Organic Reagents
Reagent Friday: Lithium Di-isopropyl Amide (LDA)
Last updated: February 21st, 2020 |
Lithium Diisopropyl Amide (LDA), A Strong, Sterically Hindered Base
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.
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.
Formation Of Less Hindered (“Kinetic”) Enolates With LDA
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:
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).
Alkylation, Halogenation, And Aldol Reaction Of Enolates Obtained With Lithium Diisopropylamide
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.
Formation of Less-Substituted Alkenes (“Non-Zaitsev” or “Hoffmann” Products) In Elimination Reactions
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:
Formation Of Less Substituted Enolates With LDA: Mechanism
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.
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.
(Advanced) References and Further Reading
- THE α-ALKYLATION OF ENOLATES FROM THE LITHIUM-AMMONIA REDUCTION OF α,β-UNSATURATED KETONES
Gilbert Stork, Perry Rosen, and Norman L. Goldman
Journal of the American Chemical Society 1961, 83 (13), 2965-2966
DOI: 10.1021/ja01474a051
This paper has one of the first descriptions of kinetic enolate formation in the literature – “The success of the trapping of the enolate ion IV depends on the alkylation reaction being faster than equilibration of the initially produced enolate IV to the more stable II via proton transfer with some initially formed neutral alkylated ketone.” - Tetrahedron report number 25: Ketone enolates: regiospecific preparation and synthetic uses
Jean d’Angelo
Tetrahedron 1976, 32 (24), 2979-2990
DOI: 10.1016/0040-4020(76)80156-1
This review covers various methods for enolate formation, and has data on the composition of various ketone-enolate mixtures formed under kinetic and thermodynamic conditions.Prof. H. O. House (MIT, then Georgia Tech) published a series of papers on carbanion and enolate chemistry, studying kinetic and thermodynamic enolate formation in detail. A selection of these papers is below: - The Chemistry of Carbanions. V. The Enolates Derived from Unsymmetrical Ketones
Herbert O. House and Vera Kramar
The Journal of Organic Chemistry 1963, 28 (12), 3362-3379
DOI: 10.1021/jo01047a022 - The Chemistry of Carbanions. IX. The Potassium and Lithium Enolates Derived from Cyclic Ketones
Herbert O. House and Barry M. Trost
The Journal of Organic Chemistry 1965 30 (5), 1341-1348
DOI: 10.1021/jo01016a001 - Chemistry of carbanions. XV. Stereochemistry of alkylation of 4-tert-butylcyclohexanone
Herbert O. House, Ben A. Tefertiller, and Hugh D. Olmstead
The Journal of Organic Chemistry 1968, 33 (3), 935-942
DOI: 10.1021/jo01267a002 - Thermodynamic and Kinetic Controlled Enolates: A Project for a Problem-Oriented Laboratory Course
Augustine Silveira Jr., Michael A. Knopp, and Jhong Kim
Journal of Chemical Education 1998, 75 (1), 78
DOI: 1021/ed075p78
A paper from J. Chem. Ed. that covers how to demonstrate the concepts of kinetic and thermodynamic enolates in an undergraduate laboratory session.
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.
Oops – typo, fixed. Thanks for the spot.
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.
In example 4, the aldol reaction, wouldn’t be Li+ instead of LiBr?
There’s no bromide anywhere in the reactant side.
The above example of shark is mind blowing. Helped understand the reagent in one stroke.
Glad to hear it!
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?
That reagent doesn’t make very much sense.
why you given reagents name friday reagent.?????
Because it was a fun way to talk about reagents, that’s all.
Is LDA basic enough to abstract the proton from a tertiary alcohol? I’ve seen NaH used but being non-soluble, the reaction can only take place on the interface of the NaH and the tertiary alcohol.
I’ve also seen some recent work in which erbium triflate is used as a catalyst for ether formation from alcohols. Makes sense, but then the choice of methylating agent becomes more limited due to solubility issues.
Oh, absolutely. pKa of tertiary alcohol is about 18, pKa of diisopropylamine is about 36.
Question is why would you want to use LDA? NaH is fine, especially in an ethereal solvent like THF that can coordinate to the sodium.
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!
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)?
in LDA there is no CO NH bond, but why this is called amide in the name?
They are both called, “amide”. I know it’s confusing.
this may because of the the parent compound from which it has been prepared was an amide
NaNH2 calledd sodamide and LiNH2 called lithium amide
in LDA, two hydrogens replaced by isopropyl group and hence called lithium diisopropylamide
Amazingly explained, thanks! One question tho, how come neither LDA nor LCHIA work with aldehydes?
They add to the aldehyde carbon instead of deprotonating the alpha carbon.
1) What is the effect of preparing LDA at higher temperature like -20 C?
2) Is LDA formation instantaneous at -20 C?
LDA formation would essentially be instantaneous at –20 °C. In fact it’s not uncommon to make the LDA at sub-zero temperature and then cool it to -78 prior to using it for enolate formation.
This might be slightly off topic. My textbook mentions that lithium enolates cannot participate in conjugate addition, only direct carbonyl addition because the lithium coordinates with the electrophile’s carbonyl oxygen and the reaction occurs through a cyclic chair-like transition state. Do you perhaps have any insight on that because I have a bunch of homework problems which does agree with this
does not*
TL;DR Your textbook is pretty much correct. “Cannot” is a pretty strong word, because there are always exceptions*, but on the whole it’s a good rule of thumb.
More detail: It depends on the nature of the carbonyl. Alpha,beta unsaturated aldehydes, for instance, will almost always undergo 1,2 addition. With alpha beta unsaturated ketones, and especially alpha beta unsaturated esters, there is a lot of wiggle room. [1,4 addition to an ester is particularly favoured vs 12 addition, since you’re going from a ketone enolate to a (less stable) ester enolate.] The steric hindrance around the carbonyl and the beta position will also be important, as will the choice of solvent. Since you’re likely dealing with an advanced textbook, I’ll use the more advanced terminology “hard” and “soft”.
A lithium enolate is a relatively “hard” nucleophile and is more likely to react at the “hard” carbonyl electrophilic site. Lithium ion coordination would help with this, as would solvents that facilitate aggregation (e.g. ethereal solvents like THF and Et2O).
It’s possible to favor 1,4 addition by using a base with a larger, less-coordinating counterion (such as potassium instead of lithium) and using a polar aprotic “co-solvent” such as HMPA which will break up aggregation. These reactions tend to go through open transition states rather than through the Zimmerman-Traxler six-membered transition state that you mentioned.
*Exceptions? Sure. Like if you formed a lithium enolate in a molecule which also contained an alpha beta unsaturated ketone, and 1,4-addition would form a 5 or 6 membered ring. Much faster than 1,2 addition in that case, due to ring closure rates.
Another example would be sterically hindered ketones.
Digging through my copy of March (5th ed) chapter 15 on addition to C-C multiple bonds doesn’t mention a specific prohibition of lithium enolates in 1,4 addition, but it’s not uncommon to see people use a Mukaiyama-Michael or a Sakurai reaction (using a Lewis acid in the presence of a silyl enol ether) to perform a 1,4 addition instead of the lithium enolate, likely for the reasons you mentioned.
Thanks for the great question.
how LDA reacts with heptanedinitrile or cn-ch2-ch2-ch2-ch2-ch2-cn
Deprotonates the carbon adjacent to CN
Does NaNH2 also give Hoffmann product like LDA in dehydrohalogenation?
No, since NaNH2 is small, I would expect it to give the Zaitsev product.
Though there is no amide group then why LDA is named as lithium Di isopropyl amide?
Confusingly, the term “amide” refers both to a deprotonated amine, and also a carbonyl derivative with a nitrogen substituent.
Will there be a change in mechanism for the reaction at room temperature?
No, but there will be a change in selectivity. It won’t be as selective for the less substituted enolate at a higher temperature.
Hello,
do you know in what cases we’d use n-BuLi over LDA?
Why LDA, NaNH2 called as amide even without amide functionality in it. Thank You
Because chemists use the word “amide” to describe two completely different functional groups: the conjugate bases of amines (e.g. sodium amide) and also carboxylic acid derivatives with nitrogens adjacent to the carbonyl. That’s just the way it is.
What does LDA do if you have equal substitution at either side of the ketone? Is it possible to can count carbons to determine least substituted (if we had methyl vs, ethyl, not isopropyl, for example in #2). In this case will addition occur on the side of the methyl?
Not sure about methyl vs ethyl, but methyl vs. primary alkyl gives about 95:5 favoring the methyl, so long as it is kept at -78 and the enolate isn’t allowed to equilibrate.
How to decompose LDA?
Why do you want to decompose it? Just cool it in an ice bath and (slowly) add saturated NH4Cl as a mild acid.
Uhm, the reaction of NaNH2 is with a terminal alkyne. Can internal alkynes react with NaNH2?
The pKa of the CH3 adjacent to a triple bond is at least 40, so without significant heating, no.
Why does it have amide in the end, even though amide linkage is not seen in LDA ?
Confusingly, the name for the amide linkage you speak of, and the name of the conjugate base of an amine are both “amide”. Some chemists pronounce the two differently but that doesn’t really translate to the written word. It’s helpful to use the term “metal amide” when referring to the conjugate base – this differentiates it from the (neutral) functional group.