Chapter 22 (Substituted Benzenes)

Question 1

Characteristics of C_Benzylic—H Bonds

Answer 1

• C_Benzylic—H bonds are weaker (i.e. lower bond-dissociation energy) than C_sp³—H bonds.
• C_Benzylic—H bonds are more acidic (i.e. lower pK_a value) than C_sp³—H bonds.

These atypical Benzylic properties are caused by the resonance stabilization facilitated by the adjacent phenyl group.

Question 2

Characteristics of Benzylic Alcohols

Answer 2

Benzylic alcohols are more easily oxidized than standard alcohol-containing compounds.

The oxidation of Benzylic alcohols requires the MnO₂ oxidative reagent. (Jones Oxidation and PCC are too strong of oxidation processes to effectively oxidize the Benzylic alcohol group.)

Question 3

Characteristics of Benzylic Halides

Answer 3

Benzylic halides are more reactive in SN1 reactions than standard alkyl halides.

This atypical Benzylic property is caused by the resonance stabilization facilitated by the adjacent phenyl group.

Question 4

Alkylbenzene ⟶ Benzylic Halide

Answer 4

Radical Benzylic Halogenation

Question 5

Reagents: Radical Benzylic Halogenation

Starting Material = Benzylic Alkane

Answer 5

• X₂, hv
• X₂, Δ

Question 6

Alkylbenzene ⟶ Haloalkylbenzene

Answer 6

Halide Electrophilic Aromatic Substitution

(Halide EAS)

Question 7

Reagents: Halide Electrophilic Aromatic Substitution

Starting Material = Benzylic Alkane

Answer 7

• X₂, FeX₃
• X₂, AlX₃

Question 8

Dominant Reaction: Radical Benzylic Halogenation vs. Electrophilic Aromatic Substitution

Answer 8

• Electrophilic Aromatic Substitution is favored if a Lewis-acid catalyst is present.
• Radical Halogenation is favored if heat (Δ) and/or light (hv) is added.

Question 9

BDE: C_Benzylic—H Bond

(BDE = Bond-Dissociation Energy)

Answer 9

87 kcal/mol

The relatively low BDE of C_Benzylic—H bonds is brought about by the resonance stabilization of the resulting benzylic radical. (Conjugation with the π electrons of the adjacent phenyl group delocalizes the radical throughout the benzene ring.)

Question 10

pK_a: C_Benzylic—H Bond

Answer 10

pK_a ≈ 41

The relatively high acidity of C_Benzylic—H bonds is brought about by the resonance stabilization of the resulting benzylic anion. (Conjugation with the π electrons of the adjacent phenyl group delocalizes the negative charge throughout the benzene ring.)

Question 11

Alkylbenzene ⟶ Benzylic Anion

Answer 11

n–Butyl Lithium Deprotonation

Question 12

Reagents: n–Butyl Lithium Deprotonation

Starting Material = Alkylbenzene

Answer 12

n–Butyl Lithium, TMEDA

n–Butyl Lithium = CH₃CH₂CH₂CH₂Li

Question 13

n–Butyl Lithium

Answer 13

n–Butyl Lithium is a strong base used to deprotonate C_Benzylic—H bonds (and C_Allylic—H bonds).

Question 14

Why does SN1 Addition to a C_Benzylic—H bond always occur at the Carbon_Benzylic (instead of another resonance-form’s cationic Carbon)?

Answer 14

SN1 attack at the Carbon_Benzylic creates the most stable addition product because the benzene’s aromaticity is maintained.

SN1 attack at a cationic Carbon of another resonance form would create a less stable addition product because the benzene’s aromaticity would be destroyed.

Question 15

1° Alkylbenzene ⟶ Acylbenzene

Answer 15

Room-Temperature Jones Oxidation

The room-temperature Jones Oxidation reaction cannot break C—C bonds.

Question 16

1° Alkylbenzene ⟶ Benzoic Acid

Answer 16

Heated Jones Oxidation

The heated Jones Oxidation reaction will break C_Benzylic—C bonds.

Question 17

Reagents: Room-Temperature Jones Oxidation

Answer 17

• Na₂Cr₂O₇, H₂SO₄
• CrO₃, H₂O, H₂SO₄

Question 18

Reagents: Heated Jones Oxidation

Answer 18

1. KMnO₄, Δ
2. H₂O, H₂SO₄

1. Na₂Cr₂O₇, H₂SO₄, Δ
2. H₂O, H₂SO₄

Question 19

Why is the Heated Jones Oxidation reaction able to break C_Benzylic—C bonds?

Answer 19

The C_Benzylic—C bond is a weak C—C bond, so it is readily broken under the strong/unstable Jones Oxidation conditions.

Question 20

Benzylic Alcohol ⟶ Benzylic Carbonyl

Answer 20

MnO₂ Oxidation

Question 21

Reagents: MnO₂ Oxidation

Starting Material = Benzylic Alcohol Compound

Answer 21

MnO₂ Oxidation

MnO₂ is a mild oxidizing agent that only oxidizes C_Benzylic—OH bonds (and C_Allylic—OH bonds).

Question 22

Benzylic Ether ⟶ 1° Alkylbenzene

Answer 22

Benzylic Hydrogenolysis

Benzylic Deprotection

Typical C_Benzylic—O bonds do not undergo Hydrogenolysis (within these conditions).

Question 23

Benzylic Ether ⟶ Alcohol

Answer 23

Benzylic Hydrogenolysis

Benzylic Deprotection

Typical C_Benzylic—O bonds do not undergo Hydrogenolysis (within these conditions).

Question 24

Reagents: Benzylic Hydrogenolysis

Answer 24

H₂, Pd-C

Any transition-metal catalyst can be used during the Benzylic Hydrogenolysis reaction (in place of Pd-C).

Question 25

Alcohol ⟶ Benzylic Ether/Ester

Answer 25

Benzylic Protection

The protected Benzylic ether product is stable under basic conditions and weakly acidic conditions.

Question 26

Characteristics of Benzylic Ether

Answer 26

• Stable under basic conditions and weakly acidic conditions.
• Does NOT react with strong bases nor organometallic reagents.

Benzylic ether compounds are highly stable.

Question 27

Reagents: Benzylic Protection

Answer 27

1. NaH
2. Benzylic Halide

Question 28

Acidity: Phenols vs. Alcohols

Answer 28

Phenols are considerably more acidic than alchols (and water) due to the resonance stabilization of the conjugate Phenoxide base.

• pK_a of Phenol ≈ 10
• pK_a of Alcohol/Water ≈ 16

Question 29

Basicity: Phenols vs. Alcohols

Answer 29

Phenols are considerably less basic than alchols/water due to the conjugation between the Oxygen_Phenolic and the Benzene ring.

(The π-electron conjugation delocalizes the Phenolic electrons to decrease the Phenol’s reactivity and lower the likelihood of protonation.)

• The positive charge on the Phenol’s conjugate acid cannot be stabilized via delocalization/conjugation with the Benzene ring (which causes this protonated form to be relatively unstable).
• Phenols can ONLY be protonated by strong acids.

Question 30

Acidity of Phenols: Electron-Withdrawing Groups

EWG = Electron-Withdrawing Group

Answer 30

• Ortho/Para-Position: EWGs increase the acidity of the Phenol (by stabilizing/delocalizing the Phenoxide base’s negative charge).
• Meta-Position: EWGs minimally impact the acidity of the Phenol (via inductive stabilization of the Phenoxide base’s negative charge).

Question 31

Acidity of Phenols: Electron-Donating Groups

EDG = Electron-Donating Group

Answer 31

• Ortho-/Para-Position: EDGs decrease the acidity of the Phenol (by destabilizing/localizing the Phenoxide base’s negative charge).
• Meta-Position: EDGs minimally impact the acidity of the Phenol (via inductive destabilization of the Phenoxide base’s negative charge).

Question 32

Phenol ⟶ Alkoxybenzene

Answer 32

Williamson Ether Synthesis

Phenolic Protection

Question 33

Reagents: Williamson Ether Synthesis

Answer 33

NaOH, CH₃I

Question 34

Alkoxybenzene ⟶ Phenol

Answer 34

Alkoxybenzene Cleavage

Phenolic Deprotection

Question 35

Reagents: Alkoxybenzene Cleavage

Answer 35

• HBr, Δ
• HI, Δ

Question 36

Mechanism: Alkoxybenzene Cleavage

Phenolic Deprotection

Answer 36

1. The nucleophilic acid (H—X) protonates the alkoxy Oxygen.
2. The halide ion (X^–) performs SN2 attack at the alkoxy Carbon to cleave the C—O bond.

Question 37

Phenol ⟶ Phenyl Ester

Answer 37

Reactive Esterification

This Reactive Esterification mechanism ONLY occurs with acyl halides or anhydrides (i.e. carboxylic acid derivatives that are more reactive/electrophilic than standard carboxylic acids).

Question 38

Reagents: Reactive Esterification

Starting Material = Phenol

Answer 38

• Acyl Halide, NaOH
• Anhydride, NaOH

Question 39

Why are Phenols unable to react with standard Carboxylic Acids?

Answer 39

The conjugation between the Oxygen_Phenolic and the Benzene ring decreases the reactivity of the Oxygen_Phenolic π electrons (and causes the esterification reaction to be endothermic).

• Phenol esterification requires the use of the more-reactive acyl halide or anhydride carboxylic acid derivatives.

Question 40

Reactive Esterification: Purpose of NaOH

Answer 40

The NaOH base is used to deprotonate the Hydrogen_Phenolic to form the Phenoxide anion. (The Phenoxide anion is a more favorable nucleophile than Phenol to attack the electrophilic carboxylic acid derivative.)

The Phenol-deprotonation step is an acid-base reaction, so it occurs before NaOH can undergo nucleophilic addition to the carboxylic acid derivative. (The acyl halide or anhydride can be added to the reaction with NaOH without concern about non-esterification side reactions.)

Question 41

Phenol ⟶ Acyl Phenol

Answer 41

Friedel-Crafts Acylation

The alcohol group (on the Phenol) must be protected (via Williamson Ether Synthesis) prior to the acylation step to avoid esterification of the alcohol group.