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Organic Chemistry 2 > Carboxylic Acid Derivatives (Chapter 20) > Flashcards

Carboxylic Acid Derivatives (Chapter 20) Flashcards

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1
Q

What characteristics causes acyl halides to be highly reactive in addition-elimination reactions?

A
  • The halide atom (bonded to the carbonyl Carbon) withdraws electron density from the carbonyl Carbon, which increases the electrophilicity of the Carbon.
  • The halide atom is a stable leaving group, which causes nucleophilic attack at the carbonyl Carbon to be a favorable process.
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2
Q

Acyl Halide ⟶ Carboxylic Acid

A

Acyl Halide Hydrolysis

Irreversible

The acyl halide hydrolysis reaction is occurs very fast and is highly exothermic.

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3
Q

Acyl Halide ⟶ Ester

A

Acyl Halide Esterification

Irreversible

The acyl halide esterification reaction requires a weak base (i.e. Triethylamine).

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4
Q

Acyl Halide ⟶ Amide

A

Acyl Halide Amidification

Irreversible

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5
Q

Reagents: Acyl Halide Hydrolysis

Starting Material = Acyl Halide

A

H2O

A halide ion and acid (i.e. HX) are produced as byproducts of acyl halide hydrolysis.

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6
Q

Reagents: Acyl Halide Amidification

Starting Material = Acyl Halide

A
  • Option #1: 2 Amine
  • Option #2: Amine, N(Et)3
  • Option #3: Amine, Pyridine

  • Acyl Halide Amidification can occur only with 0°/1°/2° Amines. (Reactions of acyl halides with 3° Amines form acyl ammonium salts rather than amides.)
  • The second reagent (Amine or N(Et)3 or Pyridine) is used to neutralize the HX byproduct to prevent amide hydrolysis.
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7
Q

Reagents: Acyl Halide Esterification

Starting Material = Acyl Halide

A

R—OH, N(Et)3

The N(Et)3 (triethylamine) catalyst is added to neutralize the HX byproduct of acyl halide esterification.

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8
Q

Why do acyl halide addition-elimination reactions not require a catalyst?

A

The carbonyl Carbon (of the acyl halide) is highly electrophilic due to the electron-withdrawing effect of the halide atom, so the nucleophile is readily able to attack the Carbon without catalyst activation.

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9
Q

Mechanism: Acyl Halide Addition-Elimination

A
  1. Nucleophilic Attack at the Carbonyl Carbon
  2. Intramolecular Proton Transfer to Neutralize Charges
  3. π-Electron Rearragement to Eliminate the Halide
  4. Depronotation to Yield Nonionic Carbonyl Group

Nucleophilic attack at the carbonyl Carbon forms a sp3-hybridized tetrahedral intermediate.

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10
Q

Examples: Acyl Halide Addition-Elimination Reactions

A
  • Acyl Halide Hydrolysis
  • Acyl Halide Esterification
  • Acyl Halide Amidification
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11
Q

Why is protonation of the carbonyl Oxygen of acyl halides unfavorable?

A

The carbonyl Oxygen (of acyl halides) is weakly basic due to the poor positive-charge compatibility of the halide atom, so protonation results in a highly unstable conjugate acid compound.

Protonation of the carbonyl Carbon forms a resonance structure that places a positive charge on the halide atom. Since the halide is highly electronegative, it is highly unfavorable for it to possess a positive charge.

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12
Q

Why is Triethylamine added during acyl halide esterification?

A
  • N(Et)3 neutralizes the HX byproduct to prevent the ester hydrolysis side reaction from occurring. (Esters are stable only under neutral conditions or mildly basic conditions.)
  • N(Et)3 is a weak base, so it cannot deprotonate the alcohol reagent’s hydroxyl Hydrogen.
  • N(Et)3 does not react with acyl halides (to form amides) due to the steric hindrance about the Nitrogen atom.
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13
Q

Carboxylic Acid ⟶ Ester

Two Mechanisms

A
  • Heated Acid-Catalyzed Alcohol Addition
  • Two-Step Substitution-Esterification

The two-step substitution-esterification mechanism is a more efficient means to synthesize esters (from carboxylic acids) than acid-catalyzed alcohol addition.

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14
Q

Carboxylic Acid ⟶ Amide

Two Mechanisms

A
  • Heated Amine Addition
  • Two-Step Substitution-Amidification

The two-step substitution-amidification mechanism is a more efficient means to synthesize amides (from carboxylic acids) than acid-catalyzed alcohol addition.

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15
Q

Reagents: Heated Amine Addition

Starting Material = Carboxylic Acid

A

Amine, Δ

High heat is required for heated amide addition to occur.

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16
Q

Reagents: Heated Acid-Catalyzed Alcohol Addition

Starting Material = Carboxylic Acid

A

R—OH + H2SO4, Δ

A strong acid catalyst (e.g. H2SO4) and high heat are required for acid-catalyzed alcohol addition to occur.

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17
Q

Reagents: Two-Step Substitution-Esterification

Starting Material = Carboxylic Acid

A
  1. SOCl2 / PBr3
  2. Alcohol, N(Et)3
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18
Q

Reagents: Two-Step Substitution-Amidification

Starting Material = Carboxylic Acid

A
  1. SOCl2 / PBr3
  2. Amine, N(Et)3

The N(Et)3 is added during the second step to neutralize the HX byproduct.

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19
Q

Heated Amine Addition vs. Two-Step Substitution-Amidification

Carboxylic Acid ⟶ Amide

A
  • Substitution-Esterification can occur under standard reaction conditions, whereas Amide Addition requires high temperatures.
  • Substitution-Esterification is irreversible, whereas Alcohol Addition is reversible.

Two-Step Substitution-Amidification is a more favorable reaction than Heated Amine Addition.

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20
Q

Acid-Catalyzed Alcohol Addition vs. Two-Step Substitution-Esterification

Carboxylic Acid ⟶ Ester

A
  • Substitution-Esterification does not require a strong acid catalyst to occur, whereas Alcohol Addition does require a strong acid.
  • Substitution-Esterification can occur under mild reaction conditions, whereas Alcohol Addition requires high temperatures.
  • Substitution-Esterification is irreversible, whereas Alcohol Addition is reversible.

Two-Step Substitution-Esterification is a more favorable reaction than Acid-Catalyzed Alcohol Addition.

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21
Q

Drawbacks of Acid-Catalyzed Alcohol Addition

A
  • The mechanism requires highly unstable reaction conditions (i.e. strong acids + high temperatures).
  • The mechanism is reversible (via excess reagents or H2O removal).
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22
Q

Drawbacks of Heated Amine Addition

A
  • The mechanism requires highly unstable reaction conditions (i.e. high temperatures).
  • The mechanism is reversible (via excess reagents or H2O removal).
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23
Q

Acyl Halide ⟶ Anhydride

A

Acyl Halide Anhydride Synthesis

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24
Q

Reagents: Acyl Halide Anhydride Synthesis

A

R—O—OH, Δ

R—O—OH = Carboxylic Acid

The acyl halide anyhydride synthesis reaction produces acid (i.e. HX) as byproduct.

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25
Q

Mechanism: Acyl Halide Anhydride Synthesis

A
  1. The carbonyl Oxygen (of the carboxylic acid) attacks the carbonyl Carbon (of the acyl halide).
  2. An intramolecular proton transfer occurs to protonate the Oxygen of the halide-bonded Carbon.
  3. π-electron rearrangement forms an oxacarbenium intermediate and eliminates the halide.
  4. Deprotonation of the oxacarbenium Oxygen forms an anhydride compound.
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26
Q

Carboxylic Acid ⟶ Anhydride

A

Acyl Halide Anhydride Synthesis

The Carboxylic Acid Dehydration reaction can also be used to synthesize anhydrides (from carboxylic acids), but the mechanism is less efficient than Acyl Halide Anhydride Synthesis.

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27
Q

Reagents: Carboxylic Acid Dehydration

Starting Material = Carboxylic Acid

A

R—O—OH, Δ

R—O—OH = Carboxylic Acid

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28
Q

Why is Carboxylic Acid Dehydration less efficient than Acyl Halide Anhydride Synthesis?

Carboxylic Acid ⟶ Anhydride

A

Carboxylic acids are less reactive (i.e. less susceptible to nucleophilic attack) than acyl halides in addition-elimination mechanisms, so carboxylic acid dehydration occurs less readily.

Acyl halides are very reactive in addition-elimination mechanisms due to the carbonyl Carbon’s highly electrophilic character.

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29
Q

Acyl Halide ⟶ Ketone

A

Organocuprate Ketone Synthesis

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30
Q

Acyl Halide ⟶ ɑ,β-Unsaturated Ketone

A

(Alkenyl) Organocuprate Ketone Synthesis

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31
Q

Reagents: Organocuprate Ketone Synthesis

Starting Material = Acyl Halide

A

R2CuLi

R2CuLi = Organocuprate

Acyl halide ketone synthesis with an alkenyl organocuprate will yield an ɑ,β-unsaturated ketone.

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32
Q

Acyl Halide ⟶ 3° Alcohol

A

Hard Organometallic Acyl Halide Addition

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33
Q

Reagents: Hard Organometallic Acyl Halide Addition

A
  1. R—MgBr / R—Li
  2. H2SO4, H2O
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34
Q

Why does Hard Organometallic Acyl Halide Addition form a 3° alcohol instead of a ketone?

A

The hard organometallic reagents are highly nucleophilic (i.e. more nucleophilic than organocuprate reagents), so they will add to the acyl chloride reagent and the ketone intermediate product.

Two equivalents of the hard organometallic reagent are consumed during Hard Organometallic Acyl Halide Addition since the organometallic is reactive enough to add to the less-electrophilic carbonyl Carbon of the ketone intermediate.

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35
Q

Examples: Hard Organometallics

A
  • R—MgBr (Grignard)
  • R—Li (Organolithium)
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36
Q

Acyl Halide ⟶ Aldehyde

A

Acyl Halide Reduction

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37
Q

Reagents: Acyl Halide Reduction

A

LiAl(OtBu)3

LiAl(OtBu)3 = Lithium Tri-(t-Butoxy) Aluminum Hydride

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38
Q

Lithium Tri-(t-Butoxy) Aluminum Hydride

LiAl(OtBu)3

A

LiAl(OtBu)3 is a bulky (i.e. less reactive) hydride reagent.

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39
Q

Why does Acyl Hydride Reduction stop at the aldehyde stage?

Why does only one reduction step occur?

A

The LiAl(OtBu)3 reductant is a less reactive reducing agent, so it is unable to add to the less-electrophilic aldehyde product.

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40
Q

Why are anhydride compounds less electrophilic than acyl halides?

A

The carbonyl Carbons of an anhydride are neighbored by a resonance-donating Oxygen atom. (The strong electron donation effect of the Oxygen reduces the carbonyl Carbon’s electrophilic character.)

Less Electrophilic = Less Reactive

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41
Q

Which types of compounds predominantly engage in addition-eliminiation mechanisms?

A
  • Acyl Halides
  • Anhydrides
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42
Q

Addition-Elimination: Acyl Halides vs. Anhydride Compounds

A
  • Leaving Group The leaving group for Acyl Halide AE is a halide anion, whereas the leaving group for Anhydride AE is a carboxylate anion.
  • Kinetics: The Acyl Halide AE reaction is fast, whereas the Anhydride AE reaction is slower.
  • Thermodynamics: The Acyl Halide AE reaction is highly exothermic, whereas the Anhydride AE reaction is slightly exothermic.

AE = Addition-Elimination

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43
Q

Anhydride ⟶ Carboxylic Acid

A

Anhydride Hydrolysis

The Anhydride Hydrolysis reaction creates two carboxylic acid molecules per every one anhydride molecule.

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44
Q

Reagents: Anhydride Hydrolysis

Starting Material = Anhydride

A

H2O

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45
Q

Acetic Anhydride

A

(CH3OC)—O—(COCH3)

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46
Q

Anhydride ⟶ Ether + Carboxylic Acid

A

Non-Catalyzed Anhydride Esterification

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47
Q

Acyl Halide Esterification vs. Anhydride Esterification

Reagents

A
  • Acyl Halide Esterification: Reaction requires alchol (R—OH) and Triethylamine (N—Et3) to occur.
  • Anhydride Esterification: Reaction requires only alcohol (R—OH) occur.

In Acyl Halide Esterification, the Triethylamine must be added to neutralize the strongly acidic H—X byproduct. In Anhydride Esterification, a strongly acidic byproduct is not formed, so no Triethylamine is necessary.

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48
Q

Reagents: Non-Catalyzed Anhydride Esterification

Starting Material = Anhydride

A

R—OH

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49
Q

Why does Non-Catalyzed Anhydride Esterification form a carboxylic acid byproduct?

Why does the non-catalyzed mechanism form one ester molecule?

A

The carboxylic acid byproduct is not sufficiently electrophilic to react with the alcohol reagent without an acid catalyst.

An acid catalyst would activate the carboxylic acid byproduct to allow the alcohol reagent to add to the CA’s carbonyl Carbon. (The result of this addition reaction is the formation of an ester.)

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50
Q

Anhydride ⟶ Ether

A

Acid-Catalyzed Anhydride Esterification

The acid-catalyzed Anhydride Esterification reaction produces two ester equivalents per every one anhydride equivalent.

51
Q

Reagents: Acid-Catalyzed Anhydride Esterification

A

R—OH, H2SO4

52
Q

Why does Acid-Catalyzed Anhydride Esterification form two ester equivalents?

Why does the acid-catalyzed reaction not form a carboxylic acid?

A

The acid catalyst activates the (unobserved) carboxylic acid intermediate byproduct (by protonating the carbonyl Carbon) to allow the alcohol reagent to add to the CA’s carbonyl Carbon.

The carboxylic acid and alcohol addition reaction results in ester formation.

53
Q

Cyclic Anhydride ⟶ (Ester + Ester) Compound

A

Acid-Catalyzed Anhydride Esterification

Esterification from a cyclic anhydride requires the addition of heat.

54
Q

Cyclic Anhydride ⟶ (Ester + Carboxylic Acid) Compound

A

Non-Catalyzed Anhydride Esterification

Esterification from a cyclic anhydride requires the addition of heat.

55
Q

Esterification: Acyclic Anhydride vs. Cyclic Anhydride

A
  • Acyclic Anhydride: Addition of heat is not required.
  • Cyclic Anhydride: Addition of heat is required.
56
Q

Reactivity: Anhydrides vs. Acyl Halides vs. Amides vs. Esters

A

Acyl Halides > Anhydrides > Esters > Amides

Addition-Elimination Mechanisms: Acyl Halides react very quickly, Anhydrides react slower, and Esters react slowly, and Amides react extremely slowly.

57
Q

Ester ⟶ Alcohol

A

Ester Hydrolysis

Reverisble

  • The Ester Hydrolysis reaction forms carboxylic acid and alcohol.
  • The addition of heat and a strong catalyst are required for the reaction to occur.
58
Q

Ester ⟶ Carboxylic Acid

A

Ester Hydrolysis

Reversible

  • The Ester Hydrolysis reaction forms carboxylic acid and alcohol.
  • The addition of heat and a strong catalyst are required for the reaction to occur.
59
Q

How can the reverse reaction of Ester Hydrolysis (i.e. Fischer Esterification) be induced?

A

An excess of alcohol (i.e. a product of Ester Hydrolysis) induces the reformation of ester.

60
Q

Reagents: Acid-Catalyzed Ester Hydrolysis

Starting Material = Ester

A

H2O, H2SO4, Δ

A strong catalyst (acid or base) is required for Ester Hydrolysis to occur.

61
Q

Reagents: Base-Catalyzed Ester Hydrolysis

Starting Material = Ester

A

H2O, NaOH, Δ

A strong catalyst (acid or base) is required for Ester Hydrolysis to occur.

62
Q

Hydrolysis: Acyl Halide vs. Anhydride vs. Ester vs. Amide

Reaction Conditions

A
  • Acyl Halide Hydrolysis: No catalyst nor heating is required.
  • Anhydride Hydrolysis: No catalyst nor heating is required.
  • Ester Hydrolysis: Strong catalyst and heating are required.
  • Amide Hydrolysis: Strong catalyst and heating are required.
63
Q

Mechanism: Acid-Catalyzed Ester Hydrolysis

A
  1. Protonation of Ester Carbonyl Carbon
  2. Addition of H2O to Ester Carbonyl Carbon
  3. Intramolecular Proton Transfer to Protonate Ester Oxygen
  4. Formation of Oxacarbenium Ion to Eliminate Alcohol
  5. Deprotonation of Oxacarbenium Ion to Form Carboxylic Acid.
64
Q

Ester Hydrolysis: Acid-Catalyzed vs. Base Catalyzed

A
  • Leaving Group: The acid-catalyzed mechanism creates an alcohol leaving group, wherease the base-catalyzed mechanism creates an alkoxide anion leaving group.
  • Nucleophile: The acid-catalyzed mechanism uses an H2O nucleophile, wherease the base-catalyzed mechanism uses a hydroxide nucleophile.

The alkoxide leaving group of the base-catalyzed mechanism is a poor leaving group. This alkoxide elimination is promoted by the instability of the tetrahedral intermediate and the formation of a resonance-stabilized carboxylate anion.

65
Q

Mechanism: Base-Catalyzed Ester Hydrolysis

A
  1. Attack of OH– at Ester Carbonyl Carbon
  2. π-Electron Rearrangement to Eliminate Alkoxide Anion
  3. Protonation of Alkoxide to Form Carboxylate Anion
66
Q

Why does Base-Catalyzed Ester Hydrolysis occur despite the poor alkoxide leaving group?

A

Leaving of the alkoxide anion (1) converts the unstable tetrahedral intermediate to a carboxylic acid and (2) results in a final carboxylate anion.

  • The tetrahedral intermediate is destabilized by steric crowding (electron-electron repulsion between the Oxygens) about the central Carbon.
  • The alkoxide anion becomes protonated (immediately following its elimination) to form the more stable carboxylate anion.
67
Q

R—CO2—R’ ⟶ R—CO2—R’’

A

Transesterification

Reverisble

Transesterification is reversible via large excess of reagent (i.e. alcohol and/or ester).

68
Q

R—OH ⟶ R’—OH

R—O– ⟶ R’—O–

A

Transesterification

Reversible

Transesterification is reversible via large excess of reagent (i.e. alcohol and/or ester).

69
Q

Reagents: Acid-Catalyzed Transesterifiction

Starting Material = Ester

A

R—OH (Excess), H2SO4

70
Q

Reagents: Base-Catalyzed Transesterifiction

Starting Material = Ester

A

NaOCH3

71
Q

Mechanism: Acid-Catalyzed Transesterification

A
  1. The acid catalyst protonates the ester’s carbonyl Carbon to “activate” the ester.
  2. The alcohol reagent attacks the ester at the carbonyl Carbon to yield a tetrahedral intermediate.
  3. The cationic alkoxy substituent’s Hydrogen is transferred to the ether Oxygen.
  4. π-electron rearrangement at the hydroxyl group creates an oxacarbenium ion and eliminates an alcohol.
  5. Deprotonation of the oxacarbenium ion’s Hydrogen yields an ester.
72
Q

Mechanism: Base-Catalyzed Transesterification

A
  1. The alkoxide reagent attacks the ester’s carbonyl Carbon to yield a tetrahedral intermediate.
  2. π-electron rearrangement at the oxide group creates an ester and eliminates an alkoxide anion.
73
Q

Why are Nitrogen-nucleophiles stronger than Oxygen-nucleophiles?

A

Nitrogen’s π electrons are more easily donated (i.e. are farther from the Nitrogen nucleus) than Oxygen’s π electrons, so N-nucleophiles are more reactive/nucleophilic that O-nucleophiles.

74
Q

Ester ⟶ Amide

A

Ester Amidification

  • The Ester Amidification reaction requires heat to occur.
  • An alcohol byproduct is formed/eliminated during the reaction.
75
Q

Reagents: Ester Amidification

Starting Material = Ester

A

Amine, Δ

Ester Amidification can occur only with 0°/1°/2° Amines. (Reactions of esters with 3° Amines do NOT occur.)

76
Q

Ester ⟶ 3° Alcohol

A

Hard Organometallic Ester Addition

The Hard Organometallic Ester Addition reaction requires two equivalents of organometallic reagent to complete the conversion to a 3° alcohol.

77
Q

Reagents: Hard Organometallic Ester Addition

A
  1. 2 R—MgBr / R—Li, THF
  2. H2O, H2SO4

THF = Tetrahydrofuran

The organometallic reagent must add to the ester/ketone twice to complete conversion to the 3° alcohol.

78
Q

Why does Hard Organometallic Ester Addition not stop at the ketone stage?

Why does the mechanism not stop after the first additon reaction?

A

The ketone intermediate product is more electrophilic than the ester reagent, so the ketone will readily be attacked by the organometallic reagent.

The resonance-donating Oyxgen of the ester reagent causes the ester to be less electrophilic than the ketone intermediate.

79
Q

Ester ⟶ 1° Alcohol

A

LiAlH4 Reduction

80
Q

Reagents: LiAlH4 Reduction

A
  1. LiAlH4
  2. H2O, H2SO4
81
Q

Ester ⟶ Aldehyde

A

Partial Reduction

82
Q

Reagents: Partial Reduction

A
  1. DIBAL, (Low Temperature)
  2. H2O, H2SO4

DIBAL = Diisobutylaluminum Hydride

83
Q

DIBAL

A

Diisobutylaluminum Hydride

DIBAL is a bulky (i.e. less reactive) hydride reagent that facilitates partial ester reduction.

84
Q

Mechanism: LiAlH4 Ester Reduction

A
  1. A Hydride ion attacks the ester’s carbonyl Carbon to yield a tetrahedral oxide intermediate.
  2. π-Electron rearrangement at the oxide ion and elimination of an alkoxide ion yields an aldehyde product.
  3. A Hydride ion attacks the aldehyde’s carbonyl Carbon to yield a tetrahedral oxide intermediate.
  4. Protonation of the oxide ion yields a 1° alcohol.
85
Q

What reagents do esters not react with?

A
  • Organocuprates
  • Carboxylic Acids
86
Q

What reagents do anhydrides not react with?

A

Carboxylic Acids

87
Q

What reagents do acyl halides not react with?

A

None

88
Q

Amide ⟶ Carboxylic Acid

A

Amide Hydrolysis

  • The Amide Hydrolysis reaction requires high temperatures AND strong acid/base catalyst.
  • The reaction forms a carboxylic acid and an ammonium/amine.
89
Q

Reagents: Acid-Catalyzed Amide Hydrolysis

A

H2O, H2SO4, Δ

The acid-catalyzed Amide Hydrolysis mechanism yields an ammonium ion byproduct. (The eliminated amine group is protonated by the strong acid catalyst to form a cationic ammonium compound.)

90
Q

Reagents: Base-Catalyzed Amide Hydrolysis

A

H2O, NaOH, Δ

The base-catalyzed Amide Hydrolysis mechanism yields an amine byproduct. (The eliminated NH2– group is protonated by the carboxylic acid product to form an amine compound.)

91
Q

Why does Base-Catalyzed Amide Hydrolysis occur despite the poor azanide leaving group?

Azanide = NH2–

A

Leaving of the azanide anion (1) converts the unstable tetrahedral intermediate to a carboxylic acid and (2) results in a final carboxylate anion.

  • The tetrahedral intermediate is destabilized by steric crowding (electron-electron repulsion between the Oxygens/Nitrogen) about the central Carbon.
  • The azanide anion becomes protonated (immediately following its elimination) to form the resonance-stabilized carboxylate anion.
92
Q

What is the driving force of Amide Hydrolysis reactions?

A
  • Acid-Catalyzed: Protonation of the amine byproduct to form the ammonium cation/salt.
  • Base-Catalyzed: Deprotonation of the carboxylic acid product to form the carboxylate ion and amine.
93
Q

Amide ⟶ Amine

A

LiAlH4 Reduction

During LiAlH4 Reduction, the carbonyl group (of the amide) is converted to a methylene group.

94
Q

Leaving Group: LiAlH4 Reduction of Amides

A

A hydroxide ion (OH–) serves as the leaving group during LiAlH4 Reduction of amides due to it being more stable than the azanide ion (NH2–).

LiAlH4 Reduction of Amides differs from other addition-elimination reactions in that the carbonyl bond (C=O) is broken (instead of the C—Heteroatom bond).

95
Q

Amide ⟶ Aldehyde

A

Partial Reduction

The Partial Reduction reaction requires the DIBAL reductant (i.e. a weak/bulky hydride reagent).

96
Q

Partial Reduction: Esters vs. Amides

A

The partial reduction of esters AND amides results in an aldehyde product.

Both partial reduction mechanisms are identical, except for the production of different tetrahedral intermediates prior to acid workup.

97
Q

Characteristics of Nitriles

A
  • Hybridization: sp2-hybridized
  • Geometry: Linear
  • Reactivity: Relatively Electrophilic
98
Q

Nitrile ⟶ Carboxylic Acid

A

Nitrile Hydrolysis

  • The Nitrile Hydrolysis reaction requires high temperatures AND strong acid/base catalyst.
  • The reaction forms a carboxylic acid and an ammonium/amine.
  • An amide intermediate is always formed prior to H2O-facilitated hydrolysis.
99
Q

Reagents: Acid-Catalyzed Nitrile Hydrolysis

A

H2O, H2SO4, Δ

The acid-catalyzed Nitrile Hydrolysis mechanism yields an ammonium ion byproduct. (The eliminated amine group is protonated by the strong acid catalyst to form a cationic ammonium compound.)

100
Q

Reagents: Base-Catalyzed Nitrile Hydrolysis

A

H2O, NaOH, Δ

The base-catalyzed Nitrile Hydrolysis mechanism yields an amine byproduct. (The eliminated NH2– group is protonated by the carboxylic acid product to form an amine compound.)

101
Q

Nitrile Hydrolysis vs. Amide Hydrolysis

A
  • Products: Identical Products (i.e. Carboxylic Acid and Ammonium/Amine).
  • Reagents: Identical Reagents (i.e. Water + Strong Acid + Heat)
  • Mechanism: Nitrile Hydrolysis involves the conversion to an Amide intermediate prior to H2O-facilitated hydrolysis.

The two hydrolysis mechanisms are identical, except that Nitrile Hydrolysis involves the nitrile-to-amide conversion prior to hydrolysis. (The Amide Hydrolysis mechanism does not involve any conversion prior to H2O-facilitated hydrolysis.)

102
Q

Mechanism: Acid-Catalyzed Nitrile-to-Amide Conversion

Conversion Step of Acid-Catalyzed Nitrile Hydrolysis

A
  1. The nitrile’s Nitrogen is protonated by the strong acid catalyst (to “activate” the central Carbon).
  2. Nucleophilic H2O adds to the nitrile’s central Carbon (to form an imine compound).
  3. The Oxygen is deprotonated (by H2O) to form a hydroxyl-substituted imine.
  4. The Oxygen’s π electrons rearrange to form an oxocarbenium ion while the C=N π electrons attack the acid to protonate the Nitrogen (and form an amine).
  5. The Oxocarbenium ion is deprotonated (by H2O) to form the Amide.
103
Q

Mechanism: Base-Catalyzed Nitrile-to-Amide Conversion

Conversion Step of Base-Catalyzed Nitrile Hydrolysis

A
  1. The hydroxide catalyst attacks the nitrile’s central Carbon (to form an imine anion).
  2. An intramolecular proton transfer occurs to protonate the Nitrogen and deprotonate the hydroxyl group (to form an amide anion).
  3. The Nitrogen is protonated (by H2O) to form the Amide.
104
Q

Reagents: Grignard Addition

A
  1. R—MgBr
    2.
105
Q

Reagents: Grignard Addition

A
  1. R—MgBr
  2. H2O, H2SO4

Since the acidic workup step occurs after the removal of the grignard reagent (from the reaction mixture), the resulting ketone compound does not experience grignard addition.

106
Q

Nitrile ⟶ Ketone

A

Grignard Addition

A single grignard addition step occurs during Grignard Nitrile Addition because the imine anion product is stable (i.e. not sufficiently electrophilic to be attacked by the grignard reagent).

107
Q

Nitrile ⟶ 1° Amine

A

LiAlH4 Reduction

108
Q

Why is the C—N bond is not cleaved during LiAlH4 Reduction of amides/nitriles?

A

Cleavage of the C—N bond would create an azanide ion (NH2–) leaving group, which is extremely unstable in non-basic conditions.

109
Q

Amides/Nitriles: LiAlH4 Reduction vs. Partial Reduction

Mechanism Differences

A
  • LiAlH4 Reduction: The C—N bond is not cleaved (i.e. H2 equivalents are being added across the C—N bond).
  • Partial Reduction: The C—N bond is cleaved (during the hydrolysis step).
110
Q

Ester ⟶ Ester Enolate

A

Deprotonation (of α-Hydrogen)

The α-Hydrogen can be deprotonated under basic conditions only.

111
Q

Ester Enolate Alkylation: Potential Side Reactions

Limitations of Ester Enolate Alkylation

A
  • E2 Elimination of Alkyl Halide (if 2°/3° Alkyl Halide)
  • Claisen Condensation (i.e. Ester Enolate Self-Alkylation)
  • Ester Hydrolysis (due to Basic Conditions)

A more effective mechanism for ester α-alkylation is β-Ketoester α-Alkylation.

112
Q

Reagents: Ester Enolate Alkylation

Poor α-Alkylation Mechanism

A

NaOCH2CH3, R—X

The alkyl halide reagent is limited to 0°/1° alkyl halides and allyl halides. (Any other alkyl halide reagent may undergo E2 elimination within the basic conditions.)

113
Q

Cα—H ⟶ Cα—R

A

Ester Enolate Alkylation

The Ester Enolate Alkation reaction is an ineffective α-alkylation mechanism due to multiple potential side reactions.

114
Q

Why is α-alkylation using acyl halides ineffective?

A

The carbonyl Carbon of acyl halides is highly electrophilic, so the basic catalyst/solvent will attack the Carbon before deprotonating the α-Hydrogen.

115
Q

Why is α-alkylation using amides ineffective?

A

Deprotonation of the the amide α-Hydrogen will create a highly unstable enolate ion (due to the strong electron-donating character of the Nitrogen).

116
Q

pKa: α-Hydrogen of β-Dicarbonyl Compounds

A

9–13

Highly Acidic

  • β-Diketone: pKa = 9
  • β-Ketoester: pKa = 11
  • β-Diester: pKa = 13
117
Q

Acidity: Ketone vs. Ester vs. β-Diketone vs. β-Ketoester vs. β-Diester

A

β-Diketone > β-Ketoester > β-Diester > Ketone > Ester

118
Q

Cα—H Deprotonation: β-Dicarbonyl Compounds vs. Monocarbonyl Compounds

A
  • β-Dicarbonyl Compounds: Deprotonation is favored (due to the stability of the conjugate base).
  • Monocarbonyl Compounds: Deprotonation is unfavorable (due to the relative instability of the ester/ketone enolate).
119
Q

Why are ester α-Hydrogens less acidic than ketone α-Hydrogens?

A

The electron-donating character of the ether Oxygen destabilizes the conjugate base of ester compounds.

120
Q

pKa: α-Hydrogen of Monocarbonyl Compounds

A

20–25

Relatively Acidic

  • Ketone: pKa = 20
  • Ester: pKa = 25
121
Q

Nitrile ⟶ Aldehyde

A

Partial Reduction

122
Q

Methods: Synthesizing Nitriles

A
  • Cyanide SN2 Addition to Alkyl Halide
  • CuCN Addition to Aryldiazonium Salt
  • Cyanide Addition to Aldehyde/Ketone
  • Cyanide Addtion to α,β-Unsaturated Aldehyde/Ketone
123
Q

Why does a second Grignard-reagent equivalent not react with the Grignard Nitrile Addition product?

Why does Grignard Nitrile Addition stop after a single additon step?

A

The Nitrogen of the imine anion product is minimally electronegative, so the imine’s central Carbon is not sufficiently nucleophilic to experience Grignard attack.

The Nitrogen is less electronegative than an Oxygen, so it cannot “activate” the central Carbon to enable grignard addition.

124
Q

Partial Reduction

DIBAL Reduction

A

A single-step reduction facilitated by a weak/bulky hydride reagent.

LiAlH4 Reduction, in constrast to Partial Reduction, is a double-step reduction facilitated by a strong reducing agent.

Organic Chemistry 2 (12 decks)

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