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Chapter 8
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
8.1 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
8.2 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 benzene’s 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
Structure and Stability of
Benzene
If six p atomic orbitals combine in a cyclic manner, six
benzene p molecular orbitals result
• The three lower-energy molecular orbitals, denoted y1, y2, and
y3, are bonding combinations
• y2 and y3 have the same energy and are said to be
•
degenerate
The three higher-energy molecular orbitals, denoted y4*, y5*,
and y6*, are antibonding combinations
• y4* and y5* have the same energy and are said to be
degenerate
Structure and Stability of
Benzene
•
y3 and y4* have nodes passing through ring carbon atoms,
thereby no p electron density on these carbons
•
The six p electrons occupy the three bonding molecular orbitals
and are delocalized over the entire conjugated system
8.3 Aromaticity and the Hückel
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 is planar and has the shape of a regular
hexagon. All bond angles are 120º, all carbon atoms
are sp2-hybridized, and all carbon-carbon bond lengths
are 139 pm
• 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 Hückel
4n + 2 Rule
The Hückel 4n + 2 rule
• Theory devised in 1931 by the German physicist
Erich Hückel
•
•
•
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 Hückel
4n + 2 Rule
Examples of the Hückel 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 Hückel
4n + 2 Rule
• Benzene
• Contains six p electrons (4n + 2 = 6 when n = 1)
• Aromatic
Aromaticity and the Hückel
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
Aromaticity and the Hückel
4n + 2 Rule
Energy Levels of Cyclic Conjugated Molecules (4n + 2 Electrons)
•
•
•
•
•
•
There is always a single lowest-lying MO, above which the MOs
come in degenerate pairs
When electrons fill the various molecular orbitals, one pair of
electrons fills the lowest-lying orbital and two pairs of electrons fill
each of the n successive energy levels – a total of 4n + 2. Any other
number would leave a bonding energy level partially unfilled
Energy levels of the six
benzene p molecular orbitals
The lowest-energy MO, y1,
occurs single and contains a
pair of electrons
y2 and y3, are degenerate,
and it takes two pairs of
electrons to fill them
The result is a stable six-pelectron aromatic molecule
with filled bonding orbitals
8.4 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
• A six-membered heterocycle with nitrogen in its ring
• Each of the five sp2-hybridized carbons has a p
orbital perpendicular to the plane of the ring and
each p orbital contains one p electron
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 Hückel 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 ring’s 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: