Stetter Reaction
TLDRThe Stetter reaction, invented by Hermann Stetter in 1973, is a catalytic process that exemplifies Umpolung, or polarity inversion. It enables the direct use of aldehydes to form 1,4-dicarbonyls without synthetic equivalents. The reaction involves a thiazolium salt catalyst, which stabilizes a zwitterion, facilitating the nucleophilic attack on electrophilic enones. Nature's thiamine, the backbone of Vitamin B1, inspired this chemistry, which has been further developed for enantioselective applications, such as synthesizing unnatural amino acids, contributing to the field of semi-synthetic biology.
Takeaways
- 🌟 The Stetter reaction, invented in 1973 by Hermann Stetter, is an example of Umpolung (polarity inversion) and a catalytic reaction.
- 🧪 The catalyst for the Stetter reaction is a thiazolium salt, which enables the condensation of an aldehyde with an enone.
- 🔬 The reaction involves the formation of a zwitterion, a species with both positive and negative charges, which is stabilized through resonance.
- 💡 Thiazolium salts are good carbon acids, allowing the formation of an anion even in the presence of a base like triethylamine.
- 🔍 The Stetter reaction does not require an 'aldehyde equivalent'; the aldehyde itself is used directly in the reaction.
- ⚔️ The reaction mechanism includes a nucleophilic attack by the zwitterion on the carbonyl group of an aldehyde, forming an adduct.
- 🔄 The process involves equilibrium reactions, with the forward reaction of the aldehyde with the thiazolium being thermodynamically favored.
- 🔬 The reaction results in the formation of 1,4-dicarbonyls without the need for synthetic equivalents, showcasing the aldehyde's nucleophilic properties.
- 🌿 The structure of the thiazolium catalyst was inspired by nature, specifically the thiamine backbone of Vitamin B1.
- 🔬 Thiamine and its derivatives are crucial in various biochemical pathways, such as the degradation of oxoglutarate to succinyl coenzyme A.
- 📈 The Stetter reaction has seen extensive development, with variations including different azolium systems and acceptors beyond enones.
- 🧬 The reaction has applications in the synthesis of unnatural amino acids, contributing to the field of semi-synthetic biology.
Q & A
Who invented the Stetter reaction and in what year?
-The Stetter reaction was invented in 1973 by German chemist Hermann Stetter.
What concept does the Stetter reaction exemplify?
-The Stetter reaction exemplifies the concept of Umpolung, or polarity inversion.
What is the role of the thiazolium salt in the Stetter reaction?
-The thiazolium salt acts as a catalyst in the Stetter reaction, enabling the condensation of an aldehyde with an enone.
How does the Stetter reaction differ from the use of an 'aldehyde equivalent' in Umpolung reactions?
-The Stetter reaction allows the direct use of an aldehyde, rather than an aldehyde equivalent, to produce an acyl anion that adds to the conjugate position of an enone.
Why are thiazolium salts considered good carbon acids?
-Thiazolium salts are good carbon acids because they can form anions even with a base like triethylamine, due to resonance stabilization through a carbene.
What is special about the enol formed in the Stetter reaction?
-The enol formed in the Stetter reaction is special because it is nucleophilic at the OH-bearing carbon due to its zwitterionic form, unlike typical enols which are nucleophilic at the beta position to the hydroxyl.
How does the Stetter reaction achieve the transformation of an aldehyde carbonyl carbon into a nucleophilic center?
-The transformation occurs through the formation of a zwitterion that attacks the enone at the conjugate position, yielding an enolate which then gets protonated, leading to the formation of a nucleophilic acyl carbon.
What is the significance of the equilibrium reactions in the Stetter reaction?
-The equilibrium reactions in the Stetter reaction determine the direction of the reaction steps, favoring thermodynamically favorable steps such as the attack of the thiazolium zwitterion on an aldehyde over a ketone.
How does the Stetter reaction contribute to the formation of 1,4-dicarbonyls?
-The Stetter reaction forms 1,4-dicarbonyls by using a catalytic amount of a chiral inducer, turning the aldehyde into a nucleophile and allowing it to react with an enone without the need for synthetic equivalents.
What is the connection between the Stetter reaction and thiamine (Vitamin B1)?
-The structure of the thiazolium catalyst used in the Stetter reaction was inspired by thiamine, with Stetter replacing the pyrimidine side-chain of thiamine with a phenyl group.
How has the Stetter reaction been developed and applied in the field of organic chemistry?
-Over the last 50 years, the Stetter reaction has been extensively developed with various azolium systems, different acceptors other than enones, and the use of aldehydes extended to 1,2 dicarbonyls, acyl silanes, and other systems. It has also been applied in enantioselective syntheses, such as the work of Frank Glorius, to produce unnatural amino acids.
Outlines
🧪 Stetter Reaction and Catalytic Cycles
The Stetter Reaction, introduced by Hermann Stetter in 1973, exemplifies the concept of Umpolung or polarity inversion and is a type of catalytic reaction. The reaction utilizes a thiazolium salt as a catalyst to condense an aldehyde with an enone, forming a 1,4-dicarbonyl without the need for an aldehyde equivalent. The process involves the formation of a stable carbene that acts as a nucleophile, attacking the aldehyde to form an adduct. This adduct undergoes further reactions, resulting in the formation of a zwitterion that is both nucleophilic and electrophilic. The reaction proceeds through the attack of this zwitterion on an enone, leading to the formation of the final product and the regeneration of the catalyst. The video script also discusses the thermodynamics of the reaction and how equilibrium favors certain steps over others, as well as the inspiration Stetter drew from nature, specifically thiamine or Vitamin B1, in designing his catalyst.
🌿 Nature's Inspiration and the Stetter Reaction's Applications
This paragraph delves into how the Stetter Reaction is inspired by natural biochemical pathways, particularly the role of thiamine in catalyzing reactions like the degradation of oxoglutarate to succinyl coenzyme A. The script explains the mechanism of this natural process, highlighting the Umpolung strategy used by thiamine. It also introduces the concept of a catalytic cycle, a symbolic representation of the catalytic intermediates and stoichiometric inputs in a reaction mechanism. The paragraph further discusses the extensive development of the Stetter Reaction over the past 50 years, including the use of various azolium systems and different acceptors. An example of an enantioselective application of the reaction is provided, illustrating how the reaction can be adapted to produce unnatural amino acids with high enantiomeric purity. The script concludes by emphasizing the relevance of the Stetter Reaction in modern organic chemistry and its potential in creating semi-synthetic bacteria with new designed functions.
Mindmap
Keywords
💡Stetter Reaction
💡Umpolung
💡Catalytic Reactions
💡Thiazolium Salt
💡Zwitterion
💡Enone
💡Carbene
💡Thiamine (Vitamin B1)
💡Catalytic Cycle
💡Enantioselective
💡Unnatural Amino Acids
Highlights
The Stetter reaction, invented by Hermann Stetter in 1973, exemplifies the concept of Umpolung or polarity inversion.
The reaction is a type of catalytic reaction, utilizing a thiazolium salt as the catalyst.
The Stetter reaction allows for the direct use of aldehydes without the need for an 'aldehyde equivalent'.
Thiazolium salts are good carbon acids and can form anions with bases like triethylamine.
The anion formed is stabilized by resonance through a carbene, categorized as a stable carbene.
The reaction involves the formation of a zwitterion that reacts with an aldehyde to form an adduct.
The thiazolium salt can stabilize negative charges at both the alpha and beta positions.
The reaction demonstrates the concept of Umpolung by turning the carbonyl carbon of the aldehyde into a nucleophile.
The Stetter reaction leads to the formation of 1,4-dicarbonyls without the need for synthetic equivalents.
The reaction mechanism involves reversible steps and an irreversible step that drives the cycle downhill in free energy.
The catalyst is regenerated at the end of the reaction cycle, ready for reuse.
The Stetter reaction was inspired by the structure of thiamine, the backbone of Vitamin B1.
Thiamine and its derivatives are involved in various biochemical pathways, including the degradation of oxoglutarate.
The Stetter reaction has been developed with various azolium systems and acceptors, expanding its applications.
The reaction has been applied to enantioselective synthesis, as demonstrated by the work of Frank Glorius.
Unnatural amino acids can be synthesized using the Stetter reaction, contributing to the field of semi-synthetic biology.
The Stetter reaction is a valuable tool in organic chemistry for polarity reversal and has numerous applications.
Transcripts
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