilic Aromatic Substitution

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Chapter 12Reactions of ArenesElectrophilic
Aromatic Substitution
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12.1Representative Electrophilic Aromatic
Substitution Reactions of Benzene
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Electrophilic aromatic substitutions include

• Nitration
• Sulfonation
• Halogenation
• Friedel-Crafts Alkylation
• Friedel-Crafts Acylation

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Nitration of Benzene
H2SO4

HONO2

H2O
Nitrobenzene(95)
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Sulfonation of Benzene
heat

HOSO2OH

H2O
Benzenesulfonic acid(100)
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Halogenation of Benzene
FeBr3

Br2

HBr
Bromobenzene(65-75)
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Friedel-Crafts Alkylation of Benzene
AlCl3

(CH3)3CCl

HCl
tert-Butylbenzene(60)
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Friedel-Crafts Acylation of Benzene
AlCl3


HCl
1-Phenyl-1-propanone(88)
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12.2Mechanistic PrinciplesofElectrophilic
Aromatic Substitution
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Step 1 Attack of Electrophileby ?-Electron
System of Aromatic Ring

• Highly endothermic.
• Carbocation is allylic, but not aromatic.

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Step 2 Loss of a Proton from the
CarbocationIntermediate
H
H
E
H

H
H
H

B


base
B

• Highly exothermic.
• This step restores aromaticity of ring.

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Based on this general mechanism

• What remains is to identify the electrophile in
  nitration, sulfonation, halogenation,
  Friedel-Crafts alkylation and Friedel-Crafts
  acylation to establish the mechanism of specific
  electrophilic aromatic substitutions.

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12.3Nitration of Benzene
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Nitration of Benzene
H2SO4

HONO2

H2O
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Step 1 Attack of Nitronium Cationby ?-Electron
System of Aromatic Ring
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Step 2 Loss of a Proton from the Carbocation
Intermediate
H
H
NO2
H

H
H
H

B

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Where Does Nitronium Ion Come from?
H2SO4
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12.4Sulfonation of Benzene
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Sulfonation of Benzene
heat

HOSO2OH

H2O
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Step 1 Attack of Sulfur Trioxideby ?-Electron
System of Aromatic Ring
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Step 2 Loss of a Proton from the Carbocation
Intermediate
H
H
SO3
H

H
H
H

B

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Step 3 Protonation of Benzenesulfonate Ion
H2SO4
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12.5Halogenation of Benzene
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Halogenation of Benzene
FeBr3

Br2

HBr
Electrophile is a Lewis acid-Lewis basecomplex
between FeBr3 and Br2.
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The Br2-FeBr3 Complex

FeBr3
Lewis base
Lewis acid

• The Br2-FeBr3 complex is more electrophilic than
  Br2 alone.

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Step 1 Attack of Br2-FeBr3 Complex by
?-Electron System of Aromatic Ring



Br
Br
FeBr3
H
H
H
H
H
H
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Step 2 Loss of a Proton from the
CarbocationIntermediate
H
H
Br
H

H
H
H

B

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12.6Friedel-Crafts Alkylation of Benzene
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Friedel-Crafts Alkylation of Benzene
AlCl3

(CH3)3CCl

HCl
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Role of AlCl3

• Acts as a Lewis acid to promote ionizationof the
  alkyl halide.

(CH3)3C
Cl
AlCl3

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Step 1 Attack of tert-Butyl Cationby ?-Electron
System of Aromatic Ring
H
H
H
H
H
H
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Step 2 Loss of a Proton from the
CarbocationIntermediate
H
H
C(CH3)3
H

H
H
H

B

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Rearrangements in Friedel-Crafts Alkylation

• Carbocations are intermediates.
• Therefore, rearrangements can occur.

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Rearrangements in Friedel-Crafts Alkylation

• Isobutyl chloride is the alkyl halide.
• But tert-butyl cation is the electrophile.

(CH3)2CHCH2Cl
Isobutyl chloride
tert-Butylbenzene(66)
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Rearrangements in Friedel-Crafts Alkylation


H


H3C
C
CH2
CH3
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Reactions Related to Friedel-Crafts Alkylation
H2SO4

Cyclohexylbenzene(65-68)

• Cyclohexene is protonated by sulfuric acid,
  giving cyclohexyl cation which is attacked by the
  benzene ring.

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12.7Friedel-Crafts Acylation of Benzene
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Friedel-Crafts Acylation of Benzene
O
O
CCH2CH3
AlCl3

CH3CH2CCl

HCl
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Step 1 Attack of the Acyl Cationby ?-Electron
System of Aromatic Ring

O
CCH2CH3
H
H
H
H
H
H
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Step 2 Loss of a Proton from the
CarbocationIntermediate

B

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Acid Anhydrides

• Can be used instead of acyl chlorides.

AlCl3

Acetophenone(76-83)
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12.8Acylation-Reduction
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Acylation-Reduction
Permits primary alkyl groups to be attachedto an
aromatic ring.
RCCl
AlCl3

• Reduction of aldehyde and ketonecarbonyl groups
  using Zn(Hg) and HCl is called the Clemmensen
  reduction.

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Acylation-Reduction
Permits primary alkyl groups to be attachedto an
aromatic ring.
RCCl
H2NNH2, KOH,triethylene glycol,heat
AlCl3

• Reduction of aldehyde and ketonecarbonyl groups
  by heating with H2NNH2 and KOH is called
  theWolff-Kishner reduction.

CH2R
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Example Prepare Isobutylbenzene
(CH3)2CHCH2Cl
CH2CH(CH3)3
AlCl3

• No! Friedel-Crafts alkylation of benzene using
  isobutyl chloride fails because of rearrangement.

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Recall

(CH3)2CHCH2Cl
Isobutyl chloride
tert-Butylbenzene(66)
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Use Acylation-Reduction Instead

AlCl3
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12.9Rate and Regioselectivity in Electrophilic
Aromatic Substitution

• A substituent already present on the ring can
  affect both the rate and regioselectivityof
  electrophilic aromatic substitution.

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Effect on Rate

• Activating substituents increase the rate of EAS
  compared to that of benzene.
• Deactivating substituents decrease the rate of
  EAS compared to benzene.

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Methyl Group

• Toluene undergoes nitration 20-25 times faster
  than benzene.
• A methyl group is an activating substituent.

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Trifluoromethyl Group

• (Trifluoromethyl)benzene undergoes nitration
  40,000 times more slowly than benzene.
• A trifluoromethyl group is adeactivating
  substituent.

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Effect on Regioselectivity

• Ortho-para directors direct an incoming
  electrophile to positions ortho and/or para to
  themselves.
• Meta directors direct an incoming electrophile
  to positions meta to themselves.

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Nitration of Toluene


34
3
63

• o- and p-Nitrotoluene together comprise 97 of
  the product.
• A methyl group is an ortho-para director.

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Nitration of (Trifluoromethyl)benzene


3
91
6

• m-Nitro(trifluoromethyl)benzene comprises 91 of
  the product.
• A trifluoromethyl group is a meta director.

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12.10Rate and Regioselectivityin theNitration
of Toluene
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Carbocation Stability Controls Regioselectivity
ortho
para
meta
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Ortho Nitration of Toluene
CH3
NO2
H
H
H
H
H

• This resonance form is a tertiary carbocation.

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Ortho Nitration of Toluene
CH3
CH3
CH3
NO2
NO2
NO2
H
H
H

H
H
H

H
H
H
H
H
H
H
H
H

• The rate-determining intermediate in the
  orthonitration of toluene has tertiary
  carbocation character.

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Para Nitration of Toluene

• This resonance form is a tertiary carbocation.

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Para Nitration of Toluene

• The rate-determining intermediate in the
  paranitration of toluene has tertiary
  carbocation character.

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Meta Nitration of Toluene

• All the resonance forms of the rate-determining
  intermediate in the meta nitration of toluene
  have their positive charge on a secondary carbon.

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Nitration of Toluene Interpretation

• Rate-determining intermediates for ortho and para
  nitration each have a resonance form that is a
  tertiary carbocation. All 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.

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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.

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Nitration of Toluene Partial Rate Factors
1
42
42
1
1
2.5
2.5
1
1
1
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• All of the available ring positions in toluene
  are more reactive than a single position of
  benzene.
• 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.

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Nitration of Toluene vs. tert-Butylbenzene

• tert-Butyl is activating and ortho-para
  directing.
• However, tert-Butyl crowds the ortho positions
  and decreases the rate of attack at those
  positions.

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Generalization

• All alkyl groups are activating and ortho-para
  directing.

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12.11Rate and Regioselectivityin theNitration
of (Trifluoromethyl)benzene
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A Key Point

• A methyl group is electron-donating and
  stabilizes a carbocation.
• Because F is so electronegative, a CF3 group
  destabilizes a carbocation.

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Carbocation Stability Controls Regioselectivity
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Ortho Nitration of (Trifluoromethyl)benzene

• This resonance form is destabilized.

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Ortho Nitration of (Trifluoromethyl)benzene
CF3
CF3
CF3
NO2
NO2
NO2
H
H
H

H
H
H

H
H
H
H
H
H
H
H
H

• One of the resonance forms of the
  rate-determining intermediate in the
  orthonitration of (trifluoromethyl)benzene is
  strongly destabilized.

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Para Nitration of (Trifluoromethyl)benzene

• This resonance form is destabilized.

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Para Nitration of (Trifluoromethyl)benzene

• One of the resonance forms of the
  rate-determining intermediate in the
  paranitration of (trifluoromethyl)benzene is
  strongly destabilized.

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Meta Nitration of (Trifluoromethyl)benzene

• None of the resonance forms of the
  rate-determining intermediate in the meta
  nitration of (trifluoromethyl)benzene have their
  positive charge on the carbon that bears the CF3
  group.

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Nitration of (Trifluoromethyl)benzene
Interpretation

• The rate-determining intermediates for ortho and
  para nitration each have a resonance form in
  which the positive charge is on a carbon that
  bears a CF3 group. Such a resonance structure is
  strongly destabilized. The intermediate in meta
  nitration avoids such a structure. It is the
  least unstable of three unstable intermediates
  and is the one from which most of the product is
  formed.

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Nitration of (Trifluoromethyl)benzenePartial
Rate Factors

• 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.

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12.12Substituent Effects in ElectrophilicAromati
c SubstitutionActivating Substituents
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Classification of Substituents in Electrophilic
Aromatic Substitution Reactions

• Very strongly activating
• Strongly activating
• Activating
• Standard of comparison is H
• Deactivating
• Strongly deactivating
• Very strongly deactivating

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Generalizations

• 1. All activating substituents are ortho-para
  directors.
• 2. Halogen substituents are slightly
  deactivating but ortho-para directing.
• 3. Strongly deactivating substituents are meta
  directors.

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Electron-Releasing Groups (ERGs)

• ERGs are ortho-para directing and activating.

ERG
ERGs include R, Ar, and CHCR2.
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Electron-Releasing Groups (ERGs)

• ERGs are ortho-para directing and activating.

ERG
ERGs such as OH and OR arestrongly activating.
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Nitration of Phenol

• Occurs about 1000 times faster than nitration of
  benzene.

HNO3

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56
84
Bromination of Anisole

• FeBr3 catalyst not necessary.

Br2
aceticacid
90
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Oxygen Lone Pair Stabilizes Intermediate
H
H
H
H
Br
H

• All atomshave octets.

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Electron-Releasing Groups (ERGs)
ERG

• ERGs with a lone pair on the atom
  directlyattached to the ring are ortho-para
  directingand strongly activating.

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Examples

• All of these are ortho-para directingand
  strongly to very strongly activating.

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Lone Pair Stabilizes Intermediates forOrtho and
Para Substitution

• Comparable stabilization not possible for
  intermediate leading to meta substitution.

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12.13Substituent Effects in ElectrophilicAromati
c SubstitutionStrongly Deactivating Substituents
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ERGs Stabilize Intermediates forOrtho and Para
Substitution
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Electron-withdrawing Groups (EWGs) Destabilize
Intermediates for Ortho and Para Substitution
EWG
EWG
X
H
H
H


H
H
H
H
H
X
H
H

• CF3 is a powerful EWG. It is strongly
  deactivating and meta directing.

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Many EWGs Have a Carbonyl GroupAttached Directly
to the Ring
EWG

• All of these are meta directing and strongly
  deactivating.

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Other EWGs Include
EWG
NO2
SO3H

• All of these are meta directing and strongly
  deactivating.

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Nitration of Benzaldehyde
HNO3
H2SO4
75-84
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Chlorination of Benzoyl Chloride
Cl
Cl2
FeCl3
62
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Disulfonation of Benzene
HO3S
SO3
SO3H
H2SO4
90
97
Bromination of Nitrobenzene
Br
Br2
NO2
NO2
FeBr3
60-75
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12.14Substituent Effects in ElectrophilicAromati
c SubstitutionHalogens

• F, Cl, Br and I are ortho-para directing,but
  deactivating.

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Nitration of Chlorobenzene
HNO3


H2SO4
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1
30

• The rate of nitration of chlorobenzene is about
  30 times slower than that of benzene.

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Nitration of Toluene vs. Chlorobenzene
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12.15Multiple Substituent Effects
102
The Simplest Case

• All possible EAS sites may be equivalent.

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Another Straightforward Case

• Directing effects of substituents reinforceeach
  other substitution takes place orthoto the
  methyl group and meta to the nitro group.

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Generalization

• Regioselectivity is controlled by themost
  activating substituent.

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Example
Strongly activating
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When activating effects are similar...

• Substitution occurs ortho to the smaller group.

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Steric Effects Control Regioselectivity
whenElectronic Effects are Similar

• Position between two substituents is
  lastposition to be substituted.

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12.16Regioselective Synthesis of Disubstituted
Aromatic Compounds
109
Factors to Consider

• Order of introduction of substituents to ensure
  correct orientation.

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Synthesis of m-Bromoacetophenone

• Which substituent should be introduced first?

111
Synthesis of m-Bromoacetophenone
para ( ortho)

• If bromine is introduced first,
  p-bromoacetophenone is major product.

meta
112
Synthesis of m-Bromoacetophenone
AlCl3
113
Factors to Consider

• Order of introduction of substituents to ensure
  correct orientation.
• Friedel-Crafts reactions (alkylation, acylation)
  cannot be carried out on strongly deactivated
  aromatics.

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Synthesis of m-Nitroacetophenone

• Which substituent should be introduced first?

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Synthesis of m-Nitroacetophenone

• If NO2 is introduced first, the next step
  (Friedel-Crafts acylation) fails.

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Synthesis of m-Nitroacetophenone
AlCl3
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Factors to Consider

• Order of introduction of substituents to ensure
  correct orientation.
• Friedel-Crafts reactions (alkylation, acylation)
  cannot be carried out on strongly deactivated
  aromatics.
• Sometimes electrophilic aromatic substitution
  must be combined with a functional group
  transformation.

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Synthesis of p-Nitrobenzoic Acid from Toluene

• Which first? (Oxidation of methyl group or
  nitration of ring?)

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Synthesis of p-Nitrobenzoic Acid from Toluene
Nitration givesm-nitrobenzoicacid.
Oxidation givesp-nitrobenzoicacid.
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Synthesis of p-Nitrobenzoic Acid from Toluene
HNO3
H2SO4
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12.17Substitution in Naphthalene
122
Naphthalene
H
H
1
H
H
2
H
H
H
H

• Two sites possible for electrophilicaromatic
  substitution.
• All other sites at which substitution can
  occurare equivalent to 1 and 2.

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EAS in Naphthalene
AlCl3
90

• Faster at C-1 than at C-2.

124
EAS in Naphthalene
E
E
H
H

• When attack is at C-1,
• carbocation is stabilized by allylic resonance
  and
• benzenoid character of other ring is maintained.

125
EAS in Naphthalene
E
H

• When attack is at C-2,
• in order for carbocation to be stabilized by
  allylic resonance, the benzenoid character of the
  other ring is sacrificed.

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12.18Substitution inHeterocyclic Aromatic
Compounds
127
Generalization

• There is none.
• There are so many different kinds of
  heterocyclicaromatic compounds that no
  generalizationis possible.
• Some heterocyclic aromatic compoundsare very
  reactive toward electrophilicaromatic
  substitution, others are very unreactive.

128
Pyridine

• Pyridine is not very reactive it
  resemblesnitrobenzene in its reactivity.
• Presence of electronegative atom (N) in
  ringcauses ? electrons to be held more strongly
  thanin benzene.

129
Pyridine
SO3, H2SO4
HgSO4, 230C
71

• Pyridine can be sulfonated at high temperature.
• EAS takes place at C-3.

130
Pyrrole, Furan, and Thiophene

• Have 1 less ring atom than benzene or pyridine
  but have same number of ? electrons (6).
• ? electrons are held less strongly than benzene.
• These compounds are relatively reactive toward
  EAS.

131
Example Furan
BF3

CCH3
O
O
75-92

• Undergoes EAS readily.C-2 is most reactive
  position.