Chemistry of Benzene:
Electrophilic Aromatic
Substitution
Michael Dann A. Superio
Contents
Electrophilic Aromatic Substitution: Bromination
Other Aromatic Substitution
Alkylation and Acylation of Aromatic Rings: The Friedel-Crafts Reaction
Substituent Effects on Aromatic Rings
An Explanation of Substituent Effects
Trisubstituted Benzenes: Additivity of Effects
Nucleophilic Aromatic Substitution
Oxidation of Aromatic Compounds
Reduction of Aromatic Compounds
Synthesis of Polysubstituted Benzenes
Electrophilic Aromatic
Substitution Reaction:
Bromination
Electrophilic Aromatic Substitution Reaction:
Bromination
Electrophilic Aromatic Substitution Reaction:
Bromination
• For bromination to take place, a catalyst (FeBr3), is used. The catalyst
makes Br2 more electrophilic by polarizing it to FeBr4-Br+ species that
reacts as if it were Br+.
Other Aromatic Substitution
Reactions
Aromatic Fluorination, Chlorination, and
Iodination
• Fluorine (F2) is too reactive; other sources of F+ is used where it is
bonded to a more stable N+.
• F-TEDA-BF4 (Selectfluor)
Aromatic Fluorination, Chlorination, and
Iodination
• Chlorination happens in the presence of FeCl3 catalyst to yield
chlorobenzenes.
Aromatic Fluorination, Chlorination, and
Iodination
• Iodine is unreactive toward aromatic rings: needs oxidizing agents
(hydrogen peroxide, copper salt such as CuCl2).
Aromatic Fluorination, Chlorination, and
Iodination
• Aromatic halogenation also occur
in the biosynthesis of many
naturally occurring molecules. Best
known among humans happens in
the thyroid gland.
Aromatic Nitration
• Addition of a nitrate occurs when aromatic rings are reacted with a
mixture of concentrated nitric and sulfuric acids.
Aromatic Nitration
• Electrophilic nitration of aromatic rings do not occur in nature but is
often induced in laboratory.
• Nitro-substituted aromatic rings can be nitrated (NO2 → NH2) using
iron, tin, or SnCl2 to yield arylamines (ArNH2): important in the
synthesis of dyes and pharmaceutical agents.
Aromatic Sulfonation
• Aromatic rings can be
sulfonated by reaction
with fuming sulfuric acid
(H2SO4 + SO3)
• Substitution occurs just
like in bromination.
• Sulfonation is reversible
• Sulfonation is favored in
strong acid
• Desulfonation is favored in
hot, diluted aqueous acid
Aromatic Sulfonation
• Does not occur naturally but is used in the preparation of dyes and
pharmaceutical agents.
• Sulfa drugs (sulfanilamide) were among the first clinically useful antibiotics.
Aromatic Hydroxylation
• Direct hydroxylation of an aromatic ring to yield a hydroxybenzene
(phenol) is difficult and rarely done in laboratory; occurs frequently in
biological pathways though.
• By analogy with other
aromatic substitution, we
expect an electrophilic
oxygen species is needed
(OH+ equivalent) is needed
for hydroxylation.
Alkylation and Acylation: The
Friedel-Crafts Reaction
Alkylation and Acylation: The Friedel-Crafts
Reaction
• Alkylation: the addition of an alkyl group (-R)
• Acylation: the addiction of an acyl group (-COR)
• Among the most useful electrophilic aromatic substitution reaction in
the laboratory
• Carried out by treating the aromatic compound with an alkyl chloride
in the presence of AlCl3 to generate a carbocation electrophile.
Alkylation and Acylation: The Friedel-Crafts
Reaction
• Has several limitations
• Only alkyl halides can be used (aromatic halides and vinyl halides cannot be
used because they are too high in energy)
• Do not succeed on aromatic rings with strong electron-withdrawing
group (carbonyl) or by a basic amino group that can be protonated
• Difficult to stop the reaction after a single substitution; goal product
cannot be easily taken.
Alkylation and Acylation: The Friedel-Crafts
Reaction
• Yet a final limitation: skeletal rearrangement of the alkyl carbocation
sometimes occur.
• Means that the product is a mix of isomers of the expected product
• Occurs either by hydride shift or alkyl shift
Alkylation and Acylation: The Friedel-Crafts
Reaction
• Recall, acylation: aromatic ring is added with a carbonyl-containing
group (-COR) in the presence of AlCl3.
Alkylation and Acylation: The Friedel-Crafts
Reaction
Alkylation and Acylation: The Friedel-Crafts
Reaction
• Aromatic alkylation occur in numerous biological pathways.
• However, no AlCl3 is involved.
• Carbocation electrophile is formed by dissociation of an organodiphosphate,
usually assisted by Mg2+.
Substituent Effect in Substituted
Aromatic Rings
Substituent Effect in Substituted Aromatic
Rings
• When benzene is subjected to a reaction, only one product is formed
(mostly). What would happen if that benzene has a substituent
attached to it?
• Substituent has two effects:
• Affect the reactivity: makes the ring more reactive, or more non-reactive
Substituent Effect in Substituted Aromatic
Rings
• When benzene is subjected to a reaction, only one product is formed
(mostly). What would happen if that benzene has a substituent
attached to it?
• Substituent has two effects:
• Affect the orientation: the three orientation (ortho, meta, para) are not
formed in equal amounts. Substituent nature and position determine the
position of the second substitution.
Substituent Effect in Substituted Aromatic
Rings
• Substituents can be divided into three groups:
• Ortho- and para-directing activators (mostly activating)
• Ortho- and para-directing deactivators
• Meta-directing deactivators (mostly deactivating)
Substituent Effect in Substituted Aromatic
Rings
• Predict the major product of the sulfonation of toluene.
+ SO3
H2SO4
???
Quick Quiz
Predict the major products of the following reactions
•
•
•
•
Nitration of bromobenzene
Bromination of nitrobenzene
Chlorination of phenol
Bromination of aniline
An Explanation of Substituent
Effects
An Explanation of Substituent Effects
• What makes a group
activating or deactivating?
• Activating: they donate
electrons
• Deactivating: they withdraw
electrons
• Withdrawal or donation of
electrons is controlled by an
interplay of inductive and
resonance effects
• Inductive effect: withdrawal or
donation of σ bonds due to
electronegativity
An Explanation of Substituent Effects
• What makes a group
activating or deactivating?
• Activating: they donate
electrons
• Deactivating: they withdraw
electrons
• Withdrawal or donation of
electrons is controlled by an
interplay of inductive and
resonance effects
• Resonance effect: withdrawal or
donation through π bond due
to overlap of p orbitals
An Explanation of Substituent Effects
• What makes a group
activating or deactivating?
• Activating: they donate
electrons
• Deactivating: they withdraw
electrons
• Withdrawal or donation of
electrons is controlled by an
interplay of inductive and
resonance effects
• Resonance effect: withdrawal or
donation through π bond due
to overlap of p orbitals
Trisubstituted Benzenes:
Additivity of Effects
Trisubstituted Benzenes: Additivity of Effects
• What if the ring contains two substituents instead of one?
• Governed by the same inductive and resonance effects
• Difference to monosubstituted benzene: the two substituents have an additive effect
• Three rules:
• If the directing effects of the two groups reinforce each other, the situation is
straightforward.
• If the directing effects of the two groups oppose each other, the more powerful
activating group has the dominant influence, but mixtures of products are often
formed.
• 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, such as by
substitution of an ortho-disubstituted compound.
Trisubstituted Benzenes: Additivity of Effects
• If the directing effects of the two groups reinforce each other, the
situation is straightforward.
Trisubstituted Benzenes: Additivity of Effects
• If the directing effects of the two groups oppose each other, the more
powerful activating group has the dominant influence, but mixtures
of products are often formed.
Trisubstituted Benzenes: Additivity of Effects
• Further substitution rarely occurs between the two groups in a metadisubstituted compound because this site is too hindered. Aromatic
rings with three adjacent substituents must therefore be prepared by
some other route, such as by substitution of an ortho-disubstituted
compound.
Trisubstituted Benzenes: Additivity of Effects
• What product would you expect from bromination of pmethylbenzoic acid?
+ Br2
Fe2Br3
???
Quick Quiz Part 2
• At what position would you expect electrophilic substitution to occur
in each of the following substances?
Quick Quiz Part 2
• Show the major product(s) from the reaction of the following
substances with (1) CH3CH2Cl, AlCl3 and (2) HNO3, H2SO4
Nucleophilic Aromatic
Substitution
Nucleophilic Aromatic Substitution
• Although aromatic substitution usually occur by electrophilic
mechanism, aryl halides that have electron-withdrawing substituents
can also undergo nucleophilic substitution reaction.
Nucleophilic Aromatic Substitution
• Much less common than electrophilic substitution; have certain uses
• Used in detection of free amino acids
• Can be used in amino acid sequencing
Nucleophilic Aromatic Substitution
• Only occurs if aromatic
ring has an electronwithdrawing
substituent in a
position ortho or para
to the leaving group to
stabilize the anion
intermediate through
resonance.
Nucleophilic Aromatic Substitution
• Difference between electrophilic and nucleophilic substitution
• ES: favored by electron-donating substituent; NS: favored by electronwithdrawing substituent
• ES: meta-directing substituents; NS: ortho-para directing substituents
• ES: replace hydrogen on the ring; NS: replace a leaving group (usually halide)
Oxidation of Aromatic
Compounds
Oxidation of Aromatic Compounds
• Despite the unsaturation, benzene ring is unreactive to strong
oxidizing agents such as KMnO4 and Na2CrO7.
• However, presence of aromatic rings has effect on alkyl side chains.
• Alkyl side chains rapidly react with oxidizing agents and convert to
carbonyl groups (-COOH). Alkylbenzene becomes benzoic acid.
Oxidation of Aromatic Compounds
• Analogous side-chain oxidation also happens in biological pathways.
Norepinephrine is biosynthesized from dopamine by benzylic
hydroxylation reaction.
Reduction of Aromatic
Compounds
Reduction of Aromatic Compounds
• Reduction = addition of hydrogen (hydrogenation)
• Benzene is generally inert to hydrogenation under typical alkene
conditions.
• Because of this, it is possible to selectively reduce an alkene double
bond in the presence of an aromatic ring.
Reduction of Aromatic Compounds
• To hydrogenate an aromatic ring, it is necessary to use a platinum
catalyst with hydrogen gas at high pressure or use a more effective
catalyst such as rhodium on carbon (Rh/C). Aromatic rings are
converted into cycloalkanes.
Synthesis of Polysubstituted
Benzenes
Synthesis of Polysubstituted Benzenes
• How do we synthesize an aromatic compound with multiple
substituent?
• You need:
• Analytical ability, knowledge of the use and limitations of organic reactions
• Know which reaction to use and when to use it
• Best way to learn organic chemistry
• Challenges your ability to think critically and analyze situations to plan
properly, a good skill that is very much needed in Dentistry.
Synthesizing a Polysubstituted Benzene
• Synthesize 4-bromo-2-nitrotoluene from benzene
• Strategy
• Draw the target molecule, identify the substituents, and recall how each
group can be introduced into the ring separately. Then plan retrosynthetically
(go backwards from the product to its reactants).
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 Friedel–Crafts
alkylation with CH3Cl/AlCl3, and a nitro group can be introduced by nitration with HNO3/H2SO4.
Synthesizing a Polysubstituted Benzene
• Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene
• Strategy
• Draw the target molecule, identify the substituents, and recall how each
group can be introduced into the ring separately. Then plan retrosynthetically
(go backwards from the product to its reactants)
The three substituents on the ring are a chlorine, a propyl group, and a sulfonic acid group. A chlorine can be
introduced by chlorination with Cl2/FeCl3, a propyl group can be introduced by Friedel–Crafts acylation with
CH3CH2COCl/AlCl3 followed by reduction with H2/Pd, and a sulfonic acid group can be introduced by
sulfonation with SO3/H2SO4.
Quick Quiz
• How might you synthesize the following substances from benzene?
a. m-chloronitrobenzene
b. m-chloroethylbenzene
c. 4-chloro-1-nitro-2-propylbenzene
d. 3-bromo-2-methylbenzenesulfonic acid