The Wacker reaction

Acetaldehyde is the product of the Wacker process. At the end of the fifties oxidation of ethene to ethanal replaced the addition of water to acetylene, because the acetylene/coal-based chemistry became obsolete, and the ethene/petrochemistry entered the commercial organic chemicals scene. The acetylene route involved one of the oldest organometallics-mediated catalytic routes started up in the 1920s the catalyst system comprised mercury in sulfuric acid. Coordination of acetylene to mercury(II) activates it toward nucleophilic attack of water, but the reaction is slow and large reactor volumes of this toxic catalyst were needed. An equally slow related catalytic process, the zinc catalysed addition of carboxylic acids to acetylene, is still in use in paint manufacture. 

Ethanal is only used as an intermediate to acetic acid and its derivatives and in the near future production of ethanal will be replaced by other routes based on methanol and syn-gas to give acetic acid and acetic anhydride. Vinyl acetate can also be made via syn-gas routes, but the major producer in Europe employs a direct Wacker route with a heterogeneous palladium catalyst (former Hoechst ethene, acetic acid -from syn-gas-, and oxygen). 

The Wacker-Hoechst process has been studied in great detail and in all textbooks it occurs as the example of a homogeneous catalyst system illustrating nucleophilic addition to alkenes. Divalent palladium is the oxidising agent and water is the oxygen donor according to the equation  

The nucleophilic attack of the water or hydroxide species takes place in an anti fashion i.e. the oxygen attacks from outside the palladium complex and the reaction is not an insertion of ethene into the palladium oxygen bond. This has been demonstrated in a model reaction by Backvall [4], The reaction studied was the Wacker reaction of dideuterio-ethene (cis and trans) in the presence of excess of LiCl, which is needed to form 2-chloroethanol as the product instead of ethanal. The latter product would not reveal the stereochemistry of the attack Note that all of the mechanistic work has been carried out, necessarily, on systems deviating in one aspect or another from the real catalytic one. The outcome depends strongly on the concentration of chloride ions [5], 

The rate equation of the Wacker process reads as follows v = k[PdCl421[C2H4][H30HT1[aT2 

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In connection with mechanistic studies on the Wacker reaction, the transmetallation of ri-ethoxy- and /3-hydroxyethylmercury(II) chloride with PdCB has been carried out, giving ethyl vinyl ether and acetaldehyde[366]. The reaction proceeds by the formation of ri-ethoxy- and /3-hydroxyethylpalladium chlorides (401), which decompose as soon as they are formed. 

The Wacker reaction can also be carried out for other olefins with terminal double bonds. With propene, for example, approximately 90% yield of acetone is obtained. 1-Butene gave approximately 80% yield of methyl ethyl ketone. 

The catalyst is similar to that of the Wacker reaction for ethylene oxidation to acetaldehyde, however, this reaction occurs in presence of carbon monoxide. 

Oxidative cyclisations representing intramolecular variant of the Wacker reaction have seen significant developments. The intramolecular oxidative cyclisation of tosylamines was found to be catalysed by the [Pd(TFA)2(IMes)(OH2)] complex (TFA = trifluoroacetate) [42], The presence of a catalytic amount of acetic or benzoic acid leads to improved activity and selectivity (Scheme 10.13). 

The Wacker Reaction and Related Oxidations. An important industrial process based on Pd-alkene complexes is the Wacker reaction, a catalytic method for conversion of ethene to acetaldehyde. The first step is addition of water to the Pd(n)-activated alkene. The addition intermediate undergoes the characteristic elimination of Pd(0) and H+ to generate the enol of acetaldehyde. 

The Wacker reaction can also be applied to laboratory-scale syntheses.104 When the Wacker conditions are applied to terminal alkenes, methyl ketones are formed.105... 

This regiochemistry is consistent with the electrophilic character of Pd(II) in the addition step. Solvent and catalyst composition can affect the regiochemistry of the Wacker reaction. Use of /-butanol as the solvent was found to increase the amount of aldehyde formed from terminal alkenes, and is attributed to the greater steric requirement of /-butanol. Hydrolysis of the enol ether then leads to the aldehyde. 

The two reactions shown below are examples of the use of the Wacker reaction in multistep synthesis. In the first case, selectivity is achieved between two terminal alkene units on the basis of a difference in steric accessibility. Both reactions use a reduced amount of Cu(I) salt. In the second reaction this helps to minimize hydrolysis of the acid-sensitive dioxolane ring. 

Since nucleophilic addition to a metal-coordinated alkene generates a cr-metal species bonded to an -hybridized carbon, facile 3-H elimination may then ensue. An important example of pertinence to this mechanism is the Wacker reaction, in which alkenes are converted into carbonyl compounds by the oxidative addition of water (Equation (108)), typically in the presence of a Pd(n) catalyst and a stoichiometric reoxidant.399 When an alcohol is employed as the nucleophile instead, the reaction produces a vinyl or allylic ether as the product, thus accomplishing an etherification process. 

Oxidative addition consumes one equivalent of expensive Pd(OAc)2 in most cases. However, progress has been made towards the catalytic oxidative addition pathway. Knolker s group described one of the first oxidative cyclizations using catalytic Pd(OAc)2 in the synthesis of indoles [19]. They reoxidized Pd(0) to Pd(II) with cupric acetate similar to the Wacker reaction, making the reaction catalytic with respect to palladium [20]. 

The metal-catalysed autoxidation of alkenes to produce ketones (Wacker reaction) is promoted by the presence of quaternary ammonium salts [14]. For example, using copper(II) chloride and palladium(II) chloride in benzene in the presence of cetyltrimethylammonium bromide, 1-decene is converted into 2-decanone (73%), 1,7-octadiene into 2,7-octadione (77%) and vinylcyclohexane into cyclo-hexylethanone (22%). Benzyltriethylammonium chloride and tetra-n-butylammo-nium hydrogen sulphate are ineffective catalysts. It has been suggested that the process is not micellar, although the catalysts have the characteristics of those which produce micelles. The Wacker reaction is also catalysed by rhodium and ruthenium salts in the presence of a quaternary ammonium salt. Generally, however, the yields are lower than those obtained using the palladium catalyst and, frequently, several oxidation products are obtained from each reaction [15]. 

If one would be able to derive from the experimental data an accurate rate equation like (12) the number of terms in the denominator gives us the number of reactions involved in forward and backward direction that should be included in the scheme of reactions, including the reagents involved. The use of analytical expressions is limited to schemes of only two reaction steps. In a catalytic sequence usually more than two reactions occur. We can represent the kinetics by an analytical expression only, if a series of fast pre-equilibria occurs (as in the hydroformylation reaction, Chapter 9, or as in the Wacker reaction, Chapter 15) or else if the rate determining step occurs after the resting state of the catalyst, either immediately, or as the second one as shown in Figure 3.1. In the examples above we have seen that often the rate equation takes a simpler form and does not even show all substrates participating in the reaction. 

At present the Wacker reaction should be regarded as a relatively slow process, with only a few hundred turnovers per hour at elevated temperatures and pressures. For internal alkenes the rate is one or two orders of magnitude lower and the reaction affords mixtures of products due to isomerisation. In the absence of isomerisation, the product of the Wacker oxidation of a 1-alkene is a... 

Polyethylene glycols (PEG) have been employed as phase transfer agents (and as solvents) in a number of reactions(11). Application of PEG-400 to the Wacker reaction results in the oxidation of both terminal and internal olefins (e.g., isomeric butenes to butanone) (12). 

It is known of the Wacker reaction, that at low chloride concentration (< 1 M) it yields exclusively acetaldehyde. However, at [Cl ] > 2.5 M, chloroethanol is produced in appreciable quantities. In a detailed kinetic study it was established, that when a chloride ligand in [PdCU] " is replaced by pyridine, the intermediate hydroxyethylpalladium complex is stable enough to undergo reaction with [CUCI2] with the formation of chloroethanol up to a yield of 98 % in 8 M chloride solutions (Scheme 8.2) [13]. 

Figure 9.2 Mechanism of the Wacker reaction. Source White)...

The palladium catalysed conversion of alkenes to enols, also known as the Wacker reaction, has also been used in the formation of oxygen heterocycles. In the example shown in 3.68. the subsequent formation of two carbon-oxygen bonds leads to the desired dioxabicyclo[3.2.1]octane derivative. The first Wacker reaction gives selectively a six membered ring formation (other possible routes would lead to even larger rings), while in the second Wacker reaction the selective formation of the five membered ring is observed.86... 

Selective oxidation of ethylene to acetaldehyde was carried out over carbon-supported Pd and Pt membrane catalysts.1322 The concept of supported liquid-phase catalysis was also successfully applied in the Wacker oxidation.1323 The Wacker reaction can be performed in alcohol-supercritical C02.1324 C02 as cosolvent accelerates reaction rates and remarkably affects the selectivity towards methyl ketone in the presence of an alcohol. 

Promising results were observed in Friedel-Crafts alkylation77 and epoxidation.78 Higher rates or better selectivities were found for hydroformylations in supercritical C02.79-84 Simple trialkyl phosphines, for examples, were shown to provide highly active Rh catalysts.81 Hydroboration showed enhanced regioselec-tivity.85 The Wacker reaction performed in alcohol-supercritical C02 exhibits high reaction rates and markedly increased selectivity toward methyl ketone.86... 

Takacs, J.M. and Jiang, X.-t. (2003) The Wacker reaction and related alkene oxidation reactions. Curr. Org. Chem., 7, 369. 

Hamed, O., Henry, P.M. and Thompson, C. (1999) Palladium(II)-catalyzed exchange and isomerization reactions. 17. Exchange of chiral allyl alcohols with hydroxide, methoxide, and phenyl at high [Cl-]. Stereochemistry of the Wacker reaction. J. Org. Chem., 64, 7745. 

Occasionally hydroxylation of the carbon nucleophile is observed during Pd-cata-lyzed C-C bond formation (Scheme8.15 third reaction in Scheme8.14 [121]). These reactions may in some instances proceed by a mechanism analogous to the Wacker reaction [130], or to the hydroxylation of organometallic compounds or boranes by peroxides or air (Section 3.5). 

Wang Z-Y, Jiang H-F, Qi C-R et al (2005) PS-BQ an efficient polymer-supported cocatalyst for the Wacker reaction in supercritical carbon dioxide. Green Chem 7(8) 582-585... 

In a recent review it was argued that such additives of copper, benzoquinone, and HPMOV are not really needed all that is needed is the presence of oxidation-resistant ligands that prevent palladium metal formation [15]. Indeed, activation of the C-H bond is not as slow as, for example, the Wacker reaction of ethene in which reoxidation of palladium must be performed by copper oxidation, although in this catalytic system the additives may still play a role in stabilizing the intermediate low-valent palladium species and thus prevent catalyst decomposition. This thesis was corroborated by the work of de Vos and Jacobs, who showed that addition of benzoic acid to the oxidative arylation reaction in the presence of oxygen led to superior results in the coupling of a variety of substituted arenes with acrylates, cinnamates, and ,/f-unsaturated ketones. Very good yields and TON up to 762 were obtained at 90 °C. A mixture of the o, m, and p isomers is obtained if substituted arenes are used [16]. 

If carboxylic acids and alcohols act as nucleophiles in the Wacker reaction, the products are vinyl esters or acetals, respectively. As mentioned, the substrate scope of these oxidations is usually limited to olefins not bearing hydrogen in allylic position, because of competing allylic oxidation. 

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 ... 

Palladium(II)-promoted oxidative cyclization of alkenes bearing tethered nucleophiles represents an intramolecular variant of the Wacker reaction. These reactions, which typically generate five- and six-membered heterocycles, have been the subject of considerable interest in organic chemistry [89-96]. Contemporary interest centers on the development of enantioselective examples [95,97] and reactions that employ dioxygen as the sole oxidant for the Pd catalyst [92-96]. 

Satisfy yourself that you can at least see what is happening here—if you are stuck on the Pd(ii)-cataiysed reaction, refer to Chapter 48 and look at oxypalladation and the Wacker reaction for clues. 

Fig. 3. Representation of the Wacker Reaction (only non-zero entries are shown)...

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