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Organic Chemistry, 6th Edition L. G. Wade, Jr.

Electrophilic Aromatic Substitution


Electrophile substitutes for a hydrogen on the benzene ring.

Chapter 17 Reactions of Aromatic Compounds

Jo Blackburn Richland College, Dallas, TX Dallas County Community College District 2006, Prentice Hall

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Chapter 17 2

Mechanism
Step 1: Attack on the electrophile forms the sigma complex.

Bromination of Benzene
Requires a stronger electrophile than Br2. Use a strong Lewis acid catalyst, FeBr3.
Br Br
H H H Br H H H

FeBr3
+ Br

Br
H H + H H

Br
H Br H

FeBr3
_ + FeBr4

Step 2: Loss of a proton gives the substitution product.

FeBr3

Br

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Chapter 17

HBr

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Comparison with Alkenes


Cyclohexene adds Br2, H = -121 kJ Addition to benzene is endothermic, not normally seen. Substitution of Br for H retains aromaticity, H = -45 kJ. Formation of sigma complex is rate-limiting.

Energy Diagram for Bromination

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Chlorination and Iodination


Chlorination is similar to bromination. Use AlCl3 as the Lewis acid catalyst. Iodination requires an acidic oxidizing agent, like nitric acid, which oxidizes the iodine to an iodonium ion.

17.2

Cl2 AlCl3

Hexachlorobenzene Hexachlorocyclohexane 5,6-Dichloro-1,3-cyclohexadiene Chlorobenzene

Chapter 17

Level 3 Challenging

Chapter 17

Nitration of Benzene
Use sulfuric acid with nitric acid to form the nitronium ion electrophile. NO2 + then forms a sigma complex with benzene, loses H+ to form nitrobenzene.

Sulfonation
Sulfur trioxide, SO3, in fuming sulfuric acid is the electrophile.

Chapter 17

Chapter 17

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Desulfonation
All steps are reversible, so sulfonic acid group can be removed by heating in dilute sulfuric acid. This process is used to place deuterium in place of hydrogen on benzene ring.

Nitration of Toluene
Toluene reacts 25 times faster than benzene. The methyl group is an activating group. The product mix contains mostly ortho and para substituted molecules.

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Sigma Complex
Intermediate is more stable if nitration occurs at the ortho or para position, their resonance structures include one tertiary carbocation.
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Energy Diagram

Chapter 17

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Activating, O-, PDirecting Substituents


Alkyl groups stabilize the sigma complex by induction, donating electron density through the sigma bond. Substituents with a lone pair of electrons stabilize the sigma complex by resonance.

Substitution on Anisole

Chapter 17

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Chapter 17

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The Amino Group


Aniline, like anisole, reacts with bromine water (without a catalyst) to yield the tribromide. Sodium bicarbonate is added to neutralize the HBr thats also formed.

Summary of Activators

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17.3

CH2CH3 HNO3 H2SO4

Deactivating MetaDirecting Substituents


Electrophilic substitution reactions for nitrobenzene are 100,000 times slower than for benzene. The product mix contains mostly the meta isomer, only small amounts of the ortho and para isomers. Meta-directors deactivate all positions on the ring, but the meta position is less deactivated. => Chapter 17 20

2- and 4-nitroethylbenzene 3-Nitroethylbenzene 2- and 4-ethylbenzenesulfonic acid 3-Ethylbenzenesulfonic acid

Level 3 Challenging

Chapter 17

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Ortho Substitution on Nitrobenzene

Para Substitution on Nitrobenzene

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Meta Substitution on Nitrobenzene

Energy Diagram

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Structure of MetaDirecting Deactivators


The atom attached to the aromatic ring will have a partial positive charge. Electron density is withdrawn inductively along the sigma bond, so the ring is less electron-rich than benzene. =>
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Summary of Deactivators

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More Deactivators

Halobenzenes
Halogens are deactivating toward electrophilic substitution, but are ortho, para-directing! Since halogens are very electronegative, they withdraw electron density from the ring inductively along the sigma bond. But halogens have lone pairs of electrons that can stabilize the sigma complex by resonance. =>
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Sigma Complex for Bromobenzene

Energy Diagram

Ortho and para attacks produce a bromonium ion and other resonance structures. No bromonium ion possible with meta attack. =>
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Summary of Directing Effects

Multiple Substituents
The most strongly activating substituent will determine the position of the next substitution. May have mixtures.

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SOLVED PROBLEM 17-1


Predict the major product(s) of bromination of p-chloroacetanilide.

Friedel-Crafts Alkylation
Solution
The amide group (NHCOCH3) is a strong activating and directing group because the nitrogen atom with its nonbonding pair of electrons is bonded to the aromatic ring. The amide group is a stronger director than the chlorine atom, and substitution occurs mostly at the positions ortho to the amide. Like an alkoxyl group, the amide is a particularly strong activating group, and the reaction gives some of the dibrominated product.

Synthesis of alkyl benzenes from alkyl halides and a Lewis acid, usually AlCl3.

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Examples of Carbocation Formation


Reactions of alkyl halide with Lewis acid produces a carbocation which is the electrophile.

Examples of Carbocation Formation


Other sources of carbocations: alkenes + HF, or alcohols + BF3.

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Formation of Alkyl Benzene

Limitations of Friedel-Crafts
Reaction fails if benzene has a substituent that is more deactivating than halogen. Carbocations rearrange. Reaction of benzene with n-propyl chloride and AlCl3 produces isopropylbenzene. The alkylbenzene product is more reactive than benzene, so polyalkylation occurs. =>

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Carbocation Rearrangements During Friedel-Crafts Alkylation

Overalkylation

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SOLVED PROBLEM 17-2


Devise a synthesis of p-nitro-t-butylbenzene from benzene.

17.5

OCH3 AlCl3 CH3CH2CH2Cl

Solution
To make p-nitro-t-butylbenzene, we would first use a FriedelCrafts reaction to make t-butylbenzene. Nitration gives the correct product. If we were to make nitrobenzene first, the FriedelCrafts reaction to add the t-butyl group would fail.

3-Propylanisole 2- and 4-propylanisole 3-Isopropylanisole 2- and 4-isopropylanisole

Level 3 Challenging

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Friedel-Crafts Acylation
Acyl chloride is used in place of alkyl chloride. The acylium ion intermediate is resonance stabilized and does not rearrange like a carbocation. The product is a phenyl ketone that is less reactive than benzene. =>
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Mechanism of Acylation

Clemmensen Reduction
Acylbenzenes can be converted to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc.

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17.6
Ethylbenzene 1-Phenylethanol 2-Phenylethanol Chlorobenzene

CH3C(=O)Cl AlCl3

Zn(Hg) HCl

Gatterman-Koch Formylation
Formyl chloride is unstable. Use a high pressure mixture of CO, HCl, and catalyst. Product is benzaldehyde.
O CO

HCl

AlCl3/CuCl Cl

H C O

- AlCl

+
Level 3 Challenging

H C O
Chapter 17

H
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Nucleophilic Aromatic Substitution


A nucleophile replaces a leaving group on the aromatic ring. Electron-withdrawing substituents activate the ring for nucleophilic substitution.

Examples of Nucleophilic Substitution

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Addition-Elimination Mechanism

Benzyne Mechanism
Reactant is halobenzene with no electron-withdrawing groups on the ring. Use a very strong base like NaNH2.

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Benzyne Intermediate

Chlorination of Benzene
Addition to the benzene ring may occur with high heat and pressure (or light). The first Cl2 addition is difficult, but the next 2 moles add rapidly. The product, benzene hexachloride, is an insecticide.

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Catalytic Hydrogenation
Elevated heat and pressure is required. Possible catalysts: Pt, Pd, Ni, Ru, Rh. Reduction cannot be stopped at an intermediate stage.
3H2, 68 atm Pd
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Birch Reduction: Regiospecific


Na o Li NH3(l) , ROH

A carbon bearing an e--withdrawing group is reduced. A carbon bearing an e--releasing group is not reduced.

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Birch Mechanism 17.7


CH2CH3 Na NH3, CH3CH2OH

1-Methyl-1,4cyclohexadiene 3-Methyl-1,4cyclohexadiene 1-Methyl-1,3cyclohexadiene


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Level 3 Challenging

2-Methyl-1,3cyclohexadiene 5-Methyl-1,3cyclohexadiene

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Side-Chain Oxidation
Alkylbenzenes are oxidized to benzoic acid by hot KMnO4 or Na2Cr2O7/H2SO4.
KMnO4, NO2
-OH

17.8

CH2CH3 Na2Cr2O7 CH3 H , heat


+

O O H
+

O OH O OH NO2

H2O, 100oC

O O

NO2

17.8 2-Ethylbenzoic acid 2-Methylbenzoic acid Phthalic acid 2-Ethyltoluene


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Level 3 Challenging

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Side-Chain Halogenation
Benzylic position is the most reactive. Chlorination is not as selective as bromination, results in mixtures. Br2 reacts only at the benzylic position.

17.9

CH2CH2CH3 Br2 light

2-Bromopropylbenzene 3-Bromopropylbenzene 4-Bromopropylbenzene


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Level 3 Challenging

1-Bromopropylbenzene

Chapter 17

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SN1 Reactions
Benzylic carbocations are resonancestabilized, easily formed. Benzyl halides undergo SN1 reactions.

SN2 Reactions
Benzylic halides are 100 times more reactive than primary halides via SN2. Transition state is stabilized by ring.

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Reactions of Phenols
Some reactions like aliphatic alcohols:
phenol + carboxylic acid ester phenol + aq. NaOH phenoxide ion

Quinones
Hydroquinone is used as a developer for film. It reacts with light-sensitized AgBr grains, converting it to black Ag. Coenzyme Q is an oxidizing agent found in the mitochondria of cells. =>

Oxidation to quinones: 1,4-diketones.

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Electrophilic Substitution of Phenols


Phenols and phenoxides are highly reactive. Only a weak catalyst (HF) required for Friedel-Crafts reaction. Tribromination occurs without catalyst. Even reacts with CO2.

17.10

O 1. CO2 2. H+

2-Hydroxybenzoic acid 3-Hydroxybenzoic acid 4-Hydroxybenzoic acid Benzoic acid

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Level 3 Challenging

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End of Chapter 17

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