Baeyer-Villiger Oxidation

What Is Baeyer-Villiger Oxidation?

The Baeyer-Villiger oxidation reaction is a reaction in which aldehydes and ketones are oxidized to esters using peroxyacids. In 1899, Baeyer and Villiger reported that persulfate could be used as an oxidant to convert cyclic ketones (such as carvone, menthone, camphor, etc.) into corresponding lactones. This was the earliest Baeyer-Villiger oxidation reaction in history.

The stereochemistry of the migrating group in the Baeyer-Villiger oxidation reaction remains unchanged, and the reaction has a certain regioselectivity, so it is of great significance for functional group transformation and ring expansion in organic synthesis. This reaction can be used to synthesize a series of valuable esters and lactones that are difficult to synthesize using other methods, and the products obtained by oxidation can be widely used in the synthesis of natural medicines.

• Reagents: Peroxyacid (such as mCPBA) or hydrogen peroxide + Lewis acid.
• Reactants: Ketones.
• Products: Esters.
• Reaction type: Oxidation reaction.
• Related reaction: Dakin-West reaction.

Fig 1. Baeyer-Villiger oxidation reaction and its mechanism. [1]

Mechanism of Baeyer-Villiger Oxidation

The mechanism of Baeyer-Villiger oxidation is carried out in two steps:

• The addition of peroxyacid to the carbonyl carbon of ketone generates an intermediate with a tetrahedral structure.
• The intermediate then rearranges to generate the corresponding ester or lactone.

Migration Rules

• The most electron-rich alkyl (more substituted carbon) migrates first. General migration rules: tertiary alkyl> secondary alkyl> cyclohexyl> benzyl> phenyl> primary alkyl> methyl> hydrogen.
• For substituted aryls: p-MeO-Ar > p-Me-Ar > p-Cl-Ar > p-Br-Ar > p-O₂N-Ar.

Development of Baeyer-Villiger Oxidation

If we study the development history of Baeyer-Villiger oxidation reaction, there are two phases to its evolution.

The first step is the classic Baeyer-Villiger oxidation reaction, and the oxidant is usually a peroxyacid like trifluoroperacetic acid, perbenzoic acid, metachloroperbenzoic acid, etc. Because the preparation of these oxidants is based on high concentration hydrogen peroxide, and high concentration hydrogen peroxide is dangerous to transport and handle, the procedure has been discarded in industry.

The primary work in the second phase is to investigate the optimization of oxidation procedure of Baeyer-Villiger oxidation reaction. Increasing universality, selectivity and environmental sustainability of the response are three of the aims. There are known better ones like: aldehyde co-oxidant, and oxidizing with molecular oxygen; catalytic oxidation with metal complexes; catalytic oxidation with organotin compounds; catalytic oxidation with organic/inorganic compounds; biocatalytic oxidation. Catalytic oxidation can make operations easier, it can also use fewer reactants, it can eliminate waste, it can increase selectivity, and it can yield and convert more.

Experimental Tips for Baeyer-Villiger oxidation

• Oxidation with peroxyacids is compatible with many functional groups, such as the double bonds in α,β-unsaturated ketones will not be oxidized.
• There are many types of oxidants that can be used, and the order of activity of commonly used oxidants is as follows: CF₃CO₃H > benzoic acid > 3,5-dinitrobenzoic acid > p-nitrobenzoic acid > mCPBA and peroxyformic acid > perbenzoic acid > peracetic acid > H₂O₂ > t-BuOOH.
• During the rearrangement, the stereocenter remains unchanged.
• Substituted selenious acid is a promising catalyst (called Syper activation) that can be generated in situ from diaryl diselenides with H₂O₂.

Application Examples of Baeyer-Villiger Oxidation

• Example 1: In the enantioselective total synthesis of (+)-salimabromide, André Palm et al. proposed a strategy for a one-pot Baeyer-Villiger/allylic oxidation via an innovative combination of free radical reagents. [2]
• Example 2: Hua Xu et al. introduced a practical synthetic route for the pilot production of entecavir that is safe, stable, and scalable to kilograms. The synthetic route starts from (S)-(+)-carvone, which involves a Baeyer-Villiger oxidation/rearrangement to provide a secondary alcohol of the correct configuration. [3]

Fig 2. Synthetic examples via Baeyer-Villiger oxidation reaction.

Related Products

CAS No.	Structure	Product
1755-15-3		2-Acetyl-5,5-dimethyl-1,3-cyclohexanedione
4056-73-9		2-Acetyl-1,3-cyclohexanedione
823-76-7		1-Cyclohexylethan-1-one
874-23-7		2-Acetylcyclohexanone
13173-09-6		(+/-)-cis-Bicyclo[3.2.0]hept-2-en-6-one
13991-08-7		1,2-Bis(diphenylphosphino)benzene
99646-28-3		(R)-Tol-BINAP
76-22-2		Camphor
4541-32-6		2,2-Dimethylcyclopentanone
3391-87-5		(+)-Menthone
2244-16-8		d(+)-Carvone

References

1. Li, Jie Jack, et al. Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications Sixth Edition, 2021, 10-12.
2. Palm, Andre, et al. Organic letters, 2019, 21(6), 1939-1942.
3. Xu, Hua, et al. Organic Process Research & Development, 2018, 22(3), 377-384.