Separation of Diethyl Malonate and Monosubstituted Diethyl Malonate: Another Phase Switching Hdrolysis

kilomentor | 29 April, 2012 20:04

In Organic Synthesis Coll. Vol. II pg 279 there is a procedure for monomethylation of ethyl malonate (diethyl methylmalonate). The crude, neat diester product is “shaken for exactly one minute with a cold solution of 10 g. of sodium hydroxide in 30 cc. of water.” The corresponding note reports that “[t]he ester is treated in this manner to remove any unchanged ethyl malonate [diethyl malonate]. Michael¹has shown that this treatment will completely remove unchanged ethyl malonate [diethyl malonate] while hardly attacking ethyl methylmalonate. No ethyl dimethyl-malonate is formed when methyl bromide is used as the methylating agent….A separation of the desired product from traces of unchanged starting material and from ethyl dimethylmalonate cannot be accomplished by distillation as the boiling points of the three esters lie within three and one-half degrees of one another.” The notes contain this additional information. “Michael found that unchanged malonic ester can be removed completely by taking advantage of the greater ease with which it is hydrolyzed by alkali ….”The references are Michael, J. Prakt. Chem. (2) 72, 537 (1905) and Fieser and Novello, J. Am. Chem. Soc. 62, 1856 (1940).
This appears to be an extraordinary example of separation by competitive reaction using heterogeneous media. For this to work the rate of hydrolysis of the starting material under these conditions must be at least one hundred times faster than that for the monomethyl product. Why would this be and how can other separations take advantage of this? It might be that the deprotonation and extraction into the aqueous basic phase of ethyl malonate in a vigorously agitated two phase mixture is much faster for an unsubstituted ethyl malonate than for one that is substituted, even with a very small group like methyl. It is very much less likely to relate to a difference in solubility between the ethyl and ethyl methyl malonates or even of their respective monoanions. Once ethyl malonate gets deprotonated and carried into the aqueous phase it is probably quickly further hydrolyzed to give carboxylates which keep it there. Kilomentor has given other examples of such ‘phase switching hydrolysis’ separating esters where there is a free phenol in only one component of a binary mixture and calls the method. http://kilomentor.chemicalblogs.com/55_kilomentor/archive/1011_extractive_and_phase_switching_hydrolysis_in_chemical_process_development.html

If the hypothesized explanation is correct this technique would be generally applicable in any monoalkylation of ethyl malonate with a hydrophobic side chain. It would mean that an excess of the inexpensive ethyl malonate could be used in such alkylation to speed up the overall rate in the knowledge that the excess ethyl malonate could be easily removed by alkaline hydrolysis and a water wash. This would also allow the amount of dialkylation to be reduced to essentially nothing.

Comments

Competitive hydrolysis

Slawomir | 30/04/2012, 07:06

That "shaking for 1 minute" would be hard to scale-up in batch mode. However, it seems to fit a continuous process just fine.

Some time ago when I made malonates for a living it was easier to over-alkylate and separate the mono product by distillation (the di-alkyl malonate was left in the pot).

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