Cyclohexanone, Oppenauer oxidation

The Oppenauer Oxidation. When a ketone in the presence of base is used as the oxidizing agent (it is reduced to a secondary alcohol), the reaction is known as the Oppenauer oxidation. This is the reverse of the Meerwein-Ponndorf-Verley reaction (16-23), and the mechanism is also the reverse. The ketones most commonly used are acetone, butanone, and cyclohexanone. The most common base is aluminum r r/-butoxide. The chief advantage of the method is its high selectivity. Although the method is most often used for the... 

The reverse reaction is known as the Oppenauer oxidation. Here aluminium tri tertiary but oxide and an involatile ketone such as cyclohexanone are used to oxidise any secondary alcohol to the corresponding ketone. 

Not surprisingly, nowadays most Oppenauer oxidations are carried out employing cyclohexanone as oxidant because—for structural reasons— this ketone possesses an exceptionally high oxidation potential among ketones. Similarly, /V-methyI -4-pi peridone is used quite often because it possesses an oxidation potential close to cyclohexanone, while it is very easy to remove together with its reduction product from the reaction mixture by washing with aqueous acid.9... 

The Oppenauer oxidation of a ster-3-ol employing the strong oxidant p-quinone, instead of the more usual acetone, cyclohexanone or lV-methyl-4-piperidone, produces an over-oxidation resulting in the formation of a dienone, instead of the usual enone. 

Acetone in conjunction with benzene as a solvent is widely employed. Alternatively cyclohexanone as the hydrogen acceptor, coupled with toluene or xylene as solvent, permits the use of higher reaction temperatures and consequently the reaction time is considerably reduced the excess of cyclohexanone can be easily separated from the reaction product by steam distillation. Usually at least 0.25 mol of aluminium alkoxide per mol of secondary alcohol is employed. However, since an excess of alkoxide has no detrimental effect, the use of 1 to 3 mol of alkoxide is desirable, particularly as water, either present in the reagents or formed during secondary reactions, will remove an equivalent quantity of the reagent. It is recommended that 50 to 200 mol of acetone or 10 to 20 mol of cyclohexanone be employed. Other oxidisable groups are usually unaffected in the Oppenauer oxidation and the reaction has found wide application in the steroid field. 

The reaction between an aluminum alkoxide and a ketone can be reversed. This is the basis of the Oppenauer oxidation of a secondary alcohol to the ketone.44 8 The aluminum derivative of the alcohol is prepared by mOans of aluminum t-butoxide and is oxidized with a large excess of acetone or cyclohexanone. 

Catalytic Oppenauer oxidations (Eq. 28) and Meerwein-Ponndorf-Verley reductions (Eq. 29) were studied in detail [232,234]. The gadolinium derivative, employed in situ without elimination of LiCl, was reported to be ten times more reactive in the MPV reduction of cyclohexanone as the standard reagent Al(OiPr)3 [235]. 

A zirconium complex, bis(cyclopenta(Uenyl)zirconium(IV) hydride will function as a catalyst for the chemoselective Oppenauer oxidation of primary alcohols in the presence of a hydrogen acceptor (cyclohexanone, benzaldehyde or benzophenone). This method appears to be of some value, since it also allows for the selective monooxidation of primary (and secondary) diols (Scheme 3). 1,2-Diols are not cleaved under these conditions and retro-aldol reactions appear not to be a problem. 

Acetone, cyclohexanone, benzophenone, cinnamaldehyde, and other carbonyl compounds are hydrogen acceptors in the Oppenauer oxidation of alcohols to carbonyl compounds. The reaction is catalyzed by Raney nickel [961], aluminum alkoxides [962], tris(isopropoxide), or tris(tert-bu-toxide) as bases soluble in organic solvents [963, 964]. These dehydrogenations of alcohols to aldehydes and ketones require refluxing or distillations and have given way to dimethyl sulfoxide oxidations, which take place at room temperature. 

Zeolite titanium beta has been tested in the liquid- and gas-phase Meerwein-Ponndorf-Verley reduction of cyclohexanones and the Oppenauer oxidation of cyclohexanols. A high selectivity towards the thermodynamically unfavourable cis-alcohol was observed, which has been ascribed to transition-state selectivity in the pores of the zeolite. Under gas-phase conditions the dehydration of alcohols to cycloalkenes is observed as a side reaction. The catalyst was found to be active even in the presence of water and ammonia. 

Ring C was investigated through a-dihydrocaranone (LXX), prepared by the Oppenauer oxidation of a a-dihydrocaranine. The ketone showed carbonyl absorption at 5.87 p, characteristic of a cyclohexanone. A neutral by-product of the oxidation was shown to be LXXI, the isolation of which provided additional evidence for the 1-hydroxyl group of caranine. Finally, LXX formed an enol acetate in wMch the double bond was conjugated with the aromatic ring. 

The Meerwein-Ponndorf-Verley reduction of aldehydes and ketones and its reverse, the Oppenauer oxidation of alcohols, are hydrogen-transfer reactions that can be performed under mild conditions and without the risk of reducing or oxidizing other functional groups [1]. The hydrogen donors are easily oxidizable secondary alcohols (e. g. i-PrOH) and the oxidants are simple ketones (e. g. cyclohexanone). Industrial applications of the MPVO reactions are found in the fragrance and pharmaceutical industries, for example. 

Horner and Kaps have used chlorinated y-Al203 in combination with a small amount of Al(Oz-Pr)3 as the catalyst for the reduction of benzaldehyde, cyclohexanone, and acetophenone by z-PrOH [4]. In the absence of Al(Oi-Pr)3, no reaction occurred. The addition of a small amount of strong base was found to enhance the reaction rate. Analogous phenomena have been observed in the Oppenauer oxidation of several secondary alcohols. Strong bases presumably assist the deprotonation of alumina-surface co-ordinated i-PrOH, thereby forming the required alkoxide surface species. The modified alumina, which contained ca 85 mmol chloride/ 100 g alumina, was obtained by heating dry alumina in thionyl chloride for 24 h. The chloride at the surface increases the Lewis acidity of the aluminum ions and the addition of the base facilitates the deprotonation of z-PrOH. 

The most extensive application of the Oppenauer oxidation has been in the oxidation of steroid molecules. The most common aluminum catalysts are aluminum /-butoxide, i-propoxide, and phenoxide. While only catalytic amounts of the aluminum alkoxide are theoretically required, in practice at least 0.25 mole of alkoxide per mole of alcohol is used. Acetone and methyl ethyl ketone have proved valuable hydride acceptors due to their accessibility and ease of separation from the product, whereas other ketones such as cyclohexanone and p-benzoquinone are useful alternatives, due to their increased oxidation potentials.4 Although the reaction can be performed neat, an inert solvent to dilute the reaction mixture can reduce the extent of condensation, and, as such, benzene, toluene, and dioxane are commonly utilized. Oxidation of the substrate takes place at temperatures ranging from room temperature to reflux, with reaction times varying from fifteen minutes to twenty-four hours and yields ranging from 37% to 95%. 

The Oppenauer oxidation with aluminium alkoxides provides an alternative method for the oxidation of secondary (and less commonly primary) alcohols. The reaction is the reverse of the Meerwein-Pondorff-Verley reduction (see Section 7.3). Typically aluminium triisopropoxide (or aluminium tri-tert-butoxide) is used, which serves to form the aluminium alkoxide of the alcohol. This is then oxidized through a cyclic transition state at the expense of acetone (or cyclohexanone or other carbonyl compound). By use of excess acetone, the equilibrium is forced to the right (6.45). 

Hydromorphone (launched by Knoll in 1926 under the brand name Dilaudid with intended connotation to laudanum ) is more active than morphine, and is indicated for medium to severe pain. Hydromorphone can cause severe dependence. The starting material for its synthesis is morphine, which is first hydrogenated, and its alcohol ftmction is then submitted to an Oppenauer oxidation with cyclohexanone. 

Rathke and coworkers found that combining this bulky alkoxide again with trifluoroacetic acid leads to a highly efficient catalytic system for the Oppenauer oxidation. For instance, cyclohexanol could be oxidised, at 0 °C within a couple of minutes, to give cyclohexanone in 88% yield, in the presence of 5 mol% of aluminium tri-tert-butoxide activated with 2.5 mol% of trifluoroacetic acid as shown in Scheme 18.5. However, the control provided by this catalytic system in the MPV/Oppenauer reactions leaves some room for improvement and the aluminium-catalysed formation of side products via concurrent aldol reactions (Scheme 18.2) could be observed when enolisable substrates were used. ... 

Selective oxidation of allylic alcohols.1 This zircononcene complex when used in catalytic amount can effect an Oppenauer-type oxidation of alcohols, including allylic ones, in the presence of a hydrogen acceptor, usually benzaldehyde or cyclohexanone. This system oxidizes primary alcohols selectively in the presence of secondary ones. Thus primary allylic alcohols are oxidized to the enals with retention of the configuration of the double bond in 75-95% yield. The method is not useful for oxidation of propargylic alcohols. 

This alcohol is oxidized using an Oppenauer reaction under typical conditions with aluminium isopropoxide and cyclohexanone in boiling toluene. 

The Meerwein-Ponndorf-Verley reduction is a reversible reaction and the reverse pathway was reported in detail a couple of years later by Oppenauer who selectively oxidised hydroxyl functions into ketones or aldehydes with the help of acetone or cyclohexanone as proton quencher (oxidant) and aluminium tert-butoxide as catalyst (other common oxidants are acetaldehyde, anisaldehyde, benzaldehyde, benzophenone and cinnamalde-hyde). This mild oxidation method was in many cases used in the synthesis of steroids and terpenoids. 

A review describes the asymmetric epoxidation of allylic alcohols,369 another the role of metal oporphyrins in oxidation reactions.370 jhe TiiOPrMi, catalysed self-epoxidation of allylic peroxides proceeds via an intermolecular mechanism.371 Racemic allyl alcohols can be resolved by asymmetric epoxidation (eq.35).372 a Pd(II)/Mn02/benzoquinone system catalyses the oxidative ring-closure of 1,5-hexadienes (eq.36).373 propenyl phenols are oxidatively degraded to aryl aldehydes and MeCHO in the presence of Co Schiff-base catalysts.374 An Oppenauer-type oxidation with Cp2ZrH2/cyclohexanone converts primary alcohols selectively into aldehydes.375 co macrocycles catalyse the oxidation of aryl liydrazones to diazo compounds in high yields.376 similar Co complexes under CO oxidise primary amines to azo compounds.377 Arene Os complexes in the presence of base convert aldehydes and water slowly into carboxylic acids and H2.378... 

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