Wacker Oxidation (Palladium-catalysed oxidation of alkenes)

The oxidation of ethene to ethanal by oxygen and a solution of a palladium(II) salt in aqueous hydrochloric acid is an important industrial process (the Wacker reaction). The palladium(II) is simultaneously reduced to the metal, but the reaction is made catalytic by addition of copper(II) chloride in the presence of air or oxygen, whereby the palladium is continuously re-oxidized to palladium(II)

Wacker Oxidation Mechanism

TheWacker reaction has found most use for the oxidation of terminal alkenes to give methyl ketones. It is believed to take place by an initial trans hydroxypalladation of the alkene to form an unstable complex that undergoes rapid beta-elimination to the enol 112. Hydropalladation then reductive elimination completes the overall process that involves transfer of hydride ion from one carbon to the other, via the palladium atom. The hydride migration is required to explain the observation that when the reaction is conducted in deuterium oxide, no deuterium is incorporated in the aldehyde produced.

Experimental Technique

Conversion of a terminal alkene to a methyl ketone is a useful transformation in organic synthesis. The reaction is typically carried out in aqueous DMF as solvent, using palladium(II) chloride as a catalyst (commonly 10 mol%) with copper(II) or copper(I) chloride and 1 atmosphere of oxygen. Copper(I) chloride is normally preferable as this avoids the formation of chlorinated ketones. Many different functional groups are tolerated and the reaction is selective for the oxidation of terminal alkenes in the presence of di- or trisubstituted alkenes. For example, only the terminal alkene is converted to a ketone on oxidation of the dienes 113 and 114

The Wacker reaction provides a method for the preparation of 1,4-dicarbonyl compounds, by formation of an enolate, allylation with an allyl halide, followed by palladium-catalysed oxidation of the terminal alkene. The product 1,4-dicarbonyl compounds can be treated with base to promote intramolecular aldol reaction

(Robinson annulation to give cyclopentenones.

Experimental Procedure

Palladium(II) acetate (0.2 mmol), benzoquinone (9 mmol), and the inorganic acid (HCl, HClO₄, HBF₄, H₂SO₄, or HNO₃, 0.1 M) were dissolved in acetonitrile/water (7:1 v/v, 50 mL). The solution was deoxygenated by purging with argon for at least 30 min and stirred vigorously until the Pd(OAc)₂ had dissolved. The olefin (10 mmol) was then added to the flask (by syringe), and the reaction mixture was stirred for 10 min. The products were separated from the catalyst by extraction into hexane or diethyl ether, washed with 30% aqueous sodium hydroxide, water and concentrated to a residue.

Reference:  J. Org. Chem. 55, 2924-2927 (1990)

Natural Product Synthesis

Thus, in a synthesis of pentalenene, Wacker oxidation of the 2-allyl ketone 115 gave the 1,4- diketone 116, which was converted to the cyclopentenone 117.

Regioselectivity of Wacker Reaction

Oxidation of 1,2-disubstituted alkenes occurs more slowly than that of terminal alkenes and a mixture of the two regioisomeric products is normally formed. With certain substrates, however, very high levels of regioselectivity have been obtained. For example, oxidation of the allylic ether 118 gave only the beta-alkoxy ketone 119.

The regioselectivity in oxidation reactions of unsymmetrical 1,2- disubstituted alkenes can be explained by electronic and neighbouring group effects, the latter involving co-ordination of a heteroatom or even an allylic hydrogen atom to the palladium atom in the intermediate.

Aldehyde synthesis from alkene

Aldehydes can be synthesized from alkenes by oxidation using ozonolysis, wacker oxidation and in some cases oxidation by KMnO₄ in THF can lead to formation of aldehyde.

Procedure:

Ozonolysis

To a mixture of alkene coumpound (284 mg, 0.72 mmol) in t-BuOH (1.8 mL) and THF (0.6 mL) at room temperature was added N-methylmorpholine N-oxide (337 mg, 1.44 mmol) followed by osmium tetroxide (0.027 mL, 0.022 mmol). The mixture was stirred at room temperature overnight. The reaction was then diluted with phosphate buffer (pH 7, 5 mL). Sodium periodate (693 mg, 3.24 mmol) was then added and the cloudy solution was stirred vigorously for 2 hours. Next it was diluted with water and extracted three times with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give aldehyde compound as a yellow solid (251 mg, 88%).

Patent reference: WO2010056564 (Merck)

Wacker oxidation (general procedure)

 Palladium(II) acetate (0.2 mmol), benzoquinone (9 mmol), and the inorganic acid (HCl, HClO₄, HBF₄, H₂SO₄, or HNO₃, 0.1 M) were dissolved in acetonitrile/water (7:1 v/v, 50 mL). The solution was deoxygenated by purging with argon for at least 30 min and stirred vigorously until the Pd(OAc)₂ had dissolved. The olefin (10 mmol) was then added to the flask (by syringe), and the reaction mixture was stirred for 10 min. The products were separated from the catalyst by extraction into hexane or diethyl ether, washed with 30% aqueous sodium hydroxide, water and concentrated to a residue.

Reference:  J. Org. Chem. 55, 2924-2927 (1990)

KMnO₄ in THF oxidation

 4-Formyl-2,2-dimethyl-1H-1,5-benzodiazepine (2, R1=R4)

To a solution of 10 g (0.036 mol) of 1 in 300 mL of THF was added 10 g (0.063 mol) of KMnO₄ dissolved in 100 mL of water, over a period of 3.5 h in small portions. The reaction mixture was allowed to warm up to 40 °C. After the addition was finished, the brown precipitate was filtered, and the filtrate was concentrated and extracted with diethyl ether. After drying, the organic phase was concentrated and the resulting oil crystallized from diisopropyl ether: 7 g (78.7%); mp 102-104°C.

Above procedure can be used to synthesize all of the other aldehydes listed in Table I. Solubility of the starting material determines the THF/H₂O ratio. In case of low solubility, a few preliminary tests should be made to determine the minimum amount of THF.

Attention: Usage of neat THF or addition of solid KMnO₄ may lead to an explosion and therefore must be avoided.

4-(2-Phenylvinyl)-2,2-dimethyl-1H-1,5-benzodiazepine (1, R1=R4, R2=H, R3=Ph)

A solution of 10 g (0.053 mol) of 2,2,4-trimethyl-1H-1,5-benzodiazepine, 5.63 g (0.053 mol) of benzaldehyde, and 0.5 g of ammonium acetate in 100 mL benzene was refluxed for 4 h and then concentrated. The resulting oil is crystallized from diisopropyl ether: 12.1 g (82.4%); mp 134-136°C.

Refrence: P. Viski, Z. Szeverenyi, and L. I. Simandi J. Org. Chem. 51, 3213-3214 (1986)