H

HH

HH

H

E+E

HH

HH

H+ H+

Electrophilic aromatic substitution:

X NO2 SO3H R CRO

Halogenation Nitration Sulfonation Alkylation Acylation

Some electrophilic aromatic substitution:

Ch.16 Chemistry of Benzene: Electrophilic Aromatic Substitution

Br2

Br

+ HBrFeBr3

Bromination:

H ClH

Cl-

H

Cl

electrophilic addition mechanism:

- similar first electrophilic addition mechanismbut aromatic rings are less reactive (more stable) than alkenes

16.1 Bromination of Aromatic Rings

FeBr3 + Br++FeBr4-Br Br Br BrBr3Fe

δ- δ+

or

a strong electrophile

- need catalyst for aromatic electrophilic substitution

Br+ Br Br Br

allylic carbocationthree resonance forms : stable

but, much less reactive than the aromatic reactant → endothermic, high Ea, slow reaction

- electrophilic aromatic substitution need higher activation energy than alkene does

Ener

gy

Reaction progress

alkene + E+

benzene + E+

Ea, alkene

Ea, benzene

E

EH

overall substitution: addition + rearomatization

Br+ Br

FeBr4-

slowH fast

Br+ HBr + FeBr3

BrH

BrXnonaromatic

intermediate

nonaromaticproduct

aromaticproduct

addition

electrophilic brominationEn

ergy

Reaction progress

benzene + Br2

Ea

EH

BrH

Br

Br+ HBr

16.2 Other Aromatic Substitutions

Chlorination

N

N

Cl

OH3C

Diazepam(tranquilizer)

Cl2Cl

+ HCl cat FeCl 3

86%

Iodination

l2I

cat CuCl 2

65%

+ 2 Cu2+l2 2 I+ + 2 Cu+

CH3O2N NO2

NO2

Trinitrotoluene (TNT)

Nitration : HNO3 + H2SO4 (cat)

N OO

O H

H+

N OO

O H

HNO2

+ + H2O

HNO3

NO2

cat H2SO4

85%

NO2

1. SnCl2, H3O+

2. OH-

NH2

reduction of nitro to aniline

NH2

SO2NH2

sulfanilimide(a sulfa drug)

Sulfonation : fuming sulfuric acid, SO3 + H2SO4 (cat)

S OO

O

H+

S OO

O

H

SO3

SO3H

cat H2SO4

95%

SO3H

2. H3O+

1. NaOH, 300oCOH

CH3 CH3

p-Cresol (72%)

alkali fusion reaction

16.3 Alkylation of Aromatic Rings: The Friedel-Craft Reactions

Friedel-Craft Alkylation

AlCl3+ HCl

Cumene (85%)

H3C CH3

Cl

+

AlCl3 H3C CH3

Cl

+ AlCl4-

H3C CH3+

AlCl3+

Y

R X NO reaction

Y = NR3+, NO2, CN, SO3H, CHO, COR, COOH, COOR

= NH2, NHR, NR 2

Limitation:- only useful for RCl not for ArCl or vinyl chloride- aromatic rings with electron-withdrawing groups are unreactive- aromatic rings with amino group are unreactive: amines under go acid-base reaction with AlCl3

AlCl3+ (CH3)3CCl

C(CH3)3 C(CH3)3

+

C(CH3)3

majorminor

polyalkylation problem

- use excess of benzene for mono alkylation

AlCl3+ +

35%65%

Cl

skeleton rearrangement: carbocation

CH2

H H

Hydride shift

carbocations: skeleton rearrangement to a more stable cation

H3C CH2

H3C CH3

H3CAlkyl shiftCH3

CH3

Cl+AlCl3

Friedel-Craft Acylation

AlCl3+ HCl

Acetophenone (95%)

Cl CH3

O

+

O CH3

80oC

AlCl3 Cl R

O+ AlCl4

-+CR

O

O C R

16.4 Acylation of Aromatic Rings

- no polyacylation: less reactive acyl product

16.5 Substituent Effects in Substituted Aromatic Rings

1. Reactivity

NO2 Cl H OH

relative rateof nitration 6 x 10-8 0.033 1 1000

2. OrientationOH

HNO3

H2SO4, 25oC

OHNO2

OH OH

NO2NO2

+ +

o-Nitrophenol m- p-

50% 0% 50%

CN

HNO3

H2SO4, 25oC

CNNO2

CN CN

NO2NO2

+ +

o-Nitrobenzonitrile m- p-

17% 81% 2%

Substituent Effects in Electrophilic Aromatic Substitution

-NO2 -SO3H -COOH -CHO -Br -F -Ph -OMe

-NH2-CN -COCH3 -COOCH3 -I -Cl -H -CH3

-OH

meta-directingdeactivators

ortho- and para-directing

deactivators

ortho- and para-directingactivators

electron-poor electron-rich

alkyl-NHCOCH3-NR3

+

no meta-directing activators

Xδ−

inductively withdrawing

CO

R

δ−

δ+CO

OR

δ−

δ+ CNδ−

δ+NO

O δ−δ+δ+

X= F, Cl, Br, I

inductive effect: electronegativity differencesresonance effect: lone pair electrons, double bond

Two factors in activating/deactivating effect:

Rinductively donating

Inductively withdrawing groups - positive charges at the neighboring atom

Resonance effect: withdraw or donate electrons through a π-bond- the effect is greatest at the ortho and para positions

CO

R CO

R CO

RCO

R

electron withdrawing resonance effect

YZ

CO

R

δ−

δ+C

Nδ−

δ+NO

O δ−δ+

δ−

δ+

OH OH O

H OH

Electron donating resonance effect- the effect is greatest at the ortho and para positions

OHNH2 OR XY

X= halogen

- inductive effect and resonance effect don't necessary act in the same direction; -X, -O, -N atoms are inductively withdrawing groups but electron-donating resonance effect

16.6 An Explanation of Substituent Effects

Activating groups: donate electrons to the ring- stabilize carbocation intermediate- lower the activation energy for carbocation formation

Deactivating groups: withdraw electrons from the ring- destabilize carbocation intermediate- raise the activation energy for carbocation formation

Activating/deactivating effect

Y H Y> >

Y H Y

E+ E+ E+

E E Estabilized

carbocationdestabilizedcarbocation

ortho, para directors: - lone pair electrons- stabilize carbocation intermediate by resonance

OHNH2 R Br

Orientating Effect

halogens: - inductively deactivating- but ortho, para directing by resonance stabilization

NO2+ NO2 NO2

CH3

CH3 CH3NO2

CH3

Most stable

CH3 CH3CH3

CH3CH3

NO2 NO2 NO2

ortho

meta

para

NO2 NO2

CH3

NO2

Most stable

63%

34%

3%

alkyl group: ortho, para activator

NO2+ NO2 NO2 NO2

OH

OH OH OHNO2

OH

Most stable

OH OHOH

OH OHOH

NO2 NO2 NO2

ortho

meta

para

NO2 NO2 NO2

OH

NO2

Most stable

50%

50%

0%

- stabilizing resonance interactions for ortho and para additions

OH, NH2 group: ortho, para activator

NO2+ NO2 NO2 NO2

Cl

Cl Cl ClNO2

Cl

Most stable

Cl ClCl

Cl ClCl

NO2 NO2 NO2

ortho

meta

para

NO2 NO2 NO2

Cl

NO2

Most stable

35%

64%

1%

- inductively deactivating- stabilizing resonance interactions for ortho and para additions

halogen group: ortho, para adectivator

Cl+ Cl Cl

C

CHO CHOCl

CHO

Least stable

CHO CHOCHO

CHOCHO

Cl Cl Cl

ortho

meta

para

Cl Cl

CHO

Cl

O Hδ−

δ+

δ+

Least stable

19%

72%

9%

destabilizing inductive interactions for ortho and para additions

EWG group: meta deactivator

A Summary of Substituent Effects in Aromatic Substitution

nonestrong; electron-withdrawingmetadeactivating-N+(CH3)3

strong; electron-withdrawing

strong; electron-withdrawingmetadeactivating

-NO2, -CN, -CHO, -CO2Me, -COCH3, -COOH

weak; electron-donating

strong; electron-withdrawing

orthopara

deactivating-F, Cl, Br, I

strong; electron-donating

weak; electron-withdrawing

orthopara

activating-OH, -NH2

noneweak; electron-donating

orthopara

activating-CH3

Resonance EffectInductive EffectOrientationReactivitySubstituents

16.7 Trisubstituted Benzenes: Additivity of Effects

CH3

NO2

HNO3

H2SO4

CH3

NO2

NO2

1. two groups reinforce each other:

CH3

OH

CH3

OH

Br2

Br

2. two groups oppose each other: more powerful directing group wins, but mixture of products often result

CH3 CH3

Cl Cl

Cl2

FeCl3

CH3Cl

Cl

ClCH3

ClCl

+

NOT formed

too hindered

3. sterically hindered site: further substitution rarely occurs between the two groups in a metadisubstituted compound

CH3 CH3

HNO3

H2SO4

O2NNO2 NO2

CH3

NO2

NO2

+

- alternative preparation 1,2,3-trisubstituted compound

16.8 Nucleophilic Aromatic Substitution

nucleophilic aromatic substitution: no SN1, SN 2 mechanism

Cl

NO2

OH

NO2

1. NaOHO2N NO2 O2N NO2

2. H3O+ + Cl-

100%

Cl+ Cl-

sp2 orbital (unstable)

Xno SN1 reaction

Cl

X no SN2 reaction

HO-

addition/elimination mechanism

Cl

NO2

-OHCl

NO2

OHOH

NO2

+ Cl-

Meisenheimer complex

- nucleophilic aromatic substitution occurs only if the aromatic ring has electron withdrawing group(s) in ortho or para position to the halogen- meta substituent has no resonance stabilization

Cl

NO2

-OHCl

NO2

OH

Cl

N

OH

O

Oortho

Cl -OHCl

OH

ClOHpara

O2N O2N NO

O

Cl -OHCl

OHmeta

NO2 NO2

X no stabilization of chargeby nitro group

nucleophilic aromatic substitution: need ortho or para EWG

16.9 Benzynenucleophilic aromatic substitution of non-activated system; need high temperature and high pressure

Cl OH

1. NaOH, H2O, 340oC, 2500psi

2. H3O++ NaCl

Cl OHH -OH H2O H

- HClelimination addition

Benzyne

benzyne intermediate; elimination/addition mechanism

Cl NH3

H KNH2 NH3H

additionBenzyne

**

HNH3

+* *

50% 50%

symmetrical

NH3

evidence for benzyne mechanism: 14C labeling at C1

BrH KNH2

Benzynedienophile

NH3

O

O

Diels-Alder adduct

trapping benzyne intermediate

C

C

C C

C

C

H

H H

H

16.10 Oxidation of Aromatic CompoundsOxidation of Alkylbenzene Side Chainsaromatic rings; inert to KMnO4benzylic CH2: oxidized to -COOH by KMnO4, Na2Cr2O7

COOHKMnO4

H2O

CH3

CH3

CH3

O2

Co (III)

COOH

COOH

industrial procedure

CH3C

CH3CH3

KMnO4

H2O NO reaction

attack benzylic C-H bonds

Bromination of Alkylbenzene Side Chains

NBS

(PhCO2)2CCl4

Br

N

O

H

O

+

R

H H

Br R

H

HBr

Br2 R

H Br

Br+

N

O

H

O

+N

O

Br

O

+HBr Br2

radical mechanism

H

H

H

H

H

H

H

H

resonance stabilized benzylic radical

16.11 Reduction of Aromatic Compounds

Catalytic Hydrogenation of Aromatic Ringsaromatic rings; inert to normal hydrogenation conditions

EtOH

H2, Pd

O O

CH3

CH3

H2 (2000 psi)

EtOH

25oC

CH3

CH3100%

Pt

but, at high pressure of H2 and high temperature or use reactive rhodium catalyst; reduced to cycloalkanes

HOEtOH

25oCRh/C

H2(1 atm)HO

100%

Reduction of Aryl Alkyl Ketones; neighboring carbonyl groups are reactive under reducing condition

EtOH

H2, Pd

OO

Cl

AlCl3

Cl

AlCl3+

EtOH

H2, Pd

OO2N H2N

nitro groups are reduced under the reaction conditions

synthesis of complex molecules starting from simple precursors;- pharmaceutical industry: new drugs- chemical industry: economical routes to known compounds- academic: applications + pure challenges

planning synthesis needs- knowledge about organic reactions- practical ability: any problems

retrosynthetic analysis: design reaction schemes backward in case complex molecules

NO2

Cl

?.....

NO2

Cl Cl

NO2HNO3H2SO4Cl2, FeCl3

X

HNO3H2SO4

16.12 Synthesis of Trisubstituted Benzenes

Br?

COOH

Br

Br2, FeBr3

COOH

COOH

Br

CH3

KMnO4

BrCH3ClAlCl3

CH3

Br2, FeBr3

Br2, FeBr3

CH3Cl, AlCl 3

Cl

NO2

Cl

NO2

HNO3H2SO4

;Cl

NO2

no correct isomerdeactivated ringwill not undergoFriedel-Craft rxn

ClO

H2, Pd/C

O

Combinatorial ChemistryChemistry @ Work

++

N

N

R1

R4O

R3

R2

Benzodiazepine library(R1-R4 are various substituents)

Chemistry @ Work

2,180,106 compounds

Chapter 16

Problem Sets

28, 33, 35, 40, 54, 64, 70