Ritter Reaction

Professor Dave Explains
11 Jan 202208:22
EducationalLearning
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TLDRThe Ritter reaction, named after chemist John Ritter, is a method for converting nitriles to amides and subsequently to primary amines through alkylation by alcohols. It's most effective with tertiary alcohols but can be adapted for secondary and primary ones. The reaction involves the formation of a carbocation, which reacts with the nitrile to form an amide. This process has been applied in the synthesis of complex drugs like Crixivan and advanced amidochlorination techniques, showcasing its versatility and importance in organic chemistry.

Takeaways
  • 🔍 The Ritter reaction is named after American chemist John Ritter, who first reported it in 1948.
  • 🧪 It is a chemical process that achieves the hydration of a nitrile to an amide with the alkylation of the amide nitrogen by an alcohol.
  • 🚀 The reaction's products are amides, which can be further hydrolyzed to yield primary amines, indirectly transforming an alcohol into an amine.
  • ✅ The Ritter reaction is most effective with tertiary alcohols but can also be applied to secondary and primary alcohols.
  • 💧 Water is typically added at the end of the reaction to quench it.
  • 🔝 The mechanism for tertiary alcohols involves protonation to form a carbocation, which is then attacked by the nitrile to form a nitrilium ion and ultimately the amide.
  • 🔁 Carbocations can also be generated from highly substituted olefins, leading to another version of the Ritter reaction.
  • 💊 The Ritter reaction has been used in the synthesis of complex drugs like Crixivan, an early effective treatment for AIDS.
  • 🧬 The reaction's stereoselectivity can be controlled, as demonstrated in the synthesis of the aminoindanol subunit of Crixivan.
  • 🏆 Recent advances in the Ritter reaction include enantioselective amidochlorination of olefins, showcasing the reaction's continued relevance in modern organic synthesis.
  • 🌟 The Nobel Prize-winning field of enantioselective organocatalysis has opened new avenues for the Ritter reaction, combining old reactions with new methodologies for highly selective operations.
Q & A

  • Who is the Ritter reaction named after and what year did he report his earliest results?

    -The Ritter reaction is named after American chemist John Ritter, who reported his earliest results in 1948.

  • What is the primary outcome of the Ritter reaction?

    -The primary outcome of the Ritter reaction is the formation of amides, which can be further hydrolyzed to yield primary amines.

  • Which type of alcohols does the Ritter reaction work best with, and can it be applied to other types of alcohols?

    -The Ritter reaction works best with tertiary alcohols but can also be applied to secondary and primary alcohols.

  • What is the role of water in the Ritter reaction?

    -In the Ritter reaction, water is usually added at the end to quench the reaction.

  • What is the first step in the mechanism for tertiary alcohols in the Ritter reaction?

    -The first step in the mechanism for tertiary alcohols is the protonation of the alcohol by a strong acid, which releases water and forms a tertiary carbocation.

  • Why are tertiary carbocations more reactive in the Ritter reaction than secondary or primary carbocations?

    -Tertiary carbocations are more reactive in the Ritter reaction because they are more stable due to hyperconjugation, following the order tertiary > secondary > primary.

  • What is a potential side reaction in the Ritter reaction involving carbocations?

    -A potential side reaction in the Ritter reaction is isomerization of the carbocation via 1,2 hydride or methanide shifts.

  • How does the Ritter reaction involve the formation of a nitrilium ion?

    -The Ritter reaction involves the formation of a nitrilium ion when the carbocation is attacked by the nitrile via the lone pair on the nitrogen.

  • What is an alternative substrate for the Ritter reaction that does not involve alcohols?

    -An alternative substrate for the Ritter reaction that does not involve alcohols is highly substituted olefins, also known as alkenes.

  • What is the significance of the Ritter reaction in the synthesis of the drug Crixivan?

    -The Ritter reaction was significant in the synthesis of Crixivan because it allowed for the preparation of the aminoindanol subunit with high regiochemical and stereochemical purity, which was a key challenge in the drug's production.

  • How does the Ritter reaction contribute to the field of enantioselective organocatalysis?

    -The Ritter reaction contributes to the field of enantioselective organocatalysis by inspiring new methodologies that combine old reactions with new techniques, such as the recent example of amidochlorination with complete enantio- and regiocontrol.

Outlines
00:00
🧪 The Ritter Reaction and Its Mechanism

The Ritter reaction, named after American chemist John Ritter, is a process for converting nitriles into amides through the alkylation of the amide nitrogen by an alcohol, facilitated by a strong acid. It is particularly effective with tertiary alcohols but can also be used with secondary and primary alcohols. The reaction involves the protonation of the alcohol to form a carbocation, which then reacts with the nitrile to form a nitrilium ion. This intermediate is electrophilic and is attacked by water to yield the amide. An alternative pathway involves the use of olefins as substrates to generate carbocations. The Ritter reaction is not the primary method for synthesizing primary amines but has found value in organic synthesis, especially in the production of complex molecules like the AIDS drug Crixivan, where it was used to control the regiochemistry and stereochemistry of the aminoindanol subunit.

05:03
🔬 Advanced Applications and Stereoselectivity in the Ritter Reaction

The Ritter reaction's stereoselectivity arises from the reversible formation of a nitrilium ion, which can be captured by an adjacent hydroxyl group to form an oxazoline. This process is exemplified in the synthesis of the aminoindanol subunit of Crixivan, where the attack of acetonitrile occurred from the same side as the alcohol, leading to high yield and purity. A more recent application by Professor Babak Borhan in 2021 demonstrated the amidochlorination of olefins with complete enantio- and regiocontrol using a chiral chlorenium ion. The reaction utilized dichloro dimethyl hydantoin (DCDMH) and a chiral catalyst, (DHQD)2PHAL, achieving high enantioselectivity and regioselectivity with minimal catalyst required. This advancement showcases the integration of traditional reactions with modern methodologies, such as enantioselective organocatalysis, which has been recognized by the Nobel Prize in Chemistry, highlighting the ongoing relevance and innovation in Ritter chemistry.

Mindmap
Keywords
💡Ritter Reaction
The Ritter Reaction is a chemical process named after American chemist John Ritter, who first reported it in 1948. It involves the conversion of a nitrile to an amide through the alkylation of the amide nitrogen by an alcohol. In the context of the video, this reaction is highlighted for its ability to indirectly transform an alcohol into an amine, which is significant in organic synthesis. The script mentions that the reaction works best with tertiary alcohols but can also be applied to secondary and primary alcohols.
💡Hydration
Hydration in chemistry refers to the process where a molecule incorporates a water molecule. In the Ritter Reaction, hydration is part of the conversion of a nitrile to an amide. The video script explains that water is usually added at the end of the Ritter Reaction to quench the reaction, indicating its role in terminating the chemical process.
💡Amide
An amide is an organic compound with a carbonyl group (C=O) bonded to a nitrogen atom. Amides are key products of the Ritter Reaction, as they can be further hydrolyzed to yield primary amines. The script discusses how amides are formed through the reaction of a carbocation with a nitrile, highlighting their importance in the reaction mechanism.
💡Alkylation
Alkylation is a chemical reaction that involves the transfer of an alkyl group to another molecule. In the Ritter Reaction, alkylation occurs when the nitrogen of an amide is alkylated by an alcohol, leading to the formation of an amide. The script emphasizes the role of alkylation in the formation of the desired products in the reaction.
💡Carbocation
A carbocation is an organic compound containing a carbon atom with a positive charge, typically due to the loss of a hydrogen atom or halide. The video script describes how the Ritter Reaction involves the protonation of an alcohol to form a carbocation, which is then attacked by a nitrile to form a nitrilium ion, a key intermediate in the reaction.
💡Nitrile
A nitrile is a functional group with the structure -C≡N, consisting of a carbon atom triple-bonded to a nitrogen atom. In the Ritter Reaction, nitriles act as nucleophiles that attack the carbocation intermediate to form a nitrilium ion. The script explains that the reaction mechanism involves the formation of a nitrilium ion, which is then attacked by water to yield the amide product.
💡Hydrolysis
Hydrolysis is a chemical reaction during which a molecule is cleaved into two parts by the addition of a water molecule. In the context of the Ritter Reaction, hydrolysis of the amide product can yield a primary amine. The script mentions hydrolysis as a subsequent step to the Ritter Reaction, allowing for the conversion of amides into amines.
💡Stereochemistry
Stereochemistry is the aspect of chemistry concerned with the three-dimensional arrangement of atoms in molecules. The script discusses the stereochemistry of the Ritter Reaction, particularly in the synthesis of the aminoindanol subunit of the drug Crixivan, where the stereoselectivity of the reaction is crucial for obtaining the desired product.
💡Regiochemistry
Regiochemistry refers to the specific region within a molecule where a reaction occurs. The script highlights the importance of regiochemistry in the Ritter Reaction, especially in the synthesis of the aminoindanol subunit, where the reaction must occur at a specific benzylic position to ensure the correct product formation.
💡Carbocation Stability
Carbocation stability is determined by the number of carbon atoms directly attached to the positively charged carbon. The script explains that tertiary carbocations are more stable and reactive than secondary or primary carbocations in the Ritter Reaction, which is why the reaction proceeds more efficiently with tertiary alcohols.
💡Enantioselective Organocatalysis
Enantioselective organocatalysis is a subfield of catalysis that involves the use of organic molecules as catalysts to control the stereochemistry of chemical reactions. The script mentions this as a modern application of the Ritter Reaction, combining old reaction mechanisms with new methodologies to achieve highly selective transformations, as demonstrated in the synthesis of amidochlorinated olefins.
Highlights

The Ritter reaction is named after American chemist John Ritter who reported his earliest results in 1948.

The reaction achieves the hydration of a nitrile to an amide with alkylation of the amide nitrogen by an alcohol.

Products of the Ritter reaction are amides, which can be hydrolyzed to yield primary amines, indirectly transforming an alcohol into an amine.

The reaction works best for tertiary alcohols but can also be applied to secondary and primary alcohols.

Water is usually added at the end of the reaction to quench it.

The mechanism for tertiary alcohols involves protonation by a strong acid to form a carbocation.

Carbocation stability and reactivity in the Ritter reaction follow the order tertiary > secondary > primary.

Carbocations can undergo isomerization via 1,2 hydride or methanide shifts, a potential side pathway in the Ritter reaction.

The carbocation is attacked by the nitrile to form a nitrilium ion, an electrophilic intermediate.

Another formulation of the Ritter reaction operates via olefins as substrates to form amides.

Hydrolysis of the amide can yield the primary amine, extending the Ritter reaction's utility.

The Ritter reaction is not the main technique for making primary amines but has value in organic synthesis.

Nitriles can act as good nucleophiles for carbocations, a key insight for the Ritter reaction.

The Ritter reaction can be extended using alternative methods to generate carbocations in the presence of nitriles.

The drug Crixivan, used against AIDS, utilized the Ritter reaction in its synthesis.

The Ritter reaction was key in preparing the aminoindanol subunit of Crixivan with high regiochemical and stereochemical purity.

Stereoselectivity in the Ritter reaction can be influenced by the reversible formation of the nitrilium ion.

An advanced application of the Ritter reaction by Professor Babak Borhan achieved amidochlorination with complete enantio- and regiocontrol.

The use of a chiral chlorenium ion and a chiral ligand in the Ritter reaction allowed for highly selective operations.

The Ritter reaction continues to inspire new reactivities and products in the field of enantioselective organocatalysis.

Transcripts

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Related Tags
Ritter ReactionOrganic SynthesisChemical ProcessAlcohol to AmineCarbocationNitrile HydrationAmidationStereoselectivityDrug SynthesisEnantioselective Catalysis