Chapter 5-2. Chemistry of Benzene: Electrophilic Aromatic Substitution
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Substitution Reactions of Benzene and Its Derivatives
Benzene is aromatic: a cyclic conjugated compound with 6 electrons
Reactions of benzene lead to the retention of the aromatic -system
Electrophilic aromatic substitution replaces a proton on benzene with another electrophile
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Bromination of Aromatic Rings Benzene’s electrons participate as a Lewis base in
reactions with Lewis acids The product is formed by loss of a proton, which is
replaced by bromine
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Bromination of Aromatic Rings FeBr3 is added as a catalyst to polarize the
bromine reagent
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Cationic Intermediate in Bromination The addition of bromine occurs in two steps In the first step the electrons act as a
nucleophile toward Br2 (in a complex with FeBr3)
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This forms a cationic addition intermediate
The intermediate is not aromatic and therefore high in energy
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Formation of Product from Intermediate The cationic addition
intermediate transfers a proton to FeBr4
- (from Br- and FeBr3)
This restores aromaticity (in contrast with addition in alkenes)
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Other Aromatic Substitutions The reaction with bromine
involves a mechanism that is similar to many other reactions of benzene with electrophiles
The cationic intermediate was first proposed by G. W. Wheland of the University of Chicago and is often called the Wheland intermediate
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Aromatic Chlorination and Iodination Chlorine and iodine (but not fluorine, which is too
reactive) can produce aromatic substitution in the presence of Lewis acids.
Chlorination requires FeCl3
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Aromatic Chlorination and Iodination Iodine must be oxidized to form a more powerful I+
species (with Cu+ or peroxide)
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Aromatic Nitration The combination of nitric acid and sulfuric
acid produces NO2+ (nitronium ion), which is
isoelectronic with CO2
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Aromatic Nitration The reaction with benzene produces nitrobenzene
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Reduction of nitro compounds to amines
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Aromatic Sulfonation Substitution of H by SO3 (sulfonation) Reaction with a mixture of sulfuric acid and SO3
(fuming sulfuric acid) Reactive species is sulfur trioxide or its conjugate acid
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Aromatic Sulfonation Sulfur trioxide, or its conjugate acid, react
by the usual mechanism:
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Useful reactions of sulfonic acids Sulfonic acids are useful as intermediates in the
synthesis of sulfa drugs and phenols:
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Alkylation of Aromatic Rings: The Friedel–Crafts Reaction Aromatic substitution of “R+” for H,
alkylating the ring
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Alkylation of Aromatic Rings: The Friedel–Crafts Reaction
Aromatic substitution of a R+ for H
Aluminum chloride promotes the formation of the carbocation
Wheland intermediate forms
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Limitations of the Friedel-Crafts Alkylation Only alkyl halides can be used (F, Cl, I, Br) Aryl halides and vinylic halides do not react
(their carbocations are too hard to form)
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Control Problems Multiple alkylations can occur because the
first alkylation is activating
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Carbocation Rearrangements During Alkylation Similar to those that occur during electrophilic
additions to alkenes
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Similar reactions:
Mechanism?
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Solution:
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Another variation:
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Acylation of Aromatic Rings Reaction of an acid chloride (RCOCl) and an
aromatic ring in the presence of AlCl3 introduces acyl group, COR
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Mechanism of Friedel-Crafts Acylation Similar to alkylation; reactive electrophile is a resonance-
stabilized acyl cation, which does not rearrange
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Problem: acid chloride reactant?
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Substituent Effects in Aromatic Rings Substituents can cause a compound to be
(much) more or (much) less reactive than benzene
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Substituent Effects in Aromatic Rings Substituents affect the orientation of the reaction – the
positional relationship is controlled ortho- and para-directing activators, ortho- and para-
directing deactivators, and meta-directing deactivators
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Origins of Substituent Effects An interplay of inductive effects and
resonance effects Inductive effect - withdrawal or donation of
electrons through a bond Resonance effect - withdrawal or donation
of electrons through a bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring
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Inductive Effects Controlled by electronegativity and the polarity
of bonds in functional groups Halogens, C=O, CN, and NO2 withdraw
electrons through bond connected to ring Alkyl groups donate electrons
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Resonance Effects – Electron Withdrawal C=O, CN, NO2 substituents withdraw electrons
from the aromatic ring by resonance
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Resonance Effects – Electron Withdrawal
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Resonance Effects – Electron Donation Halogen, OH, alkoxyl (OR), and amino
substituents donate electrons Effect is greatest at ortho and para
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Resonance Effects – Electron Donation
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Contrasting Effects Halogen, OH, OR, withdraw electrons
inductively so that they deactivate the ring
Resonance interactions are generally weaker, affecting orientation
The strongest effects dominate
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An Explanation of Substituent Effects Activating groups donate electrons to
the ring, stabilizing the Wheland intermediate (carbocation)
Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate
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Electron Donation & Withdrawal from Benzene Rings
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Ortho- and Para-Directing Activators: Alkyl Groups Alkyl groups activate: direct further
substitution to positions ortho and para to themselves
Alkyl group is most effective in the ortho and para positions
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Ortho- and Para-Directing Activators: OH and NH2
Alkoxyl, and amino groups have a strong, electron-donating resonance effect
Most pronounced at the ortho and para positions
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Ortho- and Para-Directing Deactivators: Halogens Electron-withdrawing inductive effect
outweighs weaker electron-donating resonance effect
Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate
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Meta-Directing Deactivators Inductive and resonance effects
reinforce each other Ortho and para intermediates
destabilized by deactivation from carbocation intermediate
Resonance cannot produce stabilization
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Summary Table: Effect of Substituents in Aromatic Substitution
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Trisubstituted Benzenes: Additivity of Effects If the directing effects of the two groups are
the same, the result is additive
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Substituents with Opposite Effects If the directing effects of two groups oppose
each other, the more powerful activating group decides the principal outcome
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Meta-Disubstituted Compounds Are Unreactive between the two groups The reaction site is too hindered
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Prob.: Substitution at which positions?
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Prob.: Major substitution product(s)?
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Oxidation of Aromatic Compounds Alkyl side chains can be oxidized to CO2H
by strong reagents such as KMnO4 and Na2Cr2O7 if they have a C-H next to the ring
Converts an alkylbenzene into a benzoic acid
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Prob.: Oxidation products?
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Reduction of Aromatic Compounds Aromatic rings are inert to catalytic hydrogenation under
conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the
presence of an aromatic ring Reduction of an aromatic ring requires more powerful
reducing conditions (high pressure or rhodium catalysts)
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Reduction of Aryl Alkyl Ketones Aromatic ring activates neighboring carbonyl group
toward reduction Ketone is converted into an alkylbenzene by
catalytic hydrogenation over Pd catalyst
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Synthesis Strategies These syntheses require planning and consideration of
alternative routes Work through the practice problems in this section
following the general guidelines for synthesis and retrosynthetic analysis.
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Practice Problem:
Synthesize From Benzene:
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Solutions:
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Practice Problem:Synthesize From Benzene:
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How can we make m-chloropropylbenzene?
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Putting it all together:
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Prob.: What’s wrong with these syntheses?
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Prob.: What’s wrong with these syntheses?
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Prob.: Synthesize from benzene
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Prob.: Identify the reagents