8Chapter 12a

8Chapter 12a - Chapter 12 (Part a) Reactions of Arenes:...

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Unformatted text preview: Chapter 12 (Part a) Reactions of Arenes: Electrophilic Aromatic Substitution H δ+ δ– +E Y E +H Y 12-1 12.1 Representative Electrophilic Aromatic Substitution Reactions of Benzene H δ+ δ– +E Y E +H Y 12-2 H δ+ δ– +E Y E +H Y Electrophilic aromatic substitutions include: Electrophilic aromatic substitutions include: Nitration Sulfonation Halogenation Friedel-Crafts Alkylation Friedel-Crafts Acylation 12-3 Table 12.1: Nitration of Benzene Table 12.1: Nitration of Benzene Table Nitration Table Nitration H + HONO2 H2SO4 NO2 NO + H2O Nitrobenzene (95%) 12-4 Table 12.1: Sulfonation of Benzene Table 12.1: Sulfonation of Benzene Table Sulfonation Table Sulfonation H heat + HOSO2OH SO2OH SO + H2O Benzenesulfonic acid (100%) 12-5 Table 12.1: Halogenation of Benzene Table 12.1: Halogenation of Benzene Table Halogenation Table Halogenation H + Br2 FeBr3 Br Br + HBr Bromobenzene (65-75%) 12-6 Table 12.1: Friedel-Crafts Alkylation of Benzene Table 12.1: Friedel-Crafts Alkylation of Benzene Table Friedel-Crafts Table Friedel-Crafts H + (CH3)3CCl AlCl3 C(CH3)3 C(CH + HCl tert-Butylbenzene (60%) 12-7 Table 12.1: Friedel-Crafts Acylation of Benzene Table 12.1: Friedel-Crafts Acylation of Benzene Table Friedel-Crafts Table Friedel-Crafts O O H AlCl3 + CH3CH2CCl CCH2CH3 CCH + HCl 1-Phenyl-1-propanone (88%) 12-8 12.2 Mechanistic Principles of Electrophilic Aromatic Substitution 12-9 Step 1: attack of electrophile Step 1: attack of electrophile oonπ-electron system of aromatic ring n on π-electron system of aromatic ring on H H H E+ H H H HE H H + H H H highly endothermic carbocation is allylic, but not aromatic 12-10 Step 2: loss of a proton from the carbocation Step 2: loss of a proton from the carbocation intermediate intermediate H H H E H H HE H H H+ + H H H highly exothermic this step restores aromaticity of ring 12-11 HE H H + H H H H H + E+ H H H H H H E + H+ H H H 12-12 Based on this general mechanism: Based on this general mechanism: what remains is to identify the electrophile in what nitration, sulfonation, halogenation, Friedelnitration, Crafts alkylation, and Friedel-Crafts acylation Crafts to establish the mechanism of specific electrophilic aromatic substitutions electrophilic 12-13 12.3 Nitration of Benzene 12-14 Nitration of Benzene Nitration of Benzene H + HONO2 Electrophile is nitronium ion nitronium NO2 NO H2SO4 + H2O • •O •• + N • O• •• 12-15 Step 1: attack of nitronium cation Step 1: attack of nitronium cation oonπ-electron system of aromatic ring n on π-electron system of aromatic ring on H H H NO2+ H H H H NO2 H H + H H H 12-16 Step 2: loss of a proton from the carbocation Step 2: loss of a proton from the carbocation intermediate intermediate H NO2 H H H H NO2 H H H+ H + H H H 12-17 Where does nitronium ion come from? Where does nitronium ion come from? •• • •O + N • •O •• •• – • O• •• •• • •O H2SO4 H H • •O •• + N •• – • O• •• + N +O •• H •• • O• •• + H O •• H 12-18 12.4 Sulfonation of Benzene 12-19 Sulfonation of Benzene Sulfonation of Benzene SO2OH SO H heat + HOSO2OH + H2O •• Several electrophiles present: a major one is sulfur trioxide • •O + S •• – • O• •• • •O •• 12-20 Step 1: attack of sulfur trioxide Step 1: attack of sulfur trioxide oonπ-electron system of aromatic ring n on π-electron system of aromatic ring on H H H SO3 H H H H SO3– H H + H H H 12-21 Step 2: loss of a proton from the carbocation Step 2: loss of a proton from the carbocation intermediate intermediate H H SO3– H H H H SO3– H H+ H + H H H 12-22 Step 3: protonation of benzenesulfonate ion Step 3: protonation of benzenesulfonate ion H H SO3– H H H H2SO4 H H SO3H H H H 12-23 12.5 Halogenation of Benzene 12-24 Halogenation of Benzene Halogenation of Benzene H + Br2 FeBr3 Br Br + HBr Electrophile is a Lewis acid-Lewis base complex between FeBr3 and Br2. 12-25 The Br2-FeBr3 Complex The Br2-FeBr3 Complex •• • Br • •• •• Br • • •• Lewis base + FeBr3 Lewis acid •• • Br • Br •• + •• Br •• – FeBr3 Complex Complex The Br2-FeBr3 complex is more electrophilic than Br2 alone. than 12-26 Step 1: attack of Br2-FeBr3 ccomplex Step 1: attack of Br2-FeBr3 omplex on π-electron system of aromatic ring on π-electron system of aromatic ring H H H Br Br H H H + Br – FeBr3 H Br H H + H H H + FeBr4– 12-27 Step 2: loss of a proton from the carbocation Step 2: loss of a proton from the carbocation intermediate intermediate H H Br H H H Br H H H+ H + H H H 12-28 12.6 Friedel-Crafts Alkylation of Benzene 12-29 Friedel-Crafts Alkylation of Benzene Friedel-Crafts Alkylation of Benzene H + (CH3)3CCl C(CH3)3 C(CH AlCl3 + HCl H3C Electrophile is Electrophile tert-butyl cation tert + C CH3 H3C 12-30 Role of AlCl3 Role of AlCl3 acts as a Lewis acid to promote ionization of the alkyl halide (CH3)3C •• Cl • • •• + AlCl3 (CH3)3C + •• Cl •• – AlCl3 12-31 Role of AlCl3 Role of AlCl3 acts as a Lewis acid to promote ionization of the alkyl halide (CH3)3C •• Cl • • •• + AlCl3 (CH3)3C + •• (CH3)3C + • Cl • •• + •• Cl •• – AlCl3 – AlCl3 12-32 Step 1: attack of tert-butyl cation Step 1: attack ofttert-butyl cation ert Step Step tert oonπ-electron system of aromatic ring n on π-electron system of aromatic ring on H H H + C(CH3)3 H H H H C(CH3)3 H H + H H H 12-33 Step 2: loss of a proton from the carbocation Step 2: loss of a proton from the carbocation intermediate intermediate H C(CH3)3 H H H H C(CH3)3 H H H+ H + H H H 12-34 Rearrangements in Friedel-Crafts Alkylation Rearrangements in Friedel-Crafts Alkylation Carbocations are intermediates. Therefore, rearrangements can occur H + (CH3)2CHCH2Cl Isobutyl chloride AlCl3 C(CH3)3 C(CH tert-Butylbenzene (66%) 12-35 Rearrangements in Friedel-Crafts Alkylation Rearrangements in Friedel-Crafts Alkylation Isobutyl chloride is the alkyl halide. But tert-butyl cation is the But tert-butyl electrophile. electrophile. H + (CH3)2CHCH2Cl Isobutyl chloride AlCl3 C(CH3)3 C(CH tert-Butylbenzene (66%) 12-36 Rearrangements in Friedel-Crafts Alkylation Rearrangements in Friedel-Crafts Alkylation Rearrangements H H3C C CH2 + •• Cl •• – AlCl3 CH3 H H3C + C CH2 + •• • Cl • •• – AlCl3 CH3 12-37 Reactions Related to Friedel-Crafts Alkylation Reactions Related to Friedel-Crafts Alkylation H + H2SO4 Cyclohexylbenzene (65-68%) Cyclohexene is protonated by sulfuric acid, giving cyclohexyl cation which attacks the benzene ring benzene 12-38 12.7 Friedel-Crafts Acylation of Benzene 12-39 Friedel-Crafts Acylation of Benzene Friedel-Crafts Acylation of Benzene O O CCH2CH3 CCH H AlCl3 + CH3CH2CCl + HCl Electrophile is an acyl cation + CH3CH2C •• O• • CH3CH2C + O• • 12-40 Step 1: attack of the acyl cation Step 1: attack of the acyl cation oonπ-electron system of aromatic ring n on π-electron system of aromatic ring on O H H H CCH2CH3 H+ H H O H CCH2CH3 H H + H H H 12-41 Step 2: loss of a proton from the carbocation Step 2: loss of a proton from the carbocation Step intermediate intermediate O H H O CCH2CH3 H H H H CCH2CH3 H H+ H + H H H 12-42 Acid Anhydrides Acid Anhydrides can be used instead of acyl chlorides O H OO + CH3COCCH3 AlCl3 CCH3 Acetophenone (76-83%) O + CH3COH 12-43 12.8 Acylation-Reduction 12-44 Acylation-Reduction Acylation-Reduction permits primary alkyl groups to be attached to an aromatic ring O H RCCl O CR AlCl3 Reduction of aldehyde and ketone carbonyl groups using Zn(Hg) and HCl carbonyl is called the Clemmensen reduction. Clemmensen Zn(Hg), HCl CH2R CH 12-45 Acylation-Reduction Acylation-Reduction permits primary alkyl groups to be attached to an aromatic ring O H RCCl AlCl3 Reduction of aldehyde and ketone carbonyl groups by heating with carbonyl H2NNH2 and KOH is called the and O CR H2NNH2, KOH, triethylene glycol, heat CH2R CH Wolff-Kishner reduction. 12-46 Example: Prepare isobutylbenzene Example: Prepare isobutylbenzene (CH3)2CHCH2Cl CH2CH(CH3)2 CH AlCl3 No! Friedel-Crafts alkylation of benzene No! using isobutyl chloride fails because of rearrangement. rearrangement. 12-47 Recall Recall + (CH3)2CHCH2Cl Isobutyl chloride AlCl3 C(CH3)3 C(CH tert-Butylbenzene (66%) 12-48 Use Acylation-Reduction Instead Use Acylation-Reduction Instead O (CH + (CH3)2CHCCl AlCl3 Zn(Hg) HCl CH2CH(CH3)2 CH O CCH(CH3)2 12-49 12.9 Rate and Regioselectivity in Rate Electrophilic Aromatic Substitution Electrophilic A substituent already present on the ring substituent can affect both the rate and regioselectivity rate regioselectivity of electrophilic aromatic substitution. 12-50 Effect on Rate Effect on Rate Effect Activating substituents increase the rate of EAS compared to that of benzene. of Deactivating substituents decrease the rate of EAS compared to benzene. 12-51 Methyl Group Methyl Group CH3 CH Toluene undergoes nitration Toluene 20-25 times faster than benzene. benzene. A methyl group is an methyl activating substituent. activating 12-52 Trifluoromethyl Group Trifluoromethyl Group CF3 CF (Trifluoromethyl)benzene (Trifluoromethyl)benzene undergoes nitration 40,000 times more slowly than benzene . times A trifluoromethyl group is a deactivating substituent. 12-53 Effect on Regioselectivity Effect on Regioselectivity Ortho-para directors direct an incoming Ortho-para electrophile to positions ortho and/or para to themselves. para Meta directors direct an incoming Meta electrophile to positions meta to themselves. themselves. 12-54 Nitration of Toluene Nitration of Toluene CH3 CH CH3 CH CH3 CH CH3 CH NO2 HNO3 + acetic anhydride + NO2 NO2 63% 3% 34% o- and p-nitrotoluene together comprise 97% and -nitrotoluene of the product of a methyl group is an ortho-para director 12-55 Nitration of (Trifluoromethyl)benzene Nitration of (Trifluoromethyl)benzene CF3 CF CF3 CF CF3 CF CF3 CF NO2 HNO3 + H2SO4 + NO2 NO2 6% 91% 3% m-nitro(trifluoromethyl)benzene comprises -nitro(trifluoromethyl)benzene 91% of the product 91% a trifluoromethyl group is a meta director 12-56 12.10 Rate and Regioselectivity in the Nitration of Toluene 12-57 Carbocation Stability Controls Regioselectivity Carbocation Stability Controls Regioselectivity CH3 H NO2 + H H gives ortho H H CH3 H H CH3 H H + H NO2 gives para H H + H H H NO2 gives meta 12-58 Carbocation Stability Controls Regioselectivity Carbocation Stability Controls Regioselectivity CH3 H NO2 H + H H CH3 H H H H NO2 gives para more stable H H + H gives ortho CH3 H H + H H NO2 gives meta less stable 12-59 ortho Nitration of Toluene ortho Nitration of Toluene CH3 H + H NO2 H H H 12-60 ortho Nitration of Toluene ortho Nitration of Toluene CH3 H + H H NO2 H H CH3 H H NO2 H + H H 12-61 ortho Nitration of Toluene ortho Nitration of Toluene CH3 H + H H NO2 H H CH3 H H NO2 H + H H CH3 H H + NO2 H H H this resonance form is a tertiary carbocation carbocation 12-62 ortho Nitration of Toluene ortho Nitration of Toluene CH3 H + H H NO2 H H CH3 H H NO2 H + H H CH3 H + H NO2 H H H the rate-determining intermediate in the ortho nitration of toluene has tertiary carbocation nitration character character 12-63 para Nitration of Toluene para Nitration of Toluene CH3 H H H + H H NO2 12-64 para Nitration of Toluene para Nitration of Toluene CH3 H H CH3 H H + H NO2 H H H + H H NO2 this resonance this form is a tertiary carbocation carbocation 12-65 para Nitration of Toluene para Nitration of Toluene CH3 H H CH3 H + H H NO2 H CH3 HH + H H + HH H NO2 H H NO2 this resonance this form is a tertiary carbocation carbocation 12-66 para Nitration of Toluene para Nitration of Toluene CH3 H H CH3 H + H H NO2 H CH3 HH + H H + HH H NO2 H H NO2 the rate-determining intermediate in the para nitration of toluene has tertiary carbocation nitration character character 12-67 meta Nitration of Toluene meta Nitration of Toluene CH3 H + H H H H NO2 12-68 meta Nitration of Toluene meta Nitration of Toluene CH3 H + H H CH3 H H H NO2 H H + H H NO2 12-69 meta Nitration of Toluene meta Nitration of Toluene CH3 H H + CH3 H H H NO2 H + CH3 H H H NO2 H H + H H H all the resonance forms of the ratedetermining intermediate in the meta nitration determining of toluene have their positive charge on a secondary carbon secondary H NO2 12-70 Nitration of Toluene: Interpretation Nitration of Toluene: Interpretation • The rate-determining intermediates for ortho and The para nitration each have a resonance form that is a tertiary carbocation. All of the resonance forms for the rate-determining intermediate in meta nitration are secondary carbocations. nitration • Tertiary carbocations, being more stable, are Tertiary formed faster than secondary ones. Therefore, the intermediates for attack at the ortho and para positions are formed faster than the intermediate for attack at the meta position. This explains why the major products are o- and p-nitrotoluene. 12-71 Nitration of Toluene: Partial Rate Factors Nitration of Toluene: Partial Rate Factors • The experimentally determined reaction rate can The be combined with the ortho/meta/para distribution to give partial rate factors for substitution at the various ring positions. various • Expressed as a numerical value, a partial rate Expressed factor tells you by how much the rate of substitution at a particular position is faster (or slower) than at a single position of benzene. slower) 12-72 Nitration of Toluene: Partial Rate Factors Nitration of Toluene: Partial Rate Factors CH3 CH 1 1 1 42 42 1 1 2.5 2.5 1 58 All of the available ring positions in toluene are All more reactive than a single position of benzene. more A methyl group activates all of the ring positions methyl but the effect is greatest at the ortho and para positons. positons. Steric hindrance by the methyl group makes each Steric ortho position slightly less reactive than para. ortho 12-73 Nitration of Toluene vs. tert-Butylbenzene Nitration of Toluene vs. tert-Butylbenzene CH3 CH3 CH H3C 42 42 4.5 2.5 2.5 C 3 58 CH3 4.5 3 75 tert-Butyl is activating and ortho-para directing tert-Butyl crowds the ortho positions and -Butyl decreases the rate of attack at those positions. decreases 12-74 Generalization Generalization all alkyl groups are activating and all ortho-para directing ortho-para 12-75 Theory of Directing Effects 12.11 Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 12-76 A Key Point A Key Point H3C C+ F3C C+ A methyl group is electron-donating and methyl stabilizes a carbocation. stabilizes Because F is so electronegative, a CF3 group destabilizes a carbocation. destabilizes 12-77 Carbocation Stability Controls Regioselectivity Carbocation Stability Controls Regioselectivity CF3 H NO2 + H H gives ortho H H CF3 H H CF3 H H + H NO2 gives para H H + H H H NO2 gives meta 12-78 Carbocation Stability Controls Regioselectivity Carbocation Stability Controls Regioselectivity CF3 H NO2 H + H H CF3 H H H gives ortho less stable NO2 gives para H H + H H CF3 H + H H H NO2 gives meta more stable 12-79 ortho Nitration of (Trifluoromethyl)benzene ortho Nitration of (Trifluoromethyl)benzene CF3 H + H NO2 H H H 12-80 ortho Nitration of (Trifluoromethyl)benzene ortho Nitration of (Trifluoromethyl)benzene ortho CF3 H + H H NO2 H H CF3 H H NO2 H + H H 12-81 ortho Nitration of (Trifluoromethyl)benzene ortho Nitration of (Trifluoromethyl)benzene CF3 H + H H NO2 H H CF3 H H NO2 H + H H CF3 H H + NO2 H H H this resonance form is destabilized destabilized 12-82 ortho Nitration of (Trifluoromethyl)benzene ortho Nitration of (Trifluoromethyl)benzene CF3 H H + NO2 H H CF3 H H + NO2 H H CF3 H + H NO2 H H H H H one of the resonance forms of the ratedetermining intermediate in the ortho nitration of (trifluoromethyl)benzene is nitration strongly destabilized strongly 12-83 para Nitration of (Trifluoromethyl)benzene para Nitration of (Trifluoromethyl)benzene CF3 H H H + H H NO2 12-84 para Nitration of (Trifluoromethyl)benzene para Nitration of (Trifluoromethyl)benzene CF3 H H CF3 H H + H NO2 H H H + H H NO2 this resonance this form is destabilized form 12-85 para Nitration of (Trifluoromethyl)benzene para Nitration of (Trifluoromethyl)benzene para CF3 H H CF3 H + H H NO2 H CF3 HH + H H + HH H NO2 H H NO2 this resonance this form is destabilized form 12-86 para Nitration of (Trifluoromethyl)benzene para Nitration of (Trifluoromethyl)benzene CF3 H H CF3 H + H H H + CF3 HH HH H NO2 H NO2 H one of the resonance forms of the ratedetermining intermediate in the para nitration of (trifluoromethyl)benzene is nitration strongly destabilized strongly H + H NO2 12-87 meta Nitration of (Trifluoromethyl)benzene meta Nitration of (Trifluoromethyl)benzene CF3 H + H H H H NO2 12-88 meta Nitration of (Trifluoromethyl)benzene meta Nitration of (Trifluoromethyl)benzene CF3 H + H H CF3 H H H NO2 H H + H H NO2 12-89 meta Nitration of (Trifluoromethyl)benzene meta Nitration of (Trifluoromethyl)benzene CF3 H H + CF3 H H H NO2 H + CF3 H H H NO2 H H + H NO2 H H H none of the resonance forms of the rate-determining none intermediate in the meta nitration of (trifluoromethyl)benzene have their positive charge on the carbon that bears the CF3 group on 12-90 Nitration of (Trifluoromethyl)benzene: Interpretation Nitration of (Trifluoromethyl)benzene: Interpretation The rate-determining intermediates for ortho and The para nitration each have a resonance form in which the positive charge is on a carbon that bears a CF3 group. Such a resonance structure is bears strongly destabilized. The intermediate in meta nitration avoids such a structure. It is the least unstable of three unstable intermediates and is the one from which most of the product is formed. the 12-91 Nitration of (Trifluoromethyl)benzene: Nitration of (Trifluoromethyl)benzene: Partial Rate Factors Partial Rate Factors CF3 CF 4.5 x 10-6 4.5 x 10-6 67 x 10-6 67 x 10-6 4.5 x 10-6 All of the available ring positions in All (trifluoromethyl)benzene are much less reactive than a single position of benzene. than A CF3 group deactivates all of the ring positions but the degree of deactivation is greatest at the ortho and para positons. ortho 12-92 Theory of Directing Effects 12.12 Substituent Effects in Electrophilic Aromatic Substitution: Activating Substituents 12-93 Table 12.2 Table 12.2 Classification of Substituents in Electrophilic Classification Aromatic Substitution Reactions Aromatic Very strongly activating Strongly activating Activating Standard of comparison is H Deactivating Strongly deactivating Very strongly deactivating 12-94 Generalizations Generalizations 1. All activating substituents are 1. ortho-para directors. ortho-para 2. Halogen substituents are slightly 2. deactivating but ortho-para directing. deactivating 3. Strongly deactivating substituents are 3. meta directors. meta 12-95 Electron-Releasing Groups (ERGs) Electron-Releasing Groups (ERGs) are ortho-para directing and activating ERG ERG ERGs include —R, —Ar, and —C=C 12-96 Electron-Releasing Groups (ERGs) Electron-Releasing Groups (ERGs) are ortho-para directing and strongly activating ERG ERG ERGs such as —OH, and —OR are strongly activating 12-97 Nitration of Phenol Nitration of Phenol occurs about 1000 times faster than nitration occurs of benzene of OH OH OH OH OH OH NO2 HNO3 + NO2 44% 56% 12-98 Bromination of Anisole Bromination of Anisole FeBr3 catalyst not necessary OCH3 OCH OCH3 OCH Br2 acetic acid Br 90% 12-99 Oxygen Lone Pair Stabilizes Intermediate Oxygen Lone Pair Stabilizes Intermediate •• • OCH3 • H H •• • OCH3 H H + H Br H H •• + OCH3 H H Br H H + H H H H Br all atoms have octets 12-100 Electron-Releasing Groups (ERGs) Electron-Releasing Groups (ERGs) • ERG • ERG ERGs with a lone pair on the atom directly attached to the ring are ortho-para directing and strongly activating 12-101 Examples Examples O • ERG = • ERG •• •• • OH • OH •• • OR • OR •• • OCR • OCR O • NH2 • • NHR • NHR • NR2 • • NHCR • All of these are ortho-para directing and strongly to very strongly activating 12-102 Lone Pair Stabilizes Intermediates for Lone Pair Stabilizes Intermediates for ortho and para Substitution ortho and para Substitution + ERG + ERG H H H H H H X H H H H X comparable stabilization not possible for comparable intermediate leading to meta substitution intermediate 12-103 12.13 Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents 12-104 ERGs Stabilize Intermediates for ERGs Stabilize Intermediates for ortho and para Substitution ortho and para Substitution • ERG • H • ERG • X + H H H H H H + H H H X 12-105 Electron-withdrawing Groups (EWGs) Destabilize Electron-withdrawing Groups (EWGs)Destabilize Electron-withdrawing Destabilize Electron-withdrawing Destabilize Intermediates for ortho and para Substitution Intermediates for ortho and para Substitution H EWG X + H EWG H H H H H + H H H X —CF3 is a powerful EWG. It is strongly deactivating and meta directing deactivating 12-106 Many EWGs Have a Carbonyl Group Many EWGs Have a Carbonyl Group Attached Directly to the Ring Attached Directly to the Ring O —CH —CR O O —COH —EWG = EWG O —COR O —CCl All of these are meta directing and strongly deactivating 12-107 Other EWGs Include: Other EWGs Include: —EWG = EWG —NO2 —SO3H —C N All of these are meta directing and strongly deactivating 12-108 Nitration of Benzaldehyde Nitration of Benzaldehyde O CH CH O2N HNO3 H2SO4 O CH CH 75-84% 12-109 Problem 12.14(a); page 468 Problem 12.14(a); page 468 O CCl CCl Cl O Cl2 CCl CCl FeCl3 62% 12-110 Disulfonation of Benzene Disulfonation of Benzene HO3S SO3 SO3H SO H2SO4 90% 12-111 Bromination of Nitrobenzene Bromination of Nitrobenzene Br Br NO2 Br2 Fe Fe NO2 60-75% 12-112 12.14 Substituent Effects in Electrophilic Aromatic Substitution: Halogens F, Cl, Br, and I are ortho-para directing, but deactivating 12-113 Nitration of Chlorobenzene Nitration of Chlorobenzene Cll C Cll C Cll C Cll C NO2 HNO3 + + NO2 H2SO4 NO2 30% 1% 69% The rate of nitration of chlorobenzene is about The 30 times slower than that of benzene. 30 12-114 Nitration of Toluene vs. Chlorobenzene Nitration of Toluene vs. Chlorobenzene CH3 CH Cll C 42 42 0.029 0.029 2.5 2.5 0.009 0.009 58 0.137 12-115 Halogens – thus, 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 12.15 Multiple Substituent Effects 12-116 The Simplest Case The Simplest Case all possible EAS sites may be equivalent CH3 CH3 O CH OO CCH3 CCH AlCl3 + CH3COCCH3 CH3 CH3 99% 12-117 Another Straightforward Case Another Straightforward Case CH3 CH CH3 Br Br Br2 Fe NO2 NO2 86-90% directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group 12-118 Generalization Generalization regioselectivity is controlled by the most activating substituent 12-119 The Simplest Case The Simplest Case all possible EAS sites may not be equivalent strongly strongly activating activating NHCH3 NHCH NHCH3 Br Br Br2 acetic acid Cl Cl 87% 12-120 When activating effects are similar... When activating effects are similar... CH3 CH CH3 HNO3 NO2 NO H2SO4 C(CH3)3 C(CH3)3 88% substitution occurs ortho to the smaller group 12-121 Steric effects control regioselectivity when Steric effects control regioselectivity when electronic effects are similar electronic effects are similar CH3 CH3 CH HNO3 CH3 CH H2SO4 CH3 NO2 98% position between two substituents is last position to be substituted 12-122 12.16 Regioselective Synthesis of Disubstituted Aromatic Compounds 12-123 Factors to Consider Factors to Consider order of introduction of substituents to ensure order correct orientation correct 12-124 Synthesis of m-Bromoacetophenone Synthesis of m-Bromoacetophenone Br Br Which substituent Which should be introduced first? introduced O CCH3 CCH 12-125 Synthesis of m-Bromoacetophenone Synthesis of m-Bromoacetophenone Br Br para If bromine is introduced first, If p-bromoacetophenone is major -bromoacetophenone product. product. O CCH3 CCH meta 12-126 Synthesis of m-Bromoacetophenone Synthesis of m-Bromoacetophenone Br O CCH3 OO Br2 CH3COCCH3 AlCl3 AlCl3 O CCH3 CCH 12-127 Factors to Consider Factors to Consider order of introduction of substituents to ensure order correct orientation correct Friedel-Crafts reactions (alkylation, acylation) Friedel-Crafts cannot be carried out on strongly deactivated aromatics aromatics 12-128 Synthesis of m-Nitroacetophenone Synthesis of m-Nitroacetophenone NO2 NO Which substituent Which should be introduced first? introduced O CCH3 CCH 12-129 Synthesis of m-Nitroacetophenone Synthesis of m-Nitroacetophenone NO2 NO If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails. acylation) O CCH3 CCH 12-130 Synthesis of m-Nitroacetophenone Synthesis of m-Nitroacetophenone O2N O CCH3 OO HNO3 CH3COCCH3 H2SO4 AlCl3 O CCH3 CCH 12-131 Factors to Consider Factors to Consider order of introduction of substituents to ensure order correct orientation correct Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics aromatics sometimes electrophilic aromatic substitution sometimes must be combined with a functional group transformation transformation 12-132 Synthesis of p-Nitrobenzoic Acid from Toluene Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CO CH3 CH CH3 Which first? Which (oxidation of methyl group or nitration of ring) ring) NO2 NO 12-133 Synthesis of p-Nitrobenzoic Acid from Toluene Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CO nitration gives m-nitrobenzoic acid CH3 CH CH3 oxidation gives p-nitrobenzoic acid NO2 NO 12-134 Synthesis of p-Nitrobenzoic Acid from Toluene Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CH3 CH CH3 HNO3 NO2 NO Na2Cr2O7, H2O H2SO4, heat H2SO4 NO2 NO 12-135 12.17 Substitution in Naphthalene 12-136 Naphthalene Naphthalene H H H 1 H 2 H H H H two sites possible for electrophilic two aromatic substitution all other sites at which substitution can occur are equivalent to 1 and 2 are 12-137 EAS in Naphthalene EAS in Naphthalene O CCH3 O CH3CCl AlCl3 90% is faster at C-1 than at C-2 is 12-138 EAS in Naphthalene EAS in Naphthalene E H E H + + when attack is at C-1 carbocation is stabilized by allylic resonance benzenoid character of other ring is maintained 12-139 EAS in Naphthalene EAS in Naphthalene EAS + E H E + H when attack is at C-2 iin order for carbocation to be stabilized by allylic n resonance, the benzenoid character of the other ring is sacrificed ring 12-140 12.18 Substitution in Heterocyclic Aromatic Compounds Heterocyclic 12-141 Generalization Generalization There is none. There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible. Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive.. 12-142 Pyridine Pyridine N Pyridine is very unreactive; it resembles nitrobenzene in its reactivity. Presence of electronegative atom (N) in ring causes π electrons to be held more strongly than causes in benzene. 12-143 Pyridine Pyridine SO3, H2SO4 N HgSO4, 230°C SO3H SO N 71% Pyridine can be sulfonated at high temperature. EAS takes place at C-3. 12-144 Pyrrole, Furan, and Thiophene Pyrrole, Furan, and Thiophene •• N •• O •• •• S •• H Have 1 less ring atom than benzene or Have pyridine to hold same number of π electrons (6). (6). π electrons are held less strongly. electrons These compounds are relatively reactive These toward EAS.. toward 12-145 Example: Furan Example: Furan OO O + CH3COCCH3 O BF3 CCH3 O 75-92% undergoes EAS readily C-2 is most reactive position 12-146 End of Chapter 12 (Part a) Dr. Wolf's CHM 201 & 202 12-150 ...
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