Mechanism + Description

An SN2 reaction generating the acid salt and ether products. Alkoxides in the presence of a stoichiometric amount of water generate ‘naked’ hydroxide and thus proceed by a different mechanism – hydroxide hydrolysis.

General comments

Alkoxide based reagents are frequently used for the cleavage of sterically hindered alkyl esters. The reaction can be selective in the presence of other base sensitive functional groups such as amides and nitriles, which are generally unreactive in the presence of esters. One advantage of the methodology is that the reaction is conducted under non-aqueous conditions, therefore the solubility issues encountered with aqueous hydroxide are reduced. Deprotonation elsewhere in the substrate can be a possibility (e.g. enolate formation). A related reagent, K+/Na+ trimethylsilanolate is of use for ester cleavage.

Key references

CroaticaChemicaActa., 2007, 80, 109 Trimethylsilanolates as reagents for conversion of esters to carboxylic acids
Org. Lett., 2002, 4, 2783 Acetates by methanolysis in the presence of CH3ONa/La(OTf)3
Tet. Lett., 1987, 28, 1131 Tremorgenic mycotoxins: synthesis of 6-demethoxyfumitremorgin 
J. Org. Chem., 1977, 42, 918   base-promoted hydrolysis of hindered esters at ambient temperatures
Tet. Lett., 1964, 5, 2969 Pot. tert.-butoxide in dimethylsulfoxide. hydrolysis of hindered carboxylic esters.

Relevant scale up example

None found

Green Review

  1. Atom efficiency (by-products Mwt)
    Atom efficiency can be good with low Mwt. ethers produced from MeO- or EtO-. Higher alcohols give poorer atom economy.
  2. Safety Concerns
    The generation of low Mwt. ethers may lead to highly flammable gases being produced – Me2O, MeOEt. Neat alkoxides are reactive reagents with handling considerations.
  3. Toxicity and environmental/aquatic impact
    Once neutralized and diluted, impact is that of the corresponding alcohol. Lower Mwt. alcohols are fully biodegradable. Higher Mwt., branched and tert alcohols may degrade much more slowly or accumulate.
  4. Cost, availability & sustainable feedstocks
    Most alkoxides are cheap and readily available or easily prepared. Lower Mwt. alcohols (C1-C4) can be made from biorenewable feedstocks.
  5. Sustainable implications
    Generally good for low Mwt. alcohols that are readily biodegradable.
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