Chapter 16: Aldehydes and Ketones - Notes

Chapter 16: Aldehydes and Ketones

Synthesizing Aldehydes and Ketones

  • Ozonolysis of Alkenes (Chem 008A Review)

  • Oxidation of Alcohols (Chem 008B Review)

  • Ketones from Friedel-Crafts Acylations (Chem 008B Review)

  • Aldehydes and Ketones from Carboxylic Acid Derivatives

Summary of Synthesis Methods:

  • Oxidation of Alcohols:

    • Primary alcohols to aldehydes, and secondary alcohols to ketones using PCC or Swern oxidation (NOT Jones reagent).

    • R-OH \rightarrow R=O (aldehyde or ketone)

  • Ozonolysis of Alkenes:

    • Alkenes are cleaved using ozone (O3) followed by dimethyl sulfide (Me2S) to yield aldehydes and/or ketones.

    • R \text{--} C=C \text{--} R' \rightarrow R=O + R'=O

  • Reduction of Esters and Nitriles:

    • Esters and nitriles can be reduced to aldehydes using DIBAL-H at -78 °C.

    • R-COOR' \rightarrow R-CHO

    • R-CN \rightarrow R-CHO

    • LiAlH4 and NaBH4 are NOT used because they reduce all the way to alcohols.

  • Nucleophilic Addition to Nitriles:

    • Ketones can be synthesized by adding Grignard reagents (R-MgBr) or organolithium reagents (R-Li) to nitriles.

    • R-CN + R'-MgBr \rightarrow R-CO-R'

  • Friedel-Crafts Acylation:

    • Aryl ketones are synthesized from arenes using acyl chlorides (R-COCl) with AlCl_3 (Review from Chem 008B).

Ozonolysis of Alkenes:

  • Alkenes are oxidatively cleaved with ozone (O_3) to form two carbonyl compounds (aldehydes and/or ketones).

Oxidation of Alcohols:

  • Primary and secondary alcohols are oxidized with PCC or Swern reagent to yield aldehydes and ketones, respectively.

The Problem of Carboxylic Acids:

  • Carboxylic acids are reduced all the way to alcohols with reagents like LiAlH_4, making it impossible to stop at the aldehyde stage.

  • The aldehyde intermediate is more reactive and gets immediately reduced to the alcohol.

Carbonyl Reductions:

  • Esters and nitriles can be reduced to aldehydes (NOT ketones) with DIBAL-H at –78 °C.

  • DIBAL-H is less reactive than LiAlH_4, allowing the reaction to stop at the aldehyde stage.

  • To reduce a carboxylic acid to an aldehyde, first convert it into an ester.

  • Mechanism:

    • Ester and DIBAL-H:

      • R-COOR' + DIBAL-H \rightarrow R-CHO

    • Nitrile and DIBAL-H:

      • R-CN + DIBAL-H \rightarrow R-CHO

Friedel-Crafts Acylation:

  • Aryl ketones can be synthesized via electrophilic aromatic substitution using Friedel-Crafts acylation.

From Nitriles:

  • Treatment of an electrophilic nitrile with a nucleophilic Grignard (or organolithium) reagent will generate a ketone.

  • R-CN + R'-MgBr \rightarrow R-CO-R'

Practice: Synthesizing Aldehydes and Ketones

Chemical Reactivity of Aldehydes and Ketones

Nucleophilic Addition to Aldehydes and Ketones

  • Summary of Reactivity:

    • Aldehydes (R-CHO ) and ketones (R-CO-R') undergo nucleophilic addition reactions.

    • Nucleophilic Addition (Basic Conditions):

      • Strong nucleophiles directly attack the carbonyl carbon.

    • Wittig Reaction:

      • Forms Z-alkenes.

    • HWE Reaction:

      • Forms E-alkenes.

    • Nucleophilic Addition (Acidic Conditions):

      • Weak nucleophiles require protonation of the carbonyl oxygen for activation.

Nucleophilic Addition: How to Attack an Aldehyde/Ketone

  • Nucleophiles attack at either face of the aldehyde or ketone along the Burgi-Dunitz angle (~107°), where the antibonding orbital density is located on the carbonyl carbon.

Nucleophilic Addition: Mechanism (Basic Conditions)

  • Strong nucleophiles (usually under basic conditions) irreversibly attack the carbonyl carbon of an aldehyde or ketone.

  • General Mechanism:

    • R2C=O + Nu^- \rightarrow R2C(Nu)-O^- \xrightarrow{H2O} R2C(Nu)-OH

Nucleophilic Addition: Mechanism (Acidic Conditions)

  • Weak nucleophiles (usually under acidic conditions) reversibly attack the carbonyl carbon of an aldehyde or ketone.

  • Initial activation of the carbonyl occurs via protonation.

  • General Mechanism:

    • R2C=O + H^+ \rightarrow R2C^+-OH + NuH \rightleftharpoons R2C(NuH)-OH2^+ \rightarrow R_2C(Nu)-OH + H^+

Chemical Reactivity of Aldehydes and Ketones

Hemiacetals, Hemiketals, Acetals, and Ketals

  • New Functional Groups:

    • HemiAcetals and Acetals:

      • Derivatives of aldehydes.

    • HemiKetals and Ketals:

      • Derivatives of ketones.

Nucleophilic Addition: (Hemi)Acetals and (Hemi)Ketals

  • Alcohols (weak nucleophiles) can nucleophilically attack aldehydes or ketones in a reversible process under acidic conditions.

  • This results in an unstable hemiAcetal (from Aldehydes) or hemiKetal (from Ketones).

  • Wherever possible, hemiAcetals and hemiKetals generally react further to form Acetals and Ketals.

  • General Reaction:

    • Aldehyde/Ketone + Alcohol HemiAcetal/hemiKetal Acetal/Ketal

Mechanism of hemiAcetal/hemiKetal and Acetals/Ketal formation under acidic anhydrous conditions:

  • The same mechanism applies if H is R instead.

  • Important: If water is present, the reaction will fail (acetal/ketal hydrolysis under aqueous acidic conditions).

Acetals and Ketals as Protecting Groups

  • Acetals/ketals are stable under basic conditions and can be used to protect an aldehyde/ketone.

  • Acetals/ketals are unstable under aqueous acidic conditions and will revert to the aldehyde/ketone.

Nucleophilic Addition: (Hemi)Acetals and (Hemi)Ketals

  • Mechanism of hemiAcetal/hemiKetal and Acetals/Ketal hydrolysis under aqueous acidic conditions:

    • The same mechanism applies if H is R instead.

Acetals and Ketals: Summary

  • Hemiacetals and hemiketals are synthesized en route to the acetal or ketal by using alcohol nucleophiles under acidic conditions.

  • The reaction is reversible.

  • Hydrolysis of an acetal or ketal is achieved by using aqueous acidic conditions (water as the nucleophile).

Chemical Reactivity of Aldehydes and Ketones

Nitrogen as a Nucleophile: Imines and Enamines
Nucleophilic Addition: Imines

  • Imines form from the condensation of an aldehyde/ketone and a primary (1°) amine nucleophile under anhydrous mildly acidic conditions (pH ~4–5).

Nucleophilic Addition: Enamines

  • Enamines form from the condensation of an aldehyde/ketone and a secondary (2°) amine nucleophile under anhydrous mildly acidic conditions (pH ~4–5).

Chemical Reactivity of Aldehydes and Ketones

Wittig Reaction (Making Z-Alkenes) and HWE Reaction (Making E-Alkenes)
The Wittig Reaction: Making Z-Alkenes

  • Treatment of an aldehyde or ketone with a phosphorous ylide produces a Z-alkene.

  • The phosphorous ylide is generated from an alkyl halide and a phosphine (Ph_3P) under basic conditions.

The Wittig Reaction: Making Z-Alkenes (Mechanism)

  • Phosphorous is a third-row element, allowing the formation of a 4-membered ring intermediate.

  • Generation of the P=O double bond is the thermodynamic “drive” behind this reaction.

The HWE Reaction: Making E-Alkenes

  • Treatment of an aldehyde or ketone with a phosphonate ester produces an E-alkene.

  • The active phosphorous reagent is generated from a phosphonate ester under basic conditions.

Chapter 16: Summary

  • Synthesizing aldehydes and ketones

    • Ozonolysis

    • Oxidation of alcohols

    • Reductions of esters and nitriles (aldehyde formation)

    • Nucleophilic additions to nitriles and Friedel-Crafts acylations (ketone formation)

  • Using aldehydes and ketones as electrophiles in nucleophilic addition reactions

    • With strong nucleophiles (Grignard reagents)

    • With weak nucleophiles (alcohols, water, amines)

    • Acetals, ketals, imines, enamines

  • Wittig reaction

  • Horner-Wadsworth-Emmons (HWE) reaction