What are the most acidic alpha Hydrogens of ketones? Most sub'd or least?

[FROGGBUSTER]

I'm thinking the hydrogen of the least substituted alpha carbon would be more acidic because R groups are electron-donating, which would de-stabilize the anion.

So in an aldol reaction, we would always go with de-protonating the hydrogen on the least-substituted alpha carbon and then do the attack?

Is this correct?

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[loveoforganic]

Sounds right to me, assuming alkyl substituents and not something strongly EW

 

[FROGGBUSTER]

great, thank you.

 

[axo86]

It's not necessarily true- what you have described (taking the most acidic proton) is the kinetic enolate. But consider that if you deprotonate the more highly substituted position, if you do the condensation and dehydrate, you will form a more highly substituted and thus more stable double bond (from the thermodynamic enolate). It takes more activation energy to form the thermodynamic enolate. Deciding which one will happen depends on the reaction conditions. For example, LDA at -78 gives almost exclusive kinetic control, while triethylamine at RT will give almost exclusive thermodynamic control.

 

[loveoforganic]

Good correction, thanks 🙂