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 ## Footnote 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**. ## Footnote 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. ## Footnote * **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.) ## Footnote * 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 ## Footnote 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**). ## Footnote * 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.) ## Footnote 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 ## Footnote 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.