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Chapter 12: Reactions of Arenes: Electrophilic Aromatic Substitution 12.1: Representative Electrophilic Aromatic Substitution Reactions of

E= -Cl, -Br, -I (halogenation)

-NO2 (nitration) -SO3H (sulfonation) (Table 12.1) -R () () 275

12.2: Mechanistic Principles of Electrophilic Aromatic Substitution

Recall the electophilic addition of HBr (or Br2) to (Ch. 6)

H H Br + H Br + Br

Most aromatic rings (benzene) are not sufficiently nucleophilic to react with . Catalysts are often needed to increase the reactivity of the electrophiles.

Mechanism: a π-bond of benzene acts as a nucleophile and “attacks” the electrophile leading to a stabilized cyclohexadienyl . Loss of a proton gives the substitution product and restores .

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1 H H H + E-X H H H

H H H H E E E H E H H H H H HX + H + X H H H H H H H X X H H H H

Electrophilic substitution: Resonance stabilized : product regains cyclohexadienyl cation products lose aromatic stabilization intermediate aromatic stabilization Aromaticity is worth ~ 130-150 KJ/mol

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12.3: Nitration of Benzene O HNO , H SO N 3 2 4 O

H2O

O O O HO N N + H2SO4 H2O N + H2O O O O

Nitric Nitronium pKa~ -1.3 pKa~ -2.0

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2 12.4: Sulfonation of Benzene O O S analogue of SO3, H2SO4 OH a carboxylic H2O Benzene

O O - O S + H2SO4 HO S + HSO4 O O

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12.5: Halogenation of Benzene

Cl2, FeCl3 Cl

Br Br2, FeBr3

I I2, CuCl2

For X= Cl or Br !+ !- X X FeX3 X X FeX

2+ + + I2 + Cu 2 I + 2 Cu

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3 12.6: Friedel-Crafts Alkylation of Benzene

Cl AlCl3 + + HCl

halide (electroiphile)

+ AlCl Cl AlCl3 4 strong Lewis acid carbocation

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Since the Friedel-Crafts alkylation goes through a carbocation intermediate, skeletal rearrangements of the alkyl halide are common

AlCl + Cl 3 +

(not observed)

AlCl3 + Cl +

(65 %) (35 %)

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4 alkyl halide: halide = F, Cl, Br, I must be an alkyl halide; vinyl and halides do not react the aromatic substrate: can not have strong withdrawing , nor an amino group

Y Y ≠ NO2, C≡N, -SO3H O (R= , , carboxylic acids, R ) + -NH2, NHR, NR2, -N R3,

F-C alkylation is often difficult to stop after one alkylation reaction

AlCl3 (H3C)3C-Cl + (H3C)3C-Cl AlCl3 initial product is more reactive major product than benzene 283

12.7: Friedel-Crafts Acylation of Benzene O C O R O AlCl3 R + C Cl R

O O O + AlCl C 3 C AlCl4 R Cl C R R

The acylated product is less reactive than benzene toward electrophilic aromatic substitution. F-C acylation can be

stopped after one acyl group is added 284

5 12.8: Synthesis of Alkylbenzenes by Acylation-Reduction and can be reduced to the with: Zn(Hg), HCl (Clemmensen Reduction)

H2NNH2, KOH (Wolff-Kishner Reduction)

O Zn(Hg), HCl -or-

H2NNH2, KOH Aryl Ketone

Cl + + + AlCl3

O O Zn(Hg), HCl Cl -or-

AlCl3 H2NNH2, KOH

Rearrangements and multiple are not observed for the F-C acylation 285

12.9: Rate and Regioselectivity in Electrophilic Aromatic Substitution - The nature of a already present on the benzene ring affects the rate and regioselectivity (relative position) of electrophilic aromatic substitution. A substituent (-X) is said to be activating if the rate of electrophilic aromatic substitution of the substituted benzene (C6H5X) is faster than benzene. A substituent (-X) is said to be deactivating if the rate of electrophilic aromatic substitution of the substituted benzene

(C6H5X) is slower than benzene. Relative rate of nitration:

CF3 CH3

(trifluoromethyl)benzene benzene 2.5 x 10-5 1 20-25

deactivating activating 286

6 CH3 CH3 CH3 CH3 NO H SO , HNO 2 2 4 3 + +

NO2

toluene NO2 o-nitrotoluene m-nitrotoluene p-nitrotoluene (63%) (3%) (34%)

CF3 CF3 CF3 CF3 NO H SO , HNO 2 2 4 3 + +

NO2 (trifluoromethyl)benzene NO2 o-nitro-(trifluoromethyl) m-nitro-(trifluoromethyl) p-nitro-(trifluoromethyl) benzene benzene benzene (6%) (91%) (3%)

A substituent (-X) is said to be an ortho-para director if it directs an incoming electrophile to positions ortho and/or para to itself. A substituent (-X) is said to be an meta director if it directs an incoming electrophile to position meta to itself.

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Substituents are characterized as either electron-donating or electron-withdrawing and alter the electron density of the aromatic ring through: 1. Inductive effects: ability of a substituent to donate or withdraw electron density through σ-bonds due to differences and bond polarities of a

!- !- - + O O ! ! N + C C! !- !+ X N CH3 R O

X= F, Cl, Br, I Electron-withdrawing groups Electron-donating group 2. Resonance effects: ability of a substituent to donate or withdraw through non-bonding pairs of electrons or overlap π-bonds (conjugation). O N O C C N X OCH3 R O

Electron-withdrawing groups Electron-donating groups 288

7 The rate (activating or deactivating) and regiochemistry (ortho-para vs meta directing) can be understood by examining the influence of the substituent on the stability of the cyclohexa- dienyl cation intermediate. 12.10: Rate and Regioselectivity in the Nitration of Toluene: Regioselectivity: The carbocation intermediate from o- or p-addition can be stabilized by the substituent through inductive effects and hyperconjugation.

ortho 63%

CH3 meta 3%

para 34% 289

Activating groups increase the rate of electrophilic aromatic substitution at all positions of the ring. Partial rate factors - relative rate of electrophilic aromatic substitution compared to benzene

H3C CH3 H3C CH3 C

42 42 4.5 4.5 2.5 2.5 3 3 58 75 Electron rich aromatic rings are more nucleophlic. All activating group donate electrons through inductive effects and/or resonance. Electron-donating groups stabilize the carbocation intermediate of electrophilic aromatic substitution.

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8 12.11: Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene - Regioselectivity: The carbocation intermediate from o- or p-addition is destabilized by the electron-withdrawing substituent. This directs addition to the m-position.

ortho 6%

CF3 meta 91%

para 3%

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Dactivating groups decrease the rate of electrophilic aromatic substitution at all positions of the ring. Partial rate factors - relative rate of electrophilic aromatic substitution compared to benzene

CF3

4.5 x 10-6 4.5 x 10-6 -5 6.7 x 10-5 6.7 x 10 4.5 x 10-6

Electron deficient aromatic rings are less nucleophlic. All deactivating group withdraw electrons through inductive effects and/or resonance. Electron-withdrawing groups destabilize the carbocation intermediate of electrophilic aromatic substitution.

292

9 12.12: Substituent Effects in Electrophilic Aromatic Substitution: Activating Substituents All activating substituents increase the rate of electrophilic aromatic substitution and are ortho-para directors. Nitration of : the -OH is a very strong activating group

ortho 50%

OH meta 0%

para 50%

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Substituents that have an O or N directly attached to the aromatic ring are strong activators. Phenol, anisole, and are very strong activators and do not require strong Lewis Acid catalysts to undergo electrophilic aromatic substutution.

O O -alkyl, -vinyl, -aryl H -OH, -OCH3, -NH2 O C R N C R activators strong activators very strong activators

12.13: Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents Strong deactivators are meta directors

O O O O O O

C H C R C OH C OR C N S O N CF3 O O strong deactivators very strong deactivators

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10 12.14: Substituent Effects in Electrophilic Aromatic Substitution: - Halogens are deactivating because they are strong electron withdrawing groups (inductive effect); however, they have non-bonding pairs of electrons and can also donate electrons (resonance effect), and are ortho-para directors.

ortho 30%

Cl meta 1%

para 69%

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Table 12.2, p. 491 O O

-NO2 -SO3H -CO2H C H -Br -F alkyl O C R -OR -NH2

-I -Cl -H O C N O -CO2R H -OH -NR3 C R N C R strong deactivators deactivators strong activators (meta directors) (ortho/para directors) (ortho/para directors)

12.15: Multiple Substituent Effects - The individual directing effect of each substituent must be considered in order to determine the overall directing effect of a disubstituted benzene toward further electrophilic substitution.

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11 1. When the individual directing effects of the two groups reinforce, further electrophilic substitution is directed to the common position.

-CH3 directs here -CH3 directs here CH3 CH3 -NO directs here -NO directs here Br 2 2 Br2, FeBr3

NO2 NO2 2. When the individual directing effects of two groups oppose, the stronger activating group has the dominant influence; however, mixtures of products are often produced.

OH -OH directs here OH -OH directs here Br Br2, FeBr3

-CH3 directs here -CH3 directs here CH3 CH3

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3. Further substitution between two existing substituents rarely occurs. Start with an ortho-disubstituted benzene to synthesize 1,2,3-trisubstituted

-CH3 directs here -CH3 directs here CH CH3 CH3 3 CH3 -Cl directs here -Cl directs here Br , FeBr Br Br 2 3 + +

Cl Cl Cl Cl Br not observed -CH3 directs here -Cl directs here

-Br directs here

CH3 -CH3 directs here -Cl directs here Br Br

Cl -Br directs here -Br directs here -Br directs here -Cl directs here -CH3 directs here CHO CHO CHO Cl , FeCl Br 2 3 Br Br +

-Br directs here -Br directs here Cl Cl -CHO directs here -CHO directs here 298

12 12.16: Regioselective Synthesis of Disubstituted Aromatic Compounds Consider the directing effects of the substituents to determine the order of their introduction to ensure the 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

CO2H

Br NO2

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m-director NO2 deactivating

o,p-director Cl deactivating o,p-director activating

300

13 Summary of electrophilic aromatic substitution of benzene Zanger, M.; Gennaro, A. R.; McKee, J. R. J. Chem. Ed. 1993, 70 (12) , 985-987

SO , RCOCl, 3 X2, HNO3, RCH2X, AlCl3 H2SO4 catalyst H2SO4 AlCl3 X O R SO3H NO2 CH2R [H]

(m-) (o-, p-) (m-) (o-, p-) (m-)

NBS, [O] h! [O] Br R CO2H

(o-, p-) (m-)

12.17: Substitution in (please read) 12.18: Substitution in Heterocyclic Aromatic Compounds (please read) 301

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