Download Electrophilic Aromatic Substit

Electrophilic
Aromatic Substitution
Electrophile substitutes for a hydrogen on
the benzene ring.
=>
Chapter 17
1
Mechanism
=>
Chapter 17
2
Energy Diagram
for Bromination
=>
Chapter 17
3
Bromination of Benzene
• Requires a stronger electrophile than Br2.
• Use a strong Lewis acid catalyst, FeBr3.
Br Br
FeBr3
Br
Br
H
H
H
H
H
FeBr3
H
H
H
Br
Br
Br
FeBr3
+
H
_
+ FeBr4
H
H
H
Br
+
Chapter 17
HBr
4
Chlorination
and Iodination
• Chlorination is similar to bromination.
Use AlCl3 as the Lewis acid catalyst.
• Iodination requires an acidic oxidizing
agent, like nitric acid, which oxidizes the
iodine to an iodonium ion.
+
H
+
+ HNO3 + 1/2 I2
I
+
NO2 + H2O
=>
Chapter 17
5
Nitration of Benzene
Use sulfuric acid with nitric acid to form
the nitronium ion electrophile.
O
H O
S
O H
O
H O
H O N
H O N
+
O
O
O
H O
H O N
+
O
O
H2O +
N+
O
Chapter 17
_
+ HSO4
NO2+ then forms a
sigma complex with
benzene, loses H+ to
form nitrobenzene. =>
6
Sulfonation
Sulfur trioxide, SO3, in fuming sulfuric acid
is the electrophile.
O
_
O
O
S
S+
O
O
O
O
O
S+
_
O
O
_
O
S
O
O
H O
S O
+
O
H
_
S +
O
O
HO
O
S
O
benzenesulfonic acid
=>
Chapter 17
7
Desulfonation
• All steps are reversible, so sulfonic acid
group can be removed by heating in
dilute sulfuric acid.
• This process is used to place deuterium
in place of hydrogen on benzene ring.
D
H
H
H
H
H
H
large excess
D2SO4/D2O
D
D
D
D
=>
D
Chapter 17
Benzene-d6
8
Nitration of Toluene
• Toluene reacts 25 times faster than benzene.
The methyl group is an activator.
• The product mix contains mostly ortho and
para substituted molecules.
=>
Chapter 17
9
Sigma Complex
Intermediate
is more
stable if
nitration
occurs at
the ortho
or para
position.
Chapter 17
=>
10
Energy Diagram
Chapter 17
=>
11
Activating, O-, PDirecting Substituents
• Alkyl groups stabilize the sigma complex
by induction, donating electron density
through the sigma bond.
• Substituents with a lone pair of electrons
stabilize the sigma complex by resonance.
OCH3
+
OCH3
NO2
NO2
+
H
H
Chapter 17
=>
12
NITRATION OF ANISOLE
Nitration of Anisole
BENZENIUM ION INTERMEDIATES
O CH3
+
O
N+
O
O CH3
H
NO2
+
H
ortho
O CH3
O CH3
H
+
+
H
NO2 H
meta
para
H NO2
activated
ring
O CH3
O CH3
NO2
actual
products
ortho + para
NO2
ortho
O CH3
H
NO2
+
H
+
:O
+ O CH
3
H
NO2
CH3
H
+
NO2
O CH3
H
NO2
H
H
H
EXTRA!
H
para
+
NO2
H
:O
O CH3
O CH3
H
O CH3
H
O CH3
H
+
meta
+
NO2
H
NO2
+O CH
3
CH3
O CH3
+
+
+
H NO2
H
H
H
H
H NO2
H NO2
EXTRA!
H NO2
Energy Profiles
NITRATION OF ANISOLE
RECALL:
HAMMOND
POSTULATE
benzenium
intermediate
meta
ortho
para
benzenium
intermediates
have more
resonance
ortho-para
Ea
director
BENZENIUM IONS GIVE ELIMINATION INSTEAD OF ADDITION
O CH3
H
+
H
O CH3
H
_
:B
NO2
X
H
doesn’t happen
resonance would be lost
NO2
addition
O CH3
H
O CH3
H
+
H
B
ADDITION REACTION
NO2
NO2
:B
_
elimination
ELIMINATION REACTION
restores aromatic ring
resonance
( 36 Kcal / mole )
The Amino Group
Aniline reacts with bromine water (without a
catalyst) to yield the tribromide. Sodium
bicarbonate is added to neutralize the
HBr that’s also formed.
NH2
NH2
Br
Br
3 Br2
H2O, NaHCO3
Br
Chapter 17
=>
18
Summary of
Activators
Chapter 17
19
=>
Deactivating MetaDirecting Substituents
• Electrophilic substitution reactions for
nitrobenzene are 100,000 times slower
than for benzene.
• The product mix contains mostly the
meta isomer, only small amounts of the
ortho and para isomers.
• Meta-directors deactivate all positions
on the ring, but the meta position is less
deactivated.
=>
Chapter 17
20
Ortho Substitution
on Nitrobenzene
=>
Chapter 17
21
Para Substitution
on Nitrobenzene
=>
Chapter 17
22
Meta Substitution
on Nitrobenzene
=>
Chapter 17
23
Energy Diagram
=>
Chapter 17
24
Structure of MetaDirecting Deactivators
• The atom attached to the aromatic ring
will have a partial positive charge.
• Electron density is withdrawn inductively
along the sigma bond, so the ring is less
electron-rich than benzene.
=>
Chapter 17
25
Summary of Deactivators
=>
Chapter 17
26
More Deactivators
=>
Chapter 17
27
Halobenzenes
• Halogens are deactivating toward
electrophilic substitution, but are ortho,
para-directing!
• Since halogens are very electronegative,
they withdraw electron density from the
ring inductively along the sigma bond.
• But halogens have lone pairs of electrons
that can stabilize the sigma complex by
resonance.
=>
Chapter 17
28
Sigma Complex
for Bromobenzene
Para attack
Ortho attack
Br
Br
+
(+)
+
E
Br
Br
(+)
H
E
(+)
+
(+)
(+)
E+
(+)
H E
Ortho and para attacks produce a bromonium ion
and other resonance structures.
Meta attack
Br
Br
H
(+)
+
+
H
E
(+)
No bromonium ion
possible with meta attack.
E
=>
Chapter 17
29
Energy Diagram
=>
Chapter 17
30
Summary of
Directing Effects
Chapter 17
31
=>
DIRECTIVITY OF SINGLE GROUPS
ortho, para - Directing Groups
X
Groups that donate
electron density
to the ring.
PROFILE:
X
:X
E+
increased
reactivity
+I Substituent
These groups also
“activate” the ring, or
make it more reactive.
CH3R-
+R Substituent
..
CH3-O..
..
CH3-N-
..
-NH2
The +R groups activate
the ring more strongly
than +I groups.
..
-O-H
..
meta - Directing Groups
X
Groups that withdraw
electron density from
the ring.
PROFILE:
d+
Y
X
Y
d-
E+
decreased
reactivity
-I Substituent
These groups also
“deactivate” the ring,
or make it less reactive.
R
+
N R
R
CCl3
-R Substituent
O
C R
C N
O
+ O
C OR
O
C OH
N
O
-
-SO3H
THE EXCEPTION
Halides - o,p Directors / Deactivating
Halides represent a special case:
..
:X :
E+
+R / -I / o,p / deactivating
-F
-Cl
-Br
-I
They are o,p directing groups
that are deactivating
They are o,p directors (+R effect )
They are deactivating ( -I effect )
Most other other substituents fall
into one of these four categories:
1)
2)
3)
4)
+R / o,p / activating
+I / o,p / activating
-R / m / deactivating
-I / m / deactivating
PREDICT !
CH3
NO2
o,p
m
O
O CH3
C O CH3
o,p
m
DIRECTIVITY OF MULTIPLE GROUPS
GROUPS ACTING IN CONCERT
steric
crowding
o,p director
O CH3
NO2
O 2N
O CH3
m-director
NO2
very
little
formed
HNO3
H2SO4
O CH3
NO2
When groups direct to the
same positions it is easy to
predict the product.
NO2
major
product
GROUPS COMPETING
o,p-directing groups win
over m-directing groups
O CH3
O2N
O CH3
too
crowded
X
HNO3
H2SO4
NO2
NO2
+
O CH3
NO2
NO2
RESONANCE VERSUS INDUCTIVE EFFECT
+R
O CH3
O CH3
NO2
HNO3
H2SO4
CH3
CH3
+I
resonance effects are more
important than inductive effects
major
product
SOME GENERAL RULES
1) Activating (o,p) groups (+R, +I) win over
deactivating (m) groups (-R,-I).
2) Resonance groups (+R) win over inductive (+I) groups.
3) 1,2,3-Trisubstituted products rarely form due to
excessive steric crowding.
4) With bulky directing groups, there will usually be more
p-substitution than o-substitution.
5) The incoming group replaces a hydrogen, it will not
usually displace a substituent already in place.
HOW CAN YOU MAKE ...
O
C O CH3
NO2
O 2N
NO2
NO2
CH3
NO2
only,
no para
CH2CH2CH2CH3
BROMINE - WATER REAGENT
PHENOLS AND ANILINES
BROMINE IN WATER
This reagent works only with highly-activated rings
such as phenols, anisoles and anilines.
..
H O:
..
..
: Br Br :
.. ..
H
.. ..
.. : Br :
..
H O Br
+
..
H
OMe
OMe
H
.. ..
: Br O H
..
+
+
H
bromonium
ion
etc
Br
PHENOLS AND ANILINES REACT
OH
OH
Br2
Br
Br
H2O
Br
NH2
CH3
NH2
Br2
CH3
All available
positions are
bromiated.
Br
H2O
Br
Friedel-Crafts Alkylation
• Synthesis of alkyl benzenes from alkyl
halides and a Lewis acid, usually AlCl3.
• Reactions of alkyl halide with Lewis acid
produces a carbocation which is the
electrophile.
• Other sources of carbocations:
alkenes + HF or alcohols + BF3.
=>
Chapter 17
46
Examples of
Carbocation Formation
Cl
CH3
CH CH3
_
CH3 +
C Cl AlCl3
H3C H
+ AlCl3
_
H2C CH CH3
OH
H3C CH CH3
BF3
F
+
H3C CH CH3
HF
+ BF3
H O
H3C CH CH3
Chapter 17
_
+
H3C CH CH3 + HOBF3
=>
47
Formation of
Alkyl Benzene
CH3
H
+C H
+
CH3
H
F
H
+
CH(CH3)2
CH(CH3)2
F
-
B OH
CH3
F
CH
+
CH3
H
HF
F
B OH
F
=>
Chapter 17
48
Limitations of
Friedel-Crafts
• Reaction fails if benzene has a substituent
that is more deactivating than halogen.
• Carbocations rearrange. Reaction of
benzene with n-propyl chloride and AlCl3
produces isopropylbenzene.
• The alkylbenzene product is more reactive
than benzene, so polyalkylation occurs.
=>
Chapter 17
49
Friedel-Crafts
Acylation
• Acyl chloride is used in place of alkyl
chloride.
• The acylium ion intermediate is
resonance stabilized and does not
rearrange like a carbocation.
• The product is a phenyl ketone that is
less reactive than benzene.
=>
Chapter 17
50
Mechanism of Acylation
O
R C Cl
O
+ _
R C Cl AlCl3
AlCl3
O
+ _
R C Cl AlCl3
_
AlCl4
+
+
R C O
O
O
C
C+
R
+
H
R
Cl
_
AlCl3
+
R C O
O
C
HCl
R +
AlCl3
H
=>
Chapter 17
51
Clemmensen Reduction
Acylbenzenes can be converted to
alkylbenzenes by treatment with
aqueous HCl and amalgamated zinc.
O
O
+ CH3CH2C Cl
1) AlCl3
C CH2CH3
2) H2O
Zn(Hg)
CH2CH2CH3
aq. HCl
=>
Chapter 17
52
Gatterman-Koch
Formylation
• Formyl chloride is unstable. Use a high
pressure mixture of CO, HCl, and catalyst.
• Product is benzaldehyde.
O
H C Cl
CO + HCl
+
AlCl3/CuCl
O
O
C+
C H
_
+
H C O AlCl4
+
HCl
H
Chapter 17
53
=>
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.
=>
Chapter 17
54
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
Chapter 17
CH3
=>
55
Birch Reduction:
Regiospecific
• A carbon with an e--withdrawing group
O
O
is reduced.
C
C
OH
Na, NH3
_
O
H
CH3CH2OH
• A carbon with an e--releasing group
is not reduced.
OCH3
Li, NH3
(CH3)3COH, THF
Chapter 17
OCH3
=>
56
Birch Mechanism
=>
Chapter 17
57
Side-Chain Oxidation
Alkylbenzenes are oxidized to benzoic
acid by hot KMnO4 or Na2Cr2O7/H2SO4.
CH(CH3)2
-
KMnO4, OH
CH CH2
H2O, heat
_
COO
_
COO
=>
Chapter 17
58
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, h
CHCH2CH3
=>
Chapter 17
59