View source for Chemistry:Oppenauer oxidation

{{Reactionbox
|Name = Oppenauer oxidation
|Type = Organic redox reaction
|NamedAfter = Rupert Viktor Oppenauer
|Section3 = {{Reactionbox Identifiers
|OrganicChemistryNamed = oppenauer-oxidation
|RSC_ontology_id = 0000047
}}
}}
'''Oppenauer oxidation''', named after {{ill|Rupert Viktor Oppenauer|de|Rupert Viktor Oppenauer}},<ref>{{cite journal|last = Oppenauer |first = R. V.|title = Eine Methode der Dehydrierung von Sekundären Alkoholen zu Ketonen. I. Zur Herstellung von Sterinketonen und Sexualhormonen|language = German|trans-title = Dehydration of secondary alcohols to ketones. I. Preparation of sterol ketones and sex hormones|journal = Recl. Trav. Chim. Pays-Bas|year = 1937|volume = 56|issue = 2|pages = 137–144|doi = 10.1002/recl.19370560206}}</ref> is a gentle method for selectively oxidizing secondary [[Chemistry:Alcohol|alcohol]]s to [[Chemistry:Ketone|ketone]]s.

[[Image:Oppenauer oxidation reaction scheme.png|624px|center|Oppenauer oxidation reaction scheme]]

The reaction is the opposite [[Chemistry:Meerwein–Ponndorf–Verley reduction|Meerwein–Ponndorf–Verley reduction]].<ref name = MPV-review>{{cite journal|last = Wilds|first = A. L.|year = 1944|journal = Org. React.|volume = 2|issue = 5|pages = 178–223|title = Reduction with Aluminum Alkoxides (The Meerwein-Ponndorf-Verley Reduction)|doi = 10.1002/0471264180.or002.05}}</ref> The alcohol is oxidized with [[Chemistry:Aluminium isopropoxide|aluminium isopropoxide]] in excess [[Chemistry:Acetone|acetone]]. This shifts the [[Chemistry:Chemical equilibrium|equilibrium]] toward the product side.

The oxidation is highly selective for secondary alcohols and does not oxidize other sensitive functional groups such as [[Chemistry:Amine|amine]]s and [[Chemistry:Sulfide|sulfide]]s.<ref name="sensitive functional groups">{{cite journal |author1=Otvos, L. |author2=Gruber, L. |author3=Meisel-Agoston, J. | journal = Acta Chim. Acad. Sci. Hung. | year = 1965 | volume = 43 | pages = 149–153| title = The Meerwein-Ponndorf-Verley-Oppenauer. Investigation of the reaction mechanism with radiocarbon. Racemization of secondary alcohols}}</ref> Though primary alcohols can be oxidized under Oppenauer conditions, primary alcohols are seldom oxidized by this method due to the competing [[Chemistry:Aldol condensation|aldol condensation]] of [[Chemistry:Aldehyde|aldehyde]] products. The Oppenauer oxidation is still used for the oxidation of acid labile substrates. The method has been largely displaced by oxidation methods based on [[Chemistry:Chromate ion|chromate]]s (e.g. [[Chemistry:Pyridinium chlorochromate|pyridinium chlorochromate]]) or [[Chemistry:Dimethyl sulfoxide|dimethyl sulfoxide]] (e.g. [[Chemistry:Swern oxidation|Swern oxidation]]) or [[Chemistry:Dess–Martin oxidation|Dess–Martin oxidation]] due to its use of relatively mild and non-toxic reagents (e.g. the reaction is run in acetone/benzene mixtures). The Oppenauer oxidation is commonly used in various industrial processes such as the synthesis of [[Biology:Steroid|steroid]]s, [[Biology:Hormone|hormone]]s, [[Chemistry:Alkaloid|alkaloid]]s, [[Biology:Terpene|terpene]]s, etc.

==Mechanism==
:[[Image:oppenauer oxidation mechanism layout.png|600px|centre |Oppenauer oxidation mechanism]]

In the first step of this [[Physics:Reaction mechanism|mechanism]], the alcohol (1) coordinates to the [[Chemistry:Aluminium|aluminium]] to form a complex (3), which then, in the second step, gets deprotonated by an [[Chemistry:Alkoxide|alkoxide]] ion (4) to generate an alkoxide [[Chemistry:Reaction intermediate|intermediate]] (5). In the third step, both the oxidant acetone (7) and the [[Chemistry:Substrate|substrate]] alcohol are bound to the aluminium. The acetone is coordinated to the aluminium which activates it for the [[Physics:Hydride|hydride]] transfer from the alkoxide. The aluminium-catalyzed hydride shift from the α-carbon of the alcohol to the carbonyl carbon of acetone proceeds over a six-membered [[Chemistry:Transition state|transition state]] (8). The desired ketone (9) is formed after the hydride transfer.<ref name="Corey 2005">{{cite book| title=Strategic Applications of Named Reactions in Organic Synthesis| isbn=978-7-03-019190-8| year=2005| publisher=Elsevier | first=E.J| last=Corey |author2=Nicolaou, K.C.  }}</ref>

==Advantages==
An advantage of the Oppenauer oxidation is its use of relatively inexpensive and non-toxic reagents. Reaction conditions are mild and gentle since the substrates are generally heated in acetone/[[Chemistry:Benzene|benzene]] mixtures. Another advantage of the Oppenauer oxidation which makes it unique to other oxidation methods such as [[Chemistry:Pyridinium chlorochromate|pyridinium chlorochromate]] (PCC) and [[Chemistry:Dess–Martin periodinane|Dess–Martin periodinane]] is that secondary alcohols are oxidized much faster than primary alcohols, thus [[Chemistry:Chemoselectivity|chemoselectivity]] can be achieved. Furthermore, there is no over oxidation of [[Chemistry:Aldehyde|aldehyde]]s to [[Chemistry:Carboxylic acid|carboxylic acid]]s as opposed to another oxidation methods such the [[Chemistry:Jones oxidation|Jones oxidation]].<ref name="Corey 2005"/>

==Modifications==
===Wettstein-Oppenauer reaction===
In the Wettstein-Oppenauer reaction, discovered by Wettstein in 1945, Δ 5–3β-hydroxy [[Biology:Steroid|steroid]]s are oxidized to Δ 4,6-3-ketosteroids with benzoquinone as the [[Chemistry:Hydrogen|hydrogen]] acceptor. This reaction is useful in that it affords a one-step preparation of Δ 4,6-3-ketosteroids.<ref name="Wettstein-Oppenauer">{{cite journal | author = Mandell, L. | journal = J. Am. Chem. Soc. | year = 1955 | volume = 78 | issue = 13 | pages = 3199–3201 | doi = 10.1021/ja01594a061 | title = The Mechanism of the Wettstein-Oppenauer Oxidation}}</ref>

:[[Image:wettstein oppenauer reaction.png|500px|center|Wettstein-Oppenauer reaction]]

===Woodward modification===
In the Woodward modification, Woodward substituted [[Chemistry:Potassium tert-butoxide|potassium tert-butoxide]] for the aluminium alkoxide. The Woodward modification of the Oppenauer oxidation, also called the '''Oppenauer–Woodward oxidation''', is used when certain alcohol groups do not oxidize under the standard Oppenauer reaction conditions. For example, Woodward used [[Chemistry:Potassium tert-butoxide|potassium tert-butoxide]] and [[Chemistry:Benzophenone|benzophenone]] for the oxidation of [[Chemistry:Quinine|quinine]] to quininone, as the traditional aluminium catalytic system failed to oxidize quinine due to the complex formed by coordination of the Lewis-basic [[Chemistry:Nitrogen|nitrogen]] to the aluminium centre.<ref name="Woodward">{{cite journal | doi=10.1021/ja01225a001 | journal = J. Am. Chem. Soc. | year = 1945 | volume = 67 | issue = 9 | pages = 1425| title = Quininone1 | last1 = Woodward | first1 = R. B. | last2 = Wendler | first2 = N. L. | last3 = Brutschy | first3 = F. J. }}</ref>

:[[Image:woodward modification.png|500px|center|Woodward modication]]

=== Other modifications ===
Several modified aluminium alkoxide [[Chemistry:Catalyst|catalyst]]s have been also reported. For example, a highly active aluminium catalyst was reported by Maruoka and co-workers which was utilized in the oxidation of [[Chemistry:Carveol|carveol]] to [[Chemistry:Carvone|carvone]] (a member of a family of chemicals called [[Biology:Terpenoid|terpenoid]]s) in excellent yield (94%).<ref name="carvone">{{Cite journal| pmid = 12153205|doi=10.1021/ol020094c| year = 2002| last1 = Ooi| first1 = T.| title = Practical Oppenauer (OPP) oxidation of alcohols with a modified aluminum catalyst| journal = [[Chemistry:Organic Letters|Organic Letters]]| volume = 4| issue = 16| pages = 2669–72| last2 = Otsuka| first2 = H.| last3 = Miura| first3 = T.| last4 = Ichikawa| first4 = H.| last5 = Maruoka| first5 = K.}}</ref>

:[[Image:other modification 1.png|500px|center|An Oppenauer oxidation modication]]

In another modification<ref>{{Cite journal | doi = 10.1021/ja063842s| pmid = 17002323| title = Efficient and Selective Al-Catalyzed Alcohol Oxidation via Oppenauer Chemistry| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]| volume = 128| issue = 39| pages = 12596–7| year = 2006| last1 = Graves | first1 = C. R. | last2 = Zeng | first2 = B. S. | last3 = Nguyen | first3 = S. T.}}</ref> the catalyst is [[Chemistry:Trimethylaluminium|trimethylaluminium]] and the [[Chemistry:Aldehyde|aldehyde]] 3-nitrobenzaldehyde is used as the oxidant, for example, in the oxidation of [[Chemistry:Isoborneol|isoborneol]] to [[Chemistry:Camphor|camphor]].

:[[Image:other modification 2.png|500px|center|An Oppenauer oxidation modification]]

==Synthetic applications==
The Oppenauer oxidation is used to prepare [[Biology:Analgesic|analgesic]]s in the [[Medicine:Pharmaceutical industry|pharmaceutical industry]] such as [[Biology:Morphine|morphine]] and [[Chemistry:Codeine|codeine]]. For instance, [[Chemistry:Codeinone|codeinone]] is prepared by the Oppenauer oxidation of [[Chemistry:Codeine|codeine]].<ref name="Codeine">{{cite journal |author1=Stéphane Caron |author2=Robert W. Dugger |author3=Sally Gut Ruggeri |author4=John A. Ragan |author5=David H. Brown Ripin  |name-list-style=amp | journal = [[Chemistry:Chem. Rev.|Chem. Rev.]] | year = 2006 | volume = 106 | issue = 7 | pages = 2943–89 | doi =  10.1021/cr040679f | title = Large-Scale Oxidations in the Pharmaceutical Industry | pmid=16836305}}</ref>

:[[Image:codeine syn.png|450px|center|An Oppenauer oxidation of codeine]]

The Oppenauer oxidation is also used to synthesize hormones. [[Chemistry:Progesterone|Progesterone]] is prepared by the Oppenauer oxidation of [[Chemistry:Pregnenolone|pregnenolone]].<ref>{{cite book| title= Medicinal Natural Products: A Biosynthetic Approach | edition= 2nd |isbn=0471496405 | year=2001| publisher= Wiley & Sons| first=P| last=Dewick| page =243}}</ref>

:[[Image:Pregnenolone syn.png|450px|center|An Oppenauer oxidation of pregnenolone]]

A slight variation of the Oppenauer oxidation is also used to synthesize [[Biology:Steroid|steroid]] derivatives. For example, an efficient catalytic version of the Oppenauer oxidation which employs a [[Chemistry:Ruthenium|ruthenium]] catalyst has been developed for the oxidation of 5-unsaturated 3β-hydroxy [[Biology:Steroid|steroid]]s to the corresponding 4-en-3-one derivative.<ref name="Rubidium Modification">{{cite journal | first1= Maria L.S. |last1= Almeida |first2= Paval |last2= Kočovský |first3= Jan-E. |last3= Bäckvall | journal = J. Org. Chem. | year = 1996 | volume = 61 |issue= 19 | pages = 6587–6590 | doi = 10.1021/jo960361q | title = Ruthenium-Catalyzed Oppenauer-Type Oxidation of 3β-Hydroxy Steroids. A Highly Efficient Entry into the Steroidal Hormones with 4-En-3-one Functionality|pmid= 11667525}}</ref>

:[[Image:steroid.png|450px|center|An Oppenauer oxidation of pregnenolone]]

The Oppenauer oxidation is also used in the synthesis of lactones from 1,4 and 1,5 [[Chemistry:Diol|diol]]s.<ref name="Synthesis of Lactone">{{cite journal | last1=Eignerova | first1=L. | last2=Kasal | first2=A. | year=1976 | title = Intramolecular hydride shift in Oppenauer oxidation of some dihydroxy steroids | journal = [[Chemistry:ChemPlusChem|ChemPlusChem]] | volume=41 | issue=4 | pages=1056–1065 | doi=10.1135/cccc19761056}}</ref>

:[[Image:lactone.png|450px|center|An Oppenauer oxidation of diol]]

==Side reactions==
A common side-reaction of the Oppenauer oxidation is the [[Chemistry:Base|base]]-catalyzed [[Chemistry:Aldol condensation|aldol condensation]] of [[Chemistry:Aldehyde|aldehyde]] product, which have α-hydrogens to form either β-hydroxy [[Chemistry:Aldehyde|aldehyde]]s or α, ß-[[Chemistry:Saturated and unsaturated compounds|unsaturated]] [[Chemistry:Aldehyde|aldehyde]]s.<ref name="Aldol condensation">{{Cite journal | doi = 10.1021/ja01183a522| title = The Synthesis of 1-[cyclohexen-1'-yl]-3-Methyl-1,3,5-Octatrien-7-One (C<sub>15</sub>Ketone)<sup>1</sup>| journal = [[Organization:Journal of the American Chemical Society|Journal of the American Chemical Society]]| volume = 70| issue = 3| pages = 1292| year = 1948| last1 = Milas | first1 = N. A. | last2 = Grossi | first2 = F. X. | last3 = Penner | first3 = S. E. | last4 = Kahn | first4 = S. }}</ref> 

:[[Image:aldol condensation.png|550px|center|An Oppenauer oxidation of aldehyde]]

Another side [[Chemistry:Chemical reaction|reaction]] is the Tischenko reaction of [[Chemistry:Aldehyde|aldehyde]] products with no α-hydrogen, but this can be prevented by use of [[Chemistry:Anhydrous|anhydrous]] solvents.<ref name="Corey 2005"/> Another general side reaction is the migration of the double bond during the oxidation of allylic alcohol substrates.<ref name="migration of double bond">{{Cite journal | doi = 10.1080/00397917208061988| title = Oppenauer Oxidations Using 1-Methyl-4-Piperidone as the Hydride Acceptor| journal = [[Chemistry:Synthetic Communications|Synthetic Communications]]| volume = 2| issue = 5| pages = 323| year = 1972| last1 = Reich | first1 = R. | last2 = Keana | first2 = J. F. W. }}</ref>

[[Image:Wiki-oppenaure-mxa2.tif|350px|center|Oppenauer oxidation of a steroid derivative.<ref>{{cite journal|journal= Synthetic Communications |volume=2|issue=5|year=1972|pages= 323–325|doi=10.1080/00397917208061988|title=Oppenauer Oxidations Using 1-Methyl-4-Piperidone as the Hydride Acceptor|last1=Reich|first1=Richard|last2=Keana|first2=John F. W.}}</ref>]]

==See also==
* [[Chemistry:Alcohol oxidation|Alcohol oxidation]]
* [[Chemistry:Pyridinium chlorochromate|Pyridinium chlorochromate]]
* [[Chemistry:Jones oxidation|Jones oxidation]]
* [[Chemistry:Pfitzner–Moffatt oxidation|Pfitzner–Moffatt oxidation]]
* [[Chemistry:Parikh–Doering oxidation|Parikh–Doering oxidation]]
* [[Chemistry:Albright-Goldman oxidation|Albright-Goldman oxidation]]
* [[Chemistry:Swern oxidation|Swern oxidation]]
* [[Chemistry:Corey–Kim oxidation|Corey–Kim oxidation]]
* [[Chemistry:Dess–Martin periodinane|Dess–Martin periodinane]] oxidation
* [[Chemistry:Ley oxidation|Ley oxidation]] ([[Chemistry:Tetrapropylammonium perruthenate|TPAP]] oxidation)
* [[Chemistry:TEMPO|TEMPO]] oxidation

==References==
{{Reflist|30em}}

[[Category:Organic oxidation reactions]]
[[Category:Name reactions]]

{{Sourceattribution|Oppenauer oxidation}}