Wolff Kishner Reduction

Introduction: Wolff Kishner Reduction

The Wolff Kishner reduction is a widely used organic chemistry reaction that converts carbonyl compounds into alkanes. Chemists apply this two-step process, first forming a hydrazone under basic conditions, and then reducing it to an alkane with a strong base under high temperature and pressure. The reaction can also be carried out under acidic conditions.

The Clemmensen and Mozingo reductions have modified the Wolff Kishner reduction to overcome its limitations. Pharmaceutical and natural product synthesis utilize it, and it can confirm the position of double bonds to determine the structure of natural products.

The general reaction equation for the Wolff Kishner reduction is:

R1-C(=O)-R2 + 2N2H4 + KOH -> R1-CH2-R2 + N2 + K2CO3 + 2H2O

The reaction involves treating a carbonyl compound (R1-C(=O)-R2) with hydrazine (N2H4) and a strong base such as potassium hydroxide (KOH) at high temperature and pressure. The reaction results in the conversion of the carbonyl group to a methylene group (R1-CH2-R2) through a series of intermediates. The byproducts of the reaction are nitrogen gas (N2), potassium carbonate (K2CO3), and water (H2O).

Variations of the Wolff Kishner Reduction

The original Wolff Kishner reduction suffers from several limitations, such as the requirement for high temperatures and pressures and the potential for side reactions. As a result, several modifications to the reaction have been developed to overcome these limitations.

One such modification is the Clemmensen reduction, which is a variation of the Wolff Kishner reduction that employs zinc amalgam in hydrochloric acid instead of the strong base used in the original reaction. The Clemmensen reduction is milder and more selective than the Wolff Kishner reduction, making it useful for the reduction of sensitive functional groups.

Another variation of the Wolff Kishner reduction is the Mozingo reduction, which employs an alkylated hydrazine, such as dimethylhydrazine, instead of hydrazine. The Mozingo reduction effectively reduces certain functional groups, including nitro groups and azides, which are typically challenging to reduce using hydrazine.

Mechanism of the Wolff Kishner reduction

The mechanism of the Wolff Kishner reduction involves a two-step process that converts carbonyl compounds into alkanes. The reaction proceeds through the formation of a hydrazone intermediate and its subsequent reduction.

Step 1: Formation of the Hydrazone

Under basic conditions, a hydrazine compound treats the carbonyl compound to form a hydrazone. A base, such as sodium hydroxide or potassium hydroxide, facilitates the formation of hydrazone. The reaction progresses through the formation of an imine intermediate, which the hydrazine compound attacks to form the hydrazone.

Step 2: Reduction of the Hydrazone

To effect the reduction, one subjects the hydrazone to high temperatures and pressure in the presence of a strong base, such as potassium hydroxide or sodium hydroxide. In this step, the strong base deprotonates the hydrazone, forming a carbanion which then undergoes a β-elimination to form the alkane.

The overall reaction can be represented as:

Carbonyl compound + Hydrazine → Hydrazone

Hydrazone + Strong base, high temperature and pressure → Alkane

Alternatively, under acidic conditions, the carbonyl compound is first converted into a semicarbazone or a phenylhydrazone by treatment with semicarbazide or phenylhydrazine, respectively.

Hydrazine, in the presence of a strong acid such as sulfuric acid or hydrochloric acid, reduces the semicarbazone or phenylhydrazone to the alkane.

Factors Affecting Wolff Kishner reduction

The Wolff Kishner reduction is a valuable tool for organic chemists, but its success can be affected by various factors. Understanding these factors is important to optimize the reaction conditions and improve yields. Some of the key factors that influence the Wolff Kishner reduction include:

Nature of the Carbonyl Compound: The nature of the carbonyl compound affects the rate of the reaction. Aldehydes are more reactive than ketones due to the absence of the electron-withdrawing carbonyl group in the α-position.
Hydrazine Concentration: Increasing the concentration of hydrazine can improve the reaction yield by promoting the formation of the hydrazone intermediate.
Base Concentration: The concentration of the base affects the formation of the hydrazone intermediate. Increasing the base concentration can accelerate the reaction, but it can also cause unwanted side reactions.
Reaction Temperature: The reaction is typically carried out at high temperatures (≥150 °C) to facilitate the reduction step. Higher temperatures can improve the reaction rate, but can also lead to the decomposition of the product.
Reaction Time: Longer reaction times can lead to higher yields, but can also cause over-reduction of the product.
Purity of Reagents: Impurities in the reagents, especially hydrazine, can affect the reaction yield and produce unwanted side products.

By carefully controlling these factors, chemists can optimize the Wolff Kishner reduction to obtain the desired product with high yield and purity.

Applications of Wolff Kishner reduction

Organic chemists widely use the Wolff Kishner reduction reaction, which has numerous applications in synthesizing complex organic molecules. Some of the key applications of the Wolff Kishner reduction include:

Synthesis of Pharmaceuticals: Scientists have used the reaction to synthesize a variety of pharmaceuticals, such as the antidepressant drug imipramine, the antihistamine drug chlorpheniramine, and the antimalarial drug quinine.
Synthesis of Natural Products: Scientists have used the reaction to synthesize natural products, including sesquiterpene lactone artemisinin, which is a potent antimalarial agent.
Determination of Natural Product Structures:

Scientists have used the reduction of a ketone to an alkane for confirming the position of a double bond in a natural product and for elucidating the structure of various natural products.

Preparation of Hydrocarbon Fuels: The reaction can also be used to convert bio-derived carbonyl compounds into hydrocarbon fuels. This application has the potential for the sustainable production of renewable fuels.
Synthetic Organic Chemistry: A reaction is a valuable tool in synthetic organic chemistry for the conversion of carbonyl compounds into alkanes. Its versatility has led to its wide application in the synthesis of complex organic molecules.

History of Wolff Kishner reduction

Johannes Ernst August Wolff and Hans Friedrich Franz Kishner, two German chemists, developed the Wolff Kishner reduction, a well-known reaction in organic chemistry, in the early 20th century.

In 1912, Wolff reported a new method for reducing carbonyl compounds using hydrazine and sodium ethoxide. However, this method suffered from low yields and side reactions. In 1913, Kishner improved the reaction by using potassium hydroxide as the base and high temperatures and pressure to promote the reduction step. This modification led to higher yields and fewer side reactions.

The reaction gained widespread use in the early 20th century for the synthesis of complex organic molecules. Its simplicity and effectiveness made it a valuable tool in synthetic organic chemistry.

In the 1950s, researchers elucidated the reaction mechanism, and this enabled them to optimize the reaction conditions and enhance yields further.

Since its discovery, the reaction has found a range of applications in the synthesis of pharmaceuticals, natural products, and renewable fuels. The reaction continues to be an important tool in organic chemistry, and its history serves as a reminder of the importance of innovation and collaboration in advancing scientific discovery.

Limitations of Wolff Kishner reduction

Synthetic organic chemists must consider several limitations of the Wolff-Kishner reduction, despite its value as a useful tool. Understanding these limitations is crucial for the successful application of the reaction. Some of the key limitations include:

Harsh Reaction Conditions: The reaction requires high temperatures and strong bases, which can lead to unwanted side reactions and decomposition of the product.
Loss of Stereochemistry: The reaction results in the loss of stereochemistry, making it unsuitable for reactions involving chiral compounds.
Selectivity: The reaction can be non-selective, leading to over-reduction or the formation of multiple products.
Sensitivity to Moisture: Hydrazine is highly sensitive to moisture, which can lead to unwanted side reactions and reduced yields.
Limitations on Substrates: The reaction is typically limited to carbonyl compounds, making it unsuitable for other types of functional groups.
Toxicity: Hydrazine is a toxic and carcinogenic substance, requiring careful handling and disposal procedures.

Despite these limitations, the Wolff-Kishner reduction remains a valuable tool in synthetic organic chemistry. Its simplicity and effectiveness have led to its widespread use in the synthesis of complex organic molecules. By understanding the limitations of the reaction and carefully controlling the reaction conditions, chemists can optimize the reaction for specific applications and improve yields.