24.6
Sources of Phenols
Phenol is an important industrial chemical.
Major use is in phenolic resins for adhesives
and plastics.
Annual U.S. production is about 4 billion
pounds per year.
Industrial
Preparations
of Phenol
SO3H
Cl
1. NaOH 2. H+
heat
1. NaOH
heat
2.
H+
OH
CH(CH3)2
1. O2
2. H2O
H2SO4
Laboratory Synthesis of Phenols
from arylamines via diazonium ions
O 2N
NH2
1. NaNO2,
H2SO4,
H 2O
O 2N
OH
2. H2O, heat
(81-86%)
24.7
Naturally Occurring Phenols
Many phenols occur naturally
Example: Thymol
OH
CH3
CH(CH3)2
Thymol
(major constituent of oil of thyme)
Example: 2,5 -Dichlorophenol
OH
Cl
Cl
2,5-Dichlorophenol
(from defensive secretion of
a species of grasshopper)
24.8
Reactions of Phenols:
Electrophilic Aromatic
Substitution
Hydroxyl group strongly activates the ring
toward electrophilic aromatic substitution
Electrophilic Aromatic Substitution in Phenols
Halogenation
Nitration
Nitrosation
Sulfonation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation
Halogenation
OH
OH
+ Br2
ClCH2CH 2Cl
0°C
Br
(93%)
monohalogenation in nonpolar solvent
(1,2-dichloroethane)
Halogenation
OH
OH
+ 3Br2
F
H 2O
Br
Br
25°C
F
Br
(95%)
multiple halogenation in polar solvent
(water)
Electrophilic Aromatic Substitution in Phenols
Halogenation
Nitration
Nitrosation
Sulfonation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation
Nitration
OH
OH
N O2
HNO3
acetic acid
5°C
CH3
OH group controls
regiochemistry
CH3
(73-77%)
Electrophilic Aromatic Substitution in Phenols
Halogenation
Nitration
Nitrosation
Sulfonation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation
Nitrosation
NO
OH
OH
NaNO2
H2SO4, H2O
0°C
(99%)
only strongly activated
rings undergo nitrosation
when treated with nitrous
acid
Electrophilic Aromatic Substitution in Phenols
Halogenation
Nitration
Nitrosation
Sulfonation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation
Sulfonation
OH
H 3C
OH
CH3
H2SO4
H 3C
CH3
100°C
SO3H
OH group controls
regiochemistry
(69%)
Electrophilic Aromatic Substitution in Phenols
Halogenation
Nitration
Nitrosation
Sulfonation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation
Friedel-Crafts Alkylation
OH
OH
CH3
CH3
(CH3)3COH
H3PO4
60°C
H 3C
(CH3)3COH reacts
with H3PO4 to give
(CH3)3C+
C CH3
CH3
(63%)
Electrophilic Aromatic Substitution in Phenols
Halogenation
Nitration
Nitrosation
Sulfonation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation
24.9
Acylation of Phenols
Acylation can take place either on the ring
by electrophilic aromatic substitution or on
oxygen by nucleophilic acyl substitution
Friedel-Crafts Acylation
OH
OH
O
CH3CCl
+ ortho isomer
AlCl3
under Friedel-Crafts
conditions, acylation
of the ring occurs
(C-acylation)
O
C
CH3
(74%)
(16%)
O-Acylation
O
OH
OC(CH2)6CH3
O
+ CH3(CH2)6CCl
(95%)
in the absence of AlCl3, acylation of the
hydroxyl group occurs (O -acylation)
O- versus C -Acylation
O
OH
OC(CH2)6CH3
AlCl3
C
formed faster
CH3
O
more stable
O-Acylation is kinetically controlled process; C-acylation
is thermodynamically controlled
AlCl3 catalyzes the conversion of the aryl ester to the
aryl alkyl ketones; this is called the Fries rearrangement
24.10
Carboxylation of Phenols
O
Aspirin and
the
Kolbe-Schmitt
Reaction
OCCH3
COH
O
Aspirin is prepared from salicylic acid
O O
OH
COH
CH3COCCH3
H2SO4
O
how is salicylic acid prepared?
O
OCCH3
COH
O
Preparation of Salicylic Acid
ONa
CO2
125°C, 100 atm
OH
CONa
O
called the Kolbe-Schmitt reaction
acidification converts the sodium salt shown
above to salicylic acid
What Drives the Reaction?
acid -base considerations provide an explanation:
stronger base on left; weaker base on right
•• •–
O•
••
+
••
O
H
C
•• –
O ••
••
••
CO2
•• O •
•
stronger base:
pKa of conjugate
acid = 10
weaker base:
pKa of conjugate
acid = 3
Preparation of Salicylic Acid
ONa
CO2
125°C, 100 atm
OH
CONa
O
how does carbon-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
– ••
•O •
• •
H
••
•O
•
H
H
–
H
••
H
H
H
H
H
••
••
•O
•
•O
•
H
H
–
H
H
H
H
H
••
H
H
••
–
H
H
Mechanism of ortho Carboxylation
••
•• O
•• –
O •• C
••
H
O ••
••
•• •
O•
C
H
•• •–
O•
••
•• O •
•
Mechanism of ortho Carboxylation
••
•• O
•• –
O •• C
••
•• •
O•
O ••
••
C
H
H
••
O
H
C
•• •–
O•
••
••
•• O •
•
•• •–
O•
••
•• O •
•
Why ortho?
Why not para?
••
O
H
C
•• –
O ••
••
••
•• O •
•
•• •–
O•
••
••
O
••
–• ••
•O
••
C
•• O •
•
H
Why ortho?
Why not para?
••
O
H
C
•• –
O ••
••
••
•• O •
•
weaker base:
pKa of conjugate acid = 3
•• •–
O•
••
••
O
••
–• ••
•O
••
H
C
•• O •
•
stronger base:
pKa of conjugate acid = 4.5
Intramolecular Hydrogen Bonding
in Salicylate Ion
O
H
C
O–
O
Hydrogen bonding between carboxylate and hydroxyl
group stabilizes salicylate ion. Salicylate is less basic
than para isomer and predominates under conditions
of thermodynamic control.