Organic Chemistry: Concepts and Applications - Headley Allan D. 2020

Aromaticity and Aromatic Substitution Reactions
17.7 Electrophilic Aromatic Substitution Reactions of Substituted Benzene

For substituted benzenes that are involved in electrophilic substitution reactions, as you can imagine, there are three possible products, as shown in Reaction (17-29).

(17-29)

Depending on the nature of the substituent, X in Reaction (17-29), the distribution of the products shown can be different. Compared to benzene, some substituted benzenes are more reactive than benzene, and others are less reactive than benzene. Depending on the nature of the substituent on the phenyl ring, it can make substituted benzenes more reactive or less reactive than benzene itself. For example, aniline is much more reactive toward electrophilic reagents than benzene, and the electrophile is always bonded either at the ortho or para positions of the product, relative to the amino group of aniline for electrophilic aromatic substitution reactions. Reaction (17-30) shows the products of the bromination of aniline.

(17-30)

Note that aniline is so reactive toward electrophilic aromatic substitution reactions that a catalyst is not needed for the bromination of aniline. On the other hand, if the substituent is a nitro group the product distribution is very different, as shown in Reaction (17-31), only the meta substituted product is obtained and a catalyst is needed.

(17-31)

The question now becomes why are the product distributions different for different substituted benzene and is it possible to predict the outcomes for electrophilic aromatic substitution reaction of other substituted benzenes? We will have to examine the reaction mechanism to answer these questions.

17.7.1 Electron Activators for Electrophilic Aromatic Substitution Reactions

For aniline, the electron density in the aromatic ring is greater than that of benzene owing to the presence of the lone pair of electrons of the nitrogen atom that is adjacent to the phenyl ring. The resonance structures of aniline are shown in Reaction (17-32) and illustrate the increased electron density of the phenyl ring, compared to benzene. Equally important is the location of increased charge density about the phenyl ring for aniline.

(17-32)

Thus, the phenyl ring of aniline is more nucleophilic than benzene. From the resonance structures above, note that the positions that carry a higher electron density are the ortho and the para positions. Thus, in an electrophilic aromatic substitution reaction, the electrophile will react at these positions. For substituted benzene, if the substituent has a pair of electrons adjacent to the phenyl ring, the ortho and para positions carry a higher electron density, compared to the meta position. As a result, the electrophilic aromatic substitution products involving such molecules will be the ortho and para substituted products. Reaction (17-33) gives the first step in the reaction mechanism for the reaction of anisole with an electrophile E⁺, note that the lone pair of electrons of the OCH₃ group offers an additional stability to the intermediate.

(17-33)

Reaction (17-34) gives the final step of the mechanism, in which the final product is formed from the charged benzenium intermediate.

(17-34)

A similar reaction will occur in the ortho position as shown in Reaction (17-35).

(17-35)

In the final step of the reaction mechanism, a proton is abstracted for rearomatization to produce the substituted anisole product, as shown in Reaction (17-36).

(17-36)

It is possible to have a meta substitution as shown in Reaction (17-37), but note that the OCH₃ group is not involved in the stabilization of the benzenium intermediate, compared to the stabilization of those of the para and ortho substitution given above.

(17-37)

In the final step of the reaction mechanism, a proton is lost to give the minor substitution product as shown in Reaction (17-38).

(17-38)

The reaction between anisole and ethanoyl chloride in the presence of a catalyst is given in Reaction (17-39) where all possible products are shown, but the major product is the para substituted product.

(17-39)

Note that since there is at least one pair of unshared pair of electrons on the oxygen of anisole, this group will activate the ortho and para positions of the benzene ring toward electrophilic substitution. Of the ortho and para products, typically the para product is the major product owing to steric interaction between the substituents in this position of the ortho product as shown in Reaction (17-39). Since the methoxy group does not assist in the stabilization of the intermediate that results from a meta substitution, the meta substituted product is not considered to be formed as a reaction product for these reactions.

Since alkyl groups are known to be electron-releasing groups, the major products of electrophilic aromatic substitution reactions of alkyl benzenes will also be the para substituted products. Examples of these reactions are shown in Reaction (17-40).

(17-40)

Substituents of this type are called activating substituents or ortho para directors because they activate the aromatic ring toward electrophilic aromatic substitution reactions (compared to benzene) and they direct the incoming electrophile to the ortho and para positions.

Problem 17.8

i. Give the major organic product for each of the following reactions.

ii. Give the structure of the major organic product of the reaction of anisole with each of the following reagents.

1. Br₂/FeBr₃

2. CH₃CH₂Cl/AlCl₃

3. CH₃CH(CH₃)CH₂Cl/AlCl₃

17.7.2 Electron Deactivators for Electrophilic Aromatic Substitution Reactions

On the other hand, the electron density in the aromatic ring of nitrobenzene is less than that of benzene owing to the presence of an electron withdrawing group, which has a double bond that is adjacent to the phenyl ring of nitrobenzene, as illustrated by the resonance structures of nitrobenzene shown in Reaction (17-41).

(17-41)

Thus, the phenyl ring of nitrobenzene is less nucleophilic than benzene. From the resonance structures in Reaction (17-41), note that the ortho and the para positions are positive. Thus, for an electrophilic aromatic substitution reaction, the electrophile will not react at these positions, but instead at the meta position. Thus, it appears that if a double bond is in conjugation with the phenyl ring, the electrophilic aromatic substitution product will be the meta-substituted product. This is especially true if the double bond is bonded to an electron-withdrawing atom. The first step in the reaction between nitrobenzene and an electrophile, E⁺ is shown in Reaction (17-42).

(17-42)

The product-forming step of the reaction is given in Reaction (17-43).

(17-43)

Thus, any substituted benzene that has a double bond that is adjacent to the phenyl ring and especially if the double bond is bonded to an electronegative atom as is the case with the nitro group, the electrophilic aromatic substitution products of such a substituted benzene will be the meta product. The reaction of nitrobenzene with ethanoyl chloride is given in Reaction (17-44).

(17-44)

Another example of a reaction of a substituted benzene which has a substituent that has a double bond adjacent to the phenyl ring (acetophenone) with ethanoyl chloride is given in Reaction (17-45).

(17-45)

Substituents of this type are called deactivating substituents or meta directors because they deactivate the aromatic ring toward aromatic electrophilic substitution reactions (relative to benzene), and they direct incoming electrophiles to the meta position.

Problem 17.9

i. Give the major organic product for the reactions given below.

ii. Give the structure of the major organic product of the reaction of benzaldehyde with each of the following reagents.

1. Br₂/FeBr₃

2. CH₃CH₂Cl/AlCl₃

3. CH₃CH(CH₃)CH₂Cl/AlCl₃

Examples of activating and deactivating groups for electrophilic aromatic substitution reactions are shown in Table 17.2.

17.7.3 Substitution Involving Disubstituted Benzenes

It is possible to have a substitution reaction involving benzene molecules that have two substituents, compared to one that we have discussed in the previous sections. In this case, the effect of each substituent must be examined carefully. Consider the molecule below, it has an activator and a deactivator group present.

(17-46)

Table 17.2 Examples of activating and deactivating substituents for electrophilic aromatic substitution reactions.

The reactant has cyano group, which is a deactivator, and hence, a meta director. It also has a methoxy group, which is an activator and also otho, para director. The result is that the incoming electrophile will be directed to one position, meta by the cyano and to the ortho as directed by methoxy group. Note that since the para position is blocked, only the ortho position is available for a substitution reaction. The concept can be used in the synthesis of specific compounds, such as the synthetic scheme outlined in Reaction (17-47).

(17-47)

You will recall from the previous section that the substitution reaction involving SO₃ and benzene is a reversible reaction and that the SO₃H substituent is a meta-director. The starting compound of Reaction (17.27) can be made as outlined in Reaction (17-48) from benzene.

(17-48)

Note that for the synthesis, the o,p-director goes on first so that it will direct the second electrophile in the para position. Carrying out this reaction by introducing the SO₃H substituent first would result in directing the second substituent in the wrong position and the target molecule would not be achieved. The last step in the sequence of the reaction is shown in Reaction (17-49) where the SO₃H substituent is removed to achieve the target molecule.

(17-49)