What Is Swern Oxidation?
Swern oxidation is a reaction that uses dimethyl sulfoxide (DMSO) as an oxidant to oxidize alcohols to aldehydes or ketones in synergistic reaction with oxalyl chloride (COCl)2 under alkaline conditions and low temperature. This is the first reaction in organic synthesis that does not rely on metal-containing oxidants. Swern oxidation is a common method for preparing aldehydes and ketones from primary and secondary alcohols.
The characteristics of Swern oxidation reactions include mild reaction conditions and low degree of racemization (about 5%) of α-chiral compounds (such as α-amino alcohol derivatives). Therefore, Swern oxidation has been widely used in organic synthesis in the past few decades.
- Reagents: Oxalyl chloride (COCl)2, dimethyl sulfoxide (DMSO), and base (typically triethylamine or diisopropylethylamine).
- Reactants: Primary or secondary alcohols.
- Products: aldehyde or ketone.
- Reaction type: oxidation reaction.
- Related reactions: Corey-Kim oxidation, Jones oxidation, and Dess-Martin periodinane (DMP).
Fig 1. Swern oxidation reaction and its mechanism. [1]
Mechanism of Swern Oxidation
The reaction unfolds through a three-step mechanism:
Activation
The initial step involves the formation of a highly reactive intermediate, the dimethylsulfonium oxychloride. This is achieved by treating oxalyl chloride with dimethylsulfide in a cold environment (typically -78 °C). The oxalyl chloride acts as a Lewis acid, activating the carbonyl group of the dimethylsulfide towards nucleophilic attack by chloride ions present in the reaction medium.
Alkoxy Sulfonium Ylide Formation
Subsequently, the alcohol reacts with the activated intermediate to generate the key alkoxy sulfonium ylide. This step is often considered rate-determining, as it involves the deprotonation of the alcohol by the highly basic chloride ion.
C-H Bond Cleavage and Product Formation
Finally, a unique intramolecular elimination occurs within the ylide. This syn-elimination leads to the cleavage of the C-H bond adjacent to the oxygen atom, expelling dimethyl sulfide and furnishing the desired carbonyl compound alongside regenerated chloride ions.
Application Examples of Swern Oxidation
- Example 1: Rui Ding et al. reported the successful results of dehydrating amides or aldoximes to generate nitriles using (COCl)2 and a catalytic amount of DMSO in the presence of Et3N at room temperature. Nitriles were prepared from primary amides or aldoximes using oxalyl chloride and a catalytic amount of dimethyl sulfoxide in the presence of diethyl ether. The reaction gave a variety of cyano compounds in good to excellent yields, including aromatic, heteroaromatic, cyclic and non-cyclic aliphatic substances. [2]
- Example 2: In the scale-up synthesis of tesirine (a drug linker component of an antibody-drug conjugate), the primary alcohol, upon oxidation, yields an aldehyde that undergoes spontaneous cyclization to produce the B-ring of the pyrrolobenzodiazepine (PBD) framework. The Swern oxidation is particularly well-suited for this transformation, especially in large-scale manufacturing contexts. [3]
Fig 2. Synthetic examples via Swern oxidation reaction.
Related Products
References
- Li, Jie Jack, et al. Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications Sixth Edition, 2021, 533-535.
- Ding, Rui, et al. The Journal of organic chemistry, 2018, 83(20), 12939-12944.
- Tiberghien, Arnaud C., et al. Organic Process Research & Development, 2018, 22(9), 1241-1256.
