Propose An Efficient Synthesis For The Following Transformation

Let's embark on a journey to design an efficient synthesis for a specific organic transformation. This exercise involves understanding the reaction, retrosynthetic analysis, and then proposing a forward synthesis, considering yield, cost, and practicality. To make this concrete, let's consider the transformation of cyclohexanone to 1,2-cyclohexanediol.

Proposing an Efficient Synthesis: Cyclohexanone to 1,2-Cyclohexanediol

The conversion of cyclohexanone to 1,2-cyclohexanediol involves the dihydroxylation of a ketone, specifically turning a cyclic ketone into a vicinal diol. The core challenge lies in stereoselectivity; we can obtain either a cis or trans diol, or a mixture of both. For the sake of this exercise, let's aim for a synthesis that favors the cis-1,2-cyclohexanediol as the major product.

Understanding the Transformation

The transformation requires the introduction of two hydroxyl groups (OH) across the carbonyl (C=O) group of cyclohexanone, effectively reducing it. Several reagents can achieve dihydroxylation, each with varying degrees of stereoselectivity and reactivity. Some common methods include:

• Osmium Tetroxide (OsO4): Known for cis-dihydroxylation.
• Potassium Permanganate (KMnO4): Can lead to both cis and trans diols depending on conditions, but often gives cis as the major product under mild, basic conditions.
• Epoxidation followed by Hydrolysis: This two-step process can give trans diols when the epoxide is opened under acidic conditions, and cis diols under basic conditions.
• Sharpless Asymmetric Dihydroxylation (SAD): A powerful method for enantioselective dihydroxylation of alkenes, though less commonly used directly on ketones.

Given our goal of favoring the cis diol, OsO4 and mild, basic KMnO4 are promising starting points. However, OsO4 is highly toxic and expensive, making it less desirable for large-scale synthesis. Therefore, we will focus on KMnO4 and explore alternative, more practical cis-dihydroxylation methodologies.

Retrosynthetic Analysis

Retrosynthetic analysis involves working backward from the target molecule to identify suitable starting materials and reactions. In our case, we want to convert cyclohexanone to cis-1,2-cyclohexanediol.

1. Target Molecule: cis-1,2-Cyclohexanediol.
2. Precursor: Cyclohexanone.

The direct route involves a dihydroxylation reaction. While KMnO4 can directly convert cyclohexanone to the diol, we will explore an alternative route involving epoxidation, which can be steered towards cis or trans diol formation through controlling the reaction conditions in the subsequent hydrolysis step.

This gives us the following retrosynthetic pathway:

• cis-1,2-Cyclohexanediol <= Cyclohexene Oxide + Hydrolysis (Base-Catalyzed)
• Cyclohexene Oxide <= Cyclohexene + Peracid
• Cyclohexene <= Cyclohexanone + Wittig Reaction (or other olefination method)

This approach introduces an extra step (epoxidation) but offers greater control over the stereochemistry of the final product. We will evaluate its efficiency by considering each step in detail.

Proposed Forward Synthesis

The forward synthesis will detail the specific reagents, conditions, and expected outcomes for each step.

Step 1: Conversion of Cyclohexanone to Cyclohexene

We need to introduce a double bond into the cyclohexanone ring. Several methods exist for converting ketones to alkenes, including:

• Wittig Reaction: Reaction of a ketone with a phosphorus ylide.
• Wittig-Horner Reaction: Variation of the Wittig reaction.
• Tebbe Olefination: Uses a Tebbe reagent for alkenation.

The Wittig reaction is relatively common and well-understood. We will use a stabilized Wittig reagent for this transformation.

Reagents:

• Cyclohexanone
• Methylenetriphenylphosphorane (Ph3P=CH2), generated in situ from methyltriphenylphosphonium bromide (Ph3PCH3Br) and a strong base (e.g., n-BuLi, NaH, or KOtBu)
• Solvent: Anhydrous THF or diethyl ether.

Procedure:

1. Ylide Formation: Prepare methylenetriphenylphosphorane by reacting methyltriphenylphosphonium bromide with a strong base, such as potassium tert-butoxide (KOtBu) or sodium hydride (NaH), in anhydrous THF or diethyl ether under an inert atmosphere (nitrogen or argon).

   Ph3PCH3Br + KOtBu -> Ph3P=CH2 + KBr + t-BuOH

2. Wittig Reaction: Add cyclohexanone to the ylide solution at a low temperature (e.g., 0°C) and allow the reaction to warm to room temperature. Stir the reaction mixture for several hours, typically overnight.

   Ph3P=CH2 + Cyclohexanone -> Cyclohexene + Ph3P=O

3. Workup: Quench the reaction with water, extract with an organic solvent (e.g., diethyl ether or dichloromethane), wash the organic layer with brine, dry over magnesium sulfate (MgSO4) or sodium sulfate (Na2SO4), and remove the solvent under reduced pressure.

4. Purification: Purify the crude cyclohexene by distillation or column chromatography.

Expected Outcome: Formation of cyclohexene, along with triphenylphosphine oxide (Ph3P=O) as a byproduct.

Yield: Expect a yield of 60-80%, depending on the efficiency of the ylide formation and reaction conditions.

Step 2: Epoxidation of Cyclohexene

Next, we convert cyclohexene to cyclohexene oxide. Epoxidation is typically achieved using peracids.

Reagents:

• Cyclohexene
• meta-Chloroperoxybenzoic acid (m-CPBA) or peracetic acid (CH3CO3H)
• Solvent: Dichloromethane (CH2Cl2)

Procedure:

1. Epoxidation: Dissolve cyclohexene in dichloromethane. Add m-CPBA slowly to the solution while stirring. The reaction is exothermic, so maintain a low temperature (e.g., 0°C) initially, then allow it to warm to room temperature.

   Cyclohexene + m-CPBA -> Cyclohexene Oxide + m-Chlorobenzoic acid

2. Monitoring: Monitor the reaction's progress using thin-layer chromatography (TLC) to ensure complete consumption of cyclohexene.

3. Workup: Wash the reaction mixture with a saturated solution of sodium bicarbonate (NaHCO3) to remove any remaining peracid and m-chlorobenzoic acid. Extract the organic layer with dichloromethane, wash with brine, dry over MgSO4 or Na2SO4, and remove the solvent under reduced pressure.

4. Purification: Purify the crude cyclohexene oxide by distillation or column chromatography.

Expected Outcome: Formation of cyclohexene oxide.

Yield: Expect a yield of 70-90%, depending on the purity of the peracid and the reaction conditions.

Step 3: Base-Catalyzed Hydrolysis of Cyclohexene Oxide to cis-1,2-Cyclohexanediol

Finally, we convert cyclohexene oxide to cis-1,2-cyclohexanediol via base-catalyzed hydrolysis.

Reagents:

• Cyclohexene Oxide
• Sodium hydroxide (NaOH) or potassium hydroxide (KOH)
• Solvent: Water (H2O) or a mixture of water and an alcohol (e.g., ethanol or methanol).

Procedure:

1. Hydrolysis: Dissolve cyclohexene oxide in a mixture of water and alcohol (e.g., ethanol). Add NaOH or KOH to the solution and heat the mixture under reflux.

   Cyclohexene Oxide + H2O (OH-) -> cis-1,2-Cyclohexanediol

2. Monitoring: Monitor the reaction's progress using TLC.

3. Workup: Neutralize the reaction mixture with a dilute acid (e.g., HCl) to a pH of approximately 7. Remove the alcohol by evaporation under reduced pressure. Extract the aqueous layer with an organic solvent (e.g., ethyl acetate or diethyl ether) to remove any unreacted cyclohexene oxide or byproducts.

4. Purification: Remove water in vacuo. Recrystallize the crude cis-1,2-cyclohexanediol from a suitable solvent (e.g., ethyl acetate or a mixture of ethyl acetate and hexane) to obtain a pure product.

Expected Outcome: Formation of cis-1,2-cyclohexanediol as the major product.

Yield: Expect a yield of 60-80%, depending on the efficiency of the hydrolysis and the purity of the starting materials. The basic conditions favor SN2 attack leading to cis product.

Overall Efficiency and Considerations

• Overall Yield: The overall yield for the three-step synthesis can be estimated by multiplying the individual yields: (60-80%) x (70-90%) x (60-80%) = approximately 25-58%.
• Stereoselectivity: This synthesis favors the cis-1,2-cyclohexanediol due to the base-catalyzed epoxide ring opening.
• Cost: The cost of reagents (methyltriphenylphosphonium bromide, m-CPBA, NaOH) is moderate. The use of m-CPBA can be a concern due to its potential for explosions; however, it is commonly used with appropriate safety measures. Peracetic acid is a less hazardous and potentially cheaper alternative.
• Toxicity: The reagents used are of moderate toxicity. Standard laboratory safety precautions should be followed.
• Scalability: The synthesis is scalable. The Wittig reaction is well-established in industry. Epoxidation and hydrolysis are also commonly used on large scales.
• Atom Economy: The Wittig reaction is not particularly atom-economical, as it generates triphenylphosphine oxide as a byproduct.

Alternative Considerations

• Direct Dihydroxylation using Modified KMnO4: A potentially more direct route is to use potassium permanganate under carefully controlled conditions. Using KMnO4 in the presence of a phase-transfer catalyst (e.g., tetrabutylammonium bromide) can improve the yield and stereoselectivity of the cis-diol. This could reduce the number of steps in the synthesis.
• Dihydroxylation using catalytic OsO4 with stoichiometric Oxidant: OsO4 can be used catalytically if a stoichiometric co-oxidant is employed. Commonly used co-oxidants include N-methylmorpholine N-oxide (NMO) or potassium ferricyanide. This approach reduces the amount of toxic OsO4 required. While this reaction is highly cis-selective, the cost of OsO4 and the need for careful handling remain important considerations.

Experimental Details and Characterization

For each step of the synthesis, detailed experimental procedures, including reaction times, temperatures, and stoichiometry, would need to be optimized. Product characterization using techniques such as NMR spectroscopy (1H and 13C NMR), IR spectroscopy, and mass spectrometry would be essential to confirm the identity and purity of the synthesized compounds.

• Cyclohexene: 1H NMR, 13C NMR, IR, GC-MS
• Cyclohexene Oxide: 1H NMR, 13C NMR, IR, GC-MS
• cis-1,2-Cyclohexanediol: 1H NMR, 13C NMR, IR, Melting Point

Optimization

To further enhance the efficiency of this synthetic route, the following optimizations could be considered:

1. Wittig Reaction Optimization: Experiment with different bases (NaH, KHMDS, etc.) to optimize the ylide formation and reaction conditions.
2. Epoxidation Optimization: Screen different peracids (peracetic acid, m-CPBA, dimethyldioxirane (DMDO)) to find the most efficient and cost-effective oxidant. DMDO, although more expensive, can offer cleaner reactions with fewer byproducts.
3. Hydrolysis Optimization: Investigate different bases (LiOH, NaOH, KOH) and solvent systems (water, water/alcohol mixtures) to maximize the yield and stereoselectivity of the hydrolysis.
4. Purification Techniques: Explore alternative purification techniques such as crystallization and distillation to reduce the loss of product during workup.

Safety Considerations

• Peracids: m-CPBA and peracetic acid are strong oxidizers and should be handled with care. Avoid contact with skin and eyes, and use appropriate personal protective equipment (PPE).
• Strong Bases: Strong bases like NaH, KOtBu, and NaOH can cause burns. Handle under an inert atmosphere and with appropriate PPE.
• Solvents: Use appropriate solvents in well-ventilated areas. Dispose of waste properly according to local regulations.
• Osmium Tetroxide (if considered): Extremely toxic. Use only in a well-ventilated fume hood with appropriate training. Avoid skin contact and inhalation.

Conclusion

We have proposed a three-step synthesis for converting cyclohexanone to cis-1,2-cyclohexanediol. This synthesis involves the conversion of cyclohexanone to cyclohexene via a Wittig reaction, followed by epoxidation to form cyclohexene oxide, and subsequent base-catalyzed hydrolysis to yield the target diol. While this route offers control over stereochemistry, the overall yield and atom economy could be improved. Further optimization, exploration of alternative reagents (e.g., catalytic OsO4), and rigorous experimental characterization are crucial for developing a truly efficient and practical synthesis. By carefully considering each step and implementing appropriate safety measures, this transformation can be achieved with reasonable success. The choice of reaction pathway ultimately depends on a balance of factors including cost, safety, yield, and stereoselectivity, and should be evaluated based on specific needs and resources.