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