thors.lab
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Questions about carbonyl alpha carbon alkylation with LDA
Hi,
I'm building up a wiki of useful reactions and writing SMARTS strings for all of these reactions. I came accross this reaction in my textbook and had
some questions about it:
React a ketone with LDA to form a kinetic enolate. This will have the carbanion on the less substituted carbon. Then react with alkyl halide to
alkylate the ketone.
Great! But the textbook glossed over a couple points
- What happens with aldehydes? I've found several sources that disagree on this. Some say the reaction functions as expected. Others say the aldehyde
reacts with itself to form diketones. Still others say that the carbonyl carbon would actually be deprotonated.
- What happens with LDA specficially when its on an aldehyde where the alpha carbon is tertiary? Will it deprotonate the alpha carbon, or the carbonyl
carbon, or not react at all?
- To what point will LDA react? Will it deprotonate tertiary carbons?
- What happens with a molecule like ethyl vinyl ketone? Does the alpha carbon have to be sp3 or will sp2 carbons react as well? Which carbon will it
favor? What about isopropyl vinyl ketone?
Thanks!
[Edited on 4-12-2020 by thors.lab]
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Boffis
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LDA? Reference?
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thors.lab
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Lithium diisopropylamide. "Organic Chemistry: Principles and Mechanisms", Joel Karty.
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Dr.Bob
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There are subtlies to most of these reactions, so the product can depend on 1) order of addition, 2) which reagent is added to which, 3) temperatures,
4) solvents, 5) stoiciametry, etc.
- What happens with aldehydes? - If an adelhyde is added to excess LDA at cold temps, it will form the enolate, and can then be reacted. But if you
add the LDA to the aldehyde, then the enoalate can immediately react with more aldehyde, and it tends to dimerize or worse.
- What happens with LDA specficially when its on an aldehyde where the alpha carbon is tertiary? Will it deprotonate the alpha carbon, or the carbonyl
carbon, or not react at all? If the aldehyde is so substitued so that there is no alpha carbon, it cannot act as a base at that site. There might
be other reactions, but likely not. (Depends on temp and other factors)
PS, Are you in the US? If so, I might be able to provide some texts that cover much of this.
- To what point will LDA react? Will it deprotonate tertiary carbons? It all depends on the acidity of the hydrogens on each carbon, if the
hydrogen is acid enough, LDA can remove it.
- What happens with a molecule like ethyl vinyl ketone? Does the alpha carbon have to be sp3 or will sp2 carbons react as well? Which carbon will it
favor? What about isopropyl vinyl ketone? _ my memory would suggest that vinyl protons are not acidic enough to depotonate there, so the ethyl will
be deprotonated first. Isopropyl should deprotonate, but are slower to react due to the sterics.
These are all great questions, but there are entire textbooks writen on this subject, and the fact that you realize some of the complexities is great,
as many people think that there are simple rules that answer all quiestions, when the reality is that organic experiments involving string bases can
have very complex variables and conditions, sometimes just changing one apparently minor factor can change the major product completely. Same way
that added HMPA to many LDA reactions can switch which enolate is formed and what product forms.
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