Biginelli Reaction
TLDRThe script delves into the Biginelli reaction, a century-old multi-component synthesis method for creating dihydropyrimidinone compounds, crucial in medicinal chemistry. It involves combining aromatic aldehydes, urea, and beta-keto esters, catalyzed by acids, to form heterocyclic compounds foundational in DNA and RNA. The video explores the reaction's mechanism, its potential for enantioselective synthesis, and its enduring relevance in modern organic synthesis, with a highlight on Professor Liu-Zhu Gong's work achieving high enantiomeric excess using chiral phosphoric acid.
Takeaways
- 🔍 The Biginelli reaction is a significant multicomponent reaction that has gained attention for creating large chemical libraries for biological activity screening.
- 👨🔬 Invented by Pietro Biginelli in 1891, the reaction combines an aromatic aldehyde, urea, and a beta-keto ester to produce dihydropyrimidinone compounds.
- 🌟 The reaction is catalyzed by Brønsted or Lewis acids and is known for its rapid entry into the synthesis of pyrimidine systems.
- 🧬 Pyrimidines are crucial in nature and drug design, being the backbone of pyrimidine bases in nucleic acids like DNA and RNA.
- 🔢 The Biginelli product is a 3,4-dihydropyrimidine with a carbonyl at C2 and an aryl group and an ethyl ester group at C4 and C5, respectively.
- 🛠️ Biginelli products can be further modified into biologically active substances, such as calcium-channel blockers, making them valuable for screening.
- 🤔 The exact mechanism of the Biginelli reaction is not precisely known, but a reasonable candidate involves the formation of a carbamoyl iminium ion and its reaction with a beta-keto ester.
- 🔄 An alternative mechanism suggests the beta-keto ester may attack the aldehyde first, but current evidence favors the first mechanism under typical conditions.
- 🔄 The reaction can be steered by changing the experimental protocol, as demonstrated by the preparation of the alpha,beta-unsaturated ketoacid.
- 🌀 The reaction forms a chiral product with a stereogenic center, which is of great synthetic importance for medicinal chemists.
- 🌐 Enantioselective versions of the Biginelli reaction have been developed, using chiral acids as promoters to achieve high enantiomeric excess.
Q & A
What are the two multicomponent reactions discussed before the Biginelli reaction in the script?
-The two multicomponent reactions discussed before the Biginelli reaction are the Passerini reaction and the Ugi reaction.
What is the primary purpose of using the Passerini and Ugi reactions in the script?
-The primary purpose of using the Passerini and Ugi reactions is for the creation of large chemical libraries for screening in the search for biological activity.
Who invented the Biginelli reaction and when?
-The Biginelli reaction was invented by Italian chemist Pietro Biginelli in 1891.
What are the main components involved in the Biginelli reaction?
-The main components involved in the Biginelli reaction are an aromatic aldehyde, urea, and a beta-keto ester, specifically ethyl acetoacetate.
What type of compound is produced by the Biginelli reaction?
-The Biginelli reaction produces a heterocyclic compound called dihydropyrimidinone.
What role do Brønsted or Lewis acids play in the Biginelli reaction?
-Brønsted or Lewis acids act as catalysts in the Biginelli reaction.
What is the significance of the pyrimidine system in the context of the Biginelli reaction?
-The pyrimidine system is significant because it provides the skeleton of the pyrimidine bases contained in nucleic acids like DNA and RNA, making it an important target for the Biginelli reaction.
What is the complete name of the Biginelli product mentioned in the script?
-The complete name of the Biginelli product is 4-aryl-5-carbethoxy-3,4-dihydropyrimidin-2(1H)-one.
How can Biginelli products be further utilized?
-Biginelli products can be further modified into biologically active substances, such as calcium-channel blockers, which explains their frequent use in library products for screening.
What is the proposed first step in the mechanism of the Biginelli reaction?
-The first step in the mechanism of the Biginelli reaction is the establishment of an equilibrium by the reaction of urea as a nucleophile with an aldehyde, the electrophile, forming a hemiaminal which then loses water due to acid catalysis.
What is the significance of the chiral phosphoric acid used by Professor Liu-Zhu Gong in the enantioselective Biginelli reaction?
-The chiral phosphoric acid used by Professor Liu-Zhu Gong is significant because it allows for the preferential formation of the R enantiomer with a high enantiomeric excess of 97%, demonstrating the potential for enantioselective synthesis in the Biginelli reaction.
How does the Biginelli reaction compare when using aliphatic aldehydes instead of aromatic ones?
-The Biginelli reaction works with aliphatic aldehydes but generally yields lower results, especially if enolizable aldehydes are used.
Outlines
🧪 The Biginelli Reaction: A Century-Old Multi-Component Synthesis
The paragraph introduces the Biginelli reaction, a significant multi-component reaction used for creating large chemical libraries for biological screening. It was first reported by Italian chemist Pietro Biginelli in 1891 and involves combining an aromatic aldehyde, urea, and a beta-keto ester to form a heterocyclic compound known as dihydropyrimidinone. The reaction is catalyzed by Brønsted or Lewis acids. The paragraph also delves into the chemistry of pyridine and its derivatives, highlighting the importance of pyrimidine in nucleic acids. The Biginelli reaction is noted for its potential to rapidly access these systems, with the product being a 3,4-dihydropyrimidine, which is a complex structure with a carbonyl group and an aryl and ethyl ester group attached. The paragraph concludes with the mention of the reaction's potential for further modification into biologically active substances, such as calcium-channel blockers.
🔍 Exploring the Mechanism and Enantioselective Synthesis of the Biginelli Reaction
This paragraph delves into the possible mechanisms of the Biginelli reaction, acknowledging that while the exact mechanism is not well-understood, a plausible pathway involves the formation of a hemiaminal from urea and an aldehyde, which then loses water to form a carbamoyl iminium ion. This ion reacts with a beta-keto ester, leading to the formation of a heterocyclic ring through intramolecular imine formation. An alternative mechanism is also presented, where the beta-keto ester may react with the aldehyde first, followed by a nucleophilic addition of urea. The paragraph discusses the chiral nature of the product and the efforts to develop an enantioselective version of the reaction, highlighting the use of chiral acids as promoters to induce diastereoface selection. The work of Professor Liu-Zhu Gong is featured, demonstrating the use of chiral phosphoric acid to achieve a high enantiomeric excess. The paragraph concludes by noting that while the Biginelli reaction is effective with aromatic aldehydes, it can also be applied to aliphatic aldehydes, albeit with lower yields, and emphasizes the enduring relevance of this classic reaction in modern organic synthesis.
Mindmap
Keywords
💡Multicomponent reactions
💡Biological activity
💡Pietro Biginelli
💡Dihydropyrimidinone
💡Brønsted or Lewis acids
💡Heterocyclic system
💡Pyrimidine
💡Stereogenic center
💡Enantioselective
💡Chiral phosphoric acid
💡Axial chirality
💡Aliphatic aldehydes
Highlights
The Biginelli reaction is a multicomponent reaction that has gained significant attention recently, despite being over a century old.
The reaction was invented by Italian chemist Pietro Biginelli in 1891 while working at the University of Florence.
It involves combining an aromatic aldehyde, urea, and a beta-keto ester to produce a heterocyclic compound called dihydropyrimidinone.
The reaction is catalyzed by Brønsted or Lewis acids.
Pyridine and its derivatives are important compounds in nature and drug design.
Pyrimidine provides the skeleton of the pyrimidine bases contained in nucleic acids like DNA and RNA.
The Biginelli reaction offers a rapid entry into the synthesis of pyrimidine systems.
The product of the Biginelli reaction is a 3,4-dihydropyrimidine, not a fully aromatic pyrimidine.
The complete name of the Biginelli product is 4-aryl-5-carbethoxy-3,4-dihydropyrimidin-2(1H)-one.
Biginelli products can be further modified into biologically active substances, such as calcium-channel blockers.
The mechanism of the Biginelli reaction is not known in precise detail, but a reasonable candidate mechanism is discussed.
The reaction involves the formation of a hemiaminal, which loses water to form a carbamoyl iminium ion.
The beta-keto ester reacts with the carbamoyl iminium ion, followed by intramolecular imine formation to close the ring.
An alternative mechanism involving the beta-keto ester attacking the aldehyde first is also discussed.
The Biginelli reaction forms a chiral product with a stereogenic center at the carbon that was previously the carbonyl carbon of the aldehyde.
Chemists have attempted to create an enantioselective version of the Biginelli reaction using chiral acids as promoters.
Professor Liu-Zhu Gong used a chiral phosphoric acid catalyst to achieve a high enantiomeric excess of 97%.
The Biginelli reaction also works with aliphatic aldehydes, but generally yields lower.
The Biginelli reaction remains a hot topic in modern organic synthesis due to its versatility and applications.
Transcripts
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