653

Wacker Oxidation

A. GENERAL DESCRIPTION OF THE REACTION

This reaction was first reported by Phillips in 1894.1 It is an industrial production of

acetaldehyde by the oxidation of ethylene with oxygen in the presence of aqueous acidic
solution of palladium chloride and cupric chloride. However, this reaction was not named
after Phillips, instead it is generally known as the Hoechst-Wacker process,2 or simply as the
Wacker process3 after Farbwerke Hoechst AG and Wacker Chemie GmbH, which initially
implemented this reaction for the production of acetaldehyde. Currently, the catalytic ver-
sion of this reaction is generally used to convert the terminal olefins (mono-substituted) into
methyl ketones with oxygen or air as oxidant, and such reaction is known as the Wacker-
Hoechst oxidation,4 Tsuji-Wacker oxidation,5 Tsuji-Wacker process,5b Wacker-Tsuji
oxidation,6 etc. and more generally as the Wacker oxidation.3a,3b,3f,3h,3k,4,7,8 Similarly, the
combination of palladium chloride and cupric chloride is known as the Wacker catalyst.9
Although this reaction is essentially catalyzed by palladium chloride, the reaction will not
proceed in the absence of cupric chloride and hydrochloric acid, and palladium precipitates
out from the reaction system. In addition, this reaction must be carried out under aerobic
conditions,3a,7e either in the presence of a pure oxygen atmosphere (e.g., oxygen balloon)7a
or air;7v whereas the amount of oxygen is critical for the maximal catalytic efficiency under
steady state.3h Generally, this reaction will convert the terminal olefins into methyl ketones;
however, when the reaction is carried out in acetic acid using Pd(OAc)2 as the catalyst, vinyl
acetates are formed as well.7j When the reaction is performed in an aqueous solution of
ionic liquid (e.g., [BMIM]+ [BF4 ]− ), the olefinic isomers are also obtained.7e Moreover, the
oxidation of olefins with a heteroatom adjacent to the olefinic functionality may change the
reaction path, yielding alternative products instead of methyl ketones, owing to the coor-
dination of such heteroatom with palladium.3g For example, the oxidation of allylamine

Comprehensive Organic Name Reactions and Reagents, by Zerong Wang

Copyright © 2010 John Wiley & Sons, Inc.

2920
 PROPOSED MECHANISMS 2921

yields aldehyde,7t whereas the oxidation of olefins with α-alkoxy (e.g., α-methoxy) gives
both methyl ketones and aldehydes.3g However, the presence of a β-alkoxy group does not
affect the oxidation.3g It is interesting that the oxidation of α,β-dihydroxy olefins leads to
the formation of methyl ketones only, but the oxidation on alkoxy protected α,β-dihydroxy
olefins yields only aldehydes.3g In comparison, the oxidation of internal trans- and cis-
olefins with α,β-dihydroxy groups gives β,γ-dihydroxy ketones and α,β-dihydroxy ketones,
respectively.3g Moreover, the oxidation of olefins with a γ-hydroxy group may form cyclized
ether, and it has been found that such cyclization occurs with high syn-stereochemistry in
regard to palladium and oxygen in the absence of chloride, but proceeds mainly in anti
fashion in the presence of a chloride.10 Although this reaction is highly chemoselective, as
evidenced in the exclusive oxidation of olefin with a sulfinyl group,7o the Wacker oxidation
can also be used to activate an allylic C-H bond. For example, in the presence of DMSO, the
catalytic system of Pd(OAc)2 /benzoquinone/AcOH converts olefins into linear trans-allylic
acetates with high regioselectivity and stereoselectivity;7j however, in the presence of a bis-
sulfoxide palladium acetate complex prepared from 1,2-bis(phenylmethanesulfinyl)ethane
in CH2 Cl2 instead of DMSO, the terminal olefins are converted into allylic acetates with
retention of the terminal double bond.7j The latter reaction can be performed in a variety
of solvents, such as CH2 Cl2 , dioxane, THF, Et2 O, DME, benzene, and toluene.7j

B. GENERAL REACTION SCHEME

C. PROPOSED MECHANISMS

It is assumed that the Wacker oxidation involves the initial activation of the olefinic
functionality via the coordination of the C-C double bond with the palladium cation,4
followed by a reversible nucleophilic attack of water in Markovnikov fashion, and a rate-
limiting step in which a chloride is cleaved from the σ complex.4 The resulting 14-e complex
undergoes rapid β-elimination to form palladium hydride and vinyl alcohol. Vinyl alcohol
can directly tautomerize into methyl ketone, whereas palladium hydride undergoes reductive
elimination to form palladium (0), which is then oxidized by Cu(II) to palladium (II) again
while Cu(II) is reduced to Cu(I). The oxidation of Cu(I) to Cu(II) by oxygen in the presence
of HCl completes the catalytic cycle.4 Overall, in this reaction, only oxygen and olefins are
consumed, and palladium chloride and cupric chloride are regenerated during the reaction
cycle.10 The mechanism of Wacker oxidation is displayed here.
2922 WACKER OXIDATION

D. MODIFICATION

This reaction has been extensively modified. The said modifications include the appli-
cation of a reverse phase-transfer catalyst,7s a nanoscale palladium cluster immobilized
on a TiO2 surface,7m a palladium catalyst of Pd(NO3 )2 /CuSO4 /H3 PMo12 O40 ,8i cis-
Pt(Cl)2 (TPPTS)2 [TPPTS = P(m-C6 H4 SO3 Na)3 ],7k or a palladium-polypyrrole catalytic
system,7cc and an electrochemical system with benzoquinone or FeCl3 as homo-
geneous electron transfer reagents.7p In addition, due to the limitation of mass-transfer for
higher terminal olefins, both calix[4]arenes and cyclodextrins (e.g., per(2,6-di-O-methyl)-
β-cyclodextrin8u ) have been used as mass-transfer promoters for the biphasic Wacker
oxidation, and this modification has been proved to be more efficient than the conditions by
application of surfactants and polymers.7e In addition, the Wacker oxidation has been carried
out in a fluorous biphasic system,8q ionic liquids,7e such as 1-n-butyl-3-methylimidazolium
hexafluorophosphate ([bmim][PF6 ]),8m as well as supercritical CO2 .8m

E. APPLICATIONS

This reaction has very wide application in organic synthesis.

F. RELATED REACTIONS

N/A

G. CITED EXPERIMENTAL EXAMPLES

CO2Me CO2Me

PdCl2, CuCl2, O2
N DMF/H2O O N
HO
O O
97%
Reference 11.

To a solution of 0.3 g methyl 7-allyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-8-

carboxylate (1.2 mmol) in 6 mL DMF at 25◦ C was added a solution containing 0.21 gram
of copper(II) chloride dihydrate (1.2 mmol) in 4 mL water followed by 0.021 g PdCl2
(0.11 mmol), and the reaction mixture was stirred at room temperature under an oxygen
atmosphere for 12 h. The dark reaction mixture was poured into a separatory funnel con-
taining 100 mL water and was extracted with 100 mL ethyl acetate. The organic layer was
dried over MgSO4 and filtered through Celite. Upon removal of solvent, the resulting white
solid was purified by silica gel column chromatography to afford 0.29 g methyl 2-methyl-8-
oxo-5,6,7,8-tetrahydro-1-oxa-7a-azaindacene-4-carboxylate (97%) as a white solid, which
was further purified by recrystallization from dichloromethane, m.p. 159–160◦ C.
 REFERENCES 2923

NHBz NHBz
MeO MeO
PdCl2, Cu(OAc)2, O2 O
DMF/H2O
MeO MeO
88%
Reference 7c.

A mixture of 622 mg 1-(3,4-dimethoxyphenyl)-but-3-ene benzamide (2.0 mmol), 72 mg

PdCl2 (0.40 mmol), 148 mg Cu(OAc)2 (0.80 mmol), 2 mL H2 O, and 14 mL DMF was
stirred under 1 atm oxygen for 2 days. Then 1% HCl was added to the brownish mix-
ture, and the resulting clear solution was extracted with CH2 Cl2 . The combined organic
phases were washed with saturated NaHCO3 solution and brine, and dried over anhydrous
MgSO4 . Upon removal of solvent, the residue was purified by flash chromatography using
hexanes/EtOAc (1:1) as the eluent to afford 576 mg (S)-N-[1-(3,4-dimethoxyphenyl)-3-
oxobutyl]benzamide as a colorless solid, in a yield of 88%, m.p. 139–140◦ C.

Other references related to the Wacker oxidation are cited in the literature.12

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