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Organic Reagents

By James Ashenhurst

Reagent Friday: Lithium Di-isopropyl Amide (LDA)

Last updated: October 16th, 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. 

LDA-is-like-a-hammerhead-shark

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:

lda-lithium-diisopropyl-amide-in-the-formation-of-kinetic-enolates-from-ketones

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.

alkylation-of-enolates-using-lda-through-formation-of-the-least-substituted-enolate

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:

da-as-a-base-for-forming-the-hofmann-less-substituted-alkene-product

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.

mechanism for lda used to form the least substituted ketone enolate

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

  1. 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.”
  2. 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:
  3. 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
  4. 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
  5. 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
  6. 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.

 

00 General Chemistry Review
01 Bonding, Structure, and Resonance
02 Acid Base Reactions
03 Alkanes and Nomenclature
04 Conformations and Cycloalkanes
05 A Primer On Organic Reactions
06 Free Radical Reactions
07 Stereochemistry and Chirality
08 Substitution Reactions
09 Elimination Reactions
10 Rearrangements
11 SN1/SN2/E1/E2 Decision
12 Alkene Reactions
13 Alkyne Reactions
14 Alcohols, Epoxides and Ethers
15 Organometallics
16 Spectroscopy
17 Dienes and MO Theory
18 Aromaticity
19 Reactions of Aromatic Molecules
20 Aldehydes and Ketones
21 Carboxylic Acid Derivatives
22 Enols and Enolates
23 Amines
24 Carbohydrates
25 Fun and Miscellaneous
26 Organic Chemistry Tips and Tricks
27 Case Studies of Successful O-Chem Students

Comments

Comment section

50 thoughts on “Reagent Friday: Lithium Di-isopropyl Amide (LDA)”

    1. LDA will not attach, but it may be strong enough to form an aryne. For example one could deprotonate C-H and elimination of the best leaving group (Cl) would give an aryne, which could then undergo attack by a nucleophile. When the nucleophile does attack, it will likely do so such that the negative charge is placed closer to the electron withdrawing fluoro groups.
      See this artice on arynes – possibly helpful. https://www.masterorganicchemistry.com/2018/09/17/nucleophilic-aromatic-substitution-2-benzyne/

      Reply

    1. 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.

      Reply

  6. 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?

    Reply

    1. 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.

      Reply

    1. 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.

      Reply

  11. Hi James,
    I love your site! I understand basically how LDA works, thanks so much for that. I do have a situation question to better understand. I get that if you are adding an alkyl halide to a carbonyl compound it will add to the least substituted carbon. However, if you are adding a dihalide alkene, where will the akyl compound attach? Is it still least substituted (due to bulky nature)? Is it always the end halide? IE: If we have 1,2 dibromo but-2-ene, will it attach at the 1 carbon because it always attaches at the end? Or the 1 carbon because it’s least substituted? Or the 2 carbon because things like to mess with double bonds? Or a mixture because both are likely to happen? Does it matter if the butene is cis or trans (since that makes the 2 carbon more or less accessible)? Thanks, just trying to understand better how this mechanism works.

    Reply

    1. Alkylation of enolates with alkyl halides is an SN2 reaction, and SN2 reactions will only occur at sp3-hybridized carbons. In the reaction you describe, only the 1-carbon is sp3-hybridized, and thus the enolate will perform substitution at C-1. The C-Br bond at C2 will be unaffected. Sorry for taking so long to get back to you.

      Reply

  14. 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

    Reply

    2. 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.

      Reply

    1. 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.

      Reply

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

    Reply

    2. NaNH2 calledd sodamide and LiNH2 called lithium amide
      in LDA, two hydrogens replaced by isopropyl group and hence called lithium diisopropylamide

      Reply

  18. 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)?

    Reply

  19. 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!

    Reply

  20. 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.

    Reply

    1. 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.

      Reply

  22. 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?

    Reply

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

    Reply

  25. 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.

    Reply

  26. 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.

    Reply

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