1 Substitution Reactions of Benzene and Its Derivatives: Electrophilic Addition/Elimination...

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Substitution Reactions of Benzene and Its Derivatives:Electrophilic Addition/Elimination Reactions.

Benzene is aromatic: a cyclic conjugated compound with 6 electrons

Reactions of benzene lead to the retention of the aromatic core

Electrophilic aromatic substitution replaces a proton on benzene with another electrophile

Aromatic Substitutions

via the Wheland Intermediates All electrophile additions involve a cationic intermediate that

was first proposed by G. W. Wheland of the University of Chicago and is often called the Wheland intermediate.

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

FeBr3 is added as a catalyst to polarize the bromine reagent

Addition 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) This forms a cationic addition intermediate from benzene

and a bromine cation The intermediate is not aromatic and therefore high in

energy

Formation of the Product from the Intermediate

The cationic addition intermediate transfers a proton to FeBr4

- (from Br- and FeBr3)

This restores aromaticity (in contrast with addition in alkenes)

Aromatic Chlorination and Iodination

Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution with the addition of other reagents to promote the reaction

Chlorination requires FeCl3

Iodine must be oxidized to form a more powerful I+ species (with Cu+ or peroxide)

Aromatic Nitration and Sulfonation

Alkylation of Aromatic Rings:The Friedel–Crafts Reaction

Aromatic substitution of a R+ for H

Aluminum chloride promotes the formation of the carbocation

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)

CH3CH2Br

+ HBr AlBr3+

CH3CH2 Br + AlBr3 CH3CH2 Br AlBr3

CH3CH2 Br AlBr3δ δ

CH2CH3

+ AlBr4

Alkylation of Aromatic Rings:The Friedel–Crafts Reaction

Multiple alkylations can occur because the first alkylation is activating

Carbocation Rearrangements During Alkylation

Acylation of Aromatic Rings Reaction of an acid chloride (RCOCl) and an

aromatic ring in the presence of AlCl3 introduces acyl group, COR

Mechanism of Friedel-Crafts Acylation

Reduction of Aryl Alkyl Ketones Allows Synthesis

of Non-rearranged Alkyl Benzenes. Aromatic ring activates neighboring carbonyl group toward

reduction. Ketone is converted into an alkylbenzene by catalytic

hydrogenation over Pd catalyst, or Wolff-Kishner or Clemensen reductions.

Reduction of Aryl Alkyl Ketones Allows Synthesis

of Non-rearranged Alkyl Benzenes. C

CH3H3C

Zn/Hg + HCl

Nucleophile Reaction Conditions Reaction mode(Purpose)

N2H4and derivatives

1. N2H4 / H3O+

2. OH- / DMSOIntermolecular 1,2-addition(Wolff-Kishner reduction of

aldehydes, ketones;synthesis of hydrazones, alkanes

and alkyl benzenes)

H2 / (Me/C)Me = Pd, Pt, Ni

Intermolecular 1,2-addition(reduction of aldehydes,

ketones and esters;synthesis of alcohols

and alkanes)

Zn/Hg amalgamin HCl

Clemensen Reduction(reduction of aryl ketones toalkyl aromatic compounds)

Summary of reduction nucleophiles in 1,2-additionsto aromatic C=O groups.

Substituent Effects in Aromatic Rings Substituents can cause a compound to be (much) more or (much)

less reactive than benzene and affect the orientation of the reaction.

There substituents are: ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators.

Summary Table:Effect of Substituents in Aromatic Substitution

The 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.

Origins of Substituent Effects: Inductive Effects

The overall effect of a substituent is defined by the interplay of inductive effects and resonance effects.

Inductive effect - withdrawal or donation of electrons through bonds. Controlled by electronegativity and the polarity of bonds in functional groups,

i.e. halogens, C=O, CN, and NO2 withdraw electrons through bond connected to ring.

Alkyl group inductive effect is to donate electrons.

Origins of Substituent Effects: Resonance Effects

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.

C=O, CN, and NO2 substituents withdraw electrons from the aromatic ring by resonance, i.e. the electrons flow from the rings to the substituents.

Origins of Substituent Effects: Resonance Effects

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.

Halogen, OH, alkoxyl (OR), and amino substituents donate electrons, i.e. the electrons flow from the substituents to the ring.

Ortho- and Para-Directing

Activators: Alkyl Groups

Ortho- and Para-Directing Activators:

OH and NH2

Ortho- and Para-Directing

Deactivators: Halogens

Meta-Directing Deactivators Inductive and resonance effects reinforce each other. Ortho and para intermediates destabilized by deactivation of

the carbocation intermediate

Disubstituted Benzenes:

Additivity of Effects If the directing effects of the two groups are the same, the

result is additive.

Disubstituted Benzenes:

Opposition of Effects If the directing effects of the two groups are different, the more powerful

activating group decides the principal outcome. Usually the mixture of products results.

Linked Benzenes:

Opposition of Effects

OCH3Br / AlBr3

Diazonium Salts: The Sandmeyer Reaction

Primary arylamines react with HNO2, yielding stable arenediazonium salts.

The N2 group can be replaced by a nucleophile.

Reactions of Arenediazonium Salts Allow Formation of “Impossibly” Substituted Aromatic

Rings.

Typical synthetid sequence consists of: (1) nitration, (2) reduction, (3) diazotization, and (4) nucleophilic

substitution

Preparation of Aryl Halides

Reaction of an arenediazonium salt with CuCl or CuBr gives aryl halides (Sandmeyer Reaction).

Aryl iodides form from reaction with NaI without a copper(I) salt.

Br2 / AlBr3

+N2Cl-

Fe / HCl

BF4NO2

KNO2 / HCl HBr/ CuCN

X = Br, I , F

NaI HBF4I

Preparation of Aryl Nitriles and Carboxylic Acids

An arenediazonium salt and CuCN yield the nitrile, ArCN, which can be hydrolyzed to ArCOOH.

CH3Br / AlBr3

Fe / HCl

BF4NO2

KNO2 / HCl KCN / CuCN H3O+

Reduction to a CH aromatic bond

By treatment of a diazonium salt with hypophosphorous acid, H3PO2

HCl, 0°C

0°C/H2O

0°C or RT

Reduction via diazonium salts

BrBrBrBr

fromphenol

CO2CH3

NO2 BF4

CO2CH3

NaOH CO2

CO2CH3

HCl, 0°CKNO2

CO2CH3

metameta

Preparation of complex phenols

1 Substitution Reactions of Benzene and Its Derivatives: Electrophilic Addition/Elimination...

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