⑦ Formula 1. Alpha hydrogens of carbonyl compounds are fairly acidic and exhibit a wide range of reactions: In contrast, allylic hydrogen has a pK_a of about 44

⑧ Formula 2. When acid-base reaction is competing with other organic reactions, the fastest acid-base reaction is preferred.

⑶ Types of carbonyl compound reactions

① Type 1. When the basicity of Y^- is greater than that of X^-

Figure 1. Carbonyl compound reaction Type 1

② Type 2. When the basicity of Y^- is less than that of X^-

Figure 2. Carbonyl compound reaction Type 2

③ Type 3. Enone and 1,2-addition reaction: Occurs when the nucleophile is a strong nucleophile (e.g., Grignard reagent)

Figure 3. Carbonyl compound reaction Type 3

④ Type 4. Enone and 1,4-addition reaction (Michael addition): Occurs when the nucleophile is a weak nucleophile (e.g., MeSH)

Figure 4. Carbonyl compound reaction Type 4

○ When the nucleophile attacks the alpha carbon: The intermediate does not exhibit resonance

○ When the nucleophile attacks the beta carbon: The intermediate has two resonance structures. Since the intermediate is stable, this pathway is preferred.

○ Since oxygen prefers to bear a negative charge when attacking the beta carbon, products like those in Figure 4 are formed

2. Reaction 1. Carbonyl alpha hydrogen removal reaction

⑴ Reaction 1-1. Enol-keto tautomerization

① Acid-catalyzed tautomerization

Figure 5. Acid-catalyzed tautomerization

② Base-catalyzed tautomerization

Figure 6. Base-catalyzed tautomerization

③ Principle: Generally, keto form is favored

④ Exception: Enol form is favored in some cases

Figure 7. Enol form is favored in some cases

⑤ Esters, carboxylic acids, and amides do not undergo tautomerization unlike ketones and aldehydes

○ Reason: Oxygen in -OR attempts to form a double bond rather than -OH

Figure 8. Resonance contributors of an ester

⑵ Reaction 1-2. Alkylation of aldehydes

Figure 9. Mechanism of acid-catalyzed alkylation of aldehydes

Figure 10. Mechanism of base-catalyzed alkylation of aldehydes

⑶ Reaction 1-3. Alkylation of ketones

Figure 11. Mechanism of acid-catalyzed alkylation of ketones

Figure 12. Mechanism of base-catalyzed alkylation of ketones

⑷ Reaction 1-4. Alkylation of esters

Figure 13. Mechanism of acid-catalyzed alkylation of esters

Figure 14. Mechanism of base-catalyzed alkylation of esters

⑸ Reaction 1-5. Alkylation of nitriles

Figure 15. Mechanism of acid-catalyzed alkylation of nitriles

Figure 16. Mechanism of base-catalyzed alkylation of nitriles

⑹ Common aspects of alkylation reactions

① Kinetic control

○ Influenced by steric effects

○ Occurs at low temperatures (e.g., -76 °C)

○ Slight excess of E⁺ needed (e.g., 1.05 eq) due to the slow reaction

Figure 17. Kinetic control product

② Thermodynamic control

○ Influenced by stability of multi-substituted alkene intermediates

○ Occurs at higher temperatures. Even if kinetic control product is formed, reaction may revert to thermodynamic control product due to reverse reaction

○ Slight reduction of E⁺ needed (e.g., 0.95 eq)

Figure 18. Thermodynamic control product

⑺ Reaction 1-6. Haloform reaction of methyl ketones

① Reaction conditions: 1. X₂, KOH (water/dioxane), 2. HCl, H₂O

○ The 2^nd reaction condition, HCl, H₂O, acts as a proton source to convert O^- to OH

○ Cl₂(g) or I₂(g) can be used as X₂

○ CHX₃ is referred to as haloform

○ CHI₃ is a yellow solid and is a famous precipitate used to determine the positivity of the reaction

② Insights

○ Insight 1. If OH^- attacks the ketone carbon, there is no chance for a reaction with X₂, leading to the reverse reaction

○ Insight 2. CH₃^- is not a good leaving group, so it reacts with X₂ to become a good leaving group, following Reaction Type 1

③ Significance: Can produce carboxylic acids from ketones

Figure 19. Mechanism of haloform reaction of methyl ketones

⑻ Reaction 1-7. Thiol-maleimide click reaction

Figure 20. Thiol-maleimide click chemistry

① pH = 6.5-7.5: Maleimide reacts only with thiol

② pH > 7.5: Maleimide reacts with both thiol and amine

⑼ Reaction 1-8. Hell-Volhard-Zelinsky reaction

3. Reaction 2. Carbonyl alpha condensation reaction

⑴ Overview

① Alpha hydrogen of ketones is more acidic than that of esters

② E1cB (elimination unipolar conjugate base): Removal reaction occurs after formation of a conjugate base

③ Hydroxide is typically a poor leaving group, but resonance stabilization of the conjugate base can make the reaction possible.

⑵ Reaction 2-1. Halogenation of alpha carbon in ketones: Often uses ketone + acetic acid + Br₂ conditions as an example

Figure 21. Acid-catalyzed bromination of ketone

⑶ Reaction 2-2. Aldol condensation reaction

① Characteristics

○ When a carbonyl compound is more reactive towards nucleophilic addition reactions and cannot form an enolate anion, aldol condensatin reaction is most effective.

○ (Formula) The hydrogen at the same carbonyl alpha position is removed twice.

○ (Formula) Resonance stabilization results in the =O being released by OH-.

○ (Formula) A carbonyl alpha carbon attacks another ketone carbon, removing the double-bonded oxygen; however, unsaturation is maintained, so a double bond must be formed between that carbonyl alpha carbon and the other ketone carbon.

○ The aldol condensation is a type of dehydration condensation reaction.

○ According to Bredt’s rule, the aldol reaction may not occur.

② Example 1. Acid-catalyzed aldol condensation reaction: 2 × identical aldehydes

③ Example 2. Base-catalyzed aldol condensation reaction: 2 × identical aldehydes

Figure 22. Mechanism of base-catalyzed aldol condensation reaction

④ Example 3. Intramolecular aldol condensation reaction: octane-2,7-dione is commonly used as an example

Figure 23. Intramolecular Aldol Condensation Reaction

○ In the above reaction, there can be two conjugate bases forming either a five-membered ring or a seven-membered ring.

○ Among them, the five-membered ring is more stable, so the conjugate base forms to create the five-membered ring.

⑤ Example 4. Crossed Aldol Condensation: Two different aldehydes or aldehydes + ketones

Figure 24. Overall Reaction of Crossed Aldol Condensation

Figure 25. Mechanism of Crossed Aldol Condensation

○ Base is neutralized with HCl to prevent additional reactions.

○ Point: 3,3-dimethylbutan-2-one should be added slowly.

○ Removal of carbonyl α-hydrogen by OH^- prefers 3,3-dimethylbutan-2-one, which is present in small amounts during the reaction.

○ Dehydrogenated 3,3-dimethylbutan-2-one reacts with the excess other aldehyde.

○ Without a larger amount of 3,3-dimethylbutan-2-one, a simple aldol condensation reaction can occur.

Figure 26. Simple Aldol Condensation Reaction

⑥ Example 5. Knoevenagel Condensation: Utilizes an activated methylene group

⑦ Example 6. Claisen-Schmidt Reaction: Aldehyde + Ketone

⑧ Example 7. Mukaiyama Aldol Reaction

○ 1-methylcyclohexanone + (CH₃)₃SiCl, (CH₃CH₂)₃N → Thermodynamic silyl ether is predominant.

○ 1-methylcyclohexanone + (CH₃)₃SiCl, LDA, -78 ℃ → Kinetic silyl ether predominant.

⑷ Reaction 2-3. Ester Condensation Reaction

① Overview

○ Due to resonance stabilization, -OR can become a leaving group.

② Example 1. Claisen Condensation: 2 × Identical Esters

Figure 27. Mechanism of Claisen Condensation

○ NaOEt is neutralized with HCl to prevent additional reactions.

○ Point: The base must have the same form as the OR group of the ester (∵ Ester exchange reaction)

Figure 28. Trans-esterification

③ Example 2. Crossed Claisen Condensation: 2 × Different Esters

Figure 29. Crossed Claisen Condensation

Figure 30. Mechanism of Crossed Claisen Condensation

○ NaOEt is neutralized with HCl to prevent additional reactions.

○ Point 1: Ethyl butanoate should be added slowly.

○ Carbonyl α-hydrogen elimination reaction by NaOEt prefers ethyl butanoate, which is present in small amounts during the reaction.

○ Dehydrogenated ethyl butanoate reacts with the relatively excess other ester.

○ Without a larger amount of ethyl butanoate, a simple Claisen condensation reaction can occur.

Figure 31. Simple Claisen Condensation

○ Point 2: The base must have the same form as the OR group of the ester (∵ Trans-esterification)

Figure 32. Ester Transesterification

○ Point 3: In the case of crossed Claisen condensation, the reaction must be composed of the reaction between benzoate and non-benzoate

○ Alkyl benzoates cannot react with each other

○ Due to aromatic side-chain effects, crossed Claisen reaction is faster than Claisen reaction between alkyl non-benzoates

○ When reactions are composed like ethyl propanoate + ethyl ethanoate, non-crossed Claisen reactions can occur significantly.

④ Example 3. Dieckmann Condensation Reaction

○ Intramolecular Claisen Condensation. 1. NaOEt, 2. H₃O⁺

○ Prefers 5-membered and 6-membered rings over 4-membered and 7-membered rings due to ring strain

⑤ Example 4. Darzens Condensation Reaction: EtONa, C₅H₅N

⑸ Reaction 2-4. Perkin Condensation Reaction

① (Formula) Benzaldehyde + Acid Anhydride → Cinnamic Acid + Carboxylic Acid

Figure 33. Perkin Condensation Reaction

⑹ Reaction 2-5. Benzoin Condensation Reaction: Catalyzed by CN^-

① Proceeds as a 1,2-addition reaction for α, β-unsaturated carbonyl compounds

○ It is not a kind of carbonyl alpha condensation reaction.

Figure 34. Benzoin Condensation Reaction

⑺ Reaction 2-6. Stetter Reaction

① Similar to the benzoin condensation but proceeds as a 1,4-addition reaction

⑻ Reaction 2-7. Robinson Annulation Reaction

① Definition: Ring-forming reaction between vinyl ketone and ketone

② (Formula) Vinyl beta carbon forms a ring through a double bond cleavage reaction, and the other non-vinyk beta carbon removes oxygen from the other ketone oxygen and forms a double bond.

Figure 35. Robinson Annulation Reaction

③ Mechanism: Carbonyl α-hydrogen removal reaction → Crossed aldol condensation → Carbonyl α-hydrogen removal reaction → 1,4-addition reaction

Figure 36. Mechanism of Robinson Annulation Reaction

4. Other Reactions

⑴ Reaction 3-1. CO₂ Emission Reaction

① Example 1. Acetoacetic Acid CO₂ Emission Reaction

Figure 37. Acetoacetic Acid CO₂ Emission Reaction

② Example 2. Malonic Acid or Malonic Ester CO₂ Emission Reaction

○ For malonic esters, a reaction under either acid-catalyzed or base-catalyzed conditions is required to convert them into malonic acid.

○ Heating Malonic Acid leads to the emission of CO₂.

Figure 38. Malonic Ester CO₂ Emission Reaction

⑵ Reaction 3-2. Michael Addition Reaction

① 1,4-Addition Reaction for conjugation compounds of Enolates.

② Includes Enol-Ketone Tautomerization Process

③ Other nucleophilic 1,4-addition reactions are also referred to as Michael reactions.

⑶ Reaction 3-3. Stork-Enamine Reaction

① (Formula) ** 2-methylcyclohexanone + pyrrolidine + weakly acidic conditions

② Enamines react with alkyl halides, acyl halides, carbonyl compounds, etc as nucleophiles.

③ Step 1. Amine Addition Reaction to Ketone

○ Reactivity differences based on the amine

○ Highly nucleophilic amines (pK_a = 6-10, e.g., pyrrolidine): Reaction proceeds without acid catalysis. Dehydration is rate-determining.

○ Weakly nucleophilic amines (pK_a = 3-5, e.g., Ph-NH-Me): Acid catalysis is required for the reaction and dehydration.

○ Acid catalyst: Strong acidic catalysts like p-TsOH are commonly used.

○ Yield enhancement strategy: Water (H₂O) is generated as a result of the forward reaction, so its removal increases the yield.

○ Strategy 1. Addition of chemically stable desiccants

○ Desiccants: CaCl₂, MgSO₄, Na₂SO₄, CaSO₄, K₂CO₃, MS, zeolite, etc.

○ Strategy 2. Use of the Dean-Stark trap

○ Efficient removal of water or low-boiling solvents formed during the reaction

○ Condition 1. Use of an azeotropic mixture: Mixing solvent and co-solvent to maintain a constant boiling point

○ Condition 2. The boiling point of the azeotropic mixture should be higher than that of the low-boiling solvent

○ Examples of solvents used in Dean-Stark trap: Benzene ( bp. 80.1 ℃), toluene ( bp. 110.6 ℃), xylene (bp. 139.3 ℃)

○ If H₂O is not effectively removed, alcohol byproducts can form.

④ Step 2. Stork-Enamine Alkylation

Figure 39. Stork-Enamine Reaction

⑷ Reaction 3-4. Mannich Reaction

Figure 40. Robinson’s Double Mannich Reaction

⑸ Reaction 3-5. Baylis-Hillman Reaction

① 1,4-Addition of Tertiary Amines followed by Cross Aldol-Like Reaction

② Representative tertiary amine is DABCO.

Figure 41. Baylis-Hillman Reaction

Input: 2019.06.11 10:41

Modified: 2022.09.27 08:42

1382

Chapter 17. Carbonyl Alpha Reactions

1. Overview

2. Reaction 1. Carbonyl alpha hydrogen removal reaction

3. Reaction 2. Carbonyl alpha condensation reaction

4. Other Reactions

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