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Electrophilic Aromatic Substitution. Part 2. Meta Directors. A. Highly Electron Withdrawing Groups. -CF 3. B. Atom in a Multiple Bond to a More Electronegative Atom. CF 3. CF 3. +. +. H 3 C. F 3 C. C. C. H 2 SO 4. NO 2. +. HNO 3. META DIRECTORS. NET RXN.

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meta directors
Meta Directors

A. Highly Electron Withdrawing Groups

-CF3

B. Atom in a Multiple Bond to a More Electronegative Atom

slide3

CF3

CF3

+

+

H3C

F3C

C

C

H2SO4

NO2

+

HNO3

META DIRECTORS

NET

RXN

  • A methyl group is electron-donating and stabilizes a carbocation.
  • Because F is so electronegative, a CF3 group destabilizes a carbocation.
carbocation stability controls regioselectivity

CF3

CF3

CF3

NO2

H

H

H

H

H

+

H

+

+

H

H

H

H

H

H

NO2

NO2

H

H

H

gives ortho

gives para

gives meta

less stable

more stable

Carbocation Stability Controls Regioselectivity
ortho nitration of trifluoromethyl benzene

CF3

CF3

CF3

NO2

NO2

NO2

H

H

H

+

H

H

H

+

+

H

H

H

H

H

H

H

H

H

ortho Nitration of (Trifluoromethyl)benzene

this resonance form is destabilized

para nitration of trifluoromethyl benzene

CF3

CF3

CF3

H

H

H

H

H

H

+

+

+

H

H

H

H

H

H

NO2

NO2

H

H

NO2

H

para Nitration of (Trifluoromethyl)benzene

this resonance form is destabilized

meta nitration of trifluoromethyl benzene

CF3

CF3

CF3

H

H

H

H

H

H

+

+

+

H

H

H

H

H

H

NO2

NO2

NO2

H

H

H

meta Nitration of (Trifluoromethyl)benzene

none of the resonance forms of the rate-determining intermediate in the meta nitration of (trifluoromethyl)benzene have their positive charge on the carbon that bears the CF3 group

slide8

Electron-withdrawing Groups (EWGs) DestabilizeIntermediates for ortho and para Substitution

EWG

EWG

X

H

H

H

+

+

H

H

H

H

H

X

H

H

—CF3 is a powerful EWG. It is strongly deactivating and meta directing

meta directors9
Meta Directors

A. Highly Electron Withdrawing Groups

-CF3

B. Atom in a Multiple Bond to a More Electronegative Atom

slide10

Groups With an Atom in a Multiple Bond to a More Electronegative Atom Have a Positive Formal Charge or d+ on Atom Directly Bonded to Ring

  • Resonance Effect
  • Inductive Effect
slide13

Electron-withdrawing Groups (EWGs) DestabilizeIntermediates for ortho and para Substitution

EWG

EWG

X

H

H

H

+

+

H

H

H

H

H

X

H

H

—CF3 is a powerful EWG. It is strongly deactivating and meta directing

slide15

O2N

Cl

HO3S

O

O

O

O

2 SO3

Cl2

HNO3

CH

CCl

SO3H

CCl

CH

H2SO4

FeCl3

H2SO4

substituent effects in electrophilic aromatic substitution
Substituent Effects in Electrophilic Aromatic Substitution
  • Classification of Substituents in Electrophilic Aromatic Substitution Reactions

Strongly activating

Weakly Activating

Standard of comparison is H

Weakly Deactivating

Strongly deactivating

generalizations
Generalizations

1. All activating substituents are ortho-para directors.

2. Halogen substituents are slightly deactivating but ortho-para directing.

3. Strongly deactivating substituents are meta directors.

rate effects anything that makes the ring more nucleophilic increases reaction rate
Rate EffectsAnything that makes the ring more nucleophilic increases reaction rate
  • Inductive Effects
    • Responsible for weakly activating/deactivating
  • Resonance Effects
    • Responsible for strongly activating/deactivating
weakly electron releasing groups ergs inductive effect weak activators
Weakly Electron-Releasing Groups (ERGs)Inductive EffectWeak Activators

are ortho-para directing and activating

d+

d-

ERG

ERGs include —R, —Ar, and —C=C

R groups are electron donating by dipole;

Aromatic ring more nucleophilic and more

susceptible to attack by electrophile

strongly electron releasing groups ergs resonance effect strong activators

ERG

Strongly Electron-Releasing Groups (ERGs)Resonance EffectStrong Activators

are ortho-para directing and activating

ERGs with a lone pair on the atom directlyattached to the ring are ortho-para directingand strongly activating

slide22

O

••

••

••

ERG =

OH

OR

OCR

O

NH2

NHR

NR2

NHCR

Groups that are electron releasing by resonance

delocalize a negative formal charge through out

the benzene ring

All of these are ortho-para directingand strongly to very strongly activating

slide23
Strong Activators Delocalize a (-) Formal Charge About Ring to Make it More Nucleophilic* Resonance Effect
slide24

Weakly Electron-Withdrawing Groups (EWGs)Inductive Effect

  • Halogens are very electronegative and
  • withdraw electron density away from ring

Benzene ring is becomes

more positive and less

susceptible to attack by

positive nucleophile

slide25

For halogens; the inductive effect outweighs

the resonance effect (even though halogens

have lone pair on them)

-F; most electronegative element

-Cl, -Br, - I ; not as electronegative as

F BUT larger than C so that resonance

effect is not as important

nitration of toluene vs chloro benzene

CH3

Cl

42

42

0.029

0.029

2.5

2.5

0.009

0.009

58

0.137

Nitration of Toluene vs. Chlorobenzene

-CH3 is an

ortho, para director

and ring activator

-Cl is an

ortho, para director

but a ring deactivator

-

slide27

Strongly Electron-Withdrawing Groups (EWGs)Resonance EffectStrong Deactivators

are meta directing and deactivating

EWG

Groups that are electron withdrawing by resonance

delocalize a positive formal charge through out the

benzene ring

slide28
Strong Deactivators Delocalize a (+) Formal Charge About Ring to Make it Less Nucleophilic* Resonance Effect
weak deactivators withdraw electron density from ring to make it less nucleophilic inductive effect
Weak Deactivators Withdraw Electron Density From Ring to Make it Less Nucleophilic* Inductive Effect
multiple subsistent effects

CH3

CH3

Br

Br2

FeBr3

NO2

NO2

86-90%

Multiple Subsistent Effects
  • If both constituents direct to the same spot;

then that location is major site of substitution.

multiple subsistent effects31

O

CH3

O

CH3

Multiple Subsistent Effects

CH3

CCH3

AlCl3

+

CH3CCl

CH3

99%

slide32

NHCH3

NHCH3

Br

Br2

FeBr3

Cl

Cl

87%

2. If the 2 groups direct to different positions;

regioselectivity is controlled by themost activating substituent

strongly activating

if the 2 groups direct to different sites and activating effects are similar

CH3

CH3

HNO3

NO2

H2SO4

C(CH3)3

C(CH3)3

88%

If the 2 groups direct to different sites; and activating effects are similar...

3. Substitution occurs ortho to the smaller group

steric effects control regioselectivity when electronic effects are similar

CH3

CH3

HNO3

H2SO4

CH3

CH3

NO2

98%

Steric effects control regioselectivity whenelectronic effects are similar

4. Position between two substituents is lastposition to be substituted

factors to consider in compound synthesis
Factors to Consider in Compound Synthesis
  • Order of introduction of substituents to ensure correct orientation
  • Sometimes electrophilic aromatic substitution must be combined with a functional group transformation
slide37

H

H

SO2OH

Br

FeBr3

heat

+

+

HOSO2OH

Br2

+

+

H2O

HBr

Reaction Review

A. Electrophilic Aromatic Substitution

slide38

O

O

H

H

H

CCH2CH3

NO2

C(CH3)3

H2SO4

AlCl3

AlCl3

+

+

+

(CH3)3CCl

CH3CH2CCl

HONO2

+

+

+

HCl

HCl

H2O

synthesis of m bromoacetophenone

Br

O

CCH3

Synthesis of m-Bromoacetophenone

Which substituent should be introduced first?

If bromine is introduced first, p-bromoacetophenone is major product.

para

meta

synthesis of m bromoacetophenone41

Br

O

CCH3

O

Br2

FeCl3

O

CCH3

Synthesis of m-Bromoacetophenone

CH3CCl

AlCl3

synthesis of p nitrobenzoic acid from toluene

CO2H

CH3

CH3

NO2

Synthesis of p-Nitrobenzoic Acid from Toluene

Which first? (oxidation of methyl group or nitration of ring)

substitution in naphthalene

H

H

O

1

H

H

CCH3

O

2

CH3CCl

H

H

AlCl3

H

H

Substitution in Naphthalene

Two possible sites for

electrophilic aromatic

substitution

faster at C-1 than at C-2

eas in naphthalene

E

H

+

EAS in Naphthalene

E

H

when attack is at C-1

carbocation is stabilized by allylic resonance

benzenoid character of other ring is maintained

+

There are 4 Resonance Structure With the Benzene

Ring Intact in C-1 Substitution

slide46

Electrophilic Aromatic Substituion Mechansim

  • Form Strong Electrophile
  • Electrophile adds to aromatic ring
    • See next slide. There are 4 resonance
    • Structures with one aromatic ring intact.
  • Restoration of aromaticity
eas in naphthalene48

E

E

+

H

H

+

EAS in Naphthalene

when attack is at C-2

in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is sacrificed

  • There are only 2 Resonance Structures with the
  • Benzene Ring Intact in C-2 Substitution
pyridine 6 membered ring

N

Pyridine; 6-membered ring

d+

Pyridine is very unreactive; It’s rate of reaction

is slower than benzene

d-

Due to fact that lone pair is not part of aromatic

ring; dipole effect is more important than resonance

effect.

pyridine 6 membered ring52

SO3H

N

N

Pyridine; 6-membered ring

4

SO3, H2SO4

3

Pyridine can be sulfonated at high temperature.

EAS takes place at C-3.

3

HgSO4, 230°C

2

2

1

71%

there are no acylation alkylation or halogenation reactions for pyridine
There are no acylation, alkylation, or halogenation reactions for pyridine.

The catalysts used in the above reactions

(AlCl3, FeCl3) will bond to the lone pair

On the Nitrogen and be de-activated.

slide55
C-3 Substitution is preferred in pyridine because there will never be a resonance structure with +1 on electronegative N.
pyrrole furan and thiophene 5 membered rings

••

••

••

O

S

N

••

••

H

Pyrrole, Furan, and Thiophene5-membered rings

Have 1 less ring atom than benzene or pyridine to hold same number of  electrons (6).

 electrons are held less strongly.

These compounds are relatively reactive toward EAS.

example furan 5 membered ring

O

O

Example: Furan5-membered ring

undergoes EAS readilyC-2 is most reactive position

3

3

BF3

+

CH3CCl

CCH3

2

2

O

O

1

75-92%

slide60
There are more resonance structures in C-2 substitution than C-3 substitution in 5-membered heterocycle compounds.

C-2 Addition

slide61
There are more resonance structures in C-2 substitution than C-3 substitution in 5-membered heterocycle compounds.

C-3 Addition