Chapter 12 Reactions of Arenes: Electrophilic Aromatic Substitution HE+ EY + HY ++++ ––––

12.1 Representative Electrophilic Aromatic Substitution Reactions of Benzene HE+ EY + HY ++++ ––––

HE+ EY + HY ++++ –––– Electrophilic aromatic substitutions include: NitrationSulfonationHalogenation Friedel-Crafts Alkylation Friedel-Crafts Acylation

H Nitration of Benzene + + H2OH2OH2OH2O H 2 SO 4 HONO 2 NO 2 Nitrobenzene (95%)

H Sulfonation of Benzene + + H2OH2OH2OH2O heat HOSO 2 OH SO 2 OH Benzenesulfonic acid (100%)

H Halogenation of Benzene + + HBr FeBr 3 Br 2 Br Bromobenzene (65-75%)

H Friedel-Crafts Alkylation of Benzene + + HCl AlCl 3 C(CH 3 ) 3 tert-Butylbenzene (60%) (CH 3 ) 3 CCl

H Friedel-Crafts Acylation of Benzene + + HCl AlCl 3 1-Phenyl-1-propanone (88%) O CH 3 CH 2 CCl CCH 2 CH 3 O

12.2 Mechanistic Principles of Electrophilic Aromatic Substitution

Step 1: Attack of Electrophile by  -Electron System of Aromatic Ring HH HH HH E+E+E+E+ HH H HHHE + Highly endothermic. Carbocation is allylic, but not aromatic.

Step 2: Loss of a Proton from the Carbocation Intermediate HH H H HH E + Highly exothermic. This step restores aromaticity of ring. HH HEHH + BH + B = base B

H H HH H + E + H E H HH H + H + H HH H H HH E +

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.

12.3 Nitration of Benzene

H Nitration of Benzene + + H2OH2OH2OH2O H 2 SO 4 HONO 2 NO 2 Electrophile is nitronium ion. O N O +

Step 1: Attack of Nitronium Cation by  -Electron System of Aromatic Ring HH HH HH NO 2 + HH H HHH NO 2 +

Step 2: Loss of a Proton from the Carbocation Intermediate Step 2: Loss of a Proton from the Carbocation Intermediate HH H H HH NO 2 + HH H HH + BH + B

Where Does Nitronium Ion Come from? H 2 SO 4 O N H O O + – O N H O O + –H + O N O + + H O H

12.4 Sulfonation of Benzene

H Sulfonation of Benzene + + H2OH2OH2OH2O heat HOSO 2 OH SO 2 OH 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 HH HH HH SO 3 HH H HHH SO 3 – +

Step 2: Loss of a Proton from the Carbocation Intermediate Step 2: Loss of a Proton from the Carbocation Intermediate HH H H HH SO 3 – + HH H HH + BH + B

Step 3: Protonation of Benzenesulfonate Ion HH H SO 3 – HH H 2 SO 4 HH H SO 3 H HH

12.5 Halogenation of Benzene

H Halogenation of Benzene + + HBr FeBr 3 Br 2 Br Electrophile is a Lewis acid-Lewis base complex between FeBr 3 and Br 2.

The Br 2 -FeBr 3 Complex + BrBr Lewis base Lewis acid FeBr 3 BrBr –+Complex The Br 2 -FeBr 3 complex is more electrophilic than Br 2 alone.

Step 1: Attack of Br 2 -FeBr 3 Complex by  -Electron System of Aromatic Ring HH HH HH BrBr FeBr 3 – + HH H HHHBr + + FeBr 4 –

Step 2: Loss of a Proton from the Carbocation Intermediate HH H H HH Br + HH HBrHH + BH + B

12.6 Friedel-Crafts Alkylation of Benzene

H Friedel-Crafts Alkylation of Benzene + + HCl AlCl 3 C(CH 3 ) 3 (CH 3 ) 3 CCl Electrophile is tert-butyl cation. C CH 3 H3CH3CH3CH3C H3CH3CH3CH3C+

Acts as a Lewis acid to promote ionization of the alkyl halide. Role of AlCl 3 (CH 3 ) 3 C Cl + AlCl 3 + (CH 3 ) 3 C Cl AlCl 3 – (CH 3 ) 3 C + Cl AlCl 3 – +

Step 1: Attack of tert-Butyl Cation by  -Electron System of Aromatic Ring HH HH HH HH H HHH C(CH 3 ) 3 + +

Step 2: Loss of a Proton from the Carbocation Intermediate HH H H HH C(CH 3 ) 3 + HH H HH BH + B

Rearrangements in Friedel-Crafts Alkylation Carbocations are intermediates. Therefore, rearrangements can occur. H (CH 3 ) 2 CHCH 2 Cl AlCl 3 Isobutyl chloride tert-Butylbenzene (66%) C(CH 3 ) 3 +

H Rearrangements in Friedel-Crafts Alkylation Isobutyl chloride is the alkyl halide. But tert-butyl cation is the electrophile. (CH 3 ) 2 CHCH 2 Cl AlCl 3 Isobutyl chloride tert-Butylbenzene (66%) C(CH 3 ) 3 +

Rearrangements in Friedel-Crafts Alkylation C CH 2 H3CH3CH3CH3C CH 3 HCl AlCl 3 + – C CH 2 H3CH3CH3CH3C CH 3 H + + Cl AlCl 3 –

H Reactions Related to Friedel-Crafts Alkylation H 2 SO 4 + 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

H Friedel-Crafts Acylation of Benzene + + HCl AlCl 3 O CH 3 CH 2 CCl CCH 2 CH 3 O Electrophile is an acyl cation. CH 3 CH 2 C O + O +

Step 1: Attack of the Acyl Cation by  -Electron System of Aromatic Ring HH HH HH O CCH 2 CH 3 + HH H H HH +O

Step 2: Loss of a Proton from the Carbocation Intermediate HH H HH + BH + O CCH 2 CH 3 HH H H HH +O B

Can be used instead of acyl chlorides. H Acid Anhydrides Acetophenone (76-83%) AlCl 3 O CCH 3 O CH 3 COCCH 3 O+O CH 3 COH +

12.8 Acylation-Reduction

Reduction of aldehyde and ketone carbonyl groups using Zn(Hg) and HCl is called the Clemmensen reduction. Acylation-ReductionH OCR AlCl 3 RCClO Zn(Hg), HCl CH 2 R Permits primary alkyl groups to be attached to an aromatic ring.

Reduction of aldehyde and ketone carbonyl groups by heating with H 2 NNH 2 and KOH is called the Wolff-Kishner reduction. Acylation-ReductionH OCR H 2 NNH 2, KOH, triethylene glycol, heat AlCl 3 RCClO CH 2 R Permits primary alkyl groups to be attached to an aromatic ring.

Example: Prepare Isobutylbenzene No! Friedel-Crafts alkylation of benzene using isobutyl chloride fails because of rearrangement. (CH 3 ) 2 CHCH 2 Cl AlCl 3 CH 2 CH(CH 3 ) 3

Recall (CH 3 ) 2 CHCH 2 Cl AlCl 3 Isobutyl chloride tert-Butylbenzene (66%) C(CH 3 ) 3 +

Use Acylation-Reduction Instead + (CH 3 ) 2 CHCCl O AlCl 3 O CCH(CH 3 ) 2 Zn(Hg) HCl CH 2 CH(CH 3 ) 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.

Activating substituents increase the rate of EAS compared to that of benzene. Deactivating substituents decrease the rate of EAS compared to benzene. Effect on Rate

Toluene undergoes nitration times faster than benzene. A methyl group is an activating substituent. Methyl Group CH 3

(Trifluoromethyl)benzene undergoes nitration 40,000 times more slowly than benzene. A trifluoromethyl group is a deactivating substituent. Trifluoromethyl Group CF 3

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. Effect on Regioselectivity

Nitration of Toluene CH 3 HNO 3 acetic anhydride CH 3 NO 2 CH 3 NO 2 CH 3 NO %3%63% o- and p-Nitrotoluene together comprise 97% of the product. A methyl group is an ortho-para director.

Nitration of (Trifluoromethyl)benzene CF 3 NO 2 CF 3 NO 2 CF 3 NO %91%6% m-Nitro(trifluoromethyl)benzene comprises 91% of the product. A trifluoromethyl group is a meta director. HNO 3 H 2 SO 4

12.10 Rate and Regioselectivity in the Nitration of Toluene

Carbocation Stability Controls Regioselectivity + H H H CH 3 H H NO 2 + H H H H H CH 3 + H H H H H NO 2 CH 3 ortho ortho para para meta meta More stable Less stable

Ortho Nitration of Toluene + H H H CH 3 H H NO 2 H H H CH 3 H H NO 2 + H H H CH 3 H H NO 2 + This resonance form is a tertiary carbocation.

Ortho Nitration of Toluene + H H H CH 3 H H NO 2 The rate-determining intermediate in the ortho nitration of toluene has tertiary carbocation character. H H H CH 3 H H NO 2 H H H CH 3 H H NO 2 + +

Para Nitration of Toluene This resonance form is a tertiary carbocation. H H H H H NO 2 CH H H H H H NO 2 CH 3 H H H H H NO 2 CH 3 +

Para Nitration of Toluene + H H H H H NO 2 CH 3 H H H H H NO 2 CH 3 H H H H H NO 2 CH The rate-determining intermediate in the para nitration of toluene has tertiary carbocation character.

Meta Nitration of Toluene + H H H H H NO 2 CH 3 H H H H H NO 2 CH 3 + All the resonance forms of the rate- determining intermediate in the meta nitration of toluene have their positive charge on a secondary carbon. H H H H H NO 2 CH 3 +

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.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.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.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.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 CH 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 CH tert-Butyl is activating and ortho-para directing. However, tert-Butyl crowds the ortho positions and decreases the rate of attack at those positions. CH C H3CH3CH3CH3C

All alkyl groups are activating and ortho-para directing. Generalization

12.11 Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene

A Key Point C + H3CH3CH3CH3C C + F3CF3CF3CF3C A methyl group is electron-donating and stabilizes a carbocation. Because F is so electronegative, a CF 3 group destabilizes a carbocation.

Carbocation Stability Controls Regioselectivity + H H H CF 3 H H NO 2 ortho ortho + H H H H H NO 2 CF 3 para para + H H H H H NO 2 CF 3 meta meta Less stable More stable

H H H CF 3 H H NO H H H CF 3 H H NO 2 H H H CF 3 H H NO 2 + This resonance form is destabilized. Ortho Nitration of (Trifluoromethyl)benzene

+ H H H CF 3 H H NO 2 One of the resonance forms of the rate- determining intermediate in the ortho nitration of (trifluoromethyl)benzene is strongly destabilized. H H H CF 3 H H NO 2 H H H CF 3 H H NO Ortho Nitration of (Trifluoromethyl)benzene

+ H H H H H NO 2 CF 3 H H H H H NO 2 CF 3 + H H H H H NO 2 CF 3 + This resonance form is destabilized. Para Nitration of (Trifluoromethyl)benzene

+ H H H H H NO 2 CF 3 H H H H H NO 2 CF 3 H H H H H NO 2 CF One of the resonance forms of the rate- determining intermediate in the para nitration of (trifluoromethyl)benzene is strongly destabilized. Para Nitration of (Trifluoromethyl)benzene

+ H H H H H NO 2 CF 3 H H H H H NO 2 CF 3 + 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 CF 3 group. Meta Nitration of (Trifluoromethyl)benzene H H H H H NO 2 CF 3 +

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 CF 3 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 All of the available ring positions in (trifluoromethyl)benzene are much less reactive than a single position of benzene. A CF 3 group deactivates all of the ring positions but the degree of deactivation is greatest at the ortho and para positons. CF x x x 10 -6

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

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. Generalizations

ERGs are ortho-para directing and activating. ERG ERGs include —R, —Ar, and —CH=CR 2. Electron-Releasing Groups (ERGs)

ERGs are ortho-para directing and activating. ERG ERGs such as —OH and —OR are strongly activating. Electron-Releasing Groups (ERGs)

Occurs about 1000 times faster than nitration of benzene. OH HNO 3 OH NO 2 OH + 44%56% Nitration of Phenol

FeBr 3 catalyst not necessary. OCH 3 Br 2 OCH 3 Br 90% acetic acid Bromination of Anisole

+ H H H H H Br OCH 3 H H H H H Br + H H H H H Br + Oxygen Lone Pair Stabilizes Intermediate All atoms have octets.

ERGs with a lone pair on the atom directly attached to the ring are ortho-para directing and strongly activating. ERG Electron-Releasing Groups (ERGs)

All of these are ortho-para directing and strongly to very strongly activating. Examples ERG = OH OR OCR O NH 2 NHCR O NHR NR 2

Lone Pair Stabilizes Intermediates for Ortho and Para Substitution Comparable stabilization not possible for intermediate leading to meta substitution. H H H H H X+ERG H H H H H X+ERG

12.13 Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents

ERGs Stabilize Intermediates for Ortho and Para Substitution H H H H H X + ERG H H H H H X + ERG

Electron-withdrawing Groups (EWGs) Destabilize Intermediates for Ortho and Para Substitution H H H H H X + EWG H H H H H X + EWG —CF 3 is a powerful EWG. It is strongly deactivating and meta directing.

All of these are meta directing and strongly deactivating. Many EWGs Have a Carbonyl Group Attached Directly to the Ring —EWG = O—CHO—CR O—COHO—COR O—CCl

All of these are meta directing and strongly deactivating. Other EWGs Include: —EWG = —NO 2 —SO 3 H —CN

HNO % Nitration of Benzaldehyde CHO H 2 SO 4 CH O O2NO2NO2NO2N

Cl 2 62% Chlorination of Benzoyl Chloride CClO FeCl 3 CClOCl

SO 3 90% Disulfonation of Benzene H 2 SO 4 SO 3 H HO 3 S

Br % Bromination of Nitrobenzene FeBr 3 Br NO 2

12.14 Substituent Effects in Electrophilic Aromatic Substitution: Halogens F, Cl, Br and I are ortho-para directing, but deactivating.

Nitration of Chlorobenzene Cl HNO 3 Cl NO 2 Cl Cl ++ 69%1%30% The rate of nitration of chlorobenzene is about 30 times slower than that of benzene. H 2 SO 4

Nitration of Toluene vs. Chlorobenzene CH Cl

12.15 Multiple Substituent Effects

All possible EAS sites may be equivalent. The Simplest Case CH 3 O AlCl 3 O CH 3 COCCH 3 O + CH 3 CCH 3 99%

Directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group. Another Straightforward Case CH 3 NO 2 CH 3 NO 2 Br 86-90% Br 2 FeBr 3

Generalization Regioselectivity is controlled by the most activating substituent.

Example NHCH 3 Cl Br 2 87% acetic acid NHCH 3 Cl Br Strongly activating

Substitution occurs ortho to the smaller group. When activating effects are similar... CH 3 C(CH 3 ) 3 CH 3 C(CH 3 ) 3 NO 2 HNO 3 H 2 SO 4 88%

Position between two substituents is last position to be substituted. Steric Effects Control Regioselectivity when Electronic Effects are Similar CH 3 HNO 3 H 2 SO 4 98% NO 2 CH 3

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 CCH 3 O Which substituent should be introduced first?

Synthesis of m-Bromoacetophenone Br CCH 3 Opara (& ortho) meta If bromine is introduced first, p-bromoacetophenone is major product.

Synthesis of m-Bromoacetophenone CCH 3 O O CH 3 COCCH 3 O AlCl 3 Br 2 AlCl 3 CCH 3 OBr

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 NO 2 CCH 3 O Which substituent should be introduced first?

Synthesis of m-Nitroacetophenone NO 2 CCH 3 O If NO 2 is introduced first, the next step (Friedel-Crafts acylation) fails.

Synthesis of m-Nitroacetophenone CCH 3 O O CH 3 COCCH 3 O AlCl 3 HNO 3 H 2 SO 4 CCH 3 O O2NO2NO2NO2N

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 Which first? (Oxidation of methyl group or nitration of ring?) CH 3 CO 2 H NO 2 CH 3

Synthesis of p-Nitrobenzoic Acid from Toluene CH 3 CO 2 H NO 2 CH 3 Nitration gives m-nitrobenzoic acid. Oxidation gives p-nitrobenzoic acid.

Synthesis of p-Nitrobenzoic Acid from Toluene CH 3 NO 2 CH 3 HNO 3 H 2 SO 4 NO 2 CO 2 H Na 2 Cr 2 O 7, H 2 O H 2 SO 4, heat

12.17 Substitution in Naphthalene

Two sites possible for electrophilic aromatic substitution. All other sites at which substitution can occur are equivalent to 1 and 2. Naphthalene 1 2 HH HH HH HH

EAS in Naphthalene AlCl 3 O CH 3 CCl 90% CCH 3 O Faster at C-1 than at C-2.

EAS in Naphthalene When attack is at C-1, carbocation is stabilized by allylic resonance and benzenoid character of other ring is maintained. E H E H + +

EAS in Naphthalene 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. E H +EH +

12.18 Substitution in Heterocyclic Aromatic Compounds

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. Generalization

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 N

Pyridine can be sulfonated at high temperature. EAS takes place at C-3. Pyridine N SO 3, H 2 SO 4 HgSO 4, 230°C SO 3 H N 71%

Pyrrole, Furan, and Thiophene O S N 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.

Undergoes EAS readily. C-2 is most reactive position. Example: Furan BF 3 O CH 3 COCCH 3 O+ CCH 3 O75-92% O O