Wolff-Kishner Reduction
TLDRThe script introduces the Wolff-Kishner reduction, a method for converting ketones to alkanes under basic conditions using hydrazine and a strong base at high temperatures. It discusses the mechanism involving hydrazone formation, diimide tautomerization, and carbanion formation, leading to alkane production. The method's utility in synthesis is highlighted, including its large-scale application in pharmaceuticals and the development of milder conditions by chemist Donald Cram. The summary also touches on a complex strategy involving the reduction in the synthesis of 3-alkyl pyrroles, emphasizing the technique's importance in organic chemistry.
Takeaways
- 🔍 The Clemmensen reduction and Wolff-Kishner reduction are methods to reduce aldehydes and ketones to alkanes, removing an oxygen atom.
- 🌟 Wolff-Kishner reduction was independently developed by Ludwig Wolff and Nikolai Kishner in 1911 and 1912.
- 🔥 The process involves the use of hydrazine and a strong base like potassium hydroxide at high temperatures.
- 🧪 The mechanism includes the formation of a hydrazone, which tautomerizes to a diimide, followed by deprotonation to form a carbanion.
- ⚠️ Wolff-Kishner reduction requires handling of hazardous reagents like liquid hydrazine, which is also used in rocket fuels.
- 🛠 The method has been used industrially, including for the synthesis of pharmaceuticals, despite its harsh conditions.
- 🔄 There have been many attempts to modify the original Wolff-Kishner protocol to create milder conditions.
- 🏆 Donald Cram improved the method in 1962 by using potassium tert-butoxide and dimethyl sulfoxide, allowing the reaction to occur at room temperature.
- 🔬 The reduction can be part of complex synthetic strategies, such as the preparation of 3-alkyl pyrroles from pyrrole 2-carboxylic acid.
- 📚 Understanding the Wolff-Kishner reduction is crucial for organic chemists due to its utility in organic synthesis.
- 🛑 The reaction is particularly useful when a carbonyl group is needed for a specific transformation but must be removed in the final product.
Q & A
What is the Clemmensen reduction?
-The Clemmensen reduction is a chemical reaction that reduces aldehydes and ketones to alkanes by removing an oxygen atom entirely, performed in the presence of zinc and hydrochloric acid.
What alternative method is mentioned in the script for reducing aldehydes and ketones to alkanes?
-The Wolff-Kishner reduction is an alternative method for reducing aldehydes and ketones to alkanes, which is performed under basic conditions.
Who developed the Wolff-Kishner reduction method?
-The Wolff-Kishner reduction method was developed independently by German chemist Ludwig Wolff and Russian chemist Nikolai Kishner in 1911 and 1912.
What reagents are typically used in the Wolff-Kishner reduction?
-The Wolff-Kishner reduction involves the use of hydrazine and a strong base like potassium hydroxide at very elevated temperatures in a high-boiling solvent.
What is the first step in the Wolff-Kishner reduction mechanism?
-The first step in the Wolff-Kishner reduction mechanism is the formation of a hydrazone through a condensation reaction that proceeds with the elimination of water.
Why are hydrazones sometimes advantageous to pre-form in the Wolff-Kishner reduction?
-Hydrazones are advantageous to pre-form because they are usually stable, crystalline compounds, and the yield of the reaction is often better if the first step is followed by an isolation.
What is the tautomeric form of hydrazones in the Wolff-Kishner reduction?
-The tautomeric form of hydrazones in the Wolff-Kishner reduction is the diimide, which has an additional proton on the carbon and a double bond between the nitrogens.
What is the slow step in the Wolff-Kishner reduction reaction?
-The slow step in the Wolff-Kishner reduction reaction is the deprotonation of the diimide by the strong base, leading to the loss of nitrogen gas and the formation of a carbanion.
Why is liquid hydrazine considered a hazardous reagent in the Wolff-Kishner reduction?
-Liquid hydrazine is considered hazardous because it is used in rocket fuels and can detonate in the gas phase even in the absence of oxygen, especially at the high temperatures required for the Wolff-Kishner reduction.
What modification to the Wolff-Kishner reduction was made by Donald Cram?
-Donald Cram improved the Wolff-Kishner reduction by using potassium tert-butoxide as a base and dimethyl sulfoxide as the solvent, allowing the reaction to be run at room temperature under exceptionally basic conditions.
Can you provide an example of a complex strategy involving Wolff-Kishner reduction mentioned in the script?
-An example of a complex strategy involving Wolff-Kishner reduction is the preparation of 3-alkyl pyrroles. This involves the alkylation of pyrrole at a specific carbon, conversion to an ethyl thioester for protection, Friedel-Crafts acylation at C-4, and finally, reduction of the acyl group to an alkyl group followed by decarboxylation under Wolff-Kishner conditions.
Why is it important for organic chemists to be familiar with the Wolff-Kishner reduction?
-It is important for organic chemists to be familiar with the Wolff-Kishner reduction because it is a direct way to reduce ketones to alkanes and is useful in various synthetic strategies where a carbonyl group is needed for a specific transformation but must be removed to prepare the final target molecule.
Outlines
🔍 Wolff-Kishner Reduction Method Overview
The Wolff-Kishner reduction is a chemical process that converts aldehydes and ketones into alkanes by removing an oxygen atom. It was developed by Ludwig Wolff and Nikolai Kishner and involves the use of hydrazine and a strong base like potassium hydroxide at high temperatures. The mechanism includes the formation of a hydrazone, followed by its conversion to a diimide tautomer, which is then deprotonated to form a carbanion. This reactive intermediate quickly leads to the formation of an alkane through protonation. The method has been used on an industrial scale, particularly in pharmaceutical synthesis, but requires careful handling due to the hazardous nature of liquid hydrazine. Modifications of the original protocol have been developed to make the reaction more manageable and applicable to sensitive substrates, such as the use of potassium tert-butoxide and dimethyl sulfoxide to perform the reaction at room temperature.
🛠️ Application of Wolff-Kishner Reduction in Organic Synthesis
The Wolff-Kishner reduction is highlighted for its utility in organic synthesis, especially in situations where a carbonyl group is required for a specific transformation but must be subsequently removed to obtain the final product. An example provided in the script is the synthesis of 3-alkyl pyrroles, which involves a three-step procedure starting with the alkylation of pyrrole 2-carboxylic acid. The carboxylic acid is converted to an ethyl thioester for selective Friedel-Crafts acylation at the C-4 position. The acyl group is then reduced to an alkyl group under Wolff-Kishner conditions, and the thioester is hydrolyzed to a carboxylic acid, which decarboxylates under basic conditions to yield the desired product. This strategy exemplifies the importance of the Wolff-Kishner reduction in achieving complex organic syntheses that are not accessible through direct methods.
Mindmap
Keywords
💡Clemmensen reduction
💡Wolff-Kishner reduction
💡Hydrazine
💡Potassium hydroxide
💡Ethylene glycol
💡Diethylene glycol
💡Hydrazone
💡Diimide
💡Carbanion
💡Donald Cram
💡Pyrrole 2-carboxylic acid
Highlights
Clemmensen reduction can reduce aldehydes and ketones to alkanes, removing an oxygen atom entirely.
Wolff-Kishner reduction is an alternative method to achieve the same transformation under basic conditions.
Wolff-Kishner reduction was developed by Ludwig Wolff and Nikolai Kishner in 1911 and 1912.
The process involves the use of hydrazine and a strong base like potassium hydroxide at elevated temperatures.
High-boiling solvents like ethylene glycol or diethylene glycol are used in the reaction.
The mechanism begins with the formation of a hydrazone through a condensation reaction.
Hydrazones are in equilibrium with a tautomeric form, the diimide, catalyzed by base.
The slow step is the deprotonation of the diimide by the strong base, leading to the formation of a carbanion.
The carbanion quickly protonates to form the alkane in a protic solvent.
Wolff-Kishner reduction has been used on a ton scale for the synthesis of pharmaceuticals.
Hydrazine, used in the reduction, is a hazardous reagent requiring expert handling.
Many modifications have been made to the original Wolff-Kishner protocol to develop milder conditions.
Donald Cram improved the method in 1962 using potassium tert-butoxide and dimethyl sulfoxide, allowing room temperature reactions.
Wolff-Kishner reduction is useful for complex strategies in organic synthesis, such as the preparation of 3-alkyl pyrroles.
The reduction can be part of a multi-step procedure involving protection and selective acylation.
Pyrrole 2-carboxylic acid can be converted to an ethyl thioester for selective Friedel-Crafts acylation.
The Wheland intermediate analysis explains the selectivity of the acylation at C-4 in pyrrole.
The utility of Wolff-Kishner reduction is highlighted in situations requiring the removal of a carbonyl group after a specific transformation.
Organic chemists should be familiar with the Wolff-Kishner reduction for its direct reduction of ketones to alkanes.
Transcripts
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