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-1:
(a) Acid chloride preparation:
To a solution of carboxylic acid (1 eq.) in DCM or THF or toluene (10 Vol) at 0 oC is added SOCl2 (2 – 3 eq.) and stirred at room temperature overnight (If required, catalytic amount of DMF shall be added). The reaction is monitored by TLC (If the reaction does not proceed, it shall be heated) The acid chloride formation is confirmed by adding reaction mixture to methanol and TLC is verified (whether it forms ester or not). After the completion of the reaction, excess thionyl chloride is distilled off to get the residue. (This residue is acid chloride and should be used as soon as it is prepared, as acid chlorides are usually very reactive and gets hydrolyzed on contact with moisture)n
(b) Acid chloride to amide:
resultant residue (i.e. acid chloride) is dissolved in DCM or THF. To this solution is added amine (1.2 eq.), followed by base (py or DMPA or DIPEA) and stirred at room temperature for 4h. The reaction is monitored by TLC. The reaction mixture is then successively washed with water (10 Vol x 2), aq. HCl solution and brine solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography
Note:
- The preferable solvents are DCM, THF or toluene
- During acid chloride, the by-products liberated are HCl and SO2, As both being gases, the acid chloride reaction is usually clean.
- If the acid chlorides are available commercially, it shall be used as such, following procedure (b).
Typical Procedure:
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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: