Swern oxidationFrom Wikipedia, the free encyclopedia

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.[1][2][3] The reaction is known for its mild character and wide tolerance of functional groups.[4][5][6][7]

The by-products are dimethyl sulfide (Me2S), carbon monoxide (CO), carbon dioxide (CO2) and — when triethylamine is used as base — triethylammonium chloride (Et3NHCl). Two of the by-products, dimethyl sulfide and carbon monoxide, are very toxic volatile compounds, so the reaction and the work-up needs to be performed in a fume hood. Dimethyl sulfide is a volatile liquid (B.P. 37 °C) with an extremely unpleasant odour.

Several reviews have been published.[8][9][10]

Contents  [hide] 

1 Mechanism

2 Variations

3 Considerations

4 See also

5 References

6 External links

Mechanism[edit]

The first step of the Swern oxidation is the low-temperature reaction of dimethyl sulfoxide (DMSO), 1a, formally as resonance contributor 1b, with oxalyl chloride, 2. The first intermediate, 3, quickly decomposes giving off CO2 and CO and producing dimethylchlorosulfonium chloride, 4.

After addition of the alcohol 5, the dimethylchlorosulfonium chloride 4 reacts with the alcohol to give the key alkoxysulfonium ion intermediate, 6. The addition of at least 2 equivalents of base — typically triethylamine — will deprotonate the alkoxysulfonium ion to give the sulfur ylide 7. In a five-membered ring transition state, the sulfur ylide 7decomposes to give dimethyl sulfide and the desired ketone (or aldehyde) 8.

Variations[edit]

When using oxalyl chloride as the dehydration agent, the reaction must be kept colder than −60 °C to avoid side reactions. With cyanuric chloride [11]  or trifluoroacetic anhydrideinstead of oxalyl chloride, the reaction can be warmed to −30 °C without side reactions. Other methods for the activation of DMSO to initiate the formation of the key intermediate 6are the use of carbodiimides (Pfitzner–Moffatt oxidation) and pyridine-sulfur trioxide complex (Parikh-Doering oxidation). The intermediate 4 can also be prepared from dimethyl sulfide and N - chlorosuccinimide (the Corey-Kim oxidation).

In some cases, the use of triethylamine as the base can lead to epimerisation at the carbon alpha to the newly formed carbonyl. Using the bulkier base diisopropylethylamine(iPr2NEt, Hünig's base) can mitigate this side reaction.

Considerations[edit]

Dimethyl sulfide, a byproduct of the Swern oxidation, is one of the most foul odors known in organic chemistry. Human olfactory glands can detect this compound in concentrations as low as 0.02 to 0.1 parts per million.[12] A simple remedy for this problem is to rinse used glassware with bleach (usually containing sodium hypochlorite), which will oxidize the dimethyl sulfide, eliminating the smell.

The reaction conditions allow oxidation of acid-sensitive compounds, which might decompose under the acidic conditions of a traditional method such as Jones oxidation. For example, in Thompson & Heathcock's synthesis of the sesquiterpene isovelleral,[13] the final step uses the Swern protocol, avoiding rearrangement of the acid-sensitive cyclopropanemethanol moiety.

Swern Oxidation

The Swern Oxidation of alcohols avoids the use of toxic metals such as chromium, and can be carried out under very mild conditions. This reaction allows the preparation of aldehydes and ketones from primary and secondary alcohols, resp. . Aldehydes do not react further to give carboxylic acids. A drawback is the production of the malodorous side product dimethyl sulphide.

Mechanism of the Swern Oxidation

Dimethylchlorosulphonium ion is generated in situ from DMSO and oxalyl chloride.

The reaction with an alcohol at -78°C leads to an alkoxysulphonium ion:

Deprotonation of this intermediate gives a sulphur ylide, which undergoes intramolecular deprotonation via a five-membered ring transition state and fragmentation to yield the product and DMS (odour!):

If the temperature is not kept near -78°C, mixed thioacetals may result:

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Recent Literature

New odorless method for the Corey–Kim and Swern oxidations utilizing dodecyl methyl sulfide (Dod-S-Me)S.-I. Ohsugia, K. Nishidea, K. Oonob, K. Okuyamab, M. Fudesakaa, S. Kodamaa, M. Node, Tetrahedron, 2003, 59, 8393-8398.

The fluorous Swern and Corey-Kim reaction: scope and mechanismD. Crich, S. Neelamkavil, Tetrahedron, 2002, 58, 3865-3870.

The oxidation of primary and secondary alcohols with ion-supported methyl sulfoxide and oxalyl chloride in the presence of triethylamine in dichloromethane efficiently gives carbonyl compunds in good yields with high purity. Isolation of the product was achieved very easily by simple diethyl ether extraction of the reaction mixture. Furthermore, ion-supported methyl sulfide was recovered in good yield and re-oxidized.D. Tsuchiya, K. Moriyama, H. Togo, Synlett, 2011, 2701-2704.

Tandem Oxidation/Halogenation of Aryl Allylic Alcohols under Moffatt-Swern ConditionsJ. Yin, C. E. Gallis, J. D. Chisholm, J. Org. Chem., 2007, 72, 7054-7057.