16.

Chemistry of
Benzene: Electrophilic
Aromatic Substitution

Based on
McMurry’s Organic Chemistry, 8th edition, Chapter 16
 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.

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 Why this Chapter?
 Continuation of coverage of aromatic compounds in
preceding chapter…focus shift to understanding
reactions

 Examine relationship between aromatic structure and

reactivity

 Relationship critical to understanding of how biological

molecules/pharmaceutical agents are synthesized

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 Electrophilic Aromatic Substitution
Reactions: Bromination
 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
 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

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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)

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Other Aromatic Halogenations
Chlorination
 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

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Other Aromatic Halogenations
Iodination
 Iodine must be oxidized to form a more powerful I+ species
(with Cu2+ from CuCl2)

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Other Aromatic Halogenations
Fluorination
 Fluorination take place using sources of “F+” where the fluorine
atom is bonded to a positively charged nitrogen.
 F-TEDA-BF4 which is sold under the name Selectfluor

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 Aromatic Nitration

 The combination of nitric acid and sulfuric acid produces NO2+

(nitronium ion)
 The reaction with benzene produces nitrobenzene

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 Arylamine
 The Nitro group can be reduced to an Amino group if needed

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 Aromatic Sulfonation
 Reaction with a mixture of sulfuric acid and SO3 (“Fuming
H2SO4) lead to substitution of H by SO3 (sulfonation)
 Reactive species is sulfur trioxide or its conjugate acid (HSO3+)
 Sulfonation reaction is reversible:
 Sulfonation is favored in strong acid
 Desulfonation is favored in hot, dilute aqueous acid.

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Alkylation and Acylation
of Aromatic Rings: The
Friedel–Crafts Reaction
 Alkylation among most
useful electrophilic
aromatic substitution
reactions

 Aromatic substitution of
R+ for H+

 Aluminum chloride
promotes the formation
of the carbocation

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 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

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 Other Problems with Alkylation

 Multiple alkylations can occur because the first alkylation is

activating

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 Other Problems with Alkylation

 Carbocation rearrangements occur during alkylation

 Similar to those occurring during electrophilic additions to alkene
 Can involve H or alkyl shifts

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 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

 Avoids many of the problems of alkylation

 Only substitutes once, because acyl group is deactivating
 No rearrangement because of resonance stabilized cation
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Mechanism of Friedel-Crafts Acylation
 Similar to alkylation
 Reactive electrophile: resonance-stabilized acyl cation
 An acyl cation does not rearrange

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Carbonyl Reduced to Alkyl Product
 Can reduce carbonyl to get alkyl product

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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.

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An Explanation of Substituent Effects
Activation and Deactivation of Aromatic Rings
 activating groups donate electrons to the ring, thereby making
the ring more electron-rich, stabilizing the carbocation
intermediate
 deactivating groups is that they withdraw electrons from the
ring, thereby making the ring more electron-poor, destabilizing
the carbocation.

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 Origins of Substituent Effects
 An interplay of inductive effects and resonance effects

 Inductive effect: withdrawal or donation of electrons

through a s bond = Polar Covalent Bonds

 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

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 Inductive Effects
 Controlled by electronegativity and the polarity of bonds in
functional groups
 Halogens, C=O, CN, and NO2 withdraw electrons through s
bond connected to ring
 Alkyl groups donate electrons

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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
 Look for a double (or triple) bond connected to the ring by a
single bond

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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 positions
 Look for a lone pair on an atom attached to the ring

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 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

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Ortho/Para-Directing Activators: Alkyl Groups

 Alkyl groups activate by induction: direct further substitution to

positions ortho and para to themselves
 Alkyl group
has most
effect on the
ortho and
para
positions

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 Ortho/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

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Ortho/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

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 Meta-Directing Deactivators
 Inductive and resonance effects reinforce each other
 Ortho and para intermediates destabilized by deactivation of
carbocation intermediate
 Resonance cannot produce stabilization

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Summary Table: Effect of Substituents in
Aromatic Substitution

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 Trisubstituted Benzenes: Additivity of Effects

1. If the directing effects of the two groups are the same, the result is
additive

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 Trisubstituted Benzenes: Additivity of Effects

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

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 Trisubstituted Benzenes: Additivity of Effects
3. Usually gives mixtures of products but at the meta disubstituted
compound the reaction do not occur because this site is too
hindered
 To make aromatic rings with three adjacent substituents, it is
best to start with an ortho-disubstituted compound

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 Let’s Work a Problem
 At what position would you expect electrophilic substitution to
occur in each of the following substances?

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Nucleophilic Aromatic Substitution
 It is not a SN1 or SN2 reaction
 Aryl halides with electron-withdrawing substituents ortho and
para react with nucleophiles (electron withdrawing needed to
accept electrons from the nucleophile)
 Form addition intermediate (Meisenheimer complex) that is
stabilized by electron-withdrawal. Halide is leaving group.

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Nucleophilic aromatic substitution on
nitrochlorobenzenes

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Benzyne: Substitution of Unactivated Aromatics

 Phenol is prepared industrially 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 in the ring: benzyne

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 Evidence for Benzyne as an
Intermediate
 Bromobenzene with 14Conly 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

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 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
another by weak sp2–sp2 overlap

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Oxidation of Aromatic Compounds
 Alkyl side chains can be oxidized to -CO2H by strong reagents
such as KMnO4 if they have a C-H next to the ring
 Converts an alkylbenzene into a benzoic acid, ArR  Ar-
CO2H

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Oxidation of Aromatic Compounds
Cont…
 A benzylic C-H bond is required, or no reaction takes place

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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 only at benzylic position

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 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

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 Why Benzylic Position
 Because the benzylic radical intermediate is stabilized by
resonance.

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 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

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 Reduction of Aromatic Compounds
 Reduction of an aromatic ring requires more powerful reducing
conditions (high pressure or rhodium catalysts)

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 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

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Synthesis of Trisubstituted Benzenes
 These syntheses require planning and consideration of
alternative routes
 Ability to plan a sequence of reactions in right order is valuable
to synthesis of substituted aromatic rings
 Ex: Synthesize 4-bromo-2-nitrotoluene from benzene

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49
Synthesize 4-chloro-2-propylbenzenesulfonic
acid from benzene

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Synthesize 4-chloro-2-propylbenzenesulfonic
acid from benzene Cont….

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