Chapter 12 (Part a) Reactions of Arenes: Electrophilic Aromatic Substitution + Y d+ d– Dr. Wolf's CHM 201 & 202 12-1 1

Representative Electrophilic Aromatic Substitution Reactions of Benzene + Y d+ d– Dr. Wolf's CHM 201 & 202 12-2 3

Electrophilic aromatic substitutions include: + Y d+ d– Electrophilic aromatic substitutions include: Nitration Sulfonation Halogenation Friedel-Crafts Alkylation Friedel-Crafts Acylation Dr. Wolf's CHM 201 & 202 12-3 5

Table 12.1: Nitration of Benzene H H2SO4 NO2 + HONO2 + H2O Nitrobenzene (95%) Dr. Wolf's CHM 201 & 202 12-4 6

Table 12.1: Sulfonation of Benzene H heat SO2OH + HOSO2OH + H2O Benzenesulfonic acid (100%) Dr. Wolf's CHM 201 & 202 12-5 6

Table 12.1: Halogenation of Benzene FeBr3 Br + Br2 + HBr Bromobenzene (65-75%) Dr. Wolf's CHM 201 & 202 12-6 6

Table 12.1: Friedel-Crafts Alkylation of Benzene H AlCl3 C(CH3)3 + (CH3)3CCl + HCl tert-Butylbenzene (60%) Dr. Wolf's CHM 201 & 202 12-7 6

Table 12.1: Friedel-Crafts Acylation of Benzene CCH2CH3 O O CH3CH2CCl H AlCl3 + + HCl 1-Phenyl-1-propanone (88%) Dr. Wolf's CHM 201 & 202 12-8 6

Mechanistic Principles of Electrophilic Aromatic Substitution Dr. Wolf's CHM 201 & 202 12-9 11

Step 1: attack of electrophile on p-electron system of aromatic ring + highly endothermic carbocation is allylic, but not aromatic Dr. Wolf's CHM 201 & 202 12-10 12

Step 2: loss of a proton from the carbocation intermediate + H H H H H H+ highly exothermic this step restores aromaticity of ring Dr. Wolf's CHM 201 & 202 12-11 12

H E + H + E+ E H + H+ Dr. Wolf's CHM 201 & 202 12-12 6

Based on this general mechanism: what remains is to identify the electrophile in nitration, sulfonation, halogenation, Friedel-Crafts alkylation, and Friedel-Crafts acylation to establish the mechanism of specific electrophilic aromatic substitutions Dr. Wolf's CHM 201 & 202 12-13 14

Nitration of Benzene Dr. Wolf's CHM 201 & 202 12-14 15

Electrophile is nitronium ion Nitration of Benzene H H2SO4 NO2 + HONO2 + H2O O N •• + • Electrophile is nitronium ion Dr. Wolf's CHM 201 & 202 12-15 6

Step 1: attack of nitronium cation on p-electron system of aromatic ring H NO2+ H NO2 + Dr. Wolf's CHM 201 & 202 12-16 12

Step 2: loss of a proton from the carbocation intermediate NO2 H H H H NO2 + H H H H H H+ Dr. Wolf's CHM 201 & 202 12-17 12

Where does nitronium ion come from? + •• • – O N H + •• • – H2SO4 H O •• O N •• + • + Dr. Wolf's CHM 201 & 202 12-18 21

Sulfonation of Benzene Dr. Wolf's CHM 201 & 202 12-19 22

Sulfonation of Benzene H heat SO2OH + HOSO2OH + H2O O S + •• • – Several electrophiles present: a major one is sulfur trioxide Dr. Wolf's CHM 201 & 202 12-20 6

Step 1: attack of sulfur trioxide on p-electron system of aromatic ring H SO3 H SO3– + Dr. Wolf's CHM 201 & 202 12-21 12

Step 2: loss of a proton from the carbocation intermediate + H H H H H H+ Dr. Wolf's CHM 201 & 202 12-22 12

Step 3: protonation of benzenesulfonate ion H SO3– H2SO4 H SO3H Dr. Wolf's CHM 201 & 202 12-23 12

Halogenation of Benzene Dr. Wolf's CHM 201 & 202 12-24 24

Halogenation of Benzene FeBr3 Br + Br2 + HBr Electrophile is a Lewis acid-Lewis base complex between FeBr3 and Br2. Dr. Wolf's CHM 201 & 202 12-25 6

The Br2-FeBr3 complex is more electrophilic than Br2 alone. • •• FeBr3 – + • Br •• + FeBr3 Lewis base Lewis acid Complex The Br2-FeBr3 complex is more electrophilic than Br2 alone. Dr. Wolf's CHM 201 & 202 12-26 21

Step 1: attack of Br2-FeBr3 complex on p-electron system of aromatic ring + – Br Br FeBr3 H Br + H H H H H H + FeBr4– Dr. Wolf's CHM 201 & 202 12-27 12

Step 2: loss of a proton from the carbocation intermediate Br H H H H Br + H H H H H H+ Dr. Wolf's CHM 201 & 202 12-28 12

Friedel-Crafts Alkylation of Benzene Dr. Wolf's CHM 201 & 202 12-29 27

Friedel-Crafts Alkylation of Benzene H AlCl3 C(CH3)3 + (CH3)3CCl + HCl C CH3 H3C + Electrophile is tert-butyl cation Dr. Wolf's CHM 201 & 202 12-30 6

acts as a Lewis acid to promote ionization of the alkyl halide Role of AlCl3 acts as a Lewis acid to promote ionization of the alkyl halide + (CH3)3C Cl •• AlCl3 – •• (CH3)3C • Cl + AlCl3 •• Dr. Wolf's CHM 201 & 202 12-31 29

acts as a Lewis acid to promote ionization of the alkyl halide Role of AlCl3 acts as a Lewis acid to promote ionization of the alkyl halide + (CH3)3C Cl •• AlCl3 – •• (CH3)3C • Cl + AlCl3 •• + Cl •• AlCl3 – • (CH3)3C + Dr. Wolf's CHM 201 & 202 12-32 29

Step 1: attack of tert-butyl cation on p-electron system of aromatic ring C(CH3)3 + H C(CH3)3 + H H H H H H Dr. Wolf's CHM 201 & 202 12-33 12

Step 2: loss of a proton from the carbocation intermediate C(CH3)3 H H H H C(CH3)3 + H H H H H H+ Dr. Wolf's CHM 201 & 202 12-34 12

Rearrangements in Friedel-Crafts Alkylation Carbocations are intermediates. Therefore, rearrangements can occur H C(CH3)3 AlCl3 + (CH3)2CHCH2Cl Isobutyl chloride tert-Butylbenzene (66%) Dr. Wolf's CHM 201 & 202 12-35 34

Rearrangements in Friedel-Crafts Alkylation Isobutyl chloride is the alkyl halide. But tert-butyl cation is the electrophile. H C(CH3)3 AlCl3 + (CH3)2CHCH2Cl Isobutyl chloride tert-Butylbenzene (66%) Dr. Wolf's CHM 201 & 202 12-36 34

Rearrangements in Friedel-Crafts Alkylation CH2 H3C CH3 H Cl •• AlCl3 + – H + Cl •• AlCl3 – • H3C C + CH2 CH3 Dr. Wolf's CHM 201 & 202 12-37 35

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 Dr. Wolf's CHM 201 & 202 12-38 38

Friedel-Crafts Acylation of Benzene Dr. Wolf's CHM 201 & 202 12-39 39

Friedel-Crafts Acylation of Benzene H AlCl3 CCH2CH3 + CH3CH2CCl + HCl Electrophile is an acyl cation •• CH3CH2C O • + CH3CH2C O • + Dr. Wolf's CHM 201 & 202 12-40 6

Step 1: attack of the acyl cation on p-electron system of aromatic ring CCH2CH3 + O CCH2CH3 H H H H H H H + H H H H H Dr. Wolf's CHM 201 & 202 12-41 12

Step 2: loss of a proton from the carbocation intermediate CCH2CH3 O CCH2CH3 H H H H H H + H H H H H H+ Dr. Wolf's CHM 201 & 202 12-42 12

can be used instead of acyl chlorides O Acid Anhydrides can be used instead of acyl chlorides O CCH3 O CH3COCCH3 H AlCl3 + Acetophenone (76-83%) O CH3COH + Dr. Wolf's CHM 201 & 202 12-43 43

Acylation-Reduction Dr. Wolf's CHM 201 & 202 12-44 4 4

permits primary alkyl groups to be attached to an aromatic ring Acylation-Reduction permits primary alkyl groups to be attached to an aromatic ring O CR O H RCCl AlCl3 Zn(Hg), HCl Reduction of aldehyde and ketone carbonyl groups using Zn(Hg) and HCl is called the Clemmensen reduction. CH2R Dr. Wolf's CHM 201 & 202 12-45 45

permits primary alkyl groups to be attached to an aromatic ring Acylation-Reduction permits primary alkyl groups to be attached to an aromatic ring O CR O H RCCl H2NNH2, KOH, triethylene glycol, heat AlCl3 Reduction of aldehyde and ketone carbonyl groups by heating with H2NNH2 and KOH is called the Wolff-Kishner reduction. CH2R Dr. Wolf's CHM 201 & 202 12-46 45

Example: Prepare isobutylbenzene (CH3)2CHCH2Cl CH2CH(CH3)2 AlCl3 No! Friedel-Crafts alkylation of benzene using isobutyl chloride fails because of rearrangement. Dr. Wolf's CHM 201 & 202 12-47 46

tert-Butylbenzene (66%) Recall C(CH3)3 AlCl3 + (CH3)2CHCH2Cl Isobutyl chloride tert-Butylbenzene (66%) Dr. Wolf's CHM 201 & 202 12-48 34

Use Acylation-Reduction Instead (CH3)2CHCCl O + AlCl3 CH2CH(CH3)2 Zn(Hg) HCl O CCH(CH3)2 Dr. Wolf's CHM 201 & 202 12-49 34

Rate and Regioselectivity in Electrophilic Aromatic Substitution A substituent already present on the ring can affect both the rate and regioselectivity of electrophilic aromatic substitution. Dr. Wolf's CHM 201 & 202 12-50 1

Effect on Rate Activating substituents increase the rate of EAS compared to that of benzene. Deactivating substituents decrease the rate of EAS compared to benzene. Dr. Wolf's CHM 201 & 202 12-51 2

Toluene undergoes nitration 20-25 times faster than benzene. Methyl Group Toluene undergoes nitration 20-25 times faster than benzene. A methyl group is an activating substituent. CH3 Dr. Wolf's CHM 201 & 202 12-52 3

Trifluoromethyl Group (Trifluoromethyl)benzene undergoes nitration 40,000 times more slowly than benzene . A trifluoromethyl group is a deactivating substituent. CF3 Dr. Wolf's CHM 201 & 202 12-53 3

Effect on Regioselectivity Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves. Meta directors direct an incoming electrophile to positions meta to themselves. Dr. Wolf's CHM 201 & 202 12-54 5

o- and p-nitrotoluene together comprise 97% of the product Nitration of Toluene CH3 NO2 CH3 NO2 CH3 NO2 CH3 HNO3 acetic anhydride + + 63% 3% 34% o- and p-nitrotoluene together comprise 97% of the product a methyl group is an ortho-para director Dr. Wolf's CHM 201 & 202 12-55 6

Nitration of (Trifluoromethyl)benzene CF3 NO2 CF3 NO2 CF3 NO2 CF3 HNO3 H2SO4 + + 6% 91% 3% m-nitro(trifluoromethyl)benzene comprises 91% of the product a trifluoromethyl group is a meta director Dr. Wolf's CHM 201 & 202 12-56 6

Rate and Regioselectivity in the Nitration of Toluene Dr. Wolf's CHM 201 & 202 12-57 8

Carbocation Stability Controls Regioselectivity + H CH3 NO2 + H NO2 CH3 + H NO2 CH3 gives ortho gives para gives meta Dr. Wolf's CHM 201 & 202 12-58 10

Carbocation Stability Controls Regioselectivity + H CH3 NO2 + H NO2 CH3 + H NO2 CH3 gives ortho gives para gives meta more stable less stable Dr. Wolf's CHM 201 & 202 12-59 10

ortho Nitration of Toluene CH3 + NO2 H H H H H Dr. Wolf's CHM 201 & 202 12-60 12

ortho Nitration of Toluene CH3 CH3 + NO2 NO2 H H H H + H H H H H H Dr. Wolf's CHM 201 & 202 12-61 12

ortho Nitration of Toluene CH3 CH3 CH3 + NO2 NO2 NO2 H H H + H H H + H H H H H H H H H this resonance form is a tertiary carbocation Dr. Wolf's CHM 201 & 202 12-62 12

ortho Nitration of Toluene CH3 CH3 CH3 + NO2 NO2 NO2 H H H + H H H + H H H H H H H H H the rate-determining intermediate in the ortho nitration of toluene has tertiary carbocation character Dr. Wolf's CHM 201 & 202 12-63 12

para Nitration of Toluene + H NO2 CH3 Dr. Wolf's CHM 201 & 202 12-64 12

para Nitration of Toluene H NO2 CH3 H NO2 CH3 + + this resonance form is a tertiary carbocation Dr. Wolf's CHM 201 & 202 12-65 12

para Nitration of Toluene H NO2 CH3 H NO2 CH3 H NO2 CH3 + + + this resonance form is a tertiary carbocation Dr. Wolf's CHM 201 & 202 12-66 12

para Nitration of Toluene H NO2 CH3 H NO2 CH3 H NO2 CH3 + + + the rate-determining intermediate in the para nitration of toluene has tertiary carbocation character Dr. Wolf's CHM 201 & 202 12-67 12

meta Nitration of Toluene H NO2 CH3 + Dr. Wolf's CHM 201 & 202 12-68 14

meta Nitration of Toluene H NO2 CH3 H NO2 CH3 + + Dr. Wolf's CHM 201 & 202 12-69 14

meta Nitration of Toluene H NO2 CH3 H NO2 CH3 H NO2 CH3 + + + all the resonance forms of the rate-determining intermediate in the meta nitration of toluene have their positive charge on a secondary carbon Dr. Wolf's CHM 201 & 202 12-70 14

Nitration of Toluene: Interpretation The rate-determining intermediates for ortho and 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. Tertiary carbocations, being more stable, are 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. Dr. Wolf's CHM 201 & 202 12-71 15

Nitration of Toluene: Partial Rate Factors The experimentally determined reaction rate can be combined with the ortho/meta/para distribution to give partial rate factors for substitution at the various ring positions. Expressed as a numerical value, a partial rate 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. Dr. Wolf's CHM 201 & 202 12-72 15

Nitration of Toluene: Partial Rate Factors CH3 1 1 1 42 42 1 1 2.5 2.5 1 58 All of the available ring positions in toluene are more reactive than a single position of benzene. A methyl group activates all of the ring positions but the effect is greatest at the ortho and para positons. Steric hindrance by the methyl group makes each ortho position slightly less reactive than para. Dr. Wolf's CHM 201 & 202 12-73 15

Nitration of Toluene vs. tert-Butylbenzene CH3 75 3 4.5 C H3C CH3 42 2.5 58 tert-Butyl is activating and ortho-para directing tert-Butyl crowds the ortho positions and decreases the rate of attack at those positions. Dr. Wolf's CHM 201 & 202 12-74 15

all alkyl groups are activating and ortho-para directing Generalization all alkyl groups are activating and ortho-para directing Dr. Wolf's CHM 201 & 202 12-75 17

Theory of Directing Effects

Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene Dr. Wolf's CHM 201 & 202 12-76 8

A methyl group is electron-donating and stabilizes a carbocation. A Key Point C + H3C C + F3C A methyl group is electron-donating and stabilizes a carbocation. Because F is so electronegative, a CF3 group destabilizes a carbocation. Dr. Wolf's CHM 201 & 202 12-77 17

Carbocation Stability Controls Regioselectivity + H CF3 NO2 + H NO2 CF3 + H NO2 CF3 gives ortho gives para gives meta Dr. Wolf's CHM 201 & 202 12-78 10

Carbocation Stability Controls Regioselectivity + H CF3 NO2 + H NO2 CF3 + H NO2 CF3 gives ortho gives para gives meta less stable more stable Dr. Wolf's CHM 201 & 202 12-79 10

ortho Nitration of (Trifluoromethyl)benzene CF3 + NO2 H H H H H Dr. Wolf's CHM 201 & 202 12-80 12

ortho Nitration of (Trifluoromethyl)benzene CF3 CF3 + NO2 NO2 H H H H + H H H H H H Dr. Wolf's CHM 201 & 202 12-81 12

ortho Nitration of (Trifluoromethyl)benzene CF3 CF3 CF3 + NO2 NO2 NO2 H H H + H H H + H H H H H H H H H this resonance form is destabilized Dr. Wolf's CHM 201 & 202 12-82 12

ortho Nitration of (Trifluoromethyl)benzene CF3 CF3 CF3 + NO2 NO2 NO2 H H H + H H H + H H H H H H H H H one of the resonance forms of the rate-determining intermediate in the ortho nitration of (trifluoromethyl)benzene is strongly destabilized Dr. Wolf's CHM 201 & 202 12-83 12

para Nitration of (Trifluoromethyl)benzene + H NO2 CF3 Dr. Wolf's CHM 201 & 202 12-84 12

para Nitration of (Trifluoromethyl)benzene CF3 H NO2 CF3 + + this resonance form is destabilized Dr. Wolf's CHM 201 & 202 12-85 12

para Nitration of (Trifluoromethyl)benzene CF3 H NO2 CF3 H NO2 CF3 + + + this resonance form is destabilized Dr. Wolf's CHM 201 & 202 12-86 12

para Nitration of (Trifluoromethyl)benzene CF3 H NO2 CF3 H NO2 CF3 + + + one of the resonance forms of the rate-determining intermediate in the para nitration of (trifluoromethyl)benzene is strongly destabilized Dr. Wolf's CHM 201 & 202 12-87 12

meta Nitration of (Trifluoromethyl)benzene CF3 + Dr. Wolf's CHM 201 & 202 12-88 14

meta Nitration of (Trifluoromethyl)benzene CF3 H NO2 CF3 + + Dr. Wolf's CHM 201 & 202 12-89 14

meta Nitration of (Trifluoromethyl)benzene CF3 H NO2 CF3 H NO2 CF3 + + + none of the resonance forms of the rate-determining intermediate in the meta nitration of (trifluoromethyl)benzene have their positive charge on the carbon that bears the CF3 group Dr. Wolf's CHM 201 & 202 12-90 14

Nitration of (Trifluoromethyl)benzene: Interpretation The rate-determining intermediates for ortho and 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 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. Dr. Wolf's CHM 201 & 202 12-91 15

Nitration of (Trifluoromethyl)benzene: Partial Rate Factors CF3 4.5 x 10-6 67 x 10-6 All of the available ring positions in (trifluoromethyl)benzene are much less reactive than a single position of benzene. A CF3 group deactivates all of the ring positions but the degree of deactivation is greatest at the ortho and para positons. Dr. Wolf's CHM 201 & 202 12-92 15

Theory of Directing Effects

Substituent Effects in Electrophilic Aromatic Substitution: Activating Substituents Dr. Wolf's CHM 201 & 202 12-93 8

Very strongly activating Strongly activating Activating Table 12.2 Classification of Substituents in Electrophilic Aromatic Substitution Reactions Very strongly activating Strongly activating Activating Standard of comparison is H Deactivating Strongly deactivating Very strongly deactivating Dr. Wolf's CHM 201 & 202 12-94 1

1. All activating substituents are ortho-para directors. Generalizations 1. All activating substituents are ortho-para directors. 2. Halogen substituents are slightly deactivating but ortho-para directing. 3. Strongly deactivating substituents are meta directors. Dr. Wolf's CHM 201 & 202 12-95 23

Electron-Releasing Groups (ERGs) are ortho-para directing and activating ERG ERGs include —R, —Ar, and —C=C Dr. Wolf's CHM 201 & 202 12-96 25

Electron-Releasing Groups (ERGs) are ortho-para directing and strongly activating ERG ERGs such as —OH, and —OR are strongly activating Dr. Wolf's CHM 201 & 202 12-97 25

occurs about 1000 times faster than nitration of benzene Nitration of Phenol occurs about 1000 times faster than nitration of benzene OH OH NO2 OH NO2 HNO3 + 44% 56% Dr. Wolf's CHM 201 & 202 12-98 26

Bromination of Anisole FeBr3 catalyst not necessary OCH3 OCH3 Br Br2 acetic acid 90% Dr. Wolf's CHM 201 & 202 12-99 26

Oxygen Lone Pair Stabilizes Intermediate OCH3 •• • H Br + OCH3 •• • •• H Br + OCH3 + H H H H H Br all atoms have octets Dr. Wolf's CHM 201 & 202 12-100 26

Electron-Releasing Groups (ERGs) • ERG ERGs with a lone pair on the atom directly attached to the ring are ortho-para directing and strongly activating Dr. Wolf's CHM 201 & 202 12-101 25

Examples O OH OR OCR ERG = NHCR O NH2 NHR NR2 •• OR • •• OCR • •• ERG = • • NHCR • O • NH2 • NHR • NR2 All of these are ortho-para directing and strongly to very strongly activating Dr. Wolf's CHM 201 & 202 12-102 25

Lone Pair Stabilizes Intermediates for ortho and para Substitution X + ERG H X + ERG comparable stabilization not possible for intermediate leading to meta substitution Dr. Wolf's CHM 201 & 202 12-103 26

Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents Dr. Wolf's CHM 201 & 202 12-104 8

ERGs Stabilize Intermediates for ortho and para Substitution X + ERG • H X + ERG • Dr. Wolf's CHM 201 & 202 12-105 26

—CF3 is a powerful EWG. It is strongly deactivating and meta directing Electron-withdrawing Groups (EWGs) Destabilize Intermediates for ortho and para Substitution EWG EWG X H H H + + H H H H H H X H —CF3 is a powerful EWG. It is strongly deactivating and meta directing Dr. Wolf's CHM 201 & 202 12-106 26

Many EWGs Have a Carbonyl Group Attached Directly to the Ring —CR —EWG = O —COH O —COR O —CCl All of these are meta directing and strongly deactivating Dr. Wolf's CHM 201 & 202 12-107 25

All of these are meta directing and strongly deactivating Other EWGs Include: —EWG = —NO2 —SO3H —C N All of these are meta directing and strongly deactivating Dr. Wolf's CHM 201 & 202 12-108 25

Nitration of Benzaldehyde CH O O2N CH O HNO3 H2SO4 75-84% Dr. Wolf's CHM 201 & 202 12-109 26

Problem 12.14(a); page 468 Cl O O Cl2 CCl CCl FeCl3 62% 12-110 26 Dr. Wolf's CHM 201 & 202 12-110 26

Disulfonation of Benzene HO3S SO3 SO3H H2SO4 90% Dr. Wolf's CHM 201 & 202 12-111 26

Bromination of Nitrobenzene Fe 60-75% Dr. Wolf's CHM 201 & 202 12-112 26

Substituent Effects in Electrophilic Aromatic Substitution: Halogens F, Cl, Br, and I are ortho-para directing, but deactivating Dr. Wolf's CHM 201 & 202 12-113 8

Nitration of Chlorobenzene Cl NO2 Cl NO2 Cl NO2 Cl HNO3 + + H2SO4 30% 1% 69% The rate of nitration of chlorobenzene is about 30 times slower than that of benzene. Dr. Wolf's CHM 201 & 202 12-114 6

Nitration of Toluene vs. Chlorobenzene 42 2.5 58 Cl 0.029 0.029 0.009 0.009 0.137 Dr. Wolf's CHM 201 & 202 12-115 15

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 41 41 41

Multiple Substituent Effects Dr. Wolf's CHM 201 & 202 12-116 1

all possible EAS sites may be equivalent The Simplest Case all possible EAS sites may be equivalent CH3 CH3 O O CH3COCCH3 CCH3 AlCl3 + CH3 99% Dr. Wolf's CHM 201 & 202 12-117 2

Another Straightforward Case CH3 NO2 CH3 Br Br2 Fe NO2 86-90% directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group Dr. Wolf's CHM 201 & 202 12-118 2

regioselectivity is controlled by the most activating substituent Generalization regioselectivity is controlled by the most activating substituent Dr. Wolf's CHM 201 & 202 12-119 6

all possible EAS sites may not be equivalent The Simplest Case all possible EAS sites may not be equivalent strongly activating NHCH3 Cl NHCH3 Cl Br Br2 acetic acid 87% Dr. Wolf's CHM 201 & 202 12-120 2

When activating effects are similar... CH3 C(CH3)3 CH3 HNO3 H2SO4 NO2 C(CH3)3 88% substitution occurs ortho to the smaller group Dr. Wolf's CHM 201 & 202 12-121 5

position between two substituents is last position to be substituted Steric effects control regioselectivity when electronic effects are similar CH3 NO2 CH3 HNO3 H2SO4 98% position between two substituents is last position to be substituted Dr. Wolf's CHM 201 & 202 12-122 5

Regioselective Synthesis of Disubstituted Aromatic Compounds Dr. Wolf's CHM 201 & 202 12-123 7

order of introduction of substituents to ensure correct orientation Factors to Consider order of introduction of substituents to ensure correct orientation Dr. Wolf's CHM 201 & 202 12-124 6

Synthesis of m-Bromoacetophenone Which substituent should be introduced first? CCH3 O Dr. Wolf's CHM 201 & 202 12-125 8

Synthesis of m-Bromoacetophenone para If bromine is introduced first, p-bromoacetophenone is major product. CCH3 O meta Dr. Wolf's CHM 201 & 202 12-126 8

Synthesis of m-Bromoacetophenone CCH3 O Br O CH3COCCH3 Br2 AlCl3 CCH3 O AlCl3 Dr. Wolf's CHM 201 & 202 12-127 8

order of introduction of substituents to ensure correct orientation Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics Dr. Wolf's CHM 201 & 202 12-128 6

Synthesis of m-Nitroacetophenone Which substituent should be introduced first? CCH3 O Dr. Wolf's CHM 201 & 202 12-129 8

Synthesis of m-Nitroacetophenone If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails. CCH3 O Dr. Wolf's CHM 201 & 202 12-130 8

Synthesis of m-Nitroacetophenone CCH3 O O CH3COCCH3 HNO3 H2SO4 CCH3 O AlCl3 Dr. Wolf's CHM 201 & 202 12-131 8

order of introduction of substituents to ensure correct orientation Factors to Consider order of introduction of substituents to ensure correct orientation Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics sometimes electrophilic aromatic substitution must be combined with a functional group transformation Dr. Wolf's CHM 201 & 202 12-132 6

Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CH3 Which first? (oxidation of methyl group or nitration of ring) NO2 CH3 Dr. Wolf's CHM 201 & 202 12-133 8

Synthesis of p-Nitrobenzoic Acid from Toluene CO2H nitration gives m-nitrobenzoic acid CH3 NO2 CH3 oxidation gives p-nitrobenzoic acid Dr. Wolf's CHM 201 & 202 12-134 8

Synthesis of p-Nitrobenzoic Acid from Toluene NO2 CO2H CH3 NO2 CH3 HNO3 Na2Cr2O7, H2O H2SO4, heat H2SO4 Dr. Wolf's CHM 201 & 202 12-135 8

Substitution in Naphthalene Dr. Wolf's CHM 201 & 202 12-136 1

two sites possible for electrophilic aromatic substitution Naphthalene H H 1 H H 2 H H H H two sites possible for electrophilic aromatic substitution all other sites at which substitution can occur are equivalent to 1 and 2 Dr. Wolf's CHM 201 & 202 12-137 2

is faster at C-1 than at C-2 EAS in Naphthalene CCH3 O O CH3CCl AlCl3 90% is faster at C-1 than at C-2 Dr. Wolf's CHM 201 & 202 12-138 2

carbocation is stabilized by allylic resonance 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 Dr. Wolf's CHM 201 & 202 12-139 2

EAS in Naphthalene E H + E H + when attack is at C-2 in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is sacrificed Dr. Wolf's CHM 201 & 202 12-140 2

Substitution in Heterocyclic Aromatic Compounds Dr. Wolf's CHM 201 & 202 12-141 1

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.. Dr. Wolf's CHM 201 & 202 12-142 2

Pyridine N Pyridine is very unreactive; it resembles nitrobenzene in its reactivity. Presence of electronegative atom (N) in ring causes p electrons to be held more strongly than in benzene. Dr. Wolf's CHM 201 & 202 12-143 2

Pyridine can be sulfonated at high temperature. SO3, H2SO4 SO3H N N HgSO4, 230°C 71% Pyridine can be sulfonated at high temperature. EAS takes place at C-3. Dr. Wolf's CHM 201 & 202 12-144 2

Pyrrole, Furan, and Thiophene •• O •• S •• Have 1 less ring atom than benzene or pyridine to hold same number of p electrons (6). p electrons are held less strongly. These compounds are relatively reactive toward EAS.. Dr. Wolf's CHM 201 & 202 12-145 31

undergoes EAS readily C-2 is most reactive position Example: Furan O CH3COCCH3 O BF3 + CCH3 O O 75-92% undergoes EAS readily C-2 is most reactive position Dr. Wolf's CHM 201 & 202 12-146 2

End of Chapter 12 (Part a) Dr. Wolf's CHM 201 & 202