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. [cite journal | title = Oxidation of alcohols by “activated” dimethyl sulfoxide. a preparative, steric and mechanistic study | author = Kanji Omura and Daniel Swern | journal = Tetrahedron | year = 1978 | volume = 34 | pages = 1651 | doi = 10.1016/0040-4020(78)80197-5)] [cite journal | author = A. J. Mancuso, D. S. Brownfain and D. Swern | title = Structure of the dimethyl sulfoxide-oxalyl chloride reaction product. Oxidation of heteroaromatic and diverse alcohols to carbonyl compounds | year = 1979 | journal = J. Org. Chem. | volume = 44 | issue = 23 | pages = 4148–4150 | doi = 10.1021/jo01337a028] [cite journal | author = A. J. Mancuso, S.-L. Huang and D. Swern | title = Oxidation of long-chain and related alcohols to carbonyls by dimethyl sulfoxide "activated" by oxalyl chloride | year = 1978 | journal = J. Org. Chem. | volume = 43 | issue = 12 | pages = 2480–2482 | doi = 10.1021/jo00406a041] The reaction is known for its mild character and wide tolerance of functional groups. [OrgSynth | author = Dondoni, A.; Perrone, D. | title = Synthesis of 1,1-Dimethyl Ethyl-(S)-4-formyl-2,2-dimethyl-3-oxazolidinecarboxylate by Oxidation of the Alcohol | collvol = 10 | collvolpages = 320 | year = 2004 | prep = v77p0064] [OrgSynth | author = Bishop, R. | title = 9-Thiabicyclo [3.3.1] nonane-2,6-dione | collvol = 9 | collvolpages = 692 | year = 1998 | prep = cv9p0692] [OrgSynth | author = Leopold, E. J. | title = Selective Hydroboration of a 1,3,7-Triene: Homogeraniol | collvol = 7 | collvolpages = 258 | | year = 1990 | prep = cv7p0258] [cite book | author = Gabriel Tojo and Marcos Fernández | title = Oxidation of Alcohols to Aldehydes and Ketones: A Guide to Current Common Practice | publisher = Springer | year = 2006 | isbn = 0387236074]

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 unpleasant odour. A convenient way to reduce the stench of dimethyl sulfide is to treat the crude product mixture with oxone, whereupon the sulfide is converted to dimethyl sulfoxide, which has no odor.

Several reviews have been published. [cite journal | author = Mancuso, A. J.; Swern, D. | title = Activated Dimethyl Sulfoxide: Useful Reagents for Synthesis | journal = Synthesis | year = 1981 | volume = 1981 | pages = 165–185 | doi = 10.1055/s-1981-29377 | format = Review] [cite journal | author = Tidwell, T. T. | title = Oxidation of Alcohols to Carbonyl Compounds via Alkoxysulfonium Ylides: The Moffatt, Swern, and Related Oxidations | journal = Org. React. | year = 1990 | volume = 39 | pages = 297–572 | doi = 10.1002/0471264180.or039.03 | format = Review] [cite journal | author = Tidwell, T. T. | title = Oxidation of Alcohols by Activated Dimethyl Sulfoxide and Related Reactions: An Update | journal = Synthesis | year = 1990 | volume = 1990 | pages = 857–870 | format = Review | doi = 10.1055/s-1990-27036]

Mechanism

The first step of the Swern oxidation is the low-temperature reaction of dimethyl sulfoxide (DMSO), 1a & 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 7 decomposes to give dimethyl sulfide and the desired ketone (or aldehyde) 8.

Variations

When using oxalyl chloride as the dehydration agent, the reaction must be kept colder than -60 °C to avoid side reactions. With trifluoroacetic anhydride instead 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 6 are the use of carbodiimides (Pfitzner-Moffatt oxidation) and pyridine-sulfur trioxide complex (Parikh-Doering 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 (i-Pr₂NEt, Hünig's base) can mitigate this side reaction.

Considerations

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 parts per billion. A simple remedy for this bothersome problem is to rinse used glassware with bleach (usually containing sodium hypochlorite), which will oxidize the dimethyl sulfide, eliminating the smell.

ee also

* Corey-Kim oxidation
* Pfitzner-Moffatt oxidation

References

External links

* [http://www.organic-chemistry.org/namedreactions/swern-oxidation.shtm Organic Chemistry Portal]