Fischer Indole Synthesis
TLDRThe video script discusses the synthesis of indole, an aromatic heterocycle found in bioactive molecules like tryptophan, strychnine, and serotonin. It highlights the Fischer synthesis, a method discovered by Nobel laureate Emil Fischer in 1882, detailing the steps from aryl hydrazine and ketone condensation to the formation of indole. The script further explores the complexities of the mechanism, the impact of ring substitution on reaction rates and site selectivity, and the challenges posed by different ketone types. It emphasizes the Fischer synthesis as a classic and primary approach in organic chemistry for creating indoles.
Takeaways
- πΏ Indole is a significant aromatic heterocycle and a common subunit in bioactive molecules found in nature.
- π§ͺ Tryptophan, strychnine, and serotonin are examples of biologically relevant compounds that contain indole structures.
- π Fischer synthesis, discovered by Emil Fischer in 1882, is a primary method for synthesizing indoles.
- π¬ The Fischer synthesis involves a reaction between aryl hydrazines and ketones, typically catalyzed by acids.
- π§ The initial step in the Fischer synthesis is the condensation of aryl hydrazine with a ketone, resulting in the formation of aryl hydrazones.
- π Aryl hydrazones can be converted to indoles using strong acids or Lewis acids, with a mechanism that involves the loss of one nitrogen atom.
- π A key step in the mechanism is a 3,3 sigmatropic shift, which forms the crucial carbon-carbon bond and restores aromaticity.
- π The presence of electron-donating or -withdrawing substituents on the aryl ring affects the reaction rate and site selectivity in indole synthesis.
- π Para-substituted aryl hydrazines lead to the substituent being positioned at the C-5 of the indole, while ortho-substituted result in C-7.
- π Meta-substituted aryl hydrazines can lead to two possible products, C-4 and C-6 substituted indoles, depending on the nature of the substituent.
- βοΈ The choice of ketone in the Fischer synthesis can influence the number of possible products, especially with nonsymmetrical ketones.
- π οΈ The Fischer synthesis is a classic method in organic chemistry for indole synthesis, with alternative approaches available for complex cases.
Q & A
What is an indole and why is it significant in the context of bioactive molecules?
-Indole is an aromatic heterocycle with a bicyclic structure that involves benzene fused with pyrrole. It is significant because it is widespread in nature and acts as a common subunit of bioactive molecules, playing a crucial role in various biological processes.
Can you provide some examples of biologically relevant compounds that feature indole structures?
-Examples of biologically relevant compounds featuring indole structures include tryptophan, an essential amino acid; strychnine, an alkaloid found in certain plants; and serotonin, a neurotransmitter.
Who discovered the Fischer synthesis and when was it discovered?
-The Fischer synthesis was discovered in 1882 by the famous German chemist Emil Fischer, who was awarded the Nobel Prize in 1902.
What is the general process of the Fischer synthesis for the formation of indoles?
-The Fischer synthesis involves the condensation of an aryl hydrazine with a ketone, catalyzed by an acid, to form aryl hydrazones. These hydrazones are then treated with strong acids or Lewis acids to yield indoles through a series of protonation, sigmatropic shift, and cyclization steps.
How does the mechanism of the Fischer synthesis account for the loss of one nitrogen atom?
-The mechanism involves a series of steps where the initial aryl hydrazine and ketone react to form an ene-hydrazine intermediate. A 3,3 sigmatropic shift occurs, leading to the formation of an aniline form which then cyclizes to form the indole ring. During this process, one nitrogen atom is eliminated as ammonia.
What is the role of sigmatropic shift in the Fischer synthesis?
-The sigmatropic shift is a key step in the Fischer synthesis where it generates the crucial carbon-carbon bond at the ortho position of the benzene ring, facilitating the formation of the five-membered indole ring.
How does the presence of electron-donating or electron-withdrawing substituents affect the Fischer synthesis?
-The presence of electron-donating substituents on the aryl hydrazine accelerates the reaction, while electron-withdrawing substituents hinder it. In extreme cases with electron-withdrawing groups, the reaction may not occur at all.
What is the impact of substitution on the site selectivity in the Fischer synthesis of indoles?
-Substitution affects site selectivity in the Fischer synthesis. Para-substituted aryl hydrazines lead to the substituent at the C-5 position of the indole, while ortho-substituted ones result in the C-7 position. Meta-substituted aryl hydrazines can lead to either C-4 or C-6 substitution, depending on the nature of the substituent.
How does the type of ketone used in the Fischer synthesis influence the outcome?
-The type of ketone used can greatly influence the outcome. Symmetrical ketones like acetone yield a single product, while nonsymmetrical ketones that can enolize on both sides can lead to multiple products. The major product is often formed from enolization at the less substituted side of the ketone.
What are some alternative approaches to forming indoles if complications arise with the Fischer synthesis?
-While the Fischer synthesis is a classic method for forming indoles, complications may arise, and in such cases, other synthetic routes or methodologies may be explored to achieve the desired indole structures.
Why is the Fischer synthesis considered a classic in organic synthesis?
-The Fischer synthesis is considered a classic in organic synthesis due to its historical significance, the elegance of its mechanism, and its wide applicability in the synthesis of indole-containing compounds, which are prevalent in natural products and pharmaceuticals.
Outlines
πΏ Indole Synthesis and Fischer Reaction
This paragraph delves into the synthesis of indoles, a class of aromatic heterocycles with widespread natural occurrence and biological significance. It introduces the Fischer synthesis, a method discovered by Emil Fischer in 1882, which is pivotal for the creation of indole structures. The summary explains the initial step of condensing aryl hydrazine with a ketone to form aryl hydrazones, followed by a complex mechanism involving protonation, sigmatropic shift, isomerization, and cyclization to form the indole ring. The paragraph also discusses the impact of substitution on the reaction's rate and site selectivity, noting that para-substituted aryl hydrazines lead to C-5 substitution, while meta-substituted ones can yield C-4 and C-6 substituted products.
π¬ Electron Effects and Substitution in Fischer Indole Synthesis
The second paragraph focuses on the influence of electron-releasing and electron-withdrawing groups on the Fischer indole synthesis. It describes how para-substituted electron-releasing groups typically favor the formation of the C-6 product, while electron-withdrawing groups can result in poor selectivity, leading to both C-4 and C-6 substitutions unless the substituent is bulky. The paragraph also addresses the complexities introduced by multiple substituents and the use of nonsymmetrical ketones, which can lead to multiple products. The summary highlights the role of enolization in determining the major product when using nonsymmetrical ketones and the effect of strong acids like methanesulfonic acid on the reaction's outcome.
Mindmap
Keywords
π‘Heterocycles
π‘Indole
π‘Fischer Synthesis
π‘Aryl Hydrazones
π‘Bronsted-Lowry Acids
π‘Sigmatropic Shift
π‘Anilines
π‘Iminium Ion
π‘Substitution
π‘Site Selectivity
π‘Enolization
Highlights
Indole is an important aromatic heterocycle with a bicyclic structure of benzene fused with pyrrole.
Indoles are prevalent in nature and serve as common subunits of bioactive molecules.
Examples of biologically relevant indole compounds include tryptophan, strychnine, and serotonin.
The Fischer synthesis, discovered in 1882, is a significant method for indole synthesis.
Emil Fischer, the discoverer of the Fischer synthesis, was awarded the Nobel Prize in 1902.
The Fischer synthesis involves the condensation of aryl hydrazines with ketones, catalyzed by acids.
Aryl hydrazones are formed as intermediates in the Fischer synthesis and are often crystalline.
Strong acids or Lewis acids are used to convert hydrazones into indoles.
The mechanism of the Fischer synthesis involves the loss of one nitrogen atom.
Acid catalysis initiates the formation of an ene-hydrazine intermediate in the mechanism.
A 3,3 sigmatropic shift is a key step in the formation of the carbon-carbon bond in the Fischer synthesis.
Aniline form isomerization restores the aromaticity of the benzene ring during the synthesis.
The nitrogen from the aniline moiety attacks the iminium ion to form the five-membered ring.
Ammonia is eliminated in the final step of the Fischer synthesis to yield the indole.
Electron-donating substituents on the ring accelerate the Fischer synthesis reaction.
Electron-withdrawing substituents hinder the reaction, and in extreme cases, prevent it from occurring.
Para-substituted aryl hydrazines result in the substituent being at the C-5 position of the indole.
Ortho-substituted aryl hydrazines lead to the substituent at the C-7 position due to steric hindrance.
Meta-substituted aryl hydrazines can yield two possible products with varying site selectivity.
The nature of the substituent influences the major product in meta-substituted Fischer synthesis.
The use of nonsymmetrical ketones in the Fischer synthesis can lead to multiple products.
Enolization preference in nonsymmetrical ketones depends on the side that is less substituted.
The Fischer synthesis is a classic method in organic synthesis for making indoles.
Transcripts
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