2-1

Reactions of Aromatic
Compounds

15.1
2-2

Electrophilic Aromatic Substitution Reactions

Aromatic hydrocarbons (= arenes) undergo a substitution reaction with electrophiles:

catalyst E
+ E + H

Example: Bromination of benzene

FeBr 3 Br
+ Br––Br

Review: Alkenes undergo addition reactions:

Br
+ Br––Br F
Br

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.1
2-3

X2, FeX 3 X
+ HX
X = Cl, Br

NO 2
HNO 3
+ H 2O
H 2SO 4

SO 3 SO 3H

H 2SO 4

RCl R
+ HCl
AlCl3

O
ROCl R
+ HCl
AlCl3

15.2
2-4

General Mechanism for EAS: Arenium Ions

Step 1: The electrophile attacks the
-system of benzene to form a non-aromatic
cyclohexadienyl carbocation:

H
+ E
E A + A

Step 2: The proton is removed to reform the aromatic delocalized
-system:

H
E
E
+ A + H––A

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.2
2-5

H
E
E
+ E A + H––A

+ A

15.3
2-6

Halogenation of Benzene

FeCl 3 Cl
+ Cl––Cl
25°C
F

FeBr 3 Br
+ Br––Br
heat

Mechanism:

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.4
2-7

Nitration of Benzene

HNO 3, H 2SO 4 NO 2
F
50°C

Mechanism:

15.5
2-8

Sulfonation of Benzene

SO 3, H 2SO 4 SO 3H
F

Mechanism:

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.6
2-9

Friedel-Crafts Alkylation

AlCl3 R
+ R X F

Mechanism:

2-10

The carbocation intermediate can be also generated through protonation of an alkene,

HF
+ F
0°C

or starting from an alcohol in the presence of a Lewis acid (BF3):

OH BF 3
+ F
60°C

Limitation: rearrangement reactions of carbocation intermediate:

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.7
2-11

Friedel-Crafts Acylation

O
O
AlCl3 F
+
Cl

acetophenone
Mechanism:

15.7
2-12

Friedel-Crafts acylations can be also carried using carboxylic acid anydrides:

O
O O O
1. AlCl3 F
+ +
O OH
2. H 2O
acetic anhydride

Mechanism:

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.8
2-13

Limitations of Friedel-Crafts Reactions

1. Rearrangement to more stable carbocation intermediate:

AlCl3
+ Br + F

36% 64%

2. Vinyl or aryl halide do not form stable carbocations:

AlCl3
+
Cl

Cl AlCl3
+

15.8
2-14

3. Aldehydes are not accessible through Friedel-Crafts reactions:

O
AlCl3
H Cl

4. Poor yields with electronwithdrawing substituents:

O OH O R
NO 2 N(CH 3)3 CF3 SO 3H NH 2

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.8
2-15

5. Polyalkylation often occur:

Cl
AlCl3
+

15.8
2-16

Clemmensen Reduction

Problem (slide 2-13):

AlCl3
+ Br +

36% 64%

Solution: Friedel-Crafts acylation followed by Clemmensen reduction:

O
O
AlCl3
+
Cl

O
Zn(Hg)/HCl

reflux F

Note: only arylketones (or aldehydes) are reduced (e.g. carboxylic acids remain unaffected)

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-17

Problem (15.32): Starting from benzene, outline a synthesis for

a) tert-butyl benzene:

b) 1-phenyl-2-methylbutane:

2-18

Problem: Propose a synthesis of
-tetralone starting from benzene and succinic anhydride:

O O

+ O

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.10, 15.11
2-19

Effect of Substituents on Reactivity and Orientation

Substituents affect both the rate of reaction (kinetics) and the site of attack (regioselectivity)

OCH3 CH3 H Cl NO 2

1000 25 1 0.03 0.001

activation
deactivation

15.10, 15.11
2-20

1. Activating Groups: Ortho/Para Directors

Alkyl substituents:

CH3 CH3 CH3 CH3

HNO 3 NO 2
+ +
H 2SO 4
NO 2
toluene NO 2

59% 4% 37%

-donors (e.g. -OH, -OR, NH2, NR2):

NH 2 NH 2
Br 2 Br Br

H 2O
aniline Br

>99%

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.10, 15.11
2-21

The rate determining step in electrophilic aromatic substitution of substituted benzenes

is the step that results in the formation of the arenium ion.

Because this step is endothermic, there is a strong resemblance between the arenium
cation and the transition state leading to it (Hammond-Lefer postulate)

15.10, 15.11
2-22

H
+ E
E A + A
Q Q

Effect of electronwithdrawing (left) and electrondonating substituents (right) on the free

energy proles for the formation of the arenium ion:

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.10, 15.11
2-23

CH3 CH3 CH3

H Br H Br H Br

CF3 CF3 CF3

H Br H Br H Br

15.10, 15.11
2-24

H
+ E
E A + A
H 3C H 3C

Alkyl groups: stabilization through inductive effect (hyperconjugation):

CH3 CH3 CH3

para attack:

H E H E H E

CH3 CH3 CH3

H H H
ortho attack: E E E

CH3 CH3 CH3

meta attack:
E E E
H H H

Stabilization of the arenium ion intermediate yields a lower activation barrier and thus
the fastest reaction pathway for ortho and para substitution.

CHEM 2312 Spring 2016 Notes: C.J. Fahrni
 15.10, 15.11
2-25

-donors: resonance stabilization of arenium ion

OH OH OH OH

para attack:

H E H E H E H E

OH OH OH OH
H H H H
ortho attack: E E E E

OH OH OH

meta attack:
E E E
H H H

Electron donating resonance stabilization applies with decreasing strength in the 

following order:

NR 2 NH 2 > OR OH > X

15.10, 15.11
2-26

2. Deactivating Groups: Meta Directors

NO 2 NO 2 NO 2 NO 2
HNO 3 NO 2
+ +
H 2SO 4
NO 2
nitrobenzene NO 2

6% 93% 1%

Electronwithdrawing substituents (-NO2, -CN, -COOH, -CHO, -COR, -CONR2, -SO3H)

destabilize the arenium ion intermediate.

O O O O O O
N N N
H
E
E
H E H

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.10, 15.11
2-27

CF3 CF3 CF3

para attack:

H E H E H E

CF3 CF3 CF3

H H H
ortho attack: E E E

CF3 CF3 CF3

meta attack:
E E E
H H H

Meta substitution yields the least destabilized intermediate and therefore the fastest
reaction pathway.

15.10, 15.11
2-28

3. Halo Substituents: Deactivating Ortho/Para Directors

Cl Cl Cl Cl
Cl2 Cl
+ +
FeCl 3
Cl
chlorobenzene Cl

39% 6% 55%

Cl Cl Cl Cl
HNO 3 NO 2
+ +
H 2SO 4
NO 2
chlorobenzene NO 2

30% 0% 70%

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.10, 15.11
2-29

Cl Cl Cl Cl

para attack:

H E H E H E H E

Cl Cl Cl Cl
H H H H
ortho attack: E E E E

Cl Cl Cl

meta attack:
E E E
H H H

Halo substituents stabilize the arenium ion intermediate through resonance

(
-donation):

15.10G, Table 15.2
2-30

Effect of Substituents: Overview

Ortho/Para Directors
Meta Directors

Strongly activating:
Strongly deactivating:

––NH2, ––NHR, ––NR2
––NO2

––OH, ––O––
––NR3+

––CF3, ––CCl3

Moderately activating:

––NHCOCH3, ––NHCOR
Moderately deactivating:

––OCH3, ––OR
––CN

––SO3H

Weakly activating:
––CO2H, CO2R

––CH3, ––C2H5, ––R
––CHO, ––COR

––C6H5

Weakly deactivating:

––F, ––Cl, ––Br, ––I

F

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.10, 15.11
2-31

Examples:
OCH3
Br 2

AlBr3

CF3
HNO 3

H 2SO 4

O
Br 2

FeBr 3

O
CH3COCl

AlCl3

CH3I

AlCl3

15.14B
2-32

Directing Effects on Disubstituted Rings

CH3 CH3
CH3COCl

AlCl3 F

CH3 CH3

CH3 CH3
Br 2
F
FeBr 3
NO 2 NO 2

CH3 CH3
HNO 3

H 2SO 4 F
C(CH3)3 C(CH3)3

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.14B
2-33

CH3 CH3
HNO 3
F
H 2SO 4
CH3 CH3

OCH3 OCH3
Br 2
F
HOAc
CH3 CH3

CHO CHO
HNO 3
F
H 2SO 4
OCH3 OCH3

15.14A
2-34

NH 2
HNO 3
F
H 2SO 4

Solution:

NH 2
CH3COCl
F
pyridine

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.12
2-35

Reactions of the Side Chain of Alkylbenzenes

1. Halogenation of the side chain:

NBS, light
F
CCl4

2. Addition to the double bond of alkenyl benzenes:

HBr
F
peroxides

HBr

(no peroxides) F

15.13
2-36

3. Oxidation of the side chain:

CH3 1. KMnO 4, NaOH, heat F

2. H 3O+

Alkyl, alkynyl, and acyl benzenes are also degraded to benzoic acid:

CH2R

CH3

1. KMnO 4, NaOH, heat

F
2. H 3O+

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-37

Problem (15.36): Explain why the following syntheses will fail:

1. HNO 3/H2SO 4 NO 2
2. CH3COCl/AlCl3

3. Zn(Hg)/HCl

1. NBS, CCl4, light

2. NaOEt, EtOH, heat

3. Br 2, FeBr 3
Br

15.14
2-38

Synthetic Strategies

1. Introducing substituent through electrophilic aromatic substitution:

R
R = ––Cl, ––Br, ––I, SO 3H, ––NO2, ––COR, ––alkyl

2. Modifying existing substituents:

––CO2H from ––alkyl

R1 R2 ––CH2R from ––COR
––CH2Br from CH3
––CH2OH from CH2Br

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 15.14
2-39

3. Using protective groups

Highly activating substituents such as ––NH2, ––NR2, and ––OH render the aromatic ring so
reactive that undesirable reactions may take place.

=> Reduce reactivity through a protective group:

O O

NH 2 HN HN NH 2
1. H 2O, H 2SO 4
CH3COCl heat
base 2. NaOH
R R

4. Orientation in disubstituted benzenes:

=>
Consider directing effects of other substituents and effect of reagents/conditions on

existing substituents

2-40

Problem (15.32j): Starting from benzene, outline a synthesis for p-bromonitrobenzene

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-41

Problem: Starting from benzene, outline a synthesis for m-chloroethylbenzene.

2-42

Problem: Starting from benzene, outline a synthesis for p-nitrobenzoic acid.

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-43

Problem (15.34e):
Starting from toluene, outline a synthesis for 1-chloro-3-trichloromethyl-

benzene.

20.4B
2-44

Anilines: Synthesis and Reactivity

Anilines can be prepared through reduction of nitro compounds:

NO 2 NH 2
reducing
HNO 3 reagent
F
H 2SO 4

reducing reagents
a) (1) Fe, HCl; (2) NaOH
b) (1) Zn, HCl; (2) NaOH
c) SnCl2
d) H 2/Pt (catalyst)
e) H 2S, NH 3, EtOH

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 20.6-7
2-45

Anilines react with nitrous acid to form diazonium salts, which can be converted  F
to a wide range of derivatives:

HBF 4, heat F

CuCl Cl

CuBr Br

N
NH 2 NaNO 2 N KI I

HCl
CuCN CN

H 3PO 2 H

Cu2O, Cu2+ OH

20.6
2-46

Mechanism of diazotization:

N
NH 2 NaNO 2 N

HCl

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-47

Problem: Starting from benzene, outline a synthesis for 3-chlorophenol.

OH

Cl

2-48

Problem: Suggest a synthesis for 1,3,5-tribromobenzene.

Br

Br Br

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 20.8
2-49

Diazo coupling: reaction of diazonium salts with electron-rich arenes:
F

Cl G
N
N G
+ N
N

G = ––NR2 or ––OH

20.8
2-50

Azo compounds have found a wide range of applications:

OH SO 3Na H 2N NH 2

N N N
N COONa N N
O
O2N N O S
Alizarine Yellow R Methyl orange NH 2 Prontosil
(pH Indicator) (pH Indicator) (antibiotic )

OH NO 2
COOEt N
N
N SO 3Na
N SO 3Na SO 3Na
N
N
N
O N
NaO 3S SO 3Na OH
OH
Orange B Orange G Eriochrome Black T
(food dye) (histological stain) (complexometric Indicator)

NH 2 H 2N
OH HO
NaO 3S SO 3Na
N N
N N
SO 3Na NaO 3S

Trypan Blue
(vital stain to selectively color dead cells)
The Trypan Blue exclusion assay
identies dead cells

CHEM 2312 Spring 2016 Notes: C.J. Fahrni
 21.1
2-51

Phenols

Nomenclature:

OH OH OH
OH

Cl
phenol m-chlorophenol 1-naphthol 2-naphthol
F

OH OH OH
CH3

CH3
CH3
p-cresol m-cresol o-cresol

OH OH OH
OH

OH
OH
hydroquinone resorcinol catechol

21.5
2-52

Phenols: Acidity

OH O

+ H 2O + H 3O pK a = 9.89

phenol phenolate anion

OH OH OH OH OH OH
NO 2 O2N NO 2

CH3 Cl NO 2 NO 2 NO 2

pK a = 18 10.17 8.11 7.15 3.96 0.38

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 21.5
2-53

transition state
G =
RT ln K a

free energy

G‡‡,
[H 3O + ][A –– ]
Ka =
[HA][H 2O]
HA + H2O

G

A–– + H3O+

reaction

coordinate

Electron withdrawing substituents stabilize the negatively charged phenolate anion

Electron donating substituents destabilize the negatively charged phenolate anion

21.5
2-54

The degree of resonance stabilization depends on the substituent position:

pK a = 7.15

N
O O

pK a = 8.28
O
N
O

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-55

Problem: Order the following compounds with increasing pKa:

OH OH OH

NH N N

21.4
2-56

Phenols: Synthesis

1. Hydrolysis of aryldiazonium salts (slide 2-45)

N OH
NH 2 NaNO 2 N Cu2O, Cu2+

HCl H 2O

2. Industrial syntheses:

Cl NaOH O ––Na +
Cl2
F
Fe 350°C
high pressure

OOH
O2 H 2SO 4 OH

H 3PO 4 95-135°C 50-90°C

250°C

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 21.6
2-57

Phenols: Reactions

1. Phenol oxygen as nucleophile:

O
OH
Cl

pyridine

O O
F
OH
O

pyridine

OH
1. NaOH, H 2O conc. HBr
F
2. R––Br

21.8
2-58

2. Aromatic
-system as nucleophile:

OH
excess Br 2

OH
HNO 3

H 2SO 4

OH
conc. H 2SO 4

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 21.8
2-59

Kolbe Reaction:

OH O OH O
1. NaOH 2. CO2 3. H 3O+
O

Mechanism:

2-60

Problem: Starting from phenol, suggest a synthesis for Aspirin

O O

OH Aspirin

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-61

Problem: Starting from phenol, suggest a synthesis for acetaminophen (Tylenol)

OH

Acetaminophen
NH

21.9
2-62

The Claisen Rearrangement

OH O OH
Br
heat F

NaOH

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 21.11B
2-63

Aryl Halides: Nucleophilic Aromatic Substitution

Hydrolysis reaction of halides:

H 2O
Cl r.t. OH

Cl H 2O

r.t.

Aryl halides undergo substitution only under more drastic reaction conditions:

Cl NaOH OH
F
350°C

Cl KNH 2 NH 2
F

21.11B
2-64

Labeling experiment:

14 Cl K +NH 2–– 14 NH 2 14 H
C C C
+
NH 3 (l)
NH 2

The Benzyne Elimination-Addition Mechanism:

Br Br
F
H

phenyl anion benzyne

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 21.11A
2-65

Electronwithdrawing substituents greatly facilitate the hydrolysis of aryl halides:

Cl OH
NO 2 NaOH NO 2

130°C

Cl OH
NO 2 NaOH NO 2
F
100°C

NO 2 NO 2

Cl OH
O2N NO 2 NaOH O2N NO 2

35°C

NO 2 NO 2

Note: a meta-nitro group does not produce a similar activating effect

=> underlying mechanism is different from hydrolysis of unsubstituted halides

Effect of Halide: Reaction rate decreasing with F >>

21.11A
2-66

Addition-Elimination Mechanism:

Cl

+ OH

N
O O

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-67

Problem: Rank the following compounds in descending order of reactivity toward hydroxide ion:

Br Br Br Br Br
NO 2 NO 2

NO 2 NO 2
NO 2 NO 2 NO 2

I II III IV V

2-68

Problem: Propose a mechanism for the following conversion:

NO 2
OH NaOCH 3 O

H 3C S H 3C SO2
O O NO
2
Na

CHEM 2312 Spring 2016 Notes: C.J. Fahrni

 2-69

Problem: Predict the main product(s) of the following reactions:

Cl
NO 2 H 2NNH 2

NO 2

Cl
Cl NO 2 NaOCH 3

CH3OH

NO 2

Cl
LiNEt 2

HNEt 2

CH3

2-70

Problem (21.19) The following scheme outlines the synthesis of the
-blocker toliprolol. Give the
structures of the intermediates and the nal product.

OH O
Cl
OH NH 2
C10H13 O2Cl C10H12 O2 C13H 21NO 2
toliprolol
CH3

CHEM 2312 Spring 2016 Notes: C.J. Fahrni