1
more aromatic chemistry
� Aromatic substitution
� Electrophilic
� Nucleophilic
� Addition-Elimination Mechanism
� Benzyne Mechanism
� Other ring reactions
� Side-chain reactions
2
Benzyne Mechanism� Reactant is halobenzene with no
electron-withdrawing groups on the ring.
� Use a very strong base like NaNH2.
=>
Benzyne Intermediate
=>
3
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
Ru, 100°C
1000 psi3H2,
CH3
CH3
4
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.
� A carbon with an electron-releasing group is not
reduced.
C
O
OH Na, NH3
CH3CH2OH
C
O
O
H
_
OCH3 Li, NH3
(CH3)3COH, THF
OCH3
=>
5
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,
ArR → ArCO2H
6
Side-Chain Oxidation� Alkylbenzenes are oxidized to benzoic acid
by hot KMnO4 or Na2Cr2O7/H2SO4.
CH(CH3)2
CH CH2
KMnO4, OH-
H2O, heat
COO
COO
_
_
=>
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.
=>
CHCH2CH3
Br
hνBr2,
CH2CH2CH3
7
Side-Chain Halogenation
� Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain
SN1 Reactions
� Benzylic carbocations are resonance-
stabilized, easily formed.
� Benzyl halides undergo SN1 reactions.
CH2BrCH3CH2OH, heat
CH2OCH2CH3
=>
8
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
NO2
NH2SnCl2/acid
9
Important Anilines
NH2
O
O Et
NH2
O
O NEt2
CH3
CH3
NH
O
NEt2
benzocaine procaine
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
10
Aromatic Dyes
� Isolated
� Mauve - a purple color
� Dyed white cloth
� Patented material and process
� First chemical company
CH3
NH N
N
NH2
CH3
Some Aniline Chemistry
� Anilines readily react with
nitrous acid
� Diazonium salts
� Coupling reaction giving
an azo compound
� Dyes and sulfa drugs
NH2
N2
HONO
+
aryl diazonium salt
N2
X
NN
+
aryl diazonium salt
activated ring
azo compound
11
Aniline ChemistryH
I
CN
OH
N2+
H3PO3
N2+
NaI
N2+
KCN/CuCN
N2+
Cu2O/Cu(NO3)2
Phenols
� A phenol is a hydroxyl group directly bonded to a a
benzene ring.
OH OH OHOH OH
CH3
OH
OH
OHphenol
m-cresol3-methyl phenol
catechol1,2-benzenediol
resorcinol1,3-benzenediol hydroquinone
1,4-benzenediol
12
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
H3C
CH
CH3
CH3
2-isopropyl-5-methylphenol
(Thymol an oil in thyme leaves)
OH
CHO
O
CH3
4-hydroxy-3-methoxybenzaldehyde
(Vanillin an important constituent of the vanilla bean)
Modern antiseptic phenols:
OH
OH
OH
H2C
O
CH3
CH
CH2
Eugenol
Hexylresorcinol
OH
OH
Urishol
Urishol is the active oil
ingredient in poison ivy.
Removing an OH gives a
lysol, a useful antiseptic.
13
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)
OH O
+ H2O + H3O+ pKa = 9.95
H3C
H2C
OH + H2O H3C
H2C
O+ 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?
Resonance. The charge is delocalized around the ring.
O O O O
m-cresol and p-cresol are weaker acids than phenol with pKa’s
of 10.01 and 10.17 respectively.
OH OH
CH3CH3
m-cresolp-cresol
14
Alkyl groups decrease the acidity of phenol
halogens increase the acidity of phenol
O
CH3
Electron donating alkyl group destabilizesthis resonance structure
OH
X
X = F, Cl, Br
X
O
Electron withdrawing halogen groups stabilize the delocalized negative charge
Chlorine < fluorine < bromine < chlorine.
OH
Cl
m-chlorophenol
pKa = 8.85
OH
CH3
p-cresol
pKa = 10.17
Influence of substituents on the acidity of phenol
Nitro groups increase acidity by both inductive and resonance
effects. OH OH OH
NO2
NO2phenolpKa = 9.95
m-nitrophenolpKa = 8.28 p-nitrophenol
pKa = 7.15
p-Nitrophenol is more acidic than m-nitrophenol,
O
NOO
O
NOO
Delocalization of negative charge ontoocygen futher increases the resonancestabilization of the phenoxide ion
OH
NO2O2N
NO2
picric acid2,4,6-nitrophenol
pKa = 0.38
15
Acid-Base Reactions of PhenolWhen reacted with strong bases phenols are deprotonated to give
water-soluble salts. Phenols will not react with weak bases such as
sodium bicarbonate.
OH
+ NaOH
O
+ H2O (pKa = 15.7)
Na+
pKa = 9.95stronger acid
weaker acid
OH
+ NaHCO3
O
+ H2CO3 (pKa = 6.36)
Na+
pKa = 9.95weaker acid
stronger acid
OH
OH
CH3
NaOH+
dissolved in ethyl ether
ether
OH
O-Na+
CH3
evaporation
OH
+ H+
OH
CH3
Separation of alcohols from phenols
16
Preparation of Aryl EthersAryl 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.
OH
+
NaOH, H2O
CH2Cl2
Bu4N+Br-
OCl
• Anisole can be formed from phenol plus a methylating agent, CH3I
or dimethyl sulfate.
OH
+
NaOH, H2O
CH2Cl2
Bu4N+Br-
OCH3
O S O
O
O
CH3H3C + +Na-O S O-Na+
O
O
dimethyl sulfate
anisole
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• Aryl ethers can be cleaved by hydrohalic acids, HX, to form
alkyl halides and phenol.
O
+ HBr
OH
+ Br
Kolbe Carboxylation; Synthesis of Salicyclic Acid
•This industrial method is called the high-pressure carboxylation
of sodium phenoxide.
OHNaOHH2O
O OH
O-Na+
O
CO2
H2O
OH
OH
O
HCl
H2Osalicylic acid
O O
C
O
O
O-
O
H
OH
O-
Oketo-enoltautomerism
Mech:
18
1,4-diketones� Some reactions like aliphatic alcohols:
� phenol + carboxylic acid → ester
� phenol + aq. NaOH → phenoxide ion
� Oxidation to quinones: 1,4-diketones.
OH
CH3
Na2Cr2O7, H2SO4
CH3
O
O
=>
hydroquinones
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Quinones
� Hydroquinone is used as a developer for film. It reacts with light-
sensitized 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. =>
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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-ElectrophilicSubstitution of Phenols
� Phenols and phenoxides are highly reactive.
� Only a weak catalyst (HF) required for Friedel-
Crafts reaction.
� Tribromination occurs without catalyst.
� Even reacts with CO2.
O_
CO2, OH-
O
C
O
O_
_
H+
OH
C
O
OH
salicylic acid
=>
21
Biological Halogenation
� Accomplished during biosynthesis of
thyroxine
OH
NH3H OH
NH3H
I
I
CO2-
+
tyrosine
thyroid peroxidase
CO2-
+
Hydroxylation
� Ipso-substitution
� Direct hydroxylation is difficult in lab
� Indirect method uses sulfonic acid
SO
O
OH OH1. NaOH
2. 300 oC
phenol
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Biological Hydroxylation
� Coenzyme necessary
O
O
OH
O
O
OH
OHO2
o-hydroxyphenylacetate-3-hydroxylase
FADH2
Biological Alkylations� No AlCl3 present
� Utilizes an organodiphosphate
� Dissociation is facilitated by Mg+2
� Important reaction in biosynthesis of Vitamin K1
OR P O P O
OO
O O
Mg+2
R+
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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
CH3
CO2H
O
O
O
[O] in liverwater soluble
Toluene is non-toxic
Benzene is toxic
[O] in liver triepoxidelipid solublemutagen
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Biological Oxidations of Side Chains
� Biosynthesis of norepinephrine
OH
OHNH
2
OH
OHNH
2
OHH
enzyme
enzyme = dopamine-beta-monooxygenase