Aromatic Compounds

2006 Thomson Higher Education

Early Days of Organic Chemistry

Aromatic Compounds
Formerly used to describe fragrant substances such
as benzaldehyde (from cherries, peaches, and
almonds), toluene (from Tolu balsam), and benzene
(from coal distillate)

Now used to refer to the class of compounds that

contain six-membered benzene-like rings with three

double bonds

Present Days of Organic Chemistry

Aromatic Compounds

Many naturally occurring compounds are aromatic in part

Steroidal hormone estrone

Analgesic morphine

Many synthetic drugs are aromatic in part

Antianxiety agent diazepem (Valium)
Benzene
Found to cause bone marrow depression
Leads to leukopenia, or lowered white blood cell count, on
prolonged exposure

Naming Aromatic Compounds

Aromatic substances have acquired nonsystematic names

Nonsystematic names are discouraged but allowed by

IUPAC

Common name for methylbenzene is toluene

Common name for hydroxybenzene is phenol
Common name for aminobenzene is aniline

Naming Aromatic Compounds

Monosubstituted Benzenes
Systematically named in same manner as other

hydrocarbons

Benzene used as parent name

C6H5Br is bromobenzene
C6H5NO2 is nitrobenzene
C6H5CH2CH2CH3 is propylbenzene

Naming Aromatic Compounds

Arenes
Alkyl-substituted benzenes
Named depending on the size of the alkyl group
Alkyl substituent smaller than the ring (6 or fewer
carbons), named as an alkyl substituted benzene
Alkyl substituent larger than the ring (7 or more
carbons), named as a phenyl-substituted alkane

Phenyl
Derived from the Greek pheno (I bear light)
Michael Faraday discovered benzene in 1825 from the
oily residue left by illuminating gas used in London
street lamps
Used for the C6H5 unit when the benzene ring is

considered as a substituent

Naming Aromatic Compounds

Benzyl
Used for the C6H5CH2 group

Naming Aromatic Compounds

Disubstituted benzenes

Named using one of the prefixes

1.
ortho- (o-)

2.

meta- (m-)

3.

Ortho-disubstituted benzene
has two substituents in a 1,2
relationship
Meta-disubstituted benzene
has its substituents in a 1,3
relationship

para- (p-)

Para-disubstituted benzene
has its substituents in a 1,4
relationship

Naming Aromatic Compounds

Benzenes with more than two substituents
Named by numbering the position of each so that the
lowest possible numbers are used
The substituents are listed alphabetically when writing the
name

Any of the monosubstituted aromatic compounds in Table 8.1

can serve as a parent name, with the principal substituent
(-OH in phenol or CH3 in toluene) attached to C1 on the ring

GIVE NAME FOR EACH COMPOUND!

Structure and Stability of

Benzene
Benzene
Benzene is unsaturated
Benzene is much less reactive than typical alkene
and fails to undergo the usual alkene reactions

Cyclohexene reacts rapidly with Br2 and gives the

addition product 1,2-dibromocyclohexane
Benzene reacts only slowly with Br2 and gives the
substitution product C6H5Br

Structure and Stability of

Benzene
A quantitative idea of benzenes stability is obtained
from heats of hydrogenation
Benzene is 150 kJ/mol (36 kcal/mol) more stable
than might be expected for cyclohexatriene

Structure and Stability of

Benzene
Carbon-carbon bond lengths and angles in benzene

All carbon-carbon bonds are 139 pm in length

Intermediate between typical C-C single bond (154 pm) and
typical double bond (134 pm)
Benzene is planar
All C-C-C bond angles are 120
All six carbon atoms are sp2-hybridized with p orbital
perpendicular to the plane of the ring

Structure and Stability of

Benzene
All six carbon atoms and all six p orbitals in benzene
are equivalent
Each p orbital overlaps equally well with both

neighboring p orbitals, leading to a picture of benzene

in which the six p electrons are completely delocalized
around the ring
Benzene is a hybrid of two equivalent forms

Neither form is correct by itself

The true structure of benzene is somewhere in between
the two resonance forms

Aromaticity and the Hckel

4n + 2 Rule
Benzene and other benzene-like aromatic molecules
share similar characteristics:
Benzene is cyclic and conjugated
Benzene is unusually stable, it is 150 kJ/mol (36

kcal/mol) more stable than might be expected

Benzene undergoes substitution reactions that retain
the cyclic conjugation rather than electrophilic addition
reactions that would destroy the conjugation
Benzene is a resonance hybrid whose structure is
intermediate between two line-bond structures

Aromaticity and the Hckel

4n + 2 Rule
The Hckel 4n + 2 rule
Theory devised in 1931 by the German physicist

Erich Hckel

A molecule is aromatic only if it has a planar,

monocyclic system of conjugation and contains a
total of 4n + 2 p electrons, where n is an integer
(n = 0, 1, 2, 3,)
Only molecules with 2, 6, 10, 14, 18, p
electrons can be aromatic
Molecules with 4n p electrons (4, 8, 12, 16,)
can not be aromatic, said to be antiaromatic
because delocalization of their p electrons would
lead to their destablization

Aromaticity and the Hckel

4n + 2 Rule
Examples of the Hckel 4n + 2 rule
Cyclobutadiene
Contains four p electrons
The p electrons are
localized into two double
bonds rather than
delocalized around the ring

Antiaromatic
Highly reactive
Shows none of the
properties associated with
aromaticity
Not prepared until 1965

Aromaticity and the Hckel

4n + 2 Rule
Benzene
Contains six p electrons (4n + 2 = 6 when n = 1)
Aromatic

Determine whether this compound aromatic or antiaromatic!

Aromaticity and the Hckel

4n + 2 Rule
Cyclooctatetraene
Contains eight p electrons
The p electrons are

localized onto four double

bonds rather than
delocalized around the ring
Not aromatic
The molecule is tub-shaped
rather than planar
It has no cyclic conjugation
because neighboring p
orbitals do not have the
necessary parallel alignment
for overlap
Resembles an open-chain
polyene in its reactivity

The Criteria for Aromaticity

A molecule must be cyclic
A molecule must be planar

A molecule must be completely conjugated

A molecule must satisfy Huckels rule and contain a

particular number of electrons

Compounds can be classified:

Aromatic : a cyclic, planar, completely

conjugated with 4n + 2 electrons

Antiaromatic : cyclic, planar, completely
conjugated compound with 4 electrons
Not aromatic : a compound that lacks
one or more the requirements for
aromaticity

Aromatic Heterocycles
Heterocyclic compounds can also be aromatic
Heterocycle
A cyclic compound that contains atoms of two or

more different elements in its ring, usually carbon

along with nitrogen, oxygen, or sulfur
Pyridine is much like benzene in its p electron
structure

Aromatic Heterocycles

The nitrogen atom is also sp2-hybridized and has

one electron in a p orbital, bringing the total to six
p electrons

The nitrogen lone pair electrons are in an sp2

orbital in the plane of the ring and are not involved
with the aromatic p system

Aromatic Heterocycles
Pyrimidine is much like benzene in its p electron

structure

Has two nitrogen atoms in a six-membered,

unsaturated ring
2
Both nitrogens are sp -hybridized, and each
contributes one electron to the aromatic p system

Aromatic Heterocycles
Pyrrole is a five membered heterocycle with six p

electrons

Aromatic
Each of the sp2-hybridized carbons contributes one p
electron
The sp2-hybridized nitrogen atom contributes the two
electrons from its lone pair, which occupies a p orbital

Aromatic Heterocycles
Imidazole is an analog of pyrrole that has two

nitrogen atoms in a five-membered, unsaturated ring

Both nitrogens are sp2-hybridized

One nitrogen is in a double bond and contributes only
one electron to the aromatic p system
The other nitrogen is not in a double bond and
contributes two from its lone pair

Aromatic Heterocycles
Nitrogen atoms have different roles depending on
the structure of the molecule
In pyridine and pyrimidine, the nitrogen atoms are

both in double bonds and contribute only one p

electron to the aromatic sextet, like a carbon atom in
benzene does
In pyrrole, the nitrogen atom is not in a double bond
and contributes two p electrons (the lone pair) to the
aromatic sextet
In imidazole, both a double-bonded pyridine-like
nitrogen that contributes one p electron and a
pyrrole-like nitrogen that contributes two p
electrons are present in the same molecule

Aromatic Heterocycles
Pyrimidine and imidazole rings are important in
biological chemistry
Pyrimidine is the parent ring system in cytosine, thymine,
and uracil, three of the five heterocycle amine bases
found in nucleic acids
An aromatic imidazole ring is present in histidine, one of
the twenty amino acids found in proteins

Worked Example 8.1

Accounting for the Aromaticity of a Heterocycle
Thiophene, a sulfur-containing heterocycle, undergoes
typical aromatic substitution reaction rather than
addition reactions. Why is thiophene aromatic?

Worked Example 8.1

Accounting for the Aromaticity of a Heterocycle
Strategy
Recall the requirements for aromaticity

A planar, cyclic, conjugated molecule with

4n + 2 p electrons

See how requirements for aromaticity apply

to thiophene

Worked Example 8.1

Accounting for the Aromaticity of a Heterocycle
Solution
Thiophene is the sulfur analog of pyrrole
The sulfur atom is sp2-hybridized and has a lone pair of
electrons in a p orbital perpendicular to the plane of the
ring
Sulfur also has a second lone pair of electrons in the
ring plane

8.5 Polycyclic Aromatic Compounds

The general concept of aromaticity can be extended
to include polycyclic aromatic compounds

Benzo[a]pyrene is one of the cancer-causing substances

found in tobacco smoke

Polycyclic Aromatic Compounds

All polycyclic aromatic hydrocarbons can be represented by a
number of different resonance forms

Naphthalene has three

Naphthalene shows many of the chemical properties associated

with aromaticity
Heat of hydrogenation measurements show an aromatic
stablilization energy of approximately 250 kJ/mol (60 kcal/mol)
Naphthalene reacts slowly with electrophiles to give
substitution products rather than double-bond addition
products

Polycyclic Aromatic Compounds

Aromaticity of Naphthalene
Naphthalene has a cyclic, conjugated p electron system,
with p orbital overlap both around the ten-carbon
periphery of the molecule and across the central bond
10 is a Hckel number (4n + 2 when n = 2) so there is p
electron delocalization and consequent aromaticity in
naphthalene

Polycyclic Aromatic Compounds

There are many heterocyclic analogs of naphthalene
Quinoline, isoquinoline, indole, and purine
Quinoline, isoquinoline, and purine all contain pyridinelike nitrogens that are part of a double bond and
contribute one electron to the aromatic p system
Indole and purine contain pyrrole-like nitrogens that
contribute two p electrons

Polycyclic Aromatic Compounds

Biological molecules that contain polycyclic aromatic rings
The amino acid tryptophan contains an indole ring and
the anti-malarial drug quinine contains a quinoline ring

Polycyclic Aromatic Compounds

Adenine and guanine, two of the five heterocyclic

amine bases found in nucleic acids, have rings based

on purine

8.6 Reactions of Aromatic Compounds:

Electrophilic Substitution
Electrophilic aromatic substitution
A process in which an electrophile (E+) reacts with an
aromatic ring and substitutes for one of the hydrogens
The most common reaction of aromatic compounds
This reaction is characteristic of all aromatic rings
The ability of a compound to undergo electrophilic
substitution is a good test of aromaticity

Reactions of Aromatic Compounds:

Electrophilic Substitution
Many substituents can be introduced onto an aromatic

ring through electrophilic substitution reactions

Halogen (-Cl, -Br, -I)

Nitro group (-NO2)
Sulfonic acid
group (-SO3H)
Hydroxyl group
(-OH)
Alkyl group (-R)
Acyl group (-COR)

Reactions of Aromatic Compounds:

Electrophilic Substitution
Electrophilic alkene addition
Addition of a reagent such as HCl to an alkene
The electrophilic hydrogen approaches the p electrons

of the double bond and forms a bond to one carbon,

leaving a positive charge at the other carbon
The carbocation intermediate then reacts with the
nucleophilic Cl- ion to yield the addition product

Reactions of Aromatic Compounds:

Electrophilic Substitution
One difference between electrophilic aromatic
substitution reactions and electrophilic alkene
addition reactions is that aromatic rings are
less reactive toward electrophiles than
alkenes are

Br2 in CH2Cl2 solution reacts instantly with

most alkenes but does not react with benzene
at room temperature

Reactions of Aromatic Compounds:

Electrophilic Substitution
Electrophilic aromatic substitution reaction begins in a
similar way to electrophilic alkene addition reaction

FeBr3 catalyst is needed for bromination of benzene to occur

FeBr3 polarizes Br2 molecule making it more electrophilic

Polarization makes FeBr4-Br+ species that reacts as if it were Br+
The polarized Br2 molecule reacts with the nucleophilic
benzene ring to yield a nonaromatic carbocation intermediate
which is doubly allylic and has three resonance forms

Reactions of Aromatic Compounds:

Electrophilic Substitution
The intermediate carbocation in electrophilic aromatic
substitution is more stable than a typical alkyl
carbocation because of resonance but much less
stable than the starting benzene ring
Comparison of alkene addition and aromatic substitution

Instead of adding Br- to give an addition product, the

carbocation intermediate loses H+ from the bromine-bearing
carbon

If addition occurred, the 150 kJ/mol stabilization energy of the

aromatic ring would be lost and the overall reaction would be
endergonic
When substitution occurs, the stability of the aromatic ring is
retained and the reaction is exergonic

Loss of H+ restores aromaticity to ring

The net effect is the substitution of H+ by Br+

Reactions of Aromatic Compounds:

Electrophilic Substitution
The mechanism of the electrophilic
bromination of benzene

The reaction occurs in two steps and

involves a resonance-stabilized
carbocation intermediate

Reactions of Aromatic Compounds:

Electrophilic Substitution
Aromatic Halogenation

Electrophilic substitution reactions can introduce halogens

into aromatic rings
Aromatic rings react with Cl2 in the presence of FeCl3
catalyst to yield chlorobenzenes

Reaction mechanism just like Br2 in the presence of FeBr3

Reaction used in the synthesis of numerous pharmaceutical
agents such as the antianxiety agent diazepam (Valium)

Reactions of Aromatic Compounds:

Electrophilic Substitution
Fluorine is too reactive to give mono-fluorinated products
Iodine itself is unreactive toward aromatic rings
An oxidizing agent such as hydrogen peroxide or a copper
salt such as CuCl2 must be added to the reaction
These substances oxidize I2 to a more powerful
electrophilic species that reacts as if it were I+
The aromatic ring reacts with the I+ to yield a substitution
product

Reactions of Aromatic Compounds:

Electrophilic Substitution
Electrophilic aromatic halogenations occur in the
biosynthesis of numerous naturally occurring
molecules, particularly those produced by marine
organisms

Thyroxine, synthesized in the

thyroid gland in humans, is a
thyroid hormone involved in
regulating growth and
metabolism

Reactions of Aromatic Compounds:

Electrophilic Substitution
Aromatic Nitration

Aromatic rings can be nitrated

with a mixture of concentrated
nitric and sulfuric acids
The electrophile is the
nitronium ion, NO2+ which is
generated from HNO3 by
protonation and loss of
water

The nitronium ion reacts with

benzene to yield a
carbocation intermediate,
and loss of H+
The product is a neutral
substitution product,
nitrobenzene

Reactions of Aromatic Compounds:

Electrophilic Substitution
Aromatic nitration
Does not occur naturally
Important in the laboratory
The nitro-substituted product can be reduced by reagents
such as iron or tin metal or to yield an arylamine, ArNH2
Attachment of an amino group to an aromatic ring by the
two-step nitration-reduction sequence is a key part of the
industrial synthesis of many dyes and pharmaceutical
agents

Reactions of Aromatic Compounds:

Electrophilic Substitution
Aromatic Sulfonation
Aromatic rings can be sulfonated in the laboratory by reaction
with fuming sulfuric acid, a mixture of H2SO4 and SO3
The reactive electrophile is either HSO3+ or neutral SO3
Substitution occurs by the same two-step mechanism seen for
bromination and nitration
Aromatic sulfonation does not occur naturally
Aromatic sulfonation is widely used in the preparation of dyes
and pharmaceutical agents
The sulfa drugs, such as sulfanilamide, were among the first
clinically useful antibiotics

Reactions of Aromatic Compounds:

Electrophilic Substitution
The mechanism of electrophilic sulfonation of an

aromatic ring

Reactions of Aromatic Compounds:

Electrophilic Substitution
Aromatic Hydroxylation
Direct hydroxylation of an aromatic ring to yield a

hydroxybenzene (a phenol)

Difficult and rarely done in the laboratory

Occurs much more freely in biological pathways
Hydroxylation of p-hydroxyphenyl acetate to give 3,4dihydroxyphenyl acetate
The reaction is catalyzed by p-hydroxyphenylacetate-3hydroxylase and requires molecular O2 plus the
coenzyme reduced flavin adenine dinucleotide (FADH2)

Reactions of Aromatic Compounds:

Electrophilic Substitution

Mechanism of the
electrophilic
hydroxylation of phydroxyphenyl acetate
by reaction of FAD
hydroperoxide
The hydroxylating
species is an OH+
equivalent that arises
by protonation of FAD
hydroperoxide,
RO-OH + H+ ROH

8.7 Alkylation and Acylation of

Aromatic Rings
Alkylation
The introduction of an alkyl group onto the benzene ring
Called the Friedel-Crafts reaction after its discoverers
Among the most useful electrophilic aromatic

substitution reactions in the laboratory

The reaction is carried out by treating the aromatic
compound with an alkyl chloride, RCl, in the presence
of AlCl3 to generate a carbocation electrophile, R+

Aluminum chloride catalyzes the reaction by helping the

alkyl halide to dissociate
Loss of H+ completes the reaction

Alkylation and Acylation of

Aromatic Rings
Mechanism of the Friedel-Crafts alkylation reaction

The electrophile
is a carbocation,
generated by
AlCl3-assisted
dissociation of
an alkyl halide

Alkylation and Acylation of

Aromatic Rings
Friedel-Crafts alkylation has several limitations
1. Only alkyl halides can be used

Aromatic (aryl) halides and vinylic halides do not

react because aryl and vinylic carbocations are too
high in energy to form under Friedel-Crafts conditions

Vinylic means that a substituent is attached directly

to a double bond, C=C-Cl

Alkylation and Acylation of

Aromatic Rings
2. Friedel-Crafts reactions do not succeed on aromatic

rings that are substituted either by a strongly

electron-withdrawing group such as carbonyl (C=O)
or by an amino group (-NH2, NHR, -NR2)

The presence of a substituent group already on a ring

can have a dramatic effect on that rings subsequent
reactivity toward further electrophilic substitution

Alkylation and Acylation of

Aromatic Rings

A skeletal rearrangement of the alkyl carbocation electrophile

sometimes occurs during a Friedel-Crafts reaction, particularly
when a primary alkyl halide is used

Carbocation rearrangements
occur either by hydride shift or
alkyl shift
Alkylation of benzene with
1-chloro-2,2dimethylpropane yields
(1,1dimethylpropyl)benzene

Alkylation and Acylation of

Aromatic Rings
An aromatic ring is acylated by reaction with a carboxylic
acid chloride, RCOCl, in the presence of AlCl3
An acyl group is substituted onto an aromatic ring

The reactive electrophile is a resonance-stabilized acyl

cation
An acyl cation is stabilized by interaction of the vacant
orbital on carbon with lone-pair electrons on the
neighboring oxygen
Because of stabilization, no carbocation rearrangement
occurs during acylation

Alkylation and Acylation of

Aromatic Rings
Aromatic alkylations occur in numerous biological pathways
The carbocation electrophile is typically formed by dissociation
of an organo diphosphate
A diphosphate group is a common structural feature of
many biological molecules
It can be expelled as a stable diphosphate ion
The dissociation of an organo diphosphate in a biological
reaction is typically assisted by complexation to a divalent
metal cation such as Mg2+ to help neutralize charge

Alkylation and Acylation of

Aromatic Rings
Biosynthesis of
phylloquinone, or
vitamin K1, the
human bloodclotting factor
The key step
that joins the
20-carbon
phytyl side
chain to the
aromatic ring
is an
electrophilic
substitution
reaction

Worked Example 8.2

Predicting the Product of a Carbocation
Rearrangement
The Friedel-Crafts reaction of benzene with 2chloro-3-methylbutane in the presence of
AlCl3 occurs with a carbocation
rearrangement. What is the structure of the
product?

Worked Example 8.2

Predicting the Product of a Carbocation
Rearrangement
Strategy

A Friedel-Crafts reaction involves initial formation of a

carbocation, which can rearrange by either a hydride
shift or an alkyl shift to give a more stable carbocation
Draw the initial carbocation, assess its stability, and see
if the shift of a hydride ion or an alkyl group from a
neighboring carbon will result in an increased stability

The initial carbocation is a secondary one that can

rearrange to a more stable tertiary one by a hydride
shift
Use the more stable tertiary carbocation to complete
the Friedel-Crafts reaction

Worked Example 8.2

Predicting the Product of a Carbocation
Rearrangement
Solution

8.8 Substituent Effects in

Electrophilic Substitutions
Substituent effects in the electrophilic substitution of an
aromatic ring
Substituents affect the reactivity of the aromatic
ring

Some substituents activate the ring, making it more

reactive than benzene
Some substituents deactivate the ring, making it less
reactive than benzene
Relative rates of aromatic nitration

Substituent Effects in
Electrophilic Substitutions
Substituents affect the orientation of the reaction

The three possible

disubstituted
products ortho,
meta, and para
are usually not
formed in equal
amounts
The nature of the
substituent on the
ring determines the
position of the
second substitution

Substituent Effects in
Electrophilic Substitutions
Substituents can be classified into three groups
ortho- and para-directing activators
ortho- and para-directing deactivators
meta-directing deactivators
There are no meta-directing activators
All activating groups are ortho- and para- directing
All deactivating groups other than halogen are meta-directing
The halogens are unique in that they are deactivating but orthoand para-directing

Substituent Effects in
Electrophilic Substitutions
Activating and Deactivating Effects
The common characteristic of all activating groups is

that they donate electrons to the ring

Makes the ring more electron-rich

Stabilize the carbocation intermediate
Lower activation energy

The common characteristic of all deactivating groups is

that they withdraw electrons from the ring

Makes the ring more electron-poor

Destabilizes the carbocation intermediate
Raising the activation energy for its formation

Substituent Effects in
Electrophilic Substitutions
Electrostatic potential maps of benzene, phenol (activated),
chlorobenzene (weakly deactivated), and benzaldehyde (more
strongly deactivated)
The OH substituent makes the ring more negative (red)
The Cl makes the ring less negative (orange)
The CHO makes the ring still less negative (yellow)

Substituent Effects in
Electrophilic Substitutions
The electron donation or electron withdrawal may occur by
either an inductive effect or a resonance effect
Inductive effect

Due to an electronegativity difference between the ring and

the attached substituent

Resonance effect
Due to overlap between a p orbital on the ring and an orbital
on the substituent

Substituent Effects in
Electrophilic Substitutions
Orienting Effects: Ortho and Para Directors

The ortho and para intermediates are more stable than the
meta intermediate because they have more resonance forms

Substituent Effects in
Electrophilic Substitutions
Any substituent that has a lone pair of electrons on the atom
directly bonded to the aromatic ring allows an electrondonating resonance interaction to occur

Additional electron-donating resonance interaction lowers the

energy of the hybrid
Electron-donating substituent increases electrophilicity of ortho
and para positions and acts as an ortho and para director

Substituent Effects in
Electrophilic Substitutions
Orienting Effects:
Meta Directors

Substituent Effects in
Electrophilic Substitutions
Any substituent that has a positively polarized atom (d+) directly
attached to the ring increases the activation energy leading to
the intermediate hybrid for ortho and para substitutions

Substitution at ortho or para position gives a higher energy

intermediate
Meta substitution avoids higher energy intermediate and has a
lower activation energy
Approaching electrophile is directed to the meta positions

Substituent Effects in
Electrophilic Substitutions
A Summary of Substituent Effects in Electrophilic
Substitutions

Worked Example 8.3

Predicting the Product of an Electrophilic
Aromatic Substitution Reaction
Predict the major product of the sulfonation of
toluene.

Worked Example 8.3

Predicting the Product of an Electrophilic
Aromatic Substitution Reaction
Strategy
Identify the substituent present on the ring
Decide whether the substituent is ortho- and
para-directing or meta-directing

According to Figure 8.15 an alkyl substituent is

ortho- and para-directing

Sulfonation of toluene will give primarily a mixture

of o-toluenesulfonic acid and p-toluenesulfonic
acid

Worked Example 8.3

Predicting the Product of an Electrophilic
Aromatic Substitution Reaction
Solution

8.9 Oxidation and Reduction of

Aromatic Compounds
Alkyl substituents on aromatic rings containing a benzylic
hydrogen react readily with common laboratory
oxidizing agents such as aqueous KMnO4 or Na2Cr2O7
and are converted into carboxyl groups

Net conversion of an alkylbenzene into a benzoic acid

Ar-R

Ar-CO2H

Oxidation of butylbenzene into benzoic acid

Oxidation and Reduction of

Aromatic Compounds
The mechanism of side-chain oxidation involves

reaction of a C-H bond at the position next to the

aromatic ring (the benzylic position) to form an
intermediate benzylic radical
Benzylic radicals are stabilized by resonance and
thus form more readily than typical alkyl radicals

Oxidation and Reduction of

Aromatic Compounds
Side chain oxidations occur in various biosynthetic
pathways
The neurotransmitter norepinephrine is biosynthesized
from dopamine by a benzylic hydroxylation reaction

Radical reaction
Reaction catalyzed by the copper-containing enzyme
dopamine b-monooxygenase

Oxidation and Reduction of

Aromatic Compounds
Aromatic ring
Activates a neighboring (benzylic) C-H position toward
oxidation
Activates a neighboring carbonyl group toward reduction
An aryl alkyl ketone prepared by Friedel-Crafts acylation
of an aromatic ring can be converted into an
alkylbenzene by catalytic hydrogenation over a palladium
catalyst

Propiophenone
reduced to
propylbenzene
by catalytic
hydrogenation

is

8.10 An Introduction to Organic Synthesis:

Polysubstituted Benzenes
There are many reasons for carrying out
laboratory synthesis of an organic molecule

In the pharmaceutical industry, new molecules

are designed and synthesized in the hope that
some might be useful drugs
In the chemistry industry, syntheses are done
to devise more economical routes to known
compounds
In biochemistry laboratories molecules
synthesized to probe enzyme mechanisms

An Introduction to Organic Synthesis:

Polysubstituted Benzenes
Planning a successful multistep synthesis of a
complex molecule requires knowledge of the
uses and limitations of numerous organic
reactions
The trick to planning an organic synthesis is to work
backward, often referred to as the retrosynthetic
direction
Keep starting material in mind and work backward to it

Look at the final product and determine possible

immediate precursors of that product

Work backward one step at a time

An Introduction to Organic Synthesis:

Polysubstituted Benzenes
Examples of synthetic planning using
polysubstituted aromatic compounds as the
targets

Electrophilic substitution on a disubstituted benzene

ring is governed by the same resonance and
inductive effects that affect monosubstituted rings

Must consider the additive effects of two groups

An Introduction to Organic Synthesis:

Polysubstituted Benzenes
If the directing effects of the two groups reinforces
each other, the situation is straightforward

1.

In p-nitrotoluene both the methyl and the nitro group

direct further substitution to the same position (ortho
to the methyl = meta to the nitro). A single product is
thus formed on electrophilic substitution

An Introduction to Organic Synthesis:

Polysubstituted Benzenes
2. If the directing effects of the two main groups

oppose each other, the more powerful activating

group has the dominant influence

Nitration of p-methylphenol yields primarily 4-methyl2-nitrophenol because OH is a more powerful

activator than CH3

An Introduction to Organic Synthesis:

Polysubstituted Benzenes
3. Further substitution rarely occurs between the two

groups in a meta-disubstituted compound because

this site is too hindered

Aromatic rings with three adjacent substituents must

therefore be prepared by some other route

The substitution of an ortho-disubstituted compound

Worked Example 8.4

Synthesizing a Polysubstituted Benzene
Propose a synthesis of 4-bromo-2-nitrotoluene
from benzene.

Worked Example 8.4

Synthesizing a Polysubstituted Benzene
Strategy
Draw the target molecule
Identify the substituents

1.
2.

Recall how each group can be introduced separately

3.

4.

The three substituents on the ring are a bromine, a

methyl group, and a nitro group
A bromine can be introduced by bromination with
Br2/FeBr3, a methyl group can be introduced by FriedelCrafts alkylation with CH3Cl/ AlCl3, and a nitro group
can be introduced by nitration with HNO3/H2SO4

Then plan retrosynthetically

Worked Example 8.4

Synthesizing a Polysubstituted Benzene
Solution
The final step will involve introduction of one of the
three groups bromine, methyl, or nitro

Three possibilities:

Worked Example 8.4

Synthesizing a Polysubstituted Benzene
Immediate precursors of p-bromotoluene
Toluene

Because the methyl group would direct bromination

to the ortho and para positions

Bromobenzene

Because Friedel-Crafts methylation would yield a

mixture of ortho and para products

Worked Example 8.4

Synthesizing a Polysubstituted Benzene
The immediate precursor of toluene
Benzene, which could be methylated in a Friedel-Crafts
reaction
The immediate precursor of bromobenzene
Benzene, which could be brominated

Two valid routes possible from benzene to 4-bromo-2-

nitrotoluene

Worked Example 8.5

Synthesizing a Polysubstituted Benzene
Propose a synthesis of 4-chloro-2propylbenzenesulfonic acid from benzene.

Worked Example 8.5

Synthesizing a Polysubstituted Benzene
Strategy
Draw the target molecule
2. Identify the substituents

The three substituents on the ring are chlorine, a propyl

group, and a sulfonic acid group
3. Recall how each of the three can be introduced

A chlorine can be introduced by chlorination using

Cl2/FeCl3, a propyl group can be introduced by FriedelCrafts acylation with CH3CH2COCl/ AlCl3 followed by
reduction with H2/Pd, and a sulfonic acid group can be
introduced by sulfonation with SO3/H2SO4
4. Then plan retrosynthetically
1.

Worked Example 8.5

Synthesizing a Polysubstituted Benzene
Solution
The final step will involve introduction of one of the
three groups chlorine, propyl, or sulfonic acid

Three possibilities:

Worked Example 8.5

Synthesizing a Polysubstituted Benzene

The immediate precursors to m-chloropropylbenzene

Because the two substituents have a meta relationship,
the first substituent placed on the ring must be a meta
director so that the second substitution will take place at
the proper position
Because primary alkyl groups such as propyl cannot be
introduced directly by Friedel-Crafts alkylation, the
precursor of m-chloropropylbenzene is probably mchloropropiophenone, which could be catalytically
reduced

Worked Example 8.5

Synthesizing a Polysubstituted Benzene

The immediate precursor

of m-chloropropiophenone

Propiophenone, which
could be chlorinated in
the meta position

The immediate precursor

of propiophenone

Benzene which could

undergo Friedel-Crafts
acylation with propanoyl
chloride and AlCl3

Worked Example 8.5

Synthesizing a Polysubstituted Benzene
The final synthesis is a four-step route from benzene: