Organic Chemistry: Concepts and Applications - Headley Allan D. 2020
Aromaticity and Aromatic Substitution Reactions
17.6 Electrophilic Aromatic Substitution Reactions of Benzene
The reactions that aromatic compounds undergo are unique in that they do not undergo the expected addition reactions of alkenes that we covered in Chapter 8. Addition reactions would be a predicted type of reaction owing to the electron density of these compounds. One type of reaction that these molecules undergo is described as electrophilic aromatic substitution. For these reactions, an electrophile is substituted for a hydrogen atom of the benzene or aromatic molecule to form the product as shown in Reaction (17-7). The symbol E+ is typically used to represent an electrophile. You will recall that electrophiles are electron-loving species, and another definition is that electrophiles are electron-deficient species.
(17-7)
Owing to the exceptional stability of benzene and other aromatic compounds, they are not very reactive and most require a catalyst for this type of reaction to occur. In addition, you will notice that the organic product of these types of reactions is also aromatic. If the reaction that occurred were an addition reaction, as shown in Reaction (17-8), the product would not be aromatic.
(17-8)
Since aromatic molecules are more stable than comparable molecules, aromaticity is conserved for most reactions that involve aromatic compounds. Thus, if an addition reaction were to occur for benzene, 36 kcal mol−1 would be lost since the aromaticity of the molecule would be destroyed. Instead, a substitution reaction occurs so that the aromaticity is conserved. The general mechanism for this type of substitution reaction is shown in Reaction (17-9).
(17-9)
Typical electrophiles that will be discussed in this chapter include the nitronium ion (NO2+), the halogen cation (Cl+ and Br+), carbocation (R+), and acyl cation (RC=O+). Reactions involving these electrophiles will be covered in the next sections.
17.6.1 Substitution Reactions Involving Nitronium Ion
The nitration of benzene is shown in Reaction (17-10). The electrophile for the nitration of benzene is NO2+, and it is generated from the mixture of nitric and sulfuric acid.
(17-10)
Sulfuric acid is a stronger acid than nitric acid; therefore, in a mixture of nitric and sulfuric acids, protonation of nitric acid occurs to give a very good leaving group, OH2. The elimination of water from protonated nitric acid gives the NO2+ electrophile. The mechanism for the formation of NO2+ from sulfuric and nitric acids is shown in Reaction (17-11).
(17-11)
In order to account for the formation of nitrobenzene from benzene in the presence of NO2+, it is best to understand how this reaction proceeds, i.e. the mechanism. First, since the benzene molecule is electron rich (nucleophilic), the electrons of benzene attack the electrophile to form a charged intermediate, as shown in Reaction (17-12). This step is known as the rate determining step (RDS), also known as the slow step.
(17-12)
Even though the charged intermediate is relatively stable as shown by the three possible resonance structures that can be drawn, this ion can become even more stable (aromatic) if it could rearomatize to become a neutral molecule. Aromatization can be accomplished by the loss of a proton (H+) as shown in the final step of the mechanism in Reaction (17-13).
(17-13)
The driving force for this fast and favorable step of the reaction mechanism is the formation of the very stable aromatic benzene system.
17.6.2 Substitution Reactions Involving the Halogen Cation
The mechanism for the halogenation of benzene is similar to the nitration of benzene except that the electrophile is the X+ (halogen) ion, Br+ or Cl+. The bromination of benzene is shown in Reaction (17-14).
(17-14)
For this reaction, the electrophile is Br+ and it is generated from Br2 and FeBr3. FeBr3 is a Lewis acid, and it has a vacant orbital. In a mixture of bromine and FeBr3, one of the lone pairs of electrons on bromine coordinates with FeBr3 to form a complex, as shown in the first step of the reaction mechanism, which is given in Reaction (17-15).
(17-15)
In this complex, the bromine is polarized so that the electron distribution is closer to the iron, making one of the bromine atoms electrophilic. Thus, a partial positive charge is on one of the bromine atoms, the one farthest from the iron shown in Reaction (17-15). Thus, for the bromination of benzene by Br2 and FeBr3, the Lewis acid, FeBr3, helps in the generation of the electrophilic Br+ ion from Br2. In the second step of the mechanism, the electrons from the benzene ring then react with the electrophilic Br+ ion to form a charged intermediate, which rearomatizes after the loss of a proton to form the product, bromobenzene in the final step of the mechanism.
17.6.3 Substitution Reactions Involving Carbocations
Benzene can be alkylated in the presence of an alkyl halide and a Lewis acid, as a catalyst, to form an alkylbenzene, as shown in Reaction (17-16).
(17-16)
For these substitution reactions, the electrophile is a carbocation R+. This carbocation is usually generated from the breakage of a carbon─halogen bond. In the presence of a catalyst, such as a Lewis acid, typically AlBr3 or AlCl3, a complex is formed between the Lewis acid and the alkyl halide, similar to the complex described in the previous section. In this complex, one pair of the electrons of the halogen occupies the empty orbital of the Lewis acid, and hence the carbon─halogen bond is weakened liberating the alkyl group as electrophilic, as shown in the first step of the reaction mechanism given in Reaction (17-17).
(17-17)
In the next step of the reaction mechanism, the electrophilic alkyl group is attacked by the nucleophilic electrons of the benzene ring to form the charged benzenium ion intermediate, which then rearomatizes to form the alkyl benzene, as given Reaction (17-18).
(17-18)
Reactions of this type, in which AlCl3 or AlBr3 is used as catalyst in conjunction with alkyl halides to form an alkylbenzenes from benzene are known as the Friedel Crafts Alkylation.
For these alkylation reactions, unexpected products are sometimes observed depending on the type of alkyl halide used, as given in Reaction (17-19).
(17-19)
For the reaction given in Reaction (17-19), the carbocation initially formed is CH3CH2CH2+, which is a primary carbocation. As we have seen previously, primary carbocations are unstable and will rearrange to the more stable secondary carbocation if possible. The rearrangement of the primary propyl cation generated in Reaction (17-19) to form the secondary carbocation occurs by a hydride migration, as shown in Reaction (17-20).
(17-20)
Thus, for the reaction given in Reaction (17-19), the major organic product is shown in Reaction (17-21), which occurs due to the rearrangement of the intermediate carbocation generated throughout the course of the reaction.
(17-21)
Problem 17.6
Give the expected organic products for each of the following reactions.
17.6.4 Substitution Reactions Involving Acyl Cations
The acyl cation 
, which is an electrophile, can be introduced on the aromatic ring of benzene by the electrophilic aromatic substitution reaction shown in Reaction (17-22).
(17-22)
The reaction of acid chlorides with benzene in a presence of the catalyst, AlCl3, is known as the Friedel-Crafts acylation and the product are aryl ketones. A specific example of the Friedel—Crafts acylation is given in Reaction (17-23).
(17-23)
As you can imagine, the catalyst, AlCl3 serves to liberate the acyl cation from the acid chloride, as shown in the first step of the mechanism given in Reaction (17-24). Note that owing to the stability of the acyl cation, it does not rearrange like carbocations.
(17-24)
In the next step of the mechanism, the acyl cation is attached by the electron-rich benzene ring to form the charged benzenium intermediate, which then rearomatizes to form the product shown in Reaction (17-25) along with the catalyst and HCl.
(17-25)
Problem 17.7
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 benzene with each of the following reagents.
1. Br2/FeBr3
2. CH3CH2Cl/AlCl3
3. CH3CH2COCl/AlCl3
17.6.5 Substitution Reactions Involving Sulfonium Ion
Sulfur trioxide is an electrophilic molecule and the electrophilic atom is sulfur, as shown in Reaction (17-26). Based on the structure shown below for sulfur trioxide, the sulfur is electrophilic and for the reaction with a nucleophilic reagent such as benzene, the bond is formed with benzene and sulfur.
(17-26)
This reaction is carried out in “fuming” sulfuric acid, which is 7% SO3 in H2SO4, which generates protonated sulfur trioxide and as you can imagine it is an extremely good electrophile as shown in Reaction (17-27).
(17-27)
In the next step of the reaction mechanism, the nucleophilic benzene attacks the protonated sulfur trioxide to form a benzenium intermediate, which then rearomatizes to form the stable substituted benzene, as shown in Reaction (17-28).
(17-28)
Since these reactions are reversible as shown in Reaction (17-26), this substituent can be used as a protecting group for a specific position of the benzene ring since it can be removed by reversing the reaction. This strategy will be used later in the chapter to synthesize specific target compounds.