Chapter 22 (Substituted Benzenes) Flashcards
Characteristics of CBenzylic—H Bonds
- CBenzylic—H bonds are weaker (i.e. lower bond-dissociation energy) than Csp3—H bonds.
- CBenzylic—H bonds are more acidic (i.e. lower pKa value) than Csp3—H bonds.
These atypical Benzylic properties are caused by the resonance stabilization facilitated by the adjacent phenyl group.
Characteristics of Benzylic Alcohols
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.)
Characteristics of Benzylic Halides
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.
Alkylbenzene ⟶ Benzylic Halide
Radical Benzylic Halogenation
Reagents: Radical Benzylic Halogenation
Starting Material = Benzylic Alkane
- X2, hv
- X2, Δ
Alkylbenzene ⟶ Haloalkylbenzene
Halide Electrophilic Aromatic Substitution
(Halide EAS)
Reagents: Halide Electrophilic Aromatic Substitution
Starting Material = Benzylic Alkane
- X2, FeX3
- X2, AlX3
Dominant Reaction: Radical Benzylic Halogenation vs. Electrophilic Aromatic Substitution
- 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.
BDE: CBenzylic—H Bond
(BDE = Bond-Dissociation Energy)
87 kcal/mol
The relatively low BDE of CBenzylic—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.)
pKa: CBenzylic—H Bond
pKa ≈ 41
The relatively high acidity of CBenzylic—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.)
Alkylbenzene ⟶ Benzylic Anion
n–Butyl Lithium Deprotonation
Reagents: n–Butyl Lithium Deprotonation
Starting Material = Alkylbenzene
n–Butyl Lithium, TMEDA
n–Butyl Lithium = CH3CH2CH2CH2Li
n–Butyl Lithium
n–Butyl Lithium is a strong base used to deprotonate CBenzylic—H bonds (and CAllylic—H bonds).
Why does SN1 Addition to a CBenzylic—H bond always occur at the CarbonBenzylic (instead of another resonance-form’s cationic Carbon)?
SN1 attack at the CarbonBenzylic 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.
1° Alkylbenzene ⟶ Acylbenzene
Room-Temperature Jones Oxidation
The room-temperature Jones Oxidation reaction cannot break C—C bonds.
1° Alkylbenzene ⟶ Benzoic Acid
Heated Jones Oxidation
The heated Jones Oxidation reaction will break CBenzylic—C bonds.
Reagents: Room-Temperature Jones Oxidation
- Na2Cr2O7, H2SO4
- CrO3, H2O, H2SO4
Reagents: Heated Jones Oxidation
- KMnO4, Δ
- H2O, H2SO4
- Na2Cr2O7, H2SO4, Δ
- H2O, H2SO4
Why is the Heated Jones Oxidation reaction able to break CBenzylic—C bonds?
The CBenzylic—C bond is a weak C—C bond, so it is readily broken under the strong/unstable Jones Oxidation conditions.
Benzylic Alcohol ⟶ Benzylic Carbonyl
MnO2 Oxidation
Reagents: MnO2 Oxidation
Starting Material = Benzylic Alcohol Compound
MnO2 Oxidation
MnO2 is a mild oxidizing agent that only oxidizes CBenzylic—OH bonds (and CAllylic—OH bonds).
Benzylic Ether ⟶ 1° Alkylbenzene
Benzylic Hydrogenolysis
Benzylic Deprotection
Typical CBenzylic—O bonds do not undergo Hydrogenolysis (within these conditions).
Benzylic Ether ⟶ Alcohol
Benzylic Hydrogenolysis
Benzylic Deprotection
Typical CBenzylic—O bonds do not undergo Hydrogenolysis (within these conditions).
Reagents: Benzylic Hydrogenolysis
H2, Pd-C
Any transition-metal catalyst can be used during the Benzylic Hydrogenolysis reaction (in place of Pd-C).
Alcohol ⟶ Benzylic Ether/Ester
Benzylic Protection
The protected Benzylic ether product is stable under basic conditions and weakly acidic conditions.
Characteristics of Benzylic Ether
- Stable under basic conditions and weakly acidic conditions.
- Does NOT react with strong bases nor organometallic reagents.
Benzylic ether compounds are highly stable.
Reagents: Benzylic Protection
- NaH
- Benzylic Halide
Acidity: Phenols vs. Alcohols
Phenols are considerably more acidic than alchols (and water) due to the resonance stabilization of the conjugate Phenoxide base.
- pKa of Phenol ≈ 10
- pKa of Alcohol/Water ≈ 16
Basicity: Phenols vs. Alcohols
Phenols are considerably less basic than alchols/water due to the conjugation between the OxygenPhenolic 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.
Acidity of Phenols: Electron-Withdrawing Groups
EWG = Electron-Withdrawing Group
- 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).
Acidity of Phenols: Electron-Donating Groups
EDG = Electron-Donating Group
- 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).
Phenol ⟶ Alkoxybenzene
Williamson Ether Synthesis
Phenolic Protection
Reagents: Williamson Ether Synthesis
NaOH, CH3I
Alkoxybenzene ⟶ Phenol
Alkoxybenzene Cleavage
Phenolic Deprotection
Reagents: Alkoxybenzene Cleavage
- HBr, Δ
- HI, Δ
Mechanism: Alkoxybenzene Cleavage
Phenolic Deprotection
- The nucleophilic acid (H—X) protonates the alkoxy Oxygen.
- The halide ion (X–) performs SN2 attack at the alkoxy Carbon to cleave the C—O bond.
Phenol ⟶ Phenyl Ester
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).
Reagents: Reactive Esterification
Starting Material = Phenol
- Acyl Halide, NaOH
- Anhydride, NaOH
Why are Phenols unable to react with standard Carboxylic Acids?
The conjugation between the OxygenPhenolic and the Benzene ring decreases the reactivity of the OxygenPhenolic 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.
Reactive Esterification: Purpose of NaOH
The NaOH base is used to deprotonate the HydrogenPhenolic 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.)
Phenol ⟶ Acyl Phenol
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.
