Vollhardt Capítulo 22 (Substituições com Benzeno)

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Benzene (Chapter 15) used to be a common laboratory solvent until OSHA (U.S. Occu-pational Safety and Health Administration) 
placed it on its list of carcinogens. Chemists now 
use methylbenzene (toluene) instead, which has 
very similar solvating power but is not carcino-
genic. Why not? The reason is the relatively high 
reactivity of the benzylic hydrogens that renders 
methylbenzene subject to fast metabolic degrada-
tion and extrusion from the body, unlike benzene, 
which can survive many days embedded in fatty 
and other tissues. Thus, the benzene ring, though 
itself quite unreactive because of its aromaticity, 
appears to activate neighboring bonds or, more 
generally, affects the chemistry of its substituents. 
You should not be too surprised by this fi nding, 
because it is complementary to the conclusions of 
Chapter 16. There we saw that substituents affect 
the behavior of benzene. Here we shall see the 
reverse.
 How does the benzene ring modify the behavior of neighboring reactive centers? 
This chapter takes a closer look at the effects exerted by the ring on the reactivity of 
alkyl substituents, as well as of attached hydroxy and amino functions. We shall see 
that the behavior of these groups (introduced in Chapters 3, 8, and 21) is altered by the 
occurrence of resonance. After considering the special reactivity of aryl-substituted 
(benzylic) carbon atoms, we turn our attention to the preparation and reactions of 
 phenols and benzenamines (anilines). These compounds are found widely in nature 
and are used in synthetic procedures as precursors to substances such as aspirin, dyes, 
and vitamins.
C H A P T E R T W E N T Y T W O
Chemistry of Benzene 
Substituents
Alkylbenzenes, Phenols,
and Benzenamines
Ciprofl oxacin (“Cipro”) is a 
synthetic tetrasubstituted 
benzene derivative used widely 
to treat bacterial infections, 
especially of the urinary tract. 
The photo shows a laboratory 
worker producing tablets of 
the drug.
OO
O
N N
N
F
1020 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
22-1 Reactivity at the Phenylmethyl (Benzyl) Carbon:
Benzylic Resonance Stabilization
Methylbenzene is readily metabolized because its methyl C – H bonds are relatively weak 
with respect to homolytic and heterolytic cleavage. When one of these methyl hydrogens 
has been removed, the resulting phenylmethyl (benzyl) group, C6H5CH2 (see margin), may 
be viewed as a benzene ring whose p system overlaps with an extra p orbital located on 
an attached alkyl carbon. This interaction, generally called benzylic resonance, stabilizes 
adjacent radical, cationic, and anionic centers in much the same way that overlap of a p bond 
and a third p orbital stabilizes 2-propenyl (allyl) intermediates (Section 14-1). However, 
unlike allylic systems, which may undergo transformations at either terminus and give 
product mixtures (in the case of unsymmetrical substrates), benzylic reactivity is regioselec-
tive and occurs only at the benzylic carbon. The reason for this selectivity lies in the dis-
ruption of aromaticity that goes with attack on the benzene ring.
Benzylic radicals are reactive intermediates in the halogenation
of alkylbenzenes
We have seen that benzene will not react with chlorine or bromine unless a Lewis acid is 
added. The acid catalyzes halogenation of the ring (Section 15-9).
Br–Br, FeBr3
–HBr
Br
Br–Br
No reaction
In contrast, heat or light allows attack by chlorine or bromine on methylbenzene (toluene) 
even in the absence of a catalyst. Analysis of the products shows that reaction takes place 
at the methyl group, not at the aromatic ring, and that excess halogen leads to multiple 
substitution.
�
CH2Br
Br2�
CH2H
HBr�
(Bromomethyl)-
benzene
CH3
(Chloromethyl)-
benzene
CH2Cl CHCl2
(Dichloromethyl)-
benzene
CCl3
(Trichloromethyl)-
benzene
Cl2, hv
�HCl
Cl2, hv
�HCl
Cl2, hv
�HCl
Each substitution yields one molecule of hydrogen halide as a by-product.
As in the halogenation of alkanes (Sections 3-4 through 3-6) and the allylic halogena-
tion of alkenes (Section 14-2), the mechanism of benzylic halogenation proceeds through 
radical intermediates. Heat or light induces dissociation of the halogen molecule into 
atoms. One of them abstracts a benzylic hydrogen, a reaction giving HX and a phenyl-
methyl (benzyl) radical. This intermediate reacts with another molecule of halogen to give 
the product, a (halomethyl)benzene, and another halogen atom, which propagates the 
chain process.
Phenylmethyl (benzyl) system
2-Propenyl
(allyl) system
Sole site
of reactivity
Sites of reactivity
REACTION
 C h a p t e r 2 2 1021
Mechanism of Benzylic Halogenation
Initiation:
Propagation:
X
Phenylmethyl (benzyl)
radical
CH2
�HX
j
X� j
j CH2X
XOX
CH2OH
jOXðð š� X2ðš�Xš�
� or h�
What explains the ease of benzylic halogenation? The answer lies in the stabilization of 
the phenylmethyl (benzyl) radical by the phenomenon called benzylic resonance (Figure 22-1). 
As a consequence, the benzylic C – H bond is relatively weak (DH8 5 87 kcal mol21, 
364 kJ mol21); its cleavage is relatively favorable and proceeds with a low activation energy.
Inspection of the resonance structures in Figure 22-1 reveals why the halogen attacks 
only the benzylic position and not an aromatic carbon: Reaction at any but the benzylic 
carbon would destroy the aromatic character of the benzene ring.
Remember: Single-headed 
(“fi shhook”) arrows denote 
the movement of single 
electrons.
MECHANISM
H
H
C
CH2
or
A B
C
CH2
δ
δ
δ δ
CH2 CH2CH2
Figure 22-1 The benzene 
p system of the phenylmethyl 
 (benzyl) radical enters into 
 resonance with the adjacent 
 radical center. The extent of 
 delocalization may be depicted 
by (A) resonance structures, 
(B) dotted lines, or (C) orbitals.
Benzylic cations delocalize the positive charge
Reminiscent of the effects encountered in the corresponding allylic systems (Section 14-3), 
benzylic resonance can affect strongly the reactivity of benzylic halides and sulfonates 
in nucleophilic displacements. For example, the 4-methylbenzenesulfonate (tosylate) of 
4-methoxyphenylmethanol (4-methoxybenzyl alcohol) reacts with solvent ethanol rapidly 
via an SN1 mechanism. This reaction is an example of solvolysis, specifi cally ethanolysis, 
which we described in Chapter 7.
Exercise 22-1
For each of the following compounds, draw the structure and indicate where radical 
halogenation is most likely to occur upon heating in the presence of Br2. Then rank the 
compounds in approximate descending order of reactivity under bromination conditions. 
(a) Ethylbenzene; (b) 1,2-diphenylethane; (c) 1,3-diphenylpropane; (d) diphenylmethane; 
(e) (1-methylethyl)benzene.
2 2 - 1 B e n z y l i c R e s o n a n c e S t a b i l i z a t i o n
1022 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
(4-Methoxyphenyl)methyl
4-methylbenzenesulfonate
1-(Ethoxymethyl)-4-methoxybenzene
(A primary benzylic tosylate)
CH3O CH2OS
CH3O CH2OCH2CH3
O
O
B
B
CH3
CH3
CH3CH2OH�
HO3S�
SN1
Ethanolysis
The reason is the delocalization of the positive charge of the benzylic cation through the 
benzene ring, allowing for relatively facile dissociation of the starting sulfonate.
CH3O CH2 L
�L�
CH3CH2OH
CH2
�
��
š�
CH3O�
O
ð
CH2
CH3O�ð
�
CH2
Benzylic cation
Octet form
CH3O�ð CH3O�ð
CH2
product
CH2
CH3O��
Mechanism of Benzylic Unimolecular Nucleophilic Substitution
Several benzylic cations are stable enough to be isolable. For example, the X-ray struc-
ture of the 2-phenyl-2-propyl cation (as its SbF6
2 salt) was obtained in 1997 and shows 
the phenyl
– C bond (1.41 Å) to be intermediate in length between those of pure single 
(1.54 Å) and double bonds (1.33 Å), in addition to the expected planar framework and 
trigonal arrangement of all sp2 carbons (Figure 22-2), as expected for a delocalized 
benzylic system.
REACTION
MECHANISM
ANIM
ATION ANIMATED MECHANISM:
Benzylic nucleophilic
substitution
H3C
H3C
1.41 Å
1.48 Å 1.43 Å 1.37 Å
1.40 Å
114° 116°
122°123°
+
Figure 22-2 Structure of the
2-phenyl-2-propyl cation.
Exercise 22-2
Which one of the two chlorides will solvolyze more rapidly: (1-chloroethyl)benzene,
C6H5CHCl, or chloro(diphenyl)methane, (C6H5)2CHCl? Explain your answer.
 A
 CH3
The above SN1 reaction is facilitated by the presence of the para methoxy substituent, 
which allows for extra stabilization of the positive charge. In the absence of this substituent, 
SN2 processes may dominate. Thus, the parent phenylmethyl (benzyl) halides and sulfonates 
undergo preferential and unusually rapid SN2 displacements, even under solvolytic condi-
tions, and particularly in the presence of good nucleophiles. As in allylic SN2 reactions 
(Section 14-3), two factors contribute to this acceleration. One is that the benzylic carbon 
is made relatively more electrophilic by the neighboring sp2-hybridized phenyl carbon 
 C h a p t e r 2 2 1023
(as opposed to sp3-hybridized ones; Section 13-2). The second is stabilization of the SN2 
transition state by overlap with the benzene p system (Figure 22-3).
CH2Br
�CN� Br��
81%
Phenylethanenitrile
(Phenylacetonitrile)
(Bromomethyl)benzene
(Benzyl bromide)
CH2CN
SN2
( 100 times faster than SN2 reactions of primary bromoalkanes)
‡
C
Nu −�
X −�
H
H
Figure 22-3 The benzene 
p system overlaps with the 
 orbitals of the SN2 transition state 
at a benzylic center. As a result, 
the transition state is stabilized, 
thereby lowering the activation 
barrier toward SN2 reactions 
of (halomethyl)benzenes.
ANIM
ATION ANIMATED MECHANISM:
Benzylic nucleophilic
substitution
Exercise 22-3
Phenylmethanol (benzyl alcohol) is converted into (chloromethyl)benzene in the presence of 
 hydrogen chloride much more rapidly than ethanol is converted into chloroethane. Explain.
Resonance in benzylic anions makes benzylic hydrogens
relatively acidic
A negative charge adjacent to a benzene ring, as in the phenylmethyl (benzyl) anion, is 
stabilized by conjugation in much the same way that the corresponding radical and cation 
are stabilized. The electrostatic potential maps of the three species (rendered in the margin 
at an attenuated scale for optimum contrast) show the delocalized positive (blue) and neg-
ative (red) charges in the cation and anion, respectively, in addition to the delocalized 
electron (yellow) in the neutral radical.
CH2�
�
�
CH2
Resonance in Benzylic Anions
� H�
CH2 CH2ðCH3
k
�
k
�
41pKa
The acidity of methylbenzene (toluene; pKa < 41) is therefore considerably greater than 
that of ethane (pKa < 50) and comparable to that of propene (pKa < 40), which is de-
protonated to produce the resonance-stabilized 2-propenyl (allyl) anion (Section 14-4). 
 Consequently, methylbenzene (toluene) can be deprotonated by butyllithium to generate 
phenylmethyllithium.
Phenylmethyl (benzyl)
cation
Phenylmethyl (benzyl)
anion
Phenylmethyl (benzyl)
radical
2 2 - 1 B e n z y l i c R e s o n a n c e S t a b i l i z a t i o n
1024 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
Deprotonation of Methylbenzene
� CH3CH2CH2CH2Li
CH3
Methylbenzene
(Toluene)
� CH3CH2CH2CH2H
CH2Li
Phenylmethyllithium
(Benzyllithium)
(CH3)2NCH2CH2N(CH3)2, THF, �
Exercise 22-4
Which molecule in each of the following pairs is more reactive with the indicated reagents, and why?
(a) (C6H5)2CH2 or C6H5CH3, with CH3CH2CH2CH2Li
(b) 
OCH3
or , with NaOCH3 in CH3OH
CH2Br
OCH3
CH2Cl
(c) or , with HCl
CH3CHOH
NO2
CH3CHOH
In Summary Benzylic radicals, cations, and anions are stabilized by resonance with the 
 benzene ring. This effect allows for relatively easy radical halogenations, SN1 and SN2 
reactions, and benzylic anion formation.
22-2 Benzylic Oxidations and Reductions
Because it is aromatic, the benzene ring is quite unreactive. While it does undergo electrophilic 
aromatic substitutions (Chapters 15 and 16), reactions that dismantle the aromatic six-electron 
circuit, such as oxidations and reductions, are much more diffi cult to achieve. In contrast, such 
transformations occur with comparative ease when taking place at benzylic positions. This sec-
tion describes how certain reagents oxidize and reduce alkyl substituents on the benzene ring.
Oxidation of alkyl-substituted benzenes leads to aromatic ketones
and acids
Reagents such as hot KMnO4 and Na2Cr2O7 may oxidize alkylbenzenes all the way to 
benzoic acids. Benzylic carbon – carbon bonds are cleaved in this process, which usually 
requires at least one benzylic C – H bond to be present in the starting material (i.e., tertiary 
alkylbenzenes are inert).
CH2CH2CH2CH3
1-Butyl-4-methylbenzene
H3C
COOH
1,4-Benzenedicarboxylic acid
(Terephthalic acid)
80%
Complete Benzylic Oxidations of Alkyl Chains
HOOC
1. KMnO4, HO�, �
2. H�, H2O
�3 CO2
 C h a p t e r 2 2 1025
The reaction proceeds through fi rst the benzylic alcohol and then the ketone, at which stage 
it can be stopped under milder conditions (see margin and Section 16-5).
The special reactivity of the benzylic position is also seen in the mild conditions required 
for the oxidation of benzylic alcohols to the corresponding carbonyl compounds. For example, 
manganese dioxide, MnO2, performs this oxidation selectively in the presence of other 
(nonbenzylic) hydroxy groups. (Recall that MnO2 was used in the conversion of allylic 
alcohols into a,b-unsaturated aldehydes and ketones; see Section 17-4.)
OH OH
OHH
CH3O
CH3O CH3O
Selective Oxidation of a Benzylic Alcohol with Manganese Dioxide
CH3O
MnO2, acetone, 25°C, 5 h
94%
O
Benzylic ethers are cleaved by hydrogenolysis
Exposure of benzylic alcohols or ethers to hydrogen in the presence of metal catalysts 
results in rupture of the reactive benzylic carbon – oxygen bond. This transformation is an 
example of hydrogenolysis, cleavage of a s bond by catalytically activated hydrogen.
1,2,3,4-Tetra-
hydronaphthalene
(Tetralin)
Not isolated
OH
71%
1-Oxo-1,2,3,4-tetrahydro-
naphthalene
(1-Tetralone)
O
CrO3, CH3COOH
H2O, 21°C
,
Cleavage of Benzylic Ethers by Hydrogenolysis
CH2 ORO
H2, Pd–C, 25°C
CH2H
� HOR
Hydrogenolysis is not possible for ordinary alcohols and ethers. Therefore, the phenyl-
methyl (benzyl) substituent is a valuable protecting group for hydroxy functions. The 
 following scheme shows its use in part of a synthesis of a compound in the eudesmane 
class of essential oils, which includes substances of importance in both medicine and 
 perfumery.
Exercise 22-5
Write synthetic schemes that would connect the following starting materials with their products.
(a) 
CH3CH2CH3
(b) 
CH3H3C
CH3H3C
OO
OO
OO
2 2 - 2 B e n z y l i c O x i d a t i o n s a n d R e d u c t i o n s
1026 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
Because the hydrogenolysis of the phenylmethyl (benzyl) ether in the fi nal step occurs 
under neutral conditions, the tertiary alcohol function survives untouched. A tertiary butyl 
ether would have been a worse choice as a protecting group, because cleavage of its 
 carbon – oxygen bond would have required acid (Section 9-8), which may cause dehydration 
(Section 9-2).
In Summary Benzylic oxidations of alkyl groups take place in the presence
of permanga-
nate or chromate; benzylic alcohols are converted into the corresponding ketones by man-
ganese dioxide. The benzylic ether function can be cleaved by hydrogenolysis in a 
transformation that allows the phenylmethyl (benzyl) substituent to be used as a protecting 
group for the hydroxy function in alcohols.
22-3 Names and Properties of Phenols
Arenes substituted by hydroxy groups are called phenols (Section 15-1). The p system of 
the benzene ring overlaps with an occupied p orbital on the oxygen atom, a situation result-
ing in delocalization similar to that found in benzylic anions (Section 22-1). As one result 
of this extended conjugation, phenols possess an unusual, enolic structure. Recall that enols 
are usually unstable: They tautomerize easily to the corresponding ketones because of the 
relatively strong carbonyl bond (Section 18-2). Phenols, however, prefer the enol to the keto 
form because the aromatic character of the benzene ring is preserved.
O
O
1. CH3Li,
 (CH3CH2)2O
2. H�, H2O
(Section 8-8)
H
CH3%
≥
RO
%
CCH3
98%
% A
A
CH3
OH
H2, Pd–C,
CH3CH2OH
Deprotection
 of OR
H
CH3%
≥
HO
%
CCH3
98%
% A
A
CH3
OH
H
CH3%
≥
RO
%
(Mixture of E and Z isomers)
O
93%
CH3CHP
DMSO
Wittig reaction
(Section 17-12)
P(C6H5)3,
H
CH3%
≥
RO
%
CHCH3
94%
1. BH3, THF
2. Oxidation (to alcohol)
3. Oxidation (to ketone)
Hydroboration–oxidation*
(Section 12-8)
Oxidation (Section 8-6) H
CH3%
≥
RO
%
COCH3
99%
%
O
O
O H
CH3%
≥
1. NaH, THF
2. C6H5CH2Br
O
O
HO
%
H
CH3%
≥
O
O
RO
%
Protection of OH
(Section 9-6)
CH3COOH,
H2O
Deprotection
of carbonyl group
(Section 17-8)
80%
(R � C6H5CH2)
Phenylmethyl Protection in a Complex Synthesis
*While the literature reports the use of special oxidizing agents, in principle 2. H2O2, 
2OH and 
3. CrO3 would have been satisfactory.
 C h a p t e r 2 2 1027
Keto and Enol Forms of Acetone and Phenol
2,4-Cyclohexadienone
O
H
�š
H
OHð šOHðð ð šOH
�ð
�šOH
�š
ð�
�šOH
Phenol
K ~ 1013
2-PropenolAcetone
K ~ 10�9
Oðð
H
C
H2
H3C CH2H3C
šOHð
Phenols and their ethers are ubiquitous in nature; some derivatives have medicinal 
and herbicidal applications, whereas others are important industrial materials. This section 
fi rst explains the names of these compounds. It then describes an important difference 
between phenols and alkanols — phenols are stronger acids because of the neighboring 
aromatic ring.
Phenols are hydroxyarenes
Phenol itself was formerly known as carbolic acid. It forms colorless needles (m.p. 418C), 
has a characteristic odor, and is somewhat soluble in water. Aqueous solutions of it (or its 
methyl-substituted derivatives) are applied as disinfectants, but its main use is for the prep-
aration of polymers (phenolic resins; Section 22-6). Pure phenol causes severe skin burns 
and is toxic; deaths have been reported from the ingestion of as little as 1 g. Fatal poison-
ing may also result from absorption through the skin.
Substituted phenols are named as phenols, benzenediols, or benzenetriols, according to 
the system described in Section 15-1, although some common names are accepted by IUPAC 
(Section 22-8). These substances fi nd uses in the photography, dyeing, and tanning indus-
tries. The compound bisphenol A (shown in the margin; see also Chemical Highlight 22-1) 
is an important monomer in the synthesis of epoxyresins and polycarbonates, materials that 
are widely employed in the manufacture of durable plastic materials, food packaging, dental 
sealants, and coatings inside beverage cans (Chemical Highlight 22-1).
Phenols containing the higher-ranking carboxylic acid functionality are called hydroxy-
benzoic acids. Many have common names. Phenyl ethers are named as alkoxybenzenes. 
As a substituent, C6H5O is called phenoxy.
OH
NO2
Cl
4-Chloro-
3-nitrophenol
COOH
OH
3-Hydroxybenz-
oic acid
(m-Hydroxybenzoic acid)
OH
1,4-Benzenediol
(Hydroquinone)
OH
1,2,3-Benzenetriol
(Pyrogallol)
OH
OH
4-Methylphenol
(p-Cresol)
CH3
OH
OH
Many examples of phenol derivatives, particularly those exhibiting physiological activity, 
are depicted in this book (e.g., see Chemical Highlights 5-4, 9-1, 21-1, 22-1, and 22-2, and 
OH
OH
Bisphenol A
CH3C CH3O O
2 2 - 3 N a m e s a n d P r o p e r t i e s o f P h e n o l s
1028 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
Phenols are unusually acidic
Phenols have pKa values that range from 8 to 10. Even though they are less acidic than 
carboxylic acids (pKa 5 3 – 5), they are stronger than alkanols (pKa 5 16 – 18). The reason 
is resonance: The negative charge in the conjugate base, called the phenoxide ion, is stabilized 
by delocalization into the ring.
OH
H�
�
�
šð Ošð ð Oð ð
�
�
O
Phenoxide ion
Acidity of Phenol
ð ðOð ð
k
�
k
�
pKa 10
HO
O
H3C N
O
H
Capsaicin
(Active ingredient in hot pepper,
as in jalapeño or cayenne pepper)
A
E
OH
OHHO
Resveratrol
(Cancer chemopreventive
from grapes; see also
Chemical Highlight 22-1) O
O
O
OH
OH
OH
OH
OH
OH
HO
HO
~
HO O
4-(4-Hydroxyphenyl)-2-butanone
(Flavor of raspberries)
Raspberries.
Green tea.
Chili peppers.
Sections 4-7, 9-11, 15-1, 22-9, 24-12, 25-8, and 26-1). You are very likely to have ingested 
without knowing it the four phenol derivatives shown here.
 Epigallocatechin-3 gallate
(Cancer chemopreventitive
from green tea)
 C h a p t e r 2 2 1029
The acidity of phenols is greatly affected by substituents that are capable of resonance. 
4-Nitrophenol (p-nitrophenol), for example, has a pKa of 7.15.
OHšð
H� etc.
�
�
Ošð ð Oð ð
�
k
�
�
N�
�O Oð�
HK
�½ k
N�
�O Oð�
HK
�½ k
N�
�O Oð�
HK
�½ k �O
H
�½ k
pKa � 7.15
Oð ð
N�
Oð� �O
H
�½ kO�½
Oð ð
N�
�ý E
Negative charge
delocalized into the
nitro group
The 2-isomer has similar acidity (pKa 5 7.22), whereas nitrosubstitution at C3 results in a 
pKa of 8.39. Multiple nitration increases the acidity to that of carboxylic or even mineral 
acids. Electron-donating substituents have the opposite effect, raising the pKa.
O2NNO2
NO2
2,4-Dinitrophenol
OH
pKa � 4.09
NO2
NO2
2,4,6-Trinitrophenol
(Picric acid)
OH
pKa � 0.25
CH3
4-Methylphenol
( p-Cresol)
OH
pKa � 10.26
As Section 22-5 will show, the oxygen in phenol and its ethers is also weakly basic, in the 
case of ethers giving rise to acid-catalyzed cleavage.
Exercise 22-6
Why is 3-nitrophenol (m-nitrophenol) less acidic than its 2- and 4-isomers but more acidic than 
phenol itself?
In Summary Phenols exist in the enol form because of aromatic stabilization. They 
are named according to the rules for naming aromatic compounds explained in 
Section 15-1. Those derivatives bearing carboxy groups on the ring are called hydroxy- 
benzoic acids. Phenols are acidic because the corresponding anions are resonance 
 stabilized.
Exercise 22-7
Rank in order of increasing acidity: phenol, A; 3,4-dimethylphenol, B; 3-hydroxybenzoic 
(m-hydroxybenzoic) acid, C; 4-(fl uoromethyl)phenol [p-(fl uoromethyl)phenol], D.
2 2 - 3 N a m e s a n d P r o p e r t i e s o f P h e n o l s
1030 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
CHEMICAL HIGHLIGHT 22-1
Two Phenols in the News: Bisphenol A and Resveratrol
This section mentions two phenols as examples of chemicals 
to which you have potentially frequent exposure: bisphenol 
A (p. 1027) and resveratrol (p. 1028). Bisphenol A is the 
essential ingredient
of the familiar polycarbonate plastics 
used in clear baby bottles, instant-formula cans, dental 
 sealants, the linings of food and beverage containers, and 
reusable plastic bottles. More than 2 billion pounds are 
made each year in the United States alone, and three times 
as much are made worldwide. Yet there is continuing 
 controversy surrounding this monomer, fi rst made in 1891—
a controversy that illustrates the diffi culty of interpreting 
scientifi c data in terms of human risk assessment.
The problem is that bisphenol A behaves as an estrogen 
mimic in animals. The monomer has been found to leach 
from the plastic, at increasing rates when heated, such as in 
a microwave oven. For example, a study carried out in 2003 
showed that even very low levels of bisphenol A (about 
20 ppb) caused chromosome aberrations in developing 
mouse eggs. These amounts are in the same range as are 
encountered in human blood and urine. Because the pro-
cesses through which human and mouse eggs are prepared 
for fertilization are very similar, the study is a cause for 
 concern, although it does not prove that humans are at risk. 
Moreover, in other studies carried out with adult rats, 
bisphenol A appeared to have no adverse effects on repro-
duction and development. A critique of these fi ndings, dated 
2008, pointed out that fetuses and newborns lack the liver 
enzyme needed to detoxify the chemical, again raising the 
specter of adverse effects on children. As a report by the 
National Institute of Environmental Health Sciences stresses, 
the discrepancies in studies of this type may be due to the 
use of different strains of animals, varying degrees of 
 exposure and differing background levels of estrogenic 
 pollutants, dosing regimens, and housing of the animals 
A
A B
O
n
O CC
CH3
CH3
O O
Carbonate unit
O
O
Bisphenol A unit
Polycarbonate plastics
A polycarbonate plastic bottle in 
action.
22-4 Preparation of Phenols: Nucleophilic 
Aromatic Substitution
Phenols are synthesized quite differently from the way in which ordinary substituted ben-
zenes are made. Direct electrophilic addition of OH to arenes is diffi cult because of the 
scarcity of reagents that generate an electrophilic hydroxy group, such as HO1. Instead, 
phenols are prepared by formal nucleophilic displacement of a leaving group from the arene 
ring by hydroxide, HO2, reminiscent of, but mechanistically quite different from, the 
 synthesis of alkanols from haloalkanes. This section considers the ways in which this 
transformation may be achieved.
Nucleophilic aromatic substitution may follow an 
addition – elimination pathway
Treatment of 1-chloro-2,4-dinitrobenzene with hydroxide replaces the halogen with the 
nucleophile, furnishing the corresponding substituted phenol. Other nucleophiles, such 
 C h a p t e r 2 2 1031
(singly versus group). Remember that we are talking about 
extremely small concentrations of a biologically active com-
pound (parts per billion!) that affect only a certain percent-
age of animals and to differing degrees. And then there are 
the big questions of the extent to which animal studies are 
relevant to humans and whether there is a threshold level of 
exposure that humans can tolerate because of the presence 
of evolutionary natural detoxifi cation mechanisms. In 2007 
and 2008, two government-convened groups reiterated that 
human exposure is at a level that causes adverse effects in 
humans and that there is concern about prenatal and early-
childhood exposure. As a result, both Canada and the U.S. 
Congress began moving toward a ban of bisphenol A in 
children’s products, and some retailers, such as Wal-Mart 
and Toys“R”Us, are phasing out their sale. Concurrently, 
industrial producers are replacing polycarbonate plastics 
with other polymers.
The issues surrounding the potentially harmful effects 
of chemicals in the environment are equally relevant with 
respect to their potentially benefi cial effects. An example 
is resveratrol. This compound has been used in traditional 
medicine to treat conditions of the heart and liver, and 
recently scientists took an interest in its physiological prop-
erties. It is present in various plants and foods, such as 
eucalyptus, lily, mulberries, peanuts, and, most prominently, 
in the skin of white and, especially, red grapes, where it is 
found in concentrations of 50–100 mg/g. The compound is a 
chemical weapon against invading organisms, such as fungi. 
Grapes are used for wine making, so resveratrol occurs in 
red wine, at levels of up to 160 mg per ounce. Studies have 
suggested that the regular consumption of red wine reduces 
the incidence of coronary heart disease, a fi nding described 
as the “French paradox,” namely, the low incidence of heart 
problems in France despite the relatively high-fat diet. 
 Resveratrol may be the active species, as recent research has 
indicated its potentially benefi cial cardiovascular effects, 
including its action as an antioxidant, which inhibits lipid 
peroxidation (Section 22-9), and as an antiplatelet agent 
(Chemical Highlight 22-2), which prevents atherosclerosis. 
Other investigations have shown that the molecule is also 
an active antitumor agent, involved in retarding the initia-
tion, promotion, and progression of certain cancers, with 
seemingly minimal toxicity. Perhaps most interesting, it was 
discovered that resveratrol signifi cantly extended the lifespan 
of certain species of yeast, worm, the fruit fl y, and fi sh. 
Along similar lines, it canceled the life-shortening effects 
of a high-fat diet in mice. As a result of these promising 
discoveries, resveratrol has been hailed by manufacturers as 
the “French paradox in a bottle” and pushed for wide-scale 
consumption. However, experts advise caution. For example, 
little is known about its metabolism and how it affects the 
liver, the above results are derived in large part from in 
vitro experiments, and, like bisphenol A, it has estrogen-like 
physiological effects, enhancing the growth of breast cancer 
cells. For the time being, an occasional glass of red wine 
may be the best course of action, if any!
Resveratrol protects grapes from 
fungus, such as that shown here.
as alkoxides or ammonia, may be similarly employed, forming alkoxyarenes and 
 arenamines, respectively. Processes such as these, in which a group other than hydro-
gen is displaced from an aromatic ring, are called ipso substitutions (ipso, Latin,
on itself). The products of these reactions are intermediates in the manufacture of 
 useful dyes.
NO2
� Nu�
NO2
Cl
ð
NO2
� Cl�
NO2
Nu
Nucleophilic Aromatic Ipso Substitution
Electron
withdrawing
Ipso position
REACTION
2 2 - 4 N u c l e o p h i l i c A r o m a t i c S u b s t i t u t i o n
1032 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
The transformation is called nucleophilic aromatic substitution. The key to its suc-
cess is the presence of one or more strongly electron-withdrawing groups on the benzene 
ring located ortho or para to the leaving group. Such substituents stabilize an intermedi-
ate anion by resonance. In contrast with the SN2 reaction of haloalkanes, substitution in 
these reactions takes place by a two-step mechanism, an addition – elimination sequence 
similar to the mechanism of substitution of carboxylic acid derivatives (Sections 19-7 
and 20-2).
Mechanism of Nucleophilic Aromatic Substitution
Step 1. Addition (facilitated by resonance stabilization)
�N
Cl
�
�
NO2
EO �
Nu �ð
� Oð�š
� Oð�š
ðO�
�
ðð
ð
Oðð
š�
O �ðš�
O �ðš�
EO �ðš�
EO �ðš�
B
k
�
k
NO2
NO2
�N
O
NO2
Nu Cl
NO2
ðð �š
NO2
�N
ONu Cl Nu Cl
Nu ClNu Cl
The negative charge is strongly stabilized
by resonance
involving the ortho- and para-NO2 groups.
N�NE
HN
�
E
HN
�
Oð�
NO2
NO2
Cl
NO2
� NH4Cl
NO2
85%
2,4-Dinitrobenzenamine
(2,4-Dinitroaniline)
NH2
NH3, �ð
NO2
Na2CO3, HOH, 100°C
NO2
90%
1-Chloro-2,4-
dinitrobenzene
2,4-Dinitrophenol
Cl
NO2
� NaCl
NO2
OH
MECHANISM
ANIM
ATION ANIMATED MECHANISM
Nucleophilic aromatic
substitution
 C h a p t e r 2 2 1033
Step 2. Elimination (only one resonance structure is shown)
N�
NO2
EO �ð
Oðð
š�
B
N� EO
� Cl �
�ð
Oðð
š� ððš�
Clðš� BNu
�k
NO2
Nu
In the fi rst and rate-determining step, ipso attack by the nucleophile produces an anion with 
a highly delocalized charge, for which several resonance structures may be written, as shown. 
Note the ability of the negative charge to be delocalized into the electron-withdrawing 
groups. In contrast, such delocalization is not possible in 1-chloro-3,5-dinitrobenzene, in 
which these groups are located meta; so this compound does not undergo ipso substitution 
under the conditions employed.
NO2
Cl
O2N NO2O2N
�
k
NO2O2NNO2O2N
Meta-NO2 groups do not provide resonance stabilization of the negative charge.
�
�
�k
Nu �ð Nu Cl Nu Cl Nu Cl
In the second step, the leaving group is expelled to regenerate the aromatic ring. The 
reactivity of haloarenes in nucleophilic substitutions increases with the nucleophilicity of 
the reagent and the number of electron-withdrawing groups on the ring, particularly if they 
are in the ortho and para positions.
Exercise 22-8
Write the expected product of reaction of 1-chloro-2,4-dinitrobenzene with NaOCH3 in boiling CH3OH.
2 2 - 4 N u c l e o p h i l i c A r o m a t i c S u b s t i t u t i o n
Exercise 22-9
Working with the Concepts: Using Nucleophilic Aromatic Substitution in Synthesis
Ofl oxacin, an antibiotic of the quinolone class (Section 25-7), is used in the treatment of infections of the respiratory and urinary tract, the 
eyes, the ears, and skin tissue. The quinolone antibiotics are yet another alternative in the ongoing battle against penicillin (and other 
drug)-resistant bacteria. The fi nal three steps in the synthesis of ofl oxacin are shown below, the last of which is a simple ester hydrolysis 
(Section 20-4). Formulate mechanisms for the other two transformations from A to B and then to C.
CH3
F
F
F OH
F HN
H3C
O O
O
F
O
F
O O
Na�H�, 70–90°C
O
N
CH3 CH3
F COH
N
O
NaOH, H2O
O
N
N
N
N
H
CH3
A
, toluene, 100�C
E
B
O
CH3 CH3
F
O
N
O O
O
N
NE
A
OfloxacinC
B
Strategy
Taking an inventory of the topological changes and of the nature of the bonds formed and bonds broken, we note that B and C are the result of 
two successive intra- and one intermolecular nucleophilic aromatic substitutions, respectively. The fi rst steps are ring closures and therefore espe-
cially favored for entropic and enthalpic reasons. (Formation of six-membered rings is a favorable reaction, see Sections 9-6 and 17-7.) The aromatic 
ring in A should be highly activated with respect to nucleophilic attack, because it bears four inductively electron-withdrawing fl uorine substitu-
ents, in addition to the resonance-based electron-withdrawing carbonyl group. To propose a mechanism, let’s look at the individual steps.
Solution
• In the conversion of A to B, the strong base Na1H2 is employed. Where are the acidic sites in A? Most obvious is the hydroxy function 
(pKa , 15–16, Section 8-3, Table 8-2), which will certainly be deprotonated.
• What about the amino group? Closer inspection of structure A shows that the nitrogen is connected via a double bond to two carbonyl 
moieties. Thus, the function is resonance stabilized in much the same way as an ordinary amide (but more so):
F
F
F OH
F HN
H3C
O
š
Oð ð Oð ðOð ð F
F
F OH
F
H3C
O
š�Oð ð Oð ð
HN�
F
F
F OH
F
H3C
O
š�Oð ð
HN�
Resonance in A
Consequently, it should be relatively acidic, even more acidic than an amide (pKa < 22, Section 20-7). It is therefore likely that A is 
doubly deprotonated before attacking the benzene nucleus. Nucleophilic aromatic substitution is then readily formulated to assemble the 
fi rst new ring. In the scheme below, only one—the dominating—resonance form of the anion resulting from nucleophilic attack on the 
arene is shown, that in which the negative charge is delocalized onto the carbonyl oxygen.
�
š
š
�
Oð
F
O
F
F
H3C
OðO
N
ð
š
š
�
Oð
š
�
F
O
F
F
H3C
OðO
N
ð
š
š
�
O
šš
ð
Fðð
š
š
š
�� Fðð
F
F
F
F N
H3C
O
š
Oð ð O
ð
First Ring Closure
The second nucleophilic substitution by alkoxide is unusual, inasmuch as it has to occur at a position meta to the carbonyl function. 
Therefore, the intermediate anion is not stabilized by resonance, but solely by inductive effects. The regioselectivity is controlled by strain: 
The alkoxide cannot “reach” the more favorable carbon para to the carbonyl.
F
O
F
NF
OO
�Oðð
CH3
š
š
Fðð
š
š
š
�� Fðð
F
O
N
O
F
OO
�
ð
ð
CH3
F
O
NF
OO
O CH3
B
Second Ring Closure to B
The conversion of B to C features an intermolecular substitution with an amine nucleophile. Of the two carbons bearing the potential fl uo-
ride leaving groups, the one para to the carbonyl is picked, because of the resonance stabilization of the resulting intermediate anion. The 
initial product is formed as the ammonium salt, from which the free base C is liberated by basic work-up (Chemical Highlight 21-2).
š
š
Fðð
š
F
O
NN
H
N
F
�
OO
OCH3 CH3 CH3
�HF
(on basic work-up)
CH3
B
C
A
A
A
ðð
F
H O
NN
OO
ON
ð
ð
ð ððš
�
�
1034
 C h a p t e r 2 2 1035
Haloarenes undergo substitution through benzyne intermediates
Haloarenes devoid of electron-withdrawing substituents do not undergo simple ipso substi-
tution. Nevertheless, when haloarenes are treated with nucleophiles that are also strong bases, 
if necessary at highly elevated temperatures, they convert to products in which the halide 
has been replaced by the nucleophile. For example, if exposed to hot sodium hydroxide 
 followed by neutralizing work-up, chlorobenzene furnishes phenol.
Cl
Chlorobenzene
OH
� NaCl
Phenol
1. NaOH, H2O, 340°C, 150 atm
2. H�, H2O
Treatment with potassium amide results in benzenamine (aniline).
Cl NH2
� KCl
Benzenamine
(Aniline)
1. KNH2, liquid NH3
2. H�, H2O
It is tempting to assume that these substitutions follow a mechanism similar to that 
formulated for nucleophilic aromatic ipso substitution earlier in this section. However, when 
the last reaction is performed with radioactively labeled chlorobenzene (14C at C1), a very 
curious result is obtained: Only half of the product is substituted at the labeled carbon; in 
the other half, the nitrogen is at the neighboring position.
Cl
�
Chlorobenzene-1-14C
14C label
KNH2, liquid NH3
�KCl
NH2
Benzenamine-1-14C
50%
Benzenamine-2-14C
50%
NH2
Exercise 22-10
Try It Yourself
Propose a mechanism for the following conversion. Considering that the fi rst step is rate deter-
mining, draw a potential-energy diagram depicting the progress of the reaction. (Hint: This is a 
nucleophilic aromatic substitution.)
NO2
NO2
O�
SO2H3C
O
SO2�H3C
REACTION
2 2 - 4 N u c l e o p h i l i c A r o m a t i c S u b s t i t u t i o n
1036 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
Direct substitution does not seem to be the mechanism of these reactions. What, then, 
is the answer to this puzzle? A clue
is the attachment of the incoming nucleophile only at 
the ipso or at the ortho position relative to the leaving group. This observation can be 
accounted for by an initial base-induced elimination of HX from the benzene ring, a process 
reminiscent of the dehydrohalogenation of haloalkenes to give alkynes (Section 13-4). In 
the present case, elimination is not a concerted process, but rather takes place in a sequen-
tial manner, deprotonation preceding the departure of the leaving group (step 1 of the 
mechanism shown). Both stages in step 1 are diffi cult, with the second being worse than 
the fi rst. Why is that? With respect to the initial anion formation, recall (Section 11-3) that 
the acidity of Csp2 – H is very low (pKa < 44), and the same is true in general for phenyl 
hydrogens. The presence of the adjacent p system of benzene does not help, because the 
negative charge in the phenyl anion resides in an sp2 orbital that is perpendicular to the 
p frame and is therefore incapable of resonance with the double bonds in the six-membered 
ring. Thus, deprotonation of the haloarene requires a strong base. It takes place ortho to the 
halogen, because the halogen’s inductive electron-withdrawing effect acidifi es this position 
relative to the others.
Although deprotonation is not easy, the second stage of step 1, subsequent elimination 
of X2, is even more diffi cult because of the highly strained structure of the resulting reactive 
species, called 1,2-dehydrobenzene or benzyne.
Step 1. Elimination occurs stepwise
Step 2. Addition occurs to both strained carbons
NH2
X
H
Phenyl anion
(Intermediate)
Benzyne
(Reactive intermediate; not isolated)
X
+ X−
−
−
−
−
 NH2
− HNH2
H — NH2− NH2
−
−
 NH2
−
−
 NH2
Mechanism of Nucleophilic Substitution of Simple Haloarenes
NH2 NH2
H
H — NH2− NH2
NH2
H
pKa ~ 44 sp2 - Hybrid orbital
is perpendicular to
aromatic systemπ
Highly strained
triple bond
Why is benzyne so strained? Recall that alkynes normally adopt a linear structure, a 
consequence of the sp hybridization of the carbons making up the triple bond (Sec-
tion 13-2). Because of benzyne’s cyclic structure, its triple bond is forced to be bent, 
rendering it unusually reactive. Thus, benzyne exists only as a reactive intermediate 
under these conditions, being rapidly attacked by any nucleophile present. For example 
(step 2), amide ion or even ammonia solvent can add to furnish the product benzenamine 
(aniline). Because the two ends of the triple bond are equivalent, addition can take place 
at either carbon, explaining the label distribution in the benzenamine obtained from 14C-labeled 
chlorobenzene.
Benzyne is too reactive to be isolated and stored in a bottle, but it can be observed 
spectroscopically under special conditions. Irradiation of benzocyclobutenedione at 77 K 
ANIM
ATION ANIMATED MECHANISM:
Nucleophilic aromatic 
substitution via benzynes
MECHANISM
 C h a p t e r 2 2 1037
(21968C) in frozen argon (m.p. 5 21898C) produces a species whose IR and UV spectra 
are assignable to benzyne, formed by loss of two molecules of CO.
Generation of Benzyne, a Reactive Intermediate
O
Benzocyclobutene-1,2-dione
O
� 2 COhv, 77 K
Although benzyne is usually represented as a cycloalkyne (Figure 22-4A), its triple bond 
exhibits an IR stretching frequency of 1846 cm21, intermediate between the values for nor-
mal double (cyclohexene, 1652 cm21) and triple (3-hexyne, 2207 cm21) bonds. The 13C NMR 
values for these carbons (d 5 182.7 ppm) are also atypical of pure triple bonds (Sec tion 13-3), 
indicating a considerable contribution of the cumulated triene (Section 14-5) resonance form 
(Figure 22-4B). The bond is weakened substantially by poor p orbital overlap in the plane 
of the ring.
C
1.43 Å
1.42 Å
Poor overlap
BA
1.24 Å
1.40 Å
Figure 22-4 (A) The orbital picture of benzyne reveals that the six aromatic p electrons are 
 located in orbitals that are perpendicular to the two additional hybrid orbitals making up the 
distorted triple bond. These hybrid orbitals overlap only poorly; therefore, benzyne is highly 
 reactive. (B) Resonance in benzyne. (C) The electrostatic potential map of benzyne shows 
 electron density (red) in the plane of the six-membered ring at the position of the distorted 
sp-hybridized carbons.
Exercise 22-11
1-Chloro-4-methylbenzene (p-chlorotoluene) is not a good starting material for the preparation of 
4-methylphenol (p-cresol) by direct reaction with hot NaOH, because it forms a mixture of two 
products. Why does it do so, and what are the two products?
Exercise 22-12
Explain the regioselectivity observed in the following reaction. (Hint: Consider the effect of the 
methoxy group on the selectivity of attack by amide ion on the intermediate benzyne.)
OCH3
Br NH2
OCH3
�
H2N
Major
OCH3
Minor
KNH2, liquid NH3
�KBr
2 2 - 4 N u c l e o p h i l i c A r o m a t i c S u b s t i t u t i o n
1038 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
Phenols are produced from arenediazonium salts
The most general traditional laboratory procedure for making phenols is from arenamines 
through their arenediazonium salts, ArN2
1X2. Recall that primary alkanamines can be 
N-nitrosated but that the resulting species rearrange to diazonium ions, which are unstable —
they lose nitrogen to give carbocations (Section 21-10). In contrast, primary benzenamines 
(anilines) are attacked by cold nitrous acid, in a reaction called diazotization, to give 
 relatively stable, isolable, although still reactive arenediazonium salts. Compared to their 
alkanediazonium counterparts, these species enjoy resonance stabilization and are prevented 
from undergoing immediate N2 loss by the high energy of the resulting aryl cations (to be 
discussed in more detail in Section 22-10).
When arenediazonium ions are gently heated in water, nitrogen is evolved and the 
resulting aryl cations are trapped extremely rapidly by the solvent to give phenols.
Decomposition of Arenediazonium Salts in Water to Give Phenols
R
N+
N
Aryl cation
−N2
Δ 
−H+
HOH
R R
OH+
In these reactions, the “super” leaving group N2 accomplishes what halides are only able 
to do when attached to a highly electron-defi cient benzene nucleus (nucleophilic aro-
matic substitution) or under extreme conditions (through benzyne intermediates), namely, 
replacement by hydroxide. The three mechanisms are completely different. In nucleo-
philic aromatic substitution, the nucleophile attacks prior to departure of the leaving 
group. In the benzyne mechanism, the nucleophile acts initially as a base, followed by 
extrusion of the leaving group and subsequent nucleophilic attack on the strained triple 
bond. In the arenediazonium-ion decomposition, the leaving group exits fi rst, followed 
by trapping by water.
The utility of this phenol synthesis is apparent when you recall that arenamines are 
derived from nitroarenes by reduction, and nitroarenes are made from other arenes by 
 electrophilic aromatic substitution (Chapters 15 and 16). Therefore, retrosynthetically (Sec-
tion 8-9), we can picture the hydroxy group in any position of a benzene ring that is subject 
to electrophilic nitration.
R
Diazotization
NH2
R
Arenediazonium ion
N�
N
NaNO2, H�, H2O, 0°C
c
š
 C h a p t e r 2 2 1039
Retrosynthetic Connection of Phenols to Arenes
NH2OH
OH
D(X)
NH2
D(X)
NO2
NO2
D(X) D(X)
Donor-activated or
halogen-bearing
arene
NH2 NO2OH
A A A A
Acceptor-deactivated
arene
Two examples are depicted below.
70% (separated from
the ortho isomer by
crystallization)
98%
70%
NO2
BrBr
NH2
Br
HNO3, H2SO4 CH3COOH, Fe
HNO3, H2SO4,
20�C
CH3O
80%
N2 �Cl�
Br
4-Bromophenol
(p-Bromophenol)
OH
Br
NaNO2, HCl,
H2O, 0�C
NaNO2, H2SO4,
H2O, 0�C
H2, Ni 80�C
80�C
CH3O
NO2
85%
CH3O
NH2
82%
CH3O
OH
CH3O
N2 � HSO4�
87%
1-(3-Hydroxyphenyl)ethanone
(m-Hydoxyacetophenone)
Exercise 22-13
ortho-Benzenediazoniumcarboxylate A (made by diazotization of 2-aminobenzoic acid, Prob-
lem 20-59) is explosive. When warmed in solution with trans,trans-2,4-hexadiene, it forms com-
pound B. Explain by a mechanism. (Hint: Two other products are formed, both of which are gases.)
CH3
CH3
CH3H3CN
�
�
C
O
O
A B
B
E ð
Nð
ðð
š�
q
0
%
Exercise 22-14
Propose a synthesis of 4-(phenylmethyl)phenol (p-benzylphenol) from benzene. (Caution: Remember 
that Friedel-Crafts reactions do not work with deactivated arenes.)
2 2 - 4 N u c l e o p h i l i c A r o m a t i c S u b s t i t u t i o n
1040 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
Phenols can be made from haloarenes by Pd catalysis
While we have seen that ordinary halobenzenes are resilient to reaction with hydroxide, 
they undergo such nucleophilic displacements in the presence of Pd salts and added phos-
phine ligands PR3.
X OH
KOH, Pd catalyst,
PR3, 100�C
Pd-Catalyzed Phenol Synthesis from Haloarenes
The reaction is general for substituted benzenes, providing a complement to the diazonium 
method described above.
OCH3
Cl
OCH3
OH
90%
4-Methoxyphenol
(p-Methoxyphenol)
98%
1-(3-Hydroxyphenyl)ethanone
(m-Hydoxyacetophenone)
KOH, Pd catalyst,
PR3, 100�C
KOH, Pd catalyst,
PR3, 100�C
CH3
Br
O CH3
OH
O
The mechanism is related to that of the Heck and other Pd-catalyzed reaction (Section 13-9; 
Chemical Highlight 13-1). As shown in a simplifi ed manner below, it begins by insertion 
of the metal into the aryl halide bond, exchange of the halide for hydroxide, and extrusion 
of the fi nal product with regeneration of the catalyst.
Mechanism of the Pd-Catalyzed Phenol Synthesis from Haloarenes
X OH
X
Pd
OH
Pd
Pd HO�
�X� �Pd
Similar substitutions can be carried out with alkoxides to give phenol ethers, and with amines, 
including ammonia, to furnish benzenamines.
OCH3
NH2Br
98%
3-Methoxy-N-(2-methylpropyl)benzenamine
3-Methoxy-N-(2-methylpropyl)aniline
OCH3
N
H
�
Pd catalyst,
PR3, 100�C
Br NH2
89%
2-(1-Methylethyl)benzenamine
(o-Isopropylaniline)
NH3 (14 atm),
Pd catalyst,
PR3, 90�C
 C h a p t e r 2 2 1041
In Summary When a benzene ring bears enough strongly electron-withdrawing substitu-
ents, nucleophilic addition to give an intermediate anion with delocalized charge becomes 
feasible, followed by elimination of the leaving group (nucleophilic aromatic ipso substitu-
tion). Phenols result when the nucleophile is hydroxide ion, arenamines (anilines) when it 
is ammonia, and alkoxyarenes when alkoxides are employed. Very strong bases are capable 
of eliminating HX from haloarenes to form the reactive intermediate benzynes, which are 
subject to nucleophilic attack to give substitution products. Phenols may also be prepared 
by decomposition of arenediazonium salts in water and by Pd-catalyzed hydroxylations of 
haloarenes.
22-5 Alcohol Chemistry of Phenols
The phenol hydroxy group undergoes several of the reactions of alcohols (Chapter 9), such 
as protonation, Williamson ether synthesis, and esterifi cation.
The oxygen in phenols is only weakly basic
Phenols are not only acidic but also weakly basic. They (and their ethers) can be protonated 
by strong acids to give the corresponding phenyloxonium ions. Thus, as with the alkanols, 
the hydroxy group imparts amphoteric character (Section 8-3). However, the basicity of 
phenol is even less than that of the alkanols, because the lone electron pairs on the oxygen 
are delocalized into the benzene ring (Sections 16-1 and 16-3). The pKa values for pheny-
loxonium ions are, therefore, lower than those of alkyloxonium ions.
šð
�
OH
šCH3OH � H� � H�
šO
š
H
H
CH3O
�
i
f
H 
pKa � �6.7pKa � �2.2
H �H E
pKa Values of Methyl- and Phenyloxonium Ion
Exercise 22-15
How would you make the following phenols from the given starting materials? (Hint: Consult 
Chapters 15 and 16.)
(a) 
OH
from
CF3 CF3
 (b) from
OCH3
NO2
NO2HO
OCH3
(c) from
OH
2 2 - 5 A l c o h o l C h e m i s t r y o f P h e n o l s
OOH
A “Green” Industrial
Phenol Synthesis
H3PO4Friedel-Crafts
alkylation
H2SO4
O2 (air), ROOR
�
Cheap
starting
materials
OH
�
Value-
added
products
O
Although the preceding methods are valuable in the preparation of specifi cally substituted 
phenols, the parent compound is made industrially by the air oxidation of (1-methylethyl)-
benzene (isopropylbenzene or cumene; see also Exercise 15-27) to the benzylic hydroper-
oxide and its subsequent decomposition with acid (margin). The “by-product” acetone is 
valuable in its own right and makes this process highly cost effective, quite apart from the 
environmentally benign use of air as an oxidant.
1042 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
Unlike secondary and tertiary alkyloxonium ions derived from alcohols, phenyloxonium 
derivatives do not dissociate to form phenyl cations, because such ions have too high an 
energy content (see Section 22-10). The phenyl – oxygen bond in phenols is very diffi cult 
to break. However, after protonation of alkoxybenzenes, the bond between the alkyl group 
and oxygen is readily cleaved in the presence of nucleophiles such as Br2 or I2 (e.g., from 
HBr or HI) to give phenol and the corresponding haloalkane.
�HBr,
COOH
OCH3
CH3Br
COOH
OH
90%
3-Methoxybenzoic acid
(m-Methoxybenzoic acid)
3-Hydroxybenzoic acid
(m-Hydroxybenzoic acid)
�
Alkoxybenzenes are prepared by Williamson ether synthesis
The Williamson ether synthesis (Section 9-6) permits easy preparation of many alkoxy-
benzenes. The phenoxide ions obtained by deprotonation of phenols (Section 22-3) are good 
nucleophiles. They can displace the leaving groups from haloalkanes and alkyl sulfonates.
NaOH, H2O
�NaBr, �HOH 
OH OCH2CH2CH3
CH3CH2CH2Br
ClCl
63%
3-Chlorophenol
(m-Chlorophenol)
1-Chloro-3-propoxybenzene
(m-Chlorophenyl propyl ether)
�
Esterifi cation leads to phenyl alkanoates
The reaction of a carboxylic acid with a phenol (Section 19-9) to form a phenyl ester is 
endothermic. Therefore, esterifi cation requires an activated carboxylic acid derivative, such 
as an acyl halide or a carboxylic anhydride.
NaOH, H2O
�NaCl, �HOH 
OH OCCH2CH3
CH3CH2CCl
O
4-Methylphenol
(p-Cresol)
Propanoyl chloride
�
B
O
B
CH3
4-Methylphenyl propanoate
(p-Methylphenyl propanoate)
CH3
Exercise 22-16
Why does cleavage of an alkoxybenzene by acid not produce a halobenzene and the alkanol?
Exercise 22-17
Explain why, in the preparation of acetaminophen (Chemical Highlight 22-2), the amide is formed 
rather than the ester. (Hint: Review Section 6-8.)
 C h a p t e r 2 2 1043
In Summary The oxygen in phenols and alkoxybenzenes can be protonated even though 
it is less basic than the oxygen in the alkanols and alkoxyalkanes. Protonated phenols and 
their derivatives do not ionize to phenyl cations, but the ethers can be cleaved to phenols 
and haloalkanes by HX. Alkoxybenzenes are made by Williamson ether synthesis, aryl 
alkanoates by acylation.
2 2 - 5 A l c o h o l C h e m i s t r y o f P h e n o l s
CHEMICAL HIGHLIGHT 22-2
Aspirin: A Phenyl Alkanoate Drug
The year 1997 marked the 100th birthday of the synthesis 
of the acetic ester of 2-hydroxybenzoic acid (salicylic acid); 
namely,
2-acetyloxybenzoic acid (acetylsalicylic acid), better 
known as aspirin (see Section 19-13 and Chapter 16 Opening). 
Aspirin is the fi rst drug that was clinically tested before it 
was marketed, in 1899. More than 100 billion tablets of 
aspirin per year are taken by people throughout the world to 
relieve headaches and rheumatoid and other pain, to control 
fever, and to treat gout and arthritis. Production capacity in 
the United States alone is 10,000 tons per year.
Salicylic acid (also called spiric acid, hence the name 
aspirin [“a” for acetyl]) in extracts from the bark of the 
willow tree or from the meadowsweet plant had been used 
since ancient times (see Chapter 16 Opening) to treat pain, 
fever, and swelling. This acid was fi rst isolated in pure 
form in 1829, then synthesized in the laboratory, and fi nally 
produced on a large scale in the nineteenth century and 
prescribed as an analgesic, antipyretic, and anti-infl ammatory 
drug. Its bitter taste and side effects, such as mouth irritation 
and gastric bleeding, prompted the search for better deriva-
tives that resulted in the discovery of aspirin.
In the body, aspirin functions as a precursor of salicylic 
acid, which irreversibly inhibits the enzyme cyclooxygenase. 
This enzyme causes the production of prostaglandins (see 
Chemical Highlight 11-1 and Section 19-13), molecules that in 
turn are infl ammatory and pain producing. In addition, one of 
them, thromboxane A2, aggregates blood platelets, necessary 
for the clotting of blood when injury occurs. This same pro-
cess is, however, undesirable inside arteries, causing heart 
attacks or brain strokes, depending on the location of the clot. 
Indeed, a large study conducted in the 1980s showed that 
aspirin lowered the risk of heart attacks in men by almost 50% 
and reduced the mortality rate during an actual attack by 23%.
Many other potential applications of aspirin are under 
investigation, such as in the treatment of pregnancy-related 
complications, viral infl ammation in AIDS patients, dementia, 
Alzheimer’s disease, and cancer. Despite its popularity, aspi-
rin can have some serious side effects: It is toxic to the liver, 
prolongs bleeding, and causes gastric irritation. It is sus-
pected as the cause of Reye’s syndrome, a condition that 
leads to usually fatal brain damage. Because of some of these 
drawbacks, many other drugs compete with aspirin, particu-
larly in the analgesics market, such as naproxen, ibuprofen, 
and acetaminophen (see the beginning of Chapter 16). 
 Acetaminophen, better known as Tylenol, is prepared from 
4-aminophenol by acetylation.
OH
2-Hydroxybenzoic acid
(o-Hydroxybenzoic acid,
salicylic acid)
COOH
2-Acetyloxybenzoic acid
(o-Acetoxybenzoic acid,
acetylsalicylic acid, aspirin)
CH3COCCH3, H�, �
�CH3COOH
O
B
O
B OCCH3
OCOOH
B
Aspirin prevents heart attacks by minimizing the formation of blood clots in the coronary 
arteries. The photograph shows such a blood clot (orange) in the left main pulmonary 
artery of a patient (see also p. 904).
NH2
4-Aminophenol
( p-Aminophenol)
OH
HNCCH3
O
N-(4-Hydroxyphenyl)acetamide
[N-( p-Hydroxyphenyl)acetamide, acetaminophen, Tylenol]
OH
CH3COCCH3, CH3COOH
�CH3COOH
O
B
O
B
B
1044 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
22-6 Electrophilic Substitution of Phenols
The aromatic ring in phenols is also a center of reactivity. The interaction between the OH 
group and the ring strongly activates the ortho and para positions toward electrophilic sub-
stitution (Sections 16-1 and 16-3). For example, even dilute nitric acid causes nitration.
HNO3, CHCl3, 15�C
OH
61%26%
2-Nitrophenol
(o-Nitrophenol)
OHOH
4-Nitrophenol
( p-Nitrophenol)
�
NO2
NO2
Friedel-Crafts acylation of phenols is complicated by ester formation and is better car-
ried out on ether derivatives of phenol (Section 16-5), as shown in the margin.
Phenols are halogenated so readily that a catalyst is not required, and multiple halogena-
tions are frequently observed (Section 16-3). As shown in the following reactions, tribromi-
nation occurs in water at 208C, but the reaction can be controlled to produce the 
monohalogenation product through the use of a lower temperature and a less polar solvent.
3 Br–Br, H2O, 20�C
�3 HBr
Br–Br,
CHCl3, 0�C
�HBr
OH
100%
2,4,6-TribromophenolPhenol
OHOH
4-Methylphenol
( p-Cresol)
but
CH3
Br Br
Br
80%
2-Bromo-4-methylphenol
OH
Br
CH3
Halogenation of Phenols
Electrophilic attack at the para position is frequently dominant because of steric effects. 
However, it is normal to obtain mixtures resulting from both ortho and para substitutions, 
and their compositions are highly dependent on reagents and reaction conditions.
Exercise 22-18
Friedel-Crafts methylation of methoxybenzene (anisole) with chloromethane in the presence of 
AlCl3 gives a 2;1 ratio of ortho;para products. Treatment of methoxybenzene with 2-chloro-
2-methylpropane (tert-butyl chloride) under the same conditions furnishes only 1-methoxy-4-
(1,1-dimethylethyl) benzene (p-tert-butylanisole). Explain. (Hint: Review Section 16-5.)
Exercise 22-19
Working with the Concepts: Devising Synthetic Strategies Starting with Substituted Phenols
Proparacaine is a local anesthetic that is used primarily to numb the eye before minor surgical procedures, such as the removal of foreign 
objects or stitches. Show how you would make it from 4-hydroxybenzenecarboxylic acid.
O
O
4-Hydroxybenzenecarboxylic acid Proparacaine
H2NOH
HO
O
N
O
70%
OCH3
Methoxybenzene
(Anisole)
�
H
OCH3
1-(4-Methoxyphenyl)ethanone
(p-Methoxyacetophenone)
C
B
CH3CCl
O
HKO CH3
AlCl3, CS2�HCl
 C h a p t e r 2 2 1045
Strategy
Inspection of the structures of both the starting material and the product reveals three structural modifi cations: (1) An amino group is 
introduced into the benzene core, suggesting a nitration-reduction sequence (Section 16-5) that relies on the ortho-directing effect of the 
hydroxy substituent: (2) the phenol function is etherifi ed, best done by Williamson synthesis (Section 22-5): (3) the carboxy function is 
esterifi ed with the appropriate amino alcohol (Section 20-2). What is the best sequence in which to execute these manipulations? To answer 
this question, consider the possible interference of the various functions with the suggested reaction steps.
Solution
• Modifi cation 1 could be carried out with the starting material, resulting in the corresponding amino acid. However, “unmasking” the 
amino group (from its precursor nitro) early bodes trouble with steps 2 and 3, because amines are better nucleophiles than alcohols. There-
fore, attempted etherifi cation of the aminated phenol will lead to amine alkylation (Section 21-5). Similarly, attempts to effect ester forma-
tion in the presence of an amine function will give rise to amide generation (Section 19-10). However, early introduction of the nitro group 
and maintaining it as such until the other functions are protected looks good.
• For modifi cation 2, Williamson ether synthesis in the presence of a carboxy group should be fi ne, because the carboxylate ion is a poorer 
nucleophile than phenoxide ion (Section 6-8).
• The preceding protection of the phenolic function is important to the success of modifi cation 3, ester formation with the amino alcohol, 
especially if we want to activate the carboxy group as an acyl chloride.
• Putting it all together, a possible (and, indeed, the literature) synthesis of proparacaine is as follows:
O
proparacaine
OH
HO
O
O2N
O2N
HNO3
O
N
O
O
O2N
OO
OH OH
HO
H2, Pd-C
NaOH,
CH3CH2CH2Cl
1. SOCl2
2. HOCH2CH2N(CH2CH3)2
• Why does the amino alcohol not react
with the acyl halide at nitrogen in the last step? After all, amines are more nucleophilic than 
alcohols. The answer is: It does, but because the amine function is tertiary, it can only form an acyl ammonium salt. This function has 
reactivity similar to that of an acyl chloride. Thus, attack by the hydroxy group on the acyl ammonium carbonyl carbon wins out thermo-
dynamically to give the ester in the end (Section 20-2).
B
HEC
O
R Clð
NR�3ðš
š
B
HEC
O
R NR3� Clð ð
š�
ðš
š
�
�
�
B
HEC
O
R OR��� NR�3
R��OH
Exercise 22-20
Try It Yourself
Device an alternative route to proparacaine from 4-hydroxybenzenecarboxylic acid, using Pd 
catalysis.
2 2 - 6 E l e c t r o p h i l i c S u b s t i t u t i o n o f P h e n o l s
Under basic conditions, phenols can undergo electrophilic substitution, even with very 
mild electrophiles, through intermediate phenoxide ions. An industrially important applica-
tion is the reaction with formaldehyde, which leads to o- and p-hydroxymethylation. Mech-
anistically, these processes may be considered enolate condensations, much like the aldol 
reaction (Section 18-5).
1046 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
CH2
OH
HO� �k
�
O � O O
�
� HOH
PO
Hydroxymethylation of Phenol
ððš
šš
šð ðð ðð
šš
O
H
CH2O � �
O
H� OCH2
HOH
�HO �
OH
CH2OH
�
OH
CH2OHðš
ðš
ðððð ð
š
š
šš
šš
š ðš
šš
ššš
The initial aldol products are unstable: They dehydrate on heating, giving reactive interme-
diates called quinomethanes.
HO�, �
�HOH
OH
CH2OH
O
CH2OH
CH2
OH
HO�, �
�HOH
O
p-Quinomethane
CH2
o-Quinomethane
Because quinomethanes are a,b-unsaturated carbonyl compounds, they may undergo 
Michael additions (Section 18-11) with excess phenoxide ion. The resulting phenols can be 
hydroxymethylated again and the entire process repeated. Eventually, a complex phenol – 
formaldehyde copolymer, also called a phenolic resin (e.g., Bakelite), is formed. Their 
major uses are in plywood (45%), insulation (14%), molding compounds (9%), fi brous and 
granulated wood (9%), and laminates (8%).
OH
CH2
H
O�
CH2OH
OH
CH2 O
CH2
O�
CH2
�
O O
Phenolic Resin Synthesis
O
H
CH2
OH OH
H2C
CH2
OH OH
polymer n H2O�
P� k
 C h a p t e r 2 2 1047
In the Kolbe*-Schmitt† reaction, phenoxide attacks carbon dioxide to furnish the salt 
of 2-hydroxybenzoic acid (o-hydroxybenzoic acid, salicylic acid, precursor to aspirin; see 
Chemical Highlight 22-2).
C
O �Na�
OH
C
O
NaOH, H2O, pressure
�
OH
B
O
B
ðð
ðð
O
B
ðð
ðHšš
*Professor Adolph Wilhelm Hermann Kolbe (1818–1884), University of Leipzig, Germany.
†Professor Rudolf Schmitt (1830–1898), University of Dresden, Germany.
Exercise 22-21
Working with the Concepts: Recognizing Phenol as an Enol
Formulate a mechanism for the Kolbe-Schmitt reaction.
Strategy
As always, we take an inventory of the components of the reaction: starting materials, other 
reagents and reaction conditions, and products. Phenol is an electron-rich arene (see this and 
 Section 16-3) and also acidic. Carbon dioxide has an electrophilic carbon that is attacked by 
nucleophilic carbon atoms, such as in Grignard reagents (Section 19-6). The reaction conditions 
are strongly basic. Finally, the product looks like that of an electrophilic ortho substitution.
Solution
• Under basic conditions, phenol will exist as phenoxide, which, like an enolate ion (Section 18-1), 
can be described by two resonance forms (see margin).
• Enolate alkylations occur at carbon (Section 18-10). In analogy, you can formulate a phenoxide 
attack on the electrophilic carbon of CO2. Alternatively, you can think of this reaction as an elec-
trophilic attack of CO2 on a highly activated benzene ring.
• Finally, deprotonation occurs to regenerate the aromatic arene.
O) )
O) )
O) )
p
�
O)
p
p �
OH)
p
OH
p
p
B
B
HC
O) )
B
C
O) )
O
H
B
E
C
As you will have noticed, the selectivity for ortho attack by CO2 in this process is exceptional. 
Although not completely understood, it may involve direction of the electrophile by the Na1 ion 
in the vicinity of the phenoxide negative charge.
Exercise 22-22
Try It Yourself
Phentolamine (as a water-soluble methanesulfonic acid salt) is an antihypertensive that has recently 
been introduced into dentistry: It cuts in half the time taken to recover from the numbing effect 
of local anesthetics. The key step in its preparation dates from 1886, the reaction shown below. 
What is its mechanism? (Caution: This is not a nucleophilic aromatic substitution. Hint: Think 
keto – enol tautomerism).
�
OH CH3
NH2
OH
70%
Phentolamine
160�C
CH3
OH
N
H
N
HN
CH3
OH
N
Various wood products incorpo-
rating Bakelite are used in the 
construction of houses.
2 2 - 6 E l e c t r o p h i l i c S u b s t i t u t i o n o f P h e n o l s
Phenoxide ion
O
�
) ) O) )
p
½
�
1048 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
In Summary The benzene ring in phenols is subject to electrophilic aromatic substitu-
tion, particularly under basic conditions. Phenoxide ions can be hydroxymethylated and 
carbonated.
22-7 An Electrocyclic Reaction of the Benzene Ring:
The Claisen Rearrangement
At 2008C, 2-propenyloxybenzene (allyl phenyl ether) undergoes an unusual reaction that leads 
to the rupture of the allylic ether bond: The starting material rearranges to 2-(2-propenyl)phenol 
(o-allylphenol).
2-Propenyloxybenzene
(Allyl phenyl ether)
2-(2-Propenyl)phenol
(o-Allylphenol)
75%
H
O
CH2CH CH2E P
CH2PCH2CH
OH
�
This transformation, called the Claisen* rearrangement, is another concerted reaction with 
a transition state that accommodates the movement of six electrons (Sections 14-8 and 15-3). 
The initial intermediate is a high-energy isomer, 6-(2-propenyl)-2,4-cyclohexadienone, which 
enolizes to the fi nal product (Sections 18-2 and 22-3).
Mechanism of the Claisen Rearrangement
O OH
H
O
6-(2-Propenyl)-
2,4-cyclohexadienone
O
O
O
The Claisen rearrangement is general for other systems. With the nonaromatic 1- ethenyloxy-
2-propene (allyl vinyl ether), it stops at the carbonyl stage because there is no driving force 
for enolization. This is called the aliphatic Claisen rearrangement.
Exercise 22-23
Hexachlorophene (margin) is a skin germicide formerly used in soaps. It is prepared in one step 
from 2,4,5-trichlorophenol and formaldehyde in the presence of sulfuric acid. How does this reac-
tion proceed? (Hint: Formulate an acid-catalyzed hydroxymethylation for the fi rst step.)
*Professor Ludwig Claisen (1851–1930), University of Berlin, Germany.
REACTION
MECHANISM
Hexachlorophene
Cl
Cl
OH OH
Cl
Cl
Cl Cl
 C h a p t e r 2 2 1049
Aliphatic Claisen Rearrangement
1-Ethenyloxy-2-propene
(Allyl vinyl ether)
50%
4-Pentenal
255°C
H
C
C
H
NCH2
CH2
E
KH
H2C
O
A
H
C
C
H
HCH2
CH2
K
EN
H2C
O
A
The carbon analog of the Claisen rearrangement is called the Cope* rearrangement; 
it takes place in compounds containing 1,5-diene units.
178°C
3-Phenyl-1,5-hexadiene
Cope Rearrangement
trans-1-Phenyl-1,5-hexadiene
72%
Note that all of these rearrangements are related to the electrocyclic reactions that inter-
convert cis-1,3,5-hexatriene with 1,3-cyclohexadiene (see margin and Section 14-9). The 
only difference is the absence of a double bond connecting the terminal p bonds.
2 2 - 7 C l a i s e n R e a r r a n g e m e n t
*Professor Arthur C. Cope (1909–1966), Massachusetts
Institute of Technology, Cambridge.
Exercise 22-24
Explain the following transformation by a mechanism. (Hint: The Cope rearrangement can be 
accelerated greatly if it leads to charge delocalization.)
OHC
HO
NaOH, H2O
Exercise 22-25
Working with the Concepts: Applying Claisen and Cope Rearrangements
Citral, B, is a component of lemon grass and as such used in perfumery (lemon and verbena 
scents). It is also an important intermediate in the BASF synthesis of vitamin A (Section 14-7, 
Chemical Highlight 18-3). The last step in the synthesis of citral requires simply heating the enol 
ether A. How do you get from A to B?
H
O
B
Citral
O
A
�
Electrocyclic Reaction of
cis-1,3,5-Hexatriene
�
Strategy
As always, we take an inventory of the components of the reaction: starting materials, other 
reagents and reaction conditions, and products. Here, this is straightforward: There are no reagents, 
we simply apply heat, and it appears that the reaction is an isomerization. You need to confi rm 
this suspicion, by determining the molecular formulas of A and B. Indeed, it is C10H16O for both. 
What thermal reactions could you envisage for A?
Solution
• You note that A contains a diene unit connected to an isolated double bond. Hence, in principle, 
an intramolecular Diels-Alder reaction to C might be feasible (Section 14-8; Exercise 14-24):
Potential Diels-Alder Reaction of A
C
O
A
O
• It is apparent that this pathway is unfavorable for two reasons: (1) Both the diene and the dieno-
phile are electron rich and therefore not good partners for cycloaddition (Section 14-8), and, even 
more obvious, (2) a strained ring is formed in C.
• An alternative is based on the recognition of a 1,5-hexadiene unit, the prerequisite for a Cope 
rearrangement. In A, this diene unit contains an oxygen, hence we can write a Claisen rearrange-
ment to see where it leads us.
DA
�
H
O
Claisen Rearrangement of A
O
• The product D contains a 1,5-diene substructure, capable of a Cope rearrangement, leading to 
citral B.
BD
�O
H
H
O
Cope Rearrangement of D
Exercise 22-26
Try It Yourself
The ether A provides B upon heating to 2008C. Formulate a mechanism. (Caution: The terminal 
alkenyl carbon cannot reach the para position of the benzene ring. Hint: Start with the fi rst step of a 
Claisen rearrangement.)
OH
CH3H3C
O
CH3H3C
BA
�
1050
 C h a p t e r 2 2 1051
In Summary 2-Propenyloxybenzene rearranges to 2-(2-propenyl)phenol (o-allylphenol) by 
an electrocyclic mechanism that moves six electrons (Claisen rearrangement). Similar con-
certed reactions are undergone by aliphatic unsaturated ethers (aliphatic Claisen rearrange-
ment) and by hydrocarbons containing 1,5-diene units (Cope rearrangement).
22-8 Oxidation of Phenols: Benzoquinones
Phenols can be oxidized to carbonyl derivatives by one-electron transfer mechanisms, result-
ing in a new class of cyclic diketones, called benzoquinones.
Benzoquinones and benzenediols are redox couples
The phenols 1,2- and 1,4-benzenediol (for which the respective common names cat echol 
and hydroquinone are retained by IUPAC) are oxidized to the corresponding diketones, 
ortho- and para-benzoquinone, by a variety of oxidizing agents, such as sodium dichro-
mate or silver oxide. Yields can be variable when the resulting diones are reactive, as 
in the case of o-benzoquinone, which partly decomposes under the conditions of its 
formation.
Benzoquinones from Oxidation of Benzenediols
OH
OH
O
O
Low yield
Ag2O, (CH3CH2)2O
OH
OH
O
92%
O
Na2Cr2O7, H2SO4
Hydroquinone p-Benzoquinone
O
O O
O
Catechol o-Benzoquinone
O
O O
O
The redox process that interconverts hydroquinone and p-benzoquinone can be visual-
ized as a sequence of proton and electron transfers. Initial deprotonation gives a phenoxide 
ion, which is transformed into a phenoxy radical by one-electron oxidation. Proton 
2 2 - 8 O x i d a t i o n o f P h e n o l s : B e n z o q u i n o n e s
1052 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
 dissociation from the remaining OH group furnishes a semiquinone radical anion, and a 
second one-electron oxidation step leads to the benzoquinone. All of the intermediate 
 species in this sequence benefi t from considerable resonance stabilization (two forms are 
shown for the semiquinone). We shall see in Section 22-9 that redox processes similar to 
those shown here occur widely in nature.
OH
OH
�H�
OH
O �
�e�
Phenoxide
ion
OH
Phenoxy
radical
jO
�H�
jO
Semiquinone
radical anion
�e�
O
OjO
ð
ð��
ðšðšðš ðš O �ððš
O �ðð�ð
ðð
ðð
Redox Relation Between p-Benzoquinone and Hydroquinone
�ð �ð
Exercise 22-27
Give a minimum of two additional resonance forms each for the phenoxide ion, phenoxy radical, 
and semiquinone radical anion shown in the preceding scheme.
The enone units in p-benzoquinones undergo conjugate 
and Diels-Alder additions
p-Benzoquinones function as reactive a,b-unsaturated ketones in conjugate additions (see 
Section 18-9). For example, hydrogen chloride adds to give an intermediate hydroxy dienone 
that enolizes to the aromatic 2-chloro-1,4-benzenediol.
O
OH
p-Benzoquinone
O
O
� HCl H
Cl
6-Chloro-4-hydroxy-
2,4-cyclohexadienone
OH
OH
Cl
2-Chloro-1,4-benzenediol
The double bonds also undergo cycloadditions to dienes (Section 14-8). The initial cyclo-
adduct to 1,3-butadiene tautomerizes with acid to the aromatic system.
�
OH
OH
88% overall
O
O
C6H6, 20�C, 48 h
O
O
H
%
%
H
HCl, �
Diels–Alder Reactions of p-Benzoquinone
 C h a p t e r 2 2 1053
In Summary Phenols are oxidized to the corresponding benzoquinones. The diones enter into 
reversible redox reactions that yield the corresponding diols. They also undergo conjugate 
additions and Diels-Alder additions to the double bonds.
22-9 Oxidation-Reduction Processes in Nature
This section describes some chemical processes involving hydroquinones and p-benzoquinones 
that occur in nature. We begin with an introduction to the biochemical reduction of O2. 
Oxygen can engage in reactions that cause damage to biomolecules. Naturally occurring 
antioxidants inhibit these transformations, as do several synthetic preservatives.
Ubiquinones mediate the biological reduction of oxygen to water
Nature makes use of the benzoquinone – hydroquinone redox couple in reversible oxidation 
reactions. These processes are part of the complicated cascade by which oxygen is used in 
biochemical degradations. An important series of compounds used for this purpose are the 
ubiquinones (a name coined to indicate their ubiquitous presence in nature), also collectively 
called coenzyme Q (CoQ, or simply Q). The ubiquinones are substituted p-benzoquinone 
derivatives bearing a side chain made up of 2-methylbutadiene units (isoprene; Sections 4-7 
and 14-10). An enzyme system that utilizes NADH (Chemical Highlights 8-1 and 25-2) 
converts CoQ into its reduced form (QH2).
CHEMICAL HIGHLIGHT 22-3
Chemical Warfare in Nature: The Bombardier Beetle
The oxidizing power of p-benzoquinones is used by some 
arthropods, such as millipedes, beetles, and termites, as 
chemical defense agents. Most remarkable among these 
species is the bombardier beetle. Its name is descriptive of 
its defense mechanism against predators, usually ants, which 
involves fi ring hot corrosive chemicals from glands in its 
posterior, with amazing accuracy. At the time of an attack 
(simulated in the laboratory by pinching the beetle with fi ne-
tipped forceps, see photo), two glands located near the end 
of the beetle’s abdomen secrete mainly hydroquinone and 
hydrogen peroxide, respectively,
into a reaction chamber. 
This chamber contains enzymes that trigger the explosive 
oxidation of the diol to the quinone and simultaneous 
decomposition of hydrogen peroxide to oxygen gas and 
water. This cocktail is audibly expelled at temperatures 
up to 1008C in the direction of the enemy from the end 
of the beetle’s abdomen, aided for aim by a 2708 rotational 
 capability. In some species, fi ring occurs in pulses of about 
500 per second, like a machine gun.
The bombardier beetle in action.
Exercise 22-28
Explain the following result by a mechanism. (Hint: Review Section 18-9.)
CH3
OCH3
H3C
CH3O
O
O
CH3
OCH2CH3
H3C
CH3CH2O
O
O
CH3CH2O�Na�,
CH3CH2OH
2 2 - 9 O x i d a t i o n - R e d u c t i o n P r o c e s s e s i n N a t u r e
1054 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
OH
OH
(CH2CH CCH2)nH
CH3
CH3
CH3O
CH3O
O
Ubiquinones (n � 6, 8, 10)
(Coenzyme Q)
O
P
A
(CH2CH CCH2)nH
CH3
CH3
CH3O
CH3O
Enzyme,
reducing agent
Reduced form of coenzyme Q
(Reduced Q, or QH2)
P
A
QH2 participates in a chain of redox reactions with electron-transporting iron-containing 
proteins called cytochromes (Chemical Highlight 8-1). The reduction of Fe31 to Fe21 in cyto-
chrome b by QH2 begins a sequence of electron transfers involving six different proteins. The 
chain ends with reduction of O2 to water by addition of four electrons and four protons.
O2 1 4 H
1 1 4 e2 uy 2 H2O
Phenol derivatives protect cell membranes from oxidative damage
The biochemical conversion of oxygen into water includes several intermediates, including 
superoxide, O2 .
2, the product of one-electron reduction, and hydroxy radical, . OH, which 
arises from cleavage of H2O2. Both are highly reactive species capable of initiating reactions 
that damage organic molecules of biological importance. An example is the phosphogly-
ceride shown here, a cell-membrane component derived from the unsaturated fatty acid 
cis,cis-octadeca-9,12-dienoic acid (linoleic acid).
Initiation step
R R�
CH2(CH2)6CO
CH2O C(CH2)14CH3
CH
O
O
B
O
R�
O
B
B
A
A A
O
CH2O PO(CH2)2N(CH3)3
O�
O
OH
�HOH
j
j
R R�
j
R
Pentadienyl radical
R�
j
C
H HCH3(CH2)4 11
913 �
The doubly allylic hydrogens at C11 are readily abstracted by radicals such as . OH 
(Section 14-2).
The resonance-stabilized pentadienyl radical combines rapidly with O2 in the fi rst of 
two propagation steps. Reaction occurs at either C9 or C13 (shown here), giving either of 
two peroxy radicals containing conjugated diene units.
Propagation step 1
R
Peroxy radical
R�
j
R R�O2
A
jOð�
Oðš
 C h a p t e r 2 2 1055
In the second propagation step this species removes a hydrogen atom from C11 of 
another molecule of phosphoglyceride, or more generally, lipid (Section 20-5), thereby 
forming a new dienyl radical and a molecule of lipid hydroperoxide. The dienyl radical 
may then reenter propagation step 1. In this way, a large number of lipid molecules may 
be oxidized following just a single initiation event.
Propagation step 2
� �
Lipid hydroperoxide
R RR� R�
j
O
OH
R R� R R�
A
C
H
11
H
A
jOð�
Oðš
ð�
ðš
Numerous studies have confi rmed that lipid hydroperoxides are toxic, their products of 
decomposition even more so. For example, loss of .OH by cleavage of the relatively weak 
O – O bond gives rise to an alkoxy radical, which may decompose by breaking a neighboring 
C – C bond (b-scission), forming an unsaturated aldehyde.
R
O
R�H R�H
O
R
O
H
OH
� jOH
R
-Scission of a Lipid Alkoxy Radical�
Alkoxy radical
� jR�Oj
ð�
ðš �
�
�
� ð
ð
Through related but more complex mechanisms, certain lipid hydroperoxides decom-
pose to give unsaturated hydroxyaldehydes, such as trans-4-hydroxy-2-nonenal, as well as 
the dialdehyde propanedial (malondialdehyde). Molecules of these general types are partly 
responsible for the smell of rancid fats.
Both propanedial and the a,b-unsaturated aldehydes are extremely toxic, because they 
are highly reactive toward the proteins that are present in close proximity to the lipids in 
cell membranes. For example, both dials and enals are capable of reacting with nucleo-
philic amino and mercapto groups from two different parts of one protein or from two 
different protein molecules, and these reactions produce cross-linking (Section 14-10). 
Cross-linking severely inhibits protein molecules from carrying out their biological func-
tions (Chapter 26).
R H
Cross-linking of Proteins by Reaction with Unsaturated Aldehydes
O
H
Protein1OSH
protein1 SO
R
O
Protein2ONH2
H
protein1 SO
R
N protein2O
Processes such as these are thought by many to contribute to the development of emphy-
sema, atherosclerosis (the underlying cause of several forms of heart disease and stroke), 
certain chronic infl ammatory and autoimmune diseases, cancer, and, possibly, the process 
of aging itself.
Does nature provide the means for biological systems to protect themselves from such 
damage? A variety of naturally occurring antioxidant systems defend lipid molecules inside 
cell membranes from oxidative destruction. The most important is vitamin E, a collection 
trans-4-Hydroxy-2-nonenal
CH3(CH2)4
O
H
HO
Propanedial
(Malondialdehyde)
H
O O
H
2 2 - 9 O x i d a t i o n - R e d u c t i o n P r o c e s s e s i n N a t u r e
1056 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
of eight compounds with very similar structures, commonly represented by one of them, 
a-tocopherol (margin). They all possess a long hydrocarbon chain (see Problem 46 of 
Chapter 2), a feature that makes them lipid soluble. Their reducing qualities stem from the 
presence of the hydroquinone-like aromatic ring (Section 22-8). The corresponding 
 phenoxide ion is an excellent electron donor. The protective qualities of vitamin E rest 
on its ability to break the propagation chain of lipid oxidation by the reduction of radical 
species.
O
CH3
Vitamin E
H3C
HO
CH3
Reactions of Vitamin E with Lipid Hydroperoxy and Alkoxy Radicals
�H�
�
 O
CH3
lipid O
e-Transfer
or
Lipid radicalsVitamin E phenoxide
�
O j
lipid OO OO j
�H�
O
CH3
�
H3C
O
CH3
lipid
or
-Tocopheroxy radical
�
O
lipid OO O
lipid OH
or
O
lipid OO OHO
j
CH3
R
CH3
R
�
O �ð
š
�š �š
�š
�š
�š�š
ð�š
O �ð�š
�š
�š
�š
O
CH3
H3C
CH3
R
In this process, lipid radicals are reduced and protonated. Vitamin E is oxidized to an
a-tocopheroxy radical, which is relatively unreactive because of extensive delocal-
ization and the steric hindrance of the methyl substituents. Vitamin E is regenerated
at the membrane surface by reaction with water-soluble reducing agents such as 
vitamin C.
� �
CH2OH
Vitamin C
OH
O
O
HHO
H#
CH2OH
Semidehydroascorbic
acid
OH
O
O
HHO
H#
O
CH3
H3C
CH3
Regeneration of Vitamin E by Vitamin C
O
CH3
H3C
CH3
CH3
R
CH3
R
Oj�š Oj�š� Oð�š
�
 Oð�š
The product of vitamin C oxidation eventually decomposes to lower-molecular-weight water-
soluble compounds, which are excreted by the body.
Lipid peroxidation has been 
 implicated in retinal diseases, and 
clinicians prescribe antioxidants 
to help in the treatment of diabetic 
retinopathy. This condition is 
 characterized by a compromised 
blood supply that causes the 
 development of fatty exudates 
and fi brous tissue on the retina 
(yellow areas in photo of the eye).
Exercise 22-29
Vitamin C is an effective antioxidant because its oxidation product semidehydroascorbic
acid is 
stabilized by resonance. Give other resonance forms for this species.
HO
CH3
O
CH3
R
H3C
CH3
Vitamin E
( -Tocopherol)�
R � branched C16H33 chain
 C h a p t e r 2 2 1057
Benzoquinones consume glutathione, an intracellular
reducing agent
Virtually all living cells contain the substance glutathione, a peptide that incorporates 
a mercapto functional group (see Sections 9-10 and 26-4). The mercapto function serves 
to reduce disulfi de linkages in proteins to SH groups and to maintain the iron in hemo-
globin in the 21 oxidation state (Section 26-8). Glutathione also participates in the redu-
ction of oxidants, such as hydrogen peroxide, H2O2, that may be present in the interior 
of the cell.
H3NCHCH2CH2
HSCH2
Glutathione
NHCH2COOH
COO�
C NHCH
O
� A AB
O
B
O O CO O
The molecule is converted into a disulfi de (Section 9-10) in this process but is regenerated 
by an enzyme-mediated reduction.
2 Glutathione glutathione glutathioneSH H2O2 2 H2O� �O SO SO O
Glutathione peroxidase
Glutathione reductases
Benzoquinones and related compounds react irreversibly with glutathione in the liver 
by conjugate addition. Cell death results if glutathione depletion is extensive. Acetamino-
phen is an example of a substance that exhibits such liver toxicity at very high doses. 
Cytochrome P-450, a redox enzyme system in the liver, oxidizes acetaminophen to an imine 
derivative of a benzoquinone, which in turn consumes glutathione. Vitamin C is capable of 
reversing the oxidation.
S glutathione
HNCCH3
O
OH
Cytochrome P-450
Vitamin C
B
HNCCH3
O
OH
B
NCCH3
O
Glutathione–SH
O
B
O
Acetaminophen
Synthetic analogs of vitamin E are preservatives
Synthetic phenol derivatives are widely used as antioxidants and preservatives in the food 
industry. Perhaps two of the most familiar are 2-(1,1-dimethylethyl)-4-methoxyphenol 
(butylated hydroxyanisole, or BHA) and 2,6-bis(1,1-dimethylethyl)-4-methylphenol 
(butylated hydroxytoluene, or BHT; see Exercise 16-14). For example, addition of BHA 
to butter increases its storage life from months to years. Both BHA and BHT function 
like vitamin E, reducing oxygen radicals and interrupting the propagation of oxidation 
processes.
In Summary Oxygen-derived radicals are capable of initiating radical chain reactions in 
lipids, thereby leading to toxic decomposition products. Vitamin E is a naturally occurring 
phenol derivative that functions as an antioxidant to inhibit these processes within mem-
brane lipids. Vitamin C and glutathione are biological reducing agents located in the intra- 
and extracellular aqueous environments. High concentrations of benzoquinones can bring 
C(CH3)3
OCH3
2-(1,1-Dimethylethyl)-
4-methoxyphenol
(BHA)
OH
C(CH3)3(CH3)3C
CH3
2,6-Bis(1,1-dimethylethyl)-
4-methylphenol
(BHT)
OH
2 2 - 9 O x i d a t i o n - R e d u c t i o n P r o c e s s e s i n N a t u r e
1058 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
about cell death by consumption of glutathione; vitamin C can protect the cell by reduction 
of the benzoquinone. Synthetic food preservatives are structurally designed to mimic the 
antioxidant behavior of vitamin E.
22-10 Arenediazonium Salts
As mentioned in Section 22-4, N-nitrosation of primary benzenamines (anilines) furnishes 
arenediazonium salts, which can be used in the synthesis of phenols. Arenediazonium salts 
are stabilized by resonance of the p electrons in the diazo function with those of the aromatic 
ring. They are converted into haloarenes, arenecarbonitriles, and other aromatic derivatives 
through replacement of nitrogen by the appropriate nucleophile.
Arenediazonium salts are stabilized by resonance
The reason for the stability of arenediazonium salts, relative to their alkane counterparts, is 
resonance and the high energy of the aryl cations formed by loss of nitrogen. One of the 
electron pairs making up the aromatic p system can be delocalized into the functional group, 
which results in charge-separated resonance structures containing a double bond between 
the benzene ring and the attached nitrogen.
N
N
ðš ð
N�
N
N�
N
�
B
�
ðð
N�
N
B
�
�
ðð
N�
N
�
B
�
Resonance in the Benzenediazonium Cation
At elevated temperatures (.508C), nitrogen extrusion does take place, however, to form 
the very reactive phenyl cation. When this is done in aqueous solution, phenols are produced 
(Section 22-4).
Why is the phenyl cation so reactive? After all, it is a carbocation that is part of a 
benzene ring. Should it not be resonance stabilized, like the phenylmethyl (benzyl) cation? 
The answer is no, as may be seen in the molecular-orbital picture of the phenyl cation 
(Figure 22-5). The empty orbital associated with the positive charge is one of the sp2 hybrids 
aligned in perpendicular fashion to the p framework that normally produces aromatic res-
onance stabilization. Hence, this orbital cannot overlap with the p bonds, and the positive 
+
p orbitals
Empty sp2 orbital
BA C
+
Phenyl cation
Figure 22-5 (A) Line structure of the phenyl cation. (B) Orbital picture of the phenyl cation. The 
alignment of its empty sp2 orbital is perpendicular to the six-p-electron framework of the aromatic 
ring. As a result, the positive charge is not stabilized by resonance. (C) The electrostatic potential 
map of the phenyl cation, shown at an attenuated scale for better contrast, pinpoints much of the 
positive charge (blue edge on the right) as located in the plane of the six-membered ring.
 C h a p t e r 2 2 1059
charge cannot be delocalized. Moreover, the cationic carbon would prefer sp hybridization, 
an arrangement precluded by the rigid frame of the benzene ring. We used a similar argu-
ment to explain the diffi culty in deprotonating benzene to the corresponding phenyl anion 
(Section 22-4).
Arenediazonium salts can be converted into other 
substituted benzenes
When arenediazonium salts are decomposed in the presence of nucleophiles other than 
water, the corresponding substituted benzenes are formed. For example, diazotization of 
arenamines (anilines) in the presence of hydrogen iodide results in the corresponding 
iodoarenes.
CHO
NH2
N2
OO
O
CHO
�
I
OO
O
53%
CH3COOH, HI, NaNO2
Attempts to obtain other haloarenes in this way are frequently complicated by side reac-
tions. One solution to this problem is the Sandmeyer* reaction, which makes use of the 
fact that the exchange of the nitrogen substituent for halogen is considerably facilitated by 
the presence of cuprous [Cu(I)] salts. The detailed mechanism of this process is complex, 
and radicals are participants. Addition of cuprous cyanide, CuCN, to the diazonium salt in 
the presence of excess potassium cyanide gives aromatic nitriles.
Sandmeyer Reactions
Cl
NH2
NH2
2-Methylbenzenamine
(o-Methylaniline)
2-Chlorobenzenamine
(o-Chloroaniline)
Cl
Br
1-Bromo-2-chlorobenzene
(o-Bromochlorobenzene)
73%
CH3
Cl
1-Chloro-2-methylbenzene
(o-Chlorotoluene)
79% overall
CH3
�N2
N2�Cl�
CH3
HCl, NaNO2, 0°C
1. HBr, NaNO2, 0°C
2. CuBr, 100°C
CuCl, 60°C
NH2
CH3
CN
70%
4-Methylbenzonitrile
( p-Tolunitrile)
CH3
1. HCl, NaNO2, 0°C
2. CuCN, KCN, 50°C
*Dr. Traugott Sandmeyer (1854 – 1922), Geigy Company, Basel, Switzerland.
2 2 - 1 0 A r e n e d i a z o n i u m S a l t s
1060 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
The diazonium group can be removed by reducing agents. The sequence diazotization –
 reduction is a way to replace the amino group in arenamines (anilines) with hydrogen. 
The reducing agent employed is aqueous hypophosphorous acid, H3PO2. This method is 
especially useful
in syntheses in which an amino group is used as a removable directing 
substituent in electrophilic aromatic substitution (Section 16-5).
N2�
NaNO2, H�, H2O
1-Bromo-3-methylbenzene
(m-Bromotoluene)
85%
Reductive Removal of a Diazonium Group
NH2
CH3
Br
CH3
Br
H3PO2, H2O, 25�C
CH3
Br
H
Another application of diazotization in synthetic strategy is illustrated in the synthesis 
of 1,3-dibromobenzene (m-dibromobenzene). Direct electrophilic bromination of benzene is 
not feasible for this purpose; after the fi rst bromine has been introduced, the second will 
attack ortho or para. What is required is a meta-directing substituent that can be transformed 
eventually into bromine. The nitro group is such a substituent. Double nitration of benzene 
furnishes 1,3-dinitrobenzene (m-dinitrobenzene). Reduction (Section 16-5) leads to the ben-
zenediamine, which is then converted into the dihalo derivative.
HNO3, H2SO4, �
Synthesis of 1,3-Dibromobenzene by Using a Diazotization Strategy
NO2
H2, Pd
Br
BrNO2
NH2
NH2
1. NaNO2, H�, H2O
2. CuBr, 100�C 
Exercise 22-31
Propose a synthesis of 1,3,5-tribromobenzene from benzene.
In Summary Arenediazonium salts, which are more stable than alkanediazonium salts 
because of resonance, are starting materials not only for phenols, but also for haloarenes, 
Exercise 22-30
Propose syntheses of the following compounds, starting from benzene.
(a) 
I
 (b) 
CN
CN
 (c) 
SO3H
OH
 C h a p t e r 2 2 1061
arenecarbonitriles, and reduced aromatics by displacement of nitrogen gas. The intermediates 
in some of these reactions may be aryl cations, highly reactive because of the absence of 
any electronically stabilizing features, but other, more complicated mechanisms may be 
followed. The ability to transform arenediazonium salts in this way gives considerable scope 
to the regioselective construction of substituted benzenes.
22-11 Electrophilic Substitution with Arenediazonium Salts: 
Diazo Coupling
Being positively charged, arenediazonium ions are electrophilic. Although they are not 
very reactive in this capacity, they can accomplish electrophilic aromatic substitution when 
the substrate is an activated arene, such as phenol or benzenamine (aniline). This reaction, 
called diazo coupling, leads to highly colored compounds called azo dyes. For example, 
reaction of N,N-dimethylbenzenamine (N,N-dimethylaniline) with benzenediazonium 
 chloride gives the brilliant orange dye Butter Yellow. This compound was once used as a 
food coloring agent but has been declared a suspect carcinogen by the Food and Drug 
Administration.
Diazo Coupling
N(CH3)2
Cl�
�
N�
� Cl�
)N(CH3)2
H�, H2O
pH 	 3–5
J
�
�
J
�
� N(CH3)2
�HCl
Azo
function
4-Dimethylaminoazobenzene
(p-Dimethylaminoazobenzene, Butter Yellow)
Dyes used in the clothing industry usually contain sulfonic acid groups that impart water 
solubility and allow the dye molecule to attach itself ionically to charged sites on the poly-
mer framework of the textile.
pH � 3.0, blue-violet
pH � 5.0, red 
NH2 H2N
N
N N
N
Na��O3S SO3�Na�
P P
Congo Red
J
�
� SO3�Na�
Methyl Orange
(CH3)2N
Industrial Dyes
pH � 3.1, red
pH � 4.4, yellow 
N
N
O Na
S
O
O
Dyes are important additives in 
the textile industry. Azo dyes, 
while still in widespread use, are 
becoming less attractive for this 
purpose because some have been 
found to degrade to carcinogenic 
benzenamines.
2 2 - 1 1 E l e c t r o p h i l i c S u b s t i t u t i o n w i t h A r e n e d i a z o n i u m S a l t s
1062 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
CHEMICAL HIGHLIGHT 22-4
William Perkin and the Origins of Industrial and Medicinal Chemistry
In 1851, William Perkin* was a 13-year-old pupil at City 
of London School. His teacher, Thomas Hall, recognized 
Perkin’s interest and aptitude in science but also realized his 
own limitations. Hall therefore encouraged Perkin to attend 
lectures at the Royal Institution, including a series presented 
by the legendary scientist Michael Faraday.† A few years 
earlier, Faraday and others had sponsored the founding of 
the Royal College of Chemistry in response to Justus 
Liebig’s‡ scathing criticism of the sorry state of chemical 
research in England. Liebig’s brilliant young student, August 
von Hofmann,§ was hired as its fi rst director.
London in the 1850s was perhaps the fi lthiest, most 
polluted city in the world. It was lit by gas lamps, with the 
gas extracted from coal. The residue of the extraction was 
massive quantities of coal tar, most of which was simply 
dumped into London’s streams and rivers. However, coal tar 
was rich in aromatic amines, and Hofmann, who found these 
compounds fascinating, could obtain coal tar in London by 
the barrelful, just by asking.
By 1856, Perkin had begun studying in Hofmann’s labo-
ratory. Malaria was rampant in England (indeed, in most of 
the world) at the time, and the only remedy was quinine, the 
single source of which was the bark of the South American 
cinchona tree. Perkin knew that the molecular formula of 
quinine was C20H24N2O2 and that Hofmann had isolated 
several 10-carbon amines, including naphthalenamine, 
C10H9N. Lacking any knowledge of molecular structure, 
Perkin decided to try to synthesize quinine by oxidative 
dimerization of such coal tar – derived 10-carbon aromatic 
amines. What could be more useful than to convert a major 
environmental pollutant into a desperately needed medicine? 
Perkin’s experiments gave black crude products, out of 
which could be extracted brightly colored powders. Pursuing 
these experiments with more amines and, eventually, amine 
mixtures, Perkin stumbled onto a procedure that gave a 
brilliant purple substance to which was given the name 
“mauve.”
Within a short time, dyes based on Perkin’s mauve had 
transformed the world of fashion — not exactly what he had 
in mind originally, but the discovery did make him very 
rich. Previously, the only source of purple dye (so-called 
Royal Purple, because only royalty could afford it) was from 
the shell lining of a species of mollusk found in only two 
locations on the Mediterranean coast. Thus was born the 
synthetic dye industry, the fi rst of the large-scale industries 
based on chemical science.
Remarkably, the correct basic chemical structure of 
Perkin’s mauve was not determined and published until 
1994, by Professor Otto Meth-Cohn and undergraduate 
Mandy Smith, at the University of Sunderland, England. 
The reaction that forms the major constituent of the dye is 
shown below.
*Sir William Henry Perkin (1838 – 1907), Royal College of 
Chemistry, London, England.
†This the same Faraday as the discoverer of benzene 
(Chapter 15 Opening).
‡Baron Justus von Liebig (1803 – 1873), University of Munich, 
Germany.
§This is the same Hofmann as that of the Hofmann rule 
(Section 11-6) and the Hofmann rearrangement (Section 20-7).
2
NH2
K2Cr2O7,
H2SO4, H2O
CH3
H3C
� �
N
N
�NH2
CH3
NH2 N
H
CH3
NH2
In Summary Arenediazonium cations attack activated benzene rings by diazo coupling, a 
process that furnishes azobenzenes, which are often highly colored.
Exercise 22-32
Write the products of diazo coupling of benzenediazonium chloride with each of the following 
molecules. (a) Methoxybenzene; (b) 1-chloro-3-methoxybenzene; (c) 1-(dimethylamino)-4-
(1,1-dimethylethyl)benzene. (Hint: Diazo couplings are quite sensitive to steric effects.)
 C h a p t e r 2 2 1063
The process involves oxidation of some of the amine 
starting material to nitrosobenzenes, such as C6H5NO, followed 
by acid-catalyzed electrophilic aromatic substitution reactions 
between the nitroso
compounds and other molecules of amine.
of bacteriology, began to follow up on reports that anthrax 
was caused by microscopic rod-shaped bodies found in the 
blood of infected sheep. He developed practical techniques 
for culturing and growing colonies of bacteria, a concept 
introduced by Pasteur a generation earlier but never demon-
strated. Koch went on to discover the microorganisms that 
caused tuberculosis, conjunctivitis, amebic dysentery, and 
cholera, publishing superb micrographs to support his fi nd-
ings. By the last decades of the nineteenth century, Paul 
Ehrlich** became aware of reports that Perkin’s dyes could 
be used to stain cells, and he applied these ideas to help 
better visualize Koch’s tuberculosis bacilli. He realized that 
the staining phenomena were in fact chemical reactions and 
that the dyes stained different microbiological entities differ-
ently. Ehrlich found that some dyes could be used as thera-
peutic agents to combat the effects of bacterial toxins, thus 
pioneering the fi eld of chemotherapy and making great 
strides in the development of immunology. In 1910, Ehrlich 
developed the fi rst effective drug to combat syphilis, a dis-
ease that had become a worldwide scourge. His work helped 
give birth to the fi elds of biochemistry, cell biology, and 
medicinal chemistry. Thus, Perkin’s discoveries of a half-
century earlier had changed more than the world of fashion: 
They changed the world.
Linda Evangelista models a lacy mauve dress 
from Christian Dior’s autumn collection:
lmax 5 550 nm.
¶Professor H. H. Robert Koch (1843 – 1910), University of 
 Göttingen, Germany, Nobel Prize 1905 (physiology or 
medicine).
**Professor Paul Ehrlich, (1854 – 1915), Royal Institute for 
Experimental Therapy, Frankfurt, Germany, Nobel Prize 1908 
(physiology or medicine).
Scanning electron micrograph of Mycobacterium smegmatis 
found in soil. The species is used as a model for studies of 
tuberculosis caused by Mycobacterium tuberculosis. Image 
width: 8.38 3 1026 m.
Perkin’s discovery did not help cure malaria, but it 
 nevertheless had an enormous impact on medical science. 
In the 1860s, Robert Koch¶, one of the founders of the fi eld 
THE BIG PICTURE
This chapter completes our understanding of the interplay between the benzene ring and its 
alkyl, hydroxy, and amino or modifi ed amino substituents. Just as much as the electronic 
character of such substituents may activate or deactivate the ring with respect to substitution 
(Chapter 16; Sections 22-4 and 22-6) and the way in which substitutents are positioned 
controls the location of attack by electrophiles and nucleophiles, the ring imparts special 
reactivity on attached nuclei because of its resonating capacity. In other words, and to 
repeat the underlying theme of the text, the structure of the substituted aromatic compound 
T h e B i g P i c t u r e
1064 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
determines its function. In many respects, this behavior is a simple extension of the chemistry 
of delocalized systems (Chapter 14) with the added feature of aromaticity (Chapter 15).
In the next chapter, we shall continue to examine the effect that two functional groups 
in the same molecule have on each other, now turning to carbonyl groups. In Chapter 24, 
we shall study molecules containing the carbonyl and several hydroxy groups and their 
biological relevance. Then, in Chapters 25 and 26, we conclude with biologically important 
compounds containing an array of functionality.
CHAPTER INTEGRATION PROBLEMS
22-33. 5-Amino-2,4-dihydroxybenzoic acid A is a potential intermediate in the preparation of 
 natural products of medicinal value (Section 22-3). Propose syntheses, starting from methylbenzene 
 (toluene).
OH
HO
NH2
CH3 COOH
A
SOLUTION
This problem builds on the expertise that you gained (Chapter 16) in controlling the substitution 
 patterns of target benzenes, but now with a greatly expanded range of reactions. The key is, again, 
recognition of the directing power of substituents — ortho, para or meta (Section 16-2) — and their 
interconversion (Section 16-5).
 Retrosynthetic analysis of compound A reveals one carbon-based substituent, the carboxy group, 
which can be readily envisaged to be derivable from the methyl group in the starting material (by 
oxidation, Section 22-2). In the starting material, the carbon-based substituent is ortho, para directing, 
suggesting its use (retrosynthesis 1) in the introduction of the two hydroxy functions (as in compound B, 
through nitration – reduction – diazotization – hydrolysis; Sections 22-4 and 22-10). In compound A, it 
is meta directing and potentially utilizable (retrosynthesis 2) for the amination at C3 (as in compound C, 
through nitration – reduction).
Retrosynthesis 1
HO
OH
COOH
O2N
NO2
COOH
O2N
NO2
CH3 CH3
A
B
E�
Retrosynthesis 2
NO2
COOH
NH2
COOH COOH CH3
A
C
E�
The question is, Are compounds B and C effective precursors of compound A? The answer is yes. 
Nitration of compound B should take place at the desired position (C3 in the product), ortho and para, 
respectively, to the two hydroxy substituents, thus placing the nitrogen at its position in compound A. 
Electrophilic attack between the OH groups would be expected to be sterically hindered (Section 16-5). 
 C h a p t e r 2 2 1065
Conversely, the amino group in compound C, especially when protected as an amide, should direct 
electrophilic substitution to the less hindered ortho carbon and the para carbon, again yielding the 
desired pattern. The actual proposed synthetic schemes would be then as follows.
Synthesis 1
H2N
NH2
COOH
HO
OH
COOH
O2N
NO2
COOH
O2N
NO2
CH3CH3
Na2Cr2O7, H�, H2O
1. HNO3, H2SO4
2. H2, Ni
1. NaNO2, HCl
2. H2O, �
H2, NiHNO3, H2SO4
A
Synthesis 2
O2N
NO2
COOH
NO2
COOHCOOHCH3
NH2
COOH
Na2Cr2O7, H�, H2O
1. H2, Ni
2. NaNO2, HCl
3. H2O, �
4. H�, H2O
1. CH3CCl
2. HNO3, H2SO4
H2, NiHNO3, H2SO4
AB
B
NCCH3
H
O
O
22-34. A key reaction in the early development of the “pill” (Section 4-7; Chemical Highlight 4-3) 
was the “dienone-phenol” rearrangement shown below. Write a mechanism.
CH3
H3C H
H
O
OH
H�
% %
% C
≥
H
≥
CH3
CH3
H
H
HO
OH
%
% C
≥
H
≥
SOLUTION
This is a mechanistic problem involving an acid-catalyzed rearrangement featuring a migrating 
alkyl (methyl) group. Sound familiar? Review Section 9-3 on carbocation rearrangements! How 
do we obtain a suitable carbocation from our starting material? Answer: Protonation of the carbonyl 
group, which furnishes a resonance-stabilized hydroxypentadienyl cation (Section 14-6, 14-7, and 
Exercise 18-22).
Protonation of Dienone Function
H�
CH3
%
CH3
O
%
HO
etc.
š�ð�
CH3
�
�
HO
%
�
A
C h a p t e r I n t e g r a t i o n P r o b l e m s
1066 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
 Two of the resonance structures (write all of them) place a positive charge next to the methyl 
group. Only form A is “productive,” inasmuch as it leads to product by aromatization, which is the 
major driving force for the whole process.
Methyl Shift and Phenol Formation
�H�
CH3
%
HOš�
�
�
H3C H%
HOš�
CH3
CH3
H
H
HO
OH
%
% C
C
≥
H
≥
A
New Reactions
Benzylic Resonance
 1. Radical Halogenation (Section 22-1)
RCHX RCHj
j
RCHRCH2
X2
� HX through etc.
Benzylic radical
Requires heat, light, or a radical initiator
 2. Solvolysis (Section 22-1)
RCHOR� RCH RCHRCHOSO2R
SN1
� RSO3H� R�OH through
�
�
etc.
Benzylic cation
 3. SN2 Reactions of (Halomethyl)benzenes (Section
22-1)
CH2X CH2Nu
� )Nu� � X�
Through delocalized
transition state
 4. Benzylic Deprotonation (Section 22-1)
CH3 CH2Li
� RLi � RH
Phenylmethyllithium
(Benzyllithium)pKa
 
41
Oxidation and Reduction Reactions on Aromatic Side Chains
 5. Oxidation (Section 22-2)
RCH2 COOH
1. KMnO4, HO�, �
2. H�, H2OCrO3
OR
 C h a p t e r 2 2 1067
Benzylic alcohols
RCHOH
MnO2, acetone
OR
 6. Reduction by Hydrogenolysis (Section 22-2)
CH2OR CH3
� ROHH2, Pd–C, ethanol
C6H5CH2 is a protecting group for ROH.
Phenols and Ipso Substitution
 7. Acidity (Section 22-3)
OH O O
�
�
etc.
Phenoxide ion
) )
p
p
�
H�
Much stronger acid than simple alkanols
pKa
 
10
 8. Nucleophilic Aromatic Substitution (Section 22-4)
Nu
� Cl�
NO2
NO2
NuCl
NO2
NO2
Cl
NO2
NO2
Nucleophile attacks at ipso position.
Nu)�
�
 9. Aromatic Substitution Through Benzyne Intermediates (Section 22-4)
NaNH2, liquid NH3
Nucleophile attacks at both ipso and ortho positions.
� NaCl
NH3
NH2Cl
OHX
1. NaOH, �
2. H�, H2O
10. Arenediazonium Salt Hydrolysis (Section 22-4)
NaNO2, H�, 0�C
Benzenediazonium
cation
NH2 OH
N2�
N2�
H2O, �
N e w R e a c t i o n s
1068 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
11. Substitution with Pd Catalysis
KOH, Pd catalyst,
PR3, 100�C
X OH
Reactions of Phenols and Alkoxybenzenes
12. Ether Cleavage (Section 22-5)
Aryl C–O bond is not cleaved.
OHOR
RBr�
HBr, �
13. Ether Formation (Section 22-5)
Alkoxybenzene
OR 
RX�
NaOH, H2O
Williamson method (Section 9-6)
OH
14. Esterifi cation (Section 22-5)
Phenyl alkanoate
OCR 
RCCl
O
�
Base
OH
B
O
B
15. Electrophilic Aromatic Substitution (Section 22-6)
E
OCH3
E
� H�
OCH3OCH3
� E� �
16. Phenolic Resins (Section 22-6)
NaOH HO�
OH
CH2 O�
� H2O
OH
CH2OH
, NaOH
OH OH
polymer
OH
O
CH2
P
 C h a p t e r 2 2 1069
17. Kolbe Reaction (Section 22-6)
OH
CO2�
OH
COOH1. NaOH, pressure
2. H�, H2O
18. Claisen Rearrangement (Section 22-7)
Aromatic Claisen rearrangement
O
H
O
�
OH
Aliphatic Claisen rearrangement
O
H
O
19. Cope Rearrangement (Section 22-7)
R R
20. Oxidation (Section 22-8)
2,5-Cyclohexadiene-1,4-dione
(p-Benzoquinone)
O
O
OH
OH
Na2Cr2O7, H�
21. Conjugate Additions to 2,5-Cyclohexadiene-1,4-diones (p-Benzoquinones) (Section 22-8)
O
O
�
Cl
OH
HCl
OH
N e w R e a c t i o n s
1070 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
22. Diels-Alder Cycloadditions to 2,5-Cyclohexadiene-1,4-diones (p-Benzoquinones) (Section 22-8)
O
O
O
H
H
O
�
0
%
23. Lipid Peroxidation (Section 22-9)
O2, radical chain reaction followed by
Fragmentation to alkoxy radicals,
R R�
C
HH
R R�
C
OOHH
�-scission toxic substances such as
4-hydroxy-2-alkenals 
24. Inhibition by Antioxidants (Section 22-9)
Vitamin E
(or BHA or BHT)
HO
CH3
CH3
H3C
CH3
j
R
or �
O
O
CH3
CH3
H3C
CH3
O
R
�
OOjš�
Ojš�
š�R R�
C
H
R R�
C
H
or
OOH
OH
R R�
C
H
R R�
C
H
25. Vitamin C as an Antioxidant (Section 22-9)
�e�
#
CH2OH
H
O
H
O
HO
O
OH
�
#
CH2OH
Semidehydroascorbic
acid
H
Oj
H
O
HO
O
OH
š�ð š�
Arenediazonium Salts
26. Sandmeyer Reactions (Section 22-10)
CuX, �
X 	 Cl, Br, I, CN
XN2�X�
N2�
27. Reduction (Section 22-10)
H3PO2
HN2�
N2�
 C h a p t e r 2 2 1071
28. Diazo Coupling (Section 22-11)
Azo compound
Occurs only with strongly activated rings
c
N�
H�
N
OH
OH
�
�
J
�
�
Important Concepts
1. Phenylmethyl and other benzylic radicals, cations, and anions are reactive intermediates stabi-
lized by resonance of the resulting centers with a benzene p system.
2. Nucleophilic aromatic ipso substitution accelerates with the nucleophilicity of the attacking 
 species and with the number of electron-withdrawing groups on the ring, particularly if they are 
located ortho or para to the point of attack.
3. Benzyne is destabilized by the strain of the two distorted carbons forming the triple bond.
4. Phenols are aromatic enols, undergoing reactions typical of the hydroxy group and the aro-
matic ring.
5. Benzoquinones and benzenediols function as redox couples in the laboratory and in nature.
6. Vitamin E and the highly substituted phenol derivatives BHA and BHT function as inhibitors of 
the radical-chain oxidation of lipids. Vitamin C also is an antioxidant, capable of regenerating 
vitamin E at the surface of cell membranes.
7. Arenediazonium ions furnish reactive aryl cations whose positive charge cannot be delocalized 
into the aromatic ring.
8. The amino group can be used to direct electrophilic aromatic substitution, after which it is replace-
able by diazotization and substitution, including reduction.
Problems
35. Give the expected major product(s) of each of the following reactions.
(a) 
CH2CH3
Cl2(1 equivalent), hv (b) NBS (1 equivalent), hv
36. Formulate a mechanism for the reaction described in Problem 35(b).
37. Propose syntheses of each of the following compounds, beginning in each case with 
ethylbenzene. (a) (1-Chloroethyl)benzene; (b) 2-phenylpropanoic acid; (c) 2-phenylethanol; 
(d) 2-phenyloxacyclopropane.
38. Predict the order of relative stability of the three benzylic cations derived from chloromethyl-
benzene (benzyl chloride), 1-(chloromethyl)-4-methoxybenzene (4-methoxybenzyl chloride), and 
1-(chloromethyl)-4-nitrobenzene (4-nitrobenzyl chloride). Rationalize your answer with the help 
of resonance structures.
39. By drawing appropriate resonance structures, illustrate why halogen atom attachment at the para 
position of phenylmethyl (benzyl) radical is unfavored compared with attachment at the benzylic 
position.
40. Triphenylmethyl radical, (C6H5)3C?, is stable at room temperature in dilute solution in an inert 
solvent, and salts of triphenylmethyl cation, (C6H5)3C
1, can be isolated as stable crystalline solids. 
Propose explanations for the unusual stabilities of these species.
P r o b l e m s
1072 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
41. Give the expected products of the following reactions or reaction sequences.
(a) 
H2O, �BrCH2CH2CH2 CH2Br (b) 
1. KCN, DMSO
2. H�, H2O, �
CH2Cl
(c) 
1. CH3CH2CH2CH2Li, (CH3)2NCH2CH2N(CH3)2, THF
2. C6H5CHO
3. H�, H2O, �
C16H14
42. The hydrocarbon with the common name fl uorene is acidic enough (pKa < 23) to be a useful 
indicator in deprotonation reactions of compounds of greater acidity. Indicate the most acidic 
hydrogen(s) in fl uorene. Draw resonance structures to explain the relative stability of its conju-
gate base.
43. Outline a straightforward, practical, and effi cient synthesis of each of the following compounds. 
Start with benzene or methylbenzene. Assume that the para isomer (but not the ortho isomer) 
may be separated effi ciently from any mixtures of ortho and para substitution products.
FluoreneFluorene
(a) 
CH2CH2Br
 (b) 
CONH2
Cl
 (c) 
O
COOCH3
 (d) 
COOH
BrBr
44. Rank the following compounds in descending order of reactivity toward hydroxide ion.
Br
NO2
Br Br
NO2
NO2
Br
NO2
NO2
Br
NO2
NO2
45. Predict the main product(s) of the following reactions. In each case, describe the mechanism(s) 
in operation.
(a) 
Cl
NO2
NO2
H2NNH2
 (b) 
Cl
Cl
O2N NO2
NaOCH3,
CH3OH
 (c) 
Cl
CH3
LiN(CH2CH3)2,
(CH3CH2)2NH
46. Starting
with benzenamine, propose a synthesis of aklomide, an agent used to treat certain exotic 
fungal and protozoal infections in veterinary medicine. Several intermediates are shown to give 
you the general route. Fill in the blanks that remain; each requires as many as three sequential 
reactions. (Hint: Review the oxidation of amino- to nitroarenes in Section 16-5.)
CONH2
Cl
NO2
(d)
Aklomide
CN
Cl
NO2
(c)
Br
Cl
NO2
(b)
Br
NH2NH2
(a)
 C h a p t e r 2 2 1073
47. Explain the mechanism of the following synthetic transformation. (Hint: Two equivalents of 
butyllithium are used.)
CH2CH2CH2CH3
CH2OH
OCH3
1. CH3CH2CH2CH2Li
2. H2C
3. H�, H2O
F O
OCH3
P
48. In nucleophilic aromatic substitution reactions that proceed by the addition – elimination mechanism, 
fl uorine is the most easily replaced halogen in spite of the fact that F2 is by far the worst leaving 
group among halide ions. For example, 1-fl uoro-2,4-dinitrobenzene reacts much more rapidly with 
amines than does the corresponding chloro compound. Suggest an explanation. (Hint: Consider 
the effect of the identity of the halogen on the rate-determining step.)
49. Based on the mechanism presented for the Pd-catalyzed reaction of a halobenzene with hydroxide 
ion, write out a reasonable mechanism for the Pd-catalyzed reaction of 1-bromo-3-methoxybenzene 
with 2-methyl-1-propanamine shown in Section 22-4.
50. Give the likely products of each of the following reactions. Each one is carried out in the presence 
of a Pd catalyst, a phosphine, and heat.
(a) ClF3C
N
H
� (b) Br CH3CH2CH2SH�
(c) ICH3O Na� �CN� (d) Br �
�
O
š
51. A very effi cient short synthesis of resveratrol (Chemical Highlight 22-1) was reported in 2006. 
Fill in reasonable reagents for steps (a) through (d). Refer to the referenced text sections as 
needed.
O
O
HO
HO
CHO
HO
HO
CH CH2P
B
B
CH3CO
CH3CO
CH CH2P
(a)
Section
17-12
(b)
Sections
19-9, 20-3
O
O
B
B
CH3CO O
B
OCCH3 resveratrol
CH3CO
CH CHP
(c)
Section
13-9
(d)
Section
20-4
52. The reaction sequence shown below illustrates the synthesis of 2,4,5-trichlorophenoxyacetic 
acid (2,4,5-T), a powerful herbicide. A 1 : 1 mixture of the butyl esters of 2,4,5-T and its dichlo-
rinated analog 2,4-D was used between 1965 and 1970 as a defoliant during the Vietnam War 
P r o b l e m s
1074 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
under the code name Agent Orange. Propose mechanisms for the reactions in the synthesis of 
this substance, whose effects on the health of those exposed to it remain topics of considerable 
controversy.
Cl
Cl
2,4,5-Trichlorophenol
(2,4,5-TCP)
Cl
Cl
OH
Cl
Cl
Cl
2,4,5-Trichlorophenoxyacetic acid
(2,4,5-T)
85%
OCH2COOH
Cl
Cl
Cl
1. NaOH, 150°C
2. H�, H2O
�NaCl
ClCH2COOH,
NaOH, H2O, �
�NaCl
53. Give the expected major product(s) of each of the following reactions and reaction sequences.
(a) 
1. KMnO4, �OH, �
2. H�, H2O
(b) 
1. MnO2, acetone
2. KOH, H2O, �
B
CH2OH
CH2CCH3
O (c) 
1. (CH3)2CHCl, AlCl3
2. HNO3, H2SO4
3. KMnO4, NaOH, �
4. H�, H2O
CH3
54. Rank the following compounds in order of descending acidity.
(a) CH3OH (b) CH3COOH (c) 
OH
SO3H
 (d) 
OH
OCH3
 (e) 
OH
CF3
 (f) 
OH
55. Design a synthesis of each of the following phenols, starting with either benzene or any mono-
substituted benzene derivative.
(a) 
OH
CH3
 (b) 
OH
BrBr
 (c) The three benzenediols (d) 
OH
NO2
NO2Cl
56. Starting with benzene, propose syntheses of each of the following phenol derivatives.
(a) 
OCH2COOH
Cl
Cl
The herbicide 2,4-D
 (b) 
NHCOCH3
OCH2CH3
(The active ingredient
in Midol)
Phenacetin
 (c) 
OCCH3
COOH
Br
Br
B
O
Dibromoaspirin
(An experimental drug for the
treatment of sickle-cell anemia)
 C h a p t e r 2 2 1075
58. Give the expected product(s) of each of the following reaction sequences.
(a) 
1. 2 CH2PCHCH2Br, NaOH
2. �
OH
OH
 (b) 
1. �
2. O3, then Zn, H�
3. NaOH, H2O, � 
CH3
O
 (c) 
Ag2O
OH
OH
Cl
Cl
Cl
Cl
(d) 
Ag2O
CH3
OH
OH
H3C
 (e) 
O
O
CH3CH2SH (two possibilities) (f) 
O
O
�
57. Name each of the following compounds.
(a) 
OH
Cl
Br
 (b) 
OH
CH2OH
 (c) 
OHHO
SO3H
 (d) 
O
OH
 (e) 
O
O
SCH3
59. As a children’s medicine, acetaminophen (Tylenol) has a major marketing advantage over aspirin: 
Liquid Tylenol preparations (essentially, acetaminophen dissolved in fl avored water) are stable, 
whereas comparable aspirin solutions are not. Explain.
60. Chili peppers contain signifi cant quantities of vitamins A, C, and E, as well as folic acid and 
potassium. They also contain small quantities of capsaicin, the fi ery essence responsible for the 
“hot” in hot peppers. The pure substance is in fact quite dangerous: Chemists working with 
capsaicin must work in special fi ltered-air enclosures and wear full body protection. One milli-
gram placed on the skin will cause a severe burn. Although capsaicin has no odor or fl avor of its 
own, its pungency — in the form of detectable stimulation of the nerves in the mucous membranes 
of the mouth — can be detected even when the substance is diluted to one part in 17 million of 
water. The hottest peppers exhibit about 1y20th of this level of pungency.
 The structure of capsaicin is shown on p. 1028. Some of the data that were used in its elu-
cidation are presented below. Interpret as much of this information as you can.
MS: mYz 5 122, 137 (base peak), 195 (tricky!), 305.
IR: n~ 5 972, 1660, 3016, 3445, 3541 cm21.
1H NMR: d 5 0.93 (6H, d, J 5 8 Hz), 1.35 (2H, quin, J 5 7 Hz), 1.62 (2H, quin, J 5
7 Hz), 1.97 (2H, q, J 5 7 Hz), 2.18 (2H, t, J 5 7 Hz), 2.20 (1H, m), 3.85 (3H, s), 4.33 (2H, d, 
J 5 6 Hz), 5.33 (2H, m), 5.82 (2H, broad s), 6.73 (1H, d, J 5 9 Hz), 6.78 (1H, s), 6.85 (1H, d,
J 5 9 Hz) ppm.
61. Biochemical oxidation of aromatic rings is catalyzed by a group of liver enzymes 
called aryl hydroxylases. Part of this chemical process is the conversion of toxic aromatic 
P r o b l e m s
1076 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
 hydrocarbons such as benzene into water-soluble phenols, which can be easily excreted. However, 
the primary purpose of the enzyme is to enable the synthesis of biologically useful compounds, 
such as the amino acid tyrosine.
CH2CHCOOH
A
NH2
CH2CHCOOH
A
NH2
O2, hydroxylase
OH
TyrosinePhenylalanine
(a) Extrapolating from your knowledge of benzene chemistry, which of the following three 
possibilities seems most reasonable: The oxygen is introduced by electrophilic attack on the 
ring; the oxygen is introduced by free-radical attack on the ring; or the oxygen is introduced by 
nucleophilic attack on the ring? (b) It is widely suspected that oxacyclopropanes play a role in 
arene hydroxylation. Part of the evidence is the following observation: When the site to be 
hydroxylated is initially labeled with deuterium, a substantial proportion of the product still 
contains deuterium atoms, which have apparently migrated to the position ortho to the site of 
hydroxylation.
R
O2, hydroxylase
D
R
OH
D
R
O
through
H
D
as an intermediate
 Suggest a plausible mechanism for the formation of the oxacyclopropane intermediate and its 
conversion into the observed product. (Hint: Hydroxylase converts O2 into hydrogen peroxide, 
HO – OH.) Assume the availability of catalytic amounts of acids and bases, as necessary.
 Note: In victims of the genetically transmitted disorder called phenylketonuria (PKU),
the 
hydroxylase enzyme system described here does not function properly. Instead, phenylalanine in 
the brain is converted into 2-phenyl-2-oxopropanoic (phenylpyruvic) acid, the reverse of the 
process shown in Problem 57 of Chapter 21. The buildup of this compound in the brain can lead 
to severe retardation; thus people with PKU (which can be diagnosed at birth) must be restricted 
to diets low in phenylalanine.
62. A common application of the Cope rearrangement is in ring-enlargement sequences. Fill in the 
reagents and products missing from the following scheme, which illustrates the construction of a 
10-membered ring.
(a)
1. LiAlH4, (CH3CH2)2O
2. H�, H2O(b) Excess PCC, CH2Cl2
200�C(e)
O
O
O
O
O
O
(c)
(f)(d)
 C h a p t e r 2 2 1077
67. Write the most reasonable structure of the product of each of the following reaction sequences.
63. As mentioned in Section 22-10, the Sandmeyer reactions, in which copper(I) ion catalyzes 
 substitution of the nitrogen in arenediazonium salts by Cl, Br, or CN, take place by complex 
mechanisms involving radicals. Explain why these substitutions do not follow either the SN1 or 
SN2 pathway.
64. Formulate a detailed mechanism for the diazotization of benzenamine (aniline) in the presence 
of HCl and NaNO2. Then suggest a plausible mechanism for its subsequent conversion into 
iodobenzene by treatment with aqueous iodide ion (e.g., from K1I2). Bear in mind your answer 
to Problem 63.
65. Show how you would convert 3-methylbenzenamine into each of the following compounds: 
(a) methylbenzene; (b) 1-bromo-3-methylbenzene; (c) 3-methylphenol; (d) 3-methylbenzonitrile; 
(e) N-ethyl-3-methylbenzenamine.
66. Devise a synthesis of each of the following substituted benzene derivatives, starting from 
 benzene.
(a) 
Cl
Br
 (b) 
CN
COOH
 (c) 
OH
NO2
O2N
Cl
 (d) 
OH
CN
(e) 
COOH
I
 (f) 
Cl
Br
Cl
Br
 (g) 
COOH
Br
Br Br
(a) 
NH2
SO3H
1. NaNO2, HCl, 5�C
2. HO
OH
Golden Yellow (b) 
NH2
SO3H
1. NaNO2, HCl, 5�C
2. 
NH
Metanil Yellow
 For the following reaction, assume that electrophilic substitution occurs preferentially on the most 
activated ring.
(c) 
OH
SO3H
Orange I
1. NaNO2, HCl, 5°C
2.
NH2
P r o b l e m s
1078 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
68. Show the reagents that would be necessary for the synthesis by diazo coupling of each of the 
following three compounds. For structures, see Section 22-11.
(a) Methyl Orange (b) Congo Red
(c) Prontosil, H2N
NH2
SO2NH2
N
N
J
, which is
converted microbially into sulfanilamide, H2N SO2NH2
 (The accidental discovery of the antibacterial properties of prontosil in the 1930s led indirectly 
to the development of sulfa drugs as antibiotics in the 1940s.)
69. (a) Give the key reaction that illustrates the inhibition of fat oxidation by the pre-
servative BHT. (b) The extent to which fat is oxidized in the body can be determined by measur-
ing the amount of pentane exhaled in the breath. Increasing the amount of vitamin E in the diet 
decreases the amount of pentane exhaled. Examine the processes described in Section 22-9 and 
identify one that could produce pentane. You will have to do some extrapolating from the specifi c 
reactions shown in the section.
70. The urushiols are the irritants in poison ivy and poison oak that give you rashes 
and make you itch upon exposure. Use the following information to determine the structures of 
urushiols I (C21H36O2) and II (C21H34O2), the two major members of this family of unpleasant 
compounds.
Urushiol II urushiol I
H2, Pd–C, CH3CH2OH
1. O3, CH2Cl2
2. Zn, H2OUrushiol II C23H38O2
Excess CH3I, NaOH
Dimethylurushiol II
Aldehyde A
CH3CH2CH2CH2CH2CH2CHO C16H24O3�
OCH3
Synthesis of Aldehyde A
1. SO3, H2SO4
2. HNO3, H2SO4
1. H2, Pd, CH3CH2OH
2. NaNO2, H�,H2O
3. H2O, �H�, H2O, �C7H7NSO6 C7H7NO3
B C
1. CO2, pressure, KHCO3, H2O
2. NaOH, CH3I
3. H�, H2O
1. LiAlH4, (CH3CH2)2O
2. H�, H2O
3. MnO2, acetoneC7H8O2
D
C9H10O4
E
1. C6H5CH2O(CH2)6CH
2. Excess H2, Pd–C, CH3CH2OH
3. PCC, CH2Cl2
C9H10O3
F 
aldehyde A
PP(C6H5)3
71. Is the site of reaction in the biosynthesis of norepinephrine from dopamine (see Chapter 5, 
Problem 65) consistent with the principles outlined in this chapter? Would it be easier or more 
diffi cult to duplicate this transformation nonenzymatically? Explain.
 C h a p t e r 2 2 1079
Team Problem
72. As a team, consider the following schemes that outline steps toward the total synthesis of taxo-
done D, a potential anticancer agent. For the fi rst scheme, divide your team into two groups, one 
to discuss the best option for A to effect the initial reduction step, the second to assign a structure 
to B, using the partial spectral data provided.
OHO
OCCH3
H3C
CH3CO
O
H
%
≥
B
O
B
OCCH3
B
H3C
CH3CO
O
H
%
≥
B
O
B
A H�, toluene, �
�1H NMR: 	 5.99 (dd, 1 H),
6.50 (d, 1 H) ppm.
IR: ˜� 	 1720 cm�1.
MS: m/z 	 384 (M�).
 Reconvene to discuss both parts of the fi rst scheme. Then, as a group, analyze the remainder of 
the synthesis shown in the second scheme below. Use the spectroscopic data to help you determine 
the structures of C and taxodone, D.
UV-Vis: �max (
) 	 316 (20,000) nm.
MS: m/z 	 316 (M�).
DB C
1H NMR: 	 3.51 (dd, 1 H),
3.85 (d, 1 H) ppm.
MS: m/z 	 400 (M�).
�
�OH, H2O
COOH
O
Cl
B
1H NMR: 	 6.55 (d, 1 H), 6.81 (s, 1 H) ppm,
no other alkenyl or aromatic signals.
IR: ˜
�
� 	 3610, 3500, 1628 cm�1.
Taxodone
 Propose a mechanism for the formation of D from C. (Hint: After ester hydrolysis, one of the 
phenoxide oxygens can donate its electron pair through the benzene ring to effect a reaction at 
the para position. The product contains a carbonyl group in its enol form. For the interpretation 
of some of the spectral data, see Section 17-3.)
Preprofessional Problems
73. After chlorobenzene has been boiled in water for 2 h, which of the following organic compounds 
will be present in greatest concentration?
P r o b l e m s
(a) C6H5OH (b) 
OH
Cl
 (c) 
OH
Cl
 (d) C6H5Cl (e) 
HCl
O
74. What are the products of the following reaction? C6H5OCH3 uy?
HI, DHI, D
(a) C6H5I 1 CH3OH (b) C6H5OH 1 CH3I (c) C6H5I 1 CH3I (d) 
OCH3
H2
I
�
1080 C h a p t e r 2 2 C h e m i s t r y o f B e n z e n e S u b s t i t u e n t s
75. The transformation of 4-methylbenzenediazonium bromide to toluene is best carried out
by using:
(a) H1, H2O (b) H3PO2, H2O (c) H2O, 
2OH (d) Zn, NaOH
76. What is the principal product after the slurry obtained on treating benzenamine (aniline) with 
potassium nitrite and HCl at 08C has been added to 4-ethylphenol?
(a) 
N
CH2CH3
NC6H5
OH
P
 (b) 
NHC6H5
CH2CH3
OH
 (c) 
N
CH2CH3
OH
NC6H5P
 (d) 
C6H5
CH2CH3
OH
77. Examination of the 1H NMR spectra of the following three isomeric nitrophenols reveals that one 
of them displays a hydroxy (phenolic) proton at substantially lower fi eld than do the other two. 
Which one?
(a) 
OH
NO2
 (b) 
OH
NO2
 (c) 
OH
NO2
	Chapter 22: CHEMISTRY OF BENZENE SUBSTITUENTS
	22-1: Reactivity at the Phenylmethyl (Benzyl) Carbon: Benzylic Resonance Stabilization
	22-2: Benzylic Oxidations and Reductions
	22-3: Names and Properties of Phenols
	Chemical Highlight 22-1: Two Phenols in the News: Bisphenol A and Resveratrol
	22-4: Preparation of Phenols: Nucleophilic Aromatic Substitutionnull
	22-5: Alcohol Chemistry of Phenols
	Chemical Highlight 22-2: Aspirin: A Phenyl Alkanoate Drug
	22-6: Electrophilic Substitution of Phenols
	22-7: An Electrocyclic
Reaction of the Benzene Ring: The Claisen Rearrangement
	22-8: Oxidation of Phenols: Benzoquinones
	Chemical Highlight 22-3: Chemical Warfare in Nature: The Bombardier Beetle
	22-9: Oxidation-Reduction Processes in Nature
	22-10: Arenediazonium Salts
	22-11: Electrophilic Substitution with Arenediazonium Salts: Diazo Coupling
	Chemical Highlight 22-4: William Perkin and the Origins of Industrial and Medicinal Chemistry
	Chapter Integration Problems
	New Reaction
	Important Conceptsnull
	Problems