Reaction & Reagents info
- Swern Oxidation (DMSO, Oxalyl chloride) is a mild oxidizing system that converts primary alcohol to aldehyde and secondary alcohol to ketone
- It is one of the series of oxidations involving DMSO (refer to DMSO-activated oxidations)
Advantages
- Inexpensive oxidation method on manufacturing scale
- Also, it is less toxic, compared to chromium-based alternatives (PCC and PDC)
Disadvantages
- The liberation of gases viz., malodrous dimethylsulphide (Me2S) and poisonous carbon monoxide (CO) are to be handled appropriately
- It is important to maintain the reaction mixture at -78 oC. If the temperature is not maintained, there is a possibility of formation of mixed thioacetals (see mechanism)
Useful Links on Reagent & Reaction:
- DMSO –Oxalyl Chloride (Swern Oxidation) (Reagent Guide, ACS Green Chemistry Institute) – Green Chemistry info.
- Swern oxidation (SynArchive) – Excellent compilation of reaction schemes with references
Mechanism
General Oxidation Mechanism
DMSO, as such, is not a good oxidising agent. However, it needs to be activated by an activator [such as (COCl)2 in Swern Oxidation, DCC in Moffatt oxidation] so that DMSO shall act effective oxidising agent (refer to DMSO-activated Oxidations)
Activation of DMSO by Oxalyl Chloride
Swern Oxidation
Formation of side product in Swern Oxidation
In Swern oxidation employing (COCl)2, one mole each of CO, CO2 and Me2S (all gaseous products) are released. HCl gets converted to NEt3.HCl during the reaction
It is important to maintain the reaction mixture at -78 oC. If the temperature is not maintained, there is a possibility of formation of mixed thioacetals
Image from “chemistryworld.com”
Additional details
General Procedure:
To a solution of alcohol (1 eq.) in THF (10 Vol) is added triphenyl phosphine (TPP, 1.5 eq.), DIAD (1.5 eq) and acid derivative, and stirred at room temperature for 6 to 8 h. The reaction is monitored by TLC. (The formation of triphenylphosphine oxide, TPPO, as a solid is the indication of the progress of the reaction). The reaction mixture is diluted with EtOAc or DCM (15 Vol) and filtered to remove the by-product triphenylphosphine oxide. The filtrate (i.e. organic layer) is successively washed with water (15 ml x 2), aq. NaHCO3 solution (to remove unreacted acid) and brine solution (15 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography.
Note:
- Mitsunobu reaction is the reaction between alcohol and different nucleophiles using PPh3 and azodicarbozxylate (DIAD or DEAD). The reaction proceeds with inversion of configuration (SN2)
- 1o and 2o alcohols are generally used. 3o alcohols do not react
- The most preferable solvent is THF. Other solvents such as DCM and Dioxane could also be used. The reaction is usually performed at RT
- The by-product namely triphenylphosphine oxide (TPPO) is usually removed by filtration
- DIAD is Diisopropyl azodicarboxylate. It comes as 40% in toluene. Azodicarboxylic esters are susceptible to explosion when subjected to heat, impact and friction. In order to reduce the risk, azodicarboxylic esters are available as a 40% solution in organic solvents.
- Nucleophile should be acidic enough to protonate azodicarboxylate (refer to mechanism)
| Reactant | Nucleophile | Product |
|---|---|---|
| Alcohol | Carboxylic acid | Ester |
| Alcohol | Alcohol or Phenol | Ether |
| Alcohol | Thiol | Thioether |
| Alcohol | Phthalmide | N-alkylation (on cleavage, it forms C-N bond) |
| Alcohol | DPPA | Azide |
| Alcohol | Cyanohydrin (HCN source) | Nitrile (C-CN bond) |
| Alcohol | EWG-CH2-EWG (active methylene compds) | C-C bond formation |
Typical Procedure:
- 1o and 2o alcohols are generally used. 3o alcohols do not react
WO2010045258, page No. 256
Swern oxidation could be carried out on large-scale. However, the reaction involves the liberation of 1 eq. each of the gases such as Me2S (dimethylsulphide), CO (carbon monoxide), CO2. Appropriate safety controls are to be ensured while performing manufacturing. During work-up, HCl gets converted to amine salt (such as NEt3.HCl).
- Swern Oxidation is one of the inexpensive methods to manufacture aldehydes or ketones from Alcohols
- The liberation of gases viz., malodrous dimethylsulphide (Me2S), poisonous carbon monoxide (CO) and CO2 are to be handled appropriately
- It is important to maintain the reaction mixture at -78 oC. If the temperature is not maintained, there is a possibility of formation of mixed thioacetals (see mechanism in General Info section)
Scale-Up Typical Procedure:
- An Improved and Efficient Process for the Production of Donepezil Hydrochloride (OPRD, 2008) – 4 Kg batch; 3.5 Kg of DMSO & 3.7 Kg of (COCl)2 have been used
- Convergent Catalytic Asymmetric Synthesis of Camptothecin Analog GI147211C (Tetrahedron, 1997) – 100 g batch
Green Chemistry Aspects: