[makeupgirl1107]

Hi all,

So I know that to synthesize Dimedone, you use a reaction of dimethyl malonate with mesityl oxide and it involves Michael addition, a Claisen condensation and a hydrolytic carboxylation.

I have some questions involving the steps in the synthesis.

1. Why does the beta-keto acids decarboxylate so easily but alpha0keto acides do not?

I was thinking the reason is that the carbon in between the two carbonyl systems will help stabilize the elections by forming an enol or keto and this stabilizing allows for the decarboxylation to go easier.

2. Why does the anion derived from dimethyl malonate add to the β-position (1,4-position) rather than directly to the carbonyl group of mesityl oxide?

I think that the 1-4 addition allows for a p-orbitial of pi systems to form which will stabilize the reaction but if the addition was to the carbonyl, this will just form a highly reactive and unstable system.

Let me know what you think, and if I am on the right track or need to completely change something? Thanks

[Honclbrif]

1. Look up the mechanism of decarboxylation. The answer should be clear.

2. Look up Michael Addition and conjugate addition.

[orgopete]

2. Why does the anion derived from dimethyl malonate add to the β-position (1,4-position) rather than directly to the carbonyl group of mesityl oxide?

I think that the 1-4 addition allows for a p-orbitial of pi systems to form which will stabilize the reaction but if the addition was to the carbonyl, this will just form a highly reactive and unstable system.

I reason this along a slightly more practical line of thinking. Diethyl malonate has a pKa of 13. If its anion added to an aldehyde or ketone, you create a carbinol with a pKa of about 16. Deprotonation can easily catalyze a reverse reaction. This reaction can easily be in equilibrium.

If the anion adds to the beta carbon, even though it may be slower, it can form a new ketone or aldehyde. The pKa of a ketone will be about 18-20. In the presence of the malonate, poorer leaving group, and any stereoelectronic constraints that may apply, this reverse reaction is now much slower. I reason the conjugate addition is a thermodynamic product.

If a very strong base/nucleophile is used, then even though conjugate addition can occur, 1,2-additions predominate. This isn't a proof of how the reactions actually take place. It is a rationalization of why 1,2 and 1,4-additions might occur. Weak bases, amines, thiols, HCl, beta diketones, etc., favor 1,4-addition and Grignard reagents, organolithium reagents, acetylides, etc. favor 1,2-addition.