Enolate Reactions - Direct Alkylation of Ketones With LDA

The Organic Chemistry Tutor
9 May 201813:55
EducationalLearning
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TLDRThis chemistry lesson explores the alkylation of ketones through various reagents and mechanisms. It begins with the use of lithium diisopropyl amide (LDA) to deprotonate cyclopentanone, forming an enolate ion that reacts with methyl bromide to alkylate the alpha carbon. The script delves into the kinetic versus thermodynamic control of alkylation, using LDA at low temperatures for the kinetic product and sodium hydride for the thermodynamic product. It also introduces enamine intermediates for alkylation without strong bases and their reactions with different electrophiles, resulting in monoalkylated products or diketones, highlighting the versatility of enamines in organic synthesis.

Takeaways
  • 🧪 The reaction begins with cyclopentanone and involves two steps: deprotonation with LDA (lithium diisopropyl amide) and alkylation with methyl bromide.
  • 🌟 LDA is a strong base used to remove the alpha hydrogen from a ketone, forming a resonance-stabilized enolate ion.
  • 🔁 The choice between two resonance forms of the enolate ion does not affect the final product when reacting with methyl bromide.
  • 🔄 For practice, replacing the alpha hydrogen with an R group (like ethyl in the example) gives the major product of the reaction.
  • 🔍 In unsymmetrical ketones, the position of the methyl group addition can be controlled by the choice of base and temperature.
  • 🌡️ Using LDA at low temperatures favors the kinetic product, while sodium hydride at room temperature favors the thermodynamic product.
  • ⚖️ The stability of the enolate ion is determined by the number of substituents on the carbon-carbon double bond; more substituted enolates are more stable.
  • 🔬 Steric hindrance plays a role in the selectivity of the base; LDA prefers secondary hydrogens over tertiary due to its bulkiness.
  • 🛠️ Alkylation of ketones can also be achieved through an enamine intermediate, which is formed by reacting the ketone with a secondary amine.
  • 🔄 The enamine intermediate can react with various electrophiles, including alkyl halides, alpha-beta unsaturated aldehydes, and acid chlorides.
  • 🧪 The final step in reactions involving enamines typically involves the use of water and acid (H2O+) to hydrolyze and restore the ketone form.
Q & A

  • What is the role of LDA in the first step of the described reaction?

    -LDA (Lithium Diisopropyl Amide) acts as a strong base to deprotonate the alpha hydrogen of cyclopentanone, leading to the formation of a resonance-stabilized enolate ion.

  • How does the enolate ion form in the reaction with LDA?

    -The negatively charged diisopropyl amide from LDA abstracts the alpha hydrogen from the ketone, resulting in the formation of an enolate ion which is stabilized by resonance.

  • What happens in the second step when the enolate ion reacts with methyl bromide?

    -The enolate ion acts as a nucleophile and attacks the methyl group of methyl bromide, displacing the bromide ion and forming an alkylation product at the alpha carbon of the ketone.

  • Why are there two resonance forms for the enolate ion?

    -The two resonance forms represent the delocalization of the negative charge on the adjacent carbons, which contributes to the stability of the enolate ion.

  • How can you determine the major product in the alkylation of an unsymmetrical ketone?

    -The major product is determined by the stability of the enolate ion formed. The more substituted enolate ion is generally more stable and thus forms the major product.

  • What is the difference between the kinetic and thermodynamic product in the context of enolate ion formation?

    -The kinetic product is the one formed preferentially at lower temperatures due to steric accessibility, while the thermodynamic product is the more stable enolate ion formed at higher temperatures.

  • Why is sodium hydride used instead of LDA for the formation of the thermodynamic product?

    -Sodium hydride is a smaller, less sterically hindered base that can remove the less accessible alpha hydrogens, leading to the formation of the more stable, thermodynamically favored enolate ion.

  • What is an enamine intermediate and how is it formed?

    -An enamine is an intermediate formed by the reaction of a ketone with a secondary amine, where the nitrogen atom donates a lone pair to form a double bond with the alpha carbon of the ketone.

  • How can an enamine intermediate be used to alkylate a ketone without using a strong base like LDA?

    -The enamine intermediate can react directly with alkyl halides, alpha-beta unsaturated aldehydes or ketones, and acid chlorides without the need for a strong base, facilitating the alkylation of the ketone.

  • What is the final step in converting an enamine intermediate back to the original ketone?

    -The final step involves the addition of H2O+ (a mixture of water and HCl) to protonate the nitrogen atom, which then leads to the removal of the nitrogen group and the restoration of the ketone.

  • What is the advantage of using an enamine intermediate for alkylation reactions?

    -Using an enamine intermediate allows for the alkylation of ketones without the need for strong bases, and it is an effective method for obtaining monoalkylated products.

Outlines
00:00
🧪 Alkylation of Cyclopentanone with LDA and Methyl Bromide

The script begins with a discussion on the alkylation of cyclopentanone using lithium diisopropyl amide (LDA) and methyl bromide. LDA, a strong base, is used to deprotonate the alpha hydrogen of the ketone, forming a resonance-stabilized enolate ion. This enolate ion then reacts with methyl bromide, leading to the formation of a new pi bond and the expulsion of a bromide ion, effectively adding a methyl group to the alpha carbon of the ketone. The process is explained with the option of using either of the two resonance forms for the enolate ion, resulting in the same product. The script also introduces practice problems involving the use of LDA and ethyl bromide to alkylate a ketone, emphasizing the replacement of the alpha hydrogen with an R group to determine the major product.

05:01
🔍 Selectivity in Alkylation Reactions with Unsymmetrical Ketones

The second paragraph delves into the selectivity of alkylation reactions involving unsymmetrical ketones. It explains the use of different reagents to control the position of the methyl group attachment, either on the 'right' or 'left' side of the ketone. For the kinetic product, a sterically hindered base like LDA is used at low temperatures, favoring the more accessible secondary hydrogen atoms. Conversely, for the thermodynamic product, a less hindered base like sodium hydride is used at room temperature, allowing the formation of the more substituted and stable enolate ion. The paragraph also introduces alternative methods of alkylation through enamine intermediates, which can be formed by reacting the ketone with a secondary amine, and then with an alkyl halide. The advantages of this method include avoiding the use of strong bases and achieving monoalkylated products more efficiently.

10:04
🌐 Reactions of Enamine Intermediates with Various Electrophiles

The final paragraph explores the versatility of enamine intermediates in reactions with different electrophiles beyond alkyl halides. It describes the process of reacting an enamine with an alpha-beta unsaturated aldehyde, resulting in the formation of a new double bond and a negatively charged oxygen atom. The reaction continues with the addition of water, leading to the expulsion of hydroxide and the restoration of the aldehyde. The nitrogen atom's positive charge is neutralized in the process. The paragraph also discusses the reaction of enamines with acid chlorides, resulting in the formation of a diketone after the removal of the nitrogen group with H2O+. This section highlights the ability of enamines to participate in diverse reactions, expanding the scope of organic synthesis.

Mindmap
Keywords
💡Cyclopentanone
Cyclopentanone is a cyclic ketone with a five-membered ring structure. In the context of the video, it serves as the starting compound for the described chemical reactions. The script discusses the process of alkylating the cyclopentanone by adding a methyl group to its alpha carbon, demonstrating the application of this concept in organic chemistry.
💡LDA (Lithium Diisopropyl Amide)
LDA is a strong organic base used in organic synthesis to deprotonate acidic hydrogens, such as those found on ketones. In the video, LDA is used to generate an enolate ion from cyclopentanone by removing the alpha hydrogen, which is a crucial step in the alkylation process. The script explains how LDA's structure, with a lithium cation and a nitrogen atom bonded to two isopropyl groups, contributes to its strong basicity.
💡Enolate Ion
An enolate ion is a type of anion that is formed when a ketone or aldehyde loses an alpha hydrogen. In the script, the formation of the enolate ion is central to the reaction mechanism, as it acts as a nucleophile and reacts with electrophiles like methyl bromide, leading to the formation of the major product in the reaction sequence.
💡Methyl Bromide
Methyl bromide is an alkylating agent used in the script to alkylate the enolate ion derived from cyclopentanone. The reaction of the enolate ion with methyl bromide results in the formation of a new carbon-carbon bond, illustrating a common method for modifying the structure of organic compounds.
💡Alkylation
Alkylation in organic chemistry refers to the process of adding an alkyl group to a molecule. The video script describes the alkylation of a ketone by adding a methyl group to its alpha carbon, which is a fundamental reaction type in organic synthesis and is exemplified through the reaction steps with LDA and methyl bromide.
💡Resonance
Resonance is a concept in chemistry that describes the delocalization of electrons within a molecule, leading to multiple possible structures that contribute to the overall stability of the molecule. In the script, resonance forms of the enolate ion are discussed, highlighting the importance of resonance in understanding the reactivity and stability of the intermediate species in the reaction.
💡Kinetic Product
The kinetic product is the major product formed in a reaction that proceeds through the faster pathway, often due to steric or electronic factors that favor the formation of one product over another. The script contrasts the kinetic product with the thermodynamic product, explaining how different reaction conditions can lead to the formation of either product.
💡Thermodynamic Product
The thermodynamic product is the more stable product that forms in a reaction, typically at equilibrium. In the video, the script explains how using a sterically unhindered base like sodium hydride can lead to the formation of the thermodynamic product, which is the more substituted enolate ion in the case of an unsymmetrical ketone.
💡Enamine
An enamine is a type of compound formed by the condensation of an amine with a ketone or aldehyde. In the script, the enamine intermediate is used as an alternative method for alkylating ketones, providing a route that avoids the use of strong bases like LDA and is effective for obtaining monoalkylated products.
💡Electrophile
An electrophile is a substance that seeks to accept an electron pair, often participating in reactions with nucleophiles. In the video, methyl bromide and other compounds like alpha-beta unsaturated aldehydes and acid chlorides are mentioned as electrophiles that react with the enamine intermediate to form new products.
💡Acid Chloride
An acid chloride is a compound containing a chlorine atom bonded to a carbonyl carbon. In the script, the reaction of an enamine intermediate with an acid chloride is described, leading to the formation of a diketone. This reaction illustrates the versatility of enamines in reacting with different types of electrophiles.
Highlights

Introduction of the reaction involving cyclopentanone, LDA, and methyl bromide to form a major product.

Explanation of LDA (lithium diisopropyl amide) as a strong base for deprotonating the alpha hydrogen of a ketone.

Formation of a resonance-stabilized enolate ion after deprotonation by LDA.

Reaction of the enolate ion with methyl bromide to alkylate the ketone at the alpha carbon.

Practice problem involving the reaction of a ketone with LDA and ethyl bromide to predict the major product.

Discussion on the kinetic versus thermodynamic product in unsymmetrical ketone reactions.

Use of LDA at low temperature for kinetic product formation in unsymmetrical ketones.

Use of sodium hydride and room temperature for thermodynamic product formation.

Differentiation between the steric hindrance of LDA and its preference for secondary hydrogen atoms.

Enamine intermediate formation by reacting a ketone with a secondary amine.

Enamine reaction with alkyl halides, alpha beta unsaturated aldehydes, and ketones.

Enamine reaction with acid chloride to form a diketone.

Process of converting enamine back to ketone using H2O+.

Advantage of using enamine intermediates for monoalkylated product formation without strong bases.

The versatility of enamine intermediates in reacting with various electrophiles.

Final product formation involving the removal of nitrogen group using H3O+.

Transcripts

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Related Tags
Ketone AlkylationLDAMethyl BromideEnolate IonChemical ReactionsOrganic ChemistryKinetic ProductThermodynamic ProductEnamine IntermediateDikitone Formation