23: Carbonyl Condensation Reactions
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- 448800
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- fulfill all of the detailed objectives listed under each individual section.
- design multi‑step syntheses in which the reactions introduced in this unit are used in conjunction with any of the reactions described in previous units.
- solve road‑map problems that require a knowledge of carbonyl condensation reactions.
- define, and use in context, any of the key terms introduced.
In this chapter, we consider the fourth and final general type of reaction that carbonyl compounds undergo—the carbonyl condensation reaction. Carbonyl condensation reactions take place between two carbonyl‑containing reactants, one of which must possess an alpha‑hydrogen atom. The first step of the reaction involves the removal of an alpha‑hydrogen atom by a base. In the second step, the enolate anion that results from this removal attacks the carbonyl‑carbon of the second reacting molecule. In the final step of the reaction, a proton is transferred to the tetrahedral intermediate formed in the second step, although in some cases the product that results may subsequently be dehydrated.
- 23.0: Why This Chapter?
- Most classes of biomolecules—carbohydrates, lipids, proteins, nucleic acids, and many others—are biosynthesized through pathways that involve carbonyl condensation reactions. As with the α-substitution reaction discussed in the previous chapter, the great value of carbonyl condensations is that they are one of the few general methods for forming carbon–carbon bonds, thereby making it possible to build larger molecules from smaller precursors.
- 23.1: Carbonyl Condensations - The Aldol Reaction
- The Aldol reaction is a carbonyl condensation reaction that forms carbon-carbon bonds by combining an enolate ion with an aldehyde or ketone, producing β-hydroxy aldehydes or ketones. This reaction is key in organic synthesis for creating more complex molecules. The product can further undergo dehydration to form α,β-unsaturated carbonyl compounds, which are important intermediates in both biological systems and synthetic chemistry.
- 23.2: Carbonyl Condensations versus Alpha Substitutions
- Carbonyl condensations and alpha substitutions both involve reactions at the alpha position of carbonyl compounds, but they differ in their mechanisms and products. Alpha substitutions replace an alpha hydrogen with a nucleophile, while carbonyl condensations involve the formation of carbon-carbon bonds between two carbonyl compounds. The key distinction is that condensations lead to the formation of larger molecules, while alpha substitutions do not increase the molecule's carbon count.
- 23.3: Dehydration of Aldol Products - Synthesis of Enones
- The dehydration of aldol products forms enones through a two-step process. First, aldol condensation generates a β-hydroxy carbonyl compound. Then, dehydration removes water to yield an α,β-unsaturated carbonyl compound, or enone. This reaction is common in organic synthesis and can occur under both acidic and basic conditions. The dehydration step is crucial for creating conjugated systems that stabilize the product and enhance reactivity in subsequent reactions.
- 23.4: Using Aldol Reactions in Synthesis
- The page discusses how aldol reactions are useful in organic synthesis to create complex molecules. These reactions form carbon-carbon bonds, allowing for the construction of larger molecules from smaller ones. Aldol reactions are often employed to synthesize key intermediates in pharmaceuticals, natural products, and other valuable compounds. Selectivity, control over reaction conditions, and the potential for subsequent transformations make them versatile tools in organic chemistry.
- 23.5: Mixed Aldol Reactions
- The page on mixed aldol reactions explores how these reactions involve two different aldehydes or ketones, leading to cross-condensation products. Mixed aldol reactions can create a variety of products, and selectivity is crucial to obtain the desired product. Reaction conditions, including the choice of base and solvent, can influence product formation. This strategy is used in organic synthesis to construct more complex molecules from simpler starting materials.
- 23.6: Intramolecular Aldol Reactions
- Molecules which contain two carbonyl functionalities have the possibility of forming a ring through an intramolecular aldol reaction. The term “Intramolecular” means “within the same molecule.” In this case, it means that the enolate donor and the electrophilic acceptor of an aldol reaction are contained in the same molecule such as dialdehydes, keto aldehydes, or diketones. In these cases, the small distance between the donor and acceptor leads to faster reaction rates.
- 23.7: The Claisen Condensation Reaction
- The Claisen condensation is a reaction between two ester molecules or one ester and a carbonyl compound, forming a β-keto ester or β-diketone. It requires a strong base, often an alkoxide, to generate an enolate ion that attacks another ester. This reaction is key for carbon-carbon bond formation in organic synthesis and has several variations, including crossed and intramolecular Claisen reactions.
- 23.8: Mixed Claisen Condensations
- The mixed Claisen condensation involves two different esters or an ester and a ketone, where one acts as the enolate donor and the other as the electrophile. This reaction forms β-keto esters or β-diketones and is used when at least one ester lacks α-hydrogens to prevent unwanted self-condensation. The reaction requires a strong base, such as an alkoxide, for enolate formation.
- 23.9: Intramolecular Claisen Condensations - The Dieckmann Cyclization
- The Dieckmann cyclization is an intramolecular Claisen condensation that forms a cyclic β-keto ester from a diester. This reaction occurs when the enolate of one ester reacts with the carbonyl group of another within the same molecule, leading to the formation of a six-membered ring. It is commonly used in organic synthesis for creating cyclic structures and requires a strong base to initiate the enolate formation.
- 23.10: Conjugate Carbonyl Additions - The Michael Reaction
- The Michael reaction involves a conjugate addition of nucleophiles to α,β-unsaturated carbonyl compounds, leading to the formation of a new carbon-carbon bond. This reaction is valuable in organic synthesis for constructing complex molecules and is typically catalyzed by bases or acids. The nucleophile adds to the β-carbon of the unsaturated system, resulting in a stable product. The reaction showcases the importance of conjugate addition in forming various functional groups.
- 23.11: Carbonyl Condensations with Enamines - The Stork Enamine Reaction
- The Stork enamine reaction utilizes enamines to conduct carbonyl condensations, allowing for selective alkylation at the α-carbon. In this reaction, an enamine reacts with a carbonyl compound, forming a β-substituted carbonyl product. This method is particularly useful for creating complex molecules with specific functional groups and offers advantages in regioselectivity and stereochemistry compared to traditional carbonyl reactions.
- 23.12: The Robinson Annulation Reaction
- The Robinson annulation reaction is a significant synthetic method in organic chemistry that combines an aldol condensation followed by a ring closure. It effectively forms six-membered rings and is commonly used to construct complex cyclic compounds. The process involves the formation of a β-hydroxy ketone, which undergoes dehydration and subsequent intramolecular cyclization. This reaction is valuable for creating various natural products and pharmaceuticals.
- 23.13: Some Biological Carbonyl Condensation Reactions
- This section discusses various biological carbonyl condensation reactions, highlighting their importance in metabolic pathways. Key examples include the condensation of acetyl-CoA in fatty acid synthesis and the involvement of α-keto acids in amino acid biosynthesis. These reactions play a crucial role in forming complex biomolecules, emphasizing the significance of carbonyl compounds in biological processes.
- 23.14: Chemistry Matters - A Prologue to Metabolism
- This section introduces the concept of metabolism, highlighting the significance of carbonyl condensation reactions in biochemical pathways. It emphasizes how these reactions contribute to the formation of complex molecules necessary for life, such as carbohydrates, lipids, and proteins. The discussion sets the stage for understanding metabolic processes, illustrating the intricate connections between various biochemical reactions.
- 23.16: Summary
- This chapter discusses the fourth and last of the common carbonyl-group reactions—the carbonyl condensation that takes place between two carbonyl partners and involves both nucleophilic addition and α-substitution processes. One carbonyl partner is converted by base into a nucleophilic enolate ion, which then adds to the electrophilic carbonyl group of the second partner. The first partner thus undergoes an α substitution, while the second undergoes a nucleophilic addition.
- 23.17: Summary of Reactions
- The summary of carbonyl condensation reactions outlines key mechanisms, including aldol condensation and cross-condensation. It highlights the formation of β-hydroxy carbonyl compounds followed by dehydration to yield α,β-unsaturated carbonyls. Additionally, it discusses reactions involving enolates and their role in nucleophilic additions, as well as various synthesis strategies for aldehydes and ketones. For further details, refer to the original source.