Oppenauer Oxidation

When studying organic chemistry, oxidation reactions are one of the primary reactions used to modify functional groups and produce more complex compounds. Oxidation can be achieved via a range of techniques; however, Oppenauer oxidation stands out as the most effective one. Introduced by Rupert Viktor Oppenauer in 1937, this reaction not only has theoretical application but also has a wide range of uses in pharmaceutical and steroid chemistry. Let’s explore some resourceful facts about this reaction in detail. 

1.0Oppenauer Oxidation: Definition and Reaction

Oppenauer oxidation is a chemoselective organic oxidation reaction, meaning it selectively oxidises secondary alcohols to ketones with a mild oxidising system. It is a process in a non-aqueous, basic medium in which the oxidation is performed with an aluminium alkoxide catalyst and a carbonyl compound (normally a ketone) as the hydride acceptor.

Simply put, the reaction replaces a hydrogen atom from the alcohol with the oxygen of a ketone and produces a new ketone and a secondary alcohol as a by-product. The gentle and clean conversion is immensely useful when dealing with complicated molecules such as natural products, where strong oxidising agents might introduce unwanted side reactions.

The general or the standard form of the Oppenauer oxidation reaction can be written as:

${\mathrm{R}}_2\mathrm{CHOH}+{\mathrm{R}}_2^{\prime }\mathrm{C}=\mathrm{O}+\mathrm{Al}(\mathrm{O}-\mathrm{iPr}{)}_3(\text{ Catalyst })---\to {\mathrm{R}}_2\mathrm{C}=\mathrm{O}+{\mathrm{R}}_2^{\prime }\mathrm{CHOH}$

Here, 

• R₂CHOH = Secondary alcohol
• $R_2^{\prime }C=O$ = Oxidant that is a ketone (the most commonly used ketone is Benzophenone)
• Al(O-iPr)₃ = Aluminum isopropoxide (catalyst)
• R₂C=O = Ketone (oxidation product)
• ${\mathrm{R}}_2^{\prime }\mathrm{CHOH}$= reduced alcohol (from ketone oxidant)

Note: The reaction is the converse of the Meerwein-Ponndorf-Verley (MPV) reduction reaction in which the same catalyst is used to reduce ketones to alcohols. 

2.0Oppenauer Oxidation Reagent 

A reagent in chemistry is a substance or compound that is introduced into a system to induce a chemical reaction or to test for the presence of another substance. In Oppenauer oxidation, the following reagents are employed:

• Aluminium isopropoxide [Al(O-iPr)₃] – It serves as a Lewis acid catalyst (a substance that accepts electrons in a chemical reaction) and promotes hydride transfer.
• Ketone oxidant – The most commonly used ketone oxidant in Oppenauer oxidation is benzophenone or acetone, which accepts a hydride from the alcohol.
• Solvent – The solvent used in the oxidation is usually toluene or some other non-polar, anhydrous solvent that facilitates the development of the cyclic transition state.
• Mild heat – The Oppenauer oxidation reaction is typically carried out under reflux conditions.

This reagent system is quite non-toxic and does not use strong oxidising agents such as chromium compounds, thus it is more environmentally friendly.

3.0Oppenauer Oxidation Mechanism 

The Oppenauer oxidation reaction mechanism goes through a concerted six-membered cyclic transition state. This enables the efficient transfer of a hydride ion (H⁻) from the secondary alcohol to the carbonyl compound (ketone oxidant). Here is the step-by-step guide to the Oppenauer Oxidation Mechanism:

• Coordination: The catalyst Al(O-iPr)₃ aluminium atom coordinates with the secondary alcohol to form an alkoxide complex.
• Cyclic Transition State: A six-membered ring transition state is established between the secondary alcohol, aluminium, and the ketone oxidant.
• Hydride Shift: Hydride is shifted from the α-carbon atom of the alcohol to the carbonyl carbon of the ketone oxidant, oxidising the alcohol to a ketone and reducing the ketone oxidant to an alcohol.
• Product Release: The new ketone and the lowered ketone (now an alcohol) are released, and the aluminium catalyst is regenerated.

See the following Oppenauer Oxidation Example Reaction to understand its mechanism more precisely: 

4.0Oppenauer Oxidation Applications 

The Oppenauer Oxidation Applications are quite extensive in the industries where selective oxidation without affecting other functional groups of the chemicals is a must. These industries are: 

1. Steroid Chemistry: In steroidal chemistry, where the conversion of cholestanol to cholestanone is synthesised via multi-step chemical reactions, Oppenauer Oxidation is a vital reaction. For example, it is used to prepare steroids like corticosteroids, testosterone derivatives, and progesterone analogues. 
2. Natural Product Synthesis: Natural products like alkaloids have secondary alcohols and are oxidised selectively, for which Oppenauer oxidation is often preferred. For example, compounds such as cholesteryl ketones and sapogenins are produced through this reaction. 
3. Pharmaceutical Intermediates: As mentioned earlier, the reaction is widely used for the development of active pharmaceutical intermediates (APIs). For example, Oppenauer Oxidation is used to generate APIs, like $\alpha ,\beta$-unsaturated ketones. 
4. Green Chemistry & Eco-Friendly Synthesis: As the Oppenauer Oxidation is performed using mild, non-toxic reagents, it aligns well with the principles of green chemistry. This means it avoids the production of hazardous oxidants, making it safer for both chemists and the environment. 
5. Functional Group Selectivity: Due to its nature of selective oxidation, the process is ideal for reactions where oxidising secondary alcohols without affecting primary alcohols is required.  

5.0Limitations of Oppenauer Oxidation 

Despite having a huge number of benefits and healthy applications, Oppenauer Oxidation has some limitations, which include: 

• The oxidation reaction is not able to efficiently oxidise primary alcohols, hence it is not the perfect match for Primary Alcohols. 
• As a mild oxidant is used in the process, it proceeds at a slow rate when compared with the rate of other oxidising processes with stronger oxidants. 
• Being a reversible or equilibrium-controlled reaction, an excess amount of ketone oxidant is always required to maintain a single direction of reaction. 
• Due to the presence of an aluminium catalyst, anhydrous conditions are always required to avoid being affected by moisture.