Reagent Friday: Lithium Di-isopropyl Amide (LDA)

by James

in Ketones, Organic Chemistry 2, Organic Reagents

In a blatant plug for the Reagent Guide, each Friday  I profile a different reagent that is commonly encountered in Org 1/ Org 2. Version 1.2 just got released last week, with a host of corrections and a new page index. 

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If NaNH2 is a piranha, then today’s reagent – lithium diisopropylamide (LDA) is like a hammerhead shark. It’s also got a powerful bite, but that distinctive proboscis can get in the way. So LDA can’t reach into tight spaces the same way that NaNH2 can.

In other words: LDA is a strong, bulky base. The most common use of LDA is in the formation of enolates. In the example below, notice how both carbons flanking the C=O have C-H bonds? LDA will remove the proton selectively from the carbon substituted with the fewest number of carbons:

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Also note the temperature (–78 °C). There’s nothing special about –78° relative to –72° or –60° for this to work – it’s just that cold temperatures improve the selectivity, and –78°C happens to be the temperature of a very cheaply prepared cold bath (dry ice and acetone). A common solvent for this is tetrahydrofuran (THF).

Why is LDA useful? Well, enolates are extremely useful nucleophiles, able to participate in SN2 reactions with alkyl halides as well as the aldol reaction (among many other things). If we used NaNH2 to form an enolate like this, we’d likely get a mixture of two enolates, which would lead to a mixture of products. The selectivity of LDA in forming the less substituted enolate makes it extremely useful.

3-example2 copy Although less common, LDA can also be used for the formation of “Hoffman” products in elimination reactions. The usual base for this is potassium t-butoxide, but LDA can do it too:

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How it works: 

This diagram below shows the reaction between LDA and the ketone. Note the bonds that are forming (N-H, C-C) and the bonds that are breaking (C–H, C–O). The enolate that is formed has a resonance isomer where the negative charge is on the carbon. This is, in some respects, the more “important” resonance form, as it is the carbon that tends to be a better nucleophile than oxygen in reactions of enolates.

5-lda

P.S. You can read about the chemistry of LDA and more than 80 other reagents in undergraduate organic chemistry in the “Organic Chemistry Reagent Guide”, available here as a downloadable PDF.


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{ 14 comments… read them below or add one }

zack

Dr. Ashenhurst, you say “The most common use of LDA is in the formation of enolates. In the example below, notice how both carbons flanking the C=O have C-H bonds? LDA will remove the proton selectively from the carbon substituted with the fewest number of hydrogens” however it shows that the pi bond is with the alpha carbon and the beta carbon with more hydrogens. so LDA will remove the proton from the beta carbon with the most hydrogens, ie hoffman product.

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James

Oops – typo, fixed. Thanks for the spot.

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Luke Burke

In resonance forms atoms do not move about. The picture you have of the Li cation being next to the methanide atom and then close to the oxide atom is actually a dynamic equilibrium. (The picture of a free enolate represents resonance.) This is an important distinction because, by Hard-Soft Acid-Base Theory the hard LI+ is more tightly bound to the hard O- leaving the methanide more available for attack while in KDA the the soft K+ binds preferentially to the soft methanide making the oxide more available for attack.

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Parakh

In example 4, the aldol reaction, wouldn’t be Li+ instead of LiBr?
There’s no bromide anywhere in the reactant side.

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Nitish

Sir, beautifully explained. I just have one doubt though. What will happen if end carbons of the isopropyl groups are attached toa strong -I group like NO2? Then will the H+ be abstracted by the LDA from the tertiary carbon atom of the isopropyl group?

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James

That reagent doesn’t make very much sense.

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krunal

why you given reagents name friday reagent.?????

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James

Because it was a fun way to talk about reagents, that’s all.

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Blaise

Under what conditions is LDA nucleophilic? I have a book (science of synthesis, Houben-Weyl) that says it happens in the absence of a weakly acidic proton donor. For example, it can reduce an alkenylphosphenate by 1,2 addition across the double bond with lithium. But it doesn’t go into further detail, and I’m not sure what in particular a weakly acidic proton donor has to do with this reaction. Do you know anything about LDA functioning as a nucleophile? Thanks!

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Shubham

So, basically LDA helps in anti markovnikov reaction mechanisms and hofmann eliminations right ? If that’s the case, then in example 2 shouldn’t the CH3 be on the 3 degree carbon (that’s anti markovnikov)?

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Nehru Ramaiyan

in LDA there is no CO NH bond, but why this is called amide in the name?

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James

They are both called, “amide”. I know it’s confusing.

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Sara

Amazingly explained, thanks! One question tho, how come neither LDA nor LCHIA work with aldehydes?

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James

They add to the aldehyde carbon instead of deprotonating the alpha carbon.

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