Wacker oxidation 1-alkenes

The oxidation of alkenes (Wacker oxidation, mainly styrene to acetophenone. Scheme 5.3-13) has been reported to be catalyzed by PdQz in the presence of e.g. [BMIM][PF6] [143]. The need for only a small excess (1.15 equiv.) of aqueous H2O2 was demonstrated, which is a significant improvement in H2O2 utilization compared to previously reported methods. 

In 1974, Hegedus and coworkers reported the pa]ladium(II)-promoted addition of secondary amines to a-olefins by analogy to the Wacker oxidation of terminal olefins and the platinum(II) promoted variant described earlier. This transformation provided an early example of (formally) alkene hydroamination and a remarkably direct route to tertiary amines without the usual problems associated with the use of alkyl halide electrophiles. 

The relative reactivity profile of the simple alkenes toward Wacker oxidation is quite shallow and in the order ethene > propene > 1-butene > Zi-2-butene > Z-2-butene.102 This order indicates that steric factors outweigh electronic effects and is consistent with substantial nucleophilic character in the rate-determining step. (Compare with oxymercuration see Part A, Section 5.8.) The addition step is believed to occur by an internal ligand transfer through a four-center mechanism, leading to syn addition. 

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. 

Wacker oxidation of styrene has also been performed in [bmim][BF4] and [bmim][PF6], at 60 °C with H2O2 and PdCF as a catalyst [19]. This system gave yields of acetophenone as high as 92 % after 3 h. Hydrogen peroxide may also be used under phase transfer conditions for alkene bond cleavage, to produce adipic acid (an intermediate in the synthesis of nylon-6) from cyclohexene (Scheme 9.9). 

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... 

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 well-known Wacker oxidation of terminal alkenes to methylketones has been used for many years on a large scale. It requires a catalytic amount of Pd(II) together with stoichiometric CuCl2 under aerobic conditions. But it is hmited by palladiiun decomposition and chlorinated byproducts. Therefore, a lot of research has been devoted to modifying the reaction, but most of the time copper cocatalysts were necessary. Another problem is the often observed cleavage of the double bond and the production of aldehydes. 

Wacker oxidation. Tsuji et al.s have developed two procedures for oxidation of 1-alkenes to methyl ketones with oxygen that are catalyzed by PdCl2 (7, 278 9, 327). The solvent in both cases is aqueous DMF. One method uses PdCl2-CuCl (molar ratio 1 10) the other uses PdCl2 and p-benzoquinone (molar ratio 1 100). Both procedures are about equivalent for oxidation of simple l-alkenes to methyl ketones, but the former method is usually more effective for oxidation of more complex 1-alkenes. 

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. 

Alkenes can be transformed into ketones by Wacker oxidation (Entry 2, Table 12.3), but this reaction does not seem to proceed cleanly on polymeric supports. Janda and co-workers were able to oxidize styrenes bound to macroporous polystyrene to the corresponding acetophenones, but reported that the reaction did not proceed on PEG... 

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. 

Scheme 3.4 PdCl2/CuCl-catalyzed Wacker oxidation of alkenes to methyl ketones [36]...

Karakhanov E, Buchneva T, Maximov A et al (2002) Substrate selectivity in byphasic Wacker-oxidation of alkenes in the presence of water-soluble calixarenes. J Mol Catal A Chem 184(1-2) 11-17... 

Acetals result from oxidative coupling of alcohols with electron-poor terminal olefins followed by a second, redox-neutral addition of alcohol [11-13]. Acrylonitrile (41) is converted to 3,3-dimethoxypropionitrile (42), an intermediate in the industrial synthesis of thiamin (vitamin Bl), by use of an alkyl nitrite oxidant [57]. A stereoselective acetalization was performed with methacrylates 43 to yield 44 with variable de [58]. Rare examples of intermolecular acetalization with nonactivated olefins are observed with chelating allyl and homoallyl amines and thioethers (45, give acetals 46) [46]. As opposed to intermolecular acetalizations, the intramolecular variety do not require activated olefins, but a suitable spatial relationship of hydroxy groups and the alkene[13]. Thus, Wacker oxidation of enediol 47 gave bicyclic acetal 48 as a precursor of a fluorinated analogue of the pheromone fron-talin[59]. 

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 ... 

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. 

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... 

In a synthesis of the immunosuppressant Sanglifehrin A, two hydroxyl groups and a ketone were mutually protected as an acetal [Scheme 1.33].60 The ketone was generated by a Wacker oxidation of the terminal alkene 33.1 whereupon it was immediately converted to the bicyclic acetal 33.2 on treatment with acid. The acetal 33.2 survived the many steps required to elaborate the complex intermediate 33.3 but its stability was to exact a price the synthesis languished on the cusp of completion until conditions were found to hydrolyse the acetal without insult to the remaining delicate functionality. Hie three functional groups were eventually reclaimed in a modest 33% yield by interrupting the hydrolysis at 50% completion. 

Wacker oxidation.3 The oxidation of 1-alkenes to methyl ketones by oxygen catalyzed by PdCl2 and CuCl2 can be carried out under phase-transfer conditions with cetyltrimethylammonium bromide or a closely related salt as the phase-transfer catalyst. Yields are in the range 50-75%. Several rhodium and ruthenium complexes can be used as the metal catalyst, but the yields are lower. 

---