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aromatic chemistry
Aromatic substitution
Electrophilic
Nucleophilic
Addition-Elimination Mechanism
Benzyne Mechanism
Other ring reactions
Side-chain reactions
1
Benzyne Mechanism
Reactant is halobenzene with no
electron-withdrawing groups on the ring.
Use a very strong base like NaNH2.
=>
Benzyne Intermediate
=>
2
Chlorination of Benzene
Addition to the benzene ring may occur with high
heat and pressure (or light).
The first Cl2 addition is difficult, but the next 2 moles
add rapidly.
The product, benzene hexachloride, is an
insecticide.
=>
Catalytic Hydrogenation
Elevated heat and pressure is required.
Possible catalysts: Pt, Pd, Ni, Ru, Rh.
Reduction cannot be stopped at an
intermediate stage.
CH3
CH3
3 H2, 1000 psi
Ru, 100°C
CH3
CH3 =>
3
Reduction of Aromatic
Compounds
Aromatic rings are inert to catalytic hydrogenation under
conditions that reduce alkene double bonds
Can selectively reduce an alkene double bond in the
presence of an aromatic ring
Reduction of an aromatic ring requires more powerful
reducing conditions (high pressure or rhodium catalysts)
Birch Reduction: Regiospecific
A carbon with an electron-withdrawing group is reduced.
O
O
C
C
OH
Na,
NH3
_
O
H
CH3CH2OH
A carbon with an electron-releasing group is not
reduced.
OCH3
Li,
NH3
(CH3)3COH, THF
OCH3
=>
4
Birch Mechanism
=>
Side-Chain Oxidation
Alkyl side chains can be oxidized to CO2H by strong
reagents such as KMnO4 and Na2Cr2O7 if they have a C-H
next to the ring
Converts an alkylbenzene into a benzoic acid,
ArR → ArCO2H
5
Side-Chain Oxidation
Alkylbenzenes are oxidized to benzoic acid
by hot KMnO4 or Na2Cr2O7/H2SO4.
CH(CH3)2
_
COO
-
KMnO4, OH
CH CH2
_
COO
H2O, heat
=>
Side-Chain Halogenation
Benzylic position is the most reactive.
Chlorination is not as selective as
bromination, results in mixtures.
Br2 reacts only at the benzylic position.
Br
CH2CH2CH3
Br2, hν
CHCH2CH3
=>
6
Side-Chain Halogenation
Reaction of an alkylbenzene with N-bromosuccinimide (NBS) and benzoyl peroxide (radical
initiator) introduces Br into the side chain
SN1 Reactions
Benzylic carbocations are resonancestabilized, easily formed.
Benzyl halides undergo SN1 reactions.
CH2Br
CH3CH2OH, heat
CH2OCH2CH3
=>
7
SN2 Reactions
Benzylic halides are 100 times more
reactive than primary halides via SN2.
Transition state is stabilized by ring.
=>
Nitrobenzenes: Precursors to
Anilines
Nitric acid destroys alkenes through [O]
In sulfuric acid, nitric acid reacts with benzene giving
nitrobenzene
Nitrobenzene may be reduced to aniline
Aniline useful precursors to many industrially important
organic compounds
NO 2
SnCl2 /acid
NH 2
8
Important Anilines
O
O
O
O Et
NEt2
NH2
NH2
procaine
benzocaine
CH3
H
N
NEt2
O
CH3
lidocaine
Aromatic Dyes
William Henry Perkin, Age 17
(1856)
Undergraduate student in
medicine
Reacted aniline with potassium
dichromate obtained a black
tarry mess
Attempting to synthesize
quinine and instead discovered
how to make mauveine, a
purple dye - the first industrial
organic fine-chemical
http://www.ch.ic.ac.uk/motm/perkin.html
9
Aromatic Dyes
Isolated
H3 C
N
H
N
CH 3
N
NH 2
Mauve - a purple color
Dyed white cloth
Patented material and process
First chemical company
Some Aniline Chemistry
Anilines readily react with
nitrous acid
N2
NH2
Diazonium salts
Coupling reaction giving
an azo compound
+
HONO
aryl diazonium salt
N2
+
N
N
X
azo compound
aryl diazonium salt
Dyes and sulfa drugs
activated ring
10
Aniline Chemistry
N2+
H
H3PO3
N2+
I
NaI
N2+
CN
KCN/CuCN
N2+
Cu2O/Cu(NO3)2
OH
Phenols
A phenol is a hydroxyl group directly bonded to a a
benzene ring.
OH
OH
OH
OH
OH
OH
OH
CH3
phenol
m-cresol
3-methyl phenol
catechol
1,2-benzenediol
resorcinol
1,3-benzenediol
OH
hydroquinone
1,4-benzenediol
11
Phenols
Phenol is a low melting solid that is soluble in water.
It has antiseptic properties and was used in the 19th century
in surgery. Its medical use is now limited as derivatives with
fewer side effects have become available
Phenols are found in coal tar as well as the cresols (o,m,p).
Some important phenols:
OH
CH3
CH
CH3
OH
CH3
O
H3C
2-isopropyl-5-methylphenol
(Thymol an oil in thyme leaves)
CHO
4-hydroxy-3-methoxybenzaldehyde
(Vanillin an important constituent of
the vanilla bean)
Modern antiseptic phenols:
OH
OH
OH
CH3
O
OH
H2C C CH2
H
Eugenol
OH
Urishol
Urishol is the active oil
ingredient in poison ivy.
Hexylresorcinol
Removing an OH gives a
lysol, a useful antiseptic.
12
Acidity of Phenols
• Phenols and alcohols both contain hydroxyl groups however they
are classified as separate functional groups.
• Phenols have different properties than alcohols, most noteworthy is
their acidity (pKa difference of 106)
O
OH
H3C
H2
C
OH
+
H2O
+
H2O
H3C
H2
C
O
+
H3O+
pKa = 9.95
+
H3O+
pKa = 15.9
Solutions of alcohols in water are neutral, whereas a solution of
0.1 M phenol is slightly acidic (pH 5.4).
• Why are phenols more acidic?
O
O
O
O
Resonance. The charge is delocalized around the ring.
m-cresol and p-cresol are weaker acids than phenol with pKa’s
of 10.01 and 10.17 respectively.
OH
OH
CH3
CH3
m-cresol
p-cresol
13
Influence of substituents on the
acidity of phenol
Alkyl groups decrease the acidity of phenol
halogens increase the acidity of phenol
OH
OH
O
CH3
Cl
Electron donating alkyl group destabilizes
this resonance structure
OH
pKa = 10.17
pKa = 8.85
CH3
m-chlorophenol
p-cresol
O
Electron withdrawing halogen groups
stabilize the delocalized negative charge
X = F, Cl, Br
X
X
Chlorine < fluorine < bromine < chlorine.
Nitro groups increase acidity by both inductive and resonance
effects.
OH
OH
OH
NO2
phenol
pKa = 9.95
m-nitrophenol
pKa = 8.28
NO2
p-nitrophenol
pKa = 7.15
p-Nitrophenol is more acidic than m-nitrophenol,
OH
O
O
O2N
Delocalization of negative charge onto
ocygen futher increases the resonance
stabilization of the phenoxide ion
O
N
N
O
O
O
NO2
NO2
picric acid
2,4,6-nitrophenol
pKa = 0.38
14
Acid-Base Reactions of Phenol
When reacted with strong bases phenols are deprotonated to give
water-soluble salts. Phenols will not react with weak bases such as
sodium bicarbonate.
+
O Na
OH
+
+
NaOH
H2O (pKa = 15.7)
weaker acid
pKa = 9.95
stronger acid
+
O Na
OH
+
+
NaHCO3
H2CO3 (pKa = 6.36)
stronger acid
pKa = 9.95
weaker acid
Separation of alcohols from
phenols
OH
OH
OH
ether
+
evaporation
NaOH
OH
OH
+ H+
CH3
O-Na+
CH3
dissolved in ethyl ether
CH3
15
Preparation of Aryl Ethers
Aryl ethers can be prepared from phenoxide salts and alkyl halides.
The opposite case is not true (aryl halides are not good leaving
groups).
The phase transfer catalyst transports the phenoxide anion into the
organic layer.
Cl
OH
O
NaOH, H2O
CH2Cl2
+
Bu4N+Br-
• Anisole can be formed from phenol plus a methylating agent, CH3I
or dimethyl sulfate.
OH
O
+ H3C O S O CH3
O
NaOH, H2O
CH2Cl2
O
CH3
+
Bu4N+Br-
+Na-O
O
S O-Na+
O
dimethyl sulfate
anisole
16
• Aryl ethers can be cleaved by hydrohalic acids, HX, to form
alkyl halides and phenol.
O
OH
+
Br
+
HBr
Kolbe Carboxylation; Synthesis of
Salicyclic Acid
•This industrial method is called the high-pressure carboxylation
of sodium phenoxide.
OH
O
NaOH
H2O
OH O
OH O
CO2
O-Na+
H2O
HCl
H2O
OH
salicylic acid
Mech:
O
O
C
O
O
O
H
keto-enol
tautomerism
O-
OH O
O-
17
1,4-diketones
Some reactions like aliphatic alcohols:
phenol + carboxylic acid → ester
phenol + aq. NaOH → phenoxide ion
Oxidation to quinones: 1,4-diketones.
O
OH
Na2Cr2O7, H2SO 4
CH3
CH3
=>
O
hydroquinones
18
Quinones
Hydroquinone is used as a developer for film. It reacts with lightsensitized AgBr grains, converting it to black Ag.
(http://video.uni-regensburg.de:8080/ramgen/Fakultaeten/Chemie/Org_Chemie/Demonstrationsexperimente/benzoquinone_0.rm)
Coenzyme Q is an oxidizing agent found in the mitochondria of
cells.
=>
19
hydroquinone
2e(–)
Quinone + 2H(+)
Hydroquinone
–2e(–)
The SkinSilk Color Restoration step
includes a Skin "Bleach" Cream
formulated using the innovative
ingredient Hydroquinone 2.0%
Orto-Electrophilic
Substitution of Phenols
Phenols and phenoxides are highly reactive.
Only a weak catalyst (HF) required for FriedelCrafts reaction.
Tribromination occurs without catalyst.
Even reacts with CO2.
O
_
_
O
-
CO2, OH
O
C
OH
O
_
+
O
C
H
OH
=>
salicylic acid
20
Biological Halogenation
Accomplished during biosynthesis of
thyroxine
I
CO2H NH3
+
HO
thyroid peroxidase
CO2H
HO
NH3
+
I
tyrosine
Hydroxylation
Ipso-substitution
Direct hydroxylation is difficult in lab
Indirect method uses sulfonic acid
O
S
OH
O
OH
1. NaOH
2. 300 oC
phenol
21
Biological Hydroxylation
O
HO
O
O2
FADH 2
HO
HO
O
O
o-hydroxyphenylacetate-3-hydroxylase
Coenzyme necessary
Biological Alkylations
No AlCl3 present
O
O
R O P O P O
Utilizes an organodiphosphate
O
O
Mg
+2
Dissociation is facilitated by Mg
Important reaction in biosynthesis of Vitamin K1
R+
+2
22
Oxidation of Benzene
Toluene is readily oxidized by reagents
Benzene is inert to oxidizing agents
Benzene is toxic to humans
Benzene is a suspected carcinogen
Cytochrom P
strong oxidant in Liver
Primary detoxification process used
Proposed Chemistry
Toluene is non-toxic
CH3
CO2H
[O] in liver
water soluble
Benzene is toxic
O
[O] in liver
triepoxide
O lipid soluble
mutagen
O
23
Biological Oxidations of Side
Chains
Biosynthesis of norepinephrine
H
enzyme
HO
HO
NH2
HO
HO
OH
NH2
enzyme = dopamine-beta-monooxygenase
24