The Reaction of Maleic Anhydride with Dimethyl Malonate

The Michael Reaction

The well known Michael reaction is used to generate the 1,1,2,3 propane tetracarboxylate derivatives of diesters of malonic acid and maleic acid. It was also found that the reaction is not limited to the esters of maleic but the well known eletrophile maleic anhydride can also reacts with esters of malonate in the presence of sodium acetate catalyst US4146543 E. Gutierrez. Other active methyl and methine compounds are also covered in this patent. This page will, however, go over the possible mechanism of the Michael reaction of maleic anhydride with dimethyl malonate in the presence of sodium acetate.

The methylene protons of dimethyl malonate are acidic enough (pKa of 16) to be removed by a base such as sodium methoxide. However, removal by a weaker base such as sodium acetate, however, is a much more difficult process as the following equation shows:

According to the equilibrium expression K_eq = 10^ΔpK_a = 10^{pK_a product - pK_a reactant} and inserting the above values:

means that the reverse reaction is favored and the forward reaction is not. In fact there are greater than 10¹¹ molecules of malonate to 1 of enolate at equilibrium and any enolate at equilibrium reacts quickly with acetic acid to form dimethyl malonate.

Thus, if generation of the enolate of malonate by sodium acetate is disfavored, then to bring about the reaction would require that maleic anhydride and sodium acetate form an intermediate with a lower activation energy than maleic anhydride alone, but which is capable of reacting with dimethyl malonate. The reason: maleic anhydride and dimethyl malonate do not react in the absence of sodium acetate but upon its addition, the reaction turns brown with an increase in temperature (highly exothermic). It's possible that a charge transfer complex is the reason behind the color change and that the requisite intermediate is being formed at this point.

Mechanism

Let's look at a possible mechanism. Adding sodium acetate to a mixture of maleic anhydride/dimethyl malonate can generate the following resonance forms:

This would probably make I/II more electrophilic than maleic anhydride itself and nucleophiles would most likely react faster with either of these two intermediates. The acetate counter anion, in addition, is available to react initially with malonate to produce the enolate as shown in Steps 2 and 3. The malonyl anion reacts with III to produce the anion IV which then reacts with the dimethyl malonate (solvent) to produce V and generate a molecule of the malonyl enolate which goes on to react with a second molecule of IV and so on.

A second possibility is that the malonyl enolate formed (after being generated in Step 2) can react with maleic anhydride to generate the tetracarboxylate (VI) (as shown below):

Thus, the acetate anion may initiate the formation of malonyl enolate which may then react with either maleic anhydride or the maleate intermediate(III) or both. This reaction invented in 1977 is thus a way of obtaining compounds difficult to produce via the typical Michael using strong bases such as alkoxides.

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