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
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.
(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
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
Tetrahedron 1976, 32 (24), 2979-2990
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
- 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
- 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
- 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
A paper from J. Chem. Ed. that covers how to demonstrate the concepts of kinetic and thermodynamic enolates in an undergraduate laboratory session.