Organic Chemistry

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Organic Chemistry 6th Edition Paula Yurkanis
Bruice
Chapter 16 Reactions of Substituted Benzenes
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Examples of Substituted Benzenes
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Nomenclature of Substituted Benzenes
In disubstituted benzenes, the relative positions
of the two substituents are indicated by numbers
or by prefixes
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The two substituents are listed in alphabetical
order
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• Common names are preferred in naming certain
  substituted benzenes, e.g., toluene, aniline,
  phenol.
• Do not deconstruct the common name e.g., do not
  change toluene to methylbenzene.
• The substituent that is part of the common name
  is position 1, but do not label as such in the
  chemical name.

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Some disubstituted benzenes have common names
that incorporate both substituents
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Naming Polysubstituted Benzenes
The substituents are numbered in the direction
that results in the lowest possible number
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The substituent incorporated into the common name
is the 1-position
Always give substituents the lowest possible
numbers!
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Substituted benzenes undergo the five
electrophilic aromatic substitution reactions
discussed in Chapter 15
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The slow step of an electrophilic aromatic
substitution reaction is the formation of the
carbocation intermediate

• Electron-donating substituents increase the rate
  of substitution reactions by stabilizing the
  carbocation intermediate.
• Electron-withdrawing substituents decrease the
  rate of substitution reactions by destabilizing
  the carbocation intermediate.

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Inductive Electron Withdrawal
Electron Donation by Hyperconjugation
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Resonance Electron Donation and Withdrawal
Substituents such as NH2, OH, OR, and Cl donate
electrons by resonance, but they also withdraw
electrons inductively
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Substituents such as CO, C?N, SO3H, and NO2
withdraw electrons by resonance
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Electron-donating substituents increase the
reactivity of the benzene ring toward
electrophilic aromatic substitution
Electron-withdrawing substituents decrease the
reactivity of the benzene ring toward
electrophilic aromatic substitution
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Electron-Donating Substituents
Electron donation into the benzene ring by
resonance is more significant than inductive
electron withdrawal from the ring
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Resonance donation into the benzene ring competes
with resonance donation into the carbonyl
Inductive withdrawal into the benzene ring also
occurs
Overall, these substituents weakly release
electrons
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These substituents are less effective in donating
electrons into the ring because
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Alkyl, aryl, and CHCHR groups are weakly
activating substituents because they are
slightly more electron donating than they are
electron withdrawing
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These substituents donate into the ring by
resonance and withdraw electrons from the ring
inductively
They withdraw electrons inductively more strongly
than they donate electrons by resonance
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These substituents withdraw electrons both
inductively and by resonance
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These substituents are powerful
electron-withdrawing groups
Except for the ammonium ions, these substituents
withdraw electrons both inductively and by
resonance
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The substituent already attached to the benzene
ring determines the location of the new
substituent
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All activating substituents are orthopara
directors
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The weakly deactivating halogens are orthopara
directors
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All substituents that are more deactivating than
halogens are meta directors
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An ortho,para-directing substituent
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An ortho,para-directing substituent
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An meta-directing substituent
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The Effect of Substituents on pKa
Electron-withdrawing groups stabilize a base and
therefore increase the strength of its conjugate
acid
Electron-donating groups destabilize a base and
thus decrease the strength of its conjugate acid
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The more electronic deficient a substituent on
phenol, the stronger the acid
To understand the relative pKa values, consider
the delocalization of the phenolate anion (stars
show anion distribution)
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The more electronic deficient a substituent on
benzoic acid, the stronger the acid
Substituent effect on pKa is minimal in benzoic
acids because only inductive electronic effects
are present
Why? Because the benzene ring is cross conjugated
with the carboxylate anion
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The more electronic deficient a substituent on a
protonated aniline, the stronger the acid
To understand the relative pKa values, consider
the delocalization of the aniline lone pair of
the conjugate base (stars show anion
distribution)
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The orthopara product ratio decreases with an
increase in the size of the substituents
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Methoxy and hydroxy substituents are so
strongly activating that halogenation is carried
out without a Lewis acid
The presence of Lewis acid and excess bromine
generates the tribromo derivative
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A benzene ring with a meta director cannot
undergo a FriedelCrafts reaction
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Aniline and N-substituted anilines do not
undergo FriedelCrafts reaction
Phenol and anisole undergo FriedelCrafts
reactions at the ortho and para positions
Aniline cannot be nitrated, because it is
oxidized by nitric acid
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In designing a disubstituted benzene,
consider the order of substitution
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The FriedelCrafts acylation must be carried out
first, because the nitro group is strongly
deactivating
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In the synthesis of para-chlorobenzoic acid from
toluene, the methyl group is oxidized after
chlorination
In the synthesis of meta-chlorobenzoic acid, the
methyl group is oxidized before chlorination
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• To synthesize p-propylbenzenesulfonic acid
• Introduce the propyl group by FriedelCrafts
  acylation followed by reduction.
• Sulfonation of the propylbenzene product affords
  the para derivative.

• How is the meta derivative prepared?
• FriedelCrafts acylation
• Sulfonation
• Carbonyl reduction

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Synthesis of Trisubstituted Benzenes
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Steric hindrance makes the position between
the substituents less accessible
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A strongly activating substituent will win out
over a weakly activating substituent or a
deactivating substituent
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If the two substituents have similar activating
properties, neither will dominate
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Synthesis of Substituted Benzenes Using
Arenediazonium Salts
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Preparation of the Diazonium Salt
Mechanism
Nitrosonium ion formation
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Diazonium ion formation
Caution Diazonium salts are explosive!
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The reaction stops because a secondary amine
lacks a second proton
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The bulky dialkyl amino group blocks the approach
of the nitrosonium ion to the ortho position
unnumbered fig, pg 690
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Consider the synthesis of para-chloroethylbenzene
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Fluorination and Iodination of Benzene
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Hydroxylation of Benzene
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Summary of Diazonium Reactions
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Synthesis Example
Propose a synthesis from a monosubstituted benzene
Synthetic target
Answer
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The Arenediazonium Ion as an Electrophile
Only highly activated benzene rings can undergo
this reaction
Substitution takes place preferentially at the
para position
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However, if the para position is blocked
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Mechanism
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Diazo Dyes
Diazonium coupling affords synthetic dyes
Large dipole results in deep color (high
extinction coefficient)
Electronic push-pull produces a dipole
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Diazo Dyes and Sulfa Drugs
Gerhard Domagk studied the antibiotic properties
of diazo dyes. He was awarded the Nobel Prize for
medicine in 1939 for his work.
The dye prontosil is reduced to the sulfa drug
sulfanilamide
Domagk cured his daughter of strep with
sulfanilamide
Sulfanilamide looks like PABA, a bacterial
nutrient
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Nucleophilic Aromatic Substitution Reactions
Nucleophilic aromatic substitution reactions
require at least one strongly electron-withdrawing
substituent to occur
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Electron-withdrawing substituents increase the
reactivity of the benzene ring toward
nucleophilic substitution and decrease the
reactivity of the benzene ring toward electrophili
c substitution
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The electron-withdrawing substituents must be
ortho or para to the site of nucleophile attack,
so that electrons of the attacking nucleophile
can be delocalized into these substituents
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The incoming group has to be a stronger base than
the group that is being replaced
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Agent Orange and Nucleophilic Aromatic
Substitution
Synthesis of Agent Orange
Side reaction
Dioxin is carcinogenic and causes birth defects
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Formation of Benzyne
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Benzyne Is an Extremely Reactive Species
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Polycyclic Benzoid Hydrocarbons