Vilsmeier Reaction
TLDRThe script delves into the Vilsmeier reaction, a formylation process that introduces a formyl group to aromatic compounds, creating aldehydes. It involves the formation of an iminium salt through a Friedel-Crafts-type mechanism, followed by hydrolysis. The reaction's electrophilic nature and para selectivity are highlighted, alongside alternative reagents like phosgene. The script also explores the reaction's versatility with substrates like alkenes, carbonyl compounds, and carboxylic acids, showcasing its synthetic importance and potential for new applications.
Takeaways
- π§ͺ A formylation reaction introduces a formyl group (CHO) to a compound, resulting in an aldehyde.
- π The Vilsmeier reaction, also known as the Vilsmeier-Haack reaction, is a formylation process involving dimethylformamide (DMF) and phosphorus oxychloride.
- π Named after two German chemists, the reaction was first described in 1927 and involves a Friedel-Crafts-type process.
- π The reaction exhibits para site-selectivity, following the typical reactivity of electrophilic aromatic substitution.
- π Alternative reagents like phosgene or phosphorus pentachloride can be used, but phosphorus oxychloride is preferred for convenience.
- π οΈ The mechanism includes the formation of an iminium salt, followed by hydrolysis to release the free aldehyde.
- π The Vilsmeier reagent is a powerful electrophile, capable of reacting with a variety of substrates.
- π While the reaction with simple alkenes can lead to formylation, it may not always be high yielding and can produce a mixture of E and Z isomers.
- π¬ Carbonyl compounds can react at the active methylene via their enol forms, leading to Ξ²-chloro-Ξ±,Ξ²-unsaturated aldehydes.
- π§ͺ Carboxylic acids can undergo double formylation with decarboxylation, resulting in products like 2-phenyl malonic aldehyde.
- π¬ The reaction's scope continues to expand with ongoing research into new substrates and applications for the Vilsmeier reagent.
- π‘ The script encourages the possibility of discovering new applications for the Vilsmeier reagent in the future.
Q & A
What is a formylation reaction?
-A formylation reaction is a chemical process where a formyl group (CHO) is introduced to a compound, resulting in the formation of an aldehyde.
What is the Vilsmeier reaction, and who is it named after?
-The Vilsmeier reaction, also known as the Vilsmeier-Haack reaction, is a formylation reaction of electron-rich aromatic compounds using a mixture of dimethylformamide and phosphorus oxychloride. It is named after the two German chemists who first described it in 1927.
What is the general mechanism of the Vilsmeier reaction?
-The Vilsmeier reaction involves the formation of an iminium salt through a Friedel-Crafts-type process, followed by hydrolysis to release the free aldehyde.
What is the typical site-selectivity observed in the Vilsmeier reaction?
-The typical site-selectivity observed in the Vilsmeier reaction is para, due to the reaction following the typical reactivity and site-selectivity of electrophilic aromatic substitution.
Can other reagents be used in place of dimethylformamide (DMF) in the Vilsmeier reaction?
-Yes, other reagents can be used in place of DMF, and different activators such as phosgene or phosphorus pentachloride can also be used, although liquid phosphorus oxychloride is often the preferred reagent.
How is the Vilsmeier reagent formed in the reaction?
-The Vilsmeier reagent is formed through the interaction of nitrogen's lone pair with carbon, followed by oxygen attacking phosphorus and the departure of a chlorine atom, resulting in the formation of an electrophilic carbon that can react with the aromatic substrate.
What happens during the electrophilic aromatic substitution (EAS) in the Vilsmeier reaction?
-During the EAS in the Vilsmeier reaction, the electrophilic carbon neutralizes the nitrogen, yielding an intermediate, followed by the loss of a proton to complete the reaction.
How does the iminium ion form in the Vilsmeier reaction?
-The iminium ion forms when nitrogen uses its lone pair to kick off chlorine, leading to the iminium ion, which can sometimes be isolated, especially if it crystallizes.
What is the role of water in the hydrolysis step of the Vilsmeier reaction?
-In the hydrolysis step, water attacks and neutralizes the nitrogen of the iminium ion, followed by proton transfers and the release of the amine, ultimately leading to the formation of the aldehyde product.
Can the Vilsmeier reagent react with substrates other than aromatic compounds?
-Yes, the Vilsmeier reagent can react with other substrates such as simple alkenes and carbonyl compounds, leading to formylation at the less substituted carbon or at the active methylene groups via their enol forms.
What is an example of an interesting application of the Vilsmeier reagent with carboxylic acids?
-An example of an interesting application with carboxylic acids is the double formylation with accompanying decarboxylation, such as in the case of phenyl acetic acid, which can lead to the formation of 2-phenyl malonic aldehyde and further reactions like condensation with hydrazine to form 4-phenyl pyrazole.
Outlines
π§ͺ The Vilsmeier Reaction: Formylation of Aromatic Compounds
The first paragraph introduces the Vilsmeier reaction, a formylation process that involves the introduction of a formyl group (CHO) to an electron-rich aromatic compound, resulting in an aldehyde. Named after its discoverers, the reaction utilizes a mixture of dimethylformamide (DMF) and phosphorus oxychloride. The mechanism includes the formation of an iminium salt through a Friedel-Crafts-type process, followed by hydrolysis to release the aldehyde. The reaction is characterized by para site-selectivity and can be carried out with alternative reagents. The paragraph also discusses the formation of the Vilsmeier reagent, the electrophilic aromatic substitution process, and the hydrolysis leading to the final aldehyde product. It highlights the reaction's synthetic importance and its potential with various substrates, including alkenes and carbonyl compounds, and concludes with an example involving phenyl acetic acid and the formation of a conjugated enamine.
π Applications and Extensions of the Vilsmeier Reagent
The second paragraph delves into the applications and extensions of the Vilsmeier reagent, emphasizing its ongoing research and development. It describes how the intermediate formed in the reaction with phenyl acetic acid is highly nucleophilic and can react further with the Vilsmeier reagent to yield a mixed iminium/enamine product. This product can be isolated or subjected to in situ hydrolysis to produce 2-phenyl malonic aldehyde. The paragraph also explores the reaction of this dialdehyde with hydrazine to form 4-phenyl pyrazole, showcasing the versatility of the Vilsmeier reagent. It concludes by encouraging further exploration and potential discovery of new applications for this powerful electrophile.
Mindmap
Keywords
π‘Formylation
π‘Vilsmeier Reaction
π‘Dimethylformamide (DMF)
π‘Phosphorus Oxychloride
π‘Iminium Salt
π‘Electrophilic Aromatic Substitution
π‘Para Site-Selectivity
π‘Hydrolysis
π‘Alkenes
π‘Carbonyl Compounds
π‘Enolization
π‘Carboxylic Acids
Highlights
Formylation is a reaction that introduces a formyl group (CHO) to a compound, resulting in an aldehyde.
The Vilsmeier reaction, also known as the Vilsmeier-Haack reaction, involves formylation of electron-rich aromatic compounds using a mixture of dimethylformamide and phosphorus oxychloride.
The reaction was first described by two German chemists in 1927.
It involves a Friedel-Crafts-type process to form an iminium salt, followed by hydrolysis to release the free aldehyde.
Para site-selectivity is observed due to the electrophilic nature of the aromatic substitution.
Alternative reagents such as phosgene or phosphorus pentachloride can be used in place of DMF.
The mechanism includes the formation of the Vilsmeier reagent and its reaction with the aromatic substrate.
The iminium ion intermediate can be isolated in some cases, particularly if it crystallizes.
Hydrolysis of the iminium ion leads to the formation of the desired aldehyde product.
The Vilsmeier reagent is a powerful electrophile with a wide range of substrates it can react with.
Simple alkenes can undergo formylation with the Vilsmeier reagent, leading to formylation at the less substituted carbon.
Carbonyl compounds can react at the active methylene groups via their enol forms.
Ketones that can enolize in one direction can yield iminium ions which can further react with the Vilsmeier reagent.
Carboxylic acids with Ξ±-methylene groups can undergo double formylation with decarboxylation.
Phenyl acetic acid can react to form a highly conjugated enamine, which can further react with the Vilsmeier reagent.
2-Phenyl malonic aldehyde can be obtained through in situ hydrolysis and can react with reagents like hydrazine.
The applications of the Vilsmeier reagent are still being explored, with ongoing research to find new uses.
The tutorial encourages thinking of new applications for the Vilsmeier reagent.
Transcripts
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