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Organic Chemistry 2 > Dicarbonyl Compounds (Chapter 23) > Flashcards

Dicarbonyl Compounds (Chapter 23) Flashcards

1
Q

Ester + Ester ⟶ β-Ketoester

A

Claisen Condensation

Irreversible (Cannot Undergo Retro-Claisen Condensation)

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2
Q

Ester’ + Ester’’ ⟶ β-Ketoester

A

Ester-Ester Mixed Claisen Condensation

Irreversible

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3
Q

Ketone + Ester ⟶ β-Diketone

A

Ketone-Ester Mixed Claisen Condensation

Irreversible

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4
Q

Reagents: Claisen Condensation

Starting Material = Ester (w/ two α-Hydrogens)

A
  1. NaOCH2CH3, HOCH2CH3
  2. H2O, H2SO4

The ester reagent must possess two α-Hydrogens. (Ester reagents with zero/one α-Hydrogen will not undergo Claisen Condensation.)

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5
Q

Why must one ester possess two α-Hydrogens and the other ester possess no α-Hydrogens?

Ester-Ester Mixed Claisen Condensation

A
  • One ester must possess no α-Hydrogens to ensure it is not deprotonated for form an ester enolate.
  • One ester must possess two α-Hydrogens to ensure it is deprotonated to form an ester enolate.

Only one ester should become the ester enolate.

The ester possessing no α-Hydrogens should be in large excess to ensure it is preferentially attacked by the ester enolate (in favor of self-Claisen Condenation).

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6
Q

Why must the ester possessing no α-Hydrogens be in large excess?

Ester-Ester Mixed Claisen Condensation

A

The β-ketoester product will be the major product only if the non-α-Hydrogen ester is in large excess.

Without large excess of the non-α-Hydrogen ester, the self-Claisen Condensation produce may become the major product.

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7
Q

Reagents: Ester-Ester Mixed Claisen Condensation

Starting Materials = Two Unique Esters

A
  1. NaOCH2CH3
  2. H2O, H2SO4

  • One ester must possess two α-Hydrogens, while the other ester must possess no α-Hydrogens.
  • The ester possessing no α-Hydrogens must be in large excess (to ensure that it is attacked by the ester enolate nucleophile).
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8
Q

Mechanism: Ketone-Ester Mixed Claisen Condensation

A
  1. The hydride reagent deprotonates the α-Hydrogen of the ketone (to form an enolate).
  2. The enolate nucleophile attacks the carbonyl Carbon of the ester (to form a tetrahedral intermediate).
  3. Rearrangement of the oxide’s π-electrons forms a ketone and eliminates an alkoxide.
  4. The intercarbonyl** α-Hydrogen is deprotonated** (to form the β-diketone enolate).
  5. Acid workup protonates the intercarbonyl α-Carbon to yield the β-Diketone product.
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9
Q

Why is the ketone α-Hydrogen deprotonated before the ester α-Hydrogen?

Ketone-Ester Mixed Claisen Condensation

A

The ketone α-Hydrogen is more acidic (than the ester α-Hydrogen) due to the ester’s electron-donating ether Oxygen.

The ester’s ether Oxygen destabilizes the ester enolate (i.e. the conjugate base) due its electron-donating character.

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10
Q

Mechanism: Ester-Ester Mixed Claisen Condensation

A
  1. The alkoxide reagent/catalyst deprotonates the α-Hydrogen of one ester (to form an ester enolate).
  2. The ester enolate nucleophile attacks the carbonyl Carbon of the other ester (to form a tetrahedral intermediate).
  3. Rearrangement of the oxide’s π-electrons forms a ketone and eliminates an alkoxide.
  4. The intercarbonyl α-Hydrogen is deprotonated (to form the β-ketoester enolate).
  5. Acid workup protonates the intercarbonyl α-Carbon to yield the β-Ketoester product.
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11
Q

Reagents: Ketone-Ester Mixed Claisen Condensation

Starting Materials = Ketone + Ester

A
  1. NaH
  2. H2O, H2SO4
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12
Q

Mechanism: Claisen Condensation

A
  1. Deprotonation of Ester α-Hydrogen to Yield Ester Enolate
  2. Nucleophilic Addition of Ester Enolate to Another Ester Carbonyl
  3. π-Electron Rearrangement to Eliminate Alkoxide Group
  4. Deprotonation of Intercarbonyl α-Hydrogen to Form β-Ketoester Enolate
  5. Acid Workup to protonate Intercarbonyl α-Carbon.

The final β-Ketoester product is stable under weakly acidic conditions (i.e. cannot under retro-Claisen Condensation).

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13
Q

Driving Force: Claisen Condensation

A

Final Deprotonation to Yield β-Ketoester Enolate

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14
Q

Why is the final deprotonated step of Claisen Condensation highly favorable?

A

The intercarbonyl α-Hydrogens are significanly more acidic than the hydroxyl Hydrogens (of the basic catalyst’s conjugate acid), so α-Hydrogen deprotonation (to form the hydroxyl group on the catalytic base) readily occurs.

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15
Q

Why are ester reagents with zero α-Hydrogens unable to undergo Claisen Condensation?

A

The ester enolate (formed via or α-Hydrogen deprotonation) cannot be synthesized when no α-Hydrogen is present.

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16
Q

Why are ester reagents with one α-Hydrogen unable to undergo Claisen Condensation?

A

A second α-Hydrogen is required for the final/second deprotonation step that “drives” the Claisen Condensation reaction toward the β-Ketoester enolate product.

WIthout a second α-Hydrogen, the formed β-Ketoester cannot be deprotonated within the basic Claisen Condensation conditions. (The non-deprotonated β-Ketoester is highly unstable under basic conditions, so the overall condensation reaction is thermodynamically unfavorable.)

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17
Q

β-Ketoester ⟶ Ester + Ester

A

Retro-Claisen Condensation

Reversible

Retro-Claisen Condensation must occur under basic conditions.

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18
Q

β-Diketone ⟶ Ester + Ketone

A

Retro-Claisen Condensation

Reversible

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19
Q

Reagents: Retro-Claisen Condensation

Starting Material = β-Dicarbonyl (w/o α-Hydrogens)

A

NaOCH2CH3

  • The reagent β-dicarbonyl can be either a β-Ketoester OR a β-Diketone.
  • No α-Hydrogens can be present on the reagent β-dicarbonyl to ensure alkoxide addition to a carbonyl Carbon. (f the reagent β-dicarbonyl possesses α-Hydrogens, the alkoxide will facilitate deprotonation to form a β-Dicarbonyl enolate.)
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20
Q

Why is the self-Aldol Condensation of ketones thermodynamically unfavorable?

A
  • The carbonyl Carbons of ketones are relatively stable (which decreases their susceptibility to nucleophilic attack by an enolate).
  • The carbonyl Carbons of ketones experience steric hindrance (which inhibits attack by the nucleophilic enolate).

Self-Aldol Condensation of ketones does not occur.

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21
Q

Diester ⟶ Cyclic β-Ketoester

A

Intramolecular Claisen Condensation

Dieckmann Condensation

The Intramolecular Claisen Condensation reaction is effective for forming five-membered/six-membered rings.

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22
Q

Why are Ketoesters unable to undergo Intramolecular Claisen Condensation?

A

The ketone’s alkyl substituent cannot serve as a leaving group (following intramolecular attack of the ester enolate’s α-Carbon).

Since the ketone’s alkyl substituent cannot leave, the reformation of the ketone group (C=O) cannot occur.

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23
Q

Mechanism: Intramolecular Claisen Condensation

Dieckmann Condensation

A
  1. The alkoxide reagent/catalyst deprotonates the α-Hydrogen of one ester (to form an ester enolate).
  2. The ester enolate attacks the carbonyl Carbon of the other ester (to form a five-membered/six-membered ring).
  3. Rearrangement of the oxide’s π-electrons forms a ketone and eliminates an alkoxide.
  4. The intercarbonyl α-Hydrogen is deprotonated (to form the cyclic β-ketoester enolate).
  5. Acid workup protonates the intercarbonyl α-Carbon to yield the cyclic β-Ketoester product.
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24
Q

Reagents: Intramolecular Claisen Condensation

Dieckmann Condensation

A
  1. NaOCH2CH3
  2. H2O, H2SO4
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25
β-Dicarbonyl ⟶ Alkyl-Substitued β-Dicarbonyl | β-Dicarbonyl = β-Ketoester OR β-Diketone OR β-Diester
β-Dicarbonyl Monoalkylation
26
β-Dicarbonyl ⟶ Dialkyl-Substitued β-Ketoester | β-Dicarbonyl = β-Ketoester OR β-Diketone OR β-Diester
β-Dicarbonyl Dialkylation
27
Why are 2° Alkyl Halides **able** to be used in β-dicarbonyl alkylation reactions?
The alkoxide base (used to deprotonate the α-Hydrogen) is *not present* during the alkylation step, so there are no side reactions competing with alkoxide SN2 addition to the 2° alkyl halide. ## Footnote 3° alkyl halides **cannot** to be used in β-dicarbonyl alkylation reactions due the steric hindrances against SN2 attack.
28
Why does E2-Elimination **not** occur during β-dicarbonyl alkylation reactions.
The β-dicarbonyl anion is a *weak base*, so it will preferentially perform SN2 addition to 0°/1°/2° alkyl halides. ## Footnote E2-Elimination will occur when 3° alkyl halides are used since SN2 addition is not possible (due to steric hindrance).
29
**Reagents:** β-Dicarbonyl Dialkylation
1. NaOCH2CH3 2. R—X 3. KOC(CH3)3 4. R—I ## Footnote * The alkyl halide (R—X) can be a **0°/1°/2° Alkyl Halide** or an **Allyl Halide**. (2° Alkyl Halides can be used in β-dicarbonyl alkylation reactions since the *alkoxide base* is not present during the alkylation step.) * The *more reactive* **alkyl iodide** (R—I) is used during the second α-alkylation step (since this second step is less favorable).
30
**Reagents:** β-Dicarbonyl Monoalkylation
1. NaOCH2CH3 2. R—X ## Footnote The alkyl halide (R—X) can be a **0°/1°/2° Alkyl Halide** or an **Allyl Halide**. (2° Alkyl Halides can be used in β-Dicarbonyl alkylation reactions since the *alkoxide base* is not present during the alkylation step.)
31
Why does over-alkylation **not** occur during β-Dicarbonyl Alkylation?
The basic reagent/catalyst and the alkyl halide are reacted *separately* with the β-Dicarbonyl reagent. ## Footnote Since *α-Hydrogen deprotonation* and *alkylation* occur in unique steps, only **one** alkyl group adds to the β-Dicarbonyl compound at a time.
32
Why is hydroxide (OH–) **not** used as the basic reagent/catalyst? | β-Dicarbonyl Alkylation
Hydroxide could add to the ester's carbonyl Carbon to facilitate ester hydrolysis (instead of β-Dicarbonyl Alkylation).
33
NaOCH2CH3 vs. KOC(CH3)3 | KOC(CH3)3 = Potassium *t*-Butoxide
KOC(CH3)3 is used as a **stronger alkoxide base** (than NaOCH2CH3) to promote the less reactive *second* α-Hydrogen deprotonation. ## Footnote The Potassium *t*-Butoxide is paired with an **alkyl iodie** to drive the less-favorable second α-alkylation step.
34
β-Dicarbonyl ⟶ β-1,5-Tricarbonyl | β-Dicarbonyl = β-Ketoester OR β-Diketone OR β-Diester
Michael Addition ## Footnote Michael Addition with β-dicarbonyl compounds favors **1,4-addition**.
35
**Reagents:** Michael Addition | Starting Material = **β-Dicarbonyl**
α,β-Unsaturated Carbonyl, NaOCH2CH3 (Catalyst), CH3CH2OH ## Footnote The Michael Addition reaction occurs under **basic conditions** only.
36
**Mechanism:** Michael Addition
1. The alkoxide catalyst **deprotonates** the intracarbonyl α-Hydrogen (to yield a β-dicarbonyl anion). 2. The β-dicarbonyl anion adds to the α,β-unsaturated carbonyl's β-Carbon. 3. The oxide's π-electrons rearrange to **form a ketone** *while* the new ketone's α-Carbon becomes protonated (by the ethanol reagent).
37
Which *carboxylic acid derivates* do organocuprates react with?
Acyl Halides
38
β-1,5-Tricarbonyl ⟶ α,β-Unsaturated Cyclohexanone
Intramolecular Adol Condenation | Step 2 of Robinson Annulation ## Footnote The Intramolecular Aldol Condensation reaction occurs under **basic conditions** and **high temperatures** only.
39
β-Dicarbonyl ⟶ α,β-Unsaturated Cyclohexanone
Robinson Annulation | Michael Addition + Intramolecular Adol Condensation ## Footnote The Robinson Annulation reaction occurs under **basic conditions** and **high temperatures** only.
40
Robinson Annulation
Michael Addition + Intramolecular Adol Condensation ## Footnote The Robinson Annulation reaction occurs under **basic conditions** and **high temperatures** only.
41
**Reagents:** Robinson Annulation | Starting Material = **β-Dicarbonyl**
1. α,β-Unsaturated Carbonyl, NaOCH2CH3, CH3CH2OH 2. NaOCH2CH3, Δ
42
**Reagents:** Intramolecular Aldol Condensation | Step 2 of Robinson Annulation
NaOCH2CH3, Δ
43
**Mechanism:** Intramolecular Aldol Condensation | Step 2 of Robinson Annulation
1. The terminal α-Carbon of the non-cyclic ketone is **deprotonated** (by the ethoxide base) to create a terminal enolate. 2. The terminal enolate adds to the cyclic ketone's carbonyl Carbon to form a **six-membered ring**. 3. The oxide ion is **protonated** (by ethanol) to yield a hydroxyl-substituted tetrahedral intermediate. 4. The α-Carbon of the (former enolate) ketone is **deprotonated** to yield a cyclic enolate. 5. Rearrangement of the enolate's π-electrons **reforms the ketone** and **eliminates the hydroxyl group**. ## Footnote The terminal α-Carbon (of the non-cyclic ketone) *must* possess at least **two α-Hydrogens**.
44
**Mechanism:** Robinson Annulation
1. Deprotonation of β-Dicarbonyl's α-Hydrogen (to Yield β-Dicarbonyl Anion) 2. β-Dicarbonyl Anion Attacks the α,β-Unsaturated Carbonyl's β-Carbon (to Yield α-Substituted β-Dicarbonyl) 3. Rearrangement of Oxide's π-Electrons *and* Protonation of Ketone's α-Carbon (to Yield β-1,5-Tricarbonyl) 4. Deprotonation of Noncylic Ketone's Terminal α-Hydrogen (to Yield Terminal Enolate) 5. Terminal Enolate Attacks Cyclic Ketone (to Yield Six-Membered Ring) 6. Protonation of Oxide (to Yield Hydroxyl-Substituted Tetrahedral Intermediate) 7. Deprotonation of Ketone's Alcohol-Adjacent α-Carbon (to Yield Cyclic Enolate) 8. Rearrangement of Enolate's π-Electrons to Reform Ketone (and Eliminate Hydroxyl) ## Footnote The terminal α-Carbon (Step 4) *must* possess at least **two α-Hydrogens**.
45
Decarboxylation
The conversion of a *carboxylic acid group* to a ***Hydrogen*** that involves the *elimination of CO2*.
46
β-Ketoester ⟶ Aldehyde
Hydrolysis-Decarboxylation ## Footnote * The Hydrolysis-Decarboxylation reaction can be **acid-catalyzed** OR **base-catalyzed**. (The Decarboxylation step *must* be catalyzed by **strong acid** and **requires heat**.)
47
β-Diester ⟶ Carboxylic Acid
Hydrolysis-Decarboxlation ## Footnote * The Hydrolysis-Decarboxylation reaction can be **acid-catalyzed** OR **base-catalyzed**. (The Decarboxylation step *must* be catalyzed by **strong acid** and **requires heat**.) * The Hydrolysis step hydrolyzes **both esters** to carboxylic acids.
48
β-Dicarboxylic Acid ⟶ Carboxylic Acid
Decarboxylation ## Footnote * Decarboxylation requires an **acid catalyst** (i.e. H2SO4) and **heat** to occur. * Only **one of the carboxylic acids** is decarboxylated to an aldehyde.
49
Carboxylic Acid ⟶ Aldehyde
Decarboxylation ## Footnote Decarboxylation requires an **acid catalyst** (i.e. H2SO4) and **heat** to occur.
50
**Mechanism:** Decarboxylation
1. Intramolecular proton transfer (from the enolate to the β-carbonyl) *and* cleavage of Cα—CCarbonyl bond **eliminates CO2** and **forms an enol**. 2. Tautomerization occurs to form the **aldehyde** product.
51
**Reagents:** Decarboxylation
H2O, H2SO4, Δ
52
**Reagents:** Acid-Catalyzed Hydrolysis-Decarboxylation
H2O, H2SO4, Δ
53
**Reagents:** Base-Catalyzed Hydrolysis-Decarboxylation
1. NaOH, H2O 2. H2O, H2SO4 2. H2O, H2SO4, Δ
54
Why does the Hydroxide attack the ester carbonyl (instead of the ketone carbonyl) during base-catalyzed hydrolysis? | Hydrolysis of β-Ketoesters
The ester's alkoxide group is **able** to serve as the leaving group upon Hydroxide addition to the ester's carbonyl Carbon. (The ketone does not possess a substituent that could serve as a stable leaving group following Hydroxide addition to its carbonyl Carbon.)
55
β-Ketoacid
Carboxylic acid compound with a ketone group at the β-Carbon position
56
β-Ketoester
Ester compound with a ketone group at the β-Carbon position
57
β-Ketoester ⟶ β-Ketoacid
Hydrolysis ## Footnote Hydrolysis can be **base-catalyzed** OR **acid-catalyzed**.
58
β-Diester ⟶ β-Dicarboxylic Acid
Hydrolysis ## Footnote Hydrolysis can be **base-catalyzed** OR **acid-catalyzed**.
59
Why must a carbonyl group be present at the β-Carbon of the carboxylic acid? | Decarboxylation
The Decarboxylation mechanism involves π-electron rearrangement/transfer across *both* carbonyl groups. ## Footnote A simple carboxylic acid (i.e. without the β-position carbonyl group) is **not** compatible for decarboxylation reaction
60
Malonic Ester
61
Acetoacetic Ester
62
Advantages of β-Dicarbonyl Anions
* **Strong Nucleophile** (e.g. SN2, Michael Addition) * **Weak Base** (i.e. 1°/2° Alkyl Halide Compatibility)
63
Uses of DIBAL Reduction
* Partial Ester Reduction (Ester ⟶ Aldehyde) * Partial Amide Reduction (Amide ⟶ Aldehyde) * Partial Nitrile Reduction (Nitrile ⟶ Aldehyde)
64
Uses of NaBH4 Reduction
* Ketone Reduction (Ketone ⟶ 2° Alcohol) * Aldehyde Reduction (Aldehyde ⟶ 1° Alcohol) * Complete Acyl Halide Reduction (Acyl Halide ⟶ 1° Alcohol) * Complete Anhydride Reduction (Anhydride ⟶ 1° Alcohol)
65
Uses of LiAlH4 Reduction
* Complete Ester Reduction (Ester ⟶ 1° Alcohol) * Complete Amide Reduction (Amide ⟶ Amine) * Complete Nitrile Reduction (Nitrile ⟶ Amine) * Complete Carboxylic Acid Reduction (Carboxylic Acid ⟶ 1° Alcohol) * Complete Acyl Halide Reduction (Acyl Halide ⟶ 1° Alcohol)
66
Uses of LiAl(OtBu)3H
* Partial Acyl Halide Reduction (Acyl Halide ⟶ Aldehyde) * Partial Anhydride Reduction (Anhydride ⟶ Aldehyde) ## Footnote The LiAl(OtBu)3H reduction reaction follows an **addition-elimination mechanism**.

Organic Chemistry 2 (12 decks)

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