Wacker oxidation reoxidants

Wacker oxidation of l-alkenes. The Wacker oxygenation of 1-alkenes to methyl ketones involves air oxidation catalyzed by PdCl2 and CuCU, which is necessary for reoxidation of Pd(0) to Pd(II).1 This oxygenation is fairly sluggish and can result in chlorinated by-products. A new system is comprised of catalytic amounts of Pd(OAc)2, hydroquinone, and 1, used as the oxygen activator.2 The solvent is aqueous DMF, and a trace of HClOj is added to prevent precipitation of Pd(0). Oxygenation using this system of three catalysts effects Wacker oxidation of 1-alkenes in 2-8 hours and in 67-85% yield. 

Subsequently, E releases ethanal to give a Pd(0) species which is reoxidized to Pd(II) by means of Cu(II), possibly via dinudear species such as F, and Cu(II) is regenerated from Cu(I) by reaction with 02 and HC1. From the kinetics of the Wacker oxidation, which are roughly expressed [4, 22] by the equation ... 

This domino Wacker-Heck reaction is the key step of this total synthesis. In the presence of catalytic amounts of Pd(OTFA)2, the chiral ligand (S,S)-Bn-BOXAX (5) and j -benzoquinone (13) as reoxidant, phenol 19 first undergoes an intramolecular enantioselective Wacker oxidation and then reacts with methyl vinyl ketone (9) in a Heck reaction to afford chroman 22 with part of the vitamin E side chain in 84 % yield with 97 % ee. 

Under standard catalytic conditions (10% PdCh, 1 eq. CuCI, O2, in DMF/H2O), the Wacker oxidation of 4-methoxystyrene proceeded to give a mixture of the two possible products. As expected, the Markovnikov product, methylketone 31 was predominate and only a small amount of aldehyde 30 was isolated (31 30 = 8.4 1). However, Spencer and coworkers performed the reaction in the absence of the reoxidant CuCI and observed a reversal of the usual regioselectivity.26 Thus, reaction of 4-methoxystyrene with 2 equivalents of PdCb gave aldehyde 30 as the major product. The authors explained the regioselectivity by the involvement of a possible 4-palladium-styrene complex 29. 

Overall, this transformation leads to the conversion of Pd(II) to Pd(0), which consumes one equivalent of expensive Pd(OAc)2 in most cases. However, progress has been made toward the development of catalytic versions of this transformation, in which catalytic turnover is effected by employing a second oxidant that serves to convert Pd(0) back to Pd(II). For example, Kndlker described the oxidative cyclization of 47 using catalytic Pd(OAc)2 to afford indole derivative 48.38 The reoxidation of Pd(0) to Pd(II) was accomplished using excess cupric acetate in a manner analogous to the Wacker oxidation.39... 

Dioxygen activation appears to be involved in triple catalytic systems, in which Wacker oxidation of 1,3-cyclohexadiene is coupled with Pd reoxidation by p-benzoquinone [141]. Hydroquinone in turn is reoxidized by the CoCTPpj/O system (Scheme 10). 

The last catalytic reaction we examine in this overview is the Wacker oxidation of ethylene to acetaldehyde with O2, now used to make about 4 million tons a year of aldehydes from alkenes. This reaction shows several new features of great interest. Although the work started with a commonplace observation— the stoichiometric oxidation of alkenes by Pd(II) salts with formation of Pd(0)— the authors were able to make the system catalytic by finding a clean way to reoxidize the Pd(0) to Pd(II) with air. The mechanism was obscure for years because the kinetics gave an incomplete picture and it was only with sophisticated labeling studies that the currently accepted mechanism was discovered. 

Karakhanov group performed a comparative study on the Wacker oxidation of various alkenes with different CD-based imprinted macrocycles [38]. In Table 2.4, the different CD-based MlPs assessed in terms of the oxidation reaction of several terminal alkenes are gathered. The Wacker oxidation was carried out in conditions where the rate of Pd° and Cu° reoxidation was high compared to the rate of substrate ttansformation, under oxygen pressure, at 50°C, with a PdS04 CuS04 HPA (heteropolyadd) mixture (1 10 10) in a two-phase water/ substrate system. 

Earlier studies have also shown that a catalyst system consisting of palladium(II) and copper salts plus oxygen for the reoxidation did not work well,t in contrast to the result with the Wacker oxidation. However, if quinone or hydroquinone was added to a mixture of palladium acetate and copper acetate, oxygen could be used as an efficient oxidant for conversion of alkenes into allylic acetates. Thus, cyclohexene gave better than 85% cyclohexenyl acetate (Scheme 10). The combination of oxygen and cobalt or manganese acetate also works, but less well.t ... 

Reoxidant in Palladium-Catalyzed Reactions. Cu(OAc)2 has been used as a reoxidant in the Wacker oxidation (CH2=CH2 + 02- CHsCHO) and in the Pd(OAc)2-catalyzed alkenylation of aromatic compounds with alkenes (eq 17). Pd(OAc)2 and Cu(OAc)2 are effective catalysts for the reactions... 

To illustrate the inner-sphere characteristics of the CH activation chemistry, an analogy can be made between CH activation by coordination of an alkane CH bond to a metal center and the known catalysis resulting from coordination of olefins via the CC double bond (note that the nature of the orbitals involved in bonding are quite different). It is well known that coordination of olefins to electrophilic metal centers can activate the olefin to nucleophilic attack and conversion to organometallic, M-C, intermediates. The M-C intermediates thus formed can then be more readily converted to functionalized products than the uncoordinated olefin. An important example of this in oxidation catalysis is the Wacker oxidation of ethylene to acetaldehyde. In this reaction, catalyzed by Pd(II) as shown in Fig. 7.14, ethylene is activated by coordination to the inner-sphere of an electrophilic Pd(II) center. This leads to attack by water and facile formation of an organometallic, palladium alkyl intermediate that is subsequently oxidized to acetaldehyde. The reduced catalyst is reoxidized by Cu(II) to complete the catalytic cycle. The Wacker reaction is very rapid and selective and it is possible to carry out the reaction is aqueous solvents. This is largely possible because of the favorable thermodynamics for coordination of olefins to transition metals that can be competitive with coordination to the water solvent. The reaction is very selective presumably because the bonds of the product (po-... 

Wacker process The oxidation of ethene to ethanal by air and a PdClj catalyst in aqueous solution. The Pd is reduced to Pd in the process but is reoxidized to Pd " by oxygen and Cu. ... 

Ca.ta.lysis, The most important iadustrial use of a palladium catalyst is the Wacker process. The overall reaction, shown ia equations 7—9, iavolves oxidation of ethylene to acetaldehyde by Pd(II) followed by Cu(II)-cataly2ed reoxidation of the Pd(0) by oxygen (204). Regeneration of the catalyst can be carried out in situ or ia a separate reactor after removing acetaldehyde. The acetaldehyde must be distilled to remove chloriaated by-products. 

The palladium chloride process for oxidizing olefins to aldehydes in aqueous solution (Wacker process) apparendy involves an intermediate anionic complex such as dichloro(ethylene)hydroxopalladate(II) or else a neutral aqua complex PdCl2 (CH2=CH2)(H2 0). The coordinated PdCl2 is reduced to Pd during the olefin oxidation and is reoxidized by the cupric—cuprous chloride couple, which in turn is reoxidized by oxygen, and the net reaction for any olefin (RCH=CH2) is then... 

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. 

In its stoichiometric form, the reaction had been known since the beginning of the 20th century. Direct reoxidation of palladium by oxygen is extremely slow. The invention of Smidt (Wacker Chemie) involved the intermediacy of copper in the re-oxidation of palladium ... 

Palladium-catalyzed, Wacker-type oxidative cycHzation of alkenes represents an attractive strategy for the synthesis of heterocycles [139]. Early examples of these reactions typically employed stoichiometric Pd and, later, cocat-alytic palladium/copper [140-142]. In the late 1970s, Hegedus and coworkers demonstrated that Pd-catalyzed methods could be used to prepare nitrogen heterocyles from unprotected 2-allylanilines and tosyl-protected amino olefins with BQ as the terminal oxidant (Eqs. 23-24) [143,144]. Concurrently, Hosokawa and Murahashi reported that the cyclization of allylphenol substrates can be accomplished by using a palladium catalyst with dioxygen as the sole stoichiometric reoxidant (Eq. 25) [145]. 

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