21
Organic
Chemistry
William H. Brown &
Christopher S. Foote
21-1
21
Aromatics II
Chapter 21
21-2
21 Reactions of Benzene
 The
most characteristic reaction of aromatic
compounds is substitution at a ring carbon
Halogenation:
H + Cl 2
Fe Cl 3
Cl + HCl
Chlorobenzene
Nitration:
H + HN O 3
H2 SO 4
N O2 + H2 O
Nitrobenzene
21-3
21 Reactions of Benzene
Sulfonation:
H + SO 3
H 2 SO 4
SO 3 H
Benzenesulfonic acid
Alkylation:
H + RX
A lX3
R + HX
An alkylbenzene
Acylation:
H
+
O
RCX
A lX3
O
CR + HX
An acylbenzene
21-4
21 Electrophilic Aromatic Sub
 Electrophilic
aromatic substitution: a reaction in
which a hydrogen atom of an aromatic ring is
replaced by an electrophile
H
+
+ E
 We
E
+
+ H
study
• several common types of electrophiles
• how each is generated
• the mechanism by which each replaces hydrogen
21-5
21 Chlorination
Step 1: formation of a chloronium ion
••
Cl
••
••
••
••
Cl
••
+
Cl
Fe Cl
Cl
Chlorine
Ferric chloride
(a Lewis base) (a Lewis acid)
Cl
A molecular complex
with a positive
charge on chlorine
•• +
Cl FeCl4••
••
••
••
Cl
••
Cl
+
••
Cl Fe Cl
••
An ion pair
containing a
chloronium ion
21-6
21 Chlorination
Step 2: attack of the chloronium ion on the aromatic ring
+ Cl +
slow, rate
determining
+
H
H
H
+
Cl
Cl
+ Cl
Resonance-stabilized cation intermediate; the positive
charge is delocalized onto three atoms of the ring
Step 3: proton transfer regenerates the aromatic
character of the ring
+
H
+ Cl Fe Cl 3
fast
Cl + HCl + Fe Cl 3
Cl
Cation
intermediate
Chlorobenzene
21-7
21 EAS: General Mechanism
A
general mechanism
Step 1:
+
H + E
Electrophile
+
Step 2:
H
fast
slow, rate
determining
+
H
E
Resonance-stabilized
cation intermediate
E + H+
E
 General
question: what is the electrophile and
how is it generated?
21-8
21 Nitration
 The
electrophile is NO2+, generated in this way
: :
H
+
H O N O2 + HSO4
:
H O N O2 + H O SO 3 H
Nitric acid
H
:
+
H O: + :O= N= O:
Nitronium ion
:
N O2
:
:
H
H +O
21-9
21 Nitration
Step 1: attack of the nitronium ion (an electrophile) on
the aromatic ring (a nucleophile)
H
+
+ N O2
N O2
+
H
N O2
H
+
N O2
+
Resonance-stabilized cation intermediate
Step 2: proton transfer regenerates the aromatic ring
H
••
••
H2O
NO2
+
+
NO2
+
H3O+
Nitrobenzene
21-10
21 Nitration
A
particular value of nitration is that the nitro
group can be reduced to a 1° amino group
O2 N
COOH + 3 H2
Ni
(3 atm)
4-Nitrobenzoic acid
H2 N
COOH + 2 H2 O
4-Aminobenzoic acid
21-11
21 Sulfonation
 Carried
out using concentrated sulfuric acid
containing dissolved sulfur trioxide
+ SO 3
Benzene
H2 SO 4
SO 3 H
Benzenesulfonic acid
21-12
21 Friedel-Crafts Alkylation
 Friedel-Crafts
alkylation forms a new C-C bond
between an aromatic ring and an alkyl group
Cl
+
Benzene
AlCl3
+ HCl
2-Chloropropane
Cumene
(Isopropyl chloride) (Isopropylbenzene)
21-13
21 Friedel-Crafts Alkylation
Step 1: formation of an alkyl cation as an ion pair
R
Cl
-
Cl A l Cl
:
:
R
Cl : +
+
:
:
Cl
A l-Cl
Cl
Cl
+
-
R AlCl 4
An ion pair
containing
a carbocation
Step 2: attack of the alkyl cation on the aromatic ring
+
+ R
+
H
R
+
H
H
R
+ R
A resonance-stabilized cation
Step 3: proton transfer regenerates the aromatic ring
+
H
R
+ Cl AlCl 3
R + AlCl 3 + HCl
21-14
21 Friedel-Crafts Alkylation
 There
are two major limitations on Friedel-Crafts
alkylations
1. carbocation rearrangements are common
+
Benzene
Cl
Isobutyl
chloride
A lCl 3
+ HCl
tert-Butylbenzene
21-15
21 Friedel-Crafts Alkylation
• the isobutyl chloride/AlCl3 complex rearranges to the
tert-butyl cation/AlCl4- ion pair, which is the electrophile
CH3
CH3 CHCH2 - Cl + A lCl 3
Isobutyl chloride
CH3
+
-
CH3 C-CH2 - Cl- A lCl 3
H
Isobutyl chloride-aluminum
chloride complex
CH3
CH3 C+ AlCl 4 CH3
tert-Butyl cation/AlCl4ion pair
21-16
21 Friedel-Crafts Alkylation
2. F-C alkylation fails on benzene rings bearing one or
more of these strongly electron-withdrawing groups
O
CH
O
CR
O
COH
O
COR
SO 3 H
C N
N O2
N R3
CF3
CCl3
O
CNH 2
+
21-17
21 Friedel-Crafts Acylation
 Friedel-Crafts
acylation forms a new C-C bond
between a benzene ring and an acyl group
O
O
+ CH3 CCl
Benzene
AlCl3
Acetyl
chloride
Cl
+ HCl
Acetophenone
O
O
AlCl3
4-Phenylbutanoyl
chloride
+ HCl
-Tetralone
21-18
21 Friedel-Crafts Acylation
 The
electrophile is an acylium ion
••
O
••
R-C Cl
••
An acyl
chloride
Cl
+ Al-Cl
Cl
Aluminum
chloride
(1)
O + Cl
(2)
••
R-C Cl Al Cl
••
Cl
A molecular complex
with a positive charge
charge on chlorine
O
R-C+ AlCl4An ion pair
containing an
acylium ion
21-19
21 Friedel-Crafts Acylation
• an acylium ion is a resonance hybrid of two major
contributing structures
O:
:
+
R-C
complete valence
shells
+
R-C O:
The more important
contributing structure
 F-C
acylations are free of a major limitation of F-C
alkylations; acylium ions do not rearrange
21-20
21 Friedel-Crafts Acylation
A
special value of F-C acylations is preparation of
unrearranged alkylbenzenes
O
+ Cl
A lCl 3
2-Methylpropanoyl
chloride
O
N 2 H 4 , KOH
diethylene
glycol
2-Methyl-1Isobutylbenzene
phenyl-1-propanone
21-21
21 Other Aromatic Alkylations
 Carbocations
are generated by
• treatment of an alkene with a protic acid, most
commonly H2SO4, H3PO4, or HF/BF3
+
Benzene
CH3 CH=CH2
Propene
H3 PO4
Cumene
21-22
21 Other Aromatic Alkylations
• by treating an alkene with a Lewis acid
A lCl 3
+
Benzene
Cyclohexene
Phenylcyclohexane
• and by treating an alcohol with H2SO4 or H3PO4
+
Benzene
HO
H3 PO 4
2-Methyl-2-propanol
(tert- Butyl alcohol)
+ H2 O
2-Methyl-2phenylpropane
(tert-Butylbenzene
21-23
21 Di- and Polysubstitution
 Existing
groups on a benzene ring influence
further substitution in both orientation and rate
 Orientation:
• certain substituents direct preferentially to ortho &
para positions; others direct preferentially to meta
positions
• substituents are classified as either
ortho-para directing or meta directing
21-24
21 Di- and Polysubstitution
 Rate
• certain substituents cause the rate of a second
substitution to be greater than that for benzene itself;
others cause the rate to be lower
• substituents are classified as activating or deactivating
toward further substitution
21-25
21 Di- and Polysubstitution
• -OCH3 is ortho-para directing
OCH3
+ Br2
Anisole
OCH3
OCH3
Br
+
CH3 COOH
o-Bromoanisole
(4%)
+ HBr
Br
p-Bromo
anisole
(96%)
21-26
21 Di- and Polysubstitution
• -NO2 is meta directing
N O2
+ HN O 3
H2 SO 4
100°C
Nitrobenzene
N O2
N O2
N O2
N O2
+
+
+ H2 O
N O2
m-Dinitrobenzene
(93%)
o-Dinitrobenzene
N O2
p-Dinitrobenzene
Less than 7% combined
21-27
OR
Moderately
activating
O
N HCR
O
N HCAr
O
OCR
:
:
:
O
OCAr
R
N O2
N H3
+
I:
:
Moderately
deactivating
O
O
O
CH
CR
COH
O
CNH 2
SO 3 H
:
Br :
:
:
Cl :
:
:
F:
:
Weakly
deactivating
Strongly
deactivating
:
Weakly
activating
:
Meta Directing
:
OH
:
:
N R2
:
:
N HR
:
:
N H2
:
Strongly
activating
:
Ortho-para Directing
21 Di- and Polysubstitution
O
COR
C N
CF3
CCl3
21-28
21 Di- and Polysubstitution
 From
the information in Table 21.1, we can make
these generalizations
• alkyl, phenyl, and all other groups in which the atom
bonded to the ring has an unshared pair of electrons
are ortho-para directing. All other groups are meta
directing
• all ortho-para directing groups except the halogens are
activating toward further substitution. The halogens
are weakly deactivating
21-29
21 Di- and Polysubstitution
• the order of steps is important
CH3
COOH
HNO3
K2 Cr 2 O7
H2 SO4
H 2 SO4
CH3
NO2
NO2
p-Nitrobenzoic
acid
COOH
COOH
K2 Cr 2 O7
HNO3
H2 SO4
H2 SO4
NO2
m-Nitrobenzoic
acid
21-30
21 Theory of Directing Effects
 The
rate of EAS is limited by the slowest step in
the reaction
 For almost every EAS, the rate-determining step
is attack of E+ on the aromatic ring to give a
resonance-stabilized cation intermediate
 The more stable this cation intermediate, the
faster the rate-determining step and the faster the
overall reaction
21-31
21 Theory of Directing Effects
 For
ortho-para directors, ortho-para attack forms
a more stable cation than meta attack
• ortho-para products are formed faster than meta
products
 For
meta directors, meta attack forms a more
stable cation than ortho-para attack
• meta products are formed faster than ortho-para
products
21-32
21 Theory of Directing Effects
• -OCH3; assume meta attack
OCH3
+ N O2
+
OCH3
+
H
N O2
(a)
slow
OCH3
+
H
N O2
(b)
OCH3
fast
H - H+
+ N O2
(c)
OCH3
N O2
21-33
21 Theory of Directing Effects
• -OCH3: assume ortho-para attack
OCH3
OCH3
slow
+ N O2 +
: OCH3
:
:
: OCH3
:
:
+
: OCH3
OCH3
+
N O2
(d)
fast
- H+
+
H
N O2
+
H
N O2
(e)
N O2
H
(f)
H
N O2
(g)
21-34
21 Theory of Directing Effects
• -NO2; assume meta attack
N O2
+ N O2
+
N O2
N O2
+
H
N O2
(a)
slow
N O2
N O2
+
H
N O2
(b)
fast
H - H+
+ N O2
(c)
N O2
21-35
21 Theory of Directing Effects
• -NO2: assume ortho-para attack
N O2
+ N O2 + slow
N O2
+
N O2
H
(d)
N O2
N O2
+
H
N O2
(e)
+
H
N O2
fast
- H+
N O2
(f)
N O2
21-36
21 Activating-Deactivating
 Any
resonance effect, such as that of -NH2, -OH,
and -OR, that delocalizes the positive charge on
the cation intermediate lowers the activation
energy for its formation, and has an activating
effect toward further EAS
 Any resonance or inductive effect, such as that of
-NO2, -CN, -CO, or -SO3H, that decreases electron
density on the ring deactivates the ring toward
further EAS
21-37
21 Activating-Deactivating
 Any
inductive effect, such as that of -CH3 or other
alkyl group, that releases electron density toward
the ring activates the ring toward further EAS
 Any inductive effect, such as that of -halogen, NR3+, -CCl3, or -CF3, that decreases electron
density on the ring deactivates the ring toward
further EAS
21-38
21 Halogens
• for the halogens, the inductive and resonance effects
run counter to each other, but the former is somewhat
stronger
• the net effect is that halogens are deactivating but
ortho-para directing
:Cl
+
H
E
+
:Cl
:
+ E
: :
: :
: Cl
+
H
E
21-39
21 Nucleophilic Aromatic Sub.
 Aryl
halides do not undergo nucleophilic
substitution by either SN1 or SN2 pathways
 They do undergo nucleophilic substitutions, but
by mechanisms quite different from those of
nucleophilic aliphatic substitution
 Nucleophilic aromatic substitutions are far less
common than electrophilic aromatic substitutions
21-40
21 Benzyne Intermediates
 When
heated under pressure with aqueous NaOH,
chlorobenzene is converted to sodium
phenoxide. Neutralization with HCl gives phenol.
-
Cl
+
O Na
+ 2 NaOH
Chlorobenzene
H2 O
o
pressure, 300 C
+ NaCl + H2 O
Sodium
phenoxide
21-41
21 Benzyne Intermediates
• the same reaction with 2-chlorotoluene gives a mixture
of ortho- and meta-cresol
CH3
CH3
CH3
OH
Cl 1 . Na OH, heat, pressure
2 . HCl, H2 O
+
2-Methylphenol
(o-Cresol)
OH
3-Methylphenol
(m-Cresol)
• the same type of reaction can be brought about using
of sodium amide in liquid ammonia
CH3
CH3
+ N aN H2
Cl
N H3 ( l)
(-33 oC)
N aCl +
CH3
+
N H2
4-Methylaniline
(p-Toluidine)
N H2
3-Methylaniline
(m-Toluidine)
21-42
21 Benzyne Intermediates
• -elimination of HX gives a benzyne intermediate, that
then adds the nucleophile to give products
CH3
CH3
NaNH 2
H
Cl
-elimination
A benzyne
intermediate
21-43
21 Nu Addition-Elimination
• when an aryl halide contains electron-withdrawing NO2
groups ortho and/or para to X, nucleophilic aromatic
substitution takes place readily
-
Cl
NO2
Na2 CO3 , H2 O
+
O Na
NO2
1 0 0 oC
NO2
1-Chloro-2,4dinitrobenzene
NO2
Sodium 2,4-dinitrophenoxide
• neutralization with HCl gives the phenol
21-44
21 Meisenheimer Complex
• reaction involves a Meisenheimer complex
intermediate
O
Cl +
–
O
••
+N
slow, rate
determining
Nu
(1)
NO2
–
O
+N
O
–
Cl
Nu
NO2
fast
(2)
O
+N
–
O
Nu + :Cl
NO2
A Meisenheimer complex
21-45
21 Prob 21.7
Write a mechanism for each reaction.
Cl
(a)
+
(b)
(c)
(d)
Cl
+
O
O
+
Fe Cl 3
Cl 2
A lCl 3
SnCl 4
Cl
+ CH2 Cl 2
+ 2 HCl
A lCl 3
+ 2 HCl
O
O
+ 2 HCl
+ 2 HCl
21-46
21 Prob 21.8
Offer an explanation for the preferential nitration of
pyridine in the 3 position rather than the 2 position.
+ HNO 3
N
Pyridine
H2 SO 4
300°C
NO2
N
3-Nitropyridine
+ H2 O
21-47
21 Prob 21.9
Offer an explanation for the preferential nitration of
pyrrole in the 2 position rather than in the 3 position.
+
N
H
Pyrrole
HN O 3
CH3 COOH
5°C
+
NO2
N
H
2-Nitropyrrole
H2 O
21-48
21 Prob 21.15
Predict the major product(s) from treatment of each
compound with HNO3/H2SO4.
OCH 3
(a)
N O2
(b)
CH 3
N O2
N O2
CH 3
(c)
(d)
OH
21-49
21 Prob 21.16
Account for the fact that N-phenylacetamide is less
reactive toward electrophilic aromatic substitution than
aniline.
O
N HCCH 3
N-Phenylacetamide
(Acetanilide)
NH2
Aniline
21-50
21 Prob 21.17
Propose an explanation for the fact that the
trifluoromethyl group is meta directing.
CF3
CF3
+
HN O 3
H2 SO 4
+
H2 O
N O2
21-51
21 Prob 21.19
Arrange the compounds in each set in order of decreasing
reactivity toward electrophilic aromatic substitution.
O
OCCH 3
(a)
(A)
(b)
(C)
(B)
N O2
(A)
O
COCH 3
COOH
(B)
(C)
21-52
21 Prob 21.19 (cont’d)
Arrange the compounds in each set in order of decreasing
reactivity toward electrophilic aromatic substitution.
(c)
CH3
(A)
(d)
CH2 Cl
(B)
Cl
(A)
(e)
(B)
N H2
(A)
C N
O
N HCCH 3
(B)
CHCl 2
(C)
OCH2 CH3
(C)
O
CNH CH 3
(C)
21-53
21 Prob 21.20
Draw a structural formula for the major product of
nitration of each compound.
O
N HCCH 3
OCH3
(a)
(b)
COOH
CH3
SO 3 H
(c)
(d)
Cl
CH3
CH3
CH3
O
CCH3
(e)
(f)
(g)
OCH3
COOH
N O2
(h)
Cl
COOH
N HCCH 3
O
21-54
21 Prob 21.21
Which ring in each compound undergoes electrophilic
aromatic substitution more readily? Draw the product of
nitration of each compound.
O
(a)
CNH
(b) O 2 N
O
(c)
CO
21-55
21 Prob 21.22
Propose a mechanism for the formation of bisphenol A.
2
O
OH + CH3 CCH3
H3 PO4
CH3
HO
C
OH
+ H2 O
CH3
Bisphenol A
21-56
21 Prob 21.23
Propose a mechanism for the formation of BHT.
OH
OH
+
H3 PO4
4-Methylphenol 2-Methyl(p-Cresol)
propene
2,6-Di-tert-butyl-4-methylphenol
"Butylated hydroxytoluene"
(BHT)
21-57
21 Prob 21.24
Propose a mechanism for the formation of DDT.
2
O
H2 SO 4
Cl + Cl 3 CCH
Chlorobenzene
Trichloroacetaldehyde
Cl
CH
CCl3
DDT
Cl + H2 O
21-58
21 Prob 21.27
Propose a mechanism for this reaction.
O
+
O
O
Succinic
anhydride
O
H3 PO4
COOH
4-Oxo-4-phenylbutanoic acid
21-59
21 Prob 21.28
Account for the regioselectivity of the nitration in Step 1,
and propose a mechanism for Step 2.
Cl
Cl
HNO3
(1)
CF3
O2 N
N
NO2
CF3
N
H
(2)
O2 N
NO2
CF3
Trifluralin B
21-60
21 Prob 21.29
Propose a mechanism for the displacement of chlorine by
(1) the NH2 group of the dye and (2) an -OH group of
cotton.
Cl
N
Cl
Dye-NH2
N
N
Cl
O-cotton
Cl
Cyanuryl chloride
N
N
Cl
Dye-NH N
A reactive dye
HO-cotton
N
N
O-cotton
Dye-NH N
Dye covalently
bonded to cotton
21-61
21 Prob 21.31
Show how to prepare (a) and (b) from 1-phenyl-1propanone.
O
O
O
Br
Br
1-Phenyl-1-propanone
(Propiophenone)
(a)
(b)
21-62
21 Prob 21.33
Show how to bring about each conversion.
CH3
COOH
(a)
OH
OCH2 CH3
(b)
COOH
Cl
(c)
OCH3
N O2
OCH3
(d)
N O2
CH2 CH3
CH= CH2
OCH3
O2 N
CCH3
O
(e)
21-63
21 Prob 21.35
Propose a synthesis for each compound from benzene.
H
N
(a)
(b)
Cl
O
Cl
21-64
21 Prob 21.36
Propose a synthesis of 2,4-D from chloroacetic acid and
phenol.
O
COOH
OH
Cl
OH
Cl
Cl
COOH +
Cl
2,4-Dichlorophenoxyacetic acid
(2,4-D)
Cl
Chloroacetic
acid
Phenol
21-65
21 Prob 21.41
Propose a synthesis of this compound from benzene.
O
4-Isopropylacetophenone
21-66
21 Prob 21.42
Propose a synthesis of this compound from 3methylphenol.
O2 N
N O2
OCH3
21-67
21 Prob 21.43
Propose a synthesis of this compound from toluene and
phenol.
NH2
O
Br
O
Cl
21-68
21 Prob 21.44
Propose a mechanism for this example of
chloromethylation (introduction of a CH2Cl group on an
aromatic ring). Show how to convert the product of
chloromethylation to piperonal.
+ CH2 O + HCl
chloromethylation
O
O
CHO
CH2 Cl
?
O
O
O
O
Piperonal
21-69
21 Prob 21.45
Given this retrosynthetic analysis, propose a synthesis
for Dinocap from phenol and 1-octene.
Hexyl
O
O2 N
Hexyl
O
N O2
OH
(1)
O2 N
(2)
N O2
Dinocap
OH
O2 N
(3)
OH
N O2
21-70
21 Prob 21.46
Show how to synthesize this trichloro derivative of
toluene from toluene.
N
Cl
N
Cl
Cl
Cl
O
Cl
Cl
Miconazole
Cl
2,4-Dichloro-1chloromethylbenzene
CH3
Toluene
21-71
21 Prob 21.47
Given this retrosynthetic analysis, propose a synthesis
for bupropion.
O
Cl
H
N
O
Cl
Br
Bupropion
O
Cl
21-72
21
Aromatics II
End Chapter 21
21-73