Palladium Wacker oxidation

METHOD 2 Without a doubt, this is the current world favorite for making P2Ps. This method is known as the Wacker oxidation and involves mixing safrole (or any other allylbenzene), palladium chloride, cuprous chloride and dimethylformamide in an oxygen atmosphere to get MD-P2P very quickly and in a totally clean manner [11, 12]. There s also a very nice review in ref. 13. 

The method is basically an application of the Wacker oxidation except that the catalyst used is palladium acetate ( Pd(AcO)2 or Pd(02CCH3)2). the solvent is acetic acid or tert-butyl alcohol and the oxygen source is the previously suggested hydrogen peroxide (H202)[17]. 

Palladium-catalyzed oxidation of hydrocarbons has been a matter of intense research for about four decades. The field was initiated by the development of the aerobic oxidation of ethylene to acetaldehyde catalyzed by palladium chloride and co-catalyzed by cupric chloride (the Wacker process, equation l)1. 

The phenolic oxygen on 2-allyl-4-bromophenol (7) readily underwent oxypalladation using a catalytic amount of PdCl2 and three equivalents of Cu(OAc)2, to give the corresponding benzofuran 8. This process, akin to the Wacker oxidation, was catalytic in terms of palladium, and Cu(OAc)2 served as oxidant [17]. Benzofuran 10, a key intermediate in Kishi s total synthesis of aklavinone [18], was synthesized via the oxidative cyclization of phenol 9 using stoichiometric amounts of a Pd(II) salt. 

The reaction rate is half-order in palladium and dimeric hydroxides of the type shown are very common for palladium. The reaction is first order in alcohol and a kinetic isotope effect was found for CH2 versus CD2 containing alcohols at 100 °C (1.4-2.1) showing that probably the (3-hydride elimination is rate-determining. Thus, fast pre-equilibria are involved with the dimer as the resting state. When terminal alkenes are present, Wacker oxidation of the alkene is the fastest reaction. Aldehydes are prone to autoxidation and it was found that radical scavengers such as TEMPO suppressed the side reactions and led to an increase of the selectivity [18],... 

The method involves a regioselective, trans-diastereoselective, and enantioselective three-component coupling, as shown in Scheme 7.26. In this case, the zinc enolate resulting from the 1,4-addition is trapped in a palladium-catalyzed allyla-tion [64] to afford trans-2,3-disubstituted cyclohexanone 96. Subsequent palladium-catalyzed Wacker oxidation [82] yields the methylketone 97, which in the presence of t-BuOK undergoes an aldol cyclization. This catalytic sequence provides the 5,6-(98) and 5,7- (99) annulated structures with ees of 96%. 

SAP catalysts have also been applied in the Wacker oxidation584 of higher olefins where the separation of products from the catalyst is cumbersome. Palladium(II) and copper(II) salts immobilized on controlled pore glass CPG-240 in the presence of water catalysed the oxidation of 1-heptene to 2-heptanone in conversions up to 24%.585 Significant isomerization to 2-heptene and 3-heptene (isomerization/oxidation=2/3) was also observed. However, an advantage of SAP-Wacker oxidation catalysts over classical systems is that the Cu(II) is confined to the support and therefore not corrosive whereas aqueous Cu2+ is very corrosive to steel. 

The mechanism of vinyl acetate formation is closely related to that of the Wacker oxidation (Scheme 9.11) that is, acetoxypalladation-palladium hydride elimination takes place.498,503 The coordinated alkene is attacked by the external nucleophile acetate ion, or the attack may occur within the coordination sphere. p-Hydride elimination followed by dissociation of the coordinated molecule yields directly the vinyl acetate end product. 

The synthetic applications of the palladium-catalyzed oxidation of alkenes to ketones have recently been reviewed.639 Improvements in the Wacker palladium-catalyzed ketonization of terminal alkenes have been obtained using phase-transfer catalysis,641 polyethylene glycol642 or phosphomolybdovanadic acids.643... 

Terminal alkenes can be selectively oxidized to aldehydes by reaction with oxygen, using a palladium-copper catalyst in tertiary butanol (equation 35)160. This reaction is contrary to the normal oxidation process which yields a ketone as the major product. The palladium(II) oxidation of terminal alkenes to give methyl ketones is known as the Wacker process. It is a very well established reaction in both laboratory and industrial synthesis161162. The Wacker oxidation of alkenes has been used in the key step in the synthesis of the male sex pheromone of Hylotrupes bajulus (equation 36)163. 

The Wacker Oxidation is an industrial process, which allows the synthesis of ethanal from ethene by palladium-catalyzed oxidation with oxygen. Copper serves as redox cocatalyst. 

Another example is the palladium-catalyzed oxidation of ethylene to acetaldehyde in the presence of oxygen and cupric salts, the so-called Wacker reaction. This catalytic cycle combines two stoichiometric processes, which involve first the reduction of Pd11 to Pd°, followed by reoxidation with Cu11. The understanding of the first step of this process came from the earlier work of Kharasch et al., who showed that the stoichiometric dinuclear complex shown in Figure 2.14 decomposed in the presence of water to acetaldehyde (ethanal), Pd° and HC1 [38]. 

Figure 3.31 Simplified schematic of the palladium Wacker catalytic cycle for oxidizing ethene to acetaldehyde (the reverse reaction arrows are omitted, for clarity). The broken circles represent the copper and oxygen redox cycles.

Wacker reactions, which is why we refer to them here [12, 15-17]. Finally, the general concept of a Wacker reaction could be regarded as the palladium-catalyzed oxidative coupling of heteronucleophiles and olefins, and this can obviously be extended to nitrogen nucleophiles and others [18] conversely, the principle of the Cu(I)/Cu(II)/02 reoxidation system for Pd(0) can be applied to other oxidation reactions (for example that of CO to C02), but the present overview is limited to sp2-C-H activation in olefins. 

The aqueous palladium chloride oxidation of ethylene to acetaldehyde has been developed into an important commercial process. The discovery of how to make the reaction catalytic with respect to palladium chloride was, perhaps, as important to the process as the discovery of the oxidation reaction itself. This process known as the Wacker-Process, employs cupric chloride as a catalyst for the oxygen (air) reoxidation of... 

Textbook chemistry (297,298) teaches that palladium is the preferred catalyst for aerobic oxidation of olefins. When water is the solvent, nucleophilic water addition to coordinated olefins is the key step in the so-called Wacker cycle. Wacker oxidation occurs regiospecifically because a carbonyl group is formed at that carbon atom of the double bond where the nucleophile in a Markovnikov-like addition would enter. The Wacker reaction thus yields methylketones from primary alkenes ... 

The palladium-catalyzed oxidation of ethylene to acetaldehyde (the Wacker process) was discovered by Smidt and co-workers514-518 in 1959. This process combines the stoichiometric reduction of Pd(II) with reoxidation of metal in situ by molecular oxygen in the presence of copper salts. The overall reaction constitutes a palladium-catalyzed oxidation of ethylene to acetaldehyde by molecular oxygen ... 

To overcome the problems encountered in the homogeneous Wacker oxidation of higher alkenes several attempts have been undertaken to develop a gas-phase version of the process. The first heterogeneous catalysts were prepared by the deposition of palladium chloride and copper chloride on support materials, such as zeolite Y [2,3] or active carbon [4]. However, these catalysts all suffered from rapid deactivation. Other authors applied other redox components such as vanadium pentoxide [5,6] or p-benzoquinone [7]. The best results have been achieved with catalysts based on palladium salts deposited on a monolayer of vanadium oxide spread out over a high surface area support material, such as y-alumina [8]. Van der Heide showed that with catalysts consisting of H2PdCU deposited on a monolayer vanadium oxide supported on y-alumina, ethene as well as 1-butene and styrene... 

This combination of reagents h s been used to oxidize terminal vinyl groups to methyl ketones and is known as the Wacker oxidation. The nucleophile is simply water, which attacks the activated alkene at the more substituted end in an oxypalladation step. (3-Hydride elimination from the resulting a-alkyl palladium complex releases the enol, which is rapidly converted into the more stable keto form. Overall, the reaction is a hydration of a terminal alkene that can tolerate a range of functional groups. 

For Wacker oxidation, see The Organic Chemistry of Palladium, P. M. Maitlis, Academic Press, New York, 1971 Palladium Catalyzed Oxidation of Hydrocarbons, P. M. Henry, D. Reidel, Dordrecht, 1980. 

In my opinion (and I am convinced that Ernst Otto Fischer would have agreed), Walter Hafner was one of the best Ph.D. students, probably the best Fischer ever had. After he finished his doctoral research, he joined the Consortium filr Elektrochemische Industrie, a research subsidiary of Wacker-Chemie in Munich, where he laid the foundations for the palladium-catalyzed oxidation of ethene to acetaldehyde, the Wacker process. This process has been licenced to various chemical companies all over the world and initiated an evergrowing area of synthetic organic chemistry. Walter Hafner retired in 1992 and died in 2004. 

Fig. 4.36 Water-soluble palladium complexes for Wacker oxidation.

Another active binuclear palladium intermediate was reported in 2012 in the Wacker oxidation of alkenes [50]. ESl-MS revealed several binuclear palladium species ligated by the reactant alkene... 

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