Schmidt Reaction

Professor Dave Explains
4 Oct 202108:19
EducationalLearning
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TLDRThe script delves into functional group interconversion in organic synthesis, highlighting the Curtius rearrangement and Schmidt reaction. It explains how these reactions enable the conversion of simple substrates into complex molecules, with a focus on the Schmidt reaction's two proposed mechanisms: the Baeyer-Villiger and Beckmann pathways. The discussion also addresses the selectivity of alkyl migration in ketones and innovative applications of these reactions in natural product synthesis, exemplified by Professor Jeff Aubé's work on the alkaloid stenine, showcasing the power of combining reactions in 'domino' sequences for efficient molecular structure assembly.

Takeaways
  • 🧪 Functional group interconversion is a key strategy in organic synthesis, allowing for the transformation of readily available substrates into more complex molecules.
  • 🔍 The Curtius rearrangement, first described in 1885, converts an acid chloride into an acyl azide, which then decomposes to form an isocyanate upon heating.
  • 🔥 The Schmidt reaction, introduced by Karl Friedrich Schmidt in 1924, involves the reaction of hydrazoic acid with ketones to yield amides, and has two proposed mechanisms.
  • 🛤️ The Baeyer-Villiger pathway is one of the proposed mechanisms for the Schmidt reaction, involving the migration of an R group and the loss of N2 to form an amide.
  • 🌉 The Beckmann pathway is the second proposed mechanism, which includes the formation of a diazoiminium ion intermediate and the migration of an alkyl group to form a nitrilium cation and ultimately an amide.
  • 🔍 The selectivity of alkyl migration in non-symmetrical ketones is influenced by steric considerations, with more substituted or bulkier groups migrating preferentially.
  • 🌱 Recent observations show that alkyl azides can undergo the same reaction as hydrazoic acid under acidic conditions, facilitating regiospecific Schmidt rearrangements.
  • 🔬 Professor Jeff Aubé's work demonstrates the combination of a Lewis-acid catalyzed Diels-Alder reaction with a Schmidt reaction for the synthesis of the natural alkaloid stenine.
  • 🧬 The Diels-Alder cycloaddition and subsequent Schmidt rearrangement in Aubé's work highlight the importance of regioselectivity and stereospecificity in constructing complex molecular structures.
  • 🛠️ The Schmidt reaction's versatility is showcased by its application in complex organic synthesis, where it can be combined with other reactions in 'domino' sequences for efficient molecule assembly.
  • 📚 The script emphasizes the importance of understanding and being familiar with the Schmidt reaction for students of organic synthesis, given its ongoing relevance and utility.
Q & A

  • What is the significance of functional group interconversion in organic synthesis?

    -Functional group interconversion is crucial in organic synthesis as it allows chemists to transform cheap or readily available substrates into more complex organic molecules by changing one functional group into another.

  • Who first described the Curtius rearrangement and in what year?

    -The Curtius rearrangement was first described by German chemist Theodor Curtius in 1885.

  • What is the first step of the Curtius reaction?

    -The first step of the Curtius reaction involves converting an acid chloride into an acyl azide by reacting it with azide salts like sodium azide.

  • What happens during the rearrangement step of the Curtius reaction?

    -During the rearrangement step, the acyl azide is heated to about 100°C, causing it to decompose and form an isocyanate through a process that is now believed to be a concerted mechanism.

  • How does the Schmidt reaction relate to the Curtius rearrangement?

    -A simple version of the Schmidt reaction involves the direct reaction of carboxylic acids with hydrazoic acid (HN3) to form acyl azides, which then undergo the Curtius rearrangement to yield isocyanates.

  • Who first described the reaction of hydrazoic acid with ketones, and what is this process called?

    -The reaction of hydrazoic acid with ketones, yielding amides, was first described by German chemist Karl Friedrich Schmidt in 1924 and is referred to as the Schmidt reaction.

  • What are the two proposed mechanisms for the Schmidt reaction involving ketones?

    -The two proposed mechanisms for the Schmidt reaction involving ketones are the Baeyer-Villiger pathway, where the nitrogen from hydrazoic acid attacks the protonated carbonyl, and the Beckmann pathway, which involves the formation of a diazoiminium ion intermediate.

  • How does the selectivity of alkyl migration in non-symmetrical ketones affect the Schmidt reaction?

    -In non-symmetrical ketones, the selectivity of alkyl migration is complex due to the formation of two possible isomers in the Beckmann pathway. The more substituted alkyl group migrates preferentially, affecting the outcome of the reaction.

  • What recent observation has been made regarding alkyl azides under acidic conditions?

    -It has been observed that alkyl azides can undergo the same reaction as hydrazoic acid under acidic conditions, which can activate a substrate towards a regiospecific Schmidt rearrangement.

  • Can you provide an example of how the Schmidt reaction has been applied in the synthesis of natural products?

    -An example is the synthesis of the alkaloid stenine by Professor Jeff Aubé, where a Lewis-acid catalyzed Diels-Alder reaction is combined with a Schmidt reaction to establish the correct stereochemistry and construct the skeleton of the natural alkaloid.

  • Why is the Schmidt reaction still of interest to synthetic organic chemists?

    -The Schmidt reaction is still of interest due to its ability to be extended to complex situations, providing regioselectivity and stereospecificity that can help create complicated molecular structures.

Outlines
00:00
🧪 Fundamentals of Organic Synthesis: Functional Group Interconversion

This paragraph introduces the concept of functional group interconversion as a key strategy in organic synthesis, allowing for the transformation of one functional group into another within a molecule. It discusses the Curtius rearrangement, a reaction that converts an acid chloride into an acyl azide, and then into an isocyanate through a concerted process. The Schmidt reaction is also introduced, which directly reacts carboxylic acids with hydrazoic acid to form acyl azides, and further extends to the reaction of ketones with hydrazoic acid to yield amides. Two mechanisms for the Schmidt reaction are proposed: the Baeyer-Villiger pathway, which is analogous to the mechanism of the Baeyer-Villiger reaction, and the Beckmann pathway, which resembles the Beckmann rearrangement. The paragraph also addresses the issue of selectivity in alkyl migration during the reaction, noting that more substituted or bulkier groups tend to migrate preferentially.

05:04
🌿 Innovative Applications of the Schmidt Reaction in Natural Product Synthesis

The second paragraph delves into the innovative applications of the Schmidt reaction in the synthesis of natural products, highlighting its regioselectivity and stereospecificity. It showcases the work of Professor Jeff Aubé, who combined a Lewis-acid catalyzed Diels-Alder reaction with a Schmidt reaction in a one-pot process to synthesize the alkaloid stenine. The Diels-Alder cycloaddition establishes the correct stereochemistry, and the subsequent Schmidt rearrangement constructs the molecular skeleton efficiently. The paragraph emphasizes the value of combining reactions in 'domino' sequences for rapid and efficient assembly of complex molecules, demonstrating the ongoing relevance and interest in the Schmidt reaction among synthetic organic chemists.

Mindmap
Keywords
💡Functional Group Interconversion
Functional group interconversion is the process of transforming one functional group in an organic molecule into another. This concept is central to the video's theme, as it is a fundamental strategy in organic synthesis for creating complex molecules from simpler, more readily available substrates. The video discusses how this can be achieved through various reactions, such as the Curtius rearrangement and the Schmidt reaction, which are methods to convert one functional group into another.
💡Curtius Rearrangement
The Curtius rearrangement is a specific reaction mentioned in the script, first described by Theodor Curtius in 1885. It involves the conversion of an acid chloride into an acyl azide using azide salts, which then rearranges upon heating to form an isocyanate. This reaction is crucial for the synthesis of complex organic molecules and is used as an example of functional group interconversion in the video.
💡Acyl Azide
An acyl azide is an intermediate compound formed during the Curtius rearrangement. It is created by reacting an acid chloride with azide salts and is a key step in the formation of isocyanates. In the context of the video, acyl azides are important as they demonstrate the transformation of functional groups and lead to the formation of valuable synthetic intermediates.
💡Isocyanate
Isocyanates are the products of the Curtius rearrangement, formed when an acyl azide decomposes upon heating. They are significant in organic chemistry as they can be used to synthesize a variety of compounds, including polyurethanes. The video emphasizes the formation of isocyanates as an example of functional group transformation.
💡Schmidt Reaction
The Schmidt reaction is another key concept in the video, which involves the reaction of carboxylic acids or ketones with hydrazoic acid (HN3) to form amides. The reaction is named after Karl Friedrich Schmidt, who first described it in 1924. The video discusses two proposed mechanisms for this reaction, highlighting its importance in organic synthesis.
💡Baeyer-Villiger Pathway
The Baeyer-Villiger pathway is one of the proposed mechanisms for the Schmidt reaction, where the nitrogen from hydrazoic acid attacks a protonated carbonyl group, leading to the migration of an R group and the loss of N2 to form an amide. This pathway is named after Adolf von Baeyer and Eduard Villiger and is analogous to the mechanism of the Baeyer-Villiger oxidation, which was covered in a previous tutorial mentioned in the script.
💡Beckmann Pathway
The Beckmann pathway is the second proposed mechanism for the Schmidt reaction, involving the formation of a diazoiminium ion intermediate and subsequent migration of an alkyl group to form an amide. This pathway resembles the mechanism of the Beckmann rearrangement and is named after Otto Beckmann. The video uses this pathway to illustrate the complexity and selectivity of the Schmidt reaction.
💡Alkyl Migration
Alkyl migration is a critical aspect of the Schmidt reaction, where an alkyl group migrates during the rearrangement process to form the amide. The video discusses the selectivity of alkyl migration in non-symmetrical ketones, noting that more substituted or bulkier alkyl groups tend to migrate preferentially, which is important for the regioselectivity of the reaction.
💡Regioselectivity
Regioselectivity refers to the preference for a particular direction in a chemical reaction, leading to the formation of one isomer over another. In the context of the Schmidt reaction, regioselectivity is important for determining which alkyl group migrates during the rearrangement. The video emphasizes the importance of understanding and controlling regioselectivity in organic synthesis.
💡Stereospecificity
Stereospecificity is the property of a reaction that allows it to proceed in a specific stereochemical manner, leading to the formation of a particular stereoisomer. The video mentions that the Schmidt reaction, particularly when combined with other reactions like the Diels-Alder reaction, can be highly stereospecific, which is crucial for the synthesis of complex natural products with the correct stereochemistry.
💡Diels-Alder Reaction
The Diels-Alder reaction is a [4+2] cycloaddition reaction used in organic synthesis to form six-membered rings. In the video, it is combined with the Schmidt reaction in a 'domino' sequence to construct the skeleton of a natural alkaloid called stenine. The video uses this reaction to illustrate the power of combining multiple reactions in a single synthetic sequence.
💡Domino Sequences
Domino sequences refer to a series of chemical reactions that occur consecutively in a single reaction vessel, leading to the formation of complex molecules in an efficient manner. The video highlights the use of domino sequences in organic synthesis, such as combining the Diels-Alder reaction with the Schmidt reaction, to rapidly assemble the skeleton of complex natural products.
Highlights

Functional group interconversion is essential in organic synthesis.

Curtius rearrangement was first described by Theodor Curtius in 1885.

The Curtius reaction converts an acid chloride into an acyl azide using azide salts.

Isocyanate formation through Curtius rearrangement is a concerted process.

Schmidt reaction involves the reaction of carboxylic acids with hydrazoic acid to form acyl azides.

Karl Friedrich Schmidt extended the Schmidt reaction to ketones, yielding amides.

Two proposed mechanisms for the Schmidt reaction: Baeyer-Villiger and Beckmann pathways.

Baeyer-Villiger pathway involves the migration of an R group and loss of N2.

Beckmann pathway includes the formation of a diazoiminium ion intermediate.

Selectivity of alkyl migration in non-symmetrical ketones is influenced by steric factors.

More substituted alkyl groups migrate preferentially in the Schmidt reaction.

Alkyl azides can undergo the same reaction as hydrazoic acid under acidic conditions.

Acid treatment can activate substrates for regiospecific Schmidt rearrangement.

Professor Jeff Aubé combined a Lewis-acid catalyzed Diels-Alder reaction with a Schmidt reaction.

The Diels-Alder cycloaddition and Schmidt reaction can be performed in a one-pot reaction.

The Schmidt reaction is still of current interest to synthetic organic chemists.

Organic chemists combine reactions in 'domino' sequences for efficient molecular assembly.

The Schmidt reaction's regioselectivity and stereospecificity are valuable in creating complex molecular structures.

Transcripts

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Related Tags
Organic SynthesisSchmidt ReactionCurtius RearrangementFunctional GroupIsocyanate FormationKarl Friedrich SchmidtBaeyer-Villiger PathwayBeckmann PathwayAlkyl MigrationStereochemistryNatural Alkaloids