How Fischer Indole Synthesis Works: Detailed Guide for Students
One of the oldest and most powerful methods of indole development is the Fischer Indole Synthesis. It was first patented in 1883 by Fischer. A variety of indole can be prepared from aryl hydrazine and substituted ketones or aldehydes in the presence of Brønsted or Lewis acids. It is a chemical reaction that generates the aromatic heterocyclic indole from a (substituted) phenylhydrazine and an aldehyde or ketone, under acidic conditions.
Fischer indole synthesis (FIS) is said to have a wide range of applications. This includes the synthesis of indole rings that are often present in the overall synthesis of natural products as a framework. Those are particularly found in the alkaloid domain, which comprises a ring system known as an indole alkaloid.
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The ability to use a wide range of alcohols instead of their oxidized equivalents is an obvious advantage of this process. The sequence can be performed in one pot, tolerates substitution on both hydrazine and alcohol, and gives moderate to excellent yields to the indoles. Synthesis is often done by subjecting the equimolar mixture of aryl hydrazine and aldehyde or ketone directly to the conditions of idolization without hydrazone isolation. Similarly, aryl hydrazone, prepared by a reduction of the connected aryl diazonium salt or N-nitroso arylalkylamine salt, can be directly subjected to idolization conditions in the presence of carbonyl without aryl hydrazone isolation.
The Fischer Indole Synthesis’s Main Features include:
The indole formation can be carried out in one pot, as the intermediate aryl hydrazones need not be isolated.
Two region-isomeric 2,3-disubstituted indoles are provided by unsymmetrical ketones with region-selectivity depending on medium acidity, hydrazine substitution, and steric effects.
1,2-diketones can provide both mono and bis-indoles, usually forming mono-indoles in refluxing alcohols with strong acid catalysts.
Fischer Indole Synthesis Mechanism
Fischer indole synthesis converts aldehyde or ketone aryl hydrazones into aryl hydrazones in the presence of an acid catalyst, Indoles.
The arylhydrazone, prepared from the condensation of the aryl hydrazine and carbonyl compound, is protonated and isomerized to the receiver of the enamine. An irreversible electrocyclic rearrangement is then subjected to the protonated enamine tautomer, which is [3,3]-sigmatropic rearrangement, where the N-N bond is broken.
A cyclic amino acetal (or aminal) forms the resulting imine, which removes NH3 under acid catalysis, resulting in an energetically favorable aromatic indole. The Fischer indole synthesis in which an aromatic phenylhydrazone is heated in acid is the most useful route to the indoles. The condensation product of phenylhydrazine and an aldehyde or a ketone is phenylhydrazone. A cyclic rearrangement mechanism is involved in ring closure.
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Fischer Indolization
A convergent approach known as Fischer Indole Synthesis has been developed to access the fused indoline ring system found in a multitude of bioactive molecules. The approach involves the condensation of hydrazines with latent aldehydes via an interrupted Fischer indolization sequence. This eventually delivers indoline-containing products. The method is convergent, mild, easy to operate, broad in reach, and can be used for accessing enantioenriched goods.
The first catalytic Fischer asymmetric Indolization has been made. 4-substituted cyclohexanone-derived phenylhydrazones undergo strongly enantioselective indolization in the presence of a 5 mol percent loading of a novel spirocyclic chiral phosphoric acid. The addition of a weakly acidic cation exchange resin, which removes the ammonia produced, has achieved efficient catalyst turnover. The reaction can be performed under mild conditions and gives different genera of 3-substituted tetrahydro carbazoles.
An effective way to create fused indoline ring systems present in a variety of natural alkaloids is the interrupted Fischer indolization. In alkaloids and perophoramidine, a succinct approach to the complete synthesis of communes is given. The technique is based on the use of the disrupted Fischer indolization to create the natural products’ tetracyclic indoline nucleus. Studies will be presented to test the reach and limitations of this strategy.
The disrupted Fischer indolization reaction could also be used to complete the formal overall synthesis of the natural product pyrrolidinoindoline debromoflustramine B (5) Pyrrolidinone was generated using a standard two-step sequence to hemiaminal 40.
Fischer Indole Synthesis Procedure
A heterocycle of considerable significance to biological systems is Indole. In proteins, one of the main charge carriers involved in electron transfer is the redox-active indole side-chain of tryptophan 1,2. The optical properties of indole make tryptophan one of the principal intrinsic fluorophores in the study of protein fluorescence. Indole is generated via the intermediate molecule indole pyruvic acid by reductive deamination of tryptophan. Tryptophanase catalyzes the deamination mechanism from which the amine (-NH2) group of the tryptophan molecule is removed. Indole, pyruvate, ammonium and water are the final reaction components.
The Fischer indole synthesis in which an aromatic phenylhydrazone is heated in acid is the most useful route to the indoles. An achiral molecular unit is the parent indole; the creation of chiral products using a FIS is by applying alpha-branched carbonyl molecules.
FAQs on Fischer Indole Synthesis: Mechanism, Steps & Importance
1. What is the Fischer Indole Synthesis?
The Fischer Indole Synthesis is a classic organic chemistry reaction used to create indoles, which are important aromatic heterocyclic compounds. The process involves treating a phenylhydrazine with an aldehyde or a ketone in the presence of an acid catalyst. It's a reliable and versatile method named after its discoverer, Hermann Emil Fischer.
2. What are the key steps in the mechanism of the Fischer Indole Synthesis?
The mechanism is a multi-step process that transforms simple starting materials into a complex indole ring. The main steps are:
- Formation of Phenylhydrazone: The phenylhydrazine first reacts with the aldehyde or ketone to form a phenylhydrazone intermediate.
- Tautomerization: The phenylhydrazone rearranges into its more reactive isomer, an enamine. This step is crucial and requires an alpha-hydrogen on the original carbonyl compound.
- [3,3]-Sigmatropic Rearrangement: This is the most critical step where a new carbon-carbon bond is formed, creating the basic bicyclic structure of the indole.
- Aromatization: The intermediate loses a molecule of ammonia (NH₃) and rearranges to form the final, stable, and aromatic indole ring.
3. What are the starting materials required for the Fischer Indole Synthesis?
To carry out the Fischer Indole Synthesis, you need three main components:
- A phenylhydrazine. You can use substituted phenylhydrazines to create different types of indoles.
- An aldehyde or a ketone. The key requirement is that this carbonyl compound must have at least two alpha-hydrogens to allow for the formation of the enamine intermediate.
- An acid catalyst. This can be a Brønsted acid like hydrochloric acid (HCl) or a Lewis acid like zinc chloride (ZnCl₂).
4. What kind of catalysts are used in the Fischer Indole Synthesis?
The Fischer Indole Synthesis relies on an acid catalyst to drive the reaction forward. Both Brønsted and Lewis acids are commonly used.
- Brønsted acids: These are proton donors like sulfuric acid (H₂SO₄), hydrochloric acid (HCl), and polyphosphoric acid (PPA).
- Lewis acids: These are electron-pair acceptors like zinc chloride (ZnCl₂), boron trifluoride (BF₃), and aluminum chloride (AlCl₃).
The catalyst helps in the key steps, particularly the rearrangement, by protonating the intermediates.
5. How is the Fischer Indole Synthesis different from other methods like the Madelung synthesis?
While both methods produce indoles, they are very different in their approach. The main difference lies in the starting materials and reaction conditions. The Fischer method uses a phenylhydrazine and a carbonyl compound under acidic conditions. In contrast, the Madelung synthesis starts with an N-acyl-o-toluidine and requires a strong base (like sodium amide) at very high temperatures. Each method is suited for preparing different types of substituted indoles.
6. Can you give a simple example of a Fischer Indole Synthesis reaction?
A classic example is the synthesis of 2-methylindole. This reaction starts with phenylhydrazine and acetone (a simple ketone). When heated with an acid catalyst like zinc chloride (ZnCl₂), they react to form 2-methylindole, releasing ammonia and water as byproducts. This example clearly shows how a hydrazine and a ketone combine to form the indole structure.
7. Why is the [3,3]-sigmatropic rearrangement considered the key step in this synthesis?
The [3,3]-sigmatropic rearrangement is considered the heart of the Fischer Indole Synthesis because it is the main bond-forming step. During this stage, a new, strong carbon-carbon bond is created, which connects the two parts of the molecule and forms the fused ring system. This concerted rearrangement is what transforms the linear hydrazone structure into the bicyclic framework necessary to form the final indole ring.
8. Why is the synthesis of indoles, like through the Fischer method, so important?
The synthesis of indoles is extremely important because the indole ring structure is a core component in many biologically active and commercially valuable molecules. You can find the indole framework in:
- Natural Products: Such as the essential amino acid tryptophan and the hormone melatonin.
- Pharmaceuticals: Many drugs, including the anti-migraine medication Sumatriptan and anti-cancer agents, are built around an indole core.
- Agrochemicals and Dyes: The famous dye indigo is a well-known indole derivative.
The Fischer method provides a powerful tool for chemists to build these complex molecules.
9. What are the limitations of the Fischer Indole Synthesis?
Although it is a very useful reaction, the Fischer Indole Synthesis does have some important limitations. The most significant one is that the aldehyde or ketone used must have at least two alpha-hydrogens. This is because one is needed to form the hydrazone and the second is required for the tautomerization to the enamine intermediate, which is essential for the key rearrangement step. If this condition is not met, the reaction will not proceed. Additionally, harsh acidic conditions can sometimes lead to unwanted side reactions.
