electrophilic aromatic substitution activating and directing effects of substituents already on the...

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Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

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Page 1: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Electrophilic Aromatic Substitution

Activating and Directing effects of substituents already on the ring

Page 2: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Products of Nitration

CH3 CH3

NO2

CH3

NO2

CH3

O2N

+ +HNO3

H2SO4

ortho meta para

63% 3% 34%

CN CN

NO2

CN

NO2

CN

O2N

+ +HNO3

H2SO4

17% 81% 2%

OH OH

NO2

OH

NO2

OH

O2N

+ +HNO3

H2SO4

50% 0% 50%

1 hr

48 hr

0.0003 hr

Page 3: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Mechanism of Electrophilic Aromatic Substitution

E

H

E

H

E

H

E+

E

H

GE

H

GE

H

GE

+G

With a substituent group G

Depending on the nature of the substituent, the substituent G may stabilize the carbocation intermediate and therefore speed the reaction, or it may raise the energy of the carbocation and slow the reaction. Substituents that make the ring react faster (than benzene) with electrophiles are called activators; those that make the ring react slower (than benzene) are called deactivators.

Page 4: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Substituent effects

• All activators also direct incoming electrophiles to the ortho- and the para-positions.

• Most deactivators direct incoming electrophiles to the meta position. The exceptions are the halogens, which are weakly deactivating yet ortho-para directing.

Page 5: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Classification of Substituents

H

F

Cl

Br

I

Benzene

o,p-directingdeactivators

o,p-directingactivators

Ar

R

NHCOCH3

OR NH2

OH

CHOCO2H

COR

O

CR

O

CN

SO3HNO2

NR3+

m-directingdeactivators

more activatingmore deactivating

Page 6: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Product Distribution in Nitration

(Percent %) (Percent %) X ortho meta para X ortho meta para

(meta-directing Deactivators) (ortho- and para-directing Deactivators)

-N(CH3)3 2 89 11 -F 13 1 86

-NO2 7 91 2 -Cl 35 1 64

-CO2H 22 77 2 -Br 43 1 56

-CN 17 81 2 -I 45 1 54

-CO2CH2CH3 28 72 2 (ortho- and para-directing Activators)

-COCH3 26 72 2 -CH3 63 3 34

-CHO 19 72 9 -OH 50 0 50

-NHCOCH3 19 2 79

Page 7: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

o,p-Activators (alkyl & aryl groups)

p

m

o

E

E

E

CH3

CH3

HE

CH3

H

H

E

CH3

H

HE

CH3

H

E

CH3

HE

CH3

H

H

E

CH3

H

H

E

CH3H

E

CH3

H

H

E

CH3

H

CH3

3º, especially stable

3º, especially stable

Page 8: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

o,p-Activators with a lp of electrons

OH

H

E

OH

H

H

E

OH

H

H

E

OHH

E

OH

HE

OH

HHE HE

OH

HE

OH

H

OH

OH

E

E

EHE

OH

H

E

OH

H

H

E

OH

H

E

OH

H

4 resonance forms

4 resonance forms

o-

m-

p-

Page 9: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

o,p-Deactivators (Halogens)

Cl

H

E

ClH

E

ClH

E

ClH

E

H

E

Cl

HE

Cl

H

E

Cl

HE HE

Cl

HE

Cl

Cl

Cl

E

E

EHE

Cl

Cl

Cl

H

E

4 resonance forms

4 resonance forms

o-

m-

p-

Page 10: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

meta-directing DeactivatorsCN

H

E

CNH

E

CNH

E

CN

H

E

CN

HE

CN

H

E

CN

HE

CN

HE

H

E

CN

HE

CN

CN

CN

E

E

E

Especially UNSTABLE**

Especially UNSTABLE**

o-

m-

p-

Page 11: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Additivity of substituent effects in disubstituted aromatic rings

• Rule 1: If the directing effects of two substituents reinforce each other, the predicted product predominates.

CH3

CO2H

CH3

CO2H

NO2HNO3

H2SO4

(o,p)

(m)

Page 12: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Additivity of substituent effects…

• Rule 2: If the directing effects of two substituents oppose each other, the more activating group dominates, but mixtures often result.

NH2

CH3

NH2

CH3

BrBr2

(FeBr3 catnot needed)

(o,p; STRONG activator)

(o,p; weak activator)

Page 13: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Additivity of substituent effects…

• Rule 3: Substitution almost never occurs between two substituents meta to each other.

CH3

Cl

CH3

SO3H

Cl

SO3

H2SO4

CH3

Cl

HO3S

CH3

Cl

SO3H

+

but not:

(o,p)

(o,p)

X (too crowded)

Page 14: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Additivity of substituent effects…

• Rule 4: With a bulky o,p- director and/or a bulky electrophile, para substitution predominates.

OCCH3

O

SO3H

OCCH3

O

SO3

H2SO4

(o,p; BULKY)

(HSO3+ is a

BULKY electrophile)

Page 15: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring
Page 16: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Mechanism

Page 17: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring
Page 18: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Halogenation of Benzene

Requires a Lewis acid catalyst

Reactivity: F2 >> Cl2 > Br2 >> I2

Page 19: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Catalyst

Page 20: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Mechanism (Cont’d)

Page 21: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Nitration of Benzene

Electrophile = NO2

⊕ (nitronium ion)

Page 22: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Mechanism

Page 23: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Sulfonation

r.d.s

repeat next slide

Page 24: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

repeat

Page 25: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Sulfonation & Desulfonation-useful!

(heat)

Page 26: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Friedel–Crafts Alkylation

Electrophile = R⊕ (not vinyl or aryl)

R = 2o or 3o

Page 27: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Friedel–Crafts Acylation

Acyl group:

Electrophile is R–C≡O⊕ (acylium ion)

Page 28: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

RX and Mechanism

Page 29: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Ch. 15 - 33

Acid chlorides (or acyl chlorides)

Prep

Page 30: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Ch. 15 - 35

(not formed)

Limitations of Friedel–Crafts Reactions

carbocations rearrangement

Page 31: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Ch. 15 - 36

1o cation (not stable)

Reason

3o cation

Page 32: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Ch. 15 - 3

Questions?

Page 33: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

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

generally give poor yieldsdeactivating gps

Page 34: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

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

strong electron withdrawing gps with acids

Not Friedel-Crafts reactive

Page 35: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Another problem: polyalkylations can occur

More common with activated aromatic rings

Page 36: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Substituents effect reactivity & regiochemistry of substitution

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

possibilities

metam

parap

Page 37: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Ch. 15 - 50

Ring is electron poor; Ring reacts slower than benzene with E+

Ring is electron rich; Ring reacts faster than benzene with E+

relative to benzene

Page 38: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Reactivity towards electrophilic aromatic substitution

Page 39: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Ch. 15 - 57

Regiochemistry: directing effect

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

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

Page 40: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring

Ch. 15 - 59

Page 41: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring
Page 42: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring
Page 43: Electrophilic Aromatic Substitution Activating and Directing effects of substituents already on the ring