The Benzene Ring as a Substituent

Chapter 12
Substituted benzenes

allylic radical

benzylic radical

benzylic carbon is analogous to allylic carbon

Resonance in Benzyl Radical

Resonance in Benzyl Radical

H
C

unpaired electron is delocalized between

benzylic carbon and the ring carbons that are
ortho and para to it

unpaired electron is delocalized between

benzylic carbon and the ring carbons that are
ortho and para to it

Resonance in Benzyl Radical

Resonance in Benzyl Radical

C
H

H
C

unpaired electron is delocalized between

benzylic carbon and the ring carbons that are
ortho and para to it

unpaired electron is delocalized between

benzylic carbon and the ring carbons that are
ortho and para to it

Free--radical chlorination of toluene

Free

Free--radical chlorination of toluene

Free

industrial process
highly regioselective for benzylic position

Similarly, dichlorination and trichlorination are

selective for the benzylic carbon.
carbon Further
chlorination gives:

Cl2
CH3

Toluene

light
or
heat

CH2Cl

Benzyl chloride

CHCl2

(Dichloromethyl)benzene

CCl3

(Trichloromethyl)benzene

Benzylic Bromination

N-Bromosuccinimide (NBS)

is used in the laboratory to introduce a

halogen at the benzylic position

is a convenient reagent for benzylic bromination

Br

CH2Br

CH3

CH2CH3

O
+ Br2
NO2

CCl4, 80
80C

+ HBr

light
NO2

p-Nitrotoluene

CCl4

NBr +

benzoyl
peroxide,
heat

CHCH3

O
NH +
O

p-Nitrobenzyl
bromide (71%)

(87%)

Site of Oxidation is Benzylic Carbon

CH3
or

Na2Cr2O7
H2SO4

Oxidation of Alkylbenzenes
CH2R
or
CHR2

H2O
heat

O
COH

Example

Example
O
O

COH

CH(CH3)2
Na2Cr2O7
H2SO4

COH

CH3
Na2Cr2O7
H2SO4

H2O
heat

H2O
heat

CH3

NO2

COH

NO2

p-Nitrotoluene

p-Nitrobenzoic
acid (82
(82--86%)

(45%)

Primary Benzylic Halides

O2N
Nucleophilic Substitution

CH2Cl
O

Mechanism is SN2

in Benzylic Halides
NaOCCH3
acetic acid
O
O2N

CH2OCCH3

(78--82%)
(78

What about SN1?

What about SN1?

Relative solvolysis rates in aqueous acetone

CH3
C

CH3
Cl

CH3

CH3

CH3
Cl

CH3

C+

CH3

CH3

CH3

600

Relative rates of formation:

C+
CH3

more stable
t bl

less stable

tertiary benzylic carbocation is formed

more rapidly than tertiary carbocation;
therefore, more stable

Resonance in Benzyl Cation

Compare.

H
C
C

C+

allylic carbocation

C+

+
C

benzylic carbocation
H

benzylic carbon is analogous to allylic carbon

unpaired electron is delocalized between

benzylic carbon and the ring carbons that are
ortho and para to it

Resonance in Benzyl Cation

Resonance in Benzyl Cation

+
H

unpaired electron is delocalized between

benzylic carbon and the ring carbons that are
ortho and para to it

unpaired electron is delocalized between

benzylic carbon and the ring carbons that are
ortho and para to it

Resonance in Benzyl Cation

Solvolysis
CH3

Cl

C
H

CH3

+
H

H
H

unpaired electron is delocalized between

benzylic carbon and the ring carbons that are
ortho and para to it

CH3CH2OH
CH3
C
CH3

OCH2CH3
(87%)

Nomenclature

Phenols

Nomenclature

Nomenclature

OH
OH

CH3
5-Chloro
Chloro--2-methyl
methylphenol
phenol

OH

OH

OH

Cl
OH

named on basis of phenol as parent

OH

substituents listed in alphabetical order

lowest numerical sequence: first point of
difference rule

1,2--Benzenediol
1,2

1,3--Benzenediol
1,3

1,41,4-Benzenediol

(common name:

(common name:

(common name:

pyrocatechol)

resorcinol)

hydroquinone)

Nomenclature
OH

p-Hydroxybenzoic acid

CO2H
name on basis of benzoic acid as parent

Physical Properties

The OH g
group
p of p
phenols allows hydrogen
y g bonding
g
to other phenol molecules and to water.

higher oxidation states of carbon outrank

hydroxyl group

Hydrogen Bonding in Phenols

O H

Physical Properties

O
Compared to compounds of similar size and
molecular weight, hydrogen bonding in phenol
raises its melting point, boiling point, and
solubility in water.

Physical Properties

C6H5CH3

C6H5OH

C6H5F

Molecular weight

92

94

96

Melting point ((C)

95

43

41

Boiling
point ((C,1 atm)

111

132

85

Solubility in
H2O (g/100 mL,25
mL,25C)

0.05

8.2

0.2

Acidity of Phenols

Compare

most characteristic property of

phenols is their acidity

Delocalized negative charge in phenoxide ion

O

H
Ka = 10-10
H

+ +

O
H

CH3CH2O

Ka = 10-16
H

H

+ + CH CH O

H
3
2

H
H

H
H

Delocalized negative charge in phenoxide ion

Delocalized negative charge in phenoxide ion

H
H

+ HO

stronger acid

Substituent Effects
on the
Acidity of Phenols
+ H2O
weaker acid

H
H

Phenols are converted to phenoxide ions

in aqueous base

Electron--releasing groups have little or no effect

Electron

OH

Ka:

1 x 10-10

OH

OH

CH3

OCH3

5 x 10-11

6 x 10-11

Effect of electron
electron--withdrawing groups is most
pronounced at ortho and para positions

OH

OH

OH

Electron--withdrawing groups increase acidity

Electron

OH

Ka:

1 x 10-10

OH

OH

Cl

NO2

4 x 10-9

7 x 10-8

Effect of strong electron

electron--withdrawing groups
is cumulative
OH

OH

OH
NO2

NO2

NO2

O2N

NO2

Ka:

6 x 10-8

4 x 10-9

NO2

NO2

NO2

7 x 10-8

Ka: 7 x 10-8

1 x 10-4

NO2
4 x 10-1

Resonance Depiction

O

N
+

N
+

Typical Preparation is by Williamson Synthesis

ONa + RX

SN2

Preparation of Aryl Ethers

NaX
OR + NaX

Typical Preparation is by Williamson Synthesis

ONa + RX

SN2

NaX
OR + NaX

but the other combination

X + RONa
N
fails because aryl halides are normally unreactive
toward nucleophilic substitution

Example
Carboxylation of Phenols
acetone

ONa + CH3I

OCH3

heat

(95%)

O
Aspirin and
the
Kolbe--Schmitt
Kolbe
R
Reaction
ti

OCCH3
COH
O

Preparation of Salicylic Acid

Aspirin is prepared from salicylic acid

By esterification
O O
OH
COH

CH3COCCH3
H2SO4

how is salicylic acid prepared?

O
OCCH3

ONa

CO2
125C, 100 atm
125

COH
O

OH
CONa
O

called the Kolbe

Kolbe--Schmitt reaction
acidification converts the sodium salt shown
above to salicylic acid

What Drives the Reaction?

Preparation of Salicylic Acid

acid--base considerations provide an explanation:

acid
stronger base on left; weaker base on right

O

CO2

ONa

stronger base:
pKa of conjugate
acid = 10

weaker base:
pKa of conjugate
acid = 3

O
H

125C, 100 atm

125

O
how does carboncarbon-carbon bond form?
recall electron delocalization in phenoxide ion
negative charge shared by oxygen and by the
ring carbons that are ortho and para to oxygen

H
H

H
H

CONa

Mechanism of ortho Carboxylation

OH

CO2

C
O

O
C
H

Mechanism of ortho Carboxylation

C
O

Reimer--Tiemann reaction.
Reimer

Synthesis of phenolic aldehydes

Dichlorocarbenes

Mechanism of ReimerReimer-Tiemann

Reimer--Tiemann rxn
Reimer

O-

OH

CHCl3, aq. NaOH

70 C

OCHCl2

OH- + CHCl3

OH
CHO

H2O + Cl3C:-

Cl- + Cl2C:

CHO

HCl

O-

O-

OCCl2

+ :CCl2

Strong Electrophile

CHCl2

Quinones
The most common examples of phenol oxidations
are the oxidations of 1,2
1,2-- and 1,4
1,4--benzenediols
to give quinones.
OH

Oxidation of Phenols:
Quinones

O
Na2Cr2O7, H2SO4
H2O

OH

(76--81%)
(76

Some quinones are dyes

Quinones
The most common examples of phenol oxidations
are the oxidations of 1,2
1,2-- and 1,4
1,4--benzenediols
to give quinones.

OH
OH

OH
OH

Ag2O

diethyl ether
CH3

CH3

(68%)

Alizarin
(red pigment)

Some quinones are important biomolecules

O

Some quinones are important biomolecules

O
CH3

CH3O

CH3
CH3

CH3O

n
O

Ubiquinone (Coenzyme Q)
n=6
6--10
involved in biological electron transport

CH3

CH3

CH3

CH3

Vitamin K
(blood-clotting factor)
(blood-

Nitrosation of Primary Arylamines

gives aryl diazonium ions
aryl diazonium ions are much more stable than
alkyl diazonium ions
Aryl Diazonium Salts

most aryl diazonium ions are stable under the

conditions of their formation (0(0-10
10C)

Nitrosation of Primary Arylamines

Example:

gives aryl diazonium ions

aryl diazonium ions are much more stable than
alkyl diazonium ions

(CH3)2CH

NaNO2, H2SO4
H2O, 0
0--5C

most aryl diazonium ions are stable under the

conditions of their formation (0(0-10
10C)
+
RN

+
ArN

+
R

fast
slow

+
Ar

NH2

+ N2
(CH3)2CH

+
N

N HSO4

+ N2

Synthetic Origin of Aryl Diazonium Salts

Ar

H
HNO3, H2SO4
Ar

NO2

Synthetic Transformations of Aryl Diazonium Salts

Fe, HCl or Pd, H2

Ar

NH2

NaNO2, HCl, H2O

0 - 5 C
Ar

+
N

Transformations of Aryl Diazonium Salts

Ar

Cl

Br

Ar

+
N

Ar
Ar

y
y
of a diazonium salt
hydrolysis
Ar

CN

Ar

+
N

Ar

Ar
Ar

Preparation of Phenols

N
H2O,
O heat

OH

OH

Ar

Example

Transformations of Aryl Diazonium Salts

NH2

(CH3)2CH

1. NaNO2, H2SO4
H2O, 0
0--5C

Ar
Ar

Cl

Ar

CN
+
N

Ar

Br
Ar

Ar

2. H2O, heat
Ar

OH

(CH3)2CH

Ar
(73%)

OH

Example

Preparation of Aryl Iodides

reaction of an aryl diazonium salt with
potassium
t
i
iodide
i did

NH2
Br

+
N

Ar

N
Ar

Ar

Ar

+
N

Ar
Ar

OH

Ar
Ar

Ar
Ar

Preparation of Aryl Fluorides

Br
Ar

CN

(72--83%)
(72

Transformations of Aryl Diazonium Salts

Cl

Br

2. KI, room temp.

KI

Ar

1. NaNO2, HCl
H2O, 0
0--5C

+
N

heat the tetrafluoroborate salt of a diazonium ion;

process is called the Schiemann reaction

Example

Transformations of Aryl Diazonium Salts

Ar

NH2

1 N
1.
NaNO
NO2, HCl,
HCl
H2O, 0
0--5C

CCH2CH3

Br
Ar

Ar

CCH2CH3

3.
3 heat

Ar

(68%)

Preparation of Aryl Chlorides and Bromides

Cl

Ar

Ar

OH

Example

Br
NH2

+
N

+
N

Ar

2. HBF4

Ar

Ar

CN

Ar

Ar

Cl

1 N
1.
NaNO
NO2, HCl,
HCl
H2O, 0
0--5C

aryl chlorides and aryl bromides are prepared by

heating a diazonium salt with copper(I) chloride or
bromide
substitutions of diazonium salts that use copper(I)
halides are called Sandmeyer reactions

NO2

2. CuCl, heat

Cl

NO2
(68--71%)
(68

Example

Transformations of Aryl Diazonium Salts

Ar

NH2
Cl

1 N
1.
NaNO
NO2, HBr,
HB
H2O, 0
0--10
10C

Cl

Ar

Br
Cl

CN

Ar

+
N

Ar

2. CuBr, heat
(89--95%)
(89

Ar

Preparation of Aryl Nitriles

Ar

+
N

CH3
N

aryl nitriles are prepared by heating a diazonium

salt with copper(I) cyanide
this is another type of Sandmeyer reaction

Ar

OH

Example

NH2
CN

Ar
N

H
Ar

Ar

Br

1 N
1.
NaNO
NO2, HCl,
HCl
H2O, 0
0C

CN
CH3

2. CuCN, heat
(64--70%)
(64

Transformations of Aryl Diazonium Salts

Ar

Cl

Ar

+
N

Ar
Ar

Ar
Ar

Ar

hypophosphorous acid (H3PO2) reduces diazonium

salts; ethanol does the same thing
this is called reductive deamination

Br
Ar

CN

Ar

Transformations of Aryl Diazonium Salts

Ar

CH3

OH

Example

NH2

+
N

Value of Diazonium Salts

NaNO
N NO2, H2SO4,
H3PO2

CH3

(70--75%)
(70

1) allows introduction of substituents such as

OH F,
OH,
F I,
I and CN on the ring
2) allows preparation of otherwise difficultly
accessible substitution patterns

Example
NH2

NH2
Br2

Br

Br

NaNO2, H2SO4,
H2O, CH3CH2OH

H2O

Azo Coupling
Br

Br

Br

(100%)
Br
(74--77%)
(74

Azo Coupling
Diazonium salts are weak electrophiles.
R
React
t with
ith strongly
t
l activated
ti t d aromatic
ti
compounds by electrophilic aromatic
substitution.

Azo Coupling
Diazonium salts are weak electrophiles.
electrophiles.
R
React
t with
ith strongly
t
l activated
ti t d aromatic
ti
compounds by electrophilic aromatic
substitution.
Ar

+
N

N + Ar'

Ar

Ar'

an azo compound
Ar' must bear a strongly electronelectron-releasing group
such as OH, OR, or NR2.

Example
OH
+
+ C6H5N

Cl
Halobenzenes and Nucleophilic
Aromatic Substitution

OH
N

NC6H5

Reactivity increases as we attach more electron

withdrawing groups:
Cl

NaOH, 350C

Mechanism:
If the ring is substituted by an electron withdrawing group the
reaction proceeds through a two-step carbanion intermediate.

OH

300 atm.

Cl

Slow
O2N

Cl

O2N

Fast
O2N

OH

OH

OH

O2N

Cl

NaOH, 160C
300 atm.

O2N

OH

If the ring is unsubstituted, the reaction proceeds through a

benzyne intermediate.

NO2

NO2

Cl

O2N

Cl
NO2

H2O, warm

O2N

OH
NO2

-HCl
Slow

NH2-, NH3

NH2