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16. Chemistry of Benzene: Electrophilic Aromatic Substitution Based on McMurry’s Organic Chemistry , 6 edition, Chapter

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

Substitution Reactions of Benzene and

Its Derivatives

Substitution Reactions of Benzene and Its Derivatives  Benzene is aromatic: a cyclic conjugated compound with
  • 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

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

16.1 Bromination of Aromatic Rings

16.1 Bromination of Aromatic Rings  Benzene’s  electrons participate as a Lewis base in reactions
  • 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

  • FeBr 3 is added as a catalyst to polarize the bromine reagent

16.1 Bromination of Aromatic Rings  Benzene’s  electrons participate as a Lewis base in reactions
16.1 Bromination of Aromatic Rings  Benzene’s  electrons participate as a Lewis base in reactions

Addition Intermediate in Bromination

Addition Intermediate in Bromination  The addition of bromine occurs in two steps  In the
  • The addition of bromine occurs in two steps

  • In the first step the electrons act as a nucleophile toward Br 2 (in a complex with FeBr 3 )

  • 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)

Addition Intermediate in Bromination  The addition of bromine occurs in two steps  In the

Formation of Product from

Intermediate

Formation of Product from Intermediate  The cationic addition intermediate transfers a proton to FeBr (from
  • The cationic addition intermediate transfers a proton to FeBr 4 - (from Br - and FeBr 3 )

  • This restores aromaticity (in contrast with addition in alkenes)

Formation of Product from Intermediate  The cationic addition intermediate transfers a proton to FeBr (from
Formation of Product from Intermediate  The cationic addition intermediate transfers a proton to FeBr (from

16.2 Other Aromatic Substitutions

16.2 Other Aromatic Substitutions  The reaction with bromine involves a mechanism that is similar to
  • 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

16.2 Other Aromatic Substitutions  The reaction with bromine involves a mechanism that is similar to

Aromatic Chlorination and Iodination

Aromatic Chlorination and Iodination  Chlorine and iodine (but not fluorine, which is too reactive) can
  • 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 FeCl 3

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

Aromatic Chlorination and Iodination  Chlorine and iodine (but not fluorine, which is too reactive) can

Aromatic Nitration

Aromatic Nitration  The combination of nitric acid and sulfuric acid produces NO (nitronium ion) 
  • The combination of nitric acid and sulfuric acid produces NO 2 + (nitronium ion)

  • The reaction with benzene produces nitrobenzene

Aromatic Nitration  The combination of nitric acid and sulfuric acid produces NO (nitronium ion) 

Aromatic Sulfonation

Aromatic Sulfonation  Substitution of H by SO (sulfonation)  Reaction with a mixture of sulfuric
  • Substitution of H by SO 3 (sulfonation)

  • Reaction with a mixture of sulfuric acid and SO 3

  • Reactive species is sulfur trioxide or its conjugate acid

  • Reaction occurs via Wheland intermediate and is reversible

Aromatic Sulfonation  Substitution of H by SO (sulfonation)  Reaction with a mixture of sulfuric

Alkali Fusion of Aromatic Sulfonic

Acids

Alkali Fusion of Aromatic Sulfonic Acids  Sulfonic acids are useful as intermediates  Heating with
  • Sulfonic acids are useful as intermediates

  • Heating with NaOH at 300 ºC followed by neutralization with acid replaces the SO 3 H group with an OH

  • Example is the synthesis of p-cresol

Alkali Fusion of Aromatic Sulfonic Acids  Sulfonic acids are useful as intermediates  Heating with

16.3 Alkylation of Aromatic Rings: The FriedelCrafts Reaction

16.3 Alkylation of Aromatic Rings: The Friedel – Crafts Reaction  Aromatic substitution of a R
  • Aromatic substitution of a R + for H

  • Aluminum chloride promotes the formation of the carbocation

  • Wheland intermediate forms

16.3 Alkylation of Aromatic Rings: The Friedel – Crafts Reaction  Aromatic substitution of a R

Limitations of the Friedel-Crafts

Alkylation

Limitations of the Friedel-Crafts Alkylation  Only alkyl halides can be used (F, Cl, I, Br)
  • 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

Limitations of the Friedel-Crafts Alkylation  Only alkyl halides can be used (F, Cl, I, Br)
Limitations of the Friedel-Crafts Alkylation  Only alkyl halides can be used (F, Cl, I, Br)

Control Problems

Control Problems  Multiple alkylations can occur because the first alkylation is activating McMurry Organic Chemistry
  • Multiple alkylations can occur because the first alkylation is activating

Control Problems  Multiple alkylations can occur because the first alkylation is activating McMurry Organic Chemistry

Carbocation Rearrangements During

Alkylation

Carbocation Rearrangements During Alkylation  Similar to those that occur during electrophilic additions to alkenes 
  • Similar to those that occur during electrophilic additions to alkenes

  • Can involve H or alkyl shifts

Carbocation Rearrangements During Alkylation  Similar to those that occur during electrophilic additions to alkenes 

16.4 Acylation of Aromatic Rings

16.4 Acylation of Aromatic Rings  Reaction of an acid chloride (RCOCl) and an aromatic ring
  • Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl 3 introduces acyl group, COR

    • Benzene with acetyl chloride yields acetophenone

16.4 Acylation of Aromatic Rings  Reaction of an acid chloride (RCOCl) and an aromatic ring

Mechanism of Friedel-Crafts

Acylation

Mechanism of Friedel-Crafts Acylation  Similar to alkylation  Reactive electrophile: resonance-stabilized acyl cation  An
  • Similar to alkylation

  • Reactive electrophile: resonance-stabilized acyl cation

  • An acyl cation does not rearrange

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

16.5 Substituent Effects in Aromatic

Rings

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

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

Origins of Substituent Effects

Origins of Substituent Effects  An interplay of inductive effects and resonance effects  Inductive effect
  • An interplay of inductive effects and resonance effects

  • Inductive effect - withdrawal or donation of electrons through a s 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

Inductive Effects

Inductive Effects  Controlled by electronegativity and the polarity of bonds in functional groups  Halogens,
  • Controlled by electronegativity and the polarity of bonds in functional groups

  • Halogens, C=O, CN, and NO 2 withdraw electrons through s bond connected to ring

  • Alkyl groups donate electrons

Inductive Effects  Controlled by electronegativity and the polarity of bonds in functional groups  Halogens,

Resonance Effects Electron Withdrawal

Resonance Effects – Electron Withdrawal  C=O, CN, NO substituents withdraw electrons from the aromatic ring
  • C=O, CN, NO 2 substituents withdraw electrons from the aromatic ring by resonance

  • electrons flow from the rings to the substituents

Resonance Effects – Electron Withdrawal  C=O, CN, NO substituents withdraw electrons from the aromatic ring

Resonance Effects Electron Donation

Resonance Effects – Electron Donation  Halogen, OH, alkoxyl (OR), and amino substituents donate electrons 
  • Halogen, OH, alkoxyl (OR), and amino substituents donate electrons

  • electrons flow from the substituents to the ring

  • Effect is greatest at ortho and para

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

Contrasting Effects

Contrasting Effects  Halogen, OH, OR, withdraw electrons inductively so that they deactivate the ring 
  • Halogen, OH, OR, withdraw electrons inductively so that they deactivate the ring

  • Resonance interactions are generally weaker, affecting orientation

  • The strongest effects dominate

16.6 An Explanation of Substituent

Effects

16.6 An Explanation of Substituent Effects  Activating groups donate electrons to the ring, stabilizing the
  • Activating groups donate electrons to the ring, stabilizing the Wheland intermediate

(carbocation)

  • Deactivating groups withdraw electrons from the ring, destabilizing

the Wheland

intermediate

16.6 An Explanation of Substituent Effects  Activating groups donate electrons to the ring, stabilizing the

Ortho- and Para-Directing Activators:

Alkyl Groups

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

positions ortho and para to themselves

  • Alkyl group is most effective in the ortho and para positions

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

Ortho- and Para-Directing Activators:

OH and NH 2

Ortho- and Para-Directing Activators: OH and NH  Alkoxyl, and amino groups have a strong, electron-
  • Alkoxyl, and amino groups have a strong, electron- donating resonance effect

  • Most pronounced at the ortho and para positions

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

Ortho- and Para-Directing

Deactivators: Halogens

Ortho- and Para-Directing Deactivators: Halogens  Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect  Resonance
  • Electron-withdrawing inductive effect outweighs

weaker electron-donating resonance effect

  • Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate

Ortho- and Para-Directing Deactivators: Halogens  Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect  Resonance

Meta-Directing Deactivators

Meta-Directing Deactivators  Inductive and resonance effects reinforce each other  Ortho and para intermediates destabilized
  • Inductive and resonance effects reinforce each other

  • Ortho and para intermediates destabilized by deactivation from carbocation intermediate

  • Resonance cannot produce stabilization

Meta-Directing Deactivators  Inductive and resonance effects reinforce each other  Ortho and para intermediates destabilized

Summary Table: Effect of Substituents in

Aromatic Substitution

Summary Table: Effect of Substituents in Aromatic Substitution McMurry Organic Chemistry 6th edition Chapter 16 (c)
Summary Table: Effect of Substituents in Aromatic Substitution McMurry Organic Chemistry 6th edition Chapter 16 (c)

16.7 Trisubstituted Benzenes:

Additivity of Effects

16.7 Trisubstituted Benzenes: Additivity of Effects  If the directing effects of the two groups are
  • If the directing effects of the two groups are the same, the result is additive

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

Substituents with Opposite Effects

Substituents with Opposite Effects  If the directing effects of two groups oppose each other, the
  • If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome

  • Usually gives mixtures of products

Substituents with Opposite Effects  If the directing effects of two groups oppose each other, the

Meta-Disubstituted Compounds Are

Unreactive

Meta-Disubstituted Compounds Are Unreactive  The reaction site is too hindered  To make aromatic rings
  • The reaction site is too hindered

  • To make aromatic rings with three adjacent substituents, it is best to start with an ortho- disubstituted compound

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

16.8 Nucleophilic Aromatic

Substitution

16.8 Nucleophilic Aromatic Substitution  Aryl halides with electron-withdrawing substituents ortho and para react with nucleophiles
  • 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

16.9 Benzyne

16.9 Benzyne  Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute
  • 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

16.9 Benzyne  Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute

Evidence for Benzyne as an

Intermediate

Evidence for Benzyne as an Intermediate  Bromobenzene with C only at C1 gives substitution product
  • Bromobenzene with 14 C 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 equivalentmust be benzyne

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

Structure of Benzyne

Structure of Benzyne  Benzyne is a highly distorted alkyne  The triple bond uses sp
  • Benzyne is a highly distorted alkyne

  • The triple bond uses sp 2 -hybridized carbons, not the usual sp

  • The triple bond has one bond formed by pp overlap and by weak sp 2 sp 2 overlap

Structure of Benzyne  Benzyne is a highly distorted alkyne  The triple bond uses sp

16.10 Oxidation of Aromatic

Compounds

16.10 Oxidation of Aromatic Compounds  Alkyl side chains can be oxidized to  CO H
  • Alkyl side chains can be oxidized to CO 2 H by strong reagents such as KMnO 4 and Na 2 Cr 2 O 7 if they have a C-H next to the ring

  • Converts an alkylbenzene into a benzoic acid, ArR ArCO 2 H

16.10 Oxidation of Aromatic Compounds  Alkyl side chains can be oxidized to  CO H

Bromination of Alkylbenzene Side

Chains

Bromination of Alkylbenzene Side Chains  Reaction of an alkylbenzene with N -bromo- succinimide (NBS) and
  • Reaction of an alkylbenzene with N-bromo- succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain

Bromination of Alkylbenzene Side Chains  Reaction of an alkylbenzene with N -bromo- succinimide (NBS) and

Mechanism of NBS (Radical) Reaction

Mechanism of NBS (Radical) Reaction  Abstraction of a benzylic hydrogen atom generates an intermediate benzylic
  • Abstraction of a benzylic hydrogen atom generates an intermediate benzylic radical

  • Reacts with Br 2 to yield product

  • Br· radical cycles back into reaction to carry chain

  • Br 2 produced from reaction of HBr with NBS

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

16.11 Reduction of Aromatic

Compounds

16.11 Reduction of Aromatic Compounds  Aromatic rings are inert to catalytic hydrogenation under conditions that
  • 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)

16.11 Reduction of Aromatic Compounds  Aromatic rings are inert to catalytic hydrogenation under conditions that

Reduction of Aryl Alkyl Ketones

Reduction of Aryl Alkyl Ketones  Aromatic ring activates neighboring carbonyl group toward reduction  Ketone
  • Aromatic ring activates neighboring carbonyl group toward reduction

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

Reduction of Aryl Alkyl Ketones  Aromatic ring activates neighboring carbonyl group toward reduction  Ketone

16.12 Synthesis Strategies

16.12 Synthesis Strategies  These syntheses require planning and consideration of alternative routes  Work through
  • 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)