Oppenauer oxidation, named after , is a gentle method for selectively

oxidizing Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...

secondary

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of se ...

s to

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bon ...

s. The reaction is the opposite

Meerwein–Ponndorf–Verley reduction The Meerwein–Ponndorf–Verley (MPV) reduction in organic chemistry is the reduction of ketones and aldehydes to their corresponding alcohols utilizing aluminium alkoxide catalysis in the presence of a sacrificial alcohol. The advantages of the ...

. The alcohol is oxidized with aluminium isopropoxide in excess

acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour. Acetone is miscible ...

. This shifts the equilibrium toward the product side. The

oxidation Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...

is highly selective for secondary alcohols and does not oxidize other sensitive functional groups such as

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

s and

sulfide Sulfide (British English also sulphide) is an inorganic anion of sulfur with the chemical formula S2− or a compound containing one or more S2− ions. Solutions of sulfide salts are corrosive. ''Sulfide'' also refers to chemical compounds lar ...

s. Though primary alcohols can be oxidized under Oppenauer conditions, primary alcohols are seldom oxidized by this method due to the competing

aldol condensation An aldol condensation is a condensation reaction in organic chemistry in which two carbonyl moieties (of aldehydes or ketones) react to form a β-hydroxyaldehyde or β-hydroxyketone (an aldol reaction), and this is then followed by dehydration to ...

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...

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

chromate Chromate or chromat, and their derived terms, may refer to: Chemistry * Chromate and dichromate, ions * Monochromate, an ion * Trichromate, an ion * Tetrachromate, an ion * Chromate conversion coating, a method for passivating metals Biology ...

s (e.g.

pyridinium chlorochromate Pyridinium chlorochromate (PCC) is a yellow-orange salt with the formula 5H5NHsup>+ rO3Clsup>−. It is a reagent in organic synthesis used primarily for oxidation of alcohols to form carbonyls. A variety of related compounds are known with simil ...

) or

dimethyl sulfoxide Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds ...

(e.g.

Swern oxidation The Swern oxidation, named after Daniel Swern, is a chemical reaction whereby a primary or secondary alcohol is oxidized to an aldehyde or ketone using oxalyl chloride, dimethyl sulfoxide (DMSO) and an organic base, such as triethylamine. It is ...

) or 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

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...

hormone A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...

alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar st ...

terpene Terpenes () are a class of natural products consisting of compounds with the formula (C5H8)n for n > 1. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predominantly by plants, particularly conifers. Terpenes a ...

s, etc.

Mechanism

: In the first step of this

mechanism Mechanism may refer to: * Mechanism (engineering), rigid bodies connected by joints in order to accomplish a desired force and/or motion transmission * Mechanism (biology), explaining how a feature is created * Mechanism (philosophy), a theory tha ...

, the alcohol (1) coordinates to the

aluminium Aluminium (aluminum in American and Canadian English) is a chemical element with the symbol Al and atomic number 13. Aluminium has a density lower than those of other common metals, at approximately one third that of steel. It ...

to form a complex (3), which then, in the second step, gets deprotonated by an

alkoxide In chemistry, an alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They are written as , where R is the organic substituent. Alkoxides are strong bases and, wh ...

ion (4) to generate an alkoxide intermediate (5). In the third step, both the oxidant acetone (7) and the substrate alcohol are bound to the aluminium. The acetone is coordinated to the aluminium which activates it for the

hydride In chemistry, a hydride is formally the anion of hydrogen( H−). The term is applied loosely. At one extreme, all compounds containing covalently bound H atoms are called hydrides: water (H2O) is a hydride of oxygen, ammonia is a hydride of ...

transfer from the alkoxide. The aluminium-catalyzed hydride shift from the α-carbon of the alcohol to the

carbonyl In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containing a ...

carbon of acetone proceeds over a six-membered

transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked wi ...

(8). The desired ketone (9) is formed after the hydride transfer.

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/

benzene Benzene is an organic chemical compound with the molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar ring with one hydrogen atom attached to each. Because it contains only carbon and hydrogen a ...

mixtures. Another advantage of the Oppenauer oxidation which makes it unique to other oxidation methods such as

(PCC) and Dess–Martin periodinane is that secondary alcohols are oxidized much faster than primary alcohols, thus

chemoselectivity Chemoselectivity is the preferential outcome of a chemical reaction over a set of possible alternative reactions. In another definition, chemoselectivity refers to the selective reactivity of one functional group in the presence of others; often ...

can be achieved. Furthermore, there is no over oxidation of

s to

carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

s as opposed to another oxidation methods such the

Jones oxidation The Jones oxidation is an organic reaction for the oxidation of primary and secondary alcohols to carboxylic acids and ketones, respectively. It is named after its discoverer, Sir Ewart Jones. The reaction was an early method for the oxidation of ...

Modifications

Wettstein-Oppenauer reaction

In the Wettstein-Oppenauer reaction, discovered by Wettstein in 1945, Δ 5–3β-hydroxy

s are oxidized to Δ 4,6-3-ketosteroids with

benzoquinone Benzoquinone (C6H4O2) is a quinone with a single benzene ring. There are 2 (out of 3 hypothetical) benzoquinones: * 1,4-Benzoquinone, most commonly, right image (also ''para''-benzoquinone, ''p''-benzoquinone, ''para''-quinone, or just quinone) * 1 ...

as the

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxi ...

acceptor. This reaction is useful in that it affords a one-step preparation of Δ 4,6-3-ketosteroids. :

Woodward modification

In the Woodward modification, Woodward substituted

potassium tert-butoxide Potassium ''tert''-butoxide is the chemical compound with the formula K+(CH3)3CO−. This colourless solid is a strong base (pKa of conjugate acid around 17), which is useful in organic synthesis. It exists as a tetrameric cubane-type cluster. ...

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

and

benzophenone Benzophenone is the organic compound with the formula (C6H5)2CO, generally abbreviated Ph2CO. It is a white solid that is soluble in organic solvents. Benzophenone is a widely used building block in organic chemistry, being the parent diarylket ...

for the oxidation of

quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal l ...

to quininone, as the traditional aluminium catalytic system failed to oxidize quinine due to the complex formed by coordination of the Lewis-basic

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at sevent ...

to the aluminium centre. :

Other modifications

Several modified aluminium alkoxide

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recy ...

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

carveol Carveol is a natural unsaturated, monocyclic monoterpenoid alcohol that is a constituent of spearmint essential oil in the form of ''cis''-(−)-carveol. It is a colorless fluid soluble in oils, but insoluble in water and has an odor and flavor th ...

carvone Carvone is a member of a family of chemicals called terpenoids. Carvone is found naturally in many essential oils, but is most abundant in the oils from seeds of caraway (''Carum carvi''), spearmint (''Mentha spicata''), and dill. Uses Both carvo ...

(a member of a family of chemicals called

terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeably with "terpenes ...

s) in excellent yield (94%). : In another modification the catalyst is

trimethylaluminium Trimethylaluminium is one of the simplest examples of an organoaluminium compound. Despite its name it has the formula Al2( CH3)6 (abbreviated as Al2Me6 or TMA), as it exists as a dimer. This colorless liquid is pyrophoric. It is an industriall ...

and the

3-nitrobenzaldehyde is used as the oxidant, for example, in the oxidation of

isoborneol Isoborneol is a bicyclic organic compound and a terpene derivative. The hydroxyl group in this compound is placed in an '' exo'' position. The endo diastereomer is called borneol. Being chiral, isoborneol exists as enantiomers. Preparation Isob ...

camphor Camphor () is a waxy, colorless solid with a strong aroma. It is classified as a terpenoid and a cyclic ketone. It is found in the wood of the camphor laurel (''Cinnamomum camphora''), a large evergreen tree found in East Asia; and in the ka ...

. :

Synthetic applications

The Oppenauer oxidation is used to prepare

analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...

s in the

pharmaceutical industry The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate symptoms. ...

such as

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a pain medication, and is also commonly used recreationally, or to make other illicit opioids. There ...

and

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically us ...

. For instance, codeinone is prepared by the Oppenauer oxidation of

. : The Oppenauer oxidation is also used to synthesize

hormones A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required fo ...

Progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the major ...

is prepared by the Oppenauer oxidation of

pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineralo ...

. : A slight variation of the Oppenauer oxidation is also used to synthesize

derivatives. For example, an efficient catalytic version of the Oppenauer oxidation which employs a

ruthenium Ruthenium is a chemical element with the symbol Ru and atomic number 44. It is a rare transition metal belonging to the platinum group of the periodic table. Like the other metals of the platinum group, ruthenium is inert to most other chemicals ...

catalyst has been developed for the oxidation of 5-unsaturated 3β-hydroxy

s to the corresponding 4-en-3-one derivative. : The Oppenauer oxidation is also used in the synthesis of

lactones Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the ...

from 1,4 and 1,5

diol A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol is also called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. The most common industrial diol i ...

s. :

Side reactions

A common side-reaction of the Oppenauer oxidation is the base-catalyzed

product, which have α-hydrogens to form either β-hydroxy

s or α, ß- unsaturated

s. : Another side

reaction Reaction may refer to a process or to a response to an action, event, or exposure: Physics and chemistry *Chemical reaction * Nuclear reaction *Reaction (physics), as defined by Newton's third law * Chain reaction (disambiguation). Biology and ...

is the Tischenko reaction of

products with no α-hydrogen, but this can be prevented by use of

anhydrous A substance is anhydrous if it contains no water. Many processes in chemistry can be impeded by the presence of water; therefore, it is important that water-free reagents and techniques are used. In practice, however, it is very difficult to achie ...

solvents. Another general side reaction is the migration of the double bond during the oxidation of

allylic alcohol Allyl alcohol (IUPAC name: prop-2-en-1-ol) is an organic compound with the structural formula . Like many alcohols, it is a water-soluble, colourless liquid. It is more toxic than typical small alcohols. Allyl alcohol is used as a raw material ...

substrates.

References

{{Reflist, 30em Organic oxidation reactions Name reactions