What Is Moffatt Oxidation?
The combination of dimethyl sulfoxide (DMSO) and different electrophilic reagents can form a class of widely used oxidant systems. Among them, the oxidation of alcohols to aldehydes and ketones using the DMSO-DCC system developed by Moffatt under acid catalysis is called Moffatt oxidation. This reaction is also called Pfitzner-Moffatt oxidation and was first reported by Klaus E. Pfitzner and John G.
In Moffatt oxidation, commonly used acids are pyridinium salts of strong acids, such as phosphoric acid or pyridine trifluoroacetate dichloroacetic acid. DMSO is not necessarily used as a solvent. For example, adding ethyl acetate as a co-solvent will have a better effect. In addition, phenyl dichlorophosphate has been shown to be an effective DMSO activator in this oxidation.
The disadvantage of Moffatt oxidation is that three times the amount of DCC is required, and the urea byproduct formed by the reaction often makes it difficult to separate the product. A common solution is to add malic acid to help remove the byproduct. In addition, the oxidation of homoallylic alcohol is sometimes accompanied by double bond migration. Despite this, Moffatt oxidation is used in the synthesis of many natural products due to its mild conditions.
- Reagents: Dimethyl sulfoxide (DMSO), dicyclohexylcarbodiimide (DCC).
- Reactants: Primary or secondary alcohols.
- Products: Aldehyde (from primary alcohol), ketone (from secondary alcohol).
- Reaction type: Oxidation reaction.
- Related reactions: Swern oxidation, Parikh-Doering oxidation, Kornblum oxidation.
Fig 1. Moffatt oxidation reaction and its mechanism. [1]
Mechanism of Moffatt Oxidation
The mechanisms of DMSO-based oxidation reactions all involve the activation of DMSO by electrophiles, making the sulfur atom an electrophilic center that can withstand the attack of alcohols. The mechanism of Moffatt oxidation involves several key steps:
- Activation of DMSO: DMSO is activated by a coupling reagent, typically DCC, to form a highly reactive sulfonium ion intermediate.
- Nucleophilic Attack: The alcohol, acting as a nucleophile, attacks the sulfur atom of the sulfonium ion, leading to the formation of an alkoxysulfonium ion.
- Hydride Abstraction: A base, such as pyridine or triethylamine, abstracts a hydride ion from the α-carbon of the alkoxysulfonium ion, generating a carbonyl compound and regenerating DMSO.
Application Examples of Moffatt Oxidation
- Example 1: Unlike many other oxidation methods, the Pfitzner-Moffatt procedure transforms sec and sec-1,2-diols (such as pyrocatechol) into 1,2-diketones without breaking any carbon-carbon bonds. Additionally, other functional groups, such as enolic double bonds or esters, remain unchanged due to the gentle and nearly neutral conditions of the reaction. [2]
- Example 2: The Moffatt oxidation of 2',3'-O-isopropylidene-l-adenosine, followed by the treatment of the resulting crude 5'-aldehyde with hydroxylamine and subsequent deprotection, produced l-adenosine 5'-carboxaldehyde oximes. The enantiomers of these oximes are known to effectively inhibit S-adenosyl-l-homocysteine (AdoHcy) hydrolase. However, both l-adenosine and its 5'-aldehyde oxime derivatives were determined to be inactive as inhibitors of AdoHcy hydrolase. [3]
Fig 2. Synthetic examples via Moffatt oxidation reaction.
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References
- Elbertus Kruiswijk. The comprehensive e-book of named organic reactions and their mechanisms, 1370.
- Schobert, Rainer. Synthesis, 1987, 08, 741-742.
- Wang, Mengmeng, et al. Journal of medicinal chemistry, 2005, 48(10), 3649-3653.
