# Wacker process

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{{Short description|Chemical reaction}}
The '''Wacker process''' or the '''Hoechst-Wacker process''' (named after the chemical companies of the same name) is an industrial [chemical reaction](/source/chemical_reaction): the [aerobic oxidation](/source/aerobic_oxidation) of [ethylene](/source/ethylene) to [acetaldehyde](/source/acetaldehyde) in the presence of [catalytic](/source/catalysis), aqueous [palladium(II) chloride](/source/palladium(II)_chloride) and [copper(II) chloride](/source/copper(II)_chloride). 
:Net reaction in the Wacker process|center|frameless
The '''Tsuji-Wacker oxidation''' refers to a family of reactions inspired by the Wacker process.  In Tsuji-Wacker reactions, palladium(II) catalyzes transformation of [α-olefins](/source/%CE%91-olefin) into [carbonyl compounds](/source/carbonyl_compounds) in various [solvents](/source/Solvent). 
:center|501x501px|alt=
The development of the Wacker process popularized modern [organopalladium chemistry](/source/organopalladium_chemistry), and Tsuji-Wacker oxidations remain in use today.

==History==
The Wacker process was one of the first [homogeneous catalysis](/source/homogeneous_catalysis) with [organopalladium](/source/organopalladium) chemistry applied on an industrial scale.<ref>Elschenbroich, C. "Organometallics" (2006) Wiley-VCH: Weinheim. {{ISBN|978-3-527-29390-2}}</ref>

In an 1893 doctoral dissertation on [Pennsylvanian natural gas](/source/Marcellus_natural_gas_trend), Francis Clifford Phillips had reported that [palladium(II) chloride](/source/palladium(II)_chloride) oxidized ethylene to acetaldehyde, but the reaction required stoichiometric quantities of [palladium](/source/palladium).<ref>{{Cite journal|last=Phillips |first=Francis C. |date=March–June 1894 |title=Researches upon the phenomena of oxidation and chemical properties of gases |url={{GBUrl|id=IDogE3L1RLkC|p=163}} |journal=American Chemical Journal |volume=16 |issue=3–6 |pages=163-187, 255-277, 340-365, 406-429 |quote=The reaction between ethylene and palladium chloride in solution is of the second class and complete, the gas being rapidly absorbed. Palladium is deposited as a black powder, but no trace of oxidation to carbon dioxide occurs. The reaction is almost the same in the cold and at 100°. The gas escaping from the palladium-chloride solution (after complete reduction to metallic palladium) produces no precipitate in lime-water. The reaction between palladium chloride and ethylene leads to the production of aldehyde. |via=Google Books}}</ref>  It remained a niche curiosity until [Wacker Chemie](/source/Wacker_Chemie) began developing its eponymous process in 1956.<ref name=":2">''Acetaldehyde from Ethylene — A Retrospective on the Discovery of the Wacker Process'' Reinhard Jira [Angew. Chem. Int. Ed.](/source/Angew._Chem._Int._Ed.) '''2009''', ''48'', 9034–9037 {{doi|10.1002/anie.200903992}}</ref>

At the time, many industrial compounds were produced via acetaldehyde from [acetylene](/source/acetylene), itself from [calcium carbide](/source/calcium_carbide).  The overall route exhibited poor thermodynamic efficiency and required great expense.  Esso sought to market waste [olefins](/source/Olefin) from a new, under-construction [oil refinery](/source/oil_refinery) in [Cologne](/source/Cologne) close to a Wacker site.  Wacker realized that [ethylene](/source/ethylene) would be a cheaper [feedstock](/source/feedstock) than acetylene, and began to investigate catalytic oxidation to [ethylene oxide](/source/ethylene_oxide).<ref name=":2"/>

To Wacker's surprise, they smelled{{#tag:ref|Wacker lacked a [gas chromatograph](/source/Gas_chromatography) at the time.<ref name=":2"/>|group="Note"}} not ethylene oxide but [acetaldehyde](/source/acetaldehyde) in the product stream.  From Phillips' dissertation, known properties of [Zeise's salt](/source/Zeise's_salt), and transformation of the catalyst over the course of a batch reaction, Wacker realized that they needed to reoxidize the palladium to close the catalytic cycle.<ref name=":2" />  They began publishing the process outline in 1957.<ref>J. Smidt, W. Hafner, R. Jira, J. Sedlmeier, R. Sieber, R. Rüttinger, and H. Kojer, Angew. Chem., '''1959''', 71, 176–182. {{doi|10.1002/ange.19590710503}}</ref><ref>J. Smidt, W. Hafner, J. Sedlmeier, R. Jira, R. Rottinger (Cons. f.elektrochem.Ind.), DE 1 049 845, 1959, Anm. 04.01.1957.</ref>  However, poor [patenting](/source/patenting) strategy allowed [parent](/source/Parent_corporation) corporation [Hoechst AG](/source/Hoechst_AG) to outrace Wacker to the optimal catalysis conditions.<ref name=":2" /><ref>W. Hafner, R. Jira, J. Sedlmeier, and J. Smidt, Chem. Ber., '''1962''', 95, 1575–1581.  {{doi|10.1002/cber.19620950702}}</ref><ref>J. Smidt, W. Hafner, R. Jira, R. Sieber, J. Sedlmeier, and A. Sabel, Angew. Chem. Int. Ed. Engl., '''1962''', 1, 80–88.</ref>

Wacker-Hoechst began jointly constructing pilot plants in 1958, but the relatively aggressive reaction conditions required the first large-scale use of [titanium](/source/titanium) metal in the European chemical industry to protect against corrosion.  Production plants started operation in 1960.<ref name=":2" />

The process also sparked a boom in [organopalladium chemistry](/source/organopalladium_chemistry).<ref name=":2" />  Studies from the 1960s elucidated several key points about the reaction mechanism through [kinetic isotope effects](/source/Kinetic_isotope_effect) (or lack thereof) and [stereochemistry](/source/stereochemistry).<ref name=":3">Henry, Patrick M. In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley & Sons: New York, 2002; p 2119. {{ISBN|0-471-31506-0}}</ref><ref name="K&H">{{cite journal |author=J. A. Keith |author2=P. M. Henry |year=2009 |title=The Mechanism of the Wacker Reaction: A Tale of Two Hydroxypalladations |journal=Angew. Chem. Int. Ed. |volume=48 |issue=48 |pages=9038–9049 |doi=10.1002/anie.200902194 |pmid=19834921 |bibcode=2009ACIE...48.9038K }}</ref>  Many focused on the hydroxypalladation step, which forms the C&ndash;O bond.  Early reactions used conditions much milder than the industrial plants and obtained contradictory results; the modern consensus is that the step's stereochemistry is quite sensitive to chloride concentrations.<ref name="K&H" />

Other studies investigated reaction's application to more complex [terminal olefins](/source/Terminal_alkene).  High-order olefins are insoluble in water, but Clement and Selwitz<ref>{{Cite journal |last1=Clement |first1=William H. |last2=Selwitz |first2=Charles M. |date=January 1964 |title=Improved Procedures for Converting Higher α-Olefins to Methyl Ketones with Palladium Chloride |journal=The Journal of Organic Chemistry |volume=29 |issue=1 |pages=241–243 |doi=10.1021/jo01024a517 |issn=0022-3263}}</ref> found that aqueous [DMF](/source/Dimethylformamide) as solvent allowed for the oxidation of 1-dodecene to 2-dodecanone. Fahey<ref>{{Cite journal |last1=Fahey |first1=Darryl R. |last2=Zeuch |first2=Ernest A. |date=November 1974 |title=Aqueous sulfolane as solvent for rapid oxidation of higher .alpha.-olefins to ketones using palladium chloride |journal=The Journal of Organic Chemistry |volume=39 |issue=22 |pages=3276–3277 |doi=10.1021/jo00936a023 |issn=0022-3263}}</ref> noted the use of 3-methylsulfolane in place of DMF as solvent increased the yield of oxidation of 3,3-Dimethylbut-1-ene. Two years after, Tsuji<ref>{{Cite journal |last1=Tsuji |first1=Jiro |last2=Shimizu |first2=Isao |last3=Yamamoto |first3=Keiji |date=August 1976 |title=Convenient general synthetic method for 1,4- and 1,5-diketones by palladium catalyzed oxidation of α-allyl and α-3-butenyl ketones |journal=Tetrahedron Letters |volume=17 |issue=34 |pages=2975–2976 |doi=10.1016/s0040-4039(01)85504-0 |issn=0040-4039}}</ref> applied the Clement-Selwitz conditions for selective oxidations of terminal olefins with multiple functional groups, and demonstrated its utility in synthesis of complex substrates.<ref>{{Cite journal |last=Tsuji |first=Jiro |date=1984 |title=Synthetic Applications of the Palladium-Catalyzed Oxidation of Olefins to Ketones |journal=Synthesis |volume=1984 |issue=5 |pages=369–384 |doi=10.1055/s-1984-30848 |issn=0039-7881 |s2cid=95604861}}</ref> 

[Carbonylation](/source/Carbonylation) has mainly superseded the Wacker process for modern [bulk chemical](/source/Bulk_chemicals) synthesis, but small-scale Tsuji-Wacker reactions remain important for [fine chemical](/source/fine_chemical) and laboratory-scale syntheses.<ref name=":2" />

==Reaction mechanism==
The [reaction mechanism](/source/reaction_mechanism) for the industrial Wacker process (olefin oxidation via palladium(II) chloride) has received significant attention for several decades.  Aspects of the mechanism are still debated.  A modern formulation is described below:<ref>{{Cite book |last1=Kurti |first1=Laszlo |title=Strategic Applications of named Reactions in Organic Synthesis |last2=Czako |first2=Barbara |publisher=Elsevier Academic Press |year=2005 |isbn=978-0-12-429785-2 |location=525 B Street, Suite 1900, San Diego, California 92101-4495, USA |page=474}}</ref>

center|635x635px|thumb|Catalytic cycle for the Wacker process.<ref name=K&H/>
This reaction can also be described as follows:
:[PdCl<sub>4</sub>]<sup>2 −</sup> + C<sub>2</sub>H<sub>4</sub> + H<sub>2</sub>O → CH<sub>3</sub>CHO + Pd + 2 HCl + 2 Cl<sup>−</sup>,
followed by reactions that regenerate the Pd(II) catalyst:
: Pd + 2 CuCl<sub>2</sub> + 2 Cl <sup>−</sup> → [PdCl<sub>4</sub>]<sup>2−</sup> + 2 CuCl
: 2 CuCl + {{sfrac|1|2}} O<sub>2</sub> + 2 HCl → 2 CuCl<sub>2</sub> + H<sub>2</sub>O

Only the alkene and oxygen are consumed. Without [copper(II) chloride](/source/copper(II)_chloride) as an [oxidizing agent](/source/oxidizing_agent), Pd(0) metal (resulting from [beta-hydride elimination](/source/beta-hydride_elimination) of Pd(II) in the final step) would precipitate, stopping Philips' reaction after one cycle. Air, pure oxygen, or a number of other reagents can then oxidise the resultant [CuCl](/source/Copper(I)_chloride)-chloride mixture back to CuCl<sub>2</sub>, allowing the cycle to continue.

High concentrations of chloride and [copper(II) chloride](/source/copper(II)_chloride) favor formation of a new product, [ethylene chlorohydrin](/source/ethylene_chlorohydrin).<ref>H. Stangl and R. Jira, Tetrahedron Lett., '''1970''', ''11'', 3589–3592</ref>

=== Evidence ===
Evidence for the overall mechanism includes:<ref name=":3" /><ref name="K&H" />

*No H/D exchange effects.  Experiments with C<sub>2</sub>D<sub>4</sub> in water generate CD<sub>3</sub>CDO, and runs with C<sub>2</sub>H<sub>4</sub> in D<sub>2</sub>O generate CH<sub>3</sub>CHO.  Thus, [keto-enol tautomerization](/source/keto-enol_tautomerization) is not a possible mechanistic step.
* Negligible [kinetic isotope effect](/source/kinetic_isotope_effect) with fully deuterated reactants ({{sfrac|''k'' <sub>H</sub>|''k'' <sub>D</sub>}}=1.07). Hence hydride transfer is not [rate-determining](/source/rate-determining_step).
* Significant competitive isotope effect with C<sub>2</sub>H<sub>2</sub>D<sub>2</sub>, ({{sfrac|''k'' <sub>H</sub>|''k'' <sub>D</sub>}}= ~1.9), suggests that the rate determining step precedes acetaldehyde formation.
Evidence against the mechanism is a copper-chloride containing byproduct crystallized by Hosokawa ''et al''.<ref>T. Hosokawa, T. Nomura, S.-I. Murahashi, J. Organomet. Chem., '''1998''', ''551'', 387–389</ref>  Questions remain about whether the cocatalyst also helps hydroxylate the ethylene ligand.

The ethylene ligand's hydroxylation is typically a slow process.<ref name=":4">Zaw, K., Lautens, M. and Henry P.M. ''Organometallics'', '''1985''', ''4'', 1286–1296</ref><ref name=":5">Wan W.K., Zaw K., and Henry P.M. ''[Organometallics](/source/Organometallics)'', '''1988''', ''7'', 1677–1683</ref>  Depending on experimental conditions, it can occur either intramolecularly, from a palladium-bound hydroxido ligand, or intermolecularly.  In the former case the hydroxylation is ''anti''; in the latter, ''syn''.  Assuming small amounts of [copper](/source/copper), experiments have shown that ''syn'' addition occurs at low [chloride](/source/chloride) concentrations (< 1 [mol](/source/mole_(unit))/[L](/source/liter), industrial process conditions)<ref>P. M. Henry, J. Am. Chem. Soc., '''1964''', 86, 3246–3250.</ref> and ''anti'' addition occurs at high (> 3mol/L) concentrations.<ref>James, D.E., Hines, L.F., Stille, J.K. ''J. Am. Chem. Soc.'', '''1976''', ''98'', 1806 {{doi|10.1021/ja00423a027}}</ref><ref>James, D.E., Stille, J.K. ''J. Organomet. Chem.'', '''1976''', ''108'', 401. {{doi|10.1021/ja00423a028}}</ref><ref>Bäckvall, J.E., Akermark, B., Ljunggren, S.O., ''J. Am. Chem. Soc.'', '''1979''', ''101'', 2411. {{doi|10.1021/ja00503a029}}</ref><ref>Stille, J.K., Divakarumi, R.J., ''J. Organomet. Chem.'', '''1979''', ''169'', 239;</ref>{{Excessive footnotes|date=June 2025}}  The pathway change is probably due to chloride ions [saturating](/source/Catalyst_poisoning) the catalyst.<ref name=":6">Francis, J.W., Henry, P.M. ''Organometallics'', '''1991''', ''10'', 3498. {{doi|10.1021/om00056a019}}</ref><ref name=":7">Francis, J.W., Henry, P.M. ''Organometallics'', '''1992''', ''11'', 2832.{{doi|10.1021/om00044a024}}</ref>  However, under strictly copper-free conditions, ''anti'' addition always occurs, and the rate no longer depends on the ethylene hydrogen isotopes.<ref>Comas-Vives, A., Stirling, A., Ujaque, G., Lledós, A., Chem. Eur. J., '''2010''', ''16'', 8738–8747.{{doi|10.1002/chem.200903522}}</ref><ref>Anderson, B.J., Keith, J.A., and Sigman, M.S., J. Am. Chem. Soc., '''2010''', ''132'', 11872-11874</ref>

Another key step in the Wacker process is the migration of the hydrogen from oxygen to chloride, followed by [reductive elimination](/source/reductive_elimination) to form the C-O double bond. This step is generally thought to proceed through a so-called [β-hydride elimination](/source/%CE%B2-hydride_elimination):

500px|center|Wacker hydride elimination

The cyclic four-membered [transition state](/source/transition_state) shown above is unlikely.  ''[In silico](/source/In_silico)'' studies<ref>J. A. Keith, J. Oxgaard, and W. A. Goddard, III [J. Am. Chem. Soc.](/source/J._Am._Chem._Soc.), '''2006''', ''128'', 3132 – 3133; {{doi|10.1021/ja0533139}}</ref><ref>H. E. Hosseini, S. A. Beyramabadi, A. Morsali, and M. R. Housaindokht, J. Mol. Struct. (THEOCHEM), '''2010''', ''941'', 138–143</ref><ref>P. L. Theofanis, and W. A. Goddard, III Organometallics, '''2011''', ''30'', 4941 – 4948; {{doi|10.1021/om200542w}}</ref> argue that the [transition state](/source/transition_state) for this reaction step likely involves a 7-membered ring with a (solvent) water molecule acting as a catalyst.

150px|center|alt=Wacker process alternative transition state

==Industrial process==
thumb|right|Process flow diagram for the one-stage process
thumb|right|Process flow diagram for the two-stage process
Two routes are commercialized for the production of acetaldehyde: one-stage process and two-stage.  The acetaldehyde yield is about 95% in either, and byproducts are chlorinated hydrocarbons, chlorinated acetaldehydes, and acetic acid. In general, 100 parts of ethene gives:<ref name = ullmann/>
{{div col}}
* 95 parts acetaldehyde
* 1.9 parts chlorinated aldehydes
* 1.1 parts unconverted ethene
* 0.8 parts carbon dioxide
* 0.7 parts acetic acid
* 0.1 parts chloromethane
* 0.1 parts ethyl chloride
* 0.3 parts ethane, methane, crotonaldehyde
{{div col end}}
and other minor side products.

The production costs are virtually the same across the two processes; the advantage of using dilute gases in the two-stage method is balanced by higher investment costs. Due to the [corrosive](/source/corrosive) nature of the catalyst, either process requires a reactor lined with acid-proof [ceramic](/source/ceramic) and [titanium](/source/titanium) tubing, but the two-stage process requires more reactors and piping. Generally, the choice of method is governed by the raw material and energy situations as well as by the availability of oxygen at a reasonable price.<ref name = ullmann/>

===One-stage process===
[Ethene](/source/Ethene) and [oxygen](/source/oxygen) are passed co-currently in a reaction tower at about 130&nbsp;°C and 400 kPa.<ref name = ullmann>{{Ullmann | title = Acetaldehyde | doi = 10.1002/14356007.a01_031.pub2 | author = Marc Eckert | author2 = Gerald Fleischmann | author3 = Reinhard Jira | author4 = Hermann M. Bolt | author5 = Klaus Golka}}</ref> The catalyst is an aqueous solution of [PdCl<sub>2</sub>](/source/palladium_dichloride) and [CuCl<sub>2</sub>](/source/copper_chloride). The acetaldehyde is purified by [extractive distillation](/source/extractive_distillation) followed by [fractional distillation](/source/fractional_distillation). Extractive distillation with water removes the lights ends having lower boiling points than acetaldehyde ([chloromethane](/source/chloromethane), [chloroethane](/source/chloroethane), and [carbon dioxide](/source/carbon_dioxide)) at the top,  while water and higher-boiling byproducts, such as [acetic acid](/source/acetic_acid), [crotonaldehyde](/source/crotonaldehyde) or chlorinated acetaldehydes, are withdrawn together with acetaldehyde at the bottom.<ref name = ullmann/>

===Two-stage process===
In two-stage process, reaction and [oxidation](/source/oxidation) are carried out separately in tubular reactors. Unlike one-stage process, air can be used instead of oxygen. [Ethylene](/source/Ethylene) is passed through the reactor along with catalyst at 105–110&nbsp;°C and 900–1000 kPa.<ref name = ullmann/> Catalyst solution containing acetaldehyde is separated by [flash distillation](/source/flash_distillation). The catalyst is oxidized in the oxidation reactor at 1000 kPa using air as oxidizing medium. Oxidized catalyst solution is separated and sent back to reactor. Oxygen from air is used up completely and the exhaust air is circulated as inert gas. Acetaldehyde – water vapor mixture is preconcentrated to 60–90% acetaldehyde by utilizing the [heat of reaction](/source/heat_of_reaction) and the discharged water is returned to the flash tower to maintain catalyst concentration. A two-stage distillation of the crude acetaldehyde follows. In the first stage, low-boiling substances, such as [chloromethane](/source/chloromethane), [chloroethane](/source/chloroethane) and [carbon dioxide](/source/carbon_dioxide), are separated. In the second stage, water and higher-boiling by-products, such as chlorinated acetaldehydes and [acetic acid](/source/acetic_acid), are removed and acetaldehyde is obtained in pure form overhead.<ref name = ullmann/>

== Tsuji-Wacker oxidation ==
Development of the reaction system has led to various catalytic systems to address selectivity of the reaction, as well as introduction of intermolecular and intramolecular oxidations with non-water nucleophiles.

=== Regioselectivity ===
==== Markovnikov addition ====
The oxidation of terminal olefins generally provide the [Markovnikov](/source/Markovnikov's_rule) ketone product.  In rare cases where substrate favors the aldehyde (discussed below), different ligands can be used to enforce Markovnikov regioselectivity. [Sparteine](/source/Sparteine) (Figure 2, A)<ref>{{Cite journal|last1=Balija|first1=Amy M.|last2=Stowers|first2=Kara J.|last3=Schultz|first3=Mitchell J.|last4=Sigman|first4=Matthew S.|date=March 2006|title=Pd(II)-Catalyzed Conversion of Styrene Derivatives to Acetals: Impact of (−)-Sparteine on Regioselectivity|journal=Organic Letters|volume=8|issue=6|pages=1121–1124|doi=10.1021/ol053110p|pmid=16524283|issn=1523-7060}}</ref> favors nucleopalladation at the terminal carbon to minimize steric interaction between the palladium complex and substrate. [Quinox](/source/Quinox) (Figure 2, B) favors ketone formation when the substrate contains a directing group.<ref>{{Cite journal|last1=Michel|first1=Brian W.|last2=Camelio|first2=Andrew M.|last3=Cornell|first3=Candace N.|last4=Sigman|first4=Matthew S.|date=2009-05-06|title=A General and Efficient Catalyst System for a Wacker-Type Oxidation Using TBHP as the Terminal Oxidant: Application to Classically Challenging Substrates|journal=Journal of the American Chemical Society|volume=131|issue=17|pages=6076–6077|doi=10.1021/ja901212h|issn=0002-7863|pmc=2763354|pmid=19364100|bibcode=2009JAChS.131.6076M }}</ref> When such substrate bind to Pd(Quinox)(OOtBu), this complex is coordinately saturated which prevents the binding of the directing group, and results in formation of the Markovnikov product. The efficiency of this ligand is also attributed to its electronic property, where anionic TBHP prefers to bind ''[trans](/source/Trans-alkene)'' to the oxazoline and olefin coordinate ''trans'' to the quinoline.<ref>{{Cite journal|last1=Michel|first1=Brian W.|last2=Steffens|first2=Laura D.|last3=Sigman|first3=Matthew S.|date=June 2011|title=On the Mechanism of the Palladium-Catalyzed tert -Butylhydroperoxide-Mediated Wacker-Type Oxidation of Alkenes Using Quinoline-2-Oxazoline Ligands|journal=Journal of the American Chemical Society|volume=133|issue=21|pages=8317–8325|doi=10.1021/ja2017043|issn=0002-7863|pmc=3113657|pmid=21553838|bibcode=2011JAChS.133.8317M }}</ref>
center|500x500px

==== Anti-Markovnikov addition  ====
The anti-Markovnikov addition selectivity to aldehyde can be achieved through exploiting inherent [stereoelectronics](/source/stereoelectronics) of the substrate.<ref name="Dong 734–744">{{Cite journal|last1=Dong|first1=Jia Jia|last2=Browne|first2=Wesley R.|last3=Feringa|first3=Ben L.|date=2014-11-03|title=Palladium-Catalyzed anti-Markovnikov Oxidation of Terminal Alkenes|journal=Angewandte Chemie International Edition|volume=54|issue=3|pages=734–744|doi=10.1002/anie.201404856|pmid=25367376|issn=1433-7851|url=https://pure.rug.nl/ws/files/240464098/Angew_Chem_Int_Ed_2014_Dong_Palladium_Catalyzed_anti_Markovnikov_Oxidation_of_Terminal_Alkenes.pdf }}</ref> Placement of directing group at homo-allylic (i.e. Figure 3, A)<ref>{{Cite journal|last1=Miller|first1=D. G.|last2=Wayner|first2=Danial D. M.|date=April 1990|title=Improved method for the Wacker oxidation of cyclic and internal olefins|journal=The Journal of Organic Chemistry|volume=55|issue=9|pages=2924–2927|doi=10.1021/jo00296a067|issn=0022-3263}}</ref> and [allyl](/source/allyl)ic position (i.e. Figure 3, B)<ref>{{Cite journal|last1=Stragies|first1=Roland|last2=Blechert|first2=Siegfried|date=October 2000|title=Enantioselective Synthesis of Tetraponerines by Pd- and Ru-Catalyzed Domino Reactions|journal=Journal of the American Chemical Society|volume=122|issue=40|pages=9584–9591|doi=10.1021/ja001688i|bibcode=2000JAChS.122.9584S |issn=0002-7863}}</ref> to the terminal olefin favors the anti-Markovnikov aldehyde product, which suggests that in the catalytic cycle the directing group [chelates](/source/chelation) to the palladium complex such that water attacks at the anti-Markovnikov carbon to generate the more thermodynamically stable palladacycle. Anti-Markovnikov selectivity is also observed in styrenyl substrates (i.e. Figure 3, C),<ref>{{Cite journal|last1=Wright|first1=Joseph A.|last2=Gaunt|first2=Matthew J.|last3=Spencer|first3=Jonathan B.|date=2006-01-11|title=Novel Anti-Markovnikov Regioselectivity in the Wacker Reaction of Styrenes|journal=Chemistry - A European Journal|volume=12|issue=3|pages=949–955|doi=10.1002/chem.200400644|pmid=16144020|bibcode=2006ChEuJ..12..949W |issn=0947-6539}}</ref> presumably via η<sup>4</sup>-palladium-styrene complex after water attacks anti-Markovnikov. More examples of substrate-controlled, anti-Markovnikov Tsuji-Wacker Oxidation of olefins are given in reviews by Namboothiri,<ref name=":0">{{Cite journal|last1=Baiju|first1=Thekke Veettil|last2=Gravel|first2=Edmond|last3=Doris|first3=Eric|last4=Namboothiri|first4=Irishi N.N.|date=September 2016|title=Recent developments in Tsuji-Wacker oxidation|journal=Tetrahedron Letters|volume=57|issue=36|pages=3993–4000|doi=10.1016/j.tetlet.2016.07.081|issn=0040-4039}}</ref> Feringa,<ref name="Dong 734–744"/> and Muzart.<ref>{{Cite journal|last=Muzart|first=Jacques|date=August 2007|title=Aldehydes from Pd-catalysed oxidation of terminal olefins|journal=Tetrahedron|volume=63|issue=32|pages=7505–7521|doi=10.1016/j.tet.2007.04.001|issn=0040-4020}}</ref>

Grubbs and co-workers paved way for anti-Markovnikov oxidation of [stereoelectronic](/source/stereoelectronic)ally unbiased terminal olefins, through the use of palladium-nitrite system (Figure 2, D).<ref>{{Cite journal|last1=Wickens|first1=Zachary K.|last2=Morandi|first2=Bill|last3=Grubbs|first3=Robert H.|date=2013-09-13|title=Aldehyde-Selective Wacker-Type Oxidation of Unbiased Alkenes Enabled by a Nitrite Co-Catalyst|journal=Angewandte Chemie International Edition|volume=52|issue=43|pages=11257–11260|doi=10.1002/anie.201306756|pmid=24039135|issn=1433-7851|url=https://authors.library.caltech.edu/42230/7/anie_201306756_sm_miscellaneous_information.pdf}}</ref> In his system, the terminal olefin was oxidized to the aldehyde with high selectivity through a catalyst-control pathway. The mechanism is under investigation, however evidence<ref name=":0" /> suggests it goes through a nitrite [radical](/source/Radical_(chemistry)) adds into the terminal carbon to generate the more thermodynamically stable, secondary radical. Grubbs expanded this methodology to more complex, unbiased olefins.<ref>{{Cite journal|last1=Wickens|first1=Zachary K.|last2=Skakuj|first2=Kacper|last3=Morandi|first3=Bill|last4=Grubbs|first4=Robert H.|date=2014-01-13|title=Catalyst-Controlled Wacker-Type Oxidation: Facile Access to Functionalized Aldehydes|journal=Journal of the American Chemical Society|volume=136|issue=3|pages=890–893|doi=10.1021/ja411749k|pmid=24410719|bibcode=2014JAChS.136..890W |issn=0002-7863|url=https://authors.library.caltech.edu/43469/7/ja411749k_si_001.pdf}}</ref><ref>{{Cite journal|last1=Kim|first1=Kelly E.|last2=Li|first2=Jiaming|last3=Grubbs|first3=Robert H.|last4=Stoltz|first4=Brian M.|date=2016-09-30|title=Catalytic Anti-Markovnikov Transformations of Hindered Terminal Alkenes Enabled by Aldehyde-Selective Wacker-Type Oxidation|journal=Journal of the American Chemical Society|volume=138|issue=40|pages=13179–13182|doi=10.1021/jacs.6b08788|pmid=27670712|bibcode=2016JAChS.13813179K |issn=0002-7863|url=https://authors.library.caltech.edu/70776/2/ja6b08788_si_001.pdf}}</ref>
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=== Scope ===

==== Oxygen nucleophiles  ====
The intermolecular oxidations of olefins with alcohols as [nucleophile](/source/nucleophile) typically generate [ketal](/source/ketal)s, where as the palladium-catalyzed oxidations of olefins with carboxylic acids as nucleophile generates [vinylic](/source/vinylic) or allylic [carboxylate](/source/carboxylate)s. In case of [diol](/source/diol)s, their reactions with alkenes typically generate ketals, whereas reactions of olefins bearing electron-withdrawing groups tend to form [acetal](/source/acetal)s.<ref name=":1">{{Cite book|title=Organotransition Metal Chemistry: From Bonding to Catalysis|last=Hartwig|first=John F.|publisher=University Science Books|year=2010|isbn=978-1-891389-53-5|location=USA|pages=717–734}}</ref>

Palladium-catalyzed intermolecular oxidations of [diene](/source/diene)s with carboxylic acids and alcohols as donors give [1,4-addition](/source/1%2C4-addition) products. In the case of cyclohexadiene (Figure 4, A), Backvall found that [stereochemical](/source/stereochemical) outcome of product was found to depend on concentration of LiCl.<ref>{{Cite journal|last1=Baeckvall|first1=Jan E.|last2=Bystroem|first2=Styrbjoern E.|last3=Nordberg|first3=Ruth E.|date=November 1984|title=Stereo- and regioselective palladium-catalyzed 1,4-diacetoxylation of 1,3-dienes|journal=The Journal of Organic Chemistry|volume=49|issue=24|pages=4619–4631|doi=10.1021/jo00198a010|issn=0022-3263}}</ref> This reaction proceeds by first generating the Pd(OAc)(benzoquinone)(allyl) complex, through anti-nucleopalladation of diene with acetate as nucleophile. The absence of LiCl induces an [inner sphere](/source/inner_sphere_electron_transfer) reductive elimination to afford the trans-acetate stereochemistry to give the trans-1,4-adduct. The presence of LiCl displaces acetate with chloride due to its higher binding affinity, which forces an outer sphere acetate attack anti to the palladium, and affords the cis-acetate stereochemistry to give the cis-1,4-adduct. Intramolecular oxidative cyclization: 2-(2-cyclohexenyl)phenol cyclizes to corresponding dihydro-benzofuran (Figure 4, B);<ref>{{Cite journal|last1=Hosokawa|first1=Takahiro|last2=Miyagi|first2=Shyogo|last3=Murahashi|first3=Shunichi|last4=Sonoda|first4=Akio|date=July 1978|title=Oxidative cyclization of 2-allylphenols by palladium(II) acetate. Changes in product distribution|journal=The Journal of Organic Chemistry|volume=43|issue=14|pages=2752–2757|doi=10.1021/jo00408a004|issn=0022-3263}}</ref> 1-cyclohexadiene-acetic acid in presence of acetic acid cyclizes to corresponding lactone-acetate 1,4 adduct (Figure 4, C),<ref>{{Cite journal|last1=Baeckvall|first1=Jan E.|last2=Granberg|first2=Kenneth L.|last3=Andersson|first3=Pher G.|last4=Gatti|first4=Roberto|last5=Gogoll|first5=Adolf|date=September 1993|title=Stereocontrolled lactonization reactions via palladium-catalyzed 1,4-addition to conjugated dienes|journal=The Journal of Organic Chemistry|volume=58|issue=20|pages=5445–5451|doi=10.1021/jo00072a029|issn=0022-3263}}</ref> with [cis](/source/Cis-alkene) and [trans](/source/Trans-alkene) selectivity controlled by LiCl presence.
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==== Nitrogen nucleophiles ====
{{See also|Ammoxidation}}
The oxidative [amination](/source/amination)s of olefins are generally conducted with [amide](/source/amide)s or [imide](/source/imide)s; [amine](/source/amine)s are thought to be [protonated](/source/Protonation) by the acidic medium or to bind the metal center too tightly to allow for the [catalytic](/source/Catalysis) chemistry to occur.<ref name=":1" /> These nitrogen nucleophiles are found to be competent in both intermolecular and intramolecular reactions, some examples are depicted (Figure 5, A,<ref>{{Cite journal|last1=Timokhin|first1=Vitaliy I.|last2=Stahl|first2=Shannon S.|date=December 2005|title=Brønsted Base-Modulated Regioselectivity in the Aerobic Oxidative Amination of Styrene Catalyzed by Palladium|journal=Journal of the American Chemical Society|volume=127|issue=50|pages=17888–17893|doi=10.1021/ja0562806|pmid=16351120|bibcode=2005JAChS.12717888T |issn=0002-7863}}</ref> B<ref>{{Cite journal|last1=Larock|first1=Richard C.|last2=Hightower|first2=Timothy R.|last3=Hasvold|first3=Lisa A.|last4=Peterson|first4=Karl P.|date=January 1996|title=Palladium(II)-Catalyzed Cyclization of Olefinic Tosylamides|journal=The Journal of Organic Chemistry|volume=61|issue=11|pages=3584–3585|doi=10.1021/jo952088i|pmid=11667199|issn=0022-3263}}</ref>)
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== Notes ==
<references group=Note/>

== References ==
{{reflist|2}}

{{Alkenes}}
{{Authority control}}

Category:Organic redox reactions
Category:Organometallic chemistry
Category:Homogeneous catalysis
Category:Acetylene
Category:Ethylene
Category:Palladium
Category:Name reactions

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Adapted from the Wikipedia article [Wacker process](https://en.wikipedia.org/wiki/Wacker_process) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Wacker_process?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.