Reactions of Aromatic Compounds Organic Chemistry, 7th Edition L. G. Wade, Jr. Chapter 17 Reactions of Aromatic Compounds Copyright © 2010 Pearson Education, Inc.

Electrophilic Aromatic Substitution Although benzene’s pi electrons are in a stable aromatic system, they are available to attack a strong electrophile to give a carbocation. This resonance-stabilized carbocation is called a sigma complex because the electrophile is joined to the benzene ring by a new sigma bond. Aromaticity is regained by loss of a proton. Chapter 17

Mechanism of Electrophilic Aromatic Substitution Chapter 17

Bromination of Benzene Chapter 17

Mechanism for the Bromination of Benzene: Step 1 + - B r F e 3 (stronger electrophile than Br2) Before the electrophilic aromatic substitution can take place, the electrophile must be activated. A strong Lewis acid catalyst, such as FeBr3, should be used. Chapter 17

Mechanism for the Bromination of Benzene: Steps 2 and 3 Step 2: Electrophilic attack and formation of the sigma complex. Step 3: Loss of a proton to give the products. Chapter 17

Energy Diagram for Bromination Chapter 17

Chlorination and Iodination Chlorination is similar to bromination. AlCl3 is most often used as catalyst, but FeCl3 will also work. Iodination requires an acidic oxidizing agent, like nitric acid, to produce iodide cation. H+ + HNO3 + ½ I2 I+ + NO2 + H2O Chapter 17

Solved Problem 1 Solution Predict the major product(s) of bromination of p-chloroacetanilide. Solution The amide group (–NHCOCH3) is a strong activating and directing group because the nitrogen atom with its nonbonding pair of electrons is bonded to the aromatic ring. The amide group is a stronger director than the chlorine atom, and substitution occurs mostly at the positions ortho to the amide. Like an alkoxyl group, the amide is a particularly strong activating group, and the reaction gives some of the dibrominated product. Copyright © 2006 Pearson Prentice Hall, Inc. Chapter 17

Nitration of Benzene Sulfuric acid acts as a catalyst, allowing the reaction to be faster and at lower temperatures. HNO3 and H2SO4 react together to form the electrophile of the reaction: nitronium ion (NO2+). Chapter 17

Mechanism for the Nitration of Benzene Chapter 17

Reduction of the Nitro Group Treatment with zinc, tin, or iron in dilute acid will reduce the nitro to an amino group. This is the best method for adding an amino group to the ring. Chapter 17

Sulfonation of Benzene Sulfur trioxide (SO3) is the electrophile in the reaction. A 7% mixture of SO3 and H2SO4 is commonly referred to as “fuming sulfuric acid”. The —SO3H groups is called a sulfonic acid. Chapter 17

Mechanism of Sulfonation Benzene attacks sulfur trioxide, forming a sigma complex. Loss of a proton on the tetrahedral carbon and reprotonation of oxygen gives benzenesulfonic acid. Chapter 17

Desulfonation Reaction Sulfonation is reversible. The sulfonic acid group may be removed from an aromatic ring by heating in dilute sulfuric acid. Chapter 17

Mechanism of Desulfonation In the desulfonation reaction, a proton adds to the ring (the electrophile) and loss of sulfur trioxide gives back benzene. Chapter 17

Nitration of Toluene Toluene reacts 25 times faster than benzene. The methyl group is an activator. The product mix contains mostly ortho and para substituted molecules. Chapter 17

Ortho and Para Substitution Ortho and para attacks are preferred because their resonance structures include one tertiary carbocation. Chapter 17

Energy Diagram Chapter 17

Meta Substitution When substitution occurs at the meta position, the positive charge is not delocalized onto the tertiary carbon, and the methyl groups has a smaller effect on the stability of the sigma complex. Chapter 17

Alkyl Group Stabilization Alkyl groups are activating substituents and ortho, para-directors. This effect is called the inductive effect because alkyl groups can donate electron density to the ring through the sigma bond, making them more active. Chapter 17

Substituents with Nonbonding Electrons Resonance stabilization is provided by a pi bond between the —OCH3 substituent and the ring. Chapter 17

Meta Attack on Anisole Resonance forms show that the methoxy group cannot stabilize the sigma complex in the meta substitution. Chapter 17

Bromination of Anisole A methoxy group is so strongly activating that anisole is quickly tribrominated without a catalyst. Chapter 17

The Amino Group Aniline reacts with bromine water (without a catalyst) to yield the tribromoaniline. Sodium bicarbonate is added to neutralize the HBr that is also formed. Chapter 17

Summary of Activators Chapter 17

Activators and Deactivators If the substituent on the ring is electron donating, the ortho and para positions will be activated. If the group is electron withdrawing, the ortho and para positions will be deactivated. Chapter 17

Nitration of Nitrobenzene Electrophilic substitution reactions for nitrobenzene are 100,000 times slower than for benzene. The product mix contains mostly the meta isomer, only small amounts of the ortho and para isomers. Chapter 17

Ortho Substitution on Nitrobenzene The nitro group is a strongly deactivating group when considering its resonance forms. The nitrogen always has a formal positive charge. Ortho or para addition will create an especially unstable intermediate. Chapter 17

Meta Substitution on Nitrobenzene Meta substitution will not put the positive charge on the same carbon that bears the nitro group. Chapter 17

Energy Diagram Chapter 17

Deactivators and Meta- Directors Most electron withdrawing groups are deactivators and meta-directors. The atom attached to the aromatic ring has a positive or partial positive charge. Electron density is withdrawn inductively along the sigma bond, so the ring has less electron density than benzene and thus, it will be slower to react. Chapter 17

Ortho Attack of Acetophenone In ortho and para substitution of acetophenone, one of the carbon atoms bearing the positive charge is the carbon attached to the partial positive carbonyl carbon. Since like charges repel, this close proximity of the two positive charges is especially unstable. Chapter 17

Meta Attack on Acetophenone The meta attack on acetophenone avoids bearing the positive charge on the carbon attached to the partial positive carbonyl. Chapter 17

Other Deactivators Chapter 17

Nitration of Chlorobenzene When chlorobenzene is nitrated the main substitution products are ortho and para. The meta substitution product is only obtained in 1% yield. Chapter 17

Halogens Are Deactivators Inductive Effect: Halogens are deactivating because they are electronegative and can withdraw electron density from the ring along the sigma bond. Chapter 17

Halogens Are Ortho, Para-Directors Resonance Effect: The lone pairs on the halogen can be used to stabilize the sigma complex by resonance. Chapter 17

Energy Diagram Chapter 17

Summary of Directing Effects Chapter 17

Effect of Multiple Substituents The directing effect of the two (or more) groups may reinforce each other. Chapter 17

Effect of Multiple Substituents (Continued) The position in between two groups in Positions 1 and 3 is hindered for substitution, and it is less reactive. Chapter 17

Effect of Multiple Substituents (Continued) major products obtained If directing effects oppose each other, the most powerful activating group has the dominant influence. Chapter 17

Friedel–Crafts Alkylation Synthesis of alkyl benzenes from alkyl halides and a Lewis acid, usually AlCl3. Reactions of alkyl halide with Lewis acid produces a carbocation, which is the electrophile. Chapter 17

Mechanism of the Friedel–Crafts Reaction Step 1 Step 2 Step 3 Chapter 17

Protonation of Alkenes An alkene can be protonated by HF. This weak acid is preferred because the fluoride ion is a weak nucleophile and will not attack the carbocation. Chapter 17

Alcohols and Lewis Acids Alcohols can be treated with BF3 to form the carbocation. Chapter 17

Limitations of Friedel–Crafts Reaction fails if benzene has a substituent that is more deactivating than halogens. Rearrangements are possible. The alkylbenzene product is more reactive than benzene, so polyalkylation occurs. Chapter 17

Rearrangements Chapter 17

Solved Problem 2 Solution Devise a synthesis of p-nitro-t-butylbenzene from benzene. Solution To make p-nitro-t-butylbenzene, we would first use a Friedel–Crafts reaction to make t-butylbenzene. Nitration gives the correct product. If we were to make nitrobenzene first, the Friedel–Crafts reaction to add the t-butyl group would fail. Copyright © 2006 Pearson Prentice Hall, Inc. Chapter 17

Friedel–Crafts Acylation Acyl chloride is used in place of alkyl chloride. The product is a phenyl ketone that is less reactive than benzene. Chapter 17

Mechanism of Acylation Step 1: Formation of the acylium ion. Step 2: Electrophilic attack to form the sigma complex. Chapter 17

Clemmensen Reduction The Clemmensen reduction is a way to convert acylbenzenes to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc. Chapter 17

Nucleophilic Aromatic Substitution A nucleophile replaces a leaving group on the aromatic ring. This is an addition–elimination reaction. Electron-withdrawing substituents activate the ring for nucleophilic substitution. Chapter 17

Mechanism of Nucleophilic Aromatic Substitution Step 1: Attack by hydroxide gives a resonance-stabilized complex. Step 2: Loss of chloride gives the product. Step 3: Excess base deprotonates the product. Chapter 17

Activated Positions Nitro groups ortho and para to the halogen stabilize the intermediate (and the transition state leading to it). Electron-withdrawing groups are essential for the reaction to occur. Chapter 17

Benzyne Reaction: Elimination-Addition Reactant is halobenzene with no electron-withdrawing groups on the ring. Use a very strong base like NaNH2. Chapter 17

Benzyne Mechanism Sodium amide abstract a proton. The benzyne intermediate forms when the bromide is expelled and the electrons on the sp2 orbital adjacent to it overlap with the empty sp2 orbital of the carbon that lost the bromide. Benzynes are very reactive species due to the high strain of the triple bond. Chapter 17

Nucleophilic Substitution on the Benzyne Intermediate Chapter 17

Chlorination of Benzene Addition to the benzene ring may occur with excess of chlorine under heat and pressure. The first Cl2 addition is difficult, but the next two moles add rapidly. An insecticide Chapter 17

Catalytic Hydrogenation 3 Ru, 100°C 1000 psi 2 , Elevated heat and pressure is required. Possible catalysts: Pt, Pd, Ni, Ru, Rh. Reduction cannot be stopped at an intermediate stage. Chapter 17

Birch Reduction This reaction reduces the aromatic ring to a nonconjugated 1,4-cyclohexadiene. The reducing agent is sodium or lithium in a mixture of liquid ammonia and alcohol. Chapter 17

Mechanism of the Birch Reduction Chapter 17

Limitations of the Birch Reduction Chapter 17

Side-Chain Oxidation Alkylbenzenes are oxidized to benzoic acid by heating in basic KMnO4 or heating in Na2Cr2O7/H2SO4. The benzylic carbon will be oxidized to the carboxylic acid. Chapter 17

Side-Chain Halogenation The benzylic position is the most reactive. Br2 reacts only at the benzylic position. Cl2 is not as selective as bromination, so results in mixtures. Chapter 17

Mechanism of Side-Chain Halogenation Chapter 17

SN1 Reactions Benzylic carbocations are resonance-stabilized, easily formed. Benzyl halides undergo SN1 reactions. C H 2 B r 3 O , h e a t Chapter 17

SN2 Reactions Benzylic halides are 100 times more reactive than primary halides via SN2. The transition state is stabilized by a ring. Chapter 17

Oxidation of Phenols Phenol will react with oxidizing agents to produce quinones. Quinones are conjugated 1,4-diketones. This can also happen (slowly) in the presence of air. Chapter 17