Substituent Effects
Considerations:
Does the substituent ease or hinder the addition of
a second substitution?
When adding the second substituent, what is its
position relative to the first?
E2+
+
E1
E2+
E1+
E2
E2
E2
E1
E1+
E1
E1
Substituent Effects
Nitration Experiment: Relative rate as compared to
benzene.
Starting
Material
Relative
Rate
Ortho
Meta
Para
Comments
25
63%
3%
34%
Activated
ortho/para
2.5 x 10-5
6%
91%
3%
Deactivated
meta
CH3
CF3
Reactivity
Resonance and Induction both affect placement of
substituents.
Reactivity
NH2 OCH3
OH
Alkyl
CH3 H
NHCCH3
Cl
F
I
Br
O
Ortho/Para Directing
Activating
Ortho/Para
Directing
Deactivating
O
C-H
O
C-OH
SO3H
NO2
+
C-O-CH3 C-CH3 C N NR3
O
O
Meta Directing
Deactivating
Electronic Effects
Resonance Effect: Occurs through pi system in
resonance structures.
Electron Donating Groups push pi electrons
towards arene.
Electron Withdrawing Groups pull pi electrons
from arene.
Inductive Effect: Works through sigma system via
electronegativity.
Electron Donating Groups push sigma electrons
towards arene.
Electron Withdrawing Groups pull sigma electrons
from arene.
Electron Donating Groups
Lone pairs on neighboring atoms.
Activates by increasing the electron
density on the ring.
Resonance Donating Effect: EDG’s
are ortho- para- directors because
resonance places electrons in
these positions, making these
areas more nucleophilic.
D
D +
D+
D
-
-
-
δ+
EDG
+
δ-
δ-
δ-
Electron Withdrawing Groups
Pi electrons from arene are pulled towards
electronegative atoms.
Deactivates ring and decreases electron
density on ring.
Resonance Withdrawing Effect: EWG’s are
meta directors. Resonance decreases
electron density on ortho and para
positions, making these positions less
nucleophilic.
-
O
C HR
O
-
C HR
O
C HR
+
-
O
C HR
δEWG
δ+
δ+
+
+
δ+
Halogens
Halogens have both inductive electron withdrawing
properties (electronegativity) and resonance
donating properties (lone pair donation).
Halogens are deactivating. Inductive effects lowers
reactivity.
Halogens are an ortho-/para- resonance director,
controlling regiochemistry due to the stability of
the intermediates.
Learning Check
Arrange the compounds below in order of
decreasing rate of chlorination.
A)
B)
C)
D)
1>2>3
2>3>1
3>2>1
1>3>2
Sterics
The size of the alkyl group –R increases and ‘blocks’
ortho positions.
R
HNO3
R
NO2
R
R
H2SO4
O2N
R-
NO2
Ortho-%
Meta-%
Para-%
-CH3
58
4
37
-CH2CH3
49
6
45
-CH(CH3)2
30
8
62
-C(CH3)3
16
11
73
Learning Check
Which substituent is classified as deactivating
and ortho-para directing in electrophilic
aromatic substitution?
A) -Cl
B) -CH=O
C) -NH2
D) -SCH3
Learning Check
1. Why are esters (-OCOR) and amides (-NHCOR) less
activating than ethers (-OR) and amines (-NH)?
The lone pairs in the esters and amides are involved in C=O
resonance and are less available than ethers and amines.
2. Why do esters and amides appear in the table twice, once
as an EDG and once as an EWG?
If they are attached to the benzene at N or O, it has lone pairs
to donate. If it attaches at C, it doesn’t and acts as an
EWG.
Learning Check
3. Why are amines (-NH2) better activators than
alcohols (-OH)?
Nitrogen is less electronegative than oxygen, so it
donates more.
Making Polysubstituted Benzenes
Two factors are used to determine order of reaction:
Regiochemistry: Where it reacts.
Reactivity: Some substituents are activators or
deactivators.
Making Polysubstituted Benzenes
CH3
O
O
CH3
O
O
AlCl3
CH3
CH3
CH3
CH3
Br2
Fe
NO2
NO2
Br
-R is an ortho, para
director. Since ortho is the
only available spot, that is
where the ketone goes.
-R is an ortho, para
director. Nitro is a meta
director.
Substituents reinforce
positions.
Making Polysubstituted Benzenes
OH
OH
Br
Br2
Fe
CH3
CH3
CH3
CH3
NO2
HNO3
H2SO4
H3 C
C
CH3
CH3
H3C
C
CH3
CH3
Both are ortho, para
directors but –OH is
stronger.
Strongest activator
controls positioning.
Both are ortho para
directors.
Activations that are similar
are controlled by steric
effects. Therefore, NO2
goes closer to methyl.
Learning Check
Which positions are activated for chlorination on
the compound shown below?
A)
B)
C)
D)
2 and 3
1 and 3
2 and 4
1 and 4
Making Polysubstituted Benzenes
Basic concepts for synthesis of polysubstituted
aromatic compounds:
1. Check the order of reactions for compatibility.
2. Other reactions can change directing effects:
acyl vs. alkyl.
3. Introduce the more activating group first allows
for easier addition of other substituents.
Example
Synthesize m-bromonitrobenzene from benzene:
Retrosynthesis:
Br
O
O
N
O
Bromine and the nitro
group are meta to each
other.
Bromine is an ortho, para
director.
N
O
The nitro group would
need to be added first.
Example
Synthesize m-bromonitrobenzene from benzene:
Synthesis:
Br
HNO3
H2SO4
O
N
O
Br2
Fe
O
N
O
Example
Synthesize p-nitrobenzoic acid:
Retrosynthesis:
O
OH
CH3
N
O
N
O
O
O
CH3
CH3 is an ortho, para
director, add the nitro
group after the CH3 group.
Neither group directs
Carboxylate comes from
correctly.
There must be an oxidation of a CH3 group.
intermediate step.
Example
Synthesize p-nitrobenzoic acid:
Synthesis:
O
CH3
CH3
CH3Cl
HNO3
[O]
AlCl3
H2SO4
KMnO4
N
O
O
OH
N
O
O
Learning Check
Which of the following is the most reasonable way to
begin an effective synthesis of the
compound shown?
A)
B)
C)
D)
Treat benzene with isopropyl chloride and AlCl3.
Treat chlorobenzene with propene and AlCl3.
Treat benzene with 2-chloropropene and AlCl3.
Treat benzene with 3-chloropropene and AlCl3.
Electrophilic Aromatic Substitution of
Polycyclics
Naphthalene, anthracene, etc are aromatic like
benzene, but are more reactive.
They are also less selective than benzene and give a
mixture of products.
E
E
1
2
E+
+
+
1- or alpha- substitution
2- or beta- substitution
Electrophilic Aromatic Substitution of
Polycyclics
Nitration of naphthalene gives mostly 1-nitronapthalene:
NO2
HNO3
H2SO4
Draw the resonance structures for intermediates at:
1-position: Intermediate has 7 resonances, 4 with
aromaticity of other ring.
2-position: Intermediate has 6 resonances. 2 have the
aromaticity of other ring.
Electrophilic Aromatic Substitution of
Heteroaromatics
Five membered ring heterocycles (furan, pyrrole, thiophene) are pi
electron rich aromatics, and are very reactive.
E+
E
+
E
O
B-
H
O
O
+
E
E
E
+
H
O
H
O
H
O
+
Six membered ring heterocycles: Pyridine is less reactive. These
are pi-electron deficient aromatics. Electronegativity of
nitrogen on pyridine interacts with electrophile to further
deactivate substance.