Boron Aldol Reaction - Organic Chemistry, Reaction Mechanism
TLDRThis chemistry tutorial explores the diastereoselective aldol reaction mechanism using boron Lewis acids to selectively form an enolate from a ketone. The video demonstrates the process of enolization with cyclohexyl boron chloride and triethylamine, leading to the formation of the E-enolate. It then explains the reaction with benzaldehyde, resulting in the 1,2-anti-diastereomer without enantioselectivity. The Cinnamon-Traxler model is applied to achieve diastereoselectivity, emphasizing the role of bulky groups and the transition state's chair conformation. The tutorial concludes with an oxidative workup to remove the boron, yielding the final product.
Takeaways
- 🧪 The video discusses a diastereoselective aldol reaction mechanism using boron Lewis acids to selectively analyze a ketone.
- 🔍 The E-enolate is defined relative to the oxygen, with the methyl group being trans to the oxygen, which is key for understanding the diastereoselectivity.
- 🌟 The reaction scheme involves treating a ketone with cyclohexyl boron chloride and triethylamine to form an enolate species.
- 🔑 A bulky R group compared to the methyl group is crucial for the enolization process, which is facilitated by a bulky Lewis acid.
- 🌀 The mechanism begins with the coordination of the boron center to the ketone's lone pairs, followed by deprotonation to form the enolate.
- 📚 The video emphasizes the importance of orbital alignment during deprotonation for the formation of the E-enolate.
- 🎯 Diastereoselectivity is achieved through kinetic control at low temperatures, favoring the formation of a specific enolate geometry.
- 🧬 The reaction involves an intramolecular approach, facilitated by the boron enolate's ability to activate the aldehyde component.
- 💡 The Cinnamon-Traxler model is used to explain the transition state and the formation of the anti-diastereomer as the major product.
- 🌐 The bulky cyclohexyl group plays a significant role in differentiating between possible transition states and minimizing steric interactions.
- 🛠️ An oxidative workup with hydrogen peroxide in a pH 7 buffer is used to remove the boron, yielding the final product.
Q & A
What is the main topic of the video?
-The main topic of the video is the mechanism of a diastereoselective aldol reaction using boron Lewis acids to selectively analyze a ketone and the Cinnamon-Traxler model for imparting diastereoselectivity.
What is the purpose of using cyclohexyl boron chloride and triethylamine in the reaction?
-Cyclohexyl boron chloride and triethylamine are used to form the enolate species from the ketone, which is a key intermediate in the aldol reaction.
How is the E-enolate defined in the reaction?
-The E-enolate is defined by the relative position of the methyl group being trans to the oxygen, which is determined by the higher priority group's orientation.
What is the significance of the R group's size in the enolization process?
-The size of the R group, which should be reasonably big compared to the methyl group (e.g., isopropyl or larger), is crucial for the selective formation of the enolate using the bulky Lewis acid.
Why is the boron center coordinated to the lone pairs on the ketone?
-The coordination of the boron center to the lone pairs on the ketone activates the carbonyl group, making the proton more acidic and facilitating the deprotonation step.
How does the video explain the diastereoselectivity in the deprotonation step?
-The video explains that the diastereoselectivity is achieved by aligning the CH sigma bond with the pi star of the carbonyl bond, which allows for a productive deprotonation step and the formation of the E-enolate.
What role does the solvent play in the reaction?
-The solvent can influence the reaction by precipitating out the triethylammonium chloride, driving the reaction towards the formation of the reactive cyclohexyl boron enolate.
Why is the intramolecular reaction faster than the intermolecular reaction in the aldol addition step?
-The intramolecular reaction is faster because it involves pre-coordination of the aldehyde with the boron enolate, which promotes a more direct and less sterically hindered reaction pathway.
What is the significance of the six-membered ring transition state in the aldol addition?
-The six-membered ring transition state is significant because it represents a lower energy conformation that minimizes steric interactions and is the most populated conformation under kinetic control.
How does the video describe the final product's stereochemistry?
-The video describes the final product's stereochemistry by tracing the formation of new stereocenters and using the Cinnamon-Traxler model to predict the lowest energy transition state that leads to the observed product.
What is the purpose of the oxidative workup using hydrogen peroxide in methanol?
-The oxidative workup is used to remove the boron component from the molecule, converting it into the aqueous layer and providing the necessary proton for the final product.
Outlines
🧪 Mechanism of Diastereoselective Aldol Reaction
This paragraph introduces the concept of a diastereoselective aldol reaction, focusing on the use of boron Lewis acids to selectively form an enolate from a ketone. The process involves treating a ketone with cyclohexyl boron chloride and triethylamine to form an enolate species. The 'E' configuration of the enolate is defined relative to the oxygen, with the methyl group being trans. The paragraph explains the enolization process, emphasizing the importance of the size of the R group and the steric considerations of the boron Lewis acid. It also details the deprotonation step, which is influenced by the alignment of orbitals for a productive reaction. The summary concludes with the formation of the E-enolate and the triethylammonium cation, highlighting the kinetic control at low temperatures to achieve diastereoselectivity.
🔍 Intramolecular Reaction and Cinnamon-Traxler Model
The second paragraph delves into the intramolecular reaction facilitated by the boron enolate, which also acts as a Lewis acid to activate the aldehyde component. This pre-coordination promotes a faster intramolecular reaction compared to an intermolecular one. The paragraph describes the transition state of the reaction, which is expected to be a six-membered ring due to the proximity of the reactive nucleophilic carbon of the enolate to the electrophilic aldehyde carbon. The Cinnamon-Traxler model is invoked to explain the lowest energy transition state, which places the hydrogen in the axial position and the phenyl group in the equatorial position to minimize 1,3-diaxial strain. The paragraph also discusses the role of the cyclohexyl group in differentiating between possible transition states and the importance of the boron-oxygen bond in influencing the steric interactions. The summary ends with the oxidative workup process using hydrogen peroxide in a pH 7 buffer to remove the boron and protonate the product, completing the diastereoselective transformation.
Mindmap
Keywords
💡Diastereoselective Aldol Reaction
💡Boron Lewis Acids
💡Enolate
💡Cinnamon-Traxler Model
💡Stereocenters
💡E-Enolate
💡Steric Clash
💡Transition State
💡1,3-Diaxial Strain
💡Oxidative Workup
Highlights
Introduction to the mechanism of a diastereoselective aldol reaction using boron Lewis acids.
Selective enolate formation with cyclohexyl boron chloride and triethylamine to analyze a ketone.
Definition of the E-enolate based on the relative position to the oxygen atom.
Reaction of the E-enolate with benzaldehyde to produce the 1,2-anti-diastereomer.
Explanation of the lack of enantio induction resulting in a racemic product.
Importance of the size of the R group in the enolization process.
Mechanism of boron coordination to the ketone's lone pairs and the role of the weak base.
Tautomerization from keto to enol form facilitated by triethylamine.
Diastereoselectivity achieved through orbital alignment during deprotonation.
Analysis of the diastereotopic protons and their impact on enolate geometry.
Kinetic control and low temperature favoring the formation of the E-enolate.
Use of solvents to precipitate byproducts and drive the reaction towards the enolate.
Characteristics of the boron enolate as both a nucleophile and a Lewis acid.
Intramolecular reaction promoted by pre-coordination of the aldehyde.
Six-membered ring transition state in the aldol reaction.
Cinnamon-Traxler model for the lowest energy transition state and product formation.
Steric and electronic factors contributing to the selectivity of the reaction.
Removal of the boron group through oxidative workup with hydrogen peroxide.
Final product confirmation through 3D structure analysis.
Emphasis on the practical application of the diastereoselective aldol reaction in synthesis.
Invitation to subscribe for future synthesis videos featuring this transformation.
Transcripts
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