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Chapter 15. Aldehydes and Ketones

Recommended Article: 【Organic Chemistry】 Organic Chemistry Table of Contents

1. Overview

2. Nucleophilic Addition Reactions

3. Other Reactions

4. Aldehyde Synthesis Methods

5. Ketone Synthesis Methods

1. Overview

⑴ Nomenclature

① Aldehyde Nomenclature

○ Longest chain containing CHO is the parent

○ Aldehyde carbon in CHO is numbered 1

○ Aldehyde attached to a ring is parent: Named with suffix -cycloalkanecarbaldehyde

○ Aldehyde in a chain structure is treated as a substituent: Named with oxo

○ Aldehyde in a ring structure is treated as a substituent: Named with formyl

○ Comparison of systematic nomenclature (left) and common nomenclature (right)

○ methanal / formaldehyde

○ ethanal / acetaldehyde

○ 2-bromopropanal / α-bromopropionaldehyde

○ 3-chlorobutanal / β-chlorobutyraldehyde

○ 3-methylbutanal / isovaleraldehyde

○ hexandial /

② Ketone Nomenclature

○ Longest chain containing C=O is the parent

○ End of the chain closest to C=O is numbered 1

○ Ketone attached to a ring is parent: Named with suffix -cycloalkanone

○ Ketone in a chain or ring structure is treated as a substituent: Named with oxo

○ Comparison of systematic nomenclature (left) and common nomenclature (right)

○ propanone / acetone, dimethyl ketone

○ 3-hexanone / ethyl propyl ketone

○ 6-methyl-2-heptanone / isohexyl methyl ketone

○ 2,4-pentanedione / acetylacetone

○ cyclohexanone /

○ butanedione /

⑵ Common Reaction Principles

① Nucleophilic attack, Electrophilic attack

② Proton transfer: Occurs intermolecularly, not intramolecularly

③ Tautomeric equilibrium: Enol ↔ Ketone

④ Work-up: Useful keyword for purification without specifying exact acid or base

⑶ Reactivity Comparison

① Carbonyl compound reactivity comparison

○ acyl halide ＞ acid anhydride ＞ aldehyde ＞ ketone ＞ ester ~ carboxylic acid ＞ amide ＞ carboxylate ion

② Ketone reactivity comparison based on functional groups

Figure 1. Ketone reactivity comparison based on functional groups

○ Aldehydes are more reactive, electrophilic, and have higher combustion heat than ketones

○ Reason 1: Steric hindrance: More substituents hinder nucleophilic attack, reducing nucleophilicity

○ Reason 2: Inductive effect: Substituents provide electron density to ketone carbon via hyperconjugation

③ Other Comparisons

○ Reactions involving aldehydes and ketones are quite similar

○ Ketones are more polar than aldehydes

○ Reason: Ketones stabilize carbocations in resonance contributors by methyl groups

○ Aliphatic ketones are more reactive than aromatic ketones

○ Differences in reactivity between aldehydes and ketones are observed in oxidation-reduction reactions

○ Reason: Aldehydes can undergo further oxidation, whereas ketones cannot be further oxidized

○ Example: Silver mirror reaction, Fehling’s reaction, Benedict’s reaction only occur with aldehydes

2. Nucleophilic Addition Reactions

⑴ Overview

① Bürgi–Dunitz angle: Angle at which nucleophile’s HOMO approaches the antibonding orbital (LUMO) of the carbonyl group

② Acidic conditions: Increase carbonyl’s electrophilicity

③ Basic conditions: Increase nucleophilicity of the nucleophile

④ Halide ions do not act as nucleophiles toward carbonyl compounds

⑵ Type 1. When the Basicity of Y^- is Greater than that of X^-

① Overview

○ Type 1 is frequently observed in acyl chlorides

○ Carboxylic acids also often show behavior similar to Type 1

○ Cases of aldehydes and ketones reacting as Type 1 are rare

Figure 2. Carbonyl compound reaction Type 1

② Example 1. Acyl chloride: Basicity of Cl^- is very low

Figure 3. Reaction of acyl chloride

⑶ Type 2. When the Basicity of Y^- is Less than that of X^-

① Overview

○ Aldehydes and ketones mostly follow Type 2

○ Other reactions often involve applications of Type 2

Figure 4. Carbonyl compound reaction Type 2

② Example 1. Acid-catalyzed carbonyl addition reaction

Figure 5. Acid-catalyzed carbonyl addition reaction

③ Example 2. Base-catalyzed carbonyl addition reaction

Figure 6. Base-catalyzed carbonyl addition reaction

④ Example 3. Acetal Formation Reaction: Carbonyl Carbon Protection Reaction

○ Acetal and hemiacetal

Figure 7. Structures of hemiacetal, acetal, hemiketal, and ketal

○ Reaction Mechanism : (Formula) Remove ketone oxygen and attach two -OR groups

Figure 8. Example of acetal formation reaction

○ Acetal formation reaction has reverse reaction under the same conditions

○ Dean-stark trap removes H₂O, increasing yield since H₂O is a product of the reaction

○ Solvent: Azeotropic solvents like toluene, xylene with high boiling points and constant boiling points are used ( ∵ Dean-stark trap necessary condition)

○ Excess alcohol as a reactant increases yield → usually added in excess instead of 2 equivalents

○ Esters, carboxylic acids, and amides do not form acetals under typical acidic conditions

○ Example 3-1.

Figure 9. Acetal formation reaction

○ Example 3-2.

Figure 10. Acetal formation reaction

○ Example 3-3. Corey-Seebach reaction: Thiol addition reaction

Figure 11. Thiol addition reaction

○ Reduction reaction: thioacetal + H₂ / Raney-Ni (desulfurization)

④ Example 4. Amine addition reaction

○ Mechanism: (Formula) Remove carbonyl (=O) and attach imine (=NR) instead

○ Since the reverse reaction is also possible, equilibrium is reached at a certain point.

○ Imines form best at pH 4-5

○ Example 4-1. General amine addition reaction

Figure 12. Aldehyde and ketone amine addition reaction

○ Example 4-2. p-toluenesulfonyl hydrazide (CH₃-Ph-SO₂NHNH₂)

○ Example 4-3. Enamine formation reaction

Figure 13. Enamine formation reaction

○ Secondary amines lack a proton to remove from the iminium ion, unlike primary amines, so the hydrogen attached to the alpha carbon is removed.

○ Since C=N bond strength is greater than C=C bond strength, imine formation occurs during primary amine addition

○ Stork-enamine reaction: Enamines react as nucleophiles with alkyl halides, acyl halides, carbonyl compounds, etc.

○ Example 4-4. Reduction reaction of NaBH₃CN: Imines are reduced to amines

Figure 14. Reduction reaction of NaBH3CN

○ Example 4-5. Wolff-Kishner reduction reaction

○ NH₂NH₂, strong base (e.g., KOH, NaOH), heating conditions induce additional reduction

○ When treating -C=N-NH₂ (hydrazone) with base

○ Example 4-6. Beckmann rearrangement

○ When treating -C=N-OH (oxime) with an acid

○ Example 4-7. Pomeranz-Fritsch reaction

Figure 15. Pomeranz-Fritsch reaction

○ benzaldehyde + 2,2-dialkoxyethylamine for amine addition reaction and electrophilic aromatic substitution (EAS)

○ Example 4-8. Pictet-Spengler reaction

Figure 16. Pictet-Spengler reaction

○ Amine addition reaction and Friedel-Crafts alkylation

⑤ Example 5. HCN Addition Reaction of Aldehydes and Ketones

Figure 17. Mechanism of HCN addition reaction of aldehydes and ketones

○ Example 5-1. Benzoin condensation reaction

○ Example 5-2. Stetter Reaction

⑷ Type 3. Enone and 1,2-addition reaction

① Applies when the nucleophile is a strong nucleophile (e.g.: Grignard reagent)

② Mechanism

Figure 18. Mechanism of enone and 1,2-addition reaction

⑸ Type 4. Enone and 1,4-addition reaction (Michael addition)

① Applies when the nucleophile is a weak nucleophile (e.g.: MeSH)

② Mechanism

Figure 19. Mechanism of enone and 1,4-addition reaction

③ Exception: In the case of acyl chlorides, 1,2-addition reaction occurs even with a weak nucleophile

Figure 20. Enone and acyl chloride

3. Other Reactions

⑴ Hydrogenation reaction

① Example 1. Hydrogenation with metal reagents

Figure 21. Hydrogenation of aldehydes and ketones by addition of metal reagents

② Example 2. Pd/C hydrogenation reaction: Alkene is more reactive than ketone

Figure 22. Pd/C hydrogenation under H₂ (1 eq.) conditions

Figure 23. Pd/C hydrogenation under H₂ (excess) conditions

⑵ Oxidation-reduction reaction

① Example 1. Organic metal reagent reaction with aldehydes and ketones

○ When there is an alkene and a ketone, the organic metal reagent reacts with the alkene first

Figure 24. Reaction of aldehydes and ketones with organic metal reagents

② Example 2. Wittig reaction: Addition reaction of ylide to aldehydes and ketones

○ Ylide reagent

○ Ylide refers to a molecule with adjacent atoms having opposite polarity

○ When the P=C bond forms, the inner d orbital electrons of the P atom are involved in bonding, resulting in high energy, and the zwitterion ylide, which is a separated charge, becomes the actual structure

Figure 25. Ylide reagent

○ Preparation of ylide reagents: 1. Ph₃P, CH₃Br, 2. BuLi

Figure 26. Preparation of ylide reagents

○ Example 2-1. (General) O of the ketone is replaced with C

Figure 27. Wittig reaction example

○ Example 2-2.

Figure 28. Wittig reaction example

○ Advantages: Alkene with fewer substituents becomes the sole product

○ Disadvantages: Wittig reaction generates alkenes without (E)/(Z) selectivity, while Figure 27. does show selectivity, making it worth noting

○ Solution

○ If the ylide nucleophile’s carbon is attached to an electron-withdrawing group (EWG), the reactivity is low, so thermodynamically stable alkene is predominantly formed.

○ If the ylide nucleophile’s carbon is attached to a phenyl group, the kinetically favored (less sterically hindered) alkene is predominantly formed.

③ Example 3. Horner-Wadsworth-Emmons reaction

○ Selective reaction to obtain (E)-alkenes

Figure 29. Mechanism of Horner-Wadsworth-Emmons reaction

④ Example 4. Reformatsky reaction

○ Addition reaction with organic zinc reagents

○ Organic zinc reagents are less reactive and do not react with ester groups: Unlike Grignard reagents and esters

○ After formation of the Reformatsky reagent, aldehydes and ketones undergo addition reaction

Figure 30. Reformatsky reaction

⑤ Example 5. Cannizzaro reaction

○ Intermolecular oxidation-reduction reaction of aldehydes without α-hydrogens using strong base

○ benzaldehyde + KOH + H₂O → potassium benzoate (oxidized) + benzyl alcohol (reduced)

Figure 31. Mechanism of Cannizzaro reaction

⑥ Example 6. Meerwein-Ponndorf-Verley reduction (Oppenauer oxidation)

○ Reduction of carbonyl group and oxidation of alcohol catalyzed by Al(OC(CH₃)₃)₃

○ Opposite reaction is called Oppenauer oxidation

Figure 32. Meerwein-Ponndorf-Verley reduction (Oppenauer oxidation)

⑶ Precipitation reaction: Aldehydes can be further oxidized while ketones cannot, resulting in a difference in precipitation reaction

① Silver mirror reaction (Tollens test)

Figure 33. Silver mirror reaction

○ Tollens reagent: Colorless solution

○ Step 1. Dissolve AgNO₃ in water

○ Step 2. Add NaOH or KOH to precipitate Ag as Ag₂O

○ Step 3. Add ammonia solution to form silver-ammonia complex ion Ag(NH₃)₂⁺NO₃^-

○ Experimental process

○ Step 1. Add reducing substance to silver nitrate ammonia solution (Tollens reagent) and heat

○ Step 2. Reduction of silver ion, which was in ion form, leads to the precipitation of Ag(s)

○ Reducing sugar: Formation of metallic silver

○ Aldehyde: Formation of metallic silver

○ Ag₂O acts as an Ag⁺ donor: oxygen in water moves to an aldehyde, resulting in the creation of a carboxylic acid.

○ Ketone: No reaction

○ Exception: Reacts with α-hydroxy ketones

○ Acetal: No reaction

○ Hemiacetal: Reaction

○ Reason: Hemiacetals can be cleaved into carbonyl and alcohol groups

② Fehling reaction

○ Fehling’s reagent: Copper sulfate pentahydrate (CuSO₄·5H₂O), NaOH, Rochelle salt (sodium potassium tartrate)

○ Experimental process

○ Step 1. Add reducing substance to Fehling’s solution and heat

○ Step 2. Reduction of copper ion, which was in ion form with tartaric acid, leads to the precipitation of copper(I) oxide (Cu2O)

○ Reducing sugar: Formation of copper precipitate (red-brown)

○ Aliphatic aldehyde: Formation of copper precipitate (red-brown)

○ Aromatic aldehyde: No reaction

○ Ketone: No reaction

③ Benedict’s reaction

○ Benedict’s solution: CuSO₄, Na₂CO₃, sodium citrate

○ Aldehyde: Formation of copper precipitate (red-brown)

○ Ketone: No reaction

○ Does not oxidize creatine and uric acid

○ Oxidizes glucose, fructose, and maltose, etc.: Convenient for detection reactions

⑷ Rearrangement reactions

① Example 1. Baeyer-Villiger oxidation: Mechanism of seven-membered ring structure

○ Overview

○ Under peroxy acid, excess oxygen is transferred to an aldehyde (or ketone) to produce a carboxylic acid (or ester).

○ Retention of configuration during rearrangement.

○ Migratory aptitude

○ H ＞phenyl ＞ tertiary alkyl ＞ cyclohexyl ＞ secondary alkyl ＞ primary alkyl ＞ methyl

○ Oxygen insertion occurs towards electron-rich carbon (ref)

○ 1-1. acetophenone: Benzene ring enhances reactivity

○ Acetophenone reacts with peroxidic acid (RO₃H), e.g. CF3CO₃H, to form phenyl acetate

Figure 34. Mechanism of Baeyer-Villiger oxidation

Considering the hydrogen of -OH, it can be seen that a heptagon is formed

○ 1-2. _m_CPBA

○ _m_CPBA in the form of RCO₃H oxidizes ketones

○ Oxygen insertion occurs towards electron-rich carbon

○ Competes with epoxidation of alkenes, but Baeyer-Villiger reaction is dominant

Figure 35. _m_CPBA catalyzed Baeyer-Villiger oxidation

② Example 2. Tiffeneau-Demjanov rearrangement

○ Formation of alkyl diazonium salt leads to instability and formation of carbocation

Figure 36. Mechanism of Tiffeneau-Demjanov rearrangement

③ Example 3. Johnson-Corey-Chaykovsky reaction

○ Can compete with Tiffeneau-Demjanov rearrangement

○ Example 3-1. Johnson-Corey-Chaykovsky reaction using sulfur ylide

○ Various types of sulfur ylides are as follows:

○ H₂C-S(CH₃)₂: sulfur ylide (sulfonium)

○ H₂C-SO-(CH₃)₂: Corey’s ylide (sulfoxonium)

Figure 37. Johnson-Corey-Chaykovsky reaction mechanism

○ Example 3-2. Johnson-Corey-Chaykovsky reaction of ketone under AlCl₃, CH₂N₂ conditions

Figure 38. Johnson-Corey-Chaykovsky reaction of ketone under AlCl₃, CH₂N₂ conditions

○ Example 3-3. Due to the strong nucleophilicity of sulfonium ylide, 1,2-addition is dominant

Figure 39. 1,2-addition of sulfonium ylide

○ Example 3-4. Since sulfoxonium ylide is a weak nucleophile (∵ ketone group), 1,4-addition is dominant

Figure 40. 1,4-addition of sulfoxonium ylide

> ④ Example 4. Benzilic acid rearrangement

Figure 41. Mechanism of benzilic acid rearrangement

> ⑤ Example 5. Favorskii rearrangement reaction

○ (Formula) Strong base, ketone, increase in unsaturation by one, removal of two leaving groups

Figure 42. Favorskii rearrangement reaction

4. Aldehyde Synthesis Methods

⑴ Ozonolysis of alkenes: 1. O₃, 2. Zn, H₂O or CH₃SCH₃

⑵ Hydration of terminal alkynes: 1. BH₃, 2. H₂O₂, OH^-

⑶ Synthesis of benzaldehyde via Gattermann-Koch reaction: It is a kind of Friedel-Crafts acylation for formyl group.

⑷ Reaction between benzyl chloride and nitromethane anion: benzyl chloride + nitromethane anion → benzaldehyde

⑸ Weak oxidation of primary alcohols: Oxidized to aldehydes.

⑹ HIO₄ oxidative cleavage of diols: HIO₄, H₂SO₄

⑺ Reduction of acyl chlorides, esters, and nitriles

⑻ Reimer-Tiemann reaction: CHCl₃, KOH

⑼ Corey-Seebach reaction: thioacetal + HgCl₂, MeOH, H₂O → aldehyde

① Role of sulfur atom: Reduction of negative charge through backbonding effect. Sulfur atom is easily polarized and stabilizes negative ions.

② Role of Hg²⁺: Lewis acid, solvent with hexagonal copper structure

③ Without Hg²⁺, the reverse reaction becomes dominant

5. Ketone Synthesis Methods

⑴ Ozonolysis of alkenes

⑵ Hydration of alkynes

① Overview: An alkyne with an -OH group undergoes hydration to form an enol, which then undergoes tautomerization to produce a ketone.

② Acid-catalyzed hydration reaction: H₂O, H₂SO₄ / H₂O, H₂SO₄, HgSO₄

③ Hydroboration-oxidation reaction: 1. BH₃, 2. H₂O₂, OH^- / 1. BH₃, 2. H₂O₂, OH^-

⑶ Friedel-Crafts acylation

Figure 43. Friedel-Crafts acylation of benzene

⑷ Oxidation of secondary alcohols

⑸ HIO₄ oxidative cleavage of diols: 1. HIO₄, 2. H₂SO₄

⑹ Corey-Seebach reaction: thioketal + HgCl₂, MeOH, H₂O → aldehyde

① Role of sulfur atom: Reduction of negative charge through backbonding effect. Sulfur atom is easily polarized and stabilizes negative ions.

② Role of Hg²⁺: Lewis acid, Solvation of hexagonal copper structure

③ Without Hg²⁺, the reverse reaction becomes dominant

⑺ Reaction of carboxylic acids with organolithium reagents

① Grignard and Gilman reagents do not react with carboxylic acids

⑻ Reaction of acyl chlorides with organometallic reagents

⑼ Reaction of nitriles with organometallic reagents

⑽ Imines’ acid-catalyzed hydration reaction

Input: 2019.03.29 13:54

Modification: 2023.01.30 23:12