Electrophilic/Nucleophilic Aromatic Substitution (Chapter 16 +22)

Question 1

Effect of EWD on Benzene EAS

EWD = Electron-Withdrawing Groups

Answer 1

• The para– and orth– positions become more positively charged.
• The negativity of the meta– position is unaffected.

Since the meta– position is more negatively charged relative to the para–/ortho– positions, EAS reactions with EWD-substituted benzes are meta-directing.

Question 2

Electron-Withdrawing Group

Electrophilic Aromatic Substitution

Answer 2

Meta-Directing

Since the benzene ring is more electron-deficient, it will participate in EAS reactions at a slower rate.

Question 3

Effect of EDG on Benzene EAS

EDG = Electron-Donating

Answer 3

• The para– and orth– positions become more negatively charged.
• The negativity of the meta– position is unaffected.

Since the meta– position is more negatively charged relative to the para–/ortho– positions, EAS reactions with EWD-substituted benzes are meta-directing.

Question 4

Electron-Donating Group

Electrophilic Aromatic Substitution

Answer 4

Para–Directing + Ortho–Directing

Since the benzene ring is more electron-dense, it will participate in EAS reactions at a faster rate.

Question 5

Ortho-Directing Groups + Para-Directing Groups

Answer 5

• —X
• —R
• —OR
• —OCOR
• —OH
• —NHCOR
• —NR₂
• —NHR
• —NH₂

Question 6

Meta-Directing Groups

Answer 6

• —COOH
• —COOR
• —COR
• —CF₃
• —CN
• —SO₃⁺H
• —NO₂
• —NR₃⁺

Question 7

Tri-Halogenation of EDG-Substituted Benzene

Answer 7

Since an EDG-substituted benzene is more reactive than typical benzene, EAS of a halogen to an EDG-substituted benzene proceeds to the tri-halogenated product.

Monosubstitution of the EDG-substituted benzene can only occur via the use of protecting groups to the ortho-/para- positions.

Question 8

Acid Catalyst for EDG–Benzene EAS Reactions

Answer 8

• Strong EDG-substituted benzenes do not require an acid catalyst for EAS reactions to occur.
• Weak EDG-substituted benzenes REQUIRE an acid catalyst for EAS reactions to occcur.

• Strong electron-donating groups (e.g. alkoxy groups) contribute electronegativity via resonance.
• Weak electron-donating groups (e.g. alkyl groups) contribute electronegativity via hyperconjugation.

Question 9

Steric Effects w/ EDG-Substituted Benzenes

EAS

Answer 9

Substitution at the para-position is favored (over substitution at the ortho-position) due to steric repulsion/effects at the ortho-position.

All electron-donating groups (EXCEPT alcohol groups and amino groups and methyl groups) sterically hinder EAS at the ortho-position, yet larger groups will have a greater steric effect.

Question 10

Why is the resonance effect of halogens weaker than their inductive effect?

EAS

Answer 10

Due to being highly electronegative, halogen atoms exhibit a strong inductive withdrawal force and possess relatively unpolarizable lone-pair π electrons. The inductive withdrawal force is stronger than the electron-donating resonance effect, so the halogen is weakly electron-withdrawing.

Halogen-substituents weakly deactivate the benzene ring, yet they are ortho-directing and para-directing.

Question 11

Halogen Substituents in EAS Reactions

Answer 11

• The reactivity is controlled by the electron-withdrawing effects of the halogen.
• The regioselectivity is controlled by the electron-donating resonance effect of the halogen.

Question 12

Why are Nitrogen lone pair electrons more polarizable than Oxygen lone-pair electrons?

Answer 12

Nitrogen has a lower electronegativity than Oxygen, so its lone-pair electrons exhibit are better able to delocalize.

Question 13

Which electron-donating groups exhibit a minimal steric effect?

EAS

Answer 13

• —OH
• —NH₂
• —CH₃
• —OCH₃
• —CH₂CH₃
• —CO₂H

• Substituents that are larger than these groups will greatly restrict EAS at the ortho-position.
• EAS at a position ortho to any two substituents will always be sterically restricted.

Question 14

Reactivity of Disubstituted Benzenes

Answer 14

The electronic effects of individual substituents are additive.

E.g. Two electron-withdrawing groups will express a greater overall deactivating effect on the benzene than any single electron-withdrawing group.

Question 15

Regioselectivity of Disubstituted Benzenes

EAS

Answer 15

The strongest activator (i.e. strongest electron-donating group) determines the electropilic substitution pattern to the benzene.

A weakly electron-donating groups will be a stronger activator than a stongly electron-withdrawing group.

Question 16

Amino Group to Benzene

—NH₂

Answer 16

Reduction of Nitro Group

Nitro = —NO₂

Question 17

Primary Alkyl to Benzene

—R

Answer 17

Reduction of Acyl Group

Acyl = —COR

Question 18

Alkoxy to Benzene

—OR

Answer 18

Williamson Ether Synthesis w/ Phenol

Question 19

Amide to Benzene

—NHOR

Answer 19

Acetylation of Amino Group

Acetyl = CH₃—CO—Cl

Question 20

Synthesis of Benzylic Alcohol

Answer 20

• Grignard Reagent
• Organolithium Reagent

Question 21

Monofunctionalization of Phenol

Alcohol-Substituted Benzene

Answer 21

The conversion of the alcohol group to an alkoxy group directs EAS monofunctionalization primarily to the para– position.

—OH → —OR

The alkoxy group causes para–position functionalization to be favored due to the steric effects/repulsion on the ortho–positions.

Question 22

Monofunctionalization of Aniline

Amino-Substituted Benzene

Answer 22

The conversion of the amino group to an amide group directs EAS monofunctionalization primarily to the para– position.

—NH₂ → —NHCOR

The amide group causes para–position functionalization to be favored due to the steric effects/repulsion on the ortho–positions.

Question 23

Functionalization of Benzenes w/ Strong EDG Substituents

EAS

Answer 23

EAS reactions will proceed until the tri-substituted product is formed, unless the strongly activating substituent imparts steric effects.

If the strong EDG substituent imparts steric effects, monofunctionalization at the para–position will be highly favored.

Question 24

Unreactive Aryl Compounds in Friedel-Crafts Acylation

Answer 24

Beneze compounds with strongly deactivating substituents will not undergo Friedel-Craft Acylation (due to the relatively low reactivity/electrophilicity of the acylium intermediate).

• Strongly deactivating substituents include all resonance electron-withdrawing groups (and CF₃).
• Unreactive Aryl compounds will undergo EAS reactions with all cationic electrophiles.

Question 25

Requirements of Nucleophilic Aromatic Substitution

NAS = Nucleophilic Aromatic Susbtitution

Answer 25

• Benzene compound must be highly electron-deficient (i.e. must be atleast two strong EDG substituents).
• The EDG substituents must be placed at the ortho–position and para–position.
• Nucleophilic substitution must occur at the carbon possessing a halide substituent.
• A strong nucleophilie is required for nucleophilic substitution to occur.

The placement of EDG substituents at the para-position and ortho-position enables delocalized stabilization of the negative charge. (The placement of EDG substituents at the meta-positions will not delocally stabilize the negative charge, so nucleophilic attack to meta-substituted Aryl compounds will not occur.)

Question 26

RDS of NAS

RDS = Rate-Determining Step
NAS = Nucleophilic Aromatic Substitution

Answer 26

Nucleophilic Addition to the Aryl Compound

• The nucleophilic addition to the benzene ring is slow due to the resulting loss of aromaticity.
• The second step (i.e. elimination of the halide) is rapid due to the regeneration of aromaticity.

Question 27

Nucleophiles w/ NAS Capability

Answer 27

• ^–OH (e.g. NaOH)
• ^–OR (e.g. NaOCH₃)
• ^–NH₂ (e.g. KNH₂)
• NH₃
• ^–CN (e.g. NaCN)
• ^–X (e.g. NaI)

Question 28

Aryl Cation

Answer 28

A highly unstable substituted-benzene cation that is not stabilized by aromaticity or resonance.

The positive charge results from an empty sp²–hybridized carbon orbital, which is not in-plane with the arene ring (and thus cannot be stabilized by the arene π-orbital overlap).

Question 29

Nitrile to Benzene

—C☰N

Answer 29

React Diazonium Group w/ Copper(I) Cyanide

—N☰N + CuCN → —C☰N

Question 30

Functions of Reduction/Removal of Diazonium Group

Answer 30

• Convert C—NO₂ to C—H
• Convert C—NH₂ to C—H
• Convert C—N₂ to C—H

Reduction can function to replace nitro groups, amino groups, and diazonium groups with hydrogen atoms.

Question 31

EAS of Halogens into Aryl Compounds

Halogenation

Answer 31

• Bromination of Benzene w/ Acid Catalyst
• Bromination of Benzene w/ Copper(I) Ion

Question 32

Jones Oxidation

Answer 32

Conversion of a Secondary Carbon to a Ketone

Two C—H bonds are replaced with two C—O bonds.