What is Wacker Oxidation?
Through palladium (II) chloride, Wacker oxidation converts olefins to aldehydes and ketones in the presence of air. This reaction was first described in 1962 and it is used in industry to oxidise ethylene to acetaldehyde (Wacker reaction). Tsuji invented a mixed solvent system (DMF/H2O) to oxidise more difficult substrates, so this reaction is also known as a Wacker-Tsuji reaction.
It is worth mentioning that that the electrophilic palladium π-complex of the Wacker oxidation can also be attacked by other nucleophiles besides water. Oxidative cyclisation is possible if the molecule has nucleophilic groups like hydroxyl and amino groups. If we apply chiral ligands, we can have asymmetric reactions.
- Reagents: Palladium(II) chloride (PdCl2), copper(II) chloride (CuCl2).
- Reactants: Alkene
- Products: Ketone (from internal alkenes), aldehyde (from terminal alkenes).
- Reaction type: Oxidation, catalytic reaction.
- Related reaction: Rupe reaction.
Fig 1. Wacker oxidation reaction and its mechanism. [1]
Mechanism of Wacker Oxidation
In the reaction, the electrophilic palladium-complex is first formed. Palladium chloride is oxidized to zero-valent palladium. Palladium reagents cost a fortune, so CuCl2 is commonly used as a co-oxidant to oxidise Pd(0) to Pd(II), where CuCl2 is reduced to Cu(I) and then reoxidised to Cu(II) by oxygen in the air (In fact, O2 in the air is the only oxidant actually employed).
Regioselectivity of Wacker Oxidation
Regioselectivity of Wacker oxidation is of note.
- Most common olefins are terminal olefins, and the oxidation is Markovnikov's rule to get methyl ketones.
- 1,2-disubstituted olefins are also reactive but the regioselectivity is not easily controlled.
- There is a low oxidation yield for 1,1-disubstituted olefins.
- 1,3-Butadiene is oxidized to get α,β-unsaturated aldehydes, and cycloolefins are oxidized to get cyclic ketones.
- α, β-Unsaturated aldehydes and ketones are oxidized to make β-oxidation products, i.e., 1,3-dicarbonyl groups, which are accessible for the last phase of total synthesis of indole alkaloids alstonerine.
Application Examples of Wacker Oxidation
- Example 1: The work of Jamie R. Allen et al. describes the development of an intermolecular and enantioselective aza-Wacker reaction. Using indole as the N source and some enols as coupling partners, selective β-hydride elimination of alcohols was achieved. [2]
- Example 2: Patrik A. Runeberg et al. studied Tsuji–Wacker type oxidations other than methyl ketones, i.e., aerobic Pd(AcO)2/pyridine-catalyzed oxidations of unprotected carbohydrate terminal olefins. In the "Uemura system", allylated D-mannose was used as a substrate. The oxidation reaction took place at 60 °C in a 1 bar molecular oxygen atmosphere for 20 h, resulting in quantitative conversion to two major products in a ratio of 3:2. The major product is a hemiketal, and the other is a tetrahydrofuran-dihydrofuran bicyclic spiroketal. [3]
- Example 3: Pd-catalyzed TBHP-mediated Wacker-type oxidation of internal olefins has been reported. Ryan J. DeLuca et al. used 2-(4,5-dihydro-2-oxazolyl)quinoline (Quinox) as a ligand and TBHP(aq) as an oxidant to perform Wacker-type oxidation of internal olefins, which can be used in the total synthesis of the antimalarial drug artemisinin. [4]
Fig 2. Synthetic examples via Wacker oxidation reaction.
Related Products
References
- Li, Jie Jack, et al. Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications Sixth Edition, 2021, 561-563.
- Allen J R, et al. Journal of the American Chemical Society, 2019, 141(22), 8670-8674.
- Runeberg P A, et al. Organic Letters, 2019, 21(20), 8145-8148.
- DeLuca R J, et al. The Journal of organic chemistry, 2013, 78(4), 1682-1686.
