The source of human consciousness remains elusive, but the

latest brain studies offer new insights.

Though in some ways deeply familiar,

consciousness is at the same time foreign
to those in its possession. For a long time,
the very question was considered to be in
poor taste, acceptable for philosophical
musing but outside the bounds of real
science. New experimental results have
[provided] new insights [that] could answer
questions such as whether animals, or the
Internet, or the next-generation iPhone
could ever possess consciousness. Though
a detailed definition remains elusive, in “Recipe” for consciousness:
simplest terms, consciousness is what you
1. Parietal cortex
lose when you fall into a deep sleep at
2. Frontal cortex
night and what you gain when you wake up 3. Claustrum
in the morning. A brain that is fully awake 4. Thalamus
and constructing experiences is said to be 5. Reticular activating system
fully conscious.
Science news
Rose-Hulman Institute of Technology
Department of Chemistry & Biochemistry

Today
Bruice, Chapter 18
Reactions of Aromatics
Substituent Effects
 General Reaction for Electrophilic
Aromatic Substitution (EAS)
• Benzene, like alkenes and dienes is a
nucleophile.
• Addition reactions would disrupt the aromaticity.
• Therefore benzene undergoes substitution
reactions.
E
+ E+ + H+

E+ = Electrophile
electrophilic aromatic substitution (SEAr)
 SEAr Mechanism
• We will talk about several different EAS
reactions, but they all follow the same general
mechanism.
Step 1:
E E + E
slow
+ E+ H H H
+ +

E
Step 2:
Arenium ion H
+
E A-
fast E
H
+ + HA
 Halogenation of Benzene
• Benzene does not directly react with bromine or
chlorine in the way that a normal alkene does.
• A Lewis acid catalyst (Fe3+) is required for the
SEAr reaction to occur.
Cl
FeCl3
+ Cl2 + HCl
o
25

FeCl3 Br
+ Br2 + HBr
o
25
 Nitration of Benzene
• Reaction of benzene with nitric acid and sulfuric
acid gives nitrobenzene. If this is done
repeatedly to toluene you get trinitrotoluene
(TNT).
NO2
H2SO4 catalyst
+ HNO3 + HOH

CH3
CH3
O2N NO2
excess HNO3

H2SO4 catalyst
TNT
NO2
toluene
Sulfonation of Benzene
O
OH
S
O H2SO4
O
S
O O 25o C

fuming H2SO4 SO3H

A detergent

What’s the difference between soaps

and detergents?
Friedel-Crafts Alkylation
CH3

CH3 AlCl3 catalyst CH3

Cl
CH3

CH3

CH3 AlCl3 catalyst CH3

CH3
HO CH3
CH3
 Friedel-Crafts Alkylation
Electrophile Formation:

CH3 H3C H3C H3C

+ - + -
Cl AlCl3 Cl AlCl3 + Cl AlCl3
CH3 H3C H3C H3C

Electrophile Substitution:
+
H3C slow
+ H H H
H3C + +

H3C
+ - fast
H Cl AlCl3
+ H3C + HCl + AlCl3
I say “carbocation.”
You say “______!”
rearrangement
I say “carbocation.”
You say “______!”
rearrangement
 Friedel-Crafts Acylation
• Similar to alkylation but starting from an acid
chloride or anhydride instead of a haloalkane.
• AlCl3 is NOT a catalyst, and water must be
used to destroy the AlCl3.
• Mechanism: Here the AlCl3 removes chloride (or
acetate) from the acid chloride to give a
resonance stabilized acylium ion, which is the
electrophile. Notice how the AlCl3 is consumed
in the last step of the reaction.
 Limitations to Friedel-Crafts
Reactions
• Halogenation, nitration, and sulfonation
work for nearly all aromatic compounds.
The Friedel-Crafts has some major
limitations, though:
1. Friedel-Crafts rxn does not work when there
are EWG on the benzene ring. Amino
groups also do not work well, because they
react with AlCl3. This is a problem for both
acylation and alkylation reactions.
2. Carbocation rearrangements
3. Over-alkylation can occur
 Friedel-Crafts Acylation
• In the second step, water is used to destroy the
AlCl3 and recover the desired ketone product.

-
+ AlCl3
O O

H2O
+ 3 HCl + Al(OH)3
 Limitations to Friedel-Crafts
• Alkyl substituted benzenes are more
reactive (more electron rich) than benzene
itself.
• Problems concerning rearrangements and
overalkylation can be overcome by using
acylation followed by reduction of the
ketone to an alkane.
 Clemensen Reduction
of Aromatic Ketones

O Zn(Hg)
HCl

Zn(Hg) = zinc amalgam

 Effects of Substituents on
Electrophilic Aromatic Substitution
Deactivating vs. Activating
NO2 .. .. ..
NH2 , NR2 , NHR
NR3+ .. -
.. ,
OH .. :
O
CF3 , CCl3

C N .. ..
NHCOCH3 , NHCOR
SO3H
.. ..
CO2H , CO2R OMe , OR
.. ..
CHO , COR

CH3 , C2H5
.. .. .. ..
:, :
F
.. .. : ,
Cl Br
.. , ..I : R, C6H5
Reactivity: Transition State Theory
• Reactions occur faster when the transition
state is more stable. Therefore, we would
predict that electron donating substituents would
make the reaction go faster and electron
withdrawing substituents would make it go
slower.
E

Arenium ion H
+
Q
 Effect of EDG on SEAr Reactivity

Z +
Z + + Z
Reaction
+ E+ + + is
+ + faster
+
Z releases E H E H
electrons
Transitionstate Arenium ion
is stabilized is stabilized
 Effect of EWG on SEAr Reactivity

Z +
Z + + Z
Reaction
+ E+ + + is
+ + slower
+
Z withdraws E H E H
electrons
Transitionstate Arenium ion
is destabilized is destabilized
 Relative Free Energies of
Activation of EAS Reactions
Z

+

+
E H
+

+E H Z

Z +

+
+ E H

E H + Z
Free +
E H
Energy
E H
G‡ G‡
Z
Z

+ E+ + E+ + E+ G‡

Reaction coordinate
 Directing Effects
• Inductive Effects: Electron donation or
withdrawal due exclusively to differences
in electronegativity between atoms in the
bonds.
• Resonance Effects: Electron donation or
withdrawal due to movement of electrons
as depicted in resonance structures.
 Inductive Effect
• The inductive effect of a substituent Z arises
from the electrostatic interaction of the polarized
bond to Z with the developing positive charge in
the ring as it is attacked by an electrophile.

e.g., Z = F, Cl, Br
 Resonance Effect
• The presence of Z may increase or decrease the
resonance stabilization of the intermediate
arenium ion.

z z+
+
E E

H H
 EDG Resonance Effect

Most Least
electron
donating
NH2 NR2 > OH OR > X electron
donating

This is also the activating ability of these groups.

Amino groups are highly activating, hydroxyl
groups are somewhat less activating, and halogen
substituents are weakly deactivating.
 Ortho-/Para-Directing Groups
• All groups that can act as lone pair donors,
including alkyl groups, are ortho-/para-
directors.
– The lone pair provides resonance stabiliztion
for the arenium ion, but only if substitution
occurs in the ortho or para positions.
• amino-, alkyl-, halo-
 Example: -NH2
• Inductive effect? EWG
• Resonance effect? EDG
• Draw the resonance structures for the
arenium ions that would arise from ortho,
meta, and para attack on aniline.
• What are the major product(s)?
 Ortho-/Para-Directing Groups
• When substitution occurs
– ortho to electron donor, there are 4 resonance
structures
– para to electron donor, there are 4 resonance
structures
– meta to electron donor, there are 3 resonance
structures
• The extra resonance structure in the ortho
position is a very stable structure because all of
the atoms have a full octet of electrons.
• Therefore, ortho and para arenium ions are
more stable than meta. Ortho and para
substitution will occur faster than meta.
 Alkyl Groups as o-/p- directors
• Alkyl groups do not have lone pairs.
• Why are they ortho-/para-directors?
• Alkyl groups can stabilize a carbocation by
sharing electrons in C-H bonds with the
empty orbital.
 Halogens as o-/p- directors
• All other ortho-/para-directors are
activating groups.
• Deactivating
• strong inductive electron withdrawing groups
• resonance electron donors
• like N or O, they will stabilize the positive charge if
substitution occurs ortho- or para-
 Meta- Directors
• Meta directors have full or partial positive
charges on the atom directly attached to
the ring, thus they are resonance electron
withdrawing groups. If substitution occurs
ortho or para, the substituent will
destabilize the arenium ion.
• ALL META DIRECTORS ARE
DEACTIVATING GROUPS.
• -NO2, -COOH, -CF3
Orientation in Disubstituted Benzenes
• When two different groups are present on
a benzene ring, the more powerful
activating group generally determines the
outcome of the reaction.
• Because all ortho- para-directing groups
are more activating than meta directors,
the ortho-para-director determines the
orientation of the incoming group.
 Steric Effects
• Substitution does not occur to an
appreciable extent between meta
substituents if another position is open.
 Learning Group Problem
Phenyl benzoate, when treated with chlorine
and iron(III) chloride, undergoes
chlorination to produce two products. What
are they?

O
 Learning Group Problem
Phenyl benzoate, when treated with chlorine
and iron(III) chloride, undergoes
chlorination to produce two products. What
are they?
Deactivating (EWG) group
O

Activating (EDG) group

 Learning Group Problem
One ring of phenyl benzoate undergoes electrophilic aromatic
substitution much more readily than the other.

Activated rings undergo SEAr much more

readily than deactivated rings.
Iodination of Vanillin

Laboratory Exercise
 Learning Group Problem
In what position does the halogenation (iodination) occur
in the following problem?

O
NaI (s)
H
NaOCl (aq)
HO
ethanol (90%)
OMe
 Learning Group Problem
In what position does the halogenation (iodination) occur
in the following problem?

Para-
position
O blocked
O
NaI (s) I
H
NaOCl (aq) H
HO
ethanol (90%) HO
OMe 5-iodovanillin
OMe
-OH is the strongest activating group, and it is
an ortho-/para- director. One Ortho-
position
blocked
 Learning Group Problem
What is a plausible electrophile in the following reaction?

O
O
NaI (s) I
H
NaOCl (aq) H
HO
ethanol (90%) HO
OMe 5-iodovanillin
OMe

NaI (aq) + NaOCl(aq)

Recall that the reaction turned a brownish-red color upon addition of the sodium
hypochlorite (bleach).
Learning Group Problem
Using Electrochemistry to determine the electrophile
formation:

NaI (aq) + NaOCl(aq)

o
I2(s) +
2e- 2 I- (aq) E1/2 = 534.5 mV
yellow-brown
o
I3- (aq) + 2e- 3 I- (aq) E1/2 = 535.5 mV

o
OCl- (aq) + H2O (l) + 2e- Cl- (aq) + 2OH- (aq) E1/2 = 810 mV
colorless
 Learning Group Problem
Using Electrochemistry to determine the electrophile
formation:

I- (aq) + OCl- (aq) ?

Reverse the sign for
oxidation ½ reaction

o
Oxidation 2 I- (aq) E1/2 = - 534.5 mV
I2(s) +
2e-
1/2 reaction
yellow-brown
o
Reduction OCl- (aq) + H2O (l) + 2e- Cl- (aq) + 2OH- (aq) E1/2 = 810 mV
1/2 reaction colorless
 Learning Group Problem
Using Electrochemistry to determine the electrophile
formation:

Reverse the sign for

oxidation ½ reaction

o
Oxidation 2 I- (aq) E1/2 = - 534.5 mV
I2(s) +2e-
1/2 reaction
yellow-brown
o
Reduction OCl- (aq) + H2O (l) + 2e- Cl- (aq) + 2OH- (aq) E1/2 = 810 mV
1/2 reaction colorless

o
2I- (aq) + OCl- (aq) + H2O (l) I2 (aq) + 2OH- (aq) + Cl- (aq) E = 275.5 mV
 Learning Group Problem
What is a plausible electrophile in the following reaction?

O
O
NaI (s) I
H
NaOCl (aq) H
HO
ethanol (90%) HO
OMe 5-iodovanillin
OMe

I2 (aq) more soluble in ethanol than water

Would vanillin be considered an “activated” ring?

 Notes about the following reaction:
O
O
NaI (s) I
H
NaOCl (aq) H
HO
ethanol (90%) HO
OMe 5-iodovanillin
OMe

 Color change (reddish brown color) upon addition of sodium hypochlorite to a

solution of sodium iodide and vanillin in 90% ethanol.

 Vanillin is an “activated” ring; a Lewis acid is not required to bring

about complete conversion.

 Overall redox reaction is favorable (positive E value) for the formation of I2

from iodide and hypochlorite.

I2 (aq) most likely electrophilic species for this reaction

Synthesis of Aromatic Compounds
• Synthesize m-chloroethylbenzene from
benzene.
• Why will the method you chose produce the
desired products?

Cl
?

CH2CH3
 Synthesis of
m-chloroethylbenzene from benzene

• Can we start by chlorinating benzene and

then follow with a Friedel-Crafts alkylation
using CH3CH2Cl and AlCl3?
• Why or why not?
• That method will fail because –Cl is an
ortho-/para-director
 Synthesis of
m-chloroethylbenzene from benzene
• Can we start by doing a Friedel-Crafts
alkylation to benzene and then follow with
a chlorination?
• Why or why not?
• The ethyl group is an ortho-/para-director,
so that method will fail also.
 Synthesis of
m-chloroethylbenzene from benzene
• If we start with the acylation (introduce an
acetyl group), which we can later convert
to an ethyl group, we install a meta-
director. This allows us to put chlorine in
the correct position.
 Synthesis of
m-chloroethylbenzene from benzene
O O

CH3COCl Cl2

AlCl3 FeCl3 Cl

Zn(Hg)
Cl HCl

CH2CH3
Deactivating vs. Activating
NO2 .. .. ..
NH2 , NR2 , NHR
NR3+ .. -
.. ,
OH .. :
O
CF3 , CCl3

C N .. ..
NHCOCH3 , NHCOR
SO3H
.. ..
CO2H , CO2R OMe , OR
.. ..
CHO , COR

CH3 , C2H5
.. .. .. ..
:, :
F
.. .. : ,
Cl Br
.. , ..I : R, C6H5
Table 17-1, p. 680
 Current Organic Chemistry

• Aqueous phase Suzuki coupling can be

applied to aromatic heterocycles in order
to study DNA mutation

57
 How does Suzuki Coupling
work?
• Suzuki coupling forms a C-C bond
between two aromatic carbon atoms

First published in ca. 1972

58
 Pd-Catalyzed Reactions

Buchwald-Hartwig Coupling Heck Coupling

R1
R R2
NR'R" L/Pd L/Pd
base base R3
HNR'R" R
R1 R2

X H R3
R
L/Pd L/Pd
base CuI
base
R'B(OH)2
H R'
R' R'
R R
Suzuki Coupling Sonogashira Coupling
 Relevant Products Produced
Via Suzuki Coupling
SCH3
OMe
N
COOK
N
N HN
H
O K
O H N
S N N

O C11H23

HR 720: AT1-selective antagonist, UNDECYLPRODIGIOSINE:

treatment for hypertensive diseases inhibits T-cell proliferation
Ar Ph

Ar
NH N
Ph Ph
N HN
Ar

Ph Ar
-aryltetraphenyl porphorins
Suzuki, J. Omet. Chem., 1998, 576, 147.
 The Suzuki Coupling
Mechanism
oxidative
addition
X

R3P Pd
X

B(OH)2

R3P Pd PR3 R3P Pd + PR3

XB(OH)2
transmetalation

R3P Pd
reductive
elimination
 Case Study: Synthesis of
NSAID, Diflunsial
• The synthesis of diflunisal shows the
potential utility of this methodology.
Diflunisal was synthesized in 95% yield in
a single step from commercially available
precursors with water as the only solvent
for preparation and purification.

62