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 (O-alkylaton of Phenols and activated alcohols):
To a suspension of Phenol derivative (1 eq.), Cs2CO3 or K2CO3 (2 eq.) in acetontrile (15 Vol) is added alkyl halide (usually 1o halide) at room temperature and stirred for 6 h (If the reaction does not proceed, it shall be brought to room temperature and stirred for 2 h). The reaction is monitored by TLC. After the completion of the reaction, the reaction mixture is filtered to remove inorganics. The filtrate (i.e. organic layer) is successively washed with water (10 Vol ml x 2) and brine solution (15 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography.
General Procedure-2 (O-alkylaton of unactivated alcohols):
To a suspension of NaH (1.2 e.) in THF (10 Vol) iss added alcohol derivative (1 eq.) at 0 oC and stirred for 1-2 h. A solution of alkyl halide (usually 1o halide) in THF is added at 0 oC and stirred for 4 h (If the reaction does not proceed, it shall be brought to room temperature and stirred for 2 h). The reaction is monitored by TLC. After the completion of the reaction, the reaction mixture is acidified with 6N HCl and extracted with DCM or MTBE two times. The resulatnt organic layer is successively washed with water (10 Vol ml x 2) and brine solution (15 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography.
Note:
- The nature of solvent is based on the choice of base being used
Typical Procedure:
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: