Chapter 15 1.Electrophilic Aromatic - Konkukhome.konkuk.ac.kr/~parkyong/Classes/ch15.pdf · 2 vBenzene does not undergo electrophilic addition, but it undergoes electrophilic aromatic

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Created byProfessor William Tam & Dr. Phillis Chang

Chapter 15

Reactions ofAromatic Compounds

Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.

1. Electrophilic AromaticSubstitution Reactions

v Overall reaction

© 2014 by John Wiley & Sons, Inc. All rights reserved.

R

RClAlCl3

R

O R Cl

O

AlCl3

SO3H

H2SO4SO3


v Different chemistry with alkene

CC

Br2Br C

C Br

Br2

+

+ No Reaction

2. A General Mechanism for Elec-trophilic Aromatic Substitutions


2

v Benzene does not undergo electrophilicaddition, but it undergoes electrophilicaromatic substitution

+H E A

H AE

(H substituted by E)


v Mechanism● Step 1

E+ E

slowr.d.s.

E

E


E

HB


© 2014 by John Wiley & Sons, Inc. All rights reserved. © 2014 by John Wiley & Sons, Inc. All rights reserved.

3

Reactions of Benzene Reactions of Benzene

v Benzene does not react with Br2 or Cl2unless a Lewis acid is present (a catalytic amount is usually enough)

3. Halogenation of Benzene


v Examples

● Reactivity: F2 > Cl2 > Br2 > I2© 2014 by John Wiley & Sons, Inc. All rights reserved.

4

v Mechanism

Br BrFeBr3

(weakelectrophile)

d-d+

Br Br FeBr3

Br + FeBr4

(very reactiveelectrophile)


BrBrBr

Brslow r.d.s.

v Mechanism (Cont’d)



Br

HBr FeBr3


v F2: too reactive, gives a mixture of mono-, di- and polysubstitutedproducts


5

v I2: very unreactive even in the presence of Lewis acids; usually need to add an oxidizing agent (e.g. HNO3, Cu2+, H2O2)



v Electrophile in this case is NO2Å

(nitronium ion)

4. Nitration of Benzene


6

v MechanismOSO

OHO H NO

OHO+

HSO4- N

O

OO

H

H+ N OO H2O

(NO2)

+


NO2slow r.d.s.

NO2NO2NO2




NO2

HH2O NO2

+ H3O+



5. Sulfonation of Benzene

SO3 is protonated to form SO3H+


7

● Step 2

SO3H+ reacts as an electrophile

with the benzene ring to form an

arenium ion© 2014 by John Wiley & Sons, Inc. All rights reserved.

● Step 3

Loss of a proton from the arenium ion restores

aromaticity to the ring and regenerates the acid

catalyst© 2014 by John Wiley & Sons, Inc. All rights reserved.

SO3H

SO3, conc. H2SO4

25oC - 80oC

v Sulfonation & Desulfonation

dil. H2SO4

H2O, 100oC


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v Electrophile in this case is RÅ

● R = 2o or 3o

● or (R = 1o)R ClAlCl3d+ d-

6. Friedel–Crafts Alkylation


v Mechanism

Cl AlCl3 Cl AlCl3

AlCl4+





HCl AlCl3


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v Note: Not necessary to start with alkyl halide, other possible functional groups can be used to generate a reactive carbocation

+ H+e.g.


OH

BF3

60oC+

O BF3

Hvia


v Acyl group:

v Electrophile in this case is R–C≡OÅ

(acylium ion)

7. Friedel–Crafts Acylation


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v Mechanism

O

R ClAlCl3+

R C O R C OAlCl4 +

OCR Cl AlCl3



R C O

R

O

R

O

R

O



H

OR

Cl AlCl3


v Acid chlorides (or acyl chlorides)

RCO

Cl

RCO

OH RCO

Clor

SOCl2

PCl5

● Can be prepared by


11

v When the carbocation formed from an alkyl halide, alkene, or alcohol can rearrange to one or more carbocations that are more stable, it usually does so, and the major products obtained from the reaction are usually those from the more stable carbocations.

8. Limitations of Friedel–CraftsReactions


(How is thisformed?)

(not formed)v For example

AlCl3


1o cation (not stable)v Reason

Cl AlCl3H

AlCl4+ +

1,2-hydride shift

H 3o cation(more stable)


v Friedel–Crafts reactions usually give poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an –NH2, –NHR, or –NR2 group. This applies to both alkylations and acylations.

NO2 N(CH3)3 CF3 SO3H NH2O OH O R

These usually give poor yields in Friedel-Crafts reactions


12

v The amino groups, –NH2, –NHR, and –NR2, are changed into powerful electron-withdrawing groups by the Lewis acids used to catalyze Friedel-Crafts reactions

N NH H

HH AlCl3

>

AlCl3+

Does not undergo a Friedel-Crafts

reaction© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Aryl and vinylic halides cannot be used as the halide component because they do not form carbocations readily

, AlCl3

Cl

Cl , AlCl3

No Friedel-Craftsreaction

No Friedel-Craftsreaction

sp2

sp2


v Polyalkylations often occur

+OH

+BF3

60oC

(24%) (14%)


v Rearrangements of the carbon chain do not occur in Friedel–Crafts acylations

v The acylium ion, because it is stabilized by resonance, is more stable than most other carbocations. Thus, there is no driving force for a rearrangement.

9. Synthetic Applications ofFriedel-Crafts Acylations:The Clemmensen Reduction & Wolff–Kishner Reductions


13

v The carbonyl group of an aryl ketone can be reduced to a CH2 group

[H]R

O

R


9A. The Clemmensen Reduction

HClreflux

R

O

RZn/Hg



v Clemmensen reduction of ketones● A very useful reaction for making

alkyl benzenes that cannot be made via Friedel-Crafts alkylations

?e.g.


14

v Clemmensen reduction of ketones● Cannot use Friedel-Crafts alkylation


v Rearrangements of carbon chains do not occur in Friedel-Crafts acylations

(no rearrangement of the R group)


Zn/Hgconc. HClreflux


9B. The Wolff–Kishner Reduction


15


Quiz 1


Quiz 2


Quiz 3

16

v Two questions have to be addressed:● Reactivity● Regiochemistry

10. Substituents Can Affect Boththe Reactivity of the Ring and the Orientation of the Incoming Group


● Reactivity

faster or slower than

Y = EDG (electron-donating group) or EWG (electron-withdrawing group)


● Regiochemistry

Statistical mixture of o-, m-, p-products, or any preference?


G

E A+

GE

Hotherresonancestructure

d+ d-

A substituted benzene

Electrophilic reagent Arenium

ion


17

Z> Y

>

Y withdraws electrons

Z donates electrons

The ring is electron poor and reacts more slowly with an electrophile

The ring is more electron rich and reacts faster with an electrophile


–EDG

–H

–EWG

Incr

easin

g ac

tivity

● Reactivity


Substituent

● Reactivity towards electrophilic aromatic substitution


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The energy diagrams below illustrate the effect of electron-withdrawing and electron-donating groups on the transition stateenergy of the rate-determining step.

Figure 18.6 Energy diagrams comparing the rate of electrophilic substitution of substituted benzenes

v Regiochemistry: directing effect

● General aspectst Either o-, p- directing or m-

directingt Rate-determining step is p-

electrons on the benzene ring attacking an electrophile (EÅ)


attack

YYY

-I -II -III

EEE

Y

E


attack

YYY

-I -II -IIIE E E

Y

E


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Y

E


v Classification of different substituentsY

Y (EDG)–NH2, –NR2–OH, –O-

Strongly activating

o-, p-directing

–NHCOR–OR

Moderately activating

o-, p-directing

–R (alkyl)–Ph

Weakly activating

o-, p-directing

–H NA NA© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Classification of different substituentsY

Y (EWG)

–Halide(F, Cl, Br, I)

Weakly deactivating

o-, p-directing

–COOR, –COR,–CHO, –COOH,–SO3H, –CN

Moderately deactivating

m-directing

–CF3, –CCl3,–NO2, –⊕NR3

Strongly deactivating

m-directing


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11. How Substituents AffectElectrophilic AromaticSubstitution:A Closer Look


v Two types of EDG(i)

11B.Inductive & Resonance Effects: Theory of Orientation

by resonance effect (donates electron towards the benzene ring through resonance)

OR NR2

or

CH3>(ii) by positive inductive effect (donates electron towards the benzene ring through the s bond)


v Two types of EDG

● The resonance effect is usually stronger than the positive inductiveeffect if the atoms directly attached to the benzene ring are in the same row as carbon in the periodic table


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v Similar to an EDG, an EWG can withdraw electrons from the benzene ring by the resonance effect or by the negative inductive effect

CO

CH3e.g.>

C F

F

F>>

Deactivate the ring by the resonance effect

Deactivate the ring by the negative inductive effect


v EWG = –COOR, –COR, –CHO, –CF3, –NO2, etc.

11C. Meta-Directing Groups

(EWG ≠ halogen)


v For example

(highly unstable due to the negative inductive effect of –CF3)


(highly unstable due to negative inductive effect of –CF3)


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(positive charge never attaches to the carbon directly attached to the EWG: –CF3) Þ relatively more favorable


v EDG = –NR2, –OR, –OH, etc.

11D. Ortho/Para-Directing Groups


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v For example

(extra resonance structure due to positive mesomeric effect of –OCH3)


OCH3 OCH3OCH3

OCH3

OCH3

(para)

NO2 NO2NO2

NO2

- H+

OCH3

NO2

(para)(favorable)

NO2

(extra resonance structure due to resonanceeffect of –OCH3)


(3 resonance structures only, no extra stabilization by resonance effect of –OCH3) Þ less favorable


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v For halogens, two opposing effects

Negative inductive effect:withdraws electron density from the

benzene ring

ClCl

>

Resonance effect:donates electron

density to thebenzene ring


v Overall● Halogens are weak deactivating

groupst Negative inductive effect >

resonance effect in this case


With the exception of fluorine, halogens must use 3p, 4p, and 5p orbitals to overlap with the 2p orbital of carbon - this overlap becomes progressively weaker as the size of the halogen increases.

v Regiochemistry

(extra resonance structure due to resonance effect of –Cl)


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(extra resonance structure due to resonanceeffect of –Cl)


(3 resonance structures only, no extra stabilization by the resonance effect of –Cl) Þ less favorable


99

Ortho/Para-Directing Deactivators: Halogens• Electron-withdrawing inductive effect outweighs weaker

electron-donating resonance effect.Energy Diagram

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11E. Ortho/Para Direction andReactivity of Alkylbenzenes


CH3

E

CH3

ECH3

E

CH3

E

>

v Ortho attack

Relatively stable contributor


v Meta attack


CH3

E

CH3 CH3 CH3

E E E

>

v Para attack

Relatively stable contributor


27

Summary

-H (unsubstituted)

-R or -Ar, ortho- and para- -R or -Ar, meta-

-NH2 or -OH, meta- -NH2 or -OH, ortho- and para-

-Cl or -Br, ortho- and para- -Cl or -Br, meta-

-NO2 or -CO2H, meta-

-NO2 or -CO2H, ortho- and para-

Deactivators

Activators

Reactants

[CarbocationIntermediate]

Reaction Progress

Energy

11F. Summary of Substituent Effects on Orientation and Reactivity

Y Y (EDG)

–NH2, –NR2–OH, –O-

Strongly activating

o-, p-directing

–NHCOR–OR

Moderately activating

o-, p-directing

–R (alkyl)–Ph

Weakly activating

o-, p-directing

–H NA NA© 2014 by John Wiley & Sons, Inc. All rights reserved.

Y Y (EWG)

–Halide(F, Cl, Br, I)

Weakly deactivating

o-, p-directing

–COOR, –COR,–CHO, –COOH,–SO3H, –CN

Moderately deactivating

m-directing

–CF3, –CCl3,–NO2, –⊕NR3

Strongly deactivating

m-directing


28


CH3

Methylbenzene(toluene)

Ethylbenzene Isopropylbenzene(cumene)

Phenylethene(styrene or

vinylbenzene)

12. Reactions of the Side Chainof Alkylbenzenes


12A. Benzylic Radicals and Cations

Methylbenzene(toluene)

CH2HR

- RH

CH2

The benzylradical

CC C C

Benzylic radicals are stabilized by resonance© 2014 by John Wiley & Sons, Inc. All rights reserved.

29

CC C C

Benzylic cations are stabilized by resonance© 2014 by John Wiley & Sons, Inc. All rights reserved.

12B.Benzylic Halogenation of the Side Chain


v Mechanism● Chain initiation

2 XX Xperoxidesheat orlight

● Chain propagation

XHCC6H5 HH

+H

CC6H5H

H X+


● Chain propagation

● Chain termination

XHCC6H5 XH

+H

CC6H5H

+X X

XHCC6H5 XH

+H

CC6H5H


30

v e.g.


C CC

CC C

conjugatedsystem

non-conjugatedsystem

is morestable than

13A. Stability of Conjugated Alkenyl-benzenes

v Alkenylbenzenes that have their side-chain double bond conjugated with the benzene ring are more stable than those that do not

13. Alkenylbenzenes


v ExampleH+

heatOH

(not observed)

Ha Hb

- Ha

- Hb


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13B. Additions to the Double Bond ofAlkenylbenzenes

HBr

RO ORheat

HBr(no

peroxides)

Br

Br


v Mechanism (top reaction)2 RORO OR

H Br+RO Br RO H+

+ Br Br

Br

(more stablebenzylic radical)

(less stable)

Br+ H Br

Br© 2014 by John Wiley & Sons, Inc. All rights reserved.

v Mechanism (bottom reaction)

H Br

H

H

(more stablebenzylic cation)

(less stable)d+ d-

Br

Br


13C. Oxidation of the Side Chain


32


v Using hot alkaline KMnO4, alkyl, alkenyl, alkynyl and acyl groups all oxidized to –COOH group

v For alkyl benzene, 3o alkyl groups resist oxidation

● Need benzylic hydrogen for alkyl group oxidation


CH3

NO2

How?

14. Synthetic Applications


CH3

NO2

CH3

CH3Cl

AlCl3

conc. HNO3

conc. H2SO4heat

CH3

NO2

+

v CH3 group: ortho-, para-directingv NO2 group: meta-directing


33

NO2

CH3Cl

AlCl3

conc. HNO3

conc. H2SO4heat

CH3

NO2

CH3

NO2

NOT

v If the order is reversed Þ the wrong regioisomer is produced


v We do not know how to substitute a hydrogen on a benzene ring with a –COOH group. However, side chain oxidation of alkylbenzene could provide the –COOH group

v Both the –COOH group and the NO2group are meta-directing

COOH

NO2


v Route 1


CH3Cl

AlCl3

conc. HNO3

conc. H2SO4heat

COOH

COOH

NO2

1. KMnO4, HO-, D

2. H3O+

CH3

v Route 2


34

v Which synthetic route is better?● Recall “Limitations of Friedel-Crafts

Reactions, Section 15.8”t Friedel–Crafts reactions usually give

poor yields when powerful electron-withdrawing groups are present on the aromatic ring or when the ring bears an –NH2, –NHR, or –NR2group. This applies to both alkylations and acylations

t Route 2 is a better route


v Both Br and Et groups are ortho-, para-directing

v How to make them meta to each other?

v Recall: an acyl group is meta-directing and can be reduced to an alkyl group by Clemmensen reduction

Br


Br

O

Cl

AlCl3

O

O

Br

Br2FeBr3

Zn/Hg

HCl, heat


14A. Use of Protecting and BlockingGroups

v Protected amino groups● Example


35

Problemv Not a selective synthesis, o- and p-

products + dibrominated and tribrominated products will form


v The amino groups, –NH2, –NHR, and –NR2, are changed into powerful electron-withdrawing groups by the Lewis acids used to catalyze Friedel-Crafts reactions

N NH H

HH AlCl3

>

AlCl3+

Does not undergo a Friedel-Crafts

reaction© 2014 by John Wiley & Sons, Inc. All rights reserved.

Solutionv Introduce a deactivating group on

–NH2


v The amide group is less activating than –NH2 group ● No problem for over bromination

v The steric bulkiness of this group also decreases the formation of the o-brominated product


36


Problemv Difficult to get o-product without

getting p-product v Over nitration


Solutionv Use of a –SO3H blocking group at the

p-position which can be removed later


14B. Orientation in DisubstitutedBenzenes

v Directing effect of EDG usually outweighs that of EWG

v With two EDGs, the directing effect is usually controlled by the stronger EDG


37

Examples [only major product(s) shown]



38


39

C CCH2X

C CC

R

XH

C CC

R'

XR

1o Allylic 2o Allylic 3o Allylic

1o Benzylic 2o Benzylic 3o Benzylic

CArR

HX CAr

R'

RXCAr

H

HX

15. Allylic and Benzylic Halides inNucleophilic Substitution Reactions


H3C X R CH2 X R CH XR'

v A Summary of Alkyl, Allylic, & Benzylic Halides in SN Reactions● These halides give mainly SN2

reactions:

● These halides may give either SN1 or SN2 reactions:

Ar CH2 X Ar CH XR

C CCH2 X

C CC

R

XH


v A Summary of Alkyl, Allylic, & Benzylic Halides in SN Reactions● These halides afford mainly SN1

reactions:

C CC

R'

XR

C XR'R

R"C XArR

R'


H2/Ni

slowH2/Ni

fast

H2/Nifast

+

benzene cyclohexadienes cyclohexene

cyclohexane

16. Reduction of AromaticCompounds


40

16A. The Birch Reduction

benzene

NaNH3, EtOH

1,4-cyclohexadiene


electride salt [Na(NH3)x]+ e−

v Mechanism

benzene

Na

benzene radical anion

- -etc.

EtOH

cyclohexadienyl radical

etc.

H

H

H

HNa

cyclohexadienyl anion

etc.

H

H

H

H-

- H

H

H

H

1,4-cyclohexadiene

EtOH


The solvated electrons add to the aromatic ring to give a radical anion.


kinetic product is produced

because the largest orbital coefficient of the HOMO of the conjugated pentadienyl anion intermediate is on the central carbon atom.


41


v Synthesis of 2-cyclohexenones

OCH3 Liliq. NH3EtOH

OCH3

O2-cyclohexenone

H3O+

H2O

(84%)


42


Quiz 1


Quiz 2


Quiz 3

Chapter 15 1.Electrophilic Aromatic - Konkukhome.konkuk.ac.kr/~parkyong/Classes/ch15.pdf · 2 vBenzene does not undergo electrophilic addition, but it undergoes electrophilic aromatic

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