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Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H...

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Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3 , H 2 SO 4 Ar-NO 2 + H 2 O 2. Sulfonation Ar-H + H 2 SO 4 , SO 3 Ar-SO 3 H + H 2 O 3. Halogenation Ar-H + X 2 , Fe Ar-X + HX 4. Friedel-Crafts alkylation
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Page 1: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Electrophilic Aromatic Substitution (Aromatic compounds)

Ar-H = aromatic compound1. Nitration

Ar-H + HNO3, H2SO4 Ar-NO2 + H2O

2. Sulfonation

Ar-H + H2SO4, SO3 Ar-SO3H + H2O

3. Halogenation

Ar-H + X2, Fe Ar-X + HX

4. Friedel-Crafts alkylation

Ar-H + R-X, AlCl3 Ar-R + HX

Page 2: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Friedel-Crafts alkylation (variations)

a) Ar-H + R-X, AlCl3 Ar-R + HX

b) Ar-H + R-OH, H+ Ar-R + H2O

c) Ar-H + Alkene, H+ Ar-R

Page 3: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

NO2

SO3H

Br

CH2CH3

HNO3

H2SO4

SO3

H2SO4

Br2, Fe

CH3CH2-Br

AlCl3

Page 4: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

toluene

CH3

CH3

CH3CH3

CH3

CH3CH3

CH3

CH3

Br

Br

NO2

NO2

SO3H

SO3H

HNO3

H2SO4

SO3

H2SO4

Br2, Fe

+

+

+

faster than the same reactions with benzene

Page 5: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

nitrobenzene

NO2

NO2

NO2

NO2

NO2

NO2

NO2

SO3H

Cl

HNO3

H2SO4

H2SO4

SO3

Cl2, Fe

slower than the same reactions with benzene

Page 6: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Substituent groups on a benzene ring affect electrophilic aromatic substitution reactions in two ways:

1) reactivity

activate (faster than benzene)

or deactivate (slower than benzene)

2) orientation

ortho- + para- direction

or meta- direction

Page 7: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

-CH3

activates the benzene ring towards EAS

directs substitution to the ortho- & para- positions

-NO2

deactivates the benzene ring towards EAS

directs substitution to the meta- position

Page 8: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Common substituent groups and their effect on EAS:

-NH2, -NHR, -NR2

-OH-OR-NHCOCH3

-C6H5

-R-H-X-CHO, -COR-SO3H-COOH, -COOR-CN-NR3

+

-NO2

incr

easi

ng r

eact

ivit

y ortho/para directors

meta directors

Page 9: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

OCH3

CHO

Br

Br2, Fe

HNO3, H2SO4

H2SO4, SO3

OCH3

Br

OCH3

Br

+ faster than benzene

CHO

NO2

slower than benzene

+

Br Br

SO3H

SO3H

slower than benzene

Page 10: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

If there is more than one group on the benzene ring:

1. The group that is more activating (higher on “the list”) will direct the next substitution.

2. You will get little or no substitution between groups that are meta- to each other.

Page 11: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

CH3

OH

NHCOCH3

CH3

CHO

OCH3

Br2, Fe

HNO3, H2SO4

Cl2, Fe

CH3

OH

Br

NHCOCH3

CH3

NO2

CHO

OCH3

Cl

CHO

OCH3

Cl+

Page 12: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Orientation and synthesis. Order is important!

synthesis of m-bromonitrobenzene from benzene:

NO2

Br

NO2HNO3

H2SO4

Br2, Fe

synthesis of p-bromonitrobenzene from benzene:

Br Br Br

NO2

NO2

+

Br2, Fe HNO3

H2SO4

You may assume that you can separate a pure para- isomer from an ortho-/para- mixture.

Page 13: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

note: the assumption that you can separate a pure para isomer from an ortho/para mixture does not apply to any other mixtures.

Br Br

Br

Br

Br

NO2 NO2

Br

NO2

Br

Br

NO2

Br

Br

Br

Br

NO2

+

+

Br2, Fe Br2, Fe

Br2, Fe Br2, FeHNO3H2SO4

HNO3H2SO4

synthesis of 1,4-dibromo-2-nitrobenzene from benzene

separate pure para isomer from ortho/para mixture

cannot assume that these can be separated!

Page 14: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

CH3

CH3

CH3

COOH

COOH COOH

CH3 COOH

NO2

NO2 NO2

+ ortho-

CH3Br

AlCl3

CH3Br

CH3Br

AlCl3

AlCl3

KMnO4

KMnO4

KMnO4

heat

heat

heat

HNO3

H2SO4

HNO3

H2SO4

synthesis of benzoic acids by oxidation of –CH3

Page 16: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

+HO-NO2 + H2SO4 H2O-NO2 + HSO4

-

+ +H2O-NO2 H2O + NO2

H2SO4 + H2O HSO4- + H3O+

HNO3 + 2 H2SO4 H3O+ + 2 HSO4- + NO2

+

nitration

Page 17: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

nitration:

1) HONO2 + 2 H2SO4 H3O+ + 2 HSO4- + NO2

+

2) + NO2+ RDS

electrophile

Page 18: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

H

NO2

H

NO2

H

NO2

H

NO2

resonance

Page 19: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Mechanism for nitration:

1) HONO2 + 2 H2SO4 H3O+ + 2 HSO4- + NO2

+

2) + NO2+

H

NO23)

RDS

NO2 + H+

H

NO2

Page 20: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Mechanism for sulfonation:

1) 2 H2SO4 H3O+ + HSO4- + SO3

2) + SO3

RDS

H

SO3-

3)H

SO3-

SO3- + H+

4) SO3- SO3H+ H3O+ + H2O

Page 21: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Mechanism for halogenation:

1) Cl2 + AlCl3 Cl-Cl-AlCl3

2) + Cl-Cl-AlCl3RDS

H

Cl+ AlCl4

-

3)H

Cl+ AlCl4

- Cl + HCl + AlCl3

Page 22: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Mechanism for Friedel-Crafts alkylation:

1) R-X + FeX3 R + FeX4-

2) + RRDS

3)

H

R

H

R+ FeX4

- R + HX + FeX3

Page 23: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

1) R-OH + H+ ROH2+

3) + RRDS

4)

H

R

H

RR

2) ROH2+ R + H2O

+ H+

Mechanism for Friedel-Crafts with an alcohol & acid

Page 24: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

2) + RRDS

3)

H

R

H

RR

1) C C + H+ R

+ H+

Mechanism for Friedel-Crafts with alkene & acid:

electrophile in Friedel-Crafts alkylation = carbocation

Page 25: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

“Generic” Electrophilic Aromatic Substitution mechanism:

1) + Y+Z-RDS

H

Y+ Z-

2)H

Y+ Z- Y + HZ

Page 26: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Why do substituent groups on a benzene ring affect the reactivity and orientation in the way they do?

electronic effects, “pushing” or “pulling” electrons by the substituent.

Electrons can be donated (“pushed”) or withdrawn (“pulled”) by atoms or groups of atoms via:

Induction – due to differences in electronegativities

Resonance – delocalization via resonance

Page 27: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

NH

H

unshared pair of electrons on the nitrogenresonance donating groups(weaker inductive withdrawal)

NR

R

NR

H

NR

R

R strong inductive withdrawal(no unshared pair of electrons on thenitrogen & no resonance possible

Page 28: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

H3C C

O

N

H

resonance donation(weaker inductive withdrawal)

HO

resonance donation(weaker inductive withdrawal)

RO

resonance donation(weaker inductive withdrawal)

Page 29: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

resonance donation

H3Cinductive donationsp3 sp2 ring carbon

inductive withdrawal X—

Page 30: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

HC

O

HOC

O

ROC

O

RC

O

resoance withdrawal andinductive withdrawal

Page 31: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

NO

O

resonance andinductive withdrawal

resonance andinductive withdrawal

CN

Page 32: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Common substituent groups and their effect on reactivity in EAS:

-NH2, -NHR, -NR2

-OH-OR-NHCOCH3 electron donating-C6H5

-R-H-X-CHO, -COR-SO3H-COOH, -COOR electron withdrawing-CN-NR3

+

-NO2

incr

easi

ng r

eact

ivit

y

Page 33: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Electron donating groups activate the benzene ring to electrophilic aromatic substitution.

1. electron donating groups increase the electron density in the ring and make it more reactive with electrophiles.

2. electron donation stabilizes the intermediate carbocation, lowers the Eact and increases the rate.

H Y

CH3

Page 34: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

H Y

NO2

Electron withdrawing groups deactivate the benzene ring to electrophilic aromatic substitution.

1. electron withdrawing groups decrease the electron density in the ring and make it less reactive with electrophiles.

2. electron withdrawal destabilizes the intermediate carbocation, raising the Eact and slowing the rate.

Page 35: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

CF3

PH2

PO3H

electron withdrawing = deactivating & meta-director

electron withdrawing = deactivating & meta-director

electron donating = activating & ortho-/para-director

Page 36: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Br2, FeBr + ortho-

NO2

Br2, Fe

NO2Br + ortho-

O

OBr2, Fe

O

O

Br+ ortho-

Page 37: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

How to draw resonance structures for EAS

YH

Y

HY

HY

Page 38: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

G G G

G G G

G G

H H HY Y Y

HY

HY

HY

H Y H Y

G

H Y

ortho-attack

meta-attack

para-attack

Page 39: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

G

HY

G

H Y

If G is an electron donating group, these structures are especially stable.

Page 40: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

G G G

G G G

G G

H H HY Y Y

HY

HY

HY

H Y H Y

G

H Y

ortho-attack

meta-attack

para-attack

Page 41: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Electron donating groups stabilize the intermediate carbocations for ortho- and para- in EAS more than for meta-. The Eact’s for ortho-/para- are lower and the rates are faster.

Electron donating groups direct ortho-/para- in EAS

Page 42: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

G

HY

G

H Y

If G is an electron withdrawing group, these structures are especially unstable.

Page 43: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

G G G

G G G

G G

H H HY Y Y

HY

HY

HY

H Y H Y

G

H Y

ortho-attack

meta-attack

para-attack

Page 44: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Electron withdrawing groups destabilize the intermediate carbocations for ortho- and para- in EAS more than for meta-. The Eact’s for ortho-/para- are higher and the rates are slower.

Electron withdrawing groups direct meta- in EAS

Page 45: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Halogens are electron withdrawing but are ortho/para directing in EAS.

The halogen atom is unusual in that it is highly electronegative but also has unshared pairs of electrons that can be resonance donated to the carbocation.

Page 46: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

X X X

X X X

X X

H H HY Y Y

HY

HY

HY

H Y H Y

X

H Y

X

H Y

X

HY

ortho-

meta-

para-

halogens are deactivating in EAS but direct ortho and para

Page 47: Electrophilic Aromatic Substitution (Aromatic compounds) Ar-H = aromatic compound 1. Nitration Ar-H + HNO 3, H 2 SO 4  Ar-NO 2 + H 2 O 2.Sulfonation.

Common substituent groups and their effect on EAS:

-NH2, -NHR, -NR2

-OH-OR-NHCOCH3

-C6H5

-R-H-X-CHO, -COR-SO3H-COOH, -COOR-CN-NR3

+

-NO2

incr

easi

ng r

eact

ivit

y ortho/para directors

meta directors


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