Lithium diisopropylamide

Lithium diisopropylamide is the chemical compound with the formula [(CH₃)₂CH]₂NLi. Generally abbreviated LDA, it is a strong base, used in organic chemistry for the deprotonation of hydrocarbons. The reagent has been widely accepted because it is soluble in non-polar organic solvents and it is non-pyrophoric. LDA is a non-nucleophilic base.

Additional recommended knowledge

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Preparation and structure

LDA is commonly formed by treating a cooled (0 to -78 °C) THF solution of diisopropylamine with n-butyllithium. Diisopropylamine has pKa value of 36; therefore, it is suitable for the deprotonation of most common carbon acids including alcohols and carbonyl compounds (acids, esters, aldehydes and ketones) possessing an alpha carbon with hydrogens. In THF solution, LDA exists primarily as a dimer^[1][2] and is proposed to dissociate to afford the active base.

LDA is commercially available as a solution with polar, aprotic solvents such as THF and ether, though in practice and for small scale use (less than 50 mmol) it is common (and actually more cost effective) to prepare LDA in situ.

Kinetic vs thermodynamic bases

The deprotonations of carbon acids can proceed with either kinetic or thermodynamic reaction control. Kinetic controlled deprotonation requires a base that is sterically hindered. For example in the case of phenylacetone, deprotonation can produce two different enolates. LDA has been shown to deprotonate the methyl group, which is the kinetic course of the deprotonation. A weaker base such as an alkoxide, which reversibly deprotonates the substrate, affords the more thermodynamically stable benzylic enolate. An alternative to the weaker base is to use a strong base which is present at a lower concentration than the ketone. For instance a slurry of sodium hydride in THF or DMF, the base only reacts at the solution-solid interface. It is the case that a ketone molecule might deprotonate at the kinetic site, this enolate will then encounter other ketone molecules. The thermodynamic enolate will form through the exchange of protons, even in an aprotic solvent which does not contain hydronium ions.

It is important to note that LDA can still act as a nucleophile, for instance it can react with tungsten hexacarbonyl as part of the synthesis of a diisopropylaminocarbyne.^{[citation needed]} If given the proper conditions, LDA will act like any other nucleophile and perform condensation reactions. Other even more hindered amide bases are known, for instance the deprotonation of hexamethyldisilazane (Me₃SiNHSiMe₃) forms such a base ([(Me₃SiNSiMe₃]^-).

References

1. ^ Williard, P. G.; Salvino, J. M. (1993). "Synthesis, isolation, and structure of an LDA-THF complex". Journal of Organic Chemistry 58 (1): 1-3. doi:10.1021/jo00053a001.
2. ^ (1991) "Crystal structure of lithium diisopropylamide (LDA): an infinite helical arrangement composed of near-linear nitrogen-lithium-nitrogen units with four units per turn of helix". Journal of the American Chemical Society 113 (21). doi:10.1021/ja00021a066.

Further reading

• http://www-oc.chemie.uni-regensburg.de/OCP/ch/chb/oc5/Enolate_Chemistry.pdf
• Non-nucleophilic Bases Helsinki University of Technology