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16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department of Chemistry University of Toronto
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Page 1: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

16. Chemistry of Benzene: Electrophilic Aromatic Substitution

Based onMcMurry’s Organic Chemistry, 6th edition, Chapter 16©2003 Ronald KlugerDepartment of ChemistryUniversity of Toronto

Page 2: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

2

Substitution Reactions of Benzene and Its Derivatives Benzene is aromatic: a cyclic conjugated

compound with 6 electrons Reactions of benzene lead to the retention of the

aromatic core Electrophilic aromatic substitution replaces a

proton on benzene with another electrophile

Page 3: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

3

16.1 Bromination of Aromatic Rings

Benzene’s electrons participate as a Lewis base in reactions with Lewis acids

The product is formed by loss of a proton, which is replaced by bromine

FeBr3 is added as a catalyst to polarize the bromine reagent

Page 4: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

4

Addition Intermediate in Bromination

The addition of bromine occurs in two steps In the first step the electrons act as a nucleophile

toward Br2 (in a complex with FeBr3) This forms a cationic addition intermediate from

benzene and a bromine cation The intermediate is not aromatic and therefore high in

energy (see Figure 16.2)

Page 5: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

5

Formation of Product from Intermediate The cationic addition

intermediate transfers a proton to FeBr4

- (from Br- and FeBr3)

This restores aromaticity (in contrast with addition in alkenes)

Page 6: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

6

16.2 Other Aromatic Substitutions

The reaction with bromine involves a mechanism that is similar to many other reactions of benzene with electrophiles

The cationic intermediate was first proposed by G. W. Wheland of the University of Chicago and is often called the Wheland intermediate

George Willard Wheland

1907-1974

Page 7: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

7

Aromatic Chlorination and Iodination

Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution with the addition of other reagents to promote the reaction

Chlorination requires FeCl3

Iodine must be oxidized to form a more powerful I+ species (with Cu+ or peroxide)

Page 8: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

8

Aromatic Nitration

The combination of nitric acid and sulfuric acid produces NO2

+ (nitronium ion) The reaction with benzene produces nitrobenzene

Page 9: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

9

Aromatic Sulfonation

Substitution of H by SO3 (sulfonation) Reaction with a mixture of sulfuric acid and SO3 Reactive species is sulfur trioxide or its conjugate

acid Reaction occurs via Wheland intermediate and is

reversible

Page 10: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

10

Alkali Fusion of Aromatic Sulfonic Acids Sulfonic acids are useful as intermediates Heating with NaOH at 300 ºC followed by

neutralization with acid replaces the SO3H group with an OH

Example is the synthesis of p-cresol

Page 11: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

11

16.3 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction

Aromatic substitution of a R+ for H

Aluminum chloride promotes the formation of the carbocation

Wheland intermediate forms

Page 12: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

12

Limitations of the Friedel-Crafts Alkylation Only alkyl halides can be used (F, Cl, I, Br) Aryl halides and vinylic halides do not react (their

carbocations are too hard to form) Will not work with rings containing an amino group

substituent or a strongly electron-withdrawing group

Page 13: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

13

Control Problems

Multiple alkylations can occur because the first alkylation is activating

Page 14: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

14

Carbocation Rearrangements During Alkylation Similar to those that occur during electrophilic

additions to alkenes Can involve H or alkyl shifts

Page 15: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

15

16.4 Acylation of Aromatic Rings

Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl3 introduces acyl group, COR Benzene with acetyl chloride yields acetophenone

Page 16: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

16

Mechanism of Friedel-Crafts Acylation Similar to alkylation Reactive electrophile: resonance-stabilized acyl

cation An acyl cation does not rearrange

Page 17: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

17

16.5 Substituent Effects in Aromatic Rings Substituents can cause a compound to be (much) more or

(much) less reactive than benzene Substituents affect the orientation of the reaction – the

positional relationship is controlled ortho- and para-directing activators, ortho- and para-

directing deactivators, and meta-directing deactivators

Page 18: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

18

Origins of Substituent Effects

An interplay of inductive effects and resonance effects

Inductive effect - withdrawal or donation of electrons through a bond

Resonance effect - withdrawal or donation of electrons through a bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring

Page 19: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

19

Inductive Effects

Controlled by electronegativity and the polarity of bonds in functional groups

Halogens, C=O, CN, and NO2 withdraw electrons through bond connected to ring

Alkyl groups donate electrons

Page 20: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

20

Resonance Effects – Electron Withdrawal C=O, CN, NO2 substituents withdraw electrons from

the aromatic ring by resonance electrons flow from the rings to the substituents

Page 21: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

21

Resonance Effects – Electron Donation Halogen, OH, alkoxyl (OR), and amino substituents

donate electrons electrons flow from the substituents to the ring Effect is greatest at ortho and para

Page 22: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

22

Contrasting Effects

Halogen, OH, OR, withdraw electrons inductively so that they deactivate the ring

Resonance interactions are generally weaker, affecting orientation

The strongest effects dominate

Page 23: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

23

16.6 An Explanation of Substituent Effects Activating groups

donate electrons to the ring, stabilizing the Wheland intermediate (carbocation)

Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate

Page 24: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

24

Ortho- and Para-Directing Activators: Alkyl Groups Alkyl groups activate: direct further substitution to positions

ortho and para to themselves Alkyl group is most effective in the ortho and para positions

Page 25: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

25

Ortho- and Para-Directing Activators: OH and NH2 Alkoxyl, and amino groups have a strong, electron-

donating resonance effect Most pronounced at the ortho and para positions

Page 26: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

26

Ortho- and Para-Directing Deactivators: Halogens Electron-withdrawing inductive effect outweighs

weaker electron-donating resonance effect Resonance effect is only at the ortho and para

positions, stabilizing carbocation intermediate

Page 27: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

27

Meta-Directing Deactivators

Inductive and resonance effects reinforce each other Ortho and para intermediates destabilized by

deactivation from carbocation intermediate Resonance cannot produce stabilization

Page 28: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

28

Summary Table: Effect of Substituents in Aromatic Substitution

Page 29: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

29

16.7 Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are the

same, the result is additive

Page 30: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

30

Substituents with Opposite Effects

If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome

Usually gives mixtures of products

Page 31: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

31

Meta-Disubstituted Compounds Are Unreactive The reaction site is too hindered To make aromatic rings with three adjacent

substituents, it is best to start with an ortho-disubstituted compound

Page 32: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

32

16.8 Nucleophilic Aromatic Substitution

Aryl halides with electron-withdrawing substituents ortho and para react with nucleophiles

Form addition intermediate (Meisenheimer complex) that is stabilized by electron-withdrawal

Halide ion is lost to give aromatic ring

Page 33: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

33

16.9 Benzyne

Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure

The reaction involves an elimination reaction that gives a triple bond

The intermediate is called benzyne

Page 34: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

34

Evidence for Benzyne as an Intermediate Bromobenzene with 14C only at C1 gives substitution

product with label scrambled between C1 and C2 Reaction proceeds through a symmetrical

intermediate in which C1 and C2 are equivalent— must be benzyne

Page 35: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

35

Structure of Benzyne

Benzyne is a highly distorted alkyne The triple bond uses sp2-hybridized carbons, not the

usual sp The triple bond has one bond formed by p–p

overlap and by weak sp2–sp2 overlap

Page 36: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

36

16.10 Oxidation of Aromatic Compounds Alkyl side chains can be oxidized to CO2H by strong

reagents such as KMnO4 and Na2Cr2O7 if they have a C-H next to the ring

Converts an alkylbenzene into a benzoic acid, ArR ArCO2H

Page 37: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

37

Bromination of Alkylbenzene Side Chains Reaction of an alkylbenzene with N-bromo-

succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain

Page 38: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

38

Mechanism of NBS (Radical) Reaction Abstraction of a benzylic hydrogen atom generates

an intermediate benzylic radical Reacts with Br2 to yield product Br· radical cycles back into reaction to carry chain Br2 produced from reaction of HBr with NBS

Page 39: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

39

16.11 Reduction of Aromatic Compounds Aromatic rings are inert to catalytic hydrogenation

under conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the

presence of an aromatic ring Reduction of an aromatic ring requires more powerful

reducing conditions (high pressure or rhodium catalysts)

Page 40: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

Chapter 17 40

Birch ReductionH

H

H

H

H

HNa or Li

NH3 (l), ROH

H

H

H

H

H

H

H

H

This reaction reduces the aromatic ring to a nonconjugated 1,4-cyclohexadiene.

The reducing agent is sodium or lithium in a mixture of liquid ammonia and alcohol.

Page 41: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

41

Reduction of Aryl Alkyl Ketones

Aromatic ring activates neighboring carbonyl group toward reduction

Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst

Clemmensen Reduction

Page 42: 16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry, 6 th edition, Chapter 16 ©2003 Ronald Kluger Department.

McMurry Organic Chemistry 6th edition Chapter 16 (c) 2003

42

16.12 Synthesis Strategies

These syntheses require planning and consideration of alternative routes

Work through the practice problems in this section following the general guidelines for synthesis (and retrosynthetic analysis in 8.10)


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