Electrophilic Aromatic Substitution

• Additions across rings are unusual because of the stability Electrophilic Aromatic Substitution (EAS) imparted by aromaticity. & • Reactions that keep the aromatic ring intact are favored. Other Reactions of Aromatic Compounds • The characteristic reaction of benzene is electrophilic aromatic substitution—a hydrogen atom is replaced by an electrophile.

Chapter 18

Halogenation Common • In halogenation, benzene reacts with Cl2 or Br2 in the presence of a Lewis acid catalyst, such as FeCl or FeBr , to give the aryl halides EAS 3 3 chlorobenzene or bromobenzene, respectively. • Analogous reactions with I and F are not synthetically useful because I Reactions 2 2 2 is too unreactive and F2 reacts too violently.

• Mechanism of chlorination of benzene General Mechanism of Substitution Resonance-Stabilized Aromatic Carbocation • The first step in electrophilic aromatic substitution forms a carbocation, • Regardless of the electrophile used, all electrophilic aromatic substitution reactions occur by the same two-step mechanism: for which three resonance structures can be drawn. 1. Addition of the electrophile E+ to form a resonance-stabilized carbocation. • To help keep track of the location of the positive charge: 2. Deprotonation with base.

Energy Diagram for Electrophilic Aromatic Substitution Nitration and Sulfonation • Nitration and sulfonation introduce two different functional groups into the aromatic ring. • Nitration is especially useful because the nitro group can be reduced

to an NH2 group.

• Mechanisms of Electrophile Formation for Nitration and Sulfonation Reduction of Nitro Friedel–Crafts Alkylation

• A nitro group (NO ) that has been introduced on a benzene ring by 2 • In Friedel–Crafts alkylation, treatment of benzene with an nitration with strong acid can readily be reduced to an amino group (NH ) 2 halide and a Lewis acid (AlCl ) forms an alkyl benzene. under a variety of conditions. (We will not consider mechanism.) 3

• Synthetic Example: Reduction of ethyl p-nitrobenzoate with H2 and a palladium catalyst forms a local anesthetic commonly called benzocaine.

• Mechanism of Electrophile Formation

Other considerations: Friedel–Crafts Alkylation Other considerations: Friedel–Crafts Alkylation

1) Vinyl halides and aryl halides do not react in Friedel-Crafts 3) Other functional groups that form carbocations can also be alkylation. used as starting materials.

2) Rearrangements can occur.

• Carbocations formed in the presence of benzene can then Mechanism of Rearrangement substitute onto the ring by the usual mechanism. Other considerations: Friedel–Crafts Alkylation Friedel–Crafts • In Friedel–Crafts acylation, a benzene ring is treated with an acid 4) Friedel–Crafts Reactions and Ring Activation chloride (RCOCl) and AlCl3 to form a . • Because the new group bonded to the benzene ring is called an acyl • Treatment of benzene with an alkyl halide and AlCl3 places an electron-donor R group on the ring. group, the transfer of an from one atom to another is an acylation. • 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.

• This is a significant limitation of the synthetic use of the Friedel-Crafts Alkylation. • Mechanism of Electrophile Formation

Friedel–Crafts Acylation Intramolecular Friedel–Crafts Reactions

• In Friedel–Crafts acylation, the • Starting materials that contain both a benzene ring and an electrophile

Lewis acid AlCl3 ionizes the are capable of intramolecular Friedel–Crafts reactions. carbon–halogen bond of the acid chloride, thus forming a positively charged carbon electrophile called an acylium ion, which is resonance stabilized.

Ring Deactivation

• Carbonyl groups are electron-withdrawing and deactivate the ring for EAS.

• The acylated product (C6H5C(=O)R) is now less reactive than benzene itself towards further substitution, preventing polyacylation. Substituent Effects of Substituted Benzenes Electron-Donating and Electron-Withdrawing Groups

• The NH2 group donates electron density making the benzene ring more • Many substituted benzene rings undergo electrophilic aromatic electron rich. substitution. • The CHO group withdraws electron density, making the benzene ring less electron rich. • Each substituent either increases or decreases the electron density in the benzene ring, and this affects the course of electrophilic aromatic substitution. • Donation of electron density to the ring makes benzene more electron rich and more likely to react with an electrophile. • Withdrawal of electron density from the ring makes benzene less electron rich and less likely to react with an electrophile.

• Electrophilic substitution on an already substituted benzene can produce isomers, some of which are favored over others.

Substituent Effects on Electrophilic Aromatic Substitution Ortho, Para Directors—Activators

• Electrophilic aromatic substitution is a general reaction of all aromatic • Toluene reacts faster than benzene in all substitution reactions. compounds, including polycyclic aromatic hydrocarbons, heterocycles, • The electron-donating CH3 group activates the benzene ring to and substituted benzene derivatives. electrophilic attack. • A substituent affects two aspects of the electrophilic aromatic substitution • Ortho and para products predominate. reaction: • The CH3 group is called an ortho, para director. 1. The rate of the reaction: A substituted benzene reacts faster or slower than benzene itself. 2. The orientation: The 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.

• Consider the reaction & mechanism for the nitration 25 of anisole. Meta Directors—Deactivators Substituents & Inductive Effects

• Nitrobenzene reacts more slowly than benzene in all substitution • Considering inductive effects only, the NH2 group withdraws reactions. electron density and CH3 donates electron density.

• The electron-withdrawing NO2 group deactivates the benzene ring to electrophilic attack. • The meta product predominates.

• The NO2 group is called a meta director.

• Methyl and other alkyl groups are activating for EAS because of this inductive donation of electron density.

• Even though the group withdraws electron density from the ring via inductive effects, it is still an activating group for EAS due • Consider the reaction & mechanism for the to its ability to donate electron density via resonance sulfonation of benzaldehyde.

Substituents & Resonance Effects Substituents & Resonance Effects • Resonance effects are only observed with substituents containing • Deactivating Resonance: An electron-withdrawing resonance lone pairs or bonds. π effect is observed in substituted benzenes having the general

structure C6H5-Y=Z, where Z is more electronegative than Y. • Seven resonance structures can be drawn for benzaldehyde

(C6H5CHO).

• Activating Resonance: An electron-donating resonance effect is • Because three of them place a positive charge on a carbon atom observed whenever an atom Z having a lone pair of electrons is of the benzene ring, the CHO group withdraws electrons from the directly bonded to a benzene ring. benzene ring by a resonance effect.

Inductive and Resonance Effects Categorizing Directors and Activators • To predict whether a substituted benzene is more or less electron rich • All substituents can be divided into three general types: than benzene itself, we must consider the net balance of both the inductive and resonance effects. • Alkyl groups donate electrons by an inductive effect (hyperconjugation), but they have no resonance effect because they lack nonbonded electron pairs or π bonds. • Thus, any alkyl-substituted benzene is more electron rich than benzene itself. • The same analysis can be done with groups other than alkyl.

Categorizing Directors and Deactivators Energy Diagrams Comparing Substitution Rates

• The energy diagrams below illustrate the effect of electron-withdrawing and electron-donating groups on the transition state energy of the rate- determining step. Summary: Activators and Deactivators Reactions of Activated Rings

• 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.

Friedel–Crafts Reactions and Ring Activation/Deactivation Friedel-Crafts Limitation – Deactivated Rings • Treatment of benzene with an alkyl halide and AlCl places an electron- 3 • A benzene ring deactivated by strong electron-withdrawing groups (i.e., donor R group on the ring. any of the meta directors) is not electron rich enough to undergo Friedel– • Since R groups activate the ring, the alkylated product (C6H5R) is now Crafts reactions. more reactive than benzene itself towards further substitution, and it reacts again with RCl to give products of polyalkylation.

• 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.

• Polysubstitution does not occur with Friedel–Crafts acylation. Reinforcing Directing Effects Opposing Directing Effects

1. When the directing effects of two groups reinforce, the new substituent 2. If the directing effects of two groups oppose each other, the more is located on the position directed by both groups. powerful activator wins out.

Steric Limitations to Directing Effects Steric Limitations to Directing Effects

3. A) No substitution occurs between two meta substituents 3. B) Bulky ortho-/para- directors generally direct substituents because of crowding. to the para- position because it is less crowded. Predict the products of the following reactions:

Cl

AlCl3

O H

N CH3 B) Bulky ortho-/para- directors generally direct substituents O AlCl3 to the para- position because it is less crowded. Protecting groups Protecting groups Amino groups and groups can be acetylated to “protect” the ortho positions from EAS and favor addition at the para position. It also reduces the chance of multiple additions. The following are the steps in the process:

1. The amino or alcohol group is first acetylated using in base (usually ).

2. The desired EAS reaction is carried out (to achieve para- addition)

3. The acetyl group is hydrolyzed under acidic conditions.

Blocking groups Synthesis of Alkyl Benzenes Blocking groups can be to favor addition at one position (ortho) - in lieu of an otherwise more favored addition location (para). Sometimes protecting and • We now know two different ways to introduce an alkyl group on a blocking groups are used together. The general blocking steps in the process are: benzene ring: 1. Add the group using fuming sulfuric acid. 1. A one-step method using Friedel–Crafts alkylation. 2. Carry out the desired EAS reaction (reaction may take longer and require 2. A two-step method using Friedel–Crafts acylation to form a ketone, more heat than when adding to the para- position). followed by reduction. 3. Remove the sulfonic acid group with sulfuric acid in water, followed by a basic workup. For example, o-nitroacetanilide may be synthesized by blocking the para- position with a sulfonic acid group: Synthesis of Benzene Derivatives Oxidation of Alkyl Benzenes

• Arenes containing at least one benzylic C–H bond are oxidized with

KMnO4 to benzoic acid.

• Substrates with more than one alkyl group are oxidized to dicarboxylic acids. • Compounds without a benzylic hydrogen are inert to oxidation.

Reduction of Acyl Benzenes Synthesis of Alkyl Benzenes

• formed as products of Friedel–Crafts acylation can be reduced • We now know two different ways to introduce an alkyl group on a to alkyl benzenes by two different methods: benzene ring:

1. The Clemmensen reduction—uses zinc and mercury in the presence 1. A one-step method using Friedel–Crafts alkylation. of strong acid. 2. A two-step method using Friedel–Crafts acylation to form a ketone,

2. The Wolff–Kishner reduction—uses hydrazine (NH2NH2) and strong followed by reduction. base (KOH). Synthesis of Alkyl Benzenes Multistep Synthesis • Although the two-step method seems more cumbersome, it must be used to synthesize many alkyl benzenes when Friedel–Crafts alkylation could • Suggest a synthesis of p-sulfobenzoic acid from benzene. lead to rearrangements and/or multiple alkylations. NH2

+

1,4-diisopropylbenzene • Suggest a synthesis of p-sulfobenzoic acid from benzene.

COOH

HO3S

Friedel-Crafts Acylation and via an Anhydride Friedel-Crafts Synthesis of alpha-tetralone O