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Electrophilic Aromatic Substitution and Nucleophilic Aromatic Substitution

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chem 31
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D. Electrophilic Aromatic Addition A. How Benzene Reacts As a consequence of the electrons above and below the plane of its ring, benzene is a nucleophile. It will, therefore, react with an electrophile forming a carbocation intermediate is formed. Illustration:

If the carbocation intermediate formed from the reaction of benzene with an electrophile were to react like an alkene, the aromatic character would belost If, however, the carbocation loses a proton from the site of electrophilic attack, the aromaticity of the benzene ring is restored.

As seen from a thermodynamic point of view, the substitution product is more stable than the addition product and is therefore preferentially formed.

Because electrophilic substitution of benzene involves the reaction of an electrophile with an aromatic compound, it is more precisely called an electrophilic aromatic substitution reaction. In an electrophilic aromatic substitution reaction, an electrophile substitutes for a hydrogen of an aromatic compound.

There are five most common pathways for EAS, these are, halogenation, nitration, sulfonation, Friedel-Crafts alkylation, and Friedel-Crafts acylation. All of these electrophilic aromatic substitution reactions take place by the same two-step mechanism. In the first step, benzene reacts with an electrophile forming a carbocation intermediate. The structure of the carbocation intermediate can be approximated by three resonance contributors.

In the second step of the reaction, a base in the reaction mixture pulls off a proton from the carbocation intermediate, and the electrons that held the proton move into the ring to reestablish its aromaticity. Notice that the proton is always removed from the carbon that has formed the new bond with the electrophile.

1. Halogenation The bromination or chlorination of benzene requires Lewis acid catalysts such as ferric bromide or ferric chloride. Illustration:

Mechanism:

2. Nitration Nitration of benzene with nitric acid requires sulfuric acid as a catalyst. Illustration:

Mechanism:

3. Sulfonation Fuming sulfuric acid (a solution of in sulfuric acid) or concentrated sulfuric acid is used to sulfonate aromatic rings. Mechanism:

Illustration:

4. Friedel-Crafts Acylation FriedelCrafts acylation places an acyl group on a benzene ring. Illustration:

Mechanism:

The synthesis of benzaldehyde is through the Gattermann-Kock Formylation as seen below.

5. Friedel-Crafts Alkylation The FriedelCrafts alkylation reaction substitutes an alkyl group for a hydrogen.

Illustration:

Mechanism:

The major disadvantage of FCA is that, there are carbocation rearrangements taking place.

Illustration:

The solution to this phenomenon is to use the acylation followed by reduction.

Illustration:

The Clemmensen and Wolff-Kishner Reduction These are two to reduce the acyl carbon, with the former utilizing an acidic medium and latter, a basic medium. Illustration:

B. Reactions of Monosubstituted Benzene Recall: The five reactions for benzene

Like benzene, substituted benzenes undergo the five electrophilic aromatic substitution reactions. Will substituted benzene be more reactive or less reactive than benzene itself? The answer depends on the substituent. Some substituents make the ring more reactive and some make it less reactive than benzene toward electrophilic aromatic substitution.

Illustration:

The effects of electron donating can either be through resonance or inductive effects (review). Substituents in the benzene ring can have different effects as seen from the table below.

Illustration:

Now the question is, why are activating groups with halogens as an exception are ortho/para directors and why deactivating groups are meta directors.

Illustration: ortho/para directing

Illustration: meta directing groups

All activating substituents and the weakly deactivating halogens are orthopara directors, and all substituents that are more deactivating than the halogens are meta directors.

Illustration:

The ortho, para and meta directors are best explained using the resonance structures. As seen from the resonance forms, the most stable forms occur when the positive charge is at the carbon bonded to the electron donating group (inductive effect).

Note:

All substituents that donate electrons into the ring inductively or by resonance are orthopara directors, and all substituents that cannot donate electrons into the ring inductively or by resonance are meta directors.

C. Reducing a Nitro Group The nitro group can actually be reduced to its amine form using a metal and HCl.

D. The Ortho-Para Ratio When a benzene ring with an orthopara-directing substituent undergoes an electrophilic aromatic substitution reaction, what percentage of the product is the ortho and what percentage is the para? Solely on the basis of probability, one would expect more of the ortho product because there are two ortho positions available and only one para position. The ortho position, however, is sterically hindered, whereas the para position is not. Consequently, the para isomer will be formed preferentially if either the substituent on the ring or the incoming electrophile is large.

E. Additional Notes and Substituent Effects Methoxy and hydroxy substituents are so strongly activating that halogenation is carried out without the Lewis acid catalyst. Illustration:

If the Lewis acid catalyst and excess bromine are used, the tribromide is obtained.

All FriedelCrafts reactions require the Lewis acid catalyst. However, if there is a meta director on the ring, it will be too unreactive to undergo either FriedelCrafts acylation or FriedelCrafts alkylation.

Aniline and N-substituted anilines also do not undergo FriedelCrafts reactions. The lone pair on the amino group will complex with the Lewis acid that is needed to carry out the reaction, converting the substituent into a deactivating meta director.

Phenol and anisole undergo FriedelCrafts reactionsorienting ortho and para. Aniline also cannot be nitrated because nitric acid is an oxidizing agent and primary amines are easily oxidized. (Nitric acid and aniline can be an explosive combination.)

F. Reactions of Disubstituted Benzenes When a disubstituted benzene undergoes an electrophilic aromatic substitution reaction, the directing effect of both substituents has to be considered. If both substituents direct the incoming substituent to the same position, the product of the reaction is easily predicted.

Steric effects play a role in determining the places of substitution as seen below.

If the two substituents direct the new substituent to different positions, a strongly activating substituent will win out over a weakly activating substituent or a deactivating substituent.

If the two substituents have similar activating properties, neither will dominate and a mixture of products will be obtained.

G. Synthesis using Diazonium Salts/The Sandmeyer Reaction The kinds of substituents that can be placed on benzene rings can be greatly expanded by the use of arenediazonium salts.

The drive to form a molecule of stable nitrogen gas causes the leaving group of a diazonium ion to be easily displaced by a wide variety of nucleophiles.

A primary amine can be converted into a diazonium salt by treatment with nitrous acid Because nitrous acid is unstable, it is formed in situ, using an aqueous solution of sodium nitrite and HCl or HBr. Indeed, it is such a good leaving group that the diazonium salt is synthesized at 0 C and used immediately without isolation.

Nucleophiles will replace the diazonium group if the appropriate cuprous salt is added to the solution containing the arenediazonium salt.

Mechanism:

Illustration:

KCl and KBr cannot be used in place of CuCl and CuBr in Sandmeyer reactions; the cuprous salts are required. This indicates that the cuprous ion is involved in the reaction.

Question: How will you synthesize the compound below?

H. Modified Sandmeyer Reactions An iodo substituent will replace the diazonium group if potassium iodide is added to the solution containing the diazonium ion.

Fluoro substitution occurs if the arenediazonium salt is heated with fluoroboric acid (HBF4). This reaction is known as the Schiemann reaction.

If the aqueous solution in which the diazonium salt has been synthesized is acidified and heated, an OH group will replace the diazonium group.

A hydrogen will replace a diazonium group if the diazonium salt is treated with hypophosphorous acid (H3PO2).

I. Dye Synthesis Arenediazonium ions can be used as electrophiles in electrophilic aromatic substitution reactions. In other words, only highly activated benzene rings (phenols, anilines, and N-alkylanilines) can undergo electrophilic aromatic substitution reactions with arenediazonium ion electrophiles. The product of the reaction is an azo compound. The linkage N=N is called an azo linkage. Because the electrophile is so large, substitution takes place preferentially at the less sterically hindered para position. Illustration:

Mechanism:

Azo compounds, like alkenes, can exist in cis and trans forms. Because of steric strain, the trans isomer is considerably more stable than the cis isomer

E. Nucleophilic Aromatic Substitution Aryl halides do not react with nucleophiles under standard reaction conditions because the pi electron clouds repel the approach of a nucleophile.

If, however, the aryl halide has one or more substituents that strongly withdraw electrons from the ring by resonance, nucleophilic aroma

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