Oxidation of Alcohol to Aldehyde and Ketone

Chromium-based reagent

• Jones Reagent• Sarett and Collins reagent

(Cr03.2Py)• PDC (Piridium dichromate)• PCC (Pyridium chlorocromate)

ativated Dimethyl Sulfoxide• Pfitzner–Moffatt Oxidation

(Dicyclohexilcarbodiimide/ DCC) + DMSO• Albright Goldman Oxidation

(Acetic anhydride+DMSO)• Albright Onodera Oxidation (P205 + DMSO)• Parikh Doering Oxidation (SO3.Py)• Omura sharma swern Oxidation (TFFA + DMSO)• Swern Oxidation (Oxalyl chloride)• Corey Kim Oxidation

Hypervalent Iodine Compound

• Iodine compound in a high valence state behave as a strong oxidant.

• (-): lack of solubility and poor solubility in organic solvent.

• Dess Martin Periodinane• IBX

Ruthenium-based Oxidations

• Ruthenium tetraoxide, (RuO4) - milder oxidant (Ru +8, +7, atau +6)

• TPAP (tetra-n-poluamonium perruthenante)

Oxidations Mediated by TEMPO and Related Stable Nitroxide

Radicals (Anelli Oxidation)

• TEMPO (54)

Oxidations by Hydride Transfer from a Metallic Alkoxide

• Oppenauer Oxidation,

• Mukaiyama Oxidation– ADD as oxidant with – magnesium alkoxide as catalyst

Oppenauer Oxidation

From Book. Strategic Applications of Named Reaction in Organic Synthesis

By. Barbara Czako and Laszlo Kurti

• The oxidation of primary and secondary alcohols with ketones in the presence of metal alkoxides (e.g.,aluminum isopropoxide) to the corresponding aldehydes and ketones is known as the Oppenauer oxidation

• In 1937, R.V. Oppenauer oxidized steroids with secondary alcohol functionality to the corresponding ketones using acetone in benzene in the presence of catalytic amounts of aluminum tert-butoxide.

• This oxidation proved to be high yielding and superior to other existing oxidation methods due to its mildness.

• Oppenauer's method came more than a decade after three researchers independently described reduction of carbonyl compounds with the use of aluminum alkoxides:

• 1) in 1925, H. Meerwein successfully reduced aldehydes with ethanol in the presence of aluminum ethoxide

• 2) during the same year A. Verley reduced ketones with aluminum ethoxide as well as aluminum isopropoxide but found that sterically hindered ketones (e.g., camphor) reacted very slowly and

• 3) in 1926, W. Ponndorf demonstrated that the reduction of aldehydes and ketones was general for a variety of metal alkoxides (e.g., alkali metal and aluminum alkoxides) derived from secondary alcohols, and he found the process completely reversible.

The general features of the Oppenauer oxidation

1. The reaction is completely reversible and can be driven to completion according to Le Chatelier's principle by adding large excess of the ketone (e.g., acetone) to the reaction mixture;

2. The reaction conditions are mild, since the substrates are usually heated in acetone/benzene mixtures;

3. Most functional groups are tolerated (alkenes, alkynes, esters, amides, etc.), but if the substrate contains basic nitrogen atoms, the use of alkali metal alkoxides is necessary in place of aluminum alkoxides;

4. in order to achieve reasonable reaction rates, stoichiometric amounts of the aluminum alkoxide needs to be used;

5. most commonly aluminum isopropoxide, t-butoxide, and phenoxide are used;

6. a wide range of primary and secondary alcohols are oxidized under the reaction conditions ( secondary alcohols are oxidized much faster than primary alcohols, so complete chemoselectivity can be achieved (this feature makes the Oppenauer oxidation unique compared to other oxidations);

7. overoxidation of aldehydes to carboxylic acids never happens;

8. the oxidation of 1,4- and 1,5-diols usually yields lactones.

9. acetone is used most often as the oxidant, but aromatic and aliphatic aldehydes are suitable as oxidants due to their low reduction potentials;

10. addition of protic acids dramatically increases the rate of oxidation; and 11. the oxidation can be conducted using heterogeneous catalysts (e.g.,alumina,

zeolites), which has one great advantage over the traditional homogeneous variant: the catalyst can be easily separated from the reaction mixture.

The most important side reactions are: 1) aldol condensation of aldehyde products, which have an α-hydrogen atom to

form β-hydroxy aldehydes and/or α,β-unsaturated aldehydes, but with ketones this side reaction is not common;

2) Tishchenko reaction of aldehyde products with no α-hydrogen atom, but this can be suppressed by the use of anhydrous solvents; and

3) the migration of the double bond during the oxidation of allylic and homoallylic alcohol substrates.

Persamaan Reaksi dan Mekanisme

• The mechanism of this Oppenauer oxidation• reaction involves conversion of the alcohol • (R2CHOH) to be oxidized into an alkoxide

species (R2CHO-) that transfers a hydride ion • to acetone. As a result, acetone is reduced

and the alkoxide ion becomes a carbonyl compound

ApplicationP. Kocovsky, Tetrahedron Letter. 1993, 34, 6139-6140

Oxidant : 1-metil, 4-piperidone

HN O

Tetrasiklik diol enone

Sternbach, D.D. Ensinger, C.L. Synthesis of polyquinanes. J. Org. Chem. 1990, 55, 2725-2736

Intramoleculer Diels-Alder approach (in situ) cyclopentadiene ring and , -unsaturated ketone

Shing, T.K.M, Lee., C,M, Lo, H.Y. Synthesis of the CD ring in taxol from (S)-Carvone. Tetrahedron Lett. 2001, 42. 8361-8363.

(S)- CarvoneBicyclic -hydroxy ketone

Isomerized by an intramolecular redox reaction

Modification Oppenauer OxidationHeathcock, C.H., Kleinman, E.F., Binkley, E.S. Total synthesis of licopodium alcaloids. J. Am. Chem.Soc 1982, 104, 1054-1068

Primary alcohol

N-dealkilated tricyclic amino ketone)

Aldol condensation

Tricyclic enone

Side reaction

TERIMA KASIH

15 Ponndorf (Meerwein-Verley) reduction

•Reduction of ketones/aldehydes to alcohols•The reverse reaction is known as the Oppenauer oxidation

R R'

O

R R'

OH(iPrO)3Al

H2O

• asas Le Chatelier sebagai berikut: Bila pada sistem kesetimbangan diadakan aksi, maka sistem akan mengadakan reaksi sedemikian rupa sehingga pengaruh aksi itu menjadi sekecil-kecilnya

• Nucleophilic addition to C=X and activated C=C multiple bonds (e.g., Michael Reaction). These reactions also work best when a reasonably stabilized anion is being formed. The reverse reaction (retro-Michael) occurs readily if the nucleophile was a stabilized anion.

• From reducing metals• Alkoxides can be produced by several routes starting from an alcohol. Highly

reducing metals react directly with alcohols to give the corresponding metal alkoxide. The alcohol serves as an acid, and hydrogen is produced as a by-product. A classic case is sodium methoxide produced by the addition of sodium metal to methanol:

• 2CH3OH + 2Na → 2CH3ONa + H2 Other alkali metals can be used in place of sodium, and most alcohols can be used in place of methanol.

• From electrophilic chlorides• The tetrachloride of titanium reacts with alcohols to give the corresponding

tetraalkoxides, concomitant with the evolution of hydrogen chloride:• TiCl4 + 4 (CH3)2CHOH → Ti(OCH(CH3)2)4 + 4 HCl The reaction can be accelerated

by the addition of a base, such as a tertiary amine. Many other metal and main group halides can be used instead of titanium, for example SiCl4, ZrCl4, and PCl3.

• By metathesis reactions• Many alkoxides are prepared by salt-forming reactions from a metal chloride

and sodium alkoxide:• n NaOR + MCln → M(OR)n + n NaCl Such reactions are favored by the

lattice energy of the NaCl, and purification of the product alkoxide is simplified by the fact that NaCl is insoluble in common organic solvents.

• By electrochemical processes• Many alkoxides can be prepared by anodic dissolution of the corresponding

metals in water-free alcohols in the presence of electroconductive additive. The metals may be Co, Ga, Ge, Hf, Fe, Ni, Nb, Mo, La, Re, Sc, Si, Ti, Ta, W, Y, Zr, etc. The conductive additive may be lithium chloride, quaternary ammonium halide, or other. Some examples of metal alkoxides obtained by this technique: Ti(OC3H7-iso)4, Nb2(OCH3)10, Ta2(OCH3)10, [MoO(OCH3)4]2, Re2O3(OCH3)6, Re4O6(OCH3)12, and Re4O6(OC3H7-iso).

• Metal alkoxides hydrolyse with water according to the following equation:[3]

• 2 LnMOR + H2O → [LnM]2O + 2 ROH where R is an organic substituent and L is an unspecified ligand (often an alkoxide) A well-studied case is the irreversible hydrolysis of titanium ethoxide:

• 1/n [Ti(OCH2CH3)4]n + 2 H2O → TiO2 + 4 HOCH2CH3 By controlling the stoichiometry and steric properties of the alkoxide, such reactions can be arrested leading to metal-oxy-alkoxides, which usually are oligonuclear complexes. Other alcohols can be employed in place of water. In this way one alkoxide can be converted to another, and the process is properly referred to as alcoholysis (unfortunately, there is an issue of terminology confusion with transesterification, a different process - see below). The position of the equilibrium can be controlled by the acidity of the alcohol; for example phenols typically react with alkoxides to release alcohols, giving the corresponding phenoxide. More simply, the alcoholysis can be controlled by selectively evaporating the more volatile component. In this way, ethoxides can be converted to butoxides, since ethanol (b.p. 78 °C) is more volatile than butanol (b.p. 118 °C).

• In the transesterification process, metal alkoxides react with esters to bring about an exchange of alkyl groups between metal alkoxide and ester. With the metal alkoxide complex in focus, the result is the same as for alcoholysis, namely the replacement of alkoxide ligands, but at the same time the alkyl groups of the ester are changed, which can also be the primary goal of the reaction. Sodium methoxide, for example, is commonly used for this purpose, a reaction that is relevant to the production of "bio-diesel."

• Formation of oxo-alkoxides• Many metal alkoxide compounds also feature oxo-ligands. Oxo-ligands typically arise via the hydrolysis, often

accidentally, and via ether elimination:• 2 LnMOR → [LnM]2O + R2O Additionally, low valent metal alkoxides are susceptible to oxidation by air .

• name molecular formula comment Titanium isopropoxide Ti(O-i-Pr)4 monomeric because of steric bulk, used in organic synthesis Titanium ethoxide Ti4(OEt)16 for sol-gel processing of Ti oxides Zirconium ethoxide Zr4(OEt)16 for sol-gel processing of Zr oxides Tetraethyl orthosilicate Si(OEt)4 for sol-gel processing of Si oxides; Si(OMe)4 is avoided for safety reasons Aluminium isopropoxide Al4(O-i-Pr)12 reagent for Meerwein–Ponndorf–Verley reduction Niobium ethoxide Nb2(OEt)10 for sol-gel processing of Nb oxides Tantalum ethoxide Ta2(OEt)10 for sol-gel processing of Ta oxides Potassium tert-butoxide, K4(O-t-Bu)4 basic reagent for organic elimination reactions