16.

Chemistry of
Benzene: Electrophilic
Aromatic Substitution
苯的反應 : 親電子芳香族取代反應

Based on McMurry’s Organic Chemistry, 9th edition

 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

Substitution

2
 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

3
Electrophilic Aromatic Substitution
親電子芳香族取代反應
Electrophile substitutes for a hydrogen on the
benzene ring.
H E
+ +
+ E + H

benzene as nucleophile

苯環與親電子試劑（ electrophile ）發生的親電子芳香

族取代反應 (electrophilic aromatic substitution)
4
Electrophilic Aromatic Substitution Electrophilic Addition

苯有別於烯烴的特殊穩定性
5
Mechanism of Electrophilic Aromatic Substitution

slow

rate-limiting step
resonance-delocalized

• Driving force for electrophic aromatic substitution:

Cation intermediate loss H+ to regenerate the aromatic
ring and regain its large resonance energy 6
 Electrophile in EAS
Halogenation:
Br
Br2/FeBr3
also Cl2/FeCl3 [ Cl+ ]
[ Br+ ]
nucleophile electrophile

Nitration: Alkylation:
HNO3/H2SO4 NO2

Cl / AlCl3
[ NO2+ ]

+
Sulfonation: O
OH
SO3/H2SO4 S
Acylation: O O
O

Cl
/ AlCl3
HSO3+
O

+ 7
 16.1 Electrophilic Aromatic Substitution
Reactions: Bromination
 An electrophile reacts with an aromatic ring
(nucleophile) to substitute a hydrogen on the ring
 The beginning of the reaction is similar to that of
electrophilic alkene reactions
 The difference is that alkenes react more readily with
electrophiles than aromatic rings
 In the bromination of benzene, FeBr3 is used as a
catalyst to polarize the bromine reagent

electrophile
nucleophile
 Addition Intermediate in Bromination
 The shbstitution of bromine occurs in two steps
 In the first step the  electrons act as a nucleophile toward Br 2 (in a
complex with FeBr3)
 This forms a cationic addition intermediate from benzene and a
bromine cation
 Stability of the intermediate is lesser than that of the starting benzene
ring
 Reaction of an electrophile is endergonic

FeBr3 的催化原理是形成高活性的親電子試劑

weak electrophile stronger electrophile

arenium cation 是中間體 (intermediate) 而非過渡態（ transition

state ） 9
Electrophile Reactions With an Alkene and With Benzene

A comparison of the reactions of an electrophile (E+) with an alkene

and with benzene: ΔG‡alkene < ΔG‡benzene.
Stability: Benzene > Alkene

10
Electrophilic Bromination of Benzene

rate-limiting step

restores aromaticity (in contrast with

addition in alkenes)
11
Energy Diagram for Bromination

sigma complex

12
electrophic
aromatic
addition 
unfavored
(endothermic)

electrophic
aromatic
substitution
favored
(exothermic)
13
 16.2 Other Aromatic Substitutions
Aromatic 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 often use FeCl3 as catalyst, but AlCl3 will
also work

抗焦躁治療劑 14
 Other Aromatic Substitutions
Aromatic Iodination
 Since iodine is unreactive toward aromatic rings,

oxidizing agents such as CuCl2 are used as a

catalyst
 CuCl oxidizes I to form a more powerful I +
2 2

species resulting in the production of a substitute

 Aromatic Nitration 硝化
 Electrophile is NO2+
 The combination of nitric acid and sulfuric acid produces NO2+ (nitronium
ion 硝基陽離子 )
 The reaction with benzene produces nitrobenzene

16
 Reduction of the Nitro Group
 Treatment with reducing agent Fe, Sn or Zn in dilute acid will
reduce the nitro to an amino group.
 This is the best method for adding an amino group to the ring.
R-NO2RNH2

苯胺

17
 Aromatic Sulfonation 磺酸化
 Occurs by a reaction with fuming sulphuric acid, a mixture of
H2SO4, and SO3 ( 發煙硫酸 )

Reactive electrophile is SO3 or its conjugate acid HSO3+
H2 S O 4
+ S O3 S O3 H

Benzene Benzenesulfonic acid

18
 Aromatic Hydroxylation 羥基化
 Direct hydroxylation of an aromatic ring is
difficult in the laboratory
 Usually occurs in biological pathways
Mechanism for the Electrophilic Hydroxylation of p-
hydroxyphenylacetate
 16.3 Alkylation of Aromatic Rings:
The Friedel-Crafts Reaction
 Alkylation 烷化反應 : Introducing an alkyl group onto
the benzene ring
 Also called the Friedel-Crafts reaction
 and forms a new C-C bond between an aromatic ring
and an alkyl group.
 Involves treatment of an aromatic compound with an
alkyl chloride to yield a carbocation electrophile R+
 Aluminium chloride (AlCl3) used as a catalyst which
causes dissociation of the alkyl halide and promotes the
formation of the carbocation

Friedel-Craft 烷化反應在苯環上引入烷基
Mechanism of Friedel-Crafts Alkylation

2-chloropropane

Isopropanebezene
22
 Limitations of Friedel-Crafts
Friedel-Crafts 反應的應用所受到的限制
 Only alkyl halides can be used
 Reaction fails if benzene has a substituent that is
more deactivating than halogen. 苯環上含拉電子的去活性取代
基 (–NO2 、 -SO3H 、 -COOH 、 -COR ) ，不含鹵素， Friedel-Craft 反應不會發生
 Carbocations rearrange. Reaction of benzene with
n-propyl chloride and AlCl3 produces
isopropylbenzene. 發生重排反應
 The alkylbenzene product is more reactive than
benzene, so polyalkylation occurs. 多烷基化

23
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)

24
Limitations of the Friedel-Crafts Alkylation
 Will not work with rings containing an amino group
substituent or a strongly electron-withdrawing group

苯環上含拉電子的去活性取代基 (–NO2 、 -SO3H 、 -COOH 、 -COR ) ，不含鹵

素， Friedel-Craft 反應不會發生

25
 Polyalkylation
 Multiple alkylations can occur because the first alkylation is activating
 Polyalkylation occurs

26
 Carbocation Rearrangements During Alkylation
 Occasional skeletal rearrangement of the alkyl carbocation electrophile
 Occurs more often with the use of a primary alkyl halide

1o 2o

1o 3o 27
 Acylation of Aromatic Rings
 Acylation 醯基化反應 : Reaction of an
aromatic ring with a carboxylic acid chloride
(RCOCl) in the presence of AlCl3 resulting in
an acyl group substitution

乙醯氯 苯乙酮

在苯環上引入 acyl group 醯基

Mechanism of Friedel-Crafts Acylation
 Similar to alkylation
 Reactive electrophile: resonance-stabilized acyl cation
 An acyl cation does not rearrange 醯基化反應不會重排

不會重排

29
 16.4 Substituent Effects in Aromatic Rings
 Substituents affect the reactivity of the aromatic ring
 Substituents can cause a compound to be more or 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

第一個取代基的存在會影響第二個取代反應的位置和速率

deactivating group activating groups

30
 Disubstitution
 Existing groups on benzene ring influence
further substitution in both orientation and
rate.
第一個取代基的存在會影響第二個取代反應的位置
和速率
 Orientation:
 substituents are classified as either
ortho-para director ( 鄰 - 對位 ) or meta
director ( 間位 )
CH3 NO2

ortho (1,2)
meta (1,3)
para
(1,4)
 Disubstitution
 Rate:
 certain substituents cause the rate of a second

substitution to be greater than that for benzene itself;

others cause the rate to be lower
 substituents are classified as

 activating ( 活化 ) toward further substitution, or

 deactivating ( 去活化 )

若取代基的存在使得取代反應比苯本身更為 active, 則此類取代基稱為 activating

groups ( 活化基 ); 反之則稱為 deactivating group ( 去活化基 ).
deactivating group activating groups

32
33
Classification of substituent effects in electrophilic
aromatic substitution
All activating groups are ortho- and para-directing
•

•All deactivating groups other than halogen are meta-

directing.
The halogens are unique in being deactivating but
•

ortho- and para-directing.

34
 G G
ortho

+ E+ why? + E+ why?

para meta
G releases electrons G withdraws electrons
activating group 活化基 deactivating group 去活化基
ortho-para director 鄰 - 對 meta director 間位
位

35
 Origins of Substituent Effects
 An interplay of inductive effects and
resonance effects
 Inductive effect 誘導效應 - withdrawal or
donation of electrons through a  bond
 Resonance effect 共振效應 - 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

36
 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 誘導效應拉電子
 Alkyl groups donate electrons 誘導效應推電子

37
Resonance Effects – Electron Donation
 Halogen, OH, alkoxyl (OR), and amino substituents
donate electrons 共振效應推電子
  electrons flow from the substituents to the ring
 Effect is greatest at ortho and para

38
Resonance Effects – Electron Withdrawal
 C=O, CN, NO2 substituents withdraw electrons from
the aromatic ring by resonance 共振效應拉電子
  electrons flow from the rings to the substituents

39
Activating or Deactivating Effects of Substituent
 Activating groups contribute electrons to the
aromatic ring
 The ring possesses more electrons
 The carbocation intermediate is stabilized
 Activation energy is lowered
 Deactivating groups withdraw electrons from the
aromatic ring
 The ring possesses lesser electrons
 The carbocation intermediate is destabilized
 Activation energy is increased
An Explanation of Substituent Effects

41
 • Electron-donating group: activating
G G G

+ E+ + + Reaction is faster

G releases electrons E H E H

Transition state is stabilized Arenium ion is stabilized

• Electron-withdrawing group: deactivating

G G G

+ E+ + + Reaction is slower

G withdraws electrons E H E H

Transition state is destabilized Arenium ion is destabilized 42

Electrostatic potential maps of benzene and several substituted benzenes
show that an electron-withdrawing group (−CHO or −Cl) makes the ring more
electron-poor (yellow-green), while an electron-donating group (−OH) makes
the ring more electron-rich (red).
43
Ortho- and Para-Directing Activators: Alkyl Groups
 Alkyl groups activation
 possess electron-donating inductive effect

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

活化基 : 鄰 - 對
位的中間體受到
的穩定效應大於
間位
44
 Ortho- and Para-Directing Activators: OH and NH2
 Alkoxyl, and amino groups activation
 have a strong, electron-donating resonance effect

 Most pronounced at the ortho and para positions

45
 Ortho- and Para-Directing Deactivators:
Halogens
 Halogen groups deactivation
 Caused by electron-withdrawing inductive

effect outweighs weaker electron-donating

resonance effect
 Electron donating resonance effect is present
only at the ortho and para positions
 Ortho and para reactions can cause
stabilization of the positive charge in the
carbocation intermediates
 Meta intermediates take more time to form
Ortho- and Para-Directing Dactivators: Halogens

鹵苯 :
去活化基

鄰 - 對位
47
 Meta-Directing Deactivators
 Meta-directors deactivate all positions on the ring, but the
meta position is less deactivated
 Ortho and para intermediates destabilized by deactivation of
carbocation intermediate

去活化基 : 鄰 -
對位的中間體受
到的去穩定效應
大於間位
48
Activators and Deactivators

 If the substituent on the ring is electron donating, the

ortho and para positions will be activated.
 If the group is electron withdrawing, the ortho and
para positions will be deactivated.

49
Summary Table: Effect of Substituents in
Aromatic Substitution

50
16.5 Trisubstituted Benzenes: Additivity of Effects
 The situation is straightforward if the directing
effects of the groups reinforce each other

51
 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

兩個取代基反應位置效應不一致時，由強取代基決定反應位置。
52
 Meta-Disubstituted Compounds
 Further substitution is rare when two groups are in a meta-disubstituted
compound as the site is too hindered
 To make aromatic rings with three adjacent substituents, it is best to start with
an ortho-disubstituted compound

53
*

16.6 Nucleophilic Aromatic Substitution

 Aryl halides 芳香基鹵化物 do not undergo nucleophilic
substitution by either SN1 or SN2 pathways
 Aryl halides do undergo nucleophilic substitutions, but by
mechanisms quite different from those of nucleophilic
aliphatic substitution
 Nucleophilic aromatic substitutions are far less common
than electrophilic aromatic substitutions

Two mechanism are involved:
 Addition-elimination mechanism

 Benzyne mechanism, elimination - addition

( with strong withdrawing groups)

( without strong withdrawing groups)

54
55
16.6 Nucleophilic Aromatic Substitution
 Aryl halides with electron-withdrawing substituents
ortho and para react with nucleophiles
 A nucleophile replaces a halides leaving group on
the aromatic ring.
 Electron-withdrawing substituents activate the ring
for nucleophilic substitution reaction
X
 . Nu

Nu

EWG: p- or o-position
EWG EWG

56
Mechanism of nucleophilic aromatic substitution
: Addition-elimination mechanism
 involves in two steps and a resonance-
stabilized carbanion intermediate
 First step: Addition
Form addition intermediate (Meisenheimer
complex) that is stabilized by electron-
withdrawal
 Second step: Eliminaition
Halide ion is lost to give aromatic ring

57
Addition-elimination mechanism

Nitrochlorobenzenes

Addition

reaction

Eliminaition
 Addition-Elimination Mechanism
Nitro groups ortho and para to the halogen stabilize
the intermediate. Without electron withdrawing
groups in these positions, formation of the negatively
charged sigma complex is unlikely.
碳負離子中間體很不穩定，通常只有苯環上有足夠強的拉電子基團使之穩定。所以，當
只有鄰 - 對位強的拉電子基團穩定中間體時，親核取代反應才能發生。

60
meta
 16.7 Benzyne 苯炔
 On a general basis, there are no reactions between
nucleophiles and halobenzenes that do not have
electron withdrawing substituents
 However, chlorobenzene react with nucleophiles
NaOH at high temperatures under high pressure
(extreme condition)
 The reaction involves an elimination reaction that
gives a triple bond
 The intermediate is called benzyne
 Elimination – Addition Mechanism
• Halobenzene with no electron-withdrawing groups on
the ring.
•
Use a very strong base like NaNH2 (pKa= 35) or extreme
condition (NaOH at 340 0C).
• Elimination of HBr from bromobenzene forms a benzyne
as the chemical intermediate

p. 575
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
1 1

2
2

Elimination Addition

63
 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

sp2

64
16.8 Oxidation of Alkyl Side Chains
 In the presence of an aromatic ring, alkyl side chains are
converted to carboxyl acid through oxidation
 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
 alkylbenzene 烷苯 is converted to benzoic acid,
ArR  ArCO2H

苯環不易氧化，但苯環聯接烷基後，烷基側鏈易氧化。氧化從 benzyl 位
置開始，不論烷基的長短最終都變爲羧酸。 65
 Oxidation of Aromatic Compounds
 Side-chain oxidation involves a complex
mechanism wherein C–H bonds next to the
aromatic ring react to form intermediate
benzylic radicals
 Analogous side-chain reactions are a part of
many biosynthetic pathways
 Oxidation of Aromatic Compound

• Industry method: Air (O2) and CO(III) catalyst

•
tert-Butlybenzene has no benzylic hrdrogen, and is inert
 Bromination of Alkylbenzene Side
Chains
 Reaction of an alkylbenzene 烷苯 with N-bromo-
succinimide (NBS) and benzoyl peroxide (radical
initiator) introduces Br into the side chain

or light
(Br radical source)

68
 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

69
 Bromination of Alkylbenzene Side Chains
 The reaction of HBr with NBS occurs only at
the benzylic position
 The benzylic radical intermediate is stabilized
by resonance
 The p orbital of the benzyl radical overlaps with
the ringed  electron system
16.9 Reduction of Aromatic Compounds
 Aromatic rings are inert to catalytic hydrogenation
under conditions that reduce alkene double bonds
 They can selectively reduce an alkene double
bond in the presence of an aromatic ring

71
Reduction of Aromatic Compounds
 Reduction of an aromatic ring requires either:
 A platinum catalyst and a pressure of several
hundred atmospheres
 A catalyst such as rhodium 銠 on carbon

72
 Reduction of Aryl Alkyl Ketones
 Aromatic ring activates neighboring carbonyl group 羰基 toward
reduction
 Ketone is converted into an alkylbenzene by catalytic
hydrogenation over Pd catalyst
 A method for the synthesis of unrearranged alkylbenzenes

unrearranged
alkylbenzenes

rearranged
alkylbenzenes
major

73
Reduction of Aromatic Compounds
Limitation
• Only aryl alkyl ketones can be converted into a
methylene group by catalytic hydrogenation
• diakyl ketone are not reduced.
• A nitro group is reduced to an amino group under
reduction condition.

p. 580
16.10 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
 It is best to plan a synthesis problem backward, or
retrosynthesis 逆合成

Example : Synthesize 4-bromo-2-nitrotoluene from benzene

75
Retrosynthetic analysis 逆合成分析

76
Forward synthesis 合成
 Worked Example
 Synthesize m-Chloronitrobenzene from
benzene
 Solution:
 In order to synthesize the product with the
correct orientation of substituents, benzene
must be nitrated before it is chlorinated
 Summary

 There are two phases in an electrophilic

aromatic substitution reaction:
 Initial reaction of an electrophile E+
 Loss of H+ from the resonance-stabilized
carbocation intermediate
 The Friedel-Crafts alkylation and acylation
reactions are important electrophilic aromatic
substitution reactions that involve the reaction
of an aromatic ring with carbocation
electrophiles
 Summary

 Resonance and inductive effects are the

means by which substituents influence
aromatic rings
 Nucleophilic aromatic substitution is a
reaction that halobenzenes go through and
involve an addition of a nucleophile to the ring
 In halobenzenes that are not activated by
electron-withdrawing substituents,
nucleophilic aromatic substitutions occur by
elimination of HX which yields a benzene