Chapter 17 Reactions of Aromatic Compounds Electrophilic Aromatic Substitution Electrophile substitutes for a hydrogen on the benzene ring. Chapter 17: Aromatics 2-Reactions Slide 17-2 1 Mechanism Step 1: Attack on the electrophile forms the sigma complex. Step 2: Loss of a proton gives the substitution product. => Chapter 17: Aromatics 2-Reactions Slide 17-3 Bromination of Benzene • Requires a stronger electrophile than Br2. • Use a strong Lewis acid catalyst, FeBr3. Br Br + - FeBr3 Br Br FeBr3 H H H H H H + - Br _ Br Br FeBr3 + + FeBr4 H H H H H H Br + HBr => Chapter 17: Aromatics 2-Reactions Slide 17-4 2 Comparison with Alkenes • Cyclohexene adds Br2, ΔH = -121 kJ • Addition to benzene is endothermic, not normally seen. • Substitution of Br for H retains aromaticity, ΔH = -45 kJ. • Formation of sigma complex is rate-limiting. => Chapter 17: Aromatics 2-Reactions Slide 17-5 Energy Diagram for Bromination => Chapter 17: Aromatics 2-Reactions Slide 17-6 3 Chlorination and Iodination • Chlorination is similar to bromination. Use AlCl3 as the Lewis acid catalyst. • Iodination requires an acidic oxidizing agent, like nitric acid, which oxidizes the iodine to an iodonium ion. + + H + HNO3 + 1/2 I2 I + NO2 + H2O => Chapter 17: Aromatics 2-Reactions Slide 17-7 Nitration of Benzene Use sulfuric acid with nitric acid to form the nitronium ion electrophile. + NO2 then forms a sigma complex with benzene, loses H+ to form nitrobenzene. Chapter 17: Aromatics 2-Reactions Slide 17-8 4 Sulfonation Sulfur trioxide, SO3, in fuming sulfuric acid is the electrophile. _ O O O O S S + S + S + _ _ O O O O O O O O Chapter 17: Aromatics 2-Reactions Slide 17-9 Desulfonation • All steps are reversible, so sulfonic acid group can be removed by heating in dilute sulfuric acid. • This process is used to place deuterium in place of hydrogen on benzene ring. H D H H large excess D D D2SO4/D2O H H D D H D Benzene-d 6 Chapter 17: Aromatics 2-Reactions Slide 17-10 5 Nitration of Toluene • Toluene reacts 25 times faster than benzene. The methyl group is an activating group. • The product mix contains mostly ortho and para substituted molecules. => Chapter 17: Aromatics 2-Reactions Slide 17-11 Sigma Complex Intermediate is more stable if nitration occurs at the ortho or para position. => Chapter 17: Aromatics 2-Reactions Slide 17-12 6 Energy Diagram => Chapter 17: Aromatics 2-Reactions Slide 17-13 Activating, O-, P- Directing Substituents • Alkyl groups stabilize the sigma complex by induction, donating electron density through the sigma bond. • Substituents with a lone pair of electrons stabilize the sigma complex by resonance. + OCH3 OCH3 + NO NO2 2 => H H Chapter 17: Aromatics 2-Reactions Slide 17-14 7 Substitution on Anisole => Chapter 17: Aromatics 2-Reactions Slide 17-15 The Amino Group Aniline, like anisole, reacts with bromine water (without a catalyst) to yield the tribromide. Sodium bicarbonate is added to neutralize the HBr that’s also formed. => Chapter 17: Aromatics 2-Reactions Slide 17-16 8 Summary of Activators => Chapter 17: Aromatics 2-Reactions Slide 17-17 Deactivating Meta- Directing Substituents • 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. • Meta-directors deactivate all positions on the ring, but the meta position is less deactivated. => Chapter 17: Aromatics 2-Reactions Slide 17-18 9 Ortho Substitution on Nitrobenzene => Chapter 17: Aromatics 2-Reactions Slide 17-19 Para Substitution on Nitrobenzene => Chapter 17: Aromatics 2-Reactions Slide 17-20 10 Meta Substitution on Nitrobenzene => Chapter 17: Aromatics 2-Reactions Slide 17-21 Energy Diagram => Chapter 17: Aromatics 2-Reactions Slide 17-22 11 Structure of Meta-Directing Deactivators • The atom attached to the aromatic ring will have a partial positive charge. • Electron density is withdrawn inductively along the sigma bond, so the ring is less electron-rich than benzene. => Chapter 17: Aromatics 2-Reactions Slide 17-23 Summary of Deactivators => Chapter 17: Aromatics 2-Reactions Slide 17-24 12 More Deactivators => Chapter 17: Aromatics 2-Reactions Slide 17-25 Halobenzenes • Halogens are deactivating toward electrophilic substitution, but are ortho, para-directing! • Since halogens are very electronegative, they withdraw electron density from the ring inductively along the sigma bond. • But halogens have lone pairs of electrons that can stabilize the sigma complex by resonance. => Chapter 17: Aromatics 2-Reactions Slide 17-26 13 Sigma Complex for Bromobenzene Ortho and para attacks produce a bromonium ion and other resonance structures. No bromonium ion possible with meta attack. => Chapter 17: Aromatics 2-Reactions Slide 17-27 Energy Diagram => Chapter 17: Aromatics 2-Reactions Slide 17-28 14 Summary of Directing Effects => Chapter 17: Aromatics 2-Reactions Slide 17-29 Multiple Substituents The most strongly activating substituent will determine the position of the next substitution. May have mixtures. OCH3 OCH3 OCH3 SO H SO 3 3 + H2SO4 O2N O2N O2N SO3H => Chapter 17: Aromatics 2-Reactions Slide 17-30 15 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. • Other sources of carbocations: alkenes + HF, or alcohols + BF3. => Chapter 17: Aromatics 2-Reactions Slide 17-31 Examples of Carbocation Formation Cl CH3 + _ C Cl AlCl CH3 CH CH3 + AlCl3 3 H3C H _ F HF + H2C CH CH3 H3C CH CH3 + BF3 OH H O BF + _ 3 + H3C CH CH3 H3C CH CH3 H3C CH CH3 HOBF3 => Chapter 17: Aromatics 2-Reactions Slide 17-32 16 Formation of Alkyl Benzene CH3 H +C H CH(CH3)2 + CH3 H F - CH H F B OH 3 HF CH + + CH(CH ) F F 3 2 CH B OH 3 F H => Chapter 17: Aromatics 2-Reactions Slide 17-33 Limitations of Friedel-Crafts • Reaction fails if benzene has a substituent that is more deactivating than halogen. • Carbocations rearrange. Reaction of benzene with n-propyl chloride and AlCl3 produces isopropylbenzene. • The alkylbenzene product is more reactive than benzene, so polyalkylation occurs. => Chapter 17: Aromatics 2-Reactions Slide 17-34 17 Friedel-Crafts Acylation • Acyl chloride is used in place of alkyl chloride. • The acylium ion intermediate is resonance stabilized and does not rearrange like a carbocation. • The product is a phenyl ketone that is less reactive than benzene. => Chapter 17: Aromatics 2-Reactions Slide 17-35 Mechanism of Acylation O O O HCl C R _ C R + C + Cl AlCl3 H AlCl3 R + H => Chapter 17: Aromatics 2-Reactions Slide 17-36 18 Clemmensen Reduction Acylbenzenes can be converted to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc. Works for non- aromatic ketones as well; rearrangements can occur. O O 1) C CH2CH3 CH2CH2CH3 AlCl3 Zn(Hg) + CH3CH2C Cl 2) H2O aq. HCl => Chapter 17: Aromatics 2-Reactions Slide 17-37 Wolff-Kishner Reduction Acylbenzenes can be also converted to alkylbenzenes by treatment with aqueous NH2NH2 and hydroxide (mechanism next chapter). Works for non-aromatic ketones as well. O H H NH2NH2 KOH aq. ethylene glycol Chapter 17: Aromatics 2-Reactions Slide 17-38 19 Gatterman-Koch Formylation • Formyl chloride is unstable. Use a high pressure mixture of CO, HCl, and catalyst. • Product is benzaldehyde. O + _ AlCl3/CuCl CO + HCl H C Cl H C O AlCl4 O O C + C H + + HCl H Chapter 17: Aromatics 2-Reactions Slide 17-39 Nucleophilic Aromatic Substitution • A nucleophile replaces a leaving group on the aromatic ring. • Electron-withdrawing substituents activate the ring for nucleophilic substitution. => Chapter 17: Aromatics 2-Reactions Slide 17-40 20 Examples of Nucleophilic Substitution => Chapter 17: Aromatics 2-Reactions Slide 17-41 Addition-Elimination Mechanism => Chapter 17: Aromatics 2-Reactions Slide 17-42 21 Benzyne Mechanism • Reactant is halobenzene with no electron-withdrawing groups on the ring. • Use a very strong base like NaNH2. => Chapter 17: Aromatics 2-Reactions Slide 17-43 Benzyne Intermediate => Chapter 17: Aromatics 2-Reactions Slide 17-44 22 Chlorination of Benzene • Addition to the benzene ring may occur with high heat and pressure (or light). • The first Cl2 addition is difficult, but the next 2 moles add rapidly. • The product, benzene hexachloride, is an insecticide. => Chapter 17: Aromatics 2-Reactions Slide 17-45 Catalytic Hydrogenation • Elevated heat and pressure is required. • Possible catalysts: Pt, Pd, Ni, Ru, Rh. • Reduction cannot be stopped at an intermediate stage. CH3 CH3 3H2, 1000 psi Ru, 100°C => CH3 CH3 Chapter 17: Aromatics 2-Reactions Slide 17-46 23 Birch Reduction: Regiospecific • A carbon bearing an e--withdrawing group is reduced. O O C _ C O OH Na, NH3 H CH3CH2OH • A carbon bearing an e--releasing group is not reduced. OCH OCH3 3 Li, NH3 (CH3)3COH, THF => Chapter 17: Aromatics 2-Reactions Slide 17-47 Birch Mechanism => Chapter 17: Aromatics 2-Reactions Slide 17-48 24 Side-Chain Oxidation Alkylbenzenes are oxidized to benzoic acid by hot KMnO4 or Na2Cr2O7/H2SO4. _ CH(CH3)2 COO KMnO , OH- 4 _ H2O, heat COO CH CH2 Chapter 17: Aromatics 2-Reactions Slide 17-49 Side-Chain Halogenation • Benzylic position is the most reactive. • Chlorination is not as selective as bromination, results in mixtures. • Br2 reacts only at the benzylic position. Br CH CH CH 2 2 3 CHCH2CH3 Br2, h! Chapter 17: Aromatics 2-Reactions Slide 17-50 25 SN1 Reactions • Benzylic carbocations are resonance-stabilized, easily formed. • Benzyl halides (even primary!) undergo SN1 reactions. CH3CH2OH, heat CH2Br CH2OCH2CH3 => Chapter 17: Aromatics 2-Reactions Slide 17-51 SN2 Reactions • Benzylic halides are 100 times more reactive than primary halides via SN2.