Chapter 12 Reactions of Arenes: Electrophilic Aromatic ...

Chapter 12 Reactions of Arenes: Electrophilic Aromatic ...

Chapter 12 Reactions of Arenes: Electrophilic Aromatic Substitution H + +E Y E +H Y 12.1 Representative Electrophilic Aromatic Substitution Reactions of Benzene H +

+E Y E +H Y H + +E Y E +H Electrophilic aromatic substitutions include: Nitration Sulfonation Halogenation Friedel-Crafts Alkylation

Friedel-Crafts Acylation Y Nitration of Benzene H + HONO2 H2SO4 NO2 + H2O Nitrobenzene (95%) Sulfonation of Benzene H heat

+ HOSO2OH SO2OH + H2O Benzenesulfonic acid (100%) Halogenation of Benzene H + Br2 FeBr3 Br + HBr Bromobenzene (65-75%)

Friedel-Crafts Alkylation of Benzene H + (CH3)3CCl AlCl3 C(CH3)3 + HCl tert-Butylbenzene (60%) Friedel-Crafts Acylation of Benzene O O AlCl3 H + CH3CH2CCl

CCH2CH3 + HCl 1-Phenyl-1-propanone (88%) 12.2 Mechanistic Principles of Electrophilic Aromatic Substitution Step 1: Attack of Electrophile by -Electron System of Aromatic Ring H H H

E+ H H H H E H H + H Highly endothermic. Carbocation is allylic, but not aromatic.

H H Step 2: Loss of a Proton from the Carbocation Intermediate H H H E H H H E H

H + BH+ + H H H B B = base Highly exothermic. This step restores aromaticity of ring. H E H

H + H H H H H + E+ H H H H

H H E + H+ H H H Based on this general mechanism: What remains is to identify the electrophile in nitration, sulfonation, halogenation, FriedelCrafts alkylation and Friedel-Crafts acylation to establish the mechanism of specific electrophilic aromatic substitutions. 12.3 Nitration of Benzene

Nitration of Benzene H + HONO2 Electrophile is nitronium ion. NO2 H2SO4 + H2O O + N

O Step 1: Attack of Nitronium Cation by -Electron System of Aromatic Ring H H H NO2+ H H H

H NO2 H H + H H H Step 2: Loss of a Proton from the Carbocation Intermediate H NO2 H

H H H NO2 H H + BH+ H + H H H

B Where Does Nitronium Ion Come from? O + N O O O

H2SO4 H H O + N O + N +O

H O + H O H 12.4 Sulfonation of Benzene Sulfonation of Benzene

SO2OH H heat + HOSO2OH + H2O Several electrophiles present: a major one is sulfur trioxide. O + S O

O Step 1: Attack of Sulfur Trioxide by -Electron System of Aromatic Ring H H H SO3 H H H

H SO3 H H + H H H Step 2: Loss of a Proton from the Carbocation Intermediate H H

SO3 H H H H SO3 H + BH+ H + H H

H B Step 3: Protonation of Benzenesulfonate Ion H H SO3 H H H H2SO4 H

H SO3H H H H 12.5 Halogenation of Benzene Halogenation of Benzene H + Br2 FeBr3

Electrophile is a Lewis acid-Lewis base complex between FeBr3 and Br2. Br + HBr The Br2-FeBr3 Complex Br Br Lewis base

+ FeBr3 Lewis acid Br + Br FeBr3 Complex The Br2-FeBr3 complex is more electrophilic than Br2 alone.

Step 1: Attack of Br2-FeBr3 Complex by -Electron System of Aromatic Ring H H H Br H H H + Br

FeBr3 H Br H H + H H H + FeBr4 Step 2: Loss of a Proton from the Carbocation Intermediate

H H Br H H H Br H H + BH+ H +

H H H B 12.6 Friedel-Crafts Alkylation of Benzene Friedel-Crafts Alkylation of Benzene H + (CH3)3CCl C(CH3)3 AlCl3 + HCl

H3C Electrophile is tert-butyl cation. H3C + C CH3 Role of AlCl3 Acts as a Lewis acid to promote ionization of the alkyl halide. (CH3)3C Cl

+ AlCl3 (CH3)3C + (CH3)3C + Cl AlCl3 + Cl

AlCl3 Step 1: Attack of tert-Butyl Cation by -Electron System of Aromatic Ring H H H + C(CH3)3 H H H

H C(CH3)3 H H + H H H Step 2: Loss of a Proton from the Carbocation Intermediate H C(CH3)3 H

H H H C(CH3)3 H H BH+ H + H H H

B Rearrangements in Friedel-Crafts Alkylation Carbocations are intermediates. Therefore, rearrangements can occur. H + (CH3)2CHCH2Cl Isobutyl chloride AlCl3 C(CH3)3 tert-Butylbenzene (66%) Rearrangements in Friedel-Crafts Alkylation Isobutyl chloride is the alkyl halide.

But tert-butyl cation is the electrophile. H + (CH3)2CHCH2Cl Isobutyl chloride AlCl3 C(CH3)3 tert-Butylbenzene (66%) Rearrangements in Friedel-Crafts Alkylation H H3C C

CH2 + Cl AlCl3 CH3 H H3C + C CH3 CH2

+ Cl AlCl3 Reactions Related to Friedel-Crafts Alkylation H + H2SO4 Cyclohexylbenzene (65-68%) Cyclohexene is protonated by sulfuric acid, giving cyclohexyl cation which is attacked by

the benzene ring. 12.7 Friedel-Crafts Acylation of Benzene Friedel-Crafts Acylation of Benzene O O CCH2CH3 AlCl3 H + CH3CH2CCl + HCl Electrophile is an acyl cation. + CH3CH2C

O CH3CH2C + O Step 1: Attack of the Acyl Cation by -Electron System of Aromatic Ring + O H H H

CCH2CH3 H H H O H CCH2CH3 H H + H H H

Step 2: Loss of a Proton from the Carbocation Intermediate O H H O CCH2CH3 H H H H CCH2CH3 H + BH+

H + H H H B Acid Anhydrides Can be used instead of acyl chlorides. O H O O + CH3COCCH3 AlCl3

CCH3 Acetophenone (76-83%) O + CH3COH 12.8 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 is called the Clemmensen reduction. Zn(Hg), HCl CH2R 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 H2NNH2 and KOH is called the Wolff-Kishner reduction. O CR H2NNH2, KOH, triethylene glycol, heat CH2R Example: Prepare Isobutylbenzene (CH3)2CHCH2Cl CH2CH(CH3)3 AlCl3 No! Friedel-Crafts alkylation of benzene using

isobutyl chloride fails because of rearrangement. Recall + (CH3)2CHCH2Cl Isobutyl chloride AlCl3 C(CH3)3 tert-Butylbenzene (66%) Use Acylation-Reduction Instead O + (CH3)2CHCCl AlCl3

Zn(Hg) HCl O CCH(CH3)2 CH2CH(CH3)2 12.9 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. 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.

Methyl Group CH3 Toluene undergoes nitration 20-25 times faster than benzene. A methyl group is an activating substituent. Trifluoromethyl Group CF3 (Trifluoromethyl)benzene undergoes nitration 40,000 times more slowly than benzene. A trifluoromethyl group is a deactivating substituent.

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. Nitration of Toluene CH3 CH3 CH3 CH3 NO2

HNO3 + acetic anhydride + NO2 NO2 63% 3% 34% o- and p-Nitrotoluene together comprise 97% of the product.

A methyl group is an ortho-para director. Nitration of (Trifluoromethyl)benzene CF3 CF3 CF3 CF3 NO2 HNO3 + H2SO4 +

NO2 NO2 6% 91% m-Nitro(trifluoromethyl)benzene comprises 91% of the product. A trifluoromethyl group is a meta director. 3% 12.10 Rate and Regioselectivity in the Nitration of Toluene Carbocation Stability Controls Regioselectivity

CH3 H + H NO2 H H CH3 H H + H H ortho

NO2 para More stable CH3 H H H H + H H H

NO2 meta Less stable 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. Ortho Nitration of Toluene CH3 H + H H NO2 H H CH3 H H

NO2 H + H H CH3 H NO2 + H H H

H The rate-determining intermediate in the ortho nitration of toluene has tertiary carbocation character. Para Nitration of Toluene CH3 H H CH3 H + H H NO2

H CH3 H H + H H + H H H NO2 This resonance form is a tertiary

carbocation. H NO2 H Para Nitration of Toluene CH3 H H CH3 H + H H

NO2 H CH3 H H + H H + H H H NO2 H

NO2 The rate-determining intermediate in the para nitration of toluene has tertiary carbocation character. H 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 of toluene have their positive charge on a secondary carbon. H NO2 Nitration of Toluene: Interpretation Rate-determining intermediates for ortho and para nitration each have a resonance form that is a tertiary carbocation. All 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. 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. 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. Nitration of Toluene vs. tert-Butylbenzene CH3 CH3 H3C 42 42 4.5 2.5 2.5 3

58 C CH3 4.5 3 75 tert-Butyl is activating and ortho-para directing. However, tert-Butyl crowds the ortho positions and decreases the rate of attack at those positions. Generalization All alkyl groups are activating and ortho-para directing. 12.11

Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene A Key Point H3C C+ F3C C+ A methyl group is electron-donating and stabilizes a carbocation. Because F is so electronegative, a CF3 group destabilizes a carbocation. Carbocation Stability Controls Regioselectivity

CF3 H + H NO2 H H CF3 H H + H H ortho

NO2 para Less stable CF3 H H H H + H H

H NO2 meta More stable 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. Ortho Nitration of (Trifluoromethyl)benzene CF3 H H + NO2 H H CF3 H H

+ NO2 H H CF3 H + H H H H One of the resonance forms of the ratedetermining intermediate in the ortho nitration of (trifluoromethyl)benzene is strongly destabilized.

NO2 H H Para Nitration of (Trifluoromethyl)benzene CF3 H H CF3 H + H H NO2 H

CF3 H H + H H + H H H NO2 This resonance form is destabilized. H

NO2 H Para Nitration of (Trifluoromethyl)benzene CF3 H H CF3 H + H H H

+ CF3 H H H H H NO2 H NO2 H One of the resonance forms of the ratedetermining intermediate in the para nitration of (trifluoromethyl)benzene is strongly destabilized. H + NO2 H 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 intermediate in the meta nitration of (trifluoromethyl)benzene have their positive charge

on the carbon that bears the CF3 group. 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. Nitration of (Trifluoromethyl)benzene: Partial Rate Factors CF3 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 (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. 12.12 Substituent Effects in Electrophilic Aromatic Substitution: Activating Substituents 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 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. Electron-Releasing Groups (ERGs) ERGs are ortho-para directing and activating. ERG

ERGs include R, Ar, and CH=CR2. Electron-Releasing Groups (ERGs) ERGs are ortho-para directing and activating. ERG ERGs such as OH and OR are strongly activating. Nitration of Phenol Occurs about 1000 times faster than nitration of benzene. OH OH OH NO2 HNO3

+ NO2 44% 56% Bromination of Anisole FeBr3 catalyst not necessary. OCH3 OCH3 Br2 acetic acid Br 90% Oxygen Lone Pair Stabilizes Intermediate

OCH3 H H + H Br OCH3 H H H

H + H Br + OCH3 H H H H H

H H Br All atoms have octets. 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. Examples O ERG =

OH OR OCR O NH2 NHR NR2 NHCR

All of these are ortho-para directing and strongly to very strongly activating. Lone Pair Stabilizes Intermediates for Ortho and Para Substitution + ERG + ERG H H H H H H

X H H H H X Comparable stabilization not possible for intermediate leading to meta substitution. 12.13 Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents ERGs Stabilize Intermediates for Ortho and Para Substitution

ERG H ERG X + H H H H H H

+ H H H X Electron-withdrawing Groups (EWGs) Destabilize 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. Many EWGs Have a Carbonyl Group Attached Directly to the Ring EWG = O O CH CR O O

COH COR O CCl 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.

Nitration of Benzaldehyde O CH O2N HNO3 H2SO4 O CH 75-84% Chlorination of Benzoyl Chloride O CCl Cl

O Cl2 CCl FeCl3 62% Disulfonation of Benzene HO3S SO3 SO3H H2SO4 90% Bromination of Nitrobenzene

Br NO2 Br2 FeBr3 NO2 60-75% 12.14 Substituent Effects in Electrophilic Aromatic Substitution: Halogens F, Cl, Br and I are ortho-para directing, but deactivating. Nitration of Chlorobenzene Cl

Cl Cl Cl NO2 HNO3 + H2SO4 + NO2 NO2 30%

1% 69% The rate of nitration of chlorobenzene is about 30 times slower than that of benzene. Nitration of Toluene vs. Chlorobenzene CH3 Cl 42 42 0.029 0.029

2.5 2.5 0.009 0.009 58 0.137 12.15 Multiple Substituent Effects The Simplest Case All possible EAS sites may be equivalent. CH3 CH3 O

O O CCH3 AlCl3 + CH3COCCH3 CH3 CH3 99% Another Straightforward Case CH3 CH3 Br Br2 FeBr3

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. Generalization Regioselectivity is controlled by the most activating substituent. Example Strongly activating

NHCH3 NHCH3 Br Br2 acetic acid Cl Cl 87% When activating effects are similar... CH3 CH3 HNO3 NO2

H2SO4 C(CH3)3 C(CH3)3 88% Substitution occurs ortho to the smaller group. Steric Effects Control Regioselectivity when Electronic Effects are Similar CH3 CH3 HNO3 CH3 H2SO4 CH3

NO2 98% Position between two substituents is last position to be substituted. 12.16 Regioselective Synthesis of Disubstituted Aromatic Compounds Factors to Consider Order of introduction of substituents to ensure correct orientation. Synthesis of m-Bromoacetophenone Br Which substituent should be

introduced first? O CCH3 Synthesis of m-Bromoacetophenone Br para (& ortho) If bromine is introduced first, p-bromoacetophenone is major product. O CCH3 meta Synthesis of m-Bromoacetophenone

Br O CCH3 O O Br2 CH3COCCH3 AlCl3 AlCl3 O CCH3 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. Synthesis of m-Nitroacetophenone NO2 Which substituent should be introduced first? O CCH3 Synthesis of m-Nitroacetophenone NO2 If NO2 is introduced first, the next step (Friedel-Crafts

acylation) fails. O CCH3 Synthesis of m-Nitroacetophenone O2N O CCH3 O O HNO3 CH3COCCH3 H2SO4 AlCl3

O CCH3 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. Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CH3 CH3

NO2 Which first? (Oxidation of methyl group or nitration of ring?) Synthesis of p-Nitrobenzoic Acid from Toluene CO2H Nitration gives m-nitrobenzoic acid. CH3 CH3 Oxidation gives p-nitrobenzoic acid. NO2

Synthesis of p-Nitrobenzoic Acid from Toluene CO2H CH3 CH3 HNO3 NO2 Na2Cr2O7, H2O H2SO4, heat H2SO4 NO2 12.17 Substitution in Naphthalene 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.

EAS in Naphthalene O CCH3 O CH3CCl AlCl3 90% Faster at C-1 than at C-2. EAS in Naphthalene E H E H

+ + When attack is at C-1, carbocation is stabilized by allylic resonance and benzenoid character of other ring is maintained. 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. 12.18 Substitution in Heterocyclic Aromatic Compounds 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. Pyridine

N Pyridine is not very reactive; it resembles nitrobenzene in its reactivity. Presence of electronegative atom (N) in ring causes electrons to be held more strongly than in benzene. Pyridine SO3, H2SO4 N HgSO4, 230C SO3H N 71% Pyridine can be sulfonated at high temperature. EAS takes place at C-3.

Pyrrole, Furan, and Thiophene N O S H Have 1 less ring atom than benzene or pyridine but have same number of electrons (6).

electrons are held less strongly than benzene. These compounds are relatively reactive toward EAS. Example: Furan O O + CH3COCCH3 O O BF3 CCH3 O 75-92% Undergoes EAS readily.

C-2 is most reactive position.

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