Electrophilic Aromatic Substitution

OBJECTIVES
Understand the reaction mechanisms of Benzene Predict the product of each reaction Know the different catalyst used in each reaction

Electrophilic Aromatic Substitution

Electrophilic Aromatic Substitution Background

The characteristic reaction of benzene is electrophilic aromatic substitutiona hydrogen atom is replaced by an electrophile.

The loosely held T electrons make the benzene ring electron rich. so, it reacts with electrophiles. Reactions that keep the aromatic ring intact are favored.

The General Mechanism

The General Mechanism

The energy changes in electrophilic aromatic substitution are shown below:

Five examples of electrophilic aromatic substitution

Halogenation
In halogenation, benzene reacts with Cl2 or Br2 in the presence of a Lewis acid catalyst, such as FeCl3 or FeBr3, to give the aryl halides chlorobenzene or bromobenzene respectively.

Analogous reactions with I2 and F2 are not synthetically useful because I2 is too unreactive and F2 reacts too violently.

Mechanism of Halogenation

Chlorination proceeds by a similar mechanism.

Five examples of electrophilic aromatic substitution

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Five examples of electrophilic aromatic substitution

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Nitration and Sulfonation

Generation of the electrophile in both nitration and sulfonation requires strong acid.
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Nitration and Sulfonation Formation of the electrophile

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Five examples of electrophilic aromatic substitution

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Five examples of electrophilic aromatic substitution

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Friedel-Crafts Alkylation and Friedel-Crafts Acylation A. General Features

In Friedel-Crafts alkylation, treatment of benzene with an alkyl halide and a Lewis acid (AlCl3) forms an alkyl benzene.

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 In Friedel-Crafts acylation, a benzene ring is treated with an acid chloride (RCOCl) and AlCl3 to form a ketone.

The transfer of an acyl group from one atom to another is an acylation.

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Friedel-Crafts Alkylation and Friedel-Crafts Acylation B. Mechanism : generation of carbocation!

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Other functional groups that form carbocations can also be used as starting materials.

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Friedel-Crafts Acylation: No rearrangement

D. Intramolecular Friedel-Crafts Reactions

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Electrophilic Benzenes.

Aromatic

Substitution

of

Substituted

1. The rate of the reactionA substituted benzene reacts faster or slower than benzene itself. 2. The orientationThe new group is located either ortho, meta, or para to the existing substituent. The identity of the first substituent determines the position of the second incoming substituent.

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Electrophilic Benzenes.

Aromatic

Substitution

of

Substituted

A substituent affects two aspects of the electrophilic aromatic substitution reaction: 1. The rate of the reactionA substituted benzene reacts faster or slower than benzene itself. 2. The orientationThe new group is located either ortho, meta, or para to the existing substituent. The identity of the first substituent determines the position of the second incoming substituent.

How does the substitution affects the outcome? Further stabilizing (destabilizing) the cationic intermediate

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Substituted Benzenes

Inductive Effects

Considering inductive effects only, the NH2 group withdraws electron density and CH3 donates electron density.

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Substituted Benzenes
Resonance Effects Resonance effects are only observed with substituents containing lone pairs or T bonds. Electron-donating resonance effect : An atom Z having a lone pair of electrons is directly bonded to a benzene ring

stabilization
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 Electron-withdrawing resonance effect : the general structure C6H5Y=Z, where Z is more electronegative than Y.

Benzaldehyde (C6H5CHO): Because three of them place a positive charge on a carbon atom of the benzene ring, the CHO group withdraws electrons from the benzene ring by a resonance effect.

destabilization
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Substituted Benzenes
Considering Both Inductive and Resonance Effects To predict whether a substituted benzene is more or less electron rich than benzene itself, we must consider the net balance of both the inductive and resonance effects.

Any alkyl-substituted benzene: more electron rich than benzene itself.

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 C6H5-Z : Depends on the net balance of two opposing effects

C6H5-Y=Z (with Z more electronegative than Y): Both the inductive and resonance effects are electron withdrawing.

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 Examples of the general structural features in electron-donating and electron withdrawing substituents.

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Lets try this!

1. Draw the three products that might form on reaction of toluene ( methylbenzene) with Br2. 2. Show the mechanism of the reaction benzene with nitric acid and sulfuric acid yield nitrobenzene. 3. Chlorination of o-xylene ( o-dimethylbenzene) yields a mixture of two products, but chlorination of p-xylene yields a single product. Explain.
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Lets try this!

4. How many products might be formed on chlorination of m-xylene? 5. What products would you expect t obtain from the reaction of the following to obtain from the reaction of the following compounds with chloroethane and AlCl3?
A. Benzene B. P-Xylene

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Lets try this!

6. What products would you expect to obtain from the reaction of benzene with the following reagents? a. (CH3)3CCl, AlCl3 b. CH3CH2COCl, AlCl3

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Substitution Reactions of Substituted Benzenes Toluene

Toluene reacts faster than benzene in all substitution reactions. The electron-donating CH3 group activates the benzene ring to electrophilic attack. Ortho and para products predominate. The CH3 group is called an ortho, para director.

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Nitrobenzene
It reacts more slowly than benzene in all substitution reactions. The electron-withdrawing NO2 group deactivates the benzene ring to electrophilic attack. The meta product predominates. The NO2 group is called a meta director.

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All substituents can be divided into three general types:

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 Keep in mind that halogens are in a class by themselves. Also note that:

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Why Substituents Activate or Deactivate a Benzene Ring

To understand how substituents activate or deactivate the ring, we must consider the first step in electrophilic aromatic substitution. The first step involves addition of the electrophile (E+) to form a resonance stabilized carbocation. The Hammond postulate makes it possible to predict the relative rate of the reaction by looking at the stability of the carbocation intermediate.

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Orientation Effects in Substituted Benzenes

There are two general types of ortho, para directors and one general type of meta director. All ortho, para directors are R groups or have a nonbonded electron pair on the atom bonded to the benzene ring. All meta directors have a full or partial positive charge on the atom bonded to the benzene ring.

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To evaluate the effects of a given substituent, we can use the following stepwise procedure:

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Orientation Effects in Substituted Benzenes

A. The CH3 Group An Ortho, para Director A CH3 group directs electrophilic attack ortho and para to itself because an electron-donating inductive effect stabilizes the carbocation intermediate.

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B. The NH2 Group An Ortho, para Director

An NH2 group directs electrophilic attack ortho and para to itself because the carbocation intermediate has additional resonance stabilization.

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C. The NO2 Group A meta Director

With the NO2 group (and all meta directors) meta attack occurs because attack at the ortho and para position gives a destabilized carbocation intermediate.

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Electrophilic Aromatic Substitution Orientation Effects in Substituted Benzenes

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Limitations on Electrophilic Substitution Reactions with Substituted Benzenes A. Halogenation of Activated Benzenes
Benzene rings activated by strong electron-donating groups - OH, NH2, and their derivatives (OR, NHR, and NR2) - undergo polyhalogenation when treated with X2 and FeX3.

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B. Limitations in Friedel-Crafts Reactions

A benzene ring deactivated by strong electron-withdrawing groups (i.e., any of the meta directors) is not electron rich enough to undergo Friedel-Crafts reactions.

Friedel-Crafts reactions also do not occur with NH2 groups because the complex that forms between the NH2 group and the AlCl3 catalyst deactivates the ring towards Friedel-Crafts reactions.

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 Treatment of benzene with an alkyl halide and AlCl3 places an electron-donor R group on the ring. Since R groups activate the ring, the alkylated product (C6H5R) is now more reactive than benzene itself towards further substitution, and it reacts again with RCl to give products of polyalkylation.

Polysubstitution does not occur with Friedel-Crafts acylation. No Further Reaction

Reactivity control !!
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Disubstituted Benzenes
1. When the directing effects of two groups reinforce, the new substituent is located on the position directed by both groups.

Synergistic effect

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2. If the directing effects of two groups oppose each other, the more powerful activator wins out.

3. No substitution occurs between two meta substituents because of crowding.

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Synthesis of Benzene Derivatives

For the synthesis of disubstituted benzene, the directing effects indicate which substituent must be added to the ring first. Synthetic strategy !!

Let us consider the consequences of bromination first followed by nitration, and nitration first, followed by bromination.
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- Pathway I, in which bromination precedes nitration, yields the desired product.

- Pathway II yields the undesired meta isomer.

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Other reactions on aromatic compounds

Halogenation of Alkyl Benzenes : radical reaction
Benzylic C-H bonds are weaker than most other sp3 hybridized C-H bonds, because homolysis forms a resonance-stabilized benzylic radical.

As a result, alkyl benzenes undergo selective bromination at the weak benzylic C-H bond under radical conditions to form the benzylic halide.

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Halogenation of Alkyl Benzenes

With Br2 and FeBr3 (ionic conditions), electrophilic aromatic substitution occurs, resulting in replacement of H by Br on the aromatic ring to form ortho and para isomers. With Br2 and light or heat (radical conditions), substitution of H by Br occurs at the benzylic carbon of the alkyl group.
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Halogenation of Alkyl Benzenes

mechanism

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Oxidation and Reduction of Substituted Benzenes A. Oxidation of Alkyl Benzenes

Arenes containing at least one benzylic C-H bond are oxidized with KMnO4 to benzoic acid.

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B. Reduction of Aryl Ketones to Alkyl Benzenes

Ketones formed as products of Friedel-Crafts acylation can be reduced to alkyl benzenes by two different methods:

Effectively turns into Friedel-Craft alkylation product

1. The Clemmensen reductionuses zinc and mercury in the presence of strong acid.

2. The Wolff-Kishner reductionuses hydrazine (NH2NH2) and strong base (KOH).

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We now know two different ways to introduce an alkyl group on a benzene ring: 1. A one-step method using Friedel-Crafts alkylation. 2. A two-step method using Friedel-Crafts acylation to form a ketone, followed by reduction.

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Control of the reactivity

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C. Reduction of Nitro Groups

A nitro group (NO2) that has been introduced on a benzene ring by nitration with strong acid can readily be reduced to an amino group (NH2) under a variety of conditions.

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Working backwards

Synthetic analysis

SEATWORK
1. Draw and name the three products that might form on reaction of toluene ( methylbenzene) with Br2. 2. Show the mechanism of the reactions of benzene with nitric acid and sulfuric acid to yield nitrobenzene.

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SEATWORK
3. Chlorination of o-xylene ( odimethylbenzene) yields a mixture of two products, but chlorination of p-xylene yields a single products. Explain. 4. How many products might be formed on chlorination of m-xylene?

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SEATWORK
5. What products would you expect to obtain from the reaction of the following compounds with chloroethane and AlCl3? a. Benzene b. p-xylene 6. What products would you expect to obtain from the reaction of benzene with the following reagents? a. (CH3)3CCl,AlCl3 b. CH3CH2COCl,AlCl3
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