Electrophilic Aromatic
Substitution
H
+
H
H
H
H
H
H
H + E+
H
H
Lecture 4
H E
H
H
Chemistry 391 10/14/02
H
E + H+
H
H
H
Hydrogenolysis
z
Hydrogenolysis: Bond cleavage by H2
– benzylic alcohols and ketones are cleaved under
conditions of catalytic hydrogenation
OH
H2 / Pd(C)
O
OH
H2 / Pd(C)
Chemistry 391 10/14/02
Hydrogenolysis
z
Hydrogenolysis: cleavage of a single bond by H2
– benzylic ethers are unique in that they are also cleaved
under conditions of catalytic hydrogenation
H2
O
Pd/C
O
H2
Pd/C
Chemistry 391 10/14/02
CH3
+
HO
CH3
+
HO
Chemistry 391 10/14/02
Nitrous acid….HNO2
Chemistry 391 10/14/02
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Diazonium Salts
z
The -N2+ group of an arenediazonium salt can be
replaced in a regioselective manner by these groups
Ar-N 2
+
(-N 2 )
H2 O
Ar-OH
HBF 4
Ar-F
HCl, CuCl
Ar-Cl
HBr, CuBr
Ar-Br
KCN, CuCN
Ar-CN
KI
Ar-I
H3 PO 2
Ar-H
Schiemann
reaction
Sandmeyer
reaction
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Di- and Polysubstitution
z
Existing groups on a benzene ring influence
further substitution in both orientation and rate
z
Orientation:
– certain substituents direct preferentially to ortho & para
positions; others direct preferentially to meta positions
– substituents are classified as either
ortho-para directing or
meta directing
Chemistry 391 10/14/02
Di- and Polysubstitution
z
Rate:
– certain substituents cause the rate of a second
substitution to be greater than that for benzene
itself; others cause the rate to be lower
– substituents are classified as
•
•
activating toward further substitution, or
deactivating
Chemistry 391 10/14/02
Di- and Polysubstitution
z
-OCH3 is ortho-para directing and activating
OCH 3
Br 2
CH 3 CO 2 H
Anisole
Chemistry 391 10/14/02
OCH 3
Br
o-Bromoanisole
(4%)
OCH 3
+
+ HBr
Br
p-Bromoanisole
(96%)
Di- and Polysubstitution
z
-NO2 is meta directing and deactivating!
NO 2
+ HNO 3
H 2 SO 4
NO 2
NO 2
Nitrobenzene
NO 2
+
NO 2
m-Dinitrobenzene
(93%)
Chemistry 391 10/14/02
o-Dinitrobenzene
NO 2
+
NO 2
p-Dinitrobenzene
Less than 7% combined
Methyl Group
CH3
Toluene undergoes nitration
1000 times faster than
benzene.
A methyl group is an
activating substituent.
Chemistry 391 10/14/02
Trifluoromethyl Group
CF3
Trifluoromethylbenzene
undergoes nitration 40,000
times more slowly than benzene .
The trifluoromethyl group is a
deactivating substituent.
Chemistry 391 10/14/02
Relative rates of
Nitration
OH
1000
Cl
H
1.0
0.033
Reactivity
Chemistry 391 10/14/02
NO2
6x10-8
Real Fast
Pretty fast
Kinda slow
Pretty slow
Slow
Real Slow
Chemistry 391 10/14/02
Effect on Regioselectivity
• Ortho-para directors direct an incoming
electrophile to positions ortho and/or para to
themselves.
• Meta directors direct an incoming electrophile to
positions meta to themselves.
• All meta directors are deactivating
• All ortho-para directors are activating except
halogen
Chemistry 391 10/14/02
Theory of Directing Effects
• So…what’s going on here????
• The rate of EAS is limited by the slowest step in the
mechanism…duh
• For EAS, the rate-limiting step is attack of E+ on the
aromatic ring to form a resonance-stabilized cation
intermediate
• The more stable this cation intermediate, the faster the ratelimiting step and the faster the overall reaction
Chemistry 391 10/14/02
Di- and Polysubstitution
z
Alkyl groups, phenyl groups, and all groups in
which the atom bonded to the ring has an
unshared pair of electrons are ortho-para
directing. All other groups are meta directing.
z
All ortho-para directing groups except the
halogens are activating toward further substitution.
The halogens are weakly deactivating
Chemistry 391 10/14/02
ortho Nitration of Toluene
CH3
H
+
H
H
NO2
H
H
Write the remaining resonance
structures and then do the same for
meta attack.
ortho Nitration of Toluene
CH3
H
+
H
H
NO2
H
H
CH3
H
H
NO2
H
+
H
H
ortho Nitration of Toluene
CH3
H
+
H
H
NO2
H
H
CH3
H
H
NO2
H
+
H
H
CH3
H
H
+
NO2
H
H
H
this resonance
form is a tertiary
carbocation
ortho Nitration of Toluene
CH3
H
+
H
H
NO2
H
H
CH3
H
H
NO2
H
+
H
H
CH3
H
+
H
NO2
H
H
H
the rate-determining intermediate in the ortho
nitration of toluene has tertiary carbocation
character
meta Nitration of Toluene
CH3
H
+
H
H
H
H
NO2
meta Nitration of Toluene
CH3
H
+
H
H
CH3
H
H
H
NO2
H
H
+
H
H
NO2
meta Nitration of Toluene
CH3
H
H
+
CH3
H
H
H
NO2
H
+
CH3
H
H
H
NO2
H
H
+
H
H
H
all the resonance forms of the rate-determining
intermediate in the meta nitration of toluene have
their positive charge on a secondary carbon
H
NO2
Nitration of Toluene: Interpretation
z
The rate-determining intermediates for ortho and
para nitration each have one resonance form that is
a tertiary carbocation. All of the resonance forms
for the rate-determining intermediate in meta
nitration are secondary carbocations.
z
Tertiary carbocations, being more stable, are
formed faster than secondary ones. Therefore, the
intermediates for attack at the ortho and para
positions are formed faster than the intermediate
for attack at the meta position. This explains why
the major products are o- and p-nitrotoluene.
Nitration of Toluene: Partial Rate Factors
z
The experimentally determined reaction rate can
be combined with the ortho/meta/para distribution
to give partial rate factors for substitution at the
various ring positions.
z
Expressed as a numerical value, a partial rate
factor tells you by how much the rate of
substitution at a particular position is faster (or
slower) than at a single position of benzene.
Nitration of Toluene: Partial Rate Factors
CH3
1
1
1
42
42
1
1
2.5
2.5
1
z
z
z
58
All ring positions in toluene are more reactive than any
position of benzene.
A methyl group activates all of the ring positions but the
effect is greatest at the ortho and para positons.
Steric hindrance by the methyl group makes each ortho
position slightly less reactive than para.
Let’s try Some More
Adding a Second Substiuent
Methoxy is is therefore an “o-p director”
Chemistry 391 10/14/02
Adding a Second Substiuent
Nitro is therefore a “meta director”
Chemistry 391 10/14/02
Di- and Polysubstitution
Sequence matters!
CH 3
CO2 H
HNO3
K2 Cr 2 O7
H2 SO 4
H2 SO 4
CH 3
K2 Cr 2 O7
H2 SO 4
Chemistry 391 10/14/02
NO2
NO2
p-Nitrobenzoic
acid
CO2 H
CO2 H
HNO3
H2 SO 4
NO2
m-Nitrobenzoic
acid
Synthesis of m-Bromoacetophenone
Br
CH3
O
Br
CH3
O
Which substituent
should be introduced
first?
Chemistry 391 10/14/02
Let’s use it!!
NO2
HNO3
H2SO4
NO2
Is this ok????
H2SO4
CH2CH3
Chemistry 391 10/14/02
CH3CH2Cl
AlCl3
CH2CH3
CH3CH2Cl
AlCl3
HNO3
NO2
CH2CH3
Work Backwards!!
Make this...
Br
CH3CH2Cl
AlCl3
Br
Br2
FeBr3
Br
H2, Pd/C
O
Br
Br2
FeBr3
O
O
CH3C Cl
AlCl3
Chemistry 391 10/14/02