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Electrophilic Aromatic Substitution Electrophile substitutes for a hydrogen on the benzene ring. => Chapter 17 1 Mechanism => Chapter 17 2 Energy Diagram for Bromination => Chapter 17 3 Bromination of Benzene • Requires a stronger electrophile than Br2. • Use a strong Lewis acid catalyst, FeBr3. Br Br FeBr3 Br Br H H H H H FeBr3 H H H Br Br Br FeBr3 + H _ + FeBr4 H H H Br + Chapter 17 HBr 4 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 5 Nitration of Benzene Use sulfuric acid with nitric acid to form the nitronium ion electrophile. O H O S O H O H O H O N H O N + O O O H O H O N + O O H2O + N+ O Chapter 17 _ + HSO4 NO2+ then forms a sigma complex with benzene, loses H+ to form nitrobenzene. => 6 Sulfonation Sulfur trioxide, SO3, in fuming sulfuric acid is the electrophile. O _ O O S S+ O O O O O S+ _ O O _ O S O O H O S O + O H _ S + O O HO O S O benzenesulfonic acid => Chapter 17 7 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. D H H H H H H large excess D2SO4/D2O D D D D => D Chapter 17 Benzene-d6 8 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 9 Sigma Complex Intermediate is more stable if nitration occurs at the ortho or para position. Chapter 17 => 10 Energy Diagram Chapter 17 => 11 Activating, O-, PDirecting 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 NO2 NO2 + H H Chapter 17 => 12 NITRATION OF ANISOLE Nitration of Anisole BENZENIUM ION INTERMEDIATES O CH3 + O N+ O O CH3 H NO2 + H ortho O CH3 O CH3 H + + H NO2 H meta para H NO2 activated ring O CH3 O CH3 NO2 actual products ortho + para NO2 ortho O CH3 H NO2 + H + :O + O CH 3 H NO2 CH3 H + NO2 O CH3 H NO2 H H H EXTRA! H para + NO2 H :O O CH3 O CH3 H O CH3 H O CH3 H + meta + NO2 H NO2 +O CH 3 CH3 O CH3 + + + H NO2 H H H H H NO2 H NO2 EXTRA! H NO2 Energy Profiles NITRATION OF ANISOLE RECALL: HAMMOND POSTULATE benzenium intermediate meta ortho para benzenium intermediates have more resonance ortho-para Ea director BENZENIUM IONS GIVE ELIMINATION INSTEAD OF ADDITION O CH3 H + H O CH3 H _ :B NO2 X H doesn’t happen resonance would be lost NO2 addition O CH3 H O CH3 H + H B ADDITION REACTION NO2 NO2 :B _ elimination ELIMINATION REACTION restores aromatic ring resonance ( 36 Kcal / mole ) The Amino Group Aniline reacts with bromine water (without a catalyst) to yield the tribromide. Sodium bicarbonate is added to neutralize the HBr that’s also formed. NH2 NH2 Br Br 3 Br2 H2O, NaHCO3 Br Chapter 17 => 18 Summary of Activators Chapter 17 19 => Deactivating MetaDirecting 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 20 Ortho Substitution on Nitrobenzene => Chapter 17 21 Para Substitution on Nitrobenzene => Chapter 17 22 Meta Substitution on Nitrobenzene => Chapter 17 23 Energy Diagram => Chapter 17 24 Structure of MetaDirecting 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 25 Summary of Deactivators => Chapter 17 26 More Deactivators => Chapter 17 27 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 28 Sigma Complex for Bromobenzene Para attack Ortho attack Br Br + (+) + E Br Br (+) H E (+) + (+) (+) E+ (+) H E Ortho and para attacks produce a bromonium ion and other resonance structures. Meta attack Br Br H (+) + + H E (+) No bromonium ion possible with meta attack. E => Chapter 17 29 Energy Diagram => Chapter 17 30 Summary of Directing Effects Chapter 17 31 => DIRECTIVITY OF SINGLE GROUPS ortho, para - Directing Groups X Groups that donate electron density to the ring. PROFILE: X :X E+ increased reactivity +I Substituent These groups also “activate” the ring, or make it more reactive. CH3R- +R Substituent .. CH3-O.. .. CH3-N- .. -NH2 The +R groups activate the ring more strongly than +I groups. .. -O-H .. meta - Directing Groups X Groups that withdraw electron density from the ring. PROFILE: d+ Y X Y d- E+ decreased reactivity -I Substituent These groups also “deactivate” the ring, or make it less reactive. R + N R R CCl3 -R Substituent O C R C N O + O C OR O C OH N O - -SO3H THE EXCEPTION Halides - o,p Directors / Deactivating Halides represent a special case: .. :X : E+ +R / -I / o,p / deactivating -F -Cl -Br -I They are o,p directing groups that are deactivating They are o,p directors (+R effect ) They are deactivating ( -I effect ) Most other other substituents fall into one of these four categories: 1) 2) 3) 4) +R / o,p / activating +I / o,p / activating -R / m / deactivating -I / m / deactivating PREDICT ! CH3 NO2 o,p m O O CH3 C O CH3 o,p m DIRECTIVITY OF MULTIPLE GROUPS GROUPS ACTING IN CONCERT steric crowding o,p director O CH3 NO2 O 2N O CH3 m-director NO2 very little formed HNO3 H2SO4 O CH3 NO2 When groups direct to the same positions it is easy to predict the product. NO2 major product GROUPS COMPETING o,p-directing groups win over m-directing groups O CH3 O2N O CH3 too crowded X HNO3 H2SO4 NO2 NO2 + O CH3 NO2 NO2 RESONANCE VERSUS INDUCTIVE EFFECT +R O CH3 O CH3 NO2 HNO3 H2SO4 CH3 CH3 +I resonance effects are more important than inductive effects major product SOME GENERAL RULES 1) Activating (o,p) groups (+R, +I) win over deactivating (m) groups (-R,-I). 2) Resonance groups (+R) win over inductive (+I) groups. 3) 1,2,3-Trisubstituted products rarely form due to excessive steric crowding. 4) With bulky directing groups, there will usually be more p-substitution than o-substitution. 5) The incoming group replaces a hydrogen, it will not usually displace a substituent already in place. HOW CAN YOU MAKE ... O C O CH3 NO2 O 2N NO2 NO2 CH3 NO2 only, no para CH2CH2CH2CH3 BROMINE - WATER REAGENT PHENOLS AND ANILINES BROMINE IN WATER This reagent works only with highly-activated rings such as phenols, anisoles and anilines. .. H O: .. .. : Br Br : .. .. H .. .. .. : Br : .. H O Br + .. H OMe OMe H .. .. : Br O H .. + + H bromonium ion etc Br PHENOLS AND ANILINES REACT OH OH Br2 Br Br H2O Br NH2 CH3 NH2 Br2 CH3 All available positions are bromiated. Br H2O Br 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 46 Examples of Carbocation Formation Cl CH3 CH CH3 _ CH3 + C Cl AlCl3 H3C H + AlCl3 _ H2C CH CH3 OH H3C CH CH3 BF3 F + H3C CH CH3 HF + BF3 H O H3C CH CH3 Chapter 17 _ + H3C CH CH3 + HOBF3 => 47 Formation of Alkyl Benzene CH3 H +C H + CH3 H F H + CH(CH3)2 CH(CH3)2 F - B OH CH3 F CH + CH3 H HF F B OH F => Chapter 17 48 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 49 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 50 Mechanism of Acylation O R C Cl O + _ R C Cl AlCl3 AlCl3 O + _ R C Cl AlCl3 _ AlCl4 + + R C O O O C C+ R + H R Cl _ AlCl3 + R C O O C HCl R + AlCl3 H => Chapter 17 51 Clemmensen Reduction Acylbenzenes can be converted to alkylbenzenes by treatment with aqueous HCl and amalgamated zinc. O O + CH3CH2C Cl 1) AlCl3 C CH2CH3 2) H2O Zn(Hg) CH2CH2CH3 aq. HCl => Chapter 17 52 Gatterman-Koch Formylation • Formyl chloride is unstable. Use a high pressure mixture of CO, HCl, and catalyst. • Product is benzaldehyde. O H C Cl CO + HCl + AlCl3/CuCl O O C+ C H _ + H C O AlCl4 + HCl H Chapter 17 53 => 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 54 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 3 H2, 1000 psi Ru, 100°C CH3 Chapter 17 CH3 => 55 Birch Reduction: Regiospecific • A carbon with an e--withdrawing group O O is reduced. C C OH Na, NH3 _ O H CH3CH2OH • A carbon with an e--releasing group is not reduced. OCH3 Li, NH3 (CH3)3COH, THF Chapter 17 OCH3 => 56 Birch Mechanism => Chapter 17 57 Side-Chain Oxidation Alkylbenzenes are oxidized to benzoic acid by hot KMnO4 or Na2Cr2O7/H2SO4. CH(CH3)2 - KMnO4, OH CH CH2 H2O, heat _ COO _ COO => Chapter 17 58 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 CH2CH2CH3 Br2, h CHCH2CH3 => Chapter 17 59