Untitled

There are many other kinds of electrophilic aromatic substitutions besides bromination, and all occur by the same general mechanism. Let’s look at some of these other reactions briefly.

Aromatic Halogenation

Chlorine and iodine can be introduced into aromatic rings via electrophilic substitution, similar to bromine. However, fluorine is too reactive for direct fluorination, so alternative reagents like F-TEDA-BF$_4$ are used, which involve a fluorine atom bonded to a positively charged nitrogen.

More than 20% of all pharmaceutical agents sold contain fluorine, including 30% of the top 100 drugs sold. Sitagliptin (Januvia), used to treat type 2 diabetes, fluoxetine (Prozac), an antidepressant, and atorvastatin (Lipitor), a statin used to lower cholesterol, are examples.

Aromatic rings react with Cl₂ in the presence of FeCl₃ catalyst to yield chlorobenzenes, just as they react with Br₂ and FeBr₃. This kind of reaction is used in the synthesis of numerous pharmaceutical agents, including the antiallergy medication loratadine, marketed as Claritin.

Iodine itself is unreactive toward aromatic rings, so an oxidizing agent such as hydrogen peroxide or a copper salt such as CuCl₂ must be added to the reaction. These substances accelerate the iodination reaction by oxidizing I₂ to a more powerful electrophilic species that reacts as if it were I⁺. The aromatic ring then reacts with I⁺ in the typical way, yielding a substitution product.

Electrophilic aromatic halogenations also occur in the biosynthesis of many naturally occurring molecules, particularly those produced by marine organisms. In humans, the best-known example occurs in the thyroid gland during the biosynthesis of thyroxine, a hormone involved in regulating growth and metabolism. The amino acid tyrosine is first iodinated by thyroid peroxidase, and two of the iodinated tyrosine molecules then couple. The electrophilic iodinating agent is an I⁺ species, perhaps hypoiodous acid (HIO), that is formed from iodide ion by oxidation with H₂O₂.

Aromatic Nitration

Aromatic rings are nitrated by reaction with a mixture of concentrated nitric and sulfuric acids. The electrophile is the nitronium ion, NO₂⁺, which is formed from HNO₃ by protonation and loss of water. The nitronium ion reacts with benzene to yield a carbocation intermediate, and loss of H⁺ from this intermediate gives the neutral substitution product, nitrobenzene (Figure 16.5).

Figure 16.5 The mechanism for electrophilic nitration of an aromatic ring. An electrostatic potential map of the reactive electrophile NO2+ shows that the nitrogen atom is most positive.

Electrophilic nitration, though not natural, is vital in labs for creating arylamines ($ext{ArNH}_2$) from nitro-substituted products through reduction. This two-step process is crucial for industrial synthesis of dyes and pharmaceuticals.

Aromatic Sulfonation

Aromatic rings undergo sulfonation with fuming sulfuric acid (H$<em>2$SO$</em>4$ + SO$<em>3$), using HSO$</em>3^+$ or neutral SO$_3$ as the electrophile in a reversible two-step substitution. Sulfonation is favored in strong acid, while desulfonation occurs in hot, dilute aqueous acid.

Figure 16.6 The mechanism for electrophilic sulfonation of an aromatic ring. An electrostatic potential map of the reactive electrophile HOSO2+ shows that sulfur and hydrogen are the most positive atoms.

Aromatic sulfonation does not occur naturally but is widely used in the preparation of dyes and pharmaceutical agents. For example, the sulfa drugs, such as sulfanilamide, were among the first clinically useful antibiotics. Although largely replaced today by more effective agents, sulfa drugs are still used in the treatment of meningitis and urinary tract infections. These drugs are prepared commercially by a process that involves aromatic sulfonation as its key step.

Aromatic Hydroxylation

Direct hydroxylation of an aromatic ring to yield a hydroxybenzene (a phenol) is difficult and rarely done in the laboratory but occurs much more frequently in biological pathways. An example is the hydroxylation of p-hydroxyphenylacetate to give 3,4-dihydroxyphenylacetate. The reaction is catalyzed by p-hydroxyphenylacetate-3-hydroxylase and requires molecular oxygen plus the coenzyme reduced flavin adenine dinucleotide, abbreviated FADH₂.

By analogy with other electrophilic aromatic substitutions, you might expect that an electrophilic oxygen species acting as an “OH⁺ equivalent” is needed for the hydroxylation reaction. That is just what happens, with the electrophilic oxygen arising by protonation of FAD hydroperoxide, RO–OH (Figure 16.7); that is, RO–OH+H+→ROH+OH+. The FAD hydroperoxide itself is formed by reaction of FADH₂ with O₂.

Figure 16.7 MECHANISM

Mechanism for the electrophilic hydroxylation of p-hydroxyphenylacetate, by reaction with FAD hydroperoxide. The hydroxylating species is an “OH⁺ equivalent” that arises by protonation of FAD hydroperoxide, RO–OH + H⁺ → ROH + OH⁺. The FAD hydroperoxide itself is formed by reaction of FADH₂ with O₂.

Among the most useful electrophilic aromatic substitution reactions in the laboratory is alkylation—the introduction of an alkyl group onto the benzene ring. Called the Friedel–Crafts reaction after its founders in 1877, Charles Friedel and James Crafts, the reaction is carried out by treating an aromatic compound with an alkyl chloride, RCl, in the presence of AlCl₃ to generate a carbocation electrophile, R⁺. Aluminum chloride catalyzes the reaction by helping the alkyl halide to generate a carbocation in much the same way that FeBr₃ catalyzes aromatic brominations by polarizing Br₂ (Section 16.1). Loss of H⁺ then completes the reaction (Figure 16.8).

Figure 16.8 MECHANISM

Mechanism for the Friedel–Crafts alkylation reaction of benzene with 2-chloropropane to yield isopropylbenzene (cumene). The electrophile is a carbocation, generated by AlCl₃-assisted dissociation of an alkyl halide.

Despite its utility, the Friedel–Crafts alkylation has several limitations. For one thing, only alkyl halides can be used. Aromatic (aryl) halides and vinylic halides don’t react because aryl and vinylic carbocations are too high in energy to form under Friedel–Crafts conditions.

Another limitation is that Friedel–Crafts reactions don’t succeed on aromatic rings that are substituted either by a strongly electron-withdrawing group such as carbonyl (C=O) or by a basic amino group that can be protonated. We’ll see in the next section that the presence of a substituent group already on a ring can have a dramatic effect on that ring’s reactivity to further electrophilic substitution. Rings that contain any of the substituents listed in Figure 16.9 do not undergo Friedel–Crafts alkylation.

Figure 16.9 Limitations on the aromatic substrate in Friedel–Crafts reactions. No reaction occurs if the substrate has either an electron-withdrawing substituent or a basic amino group.

A third limitation to the Friedel–Crafts alkylation is that it’s often difficult to stop the reaction after a single substitution. Once the first alkyl group is on the ring, a second substitution reaction is facilitated for reasons we’ll discuss in the next section. Thus, we often observe polyalkylation. Reaction of benzene with 1 mol equivalent of 2-chloro-2-methylpropane, for example, yields p-di-tert-butylbenzene as the major product, along with small amounts of tert-butylbenzene and unreacted benzene. A high yield of mono-alkylation product is obtained only when a large excess of benzene is used.

A final limitation to the Friedel–Crafts reaction is that a skeletal rearrangement of the alkyl carbocation electrophile sometimes occurs during reaction, particularly when a primary alkyl halide is used. Treatment of benzene with 1-chlorobutane at 0 °C, for instance, gives an approximately 2 : 1 ratio of rearranged (sec-butyl) to unrearranged (butyl) products.

The carbocation rearrangements that accompany Friedel–Crafts reactions are like those that accompany electrophilic additions to alkenes (Section 7.11) and occur either by hydride shift or alkyl shift. For example, the relatively unstable primary butyl carbocation produced by reaction of 1-chlorobutane with AlCl₃ rearranges to the more stable secondary butyl carbocation by the shift of a hydrogen atom and its electron pair (a hydride ion, H:^–) from C2 to C1. Similarly, alkylation of benzene with 1-chloro-2,2-dimethylpropane yields (1,1-dimethylpropyl)benzene. The initially formed primary carbocation rearranges to a tertiary carbocation by shift of a methyl group and its electron pair from C2 to C1.

Aromatic rings can be acylated by reacting with a carboxylic acid chloride (RCOCl) in the presence of AlCl$_3$, substituting an acyl group (–COR) onto the ring. For example, benzene reacts with acetyl chloride to yield acetophenone.

The mechanism of Friedel–Crafts acylation is similar to that of Friedel–Crafts alkylation, and the same limitations on the aromatic substrate noted previously in Figure 16.9 for alkylation also apply to acylation. The reactive electrophile is a resonance-stabilized acyl cation, generated by reaction between the acyl chloride and AlCl₃ (Figure 16.10). As the resonance structures in the figure indicate, an acyl cation is stabilized by interaction of the vacant orbital on carbon with lone-pair electrons on the neighboring oxygen. Because of this stabilization, no carbocation rearrangement occurs during acylation.

Figure 16.10 Mechanism of the Friedel–Crafts acylation reaction. The electrophile is a resonance-stabilized acyl cation, whose electrostatic potential map indicates that carbon is the most positive atom.

Unlike the multiple substitutions that often occur in Friedel–Crafts alkylations, acylations never occur more than once on a ring because the product acylbenzene is less reactive than the nonacylated starting material. We’ll account for this reactivity difference in the next section.

Aromatic alkylations occur in numerous biological pathways, although there is of course no AlCl₃ present in living systems to catalyze the reaction. Instead, the carbocation electrophile is typically formed by dissociation of an organodiphosphate, as we saw in Section 11.6. The dissociation is usually assisted by complexation to a divalent metal cation such as Mg²⁺, just as dissociation of an alkyl chloride is assisted by AlCl₃.

An example of a biological Friedel–Crafts reaction occurs during the biosynthesis of phylloquinone, or vitamin K₁, the human blood-clotting factor. Phylloquinone is formed by reaction of 1,4-dihydroxynaphthoic acid with phytyl diphosphate. Phytyl diphosphate first dissociates to a resonance-stabilized allylic carbocation, which then substitutes onto the aromatic ring in the typical way. Several further transformations lead to phylloquinone (Figure 16.11).

Figure 16.11 Biosynthesis of phylloquinone (vitamin K₁) from 1,4-dihydroxynaphthoic acid. The key step that joins the 20-carbon phytyl side chain to the aromatic ring is a Friedel–Crafts-like electrophilic substitution reacti with a diphosphate ion as the leaving group.

Only one product can form when an electrophilic substitution occurs on benzene, but what would happen if we were to carry out a reaction on an aromatic ring that already has a substituent? The initial presence of a substituent on the ring has two effects.

• Substituents affect the reactivity of the aromatic ring. Some substituents activate the ring, making it more reactive than benzene, and some deactivate the ring, making it less reactive than benzene. In aromatic nitration, for instance, an –OH substituent makes the ring 1000 times more reactive than benzene, while an –NO₂ substituent makes the ring more than 10 million times less reactive.
  

  

• Substituents affect the orientation of the reaction. The three possible disubstituted products—ortho, meta, and para—are usually not formed in equal amounts. Instead, the nature of the substituent initially present on the benzene ring determines the position of the second substitution. An –OH group directs substitution toward the ortho and para positions, for instance, while a carbonyl group such as –CHO directs substitution primarily toward the meta position. Table 16.1 lists experimental results for the nitration of some substituted benzenes.

Table 16.1 Orientation of Nitration in Substituted Benzenes

	Product (%)
	Ortho	Meta	Para
Meta-directing deactivators
–N+(CH3)3	2	87	11
–NO2	7	91	2
–CO2H	22	76	2
–CN	17	81	2
–CO2CH3	28	66	6
–COCH3	26	72	2
–CHO	19	72	9
Ortho- and para-directing deactivators
–F	13	1	86
–Cl	35	1	64
–Br	43	1	56
–I	45	1	54
Ortho- and para-directing activators
–CH3	63	3	34
–OH	50	0	50
–NHCOCH3	19	2	79

Substituents can be classified into three groups, as shown in Figure 16.12: ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators. There are no meta-directing activators. Notice how the directing effect of a group correlates with its reactivity. All meta-directing groups are strongly deactivating, and most ortho- and para-directing groups are activating. The halogens are unique in being ortho- and para-directing but weakly deactivating.

Figure 16.12 Classification of substituent effects in electrophilic aromatic substitution. All activating groups are ortho- and para-directing, and all deactivating groups other than halogen are meta-directing. Halogens are unique in being deactivating but ortho- and para-directing.

Worked Example 16.2

Predicting the Product of an Electrophilic Aromatic Substitution Reaction

Predict the major product of the sulfonation of toluene.

Strategy

Identify the substituent present on the ring, and decide whether it is ortho- and para-directing or meta-directing. According to Figure 16.12, an alkyl substituent is ortho- and para-directing, so sulfonation of toluene will primarily give a mixture of o-toluenesulfonic acid and p-toluenesulfonic acid.

Solution

Problem16-8

Rank the compounds in each of the following groups in order of their reactivity to electrophilic substitution:

(a)

Nitrobenzene, phenol, toluene, benzene

(b)

Phenol, benzene, chlorobenzene, benzoic acid

(c)

Benzene, bromobenzene, benzaldehyde, aniline

Problem16-9

Predict the major products of the following reactions:

(a)

Nitration of bromobenzene

(b)

 Bromination of nitrobenzene

(c)

Chlorination of phenol

(d)

Bromination of aniline

Activating and Deactivating Effects

What makes a group either activating or deactivating? The common characteristic of all activating groups is that they donate electrons to the ring, thereby making the ring more electron-rich, stabilizing the carbocation intermediate, and lowering the activation energy for its formation. Conversely, the common characteristic of all deactivating groups is that they withdraw electrons from the ring, thereby making the ring more electron-poor, destabilizing the carbocation intermediate, and raising the activation energy for its formation.

Compare the electrostatic potential maps of benzaldehyde (deactivated), chlorobenzene (weakly deactivated), and phenol (activated) with that of benzene. As shown in Figure 16.13, the ring is more positive (yellow-green) when an electron-withdrawing group such as –CHO or –Cl is present and more negative (red) when an electron-donating group such as –OH is present.

Figure 16.13 Electrostatic potential maps of benzene and several substituted benzenes show that an electron-withdrawing group (–CHO or –Cl) makes the ring more electron-poor, while an electron-donating group (–OH) makes the ring more electron-rich.

The withdrawal or donation of electrons by a substituent group is controlled by an interplay of inductive effects and resonance effects. As we saw in Section 2.1, an inductive effect is the withdrawal or donation of electrons through a σ bond due to electronegativity. Halogens, hydroxyl groups, carbonyl groups, cyano groups, and nitro groups inductively withdraw electrons through the σ bond linking the substituent to a benzene ring. This effect is most pronounced in halobenzenes and phenols, in which the electronegative atom is directly attached to the ring, but is also significant in carbonyl compounds, nitriles, and nitro compounds, in which the electronegative atom is farther removed. Alkyl groups, on the other hand, inductively donate electrons. This is the same hyperconjugative donating effect that causes alkyl substituents to stabilize alkenes (Section 7.6) and carbocations (Section 7.9).

A resonance effect is the withdrawal or donation of electrons through a π bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring. Carbonyl, cyano, and nitro substituents, for example, withdraw electrons from the aromatic ring by resonance. The π electrons flow from the ring to the substituent, leaving a positive charge in the ring. Note that substituents with an electron-withdrawing resonance effect have the general structure –Y=Z, where the Z atom is more electronegative than Y.

Conversely, halogen, hydroxyl, alkoxyl (–OR), and amino substituents donate electrons to the aromatic ring by resonance. Lone-pair electrons flow from the substituents to the ring, placing a negative charge on the ring. Substituents with an electron-donating resonance effect have the general structure –Ÿ, where the Y atom has a lone pair of electrons available for donation to the ring.

One further point: inductive effects and resonance effects don’t necessarily act in the same direction. Halogen, hydroxyl, alkoxyl, and amino substituents, for instance, have electron-withdrawing inductive effects because of the electronegativity of the –X, –O, or –N atom bonded to the aromatic ring but have electron-donating resonance effects because of the lone-pair electrons on those –X, –O, or –N atoms. When the two effects act in opposite directions, the stronger effect dominates. Thus, hydroxyl, alkoxyl, and amino substituents are activators because their stronger electron-donating resonance effect outweighs their weaker electron-withdrawing inductive effect. Halogens, however, are deactivators because their stronger electron-withdrawing inductive effect outweighs their weaker electron-donating resonance effect.

Problem16-10

Use Figure 16.12 to explain why Friedel–Crafts alkylations often give polysubstitution but Friedel–Crafts acylations do not.

Problem16-11

An electrostatic potential map of (trifluoromethyl)benzene, C₆H₅CF₃, is shown. Would you expect (trifluoromethyl)benzene to be more reactive or less reactive than toluene toward electrophilic substitution? Explain.

Ortho- and Para-Directing Activators: Alkyl Groups

Inductive and resonance effects account not only for reactivity but also for the orientation of electrophilic aromatic substitutions. Take alkyl groups, for instance, which have an electron-donating inductive effect and are ortho and para directors. The results of toluene nitration are shown in Figure 16.14.

Figure 16.14 Carbocation intermediates in the nitration of toluene. Ortho and para intermediates are more stable than the meta intermediate because the positive charge is on a tertiary carbon rather than a secondary carbon.

Nitration of toluene might occur either ortho, meta, or para to the methyl group, giving the three carbocation intermediates shown in in Figure 16.14. Although all three intermediates are resonance-stabilized, the ortho and para intermediates are more stabilized than the meta intermediate. For both the ortho and para reactions, but not for the meta reaction, a resonance form places the positive charge directly on the methyl-substituted carbon, where it is in a tertiary position and can be stabilized by the electron-donating inductive effect of the methyl group. The ortho and para intermediates are thus lower in energy than the meta intermediate and form faster.

Ortho- and Para-Directing Activators: OH and NH₂

Hydroxyl, alkoxyl, and amino groups are also ortho–para activators, but for a different reason than for alkyl groups. As described earlier in this section, hydroxyl, alkoxyl, and amino groups have a strong, electron-donating resonance effect that outweighs a weaker electron-withdrawing inductive effect. When phenol is nitrated, for instance, reaction can occur either ortho, meta, or para to the –OH group, giving the carbocation intermediates shown in Figure 16.15. The ortho and para intermediates are more stable than the meta intermediate because they have more resonance forms, including one particularly favorable form that allows the positive charge to be stabilized by electron donation from the substituent oxygen atom. The intermediate from the meta reaction has no such stabilization.

Figure 16.15 Carbocation intermediates in the nitration of phenol. The ortho and para intermediates are more stable than the meta intermediate because they have more resonance forms, including one particularly favorable form that involves electron donation from the oxygen atom.

Problem16-12

Acetanilide is less reactive than aniline toward electrophilic substitution. Explain.

Ortho- and Para-Directing Deactivators: Halogens

Halogens are deactivating because their stronger electron-withdrawing inductive effect outweighs their weaker electron-donating resonance effect. Although weak, that electron-donating resonance effect is nevertheless felt only at the ortho and para positions and not at the meta position (Figure 16.16). Thus, a halogen substituent can stabilize the positive charge of the carbocation intermediates from ortho and para reaction in the same way that hydroxyl and amino substituents can. The meta intermediate, however, has no such stabilization and is therefore formed more slowly.

Figure 16.16 Carbocation intermediates in the nitration of chlorobenzene. The ortho and para intermediates are more stable than the meta intermediate because of electron donation of the halogen lone-pair electrons.

Note again that halogens, hydroxyl, alkoxyl, and amino groups all withdraw electrons inductively but donate electrons by resonance. Halogens have a stronger electron-withdrawing inductive effect but a weaker electron-donating resonance effect and are thus deactivators. Hydroxyl, alkoxyl, and amino groups have a weaker electron-withdrawing inductive effect but a stronger electron-donating resonance effect and are thus activators. All are ortho and para directors, however, because of the lone pair of electrons on the atom bonded to the aromatic ring.

Meta-Directing Deactivators

The influence of meta-directing substituents can be explained using the same kinds of arguments used for ortho and para directors. Look at the nitration of benzaldehyde, for instance (Figure 16.17). Of the three possible carbocation intermediates, the meta intermediate has three favorable resonance forms, whereas the ortho and para intermediates have only two. In both ortho and para intermediates, the third resonance form is unfavorable because it places the positive charge directly on the carbon that bears the aldehyde group, where it is disfavored by a repulsive interaction with the positively polarized carbon atom of the C=O group. Hence, the meta intermediate is more favored and is formed faster than the ortho and para intermediates.

Figure 16.17 Carbocation intermediates in the nitration of benzaldehyde. The ortho and para intermediates are less stable than the meta intermediate. The meta intermediate is more favorable than ortho and para intermediates because it has three favorable resonance forms rather than two.

In general, any substituent that has a positively polarized atom (δ⁺) directly attached to the ring will make one of the resonance forms of the ortho and para intermediates unfavorable and will thus act as a meta director.