Ch. 15 - 1

Electrophilic Aromatic SubstitutionGeneral MechanismHalogention, Nitration, sulfonationFriedel-Crafts Alkylation & AcylationFriedel-Crafts limitationsSubstituent Affects activation, deactivation, orientationDetails of affects ortho-para directing, meta-directingBenzylic chemistriesAlkenylbenzeneSynthesis blocking & protecting groupsDisubstituted benzeneAllylic benzylic substitutionBirch reduction

Chapter 15 (test 2)Chapter 15 (test 2)

Modified from sides of William Tam & Phillis Chang

27

Ch. 15 - 2

Electrophilic Aromatic Substitution RXs (EAS)

Overall reaction

Ch. 15 - 4

General Mechanism for Electrophilic Aromatic Substitution

Different chemistry with alkene

Ch. 15 - 3

Ch. 15 - 5

Electrophilic Aromatic SubstitutionBenzene does not undergo electrophilic addition

Ch. 15 - 6

Mechanism

Er.d.s.slow

E

H

E

H-H(+)

Efast+ H(+)

:B

H-B

Ch. 15 - 9

Halogenation of Benzene

Requires a Lewis acid catalyst

Reactivity: F2 >> Cl2 > Br2 >> I2

H Cl2

FeCl3

Cl+ H-Cl

H Br+ H-Br

Br2

FeBr3

Ch. 15 - 11

Catalyst

Br Br FeBr

BrBr

+ Fe

Br

Br

Br

BrBr +

Fe

Br

BrBr

BrBrδ+ δ-

Ch. 15 - 12

Mechanism (Cont’d)

r.d.s.slow

H BrBr

H

BrH

Br

H

Fe

Br

Br

Br

Br

+

Br

+ FeBr3+

HBr

Ch. 15 - 14

F2: too reactive

mixture

Lewisacid

H F2F FF

FF

+ + + etc.

Ch. 15 - 15

I2: very unreactive needs

LA-oxidizing agent (e.g. HNO3, Cu2+, H2O2)

Ch. 15 - 16

Nitration of Benzene

Electrophile = NO2

⊕ (nitronium ion)

Ch. 15 - 17

Mechanism

N OO

O

H

+ S O

O

O

H

OH

N OO

O

H

+ S O

O

O

H

OH

N

O

O+ O

H

H

H

N

O

O

H

NO

O

H

N

O

O-H (+)

NO

O

Ch. 15 - 20

Sulfonation

S O

O

O

H

O

H

+ S O

O

O

H

OH

SO

O

O OH

H

H+

+

S O

O

O

HO

S O

O

O

HO

H+ S O

O

O

HO

H

r.d.s

H

SO

O

O

H

SO

O

O

H

SO

O

O

repeat next slide

Ch. 15 - 21

H

SO

O

O

H

SO

O

O

H

SO

O

O +

OH

H

H

H

SO

O

OH O

H

H

+

other (p,o)resonancestructures

S O

O

O

HS O

O

O

H

O

H

repeat

S O

O

O

HO

Ch. 15 - 22

Sulfonation & Desulfonation-useful!

(heat)

Ch. 15 - 23

Friedel–Crafts Alkylation

Electrophile = R⊕ (not vinyl or aryl)

R = 2o or 3o

RX

Ch. 15 - 24

Mechanism

Al

Cl

ClCl

Cl+Al

Cl

ClCl

Clδ+ δ-δ+

HHH

Cl

Al

Cl

ClCl

+

-H(+)

Ch. 15 - 27

Other carbocation

Ch. 15 - 28

Ch. 15 - 29

Friedel–Crafts Acylation

Acyl group:

Electrophile is R–C≡O⊕ (acylium ion)

R

O

Ch. 15 - 30

RX and Mechanism

RO

O

Cl

Al

Cl

ClCl

+Al

Cl

Cl

Cl

Clδ+

δ-

Oδ+ O

Al

Cl

Cl

Cl

Cl +

OCl4Al

RO H

RO H

RO H

-H(+)

Ch. 15 - 33

Acid chlorides (or acyl chlorides)

Prep

Ch. 15 - 35

(not formed)

Limitations of Friedel–Crafts Reactions

carbocations rearrangement

Cl3Al

Ch. 15 - 36

1o cation (not stable)Reason

3o cation

Ch. 15 - 3Questions?

Ch. 15 - 37

Problems: Friedel–Crafts alkylations, acylations, etc. with withdrawing groups & amines (basic)

generally give poor yieldsdeactivating gps

Ch. 15 - 38

Basic amino groups (–NH2,–NHR, & –NR2) form

strong electron withdrawing gps with acids

Not Friedel-Crafts reactive

Ch. 15 - 40

Another problem: polyalkylations can occur

More common with activated aromatic rings

Ch. 15 - 41

Clemmensen Reduction

Use Clemmensen reduction to avoiding rearrangements

gives not

recall

Ch. 15 - 45

How?

OO

Cl

Cl3Al

Ch. 15 - 46

Substituents effect reactivity & regiochemistry of substitution

faster or slower than

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

Ch. 15 - 48

Y

Substituents effect reactivity & regiochemistry of substitution

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

possibilitiesY

EE+

orthoo

Y

Emeta

m

Y

Epara

p

Ch. 15 - 56

Reactivity towards electrophilic aromatic substitution

Ch. 15 - 57

Regiochemistry: directing effect

General aspects Either o-, p- directing or m-directing

E+

Y

ortho

YE

YE

YE

Rate-determining-step: aromatic ring -electrons attacking the Eπ

Ch. 15 - 59

E+

Y

para

Y

E

Y

E

Y

E

E+

Y

meta

Y

E

Y

E

Y

E

Ch. 15 - 64

Classification of substituents

Y (EDG) reactivity regiochemistry

–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

Ch. 15 - 65

Classification of substituents

Y (EWG) reactivity regiochem

–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

Ch. 15 - 67

then reaction is faster than with benzene

EffectEffect of of Electron-Donating Electron-Donating (releasing) and (releasing) and Electron-Withdrawing GroupsElectron-Withdrawing Groups

G

E(+)

+

G

E Hδ+

δ+

t.s.stabilized

arenium ionstabilized

G

E H

G

E H

If G is electron-donating group

Ch. 15 - 68

If G is an electron-withdrawingthen reaction is slower than with benzene

G

E(+)

+

E H

G

E Hδ+

δ+

G

t.s.destabilized

E H

G

arenium iondestabilized

Ch. 15 - 69

Ch. 15 - 70

(1)

InductiveInductive and and Resonance Effects: Resonance Effects: OrientationOrientation

resonance donation of e(-)s into the benzene ring

(2) e(-)-inductive donation (through σ bond)

Two types of EDG

Ch. 15 - 71

Positive resonance effect is stronger than positive inductive effect

Two types of EDG

(if the atom directly attacked to the benzene is in the same row as carbon)

O

CH3

Ch. 15 - 72

EWG negative resonance (mesomeric) or by negative inductive effect

Deactivate the ring by resonance effect

Deactivate the ring by negative inductive effect

O

Ch. 15 - 73

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

Meta-Directing GroupsMeta-Directing Groups

(EWG ≠ halogen)

EWG

E(+)

EWG

E

Ch. 15 - 74

For example “if” ortho or para

CF3

O N O

CF3

O N O

etc.

CF3

NO2

CF3

NO2

CF 3

NO2

CF3

NO2

CF3

NO2

CF3

NO2

etc.

(highly unstable,negative inductive effect of –CF3)

Ch. 15 - 76

positive charge never on a carbon adjacent to the EWG

meta

CF3

O N O

CF3

NO2H

CF3

NO2

CF3

NO2

-H (+)

CF3

NO2

Ch. 15 - 77

EDG = –NR2, –OR, –OH, etc.

Ortho–Para-Directing GroupsOrtho–Para-Directing Groups

EDG

E (+)

EDG

E

EDG

E

+

Ch. 15 - 78

extra resonance structure, positive resonance effect

N

O

H

Cl(+)

(-)AlCl4

EDG - para

N

O

H

Cl

N

O

H

Cl

N

O

H

Cl

N

O

H

Cl

N

O

H-H(+)

Cl

H

Ch. 15 - 79

(extra resonance)

EDG - ortho

N

O

H

Cl(+)

(-)AlCl4

N

O

H

Cl

N

O

H

Cl

N

O

H

ClN

O

H

ClH

-H(+)

N

O

H

Cl

Ch. 15 - 80

EDG - (if meta: no extra stabilization)

N

O

H

Cl

N

O

H

Cl

N

O

H

Cl

N

O

H

Cl(+)

(-)AlCl4

H

N

O

H

Cl

-H(+)

Ch. 15 - 81

halogens, two opposing effects

negative inductive effect

positive resonance effect

halogens - weak deactivating negative inductive effect > positive resonance

X X X X X

Ch. 15 - 83

But regiochemistry -o,p

extra resonance

Cl

O N OH

Cl

NO2

-H(+)

Cl

O N O

Cl

NO2

Cl

NO2

Cl

NO2

Cl

NO2

-H(+)

Cl

NO2

Cl

NO2

Cl

NO2

Cl

NO2

Cl

NO2

Ch. 15 - 85

meta: (no extra stabilization resonance, higherenergy rx path)

Cl

O N O

Cl

NO2

Cl

NO2H

Cl

NO2

-H(+)

Cl

NO2

Ch. 15 - 90

Reactions of Alkylbenzenes Weak activating,o,p-directing

Side Chain

Ch. 15 - 91

Recall Benzylic Radicals Recall Benzylic Radicals andand Cations Cations

Benzylic radicals are stabilized by resonance

Ch. 15 - 92

Benzylic cations are stabilized by resonance

Ch. 15 - 93

Halogenation of the Side ChainHalogenation of the Side Chain

N-Bromosuccinimide (NBS) = Br2

Ch. 15 - 96

e.g. (more stable benzylic radicals)

(less stable 1o radicals)

(major) (very little)

Ch. 15 - 97

Conjugated AlkenylbenzenesConjugated Alkenylbenzenesolefin conjugated with a benzene ring more stable

Ch. 15 - 98

Example

(not observed)

Ch. 15 - 99

AdditionsAdditions to to Alkenylbenzenes Double BondAlkenylbenzenes Double Bond

HBrROOH Δ

HBr

cool

Br

Br

Ch. 15 - 100

radical addition mechanism

Ch. 15 - 101

ionic addition mechanism

Ch. 15 - 102

Oxidation of the Side ChainOxidation of the Side Chain

Ch. 15 - 103

Oxidation of the Side ChainOxidation of the Side Chain

Ch. 15 - 104

3o alkyl groups resist oxidation

Need benzylic hydrogen, oxygen or unsatuation.

Ch. 15 - 105

Oxidation Oxidation of the of the Benzene RingBenzene Ring

Ch. 15 - 106

Synthesis

NO2

CH3

How?

How? CO2H

NO2

Ch. 15 - 107

CH3 group: ortho-, para-directing

NO2 group: meta-directing

CH3ClAlCl3(cat)

CH3 HNO3

H2SO4(cat.)

Δ O2N

CH3

CH3

NO2

+

Ch. 15 - 108

reversed order the wrong regioisomer

Friedel-Craft with NO2

(strong EWG)??

HNO3

H2SO4(cat.)

ΔNO2

CH3ClAlCl3(cat)

???NO2

CH3

NO2

CH3

Not

Ch. 15 - 109

–CO2H group: side chain oxidation of alkylbenzene could provide the –CO2H group

–CO2H group and the NO2 group are meta-directing

CH3 CO2H CO2H

NO2

KMnO4(-)OHΔ

H3O(+) HNO3

H2SO4(cat)

Δ

Ch. 15 - 110

? Possible reverse

HNO3

H2SO4(cat.)

ΔNO2

CH3ClAlCl3(cat)

???NO2

CH3

1. KMnO4 (-)OH/Δ2.H3O(+)

(neut.)CO2H

NO2

Route

CH3ClAlCl3(cat)

CH31. KMnO4/(-)OH/Δ

2.H3O(+)(neut.)

CO2H

CO2H

NO2

HNO3

H2SO4(cat.)

Δ

Ch. 15 - 112

Friedel–Crafts poor with powerful electron-withdrawing & –NH2, –NHR, or –NR2 group.

Limits of Friedel-Crafts, Section 15.8

Ch. 15 - 113

Both Br and Et are ortho-, para-directingHow to form them meta to each other?

Recall: acyl group is meta-directing and can be reduced to an alkyl group.

Zn(Hg) HCl

Ch. 15 - 114

AlCl3(cat)

Cl

O O

Br2

FeBr3(cat)

O

Br

Zn/HgHCl, Δ

Br

Ch. 15 - 115

Use of Protecting and Blocking GroupsUse of Protecting and Blocking Groups

Protected amino groups

Ch. 15 - 116

ProblemNot a selective synthesis, o- and p-products +

dibromo and tribromo products

NH2 Br2

NH2

Br

NH2

Br Br+

+

NH2

Br Br

Br

+ others

Ch. 15 - 117

SolutionReduce the reactivity of –NH2

amide less reactive sterically bulky =>p

NH2

pyridine

Cl

O HN

O

NH2

NH2

Br

pyridine

Cl

O HN

O

HN

OBr

1. H2SO4

H2O/Δ2.HO(-)

(neut)

Ch. 15 - 120

Problemso-product without/little p-product over nitration

Ch. 15 - 121

Solution –SO3H p-blocking group

removed later

pyridine

Cl

OHN

O

SO3

H2SO4

(conc.)

Δ

HN

OHO3S

HNO3

H2SO4(conc.)

Δ

NH2

NO2HO3S

1. H2SO4(dil)

H2O/Δ

2.HO(-)

(neut)

NH2

NH2

NO2HO3S

Ch. 15 - 122

Orientation Orientation in in Disubstituted BenzenesDisubstituted Benzenes

With two EDGs, the directing controlled by the stronger EDG

Assume: EDG usually outweighs that of EWG

Br2

FeBr3(cat)

OOMe O

Br

OMeOOMe

Br

+

CH3

OMe Cl2FeCl3(cat)

CH3

OMe CH3

OMe

Cl

Cl+

Ch. 15 - 123

Example of mixed groups (major product(s) shown)

CH3

F3C

HNO3

H2SO4(conc.)

Δ

CH3

F3C NO2

Substitution does not occur between meta-substituents if another position is open

Br

Cl

HNO3

H2SO4(conc.)

Δ

Br

Cl

O2N

Br

Cl

NO2

Br

Cl

NO2

+ +

1%37% 62%

Ch. 15 - 125

HN

O

MeO2C HNO3

H2SO4(conc.)

Δ

HN

O

MeO2C

O2N

HN

O

MeO2C

O2N NO2

+

O2N Cl

Br2

FeBr3(cat)

O2N Cl

Br+

O2N Cl

Br

Ch. 15 - 128

Review: Allylic & Benzylic Halides in SN1 & SN2 Reactions

CC C

X

H H

CC C

X

H R

CC C

X

R' R

1o allylic 2o allylic 3o allylic

CX

H H

1o benzylic

CX

H R

2o benzylic

CX

R'R

3o benzylic

Ch. 15 - 129

Recall: These halides give mainly SN2 rxs:

These halides may give either SN1 or SN2 reactions:

Ch. 15 - 130

These halides give mainly SN1 reactions:

Ch. 15 - 131

Reduction of Aromatic Compounds

H2

Nipressure

ΔSlow!

+

H2

Nipressure

ΔFAST!

H2

Nipressure

ΔFAST!

The The Birch ReductionBirch Reduction

Nao

NH3(liq)

ROH

Lio NH3(liq)tBuOH

Ch. 15 - 133

Mechanism

Na

H H

H

H-OR

H HHH

H HNa

H H

H

H HHH

H H

RO H

H H

H H

End

Use: synthesis of 2-cyclohexenones

Lio

NH3(liq)tBuOH

OMe OMe OH(+)

H2O