In 1978, Daniel Swern and Kanji Omura published their famous paper introducing the Swern Reaction, a reaction that was to become one of the most commonly used oxidation methods in organic synthesis.
Introduction
The Swern oxidation is a crucial reaction in the organic chemist's repertoire, allowing the efficient transformation of primary and secondary alcohols into aldehydes and ketones, respectively.[1] Named after the pioneering chemist Daniel Swern, this reaction offered a mild and versatile alternative to some of the harsher oxidation methods employed at the time. Its compatibility with a wide array of functional groups, as well as its capacity for selective oxidation, renders the reaction indispensable in synthetic chemistry. However, we should not forget the importance of some of the other 'activated dimethylsulfoxide (DMSO)' oxidations and the role of these forerunners in the development of mild and selective oxidation conditions. In this review, we take a close look at the Swern reaction alongside some of the earlier versions of the reaction, comparing the pros and cons associated with each one.
First, we will consider the mechanism of the classic Swern oxidation. The protocol is based on 'activated DMSO'. DMSO is activated by oxalyl chloride to form a chlorodimethylsulfonium ion, which then reacts with primary and secondary alcohols to produce a dimethylalkoxysulfonium salt. This salt undergoes an intramolecular rearrangement to yield the corresponding aldehyde or ketone.[1] Chemists who have performed this reaction will be all too familiar with the foul cabbage-like smell of the reaction by-product, dimethylsulfide (DMS).
The popularity of the Swern protocol arises from the fact that it avoids some of the problems associated with other activated DMSO reactions (such as an unwanted Pummerer rearrangement), thus offering the best balance of yield, cost, availability of reagents, and ease of performance.[1] However, as we already mentioned, the Swern oxidation (1978) was not the first activated DMSO oxidation to be reported. Between 1957 and 1978, many variations on the protocol were reported, each with their own advantages and disadvantages. We will now look at the discovery timeline of the forerunners to the Swern oxidation.
The History of 'Activated DMSO' Oxidations
First Activated DMSO Oxidations: Kornblum Oxidation (1959) and Barton Modification (1964)
Probably the earliest 'activated DMSO' oxidation can be attributed to Nathan Kornblum, who developed an oxidation process that could transform alkyl halides and tosylates into carbonyl compounds.[2] Much like the later sulfonium-based oxidation of alcohols to carbonyls, this reaction generates an intermediate alkoxysulfonium ion. In the presence of a base, such as triethylamine, this ion undergoes an elimination reaction to yield the desired aldehyde or ketone.
The mechanism was originally believed to be a direct E2 elimination. However, Torsell proved in 1967 that these types of eliminations occur via an intramolecular process.[3] Thus, a base deprotonates the methyl group attached to the sulfur to form an ylid, and then this ylid decomposes via intramolecular deprotonation to produce the carbonyl product and the dimethyl sulfide (DMS) by-product.
A limitation of the Kornblum procedure was the high temperature required to generate the dimethylalkoxysulfonium salt. Barton and co-workers were able to generate dimethylalkoxysulfonium salts at lower temperatures by employing alkyl chloroformates.[4] These react with DMSO to generate the desired product at lower temperatures, alongside carbon dioxide and DMS. A downside is that formation of the starting chloroformate requires the use of toxic phosgene.
Pfitzner–Moffatt Oxidation (1963)
As an alternative method to the Kornblum reaction, William Pfitzner and James E. Moffatt developed the Pfitzner–Moffatt oxidation in 1963, converting primary and secondary alcohols into aldehydes and ketones, respectively.
Like the Kornblum reaction, the Pfitzner–Moffatt oxidation employs DMSO as the oxidant. However, rather than having a leaving group on the alkyl substrate, the leaving group is created on DMSO itself, which then reacts with the alcohol substrate. This activation is achieved using N,N'-dicyclohexylcarbodiimide (DCC), forming an active electrophile able to react with an alcohol to form the alkoxysulfonium ion. After deprotonation by a base, the alkoxysulfonium ion then undergoes the same intramolecular rearrangement that occurs in the Kornblum reaction, yielding the desired carbonyl compound, alongside DMS and dicyclohexylurea.[5] A significant limitation of the Pfitzner–Moffatt oxidation is that the dicyclohexylurea by-product is difficult to separate from the product.
Albright–Goldman Oxidation (1965)
The Albright–Goldman oxidation was reported in 1965. The reaction employs a similar principle to the Pfitzner–Moffatt oxidation, but acetic anhydride is used to activate DMSO instead of DCC. This reaction is particularly useful for the oxidation of sterically hindered alcohols. When the substrate is not sterically hindered, a competing Pummerer reaction diminishes the yield.[6]
Parikh–Doering Oxidation (1967)
The Parikh–Doering oxidation offers a robust method for the conversion of alcohols into carbonyl compounds. As with its predecessors, DMSO is used as both the oxidant and solvent (often alongside a co-solvent). The key to the efficacy of the Parikh–Doering oxidation is the use of sulfur trioxide pyridine complex (SO3•pyridine). The process also requires the use of triethylamine or diisopropylethylamine as a base.
An advantage of the Parikh–Doering oxidation over other activated DMSO oxidations is that the reaction can be performed at non-cryogenic temperatures (typically 0 °C to room temperature), without the formation of methyl thiomethylether side products. Another advantage is that the SO3•pyridine complex is a bench-stable solid and is therefore easier to handle than oxalyl chloride or acetic anhydride. The disadvantages of the reaction are the need for excess reagents and long reaction times.[7]
Corey–Kim Oxidation (1972)
This reaction, named after the esteemed American chemist Elias James Corey alongside Korean-American chemist Choung Un Kim, provides a reliable pathway for the transformation of primary and secondary alcohols into aldehydes and ketones.
The mechanism is similar to the Swern reaction, in the sense that the key intermediate is a chlorodimethylsulfonium ion. The key difference is that dimethylsulfide (DMS) is employed as a starting material instead of dimethylsulfoxide (DMSO). Here, DMS is treated with N-chlorosuccinimide (NCS) to produce the 'active DMSO' species that activates the alcohol.
An advantage of the Corey–Kim oxidation is that the reaction can be conducted above –25 °C. However, the use of NCS can result in chlorinated reaction products. Some successful efforts have been made to avoid the use of malodorous and volatile DMS. For example, longer chain sulfides and polymer-supported sulfides have both been employed in this oxidation procedure.[8]
Swern's Triflouroacetic Anhydride Method (1976)
Two years prior to discovering his oxalyl chloride method, Swern published the use of trifluoroacetic anhydride (TFAA) as an alternative to the Albright–Goldman oxidation, which uses acetic anhydride. The downside to this protocol is that the use of DMSO and TFAA can result in an explosive combination, forming an unstable intermediate.[9] Therefore, the reaction should be conducted below –50 °C. Ultimately, this original Swern reaction was superseded by the classic Swern reaction that uses oxalyl chloride, which was reported two years later.
Swern's Oxalyl Chloride activated DMSO Oxidation (1978)
As already mentioned, Swern published his revised oxidation conditions in 1978. Today, this reaction is the most popular choice of 'activated DMSO' oxidation, with the original paper having been cited thousands of times. The Swern oxidation has been extensively studied and utilized since its development, resulting in a well-established methodology with numerous applications in the synthesis of natural products, pharmaceuticals, and other organic compounds.
Comparison with Other Oxidation Methods
The Swern reaction offers cheaper starting reagents than other oxidations, such as Dess-Martin periodinane (DMP) or tetrapropylammonium perruthenate (TPAP) oxidations, while affording comparable yields and ease of operation. The Swern reaction uses milder conditions than the common chromium-based oxidations. Overall, the Swern reaction is a very good option for oxidising sensitive alcohol substrates.
1. Omura, K.; Swern, D. Oxidation of alcohols by “activated” dimethyl sulfoxide. a preparative, steric and mechanistic study. Tetrahedron 1978, 34, 1651–1660. DOI: 10.1016/0040-4020(78)80197-5.
2. Kornblum, N.; Jones, W. J.; Anderson, G. J. A new and selective method of oxidation. The conversion of alkyl halides and alkyl tosylates to aldehydes. J. Am. Chem. Soc. 1959, 81, 4113–4114. doi:10.1021/ja01524a080
3. Torssell, K. Preparation of dimethylsulfonium salts and their role in the Kornblum oxidation. Revision of the structure for the olefin-bromotrinitromethane adduct. Acta Chem. Scand. 1967, 21, 1–14. http://actachemscand.org/pdf/acta_vol_21_p0001-0014.pdf
4. Barton, D. H. R.; Garner, B. J.; Wightman, R. H. J. Chem. Soc., 1964, 1855.
5. Pfitzner, K.; E.; Moffatt, J. G. A new and selective oxidation of alcohols. J. Am. Chem. Soc. 1963, 85, 3027–3028. DOI: 10.1021/ja00902a036.
6. Albright, J. D.; Goldman, L. Dimethyl sulfoxide-acid anhydride mixtures. New reagents for oxidation of alcohols. J. Am. Chem. Soc. 1965, 87, 4214–4216. DOI: 10.1021/ja01096a055.
7. Parikh, J. R.; Doering, W. v. E. Sulfur trioxide in the oxidation of alcohols by dimethyl sulfoxide. J. Am. Chem. Soc. 1967, 89, 5505–5507. DOI: 10.1021/ja00997a067.
8. Corey, E. J.; Kim, C. U. New and highly effective method for the oxidation of primary and secondary alcohols to carbonyl compounds. J. Am. Chem. Soc. 1972, 94, 7586–7587. doi:10.1021/ja00776a056
9. Omura, K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976, 41, 957-962. DOI: 10.1021/jo00868a012
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