Slide 1

• Aldehydes, Ketones & Carboxylic Acids
• Cross Aldol Reaction

Slide 2

• The aldol reaction involves the nucleophilic addition of an enolate ion to the carbonyl group of another molecule, resulting in the formation of a β-hydroxy aldehyde or ketone.
• In the aldol reaction, an aldehyde or ketone acts as both the nucleophile and the electrophile.
• The reaction is catalyzed by a base, which helps generate the enolate ion.
• The cross aldol reaction involves the reaction between two different aldehydes or ketones to form a β-hydroxy aldehyde or ketone.
• The reaction can be used to form complex molecules and is widely used in organic synthesis.

Slide 3

• In the cross aldol reaction, the enolate ion of one aldehyde or ketone attacks the carbonyl group of another aldehyde or ketone.
• The resulting intermediate can undergo dehydration to form an α,β-unsaturated aldehyde or ketone.
• The reaction can be controlled by using different aldehydes or ketones in specific ratios.
• The reaction can also be directed towards the formation of only one enantiomer by using chiral starting materials or chiral catalysts.
• The cross aldol reaction can be carried out in both acidic and basic conditions.

Slide 4

• Example 1: Cross aldol reaction between benzaldehyde and acetone:
  • Benzaldehyde: C6H5CHO
  • Acetone: CH3COCH3
  • In the presence of a base catalyst, the enolate ion of acetone attacks the carbonyl group of benzaldehyde.
  • The resulting intermediate is then dehydrated to form dibenzalacetone.
• Example 2: Cross aldol reaction between propanal and butanone:
  • Propanal: CH3CH2CHO
  • Butanone: CH3COCH2CH3
  • In the presence of a base catalyst, the enolate ion of butanone attacks the carbonyl group of propanal.
  • The resulting intermediate is then dehydrated to form 2,4-pentanedione.

Slide 5

• Factors influencing the cross aldol reaction:
  • Temperature: The reaction is typically conducted at room temperature or slightly above.
  • Solvent: Nonpolar solvents such as ether or hydrocarbon solvents are commonly used.
  • Catalyst: A base catalyst is usually used to generate the enolate ion.
  • Steric hindrance: Bulky substituents can affect the reactivity and selectivity of the reaction.
  • Substrate concentration: Higher concentrations of the reactants can increase the reaction rate.

Slide 6

• Mechanism of cross aldol reaction:
  • Step 1: Deprotonation of the α-carbon by the base catalyst to generate the enolate ion.
  • Step 2: Nucleophilic attack of the enolate ion on the carbonyl group of the other aldehyde or ketone.
  • Step 3: Formation of the aldol intermediate.
  • Step 4: Dehydration of the aldol intermediate to form the β-hydroxy aldehyde or ketone.
• It is important to note that the reaction can undergo multiple cycles of nucleophilic addition and dehydration, leading to the formation of more complex products.
• The reaction can also proceed via an intramolecular cross aldol reaction by using a single aldehyde or ketone with multiple carbonyl groups.

Slide 7

• Synthetic applications of the cross aldol reaction:
  • Formation of complex natural products and pharmaceuticals.
  • Introduction of new functional groups to a molecule.
  • Stereoselective synthesis of chiral molecules.
  • Construction of carbon-carbon bonds in organic synthesis.
  • Preparation of building blocks for further reactions.
• The cross aldol reaction is a versatile tool in organic chemistry and is widely used in industrial and academic research.

Slide 8

• Limitations and challenges of the cross aldol reaction:
  • Side reactions such as self-condensation or polymerization can occur.
  • Selectivity can be challenging due to the presence of multiple carbonyl groups or reactive sites in the reactants.
  • Steric hindrance can affect the reactivity and selectivity of the reaction.
  • Substrate compatibility and reactivity can vary depending on the reactants used.
  • Optimization of reaction conditions may be required for specific substrates.
• Despite these challenges, the cross aldol reaction remains an important tool in organic synthesis.

Slide 9

• Industrial applications of the cross aldol reaction:
  • Production of flavors and fragrances.
  • Synthesis of pharmaceutical intermediates.
  • Manufacture of fine chemicals and specialty products.
  • Development of new materials and polymers.
  • Catalyst and process development for sustainable chemistry.
• The cross aldol reaction has significant contributions in various industries and plays a crucial role in the advancement of chemical synthesis.

Slide 10

• Summary:
  • The cross aldol reaction involves the nucleophilic addition of an enolate ion to the carbonyl group of another aldehyde or ketone.
  • The reaction is catalyzed by a base and can be conducted under both acidic and basic conditions.
  • The reaction can be controlled by using different reactants in specific ratios.
  • The cross aldol reaction has applications in organic synthesis, pharmaceuticals, flavors and fragrances, and materials development.
  • Despite challenges, the reaction remains an important tool in industrial and academic research.

Slide 11

• Applications of Aldehydes and Ketones:
  • Aldehydes are used in the preparation of perfumes and flavorings.
  • Ketones are used as solvents in industries.
  • Formaldehyde is used as a disinfectant and preservative.
  • Acetone is used as a nail polish remover and paint thinner.
  • Many aldehydes and ketones are used as starting materials in the synthesis of pharmaceuticals and agrochemicals.

Slide 12

• Nomenclature of Aldehydes and Ketones:
  • Aldehydes: Replace the -e ending of the alkane name with -al. Example: Methane → Methanal, Propane → Propanal
  • Ketones: Replace the -e ending of the alkane name with -one. Example: Propane → Propanone, Butane → Butanone

Slide 13

• Reactivity of Aldehydes and Ketones:
  • Aldehydes are more reactive than ketones due to the presence of a hydrogen atom on the carbonyl carbon.
  • Aldehydes undergo oxidation reactions to form carboxylic acids.
  • Aldehydes and ketones can undergo nucleophilic addition reactions with nucleophiles such as water, alcohols, and amines.
  • Aldehydes and ketones can undergo condensation reactions to form larger molecules.

Slide 14

• Oxidation of Aldehydes:
  • Aldehydes can be oxidized to carboxylic acids using oxidizing agents such as potassium permanganate (KMnO4) or chromic acid (H2CrO4).
  • The carbon atom in the aldehyde is oxidized from a +1 oxidation state to a +3 oxidation state.
  • The oxidation reaction involves the loss of two hydrogen atoms from the aldehyde.

Slide 15

• Nucleophilic Addition Reactions:
  • Aldehydes and ketones can undergo nucleophilic addition reactions at the carbon atom of the carbonyl group.
  • Water adds to aldehydes and ketones to form geminal diols (hydrates).
  • Alcohol adds to aldehydes and ketones to form hemiacetals and acetals.
  • Amines add to aldehydes and ketones to form imines and enamines.

Slide 16

• Condensation Reactions:
  • Aldehydes and ketones can undergo condensation reactions to form larger molecules.
  • The condensation reaction involves the loss of a small molecule such as water.
  • Aldol condensation is a common type of condensation reaction between two aldehydes or ketones.
  • Coupling of two carbonyl compounds results in the formation of a β-hydroxy aldehyde or ketone.

Slide 17

• Aldol Condensation:
  • Aldol condensation involves the reaction between the enolate ion of one aldehyde or ketone and the carbonyl group of another aldehyde or ketone.
  • The reaction can be catalyzed by a base such as hydroxide ion (OH-) or sodium hydroxide (NaOH).
  • The resulting product is a β-hydroxy aldehyde or ketone.
  • The reaction can undergo dehydration to form an α,β-unsaturated aldehyde or ketone.

Slide 18

• Mechanism of Aldol Condensation:
  • Step 1: Deprotonation of the α-carbon by the base to generate the enolate ion.
  • Step 2: Nucleophilic attack of the enolate ion on the carbonyl group of another aldehyde or ketone.
  • Step 3: Formation of the aldol product.
  • Step 4: Dehydration of the aldol product to form the α,β-unsaturated aldehyde or ketone.

Slide 19

• Cross Aldol Condensation:
  • In the cross aldol condensation, two different aldehydes or ketones are used as reactants.
  • The reaction can be used to form complex molecules and introduce new functional groups.
  • The selectivity of the reaction can be controlled by using specific reactants in specific ratios.
  • Cross aldol condensation can be carried out under both acidic and basic conditions.

Slide 20

• Example of Cross Aldol Condensation:
  • Cross aldol condensation between benzaldehyde and acetone:
    • Benzaldehyde: C6H5CHO
    • Acetone: (CH3)2CO
    • The enolate ion of acetone attacks the carbonyl group of benzaldehyde.
    • The resulting intermediate undergoes dehydration to form dibenzalacetone.
  • This type of reaction can be used to synthesize various aromatic compounds and chalcones.

Slide 21

• Chalcones:
  • Chalcones are a class of organic compounds that feature a phenyl ring linked to a ketone group and an aldehyde or two ketone groups.
  • They exhibit interesting biological activities and have a variety of applications in medicine and agriculture.
  • Chalcones can be synthesized by the cross aldol condensation reaction between an aldehyde and a ketone.
• Example: Synthesis of Chalcone
  • Benzaldehyde + Acetophenone → Chalcone
  • C6H5CHO + C6H5COCH3 → C6H5CH=CHC6H5 + H2O

Slide 22

• Synthetic applications of Chalcones:
  • Chalcones exhibit antitumor, antioxidant, and anti-inflammatory properties, making them potential candidates for drug development.
  • They have been investigated as potential inhibitors of various enzymes and receptors.
  • Chalcones also show promising antibacterial and antifungal activities.
  • Chalcones can be used as intermediates in the synthesis of other biologically active compounds.
• Example: Synthesis of Flavonoids
  • Chalcone + OH- → Flavonoid
  • C6H5CH=CHC6H5 + OH- → C6H5OC6H4CH=CC6H3OH + H2O

Slide 23

• Claisen-Schmidt Condensation:
  • Claisen-Schmidt condensation is also a type of cross aldol condensation reaction.
  • It involves the reaction between an aldehyde and a ketone to form an α,β-unsaturated carbonyl compound.
  • The reaction is catalyzed by a base and can be conducted under both basic and acidic conditions.
• Example: Claisen-Schmidt Condensation
  • Benzaldehyde + Acetophenone → α,β-unsaturated ketone
  • C6H5CHO + C6H5COCH3 → C6H5CH=CHCOC6H5 + H2O

Slide 24

• Can the Cross Aldol Reaction be Stereoselective?
  • Yes, the cross aldol reaction can be stereoselective.
  • The stereoselectivity can be controlled by using chiral starting materials or chiral catalysts.
  • Chiral aldehydes or ketones can lead to the formation of one enantiomer over the other.
• Example: Stereoselective Cross Aldol Reaction
  • (R)-2-hydroxyacetophenone + (S)-propanal → (2R, 3S)-2-hydroxy-3-phenylpropanal
  • (R)-C6H5CH(OH)COCH3 + (S)-CH3CH2CHO → (2R, 3S)-C6H5CH(OH)CH(CH3)CHO

Slide 25

• Synthetic Applications of Stereoselective Cross Aldol Reaction:
  • Stereoselective cross aldol reactions are useful in the synthesis of chiral building blocks.
  • They can be used to create complex natural products and pharmaceutical intermediates.
  • Stereoselective cross aldol reactions have been employed in the synthesis of various drugs, including anticancer agents.
• Example: Synthesis of Chiral Building Blocks
  • (R)-C6H5CH(OH)COCH3 + (R)-CH3CH2CHO → (2S, 3R)-C6H5CH(OH)CH(CH3)CHO

Slide 26

• Problems with Stereoselective Cross Aldol Reactions:
  • Achieving high stereoselectivity can be challenging due to competing reactions and side reactions.
  • Selectivity can be affected by the choice of catalyst and reaction conditions.
  • The use of chiral catalysts can significantly improve the stereoselectivity of the cross aldol reaction.
  • Reaction optimization and careful substrate design are crucial for obtaining desired stereochemistry.
• Example: Stereoselectivity Control
  • (R)-C6H5CHO + (S)-C6H5CHO → major (2R, 3R) + minor (2R, 3S) products

Slide 27

• Industrial Applications of Stereoselective Cross Aldol Reactions:
  • Stereoselective cross aldol reactions are employed in the synthesis of enantiopure pharmaceuticals.
  • They are used in the production of chiral intermediates for the synthesis of agrochemicals and fine chemicals.
  • Stereoselective cross aldol reactions have applications in the development of new materials and catalyst design.
• Example: Synthesis of Enantiopure Pharmaceuticals
  • (R)-C6H5CH(OH)COCH3 + (R)-CH3CH2CHO → (2S, 3R)-C6H5CH(OH)CH(CH3)CHO

Slide 28

• Green Chemistry and Cross Aldol Reaction:
  • Green chemistry aims to reduce the environmental impact of chemical processes.
  • Cross aldol reactions can contribute to green chemistry principles.
  • They allow the use of renewable starting materials and avoid the generation of hazardous byproducts.
  • Additionally, they can be conducted in water as a green solvent.
• Example: Green Cross Aldol Reaction
  • Benzaldehyde + Acetophenone → Chalcone + Water
  • C6H5CHO + C6H5COCH3 → C6H5CH=CHC6H5 + H2O

Slide 29

• Overall Benefits of Cross Aldol Reaction:
  • Versatile tool for the synthesis of complex molecules and pharmaceuticals.
  • Introduction of new functional groups and the creation of carbon-carbon bonds.
  • Stereoselective synthesis of chiral compounds.
  • Industrial applications in the production of flavors, fragrances, and fine chemicals.
  • Green chemistry compatibility, especially with water as a solvent.

Slide 30

• Summary:
  • The cross aldol reaction involves the nucleophilic addition of an enolate ion to the carbonyl group of another aldehyde or ketone.
  • It can be used to form β-hydroxy aldehydes or ketones, which can undergo dehydration to form α,β-unsaturated compounds.
  • Cross aldol reactions are applicable in the synthesis of chalcones, flavonoids, and other important compounds.
  • Stereoselective cross aldol reactions offer control over the formation of one enantiomer, enhancing their synthetic utility.
  • The reaction has industrial applications and contributes to green chemistry principles.