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18-Aromatic Substitutions PDF
18-Aromatic Substitutions PDF
Daley
www.ochem4free.com
Organic
Chemistry
Chapter 18
Aromatic Substitution Reactions
Chapter 18
Aromatic Substitution
Reactions
Chapter Outline
18.1 Mechanism of Electrophilic Aromatic Substitution
The mechanism of electrophilic substitution of benzene
18.2 The Nitration of Benzene
A case study of aromatic electrophilic substitution
18.3 Halogenation and Sulfonation of Benzene
The mechanism of chlorination, bromination, and sulfonation of
benzene
18.4 Friedel-Crafts Alkylation
Formation of alkyl benzenes
18.5 Effects of Monosubstituted Arenes on Substitution
The effects of one substituent on the position of reaction by a second
substituent
18.6 Rate Effects with Monosubstituted Arenes
The effect of one substituent on the rate of reaction by a second
substituent
18.7 Classification of Substituents
A listing of common substituents showing their directive and rate
controlling effects
18.8 Friedel-Crafts Acylation
Formation of acyl benzenes
18.9 Multiple Substituent Effects
Predicting the position of substitution when two or more substituents
are on the ring
18.10 Substitution on Polycyclic Arenes
Aromatic electrophilic substitution on polycyclic aromatic compounds
18.11 Diazotization
Diazotization and the use of the diazonium ion as an electrophile
18.12 Other Diazonium Salt Reactions
Replacement of the diazonium ion with a variety of groups
18.13 Nucleophilic Aromatic Substitution
Nucleophilic substitution on an aromatic ring
18.14 Benzyne
The formation and reaction of the reactive benzyne intermediate
18.15 Synthesis Examples
Organic synthesis using aromatic electrophilic substitution reactions
Objectives
E Nu E
E Nu:
Step 1
E
+
Step 2
Base:
H H
+ E H + E
+ E
‡
G2
G1‡
+ H
+ E Go
Reaction Progress
Figure 18.1. Reaction progress diagram for electrophilic aromatic substitution.
•• H OSO3H ••
HO NO2 HO NO2 NO2
••
NO2 NO2
+
σ complex
H
NO2
NO2
D
D2SO4
Solution
In this reaction, a deuterium replaces one of the hydrogens on the ring. The
D2SO4 is the source of D⊕ electrophile. The formation of the σ complex
involves reaction of the ring with the electrophile.
D
D OSO3D
H
The DSO4c
- anion removes the proton to form the final product.
D D
OSO3D
H
Exercise 18.2
•• •• FeCl3 •• ••
•
• Cl Cl •
•
•
• Cl Cl FeCl3
•• •• •• ••
•• •• FeBr3 •• ••
•
• Br Br •
•
•
• Br Br FeBr3
•• •• •• ••
•• ••
H •• Br
•
• Br Br FeBr3
•
• Br
••
FeBr3
•• ••
Br
Figure 18.2 shows the reaction progress diagram for the bromination
of benzene. Note that ∆G2‡ < ∆G1‡ , so formation of the σ complex is
the rate-determining step.
H H Br
+ Br Br H + Br
+ Br
‡
G2
‡
G1
Br
+ HBr
+ Br2 Go
Reaction Progress
Figure 18.2. The reaction progress diagram for the bromination of benzene.
Cl
Cl2
FeCl3
Chlorobenzene
(83%)
Iodobenzene
(86%)
Exercise 18.3
O
O
Tl(OCCF3)2 F
Tl(OCCF3)3 KF, BF3
SO3H
H2SO4
Benzenesulfonic acid
(95%)
OSO3H
O
O
H H
S O
S
OH
O
O
SO3H
Exercise 18.4
CH2CH3
CH3CH2Cl
AlCl3
Ethylbenzene
(84%)
•• AlCl3 ••
CH3CH2 Cl •
• CH3CH2 Cl
••
AlCl3
••
••
CH2CH3
CH3CH2 Cl
••
AlCl3 AlCl4
H
CH2CH3
CH(CH3)2
67%
CH3CH2CH2Cl Isopropylbenzene
AlCl3
CH2CH2CH3
33%
Propylbenzene
•• AlCl3 ••
CH3CH2CH2 Cl •
• CH3CHCH2 Cl
••
AlCl3
••
••
•
• Cl
••
AlCl3
CH3CHCH3
As you may recall from The driving force for the rearrangement is the stability of the
Section 12.5 (page 000), carbocations (3o > 2o > 1o). The rearrangement of the carbocation is a
more highly
substituted
major limitation of the synthetic utility of the Friedel-Crafts reaction.
carbocations are more The reaction generally works well if the desired product comes from
stable. the more stable carbocation.
CH2Cl
AlCl3
Solution
In the presence of a Lewis acid catalyst like AlCl3, benzyl chloride forms the
benzyl cation. The benzyl cation is the electrophile that reacts with the
benzene to form diphenylmethane.
CH2Cl CH2
AlCl3
Diphenylmethane
Exercise 18.5
CH(CH3)2
CH3CH CH2
HF
Isopropylbenzene
(75%)
Exercise 18.6
C(CH3)3
(CH3)2CHCH2OH
BF3
tert-Butylbenzene
(64%)
remaining 97% forms in the ortho and para positions (63% ortho and
34% para.
Ortho Substitution
CH3 CH3 CH3
NO2 NO2 NO2
H H H
Para Substitution
CH3 CH3 CH3
CH3 CH3
NO2
Site of the more stable
tertiary carbocation.
H
H NO2
Ortho complex Para complex
Meta Substitution
CH3 CH3 CH3
H H H
F
C
F
F
σ complex. Both the ortho and the para σ complexes have one
resonance contributor with a positive charge on the carbon bearing the
CF3 group; whereas, none of the resonance contributors in the meta σ
complex has a positive charge on the carbon bearing the CF3 group.
Ortho Substitution
CF3 CF3 CF3
NO2 NO2 NO2
H H H
Para Substitution
CF3 CF3 CF3
Meta Substitution
CF3 CF3 CF3
H H H
The positive charge on the carbon of the ring and the partial
positive charge on the trifluoromethyl group strongly destabilize the
ortho and para σ complexes.
+ CF3 +
CF3
NO2 These positive sites
repel one another.
H
H NO2
Ortho complex Para complex
Relative Rates
Benzene Toluene (Trifluoromethyl)benzene
Ortho 1 44 4.6 x 10–6
Meta 1 2.4 69. x 10–6
Para 1 59 4.5 x 10–6
Table 18.1. Relative rates for the nitration of benzene, toluene, and
(trifluoromethyl)benzene.
the meta σ complex contributors are more stable than the others.
Nevertheless the meta σ complex benefits from the electron-donating
ability of the methyl group. Thus, the σ complex from toluene is more
stable than the σ complex formed from benzene, and it reacts faster than
benzene in electrophilic aromatic substitution reactions. The presence
of the methyl group increases the rate of reaction of toluene at all
three sites, especially the ortho and para positions. Because of this
increased rate of reaction in comparison to benzene, the methyl group
is called an activating ortho, para director.
The greater the stability of the product of a reaction in a
family of related reactions, in this case the intermediate σ complex,
the less energy of activation required to form it. Figure 18.3 shows the
relationship of the energies of activation for the formation of benzene’s
one σ complex and toluene’s three. All three σ complexes from the
reaction of toluene are more stable than the σ complex from benzene;
therefore, they need less energy to form.
Figure 18.3 also shows the energy relationship among the
various σ complexes of toluene. Recall from Section 18.5 that 63% of
the product forms in the ortho position and 34% in the para position.
Thus, the ortho position has nearly twice as much substitution as does
the para position. Because there are two ortho sites and only one para
site, you would expect exactly a 2:1 ratio of product if both had
identical reactivity. However, the methyl group sterically hinders the
ortho position slightly, which causes the reaction to require more
energy to place the electrophile in an ortho position.
+ NO2
‡ Meta
G1
Ortho
Para
CH3
+ NO2 + NO2
Reaction Progress
Figure 18.3. The relative activation energies for the formation of the σ complexes of
benzene and ortho, meta, and para substitutions in toluene.
+ NO2
Ortho
Para
Meta
‡
G1
CF3
+ NO2 + NO2
Reaction Progress
Figure 18.4. The relative activation energies for the formation of the σ complexes of
benzene and ortho, meta, and para substitutions in (trifluoromethyl)benzene.
Exercise 18.8
•• •• ••
• •
• OCH3 •
• OCH3 • OCH3 •
• OCH3
H E H E H E H E
The first three resonance structures are identical to the ones drawn
for para-substituted toluene in Section 18.5. The fourth resonance
structure, however, is particularly stable because the nonbonding pair
of electrons on the oxygen atom helps stabilize the positive charge. In
fact, this is the major resonance contributor because all the atoms
have filled orbitals in their valence shells.
All meta directors inductively destabilize the σ complex
because they have a partial positive or a full positive charge on the
atom attached to the ring thereby discouraging substitution at sites
ortho or para to the substituent. By default, the reactive site is the
meta position because it is not directly destabilized by the substituent.
For example, the least stable resonance contributor for nitrobenzene
has a positive charge on the carbon bearing the nitrogen. The nitro
group nitrogen also has a formal positive charge.
•• ••
•
• O O••
••
N
H E
Ar Ortho, Para
Reference H
Deactivating ••
X••
•• Ortho, Para
(X=F,Cl,Br,I)
••
CH2••
X•• Ortho, Para
Strongly deactivating ••
•
• O Meta
CR
••
•
• O Meta
••
COR
••
••
•
• O Meta
CH
••
•
• O Meta
••
CCl
••
•
•
C N •• Meta
SO3H Meta
Meta
NH3
NO2 Meta
Meta
NR 3
Ortho Substitution
•• •• ••
•
•OH •
• OH •
•OH •
• OH
NO2 NO2 NO2 NO2
H H H H
Major contributor
Para Substitution
•• •• •• ••
•
•OH •
• OH •
• OH OH
Meta Substitution
•• •• ••
•
• OH •
• OH •
• OH
H H H
Br Br Br Br
HNO3
+ +
H2SO4
NO2 NO2
NO2
39% 1% 60%
•• ••
Br
••
•
• Br••
Both resonance
H H contributors have
full octets on all
NO2 NO2 atoms.
•• ••
Br•• Br••
••
NO2 NO2
H H
Exercise 18.9
OH OH
Br Br
Br2
H2O
Br
2,4,6-Tribromophenol
(100%)
a)
Br
Br2
Fe
Solution
Bromine is a weakly deactivating ortho, para directing group. Thus, you will
get a mixture of ortho and para substitution products. Because bromine is
large, there will be a larger fraction of para than ortho product.
Br Br Br
Br2
+
Fe
Br Br
b)
OCH3
CH3CH2CH2Cl
AlCl3
Solution
The methoxy group is an activating ortho, para directing group. Thus, you
will get a mixture of ortho and para substitution. Because the oxygen is
small, the ortho product will likely predominate. In this case, the electrophile
will rearrange to form a secondary carbocation. Thus, the product is an
isopropyl-substituted anisole.
c)
O
COCH3
HNO3
H2SO4
Solution
The ester functional group is a deactivating meta directing group. Thus, the
product will have a nitro group substituted meta to the ester group.
O O
COCH3 COCH3
HNO3
H2SO4
NO2
O
O
CCH3
CH3CCl
AlCl3
••
•
• O •
• O AlCl3
AlCl3
CH3CH2CCl CH3CH2CCl
Acid-base complex
••
•
• O
•
AlCl3 CH3CH2C
• O
CH3CH2CCl
••
CH3CH2C O
Acyl cation
An acyl cation reacts with benzene in much the same way as any other
electrophile.
•• ••
••
•
• O •
• O
•
• O
CCH2CH3 CCH2CH3
CH3CH2C AlCl4
H
O O O O
AlCl3
RC OCR RC + Cl3Al OCR
Exercise 18.10
In some low polarity solvents, the acid/base complex does not readily
form the acylium ion. Thus, the acid/base complex is the reacting
species. Write a mechanism for this reaction. (Hint: Refer to Chapter 8
for a starter.)
O
O
CR CH2R
RCCl reduce
AlCl3
O
O
CCH2CH3 CH2CH2CH3
CH3CH2CCl Zn(Hg)
AlCl3 HCl
Propylbenzene
(71% overall)
O
O
CC(CH3)3 CH2C(CH3)3
(CH3)3CCCl NH2NH2, KOH
AlCl3 Diethylene glycol
reflux
(2,2-Dimethyl-1-propyl)benzene
(76% overall)
Exercise 18.11
a) tert-Butylbenzene b) 2-Methyl-1-phenylpropane
c) Butylbenzene d) Toluene
e) Neopentylbenzene [PhCH2C(CH3)3]
Sample solution
c)
O
O
CCH2CH2CH3
CH3CH2CH2CCl
AlCl3
NH2NH2, KOH
Diethylene glycol
reflux
CH2CH2CH2CH3
O O
O
AlCl3
OH
O
O
Phthalic anhydride o-Benzoylbenzoic acid
(55%)
Discussion Questions
1. The Friedel-Crafts acylation does not work well with a carboxylic acid because an
acylium ion cannot readily form from the acid. Explain why the acylium ion cannot
readily form.
2. What is the purpose of dissolving the crude product in sodium carbonate solution?
CH3 CH3
Br
Br2
Fe
CH3 CH3
All sites are
equivalent
CH3 CH3
Br
Br2
Fe
C(CH3)3 C(CH3)3
More sterically hindered
CH3 CH3
Br
Br2
Fe
NO2 NO2
Ortho to the CH3
and meta to the NO2
Activated by NH2
NH2 NH2
Br
Br2
Fe
Cl Cl
Deactivated by Cl
a)
O
NHCCH3
Cl
Solution
Because of the nonbonding electrons on the nitrogen attached to the ring, the
amide group is a strongly activating ortho, para director. The chlorine is a
weakly deactivating ortho, para director. Thus, the sites ortho to the amide
group are more reactive than the sites ortho to the chlorine.
O O
NHCCH3 NHCCH3
Br2
Fe
Cl Cl Br
b)
O
O2N COCH3
Both the ester and the nitro groups are deactivating meta directors. Because
they are meta to each other, they both direct towards the same site on the
ring.
O O
Br
Exercise 18.12
Sample solution
OH OH
NO2
HNO3
H2SO4
CH3 CH3
NO2
8 1
9 NO2
7 2
HNO3
+
6 3 CH3COOH
10
5 4
(CH3CO)2O
warm
Naphthalene 1-Nitronaphthalene 2-Nitronaphthalene
91% 9%
Reaction at C1
H NO2 H NO2 H NO2
H NO2 H NO2
The first two contributors possess two factors that give them more
stability than the other three resonance contributors and the
resonance contributors in the C2 σ complex. Both resonance
contributors have one ring in which the aromaticity is undisturbed,
and each of the two aromatic contributors in the other ring also has an
allylic resonance. Thus, these two contributors have a special stability
due to the delocalization of the positive charge between C2 and C4.
On the other hand, only one of the resonance contributors for
the reaction at C2 has aromatic character in either ring. The
remaining resonance contributors are not aromatic. Formation of the
C2 σ complex is a higher energy pathway than electrophilic attack at
C1.
Reaction at C2
NO2 NO2 NO2
H H H
NO2 NO2
H H
Steric interference
Less interference
H SO3H H
SO3H
Exercise 18.13
Following an analysis similar to that above, find the most reactive site
for electrophilic substitution on anthracene.
Anthracene
18.11 Diazotization
An aryl diazonium salt Chemists synthesize aryl diazonium salts from aryl amines.
has the formula
ArN2⊕. An aryl
diazonium salt is made NH2 N N••
from an aryl amine. NaNO2, HCl
Cl
H2O, 0-5oC
The electrophile used to react with the amine to form the aryl
diazonium salt is the mild ⊕NO electrophile. The following
mechanism shows how the aryl diazonium salt forms from HCl and
NaNO2. The ⊕NO ion is resonance-stabilized, so it forms relatively
easily.
•• ••
NaNO2 + HCl HO
••
N O•• + NaCl
•• ••
•• ••
HO N O •• + H HO N O ••
••
H
••
•
• N O••
•• ••
HO N O•• + H2O
H
N
•
• O••
H
•• •• •• •• ••
••
NH2 •• N N O•• N N O •
•
•
• N O •
•
H H
•• •• ••
•• •• ••
N N •• N N OH2 N N OH
••
H
••
H2O••
•• •• H
N N•• •• N N
OH
••
OH
••
•• ••
N N
••
OH
••
4-Phenylazophenol
An azo compound
N N•• OH
+
O2N COOH
N N OH
COOH
O2N
Alizarin yellow
(82%)
N N•• N(CH3)2
+
HO3S
N N N(CH3)2
HO3S
Methyl orange
(70%)
HO
N N••
HO
+
O2N
N N
O2N
Para red
(76%)
N(CH3)2
NH2
1) Na2CO3
2) NaNO2, HCl < 5oC
HO3S N N
Sulfanilic acid
HO3S N(CH3)2
Methyl orange
(70%)
Dissolve 0.6 g of anhydrous sodium carbonate in 50 mL of water. Add 1.75 g (10 mmol)
of sulfanilic acid to the solution and heat until it dissolves. Cool the solution to room
temperature and add 0.8 g of sodium nitrite. Cool in an ice bath until the temperature
is below 10oC then add 2.5 mL of concentrated hydrochloric acid. A precipitate of
diazonium salt will form. Keep this reaction mixture cold. In a separate flask, dissolve
1.3 mL (10 mmol) of N,N-dimethyl aniline in 1.0 mL of glacial acetic acid. Add this
solution to the reaction mixture. Keep cold for about 15 minutes. During this time a
red precipitate will form. Add 15 mL of 10% sodium hydroxide. Check to see if the
solution is basic. If not, add more 10% sodium hydroxide until the solution is basic.
Heat this solution to boiling and boil until most of the solid is dissolved. Carefully add
5 g of sodium chloride to the boiling solution. Allow the mixture to cool, then cool it
further in ice. Filter the solution. Wash the flask with two ice-cold portions of
saturated sodium chloride solution and pour these through the methyl orange in the
filter. Dissolve the solid in 150 mL of boiling water. All of the solid will not dissolve,
but the sodium chloride contaminant will dissolve. Boil the solution for 5-10 minutes.
Cool the solution to room temperature then place in an ice bath. When cold, filter the
solid and allow it to dry. Yield of methyl orange is 2.15 g (70%), m.p. decomposes.
Discussion Questions
1. The pH of the reaction mixture is important to the course of the coupling reaction
with N,N-dimethylaniline. The rate of the coupling reaction increases with
increasing pH. Explain this behavior.
2. Methyl orange, and all other azo compounds, is brightly colored. What molecular
features of azo compounds explain the colors of these molecules?
Exercise 18.14
a) b)
CH3 N N
N N
(CH3)2N SO2NH2
CH3 OCH3
c) d)
N N N N
NH2 N(CH3)2
NO2
Cl
Sample Solution
c)
NH2 N N
NaNO2, H2SO4 NH2
H2O, 0 - 5oC
NH2
NO2 NO2
[SIDEBAR]
Sulfa Drugs
The introduction of sulfa drugs in the 1930s hailed the
beginning of modern drug therapy. Before their introduction, even a
minor bacterial infection could become potentially life-threatening.
Because at first no one understood how sulfa drugs worked, even
physicians considered them as almost magical.
NH2
N N
H2N SO2NH2
p-[(2,4-Diaminophenyl)azo]benzenesulfonamide
NH2
N N H2N
in vivo
H2N H2N
SO2NH2 COOH
Sulfanilamide p-Aminobenzoic acid
H2N H2N
S N
SO2NH N SO2NH N
Sulfathiazole Sulfadiazine
NH2 X
NaNO2, H2SO4 CuX
H2O, 0 - 5oC (X = Cl, Br or CN)
NH2 Br
NaNO2, H2SO4 CuBr
H2O, 0 - 5oC
NO2 NO2
1-Bromo-3-nitrobenzene
(87%)
NH2 CN
NaNO2, H2SO4 CuCN
H2O, 0 - 5oC
Cl Cl
2-Chlorobenzonitrile
(75%)
NH2 Cl
NaNO2, H2SO4 CuCl
H2O, 0 - 5oC
NH2O2S NH2O2S
4-Chlorobenzenesulfonamide
(71%)
Fluorobenzene
(83%)
3-Iodotoluene
(82%)
NH2 OH
NaNO2, H2SO4 warm
H2O, 0 - 5oC
CH3 CH3
3-Methylphenol
(74%)
Br Br
NH2 H
NaNO2, H2SO4 H3PO2
H2O, 0 - 5oC
Br Br Br Br
2,4,6-Tribromobenzene
(68%)
NH2 D
NaNO2, H2SO4 D3PO2
H2O, 0 - 5o
Deuterobenzene
(81%)
Exercise 18.15
Cl OH
NO2 NO2
NaOH H
80oC
NO2 NO2
2,4-Dinitrophenol
(95%)
•• ••
•• ••
•
• Cl•• •
O••
•• ••
•
O••
•
• OH •
••
O••
• •
• Cl•• •
•OH • •
N •• N N
O •• •
• OH
••
•
• O•• O••
•• ••
••
•• •• •• ••
•• • ••
•
Cl•• OH • O•• •• •• •
O•• Cl••
••
OH O
• •
• •
• •
• Cl •• •
•OH • •
• •
•
• •
N N N
• ••
•
O •
•• • O •
• O••
•• ••
••
Fluorine is also the smallest of the halides, thus giving less steric
hindrance to the reaction of the nucleophile than the other halides.
Table 18.3 shows the relative rates of reaction for the halogens.
Substitution Rate
None 1.4 x 10–8
4-Nitro 1
2,4-Dinitro 2.9 x 105
2,4,6-Trinitro Too fast
to measure
Table 18.4. Relative rate of reaction for various chloronitrobenzenes with sodium
methoxide in methanol at 50oC.
Exercise 18.16
18.14 Benzyne
Although aryl halides without electron-withdrawing
substituents also undergo nucleophilic substitution reactions, they
require extreme conditions or very strong bases. For example the
commercial “Dow process” used for making phenol involves heating
chlorobenzene with sodium hydroxide at 350oC.
Cl OH
NaOH H
350oC
Phenol
(98%)
Cl NH2
NaNH2
NH3, -33oC
Aniline
(100%)
NaNH2
+
NH3, –33oC
NH2
Br NH2
4-Methylaniline 3-Methylaniline
(p-Toluidine) (m-Toluidine)
50% 50%
a Benzyne
CH3
Poor overlap
After benzyne forms, the amide ion can attack it on either end
of its weak, reactive triple bond. This part of the reaction produces a
benzene anion. The benzene anion then removes a proton from an
ammonia molecule giving the final products, 3-methylaniline and 4-
methylaniline.
•• NH2 NH2
H
3-Methylaniline
F F
o-Bromofluorobenzene
(78%)
Synthesis of Trypticene
NH2
(CH3)2CHCH2CH2NO2
COOH
Anthranilic acid
Trypticene
(70%)
Discussion Questions
Exercise 18.17
O
CCH3
?
Br
p-Bromoacetophenone
O
O
CCH3
CH3CCl
AlCl3
Br Br
4-Bromoacetophenone
O
O
CCH3
Br2 CH3CCl
Fe AlCl3
Br Br
18.2 (page 000), however, that the sulfonic acid group brominates meta
to itself, which would be in the wrong position. An amine group, on the
other hand, is an ortho, para director, so it would place the bromine in
the correct position. In fact, an amine group is such a strong activating
group that it usually causes trisubstitution on a benzene ring.
NH2 NH2
Br Br
Br2
H2O, NaHCO3
Br
2,4,6-Tribromobenzene
NO2 NH2
Zn (or Sn)
HCl
NO2 NH2
HNO3 Zn
H2SO4 HCl
Br2
H2O, NaHCO3
NH2
Br Br Br Br
H3PO2 NaNO2, H2SO4
H2O, 0 - 10oC
Br Br
OH
?
O2N
4-Nitro-3-propylphenol
OH OH
O2N
O2N
OH
O2N
NH2 OH
NaNO2, H2SO4 warm
H2O, 0 - 10oC
3-Propylphenol
O
NO2
CH3CH2CCl HNO3
AlCl3 H2SO4
O O
1-(3-Nitrophenyl)-1-propanone
NO2 NH2
Zn(Hg)
HCl
O
3-Propylaniline
O
NO2
CH3CH2CCl HNO3
AlCl3 H2SO4
O O
Zn(Hg)
HCl
OH OH NH2
HNO3 warm NaNO2, H2SO4
Exercise 18.18
a)
Cl
Br Br
CH3CH2CH2Cl Cl2
AlCl3 Fe
CH3CH2CH2
b)
OCH3 OCH3
NO2
HNO3 Br2
H2SO4 Fe
Br
c)
COOH COOH
O
CH3CH2CCl HNO3
AlCl3 H2SO4
O2N CCH2CH3