organic chemistry - Regioselectivity in Claisen condensation and aldol reaction

I'm having a hard time determining regio-selectivity in those two reactions.

At the image above I've drawn one example for each on of them. My question is how do we choose where the deprotonation will occur. My approach was that the base will deprotonate the substrate in order to produce the most stable enolate. In the Claisen condensation, A should be the main product since the -CH2- group is present thus corresponding the mechanism. For B there will be no acidic hydrogens so it is not favoured, or at least that's what I thought.

Moving to the aldol condensation I can't figure out which product will be the main. Theoretically in C, the enolate is more stable than that of D, but the final unsaturated ketone isn't more stable in D?

Either way, I can't comprehend how can we determine what enolate will be produced each time.

Answer

Claisen and aldol condensations are thermodynamically controlled,* so it is not a question of which enolate forms, it is a question of which product forms.

In your first example, product A can be deprotonated by ethoxide as there is still an acidic hydrogen between the two carbonyls. Product B, on the other hand, has a quaternary carbon between the two carbonyls and cannot be deprotonated.

Because the pK_a of a 1,3-dicarbonyl (~10) is significantly smaller than the pK_a of ethanol (~15),** this deprotonation of A is almost complete and it therefore pulls the equilibrium position over to one which favours product A, simply by le Chatelier's principle. In fact if you somehow make product B via a different route and then treat it with ethoxide, you should exclusively get product A out of your flask, via retro-Claisen and Claisen condensation.

For the second example I would expect product D (tetrasubstituted alkene) to be preferentially formed over C (trisubstituted).

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* Unless you use kinetic deprotonation conditions such as LDA. In this case you will then have to look at the stability of the transition states leading to enolate formation, but that's a story for another day.

** Very rough values.