Reactions of Benzene The most characteristic reaction of aromatic compounds is substitution at a ring carbon.

Reactions of Benzene

Electrophilic Aromatic Substitution Electrophilic aromatic substitution: A reaction in which a hydrogen atom of an aromatic ring is replaced by an electrophile. We study several common electrophiles(E+): How each is generated. The mechanism by which each replaces hydrogen. Only the strongest E+ can react with a “normally” unreactive arene.

Chlorination and Bromination Step 1: Lewis acid-Lewis base reaction: Step 2: Make a bond between a nucleophile and an electrophile C l F e 4 + A molecular complex with a positive charge on chlorine Ferric chloride (a Lewis acid) Chlorine base) An ion pair containing a chloronium ion + R e s o n a c - t b i l z d r m ; h p v g f w , C H

Chlorination and Bromination Step 1: Lewis acid-Lewis base reaction. Step 2: Make a bond between a nucleophile (arene ring) and an electrophile.

Chlorination and Bromination Step 3: Take a proton away which regenerates the Lewis acid catalyst and gives the haloarene.

EAS: General Mechanism A general mechanism General question: What is the electrophile and how is it generated?

Bromination Figure 22.1 Energy diagram for the reaction of benzene with bromine.

Nitration Generation of the nitronium ion, NO2+ Step 1: Add a proton. Proton transfer from sulfuric acid to the -OH of nitric acid gives the conjugate acid of nitric acid. Step 2: Break a bond to give stable molecules or ions. Loss of H2O gives the nitronium ion, a very strong electrophile.

Nitration Step 1: Electrophilic aromatic addition. Make a new bond between a nucleophile (arene ring) and an electrophile. Step 2: Take a proton away. Proton transfer regenerates the aromatic ring. H N O 2 + Resonance-stabilized cation intermediate O H N 2 +

Nitration A particular value of nitration is that the nitro group can be reduced to a 1° amino group, -NH2, by hydrogen in the presence of transition metal catalyst.

Sulfonation Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide. The electrophile is either SO3 or HSO3+ depending on experimental conditions.

Friedel-Crafts Alkylation Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group.

Friedel-Crafts Alkylation Step 1: Lewis acid-Lewis base reaction to form an alkyl cation as an ion pair. Step 2: Electrophilic aromatic addition. Step 3: Take a proton away to regenerate the aromatic ring. + R H A resonance-stabilized cation

Friedel-Crafts Alkylation There are two major limitations on Friedel-Crafts alkylations: 1. Carbocation rearrangements are common.

Friedel-Crafts Alkylation 2. Alkylation fails on benzene rings bearing one or more strongly electron-withdrawing groups. 3. Overalkylation can occur.

Friedel-Crafts Acylation Friedel-Crafts acylation forms a new C-C bond between a benzene ring and an acyl group.

Friedel-Crafts Acylation Step 1: Lewis acid-Lewis base reaction. Step 2: Break a bond to give stable molecules or ions, in this case an acylium ion. R - C l O A + 4 Aluminum chloride An acyl A molecular complex with a positive charge charge on chlorine n ion pair containing an acylium ion •• (1) (2)

Friedel-Crafts Acylation An acylium ion is represented as a resonance hybrid of two major contributing structures. Friedel-Crafts acylations are free of a major limitation of Friedel-Crafts alkylations; acylium ions do not rearrange.

Friedel-Crafts Acylation A special value of Friedel-Crafts acylations is preparation of unrearranged alkylbenzenes. The Wolff-Kishner and Clemmensen reductions can be used to remove a carbonyl group.

Other Electrophilic Aromatic Alkylations Carbocations are generated by Treatment of an alkene with a proton acid, most commonly HX, H2SO4, H3PO4, or HF/BF3. Treatment of an alkene with a Lewis acid.

Other Aromatic Alkylations Treatment of an alcohol with H2SO4 or H3PO4 or HF/BF3 generates a carbocation electrophile.

Di- and Polysubstitution

Di- and Polysubstitution Orientation: Certain substituents direct preferentially to ortho & para positions; others to meta positions. Substituents are classified as either ortho-para directing or meta directing toward further substitution. Rate Certain substituents cause the rate of a second substitution to be greater than that for benzene itself; others cause the rate to be lower. Substituents are classified as activating or deactivating toward further substitution.

Di- and Polysubstitution -OCH3 is ortho-para directing. -COOH is meta directing.

Di- and Polysubstitution Table 22.2 Directing Effects of Substituents Weakly activating Ortho-para Directing deactivating Moderately Strongly N H 2 R O C A r F l B I : S 3 + Meta Directing

Di- and Polysubstitution From the information in Table 22.1, we can make these generalizations: Alkyl, phenyl, and all other substituents in which the atom bonded to the ring has an unshared pair of electrons are ortho-para directing. All other substituents are meta directing. All ortho-para directing groups except the halogens are activating toward further substitution. The halogens are weakly deactivating.

Di- and Polysubstitution The order of steps is important.

Theory of Directing Effects The rate of EAS is limited by the slowest step in the reaction. For almost every EAS, the rate-determining step is attack of E+ on the aromatic ring to give a resonance-stabilized cation intermediate. The more stable this cation intermediate, the faster the rate-determining step and the faster the overall reaction.

Theory of Directing Effects For ortho-para directors, ortho-para attack forms a more stable cation than meta attack. Ortho-para products are formed faster than meta products. For meta directors, meta attack forms a more stable cation than ortho-para attack. Meta products are formed faster than ortho-para products.

Theory of Directing Effects -OCH3; assume meta attack.

Theory of Directing Effects -OCH3: assume ortho-para attack. Only para attack is shown.

Theory of Directing Effects -NO2; assume meta attack.

Theory of Directing Effects -NO2: assume ortho-para attack.

Activating-Deactivating Any resonance effect, such as that of -NH2, -OH, and -OR, that delocalizes the positive charge on the cation intermediate lowers the activation energy for its formation, and has an activating effect toward further EAS. Any resonance or inductive effect, such as that of -NO2, -CN, -C=O, and -SO3H, that decreases electron density on the ring deactivates the ring toward further EAS.

Activating-Deactivating Any inductive effect, such as that of -CH3 or other alkyl group that releases electron density toward the ring activates the ring toward further EAS. Any inductive effect, such as that of halogen, -NR3+, -CCl3, or -CF3 that decreases electron density on the ring deactivates the ring toward further EAS.

Activating-Deactivating For the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger. The net effect is that halogens are deactivating but ortho-para directing. + E H C l :

Nucleophilic Aromatic Substitution Aryl halides do not undergo nucleophilic substitution by either SN1 or SN2 pathways. They do undergo nucleophilic substitutions, but by mechanisms quite different from those of nucleophilic aliphatic substitution. Nucleophilic aromatic substitutions are far less common than electrophilic aromatic substitutions.

Nucleophilic Aromatic Substitution When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide. Neutralization with HCl gives phenol.

Nucleophilic Aromatic Substitution The same reaction with 2-chlorotoluene gives a mixture of ortho- and meta-cresol. The same type of reaction can be brought about using sodium amide in liquid ammonia.

Nucleophilic Aromatic Substitution Step 1: Take a proton away and simultaneously break a bond to make stable molecules or ions. Dehydrohalogenation gives a benzyne intermediate.

Nucleophilic Aromatic Substitution Step 2: Make a new bond between a nucleophile and an electrophile.

Nucleophilic Aromatic Substitution Step 3: Add a proton. Proton transfer from NH3 to the carbanion intermediate gives one of the observed substitution products and generates a new amide ion.

Benzyne Intermediates According to MO theory, the benzene ring retains its planarity, p bonding, and aromatic character.

Nuc. Substitution by Addition-Elimination When an aryl halide contains electron-withdrawing NO2 groups ortho and/or para to X, nucleophilic aromatic substitution takes place readily. Neutralization with HCl gives the phenol.

Nucleophilic Aromatic Substitution Step 1: Make a new bond between a nucleophile and an electrophile. Step 2: Break a bond to give stable molecules and ions. N C l O 2 u - : f a s t o w , r e d m i n g + A M h c p x ( 1 )

Problem 22.48 When certain aromatic compounds are treated with formaldehyde, CH2O, and HCl, a chloromethyl group, -CH2Cl, is introduced onto the ring. This reaction is known as chloromethylation. Propose a mechanism for chloromethylation.

Problem 22.48 The most likely mechanism involves an acid-catalyzed electrophilic aromatic substitution followed by replacement of the resulting -OH group with Cl via a benzylic cation intermediate

Problem 22.48 Step 2: Make a new bond between a nucleophile ( bond) and an electrophile.

Problem 22.48

Problem 22.48

Problem 22.48

Problem 22.48