Lithium diisopropylamide (LDA)-Preparation and usage

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 weakly acidic compounds. 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. Potassium diisopropylamide (KDA) is a similar compound, but it has a potassium cation instead of a lithium cation.  LDA is cheaper than KDA and is more widely used.

Preparation:

In the preparation of lithium diisopropylamide (LDA), the only other product is the gaseous alkane butane.  Because of its solubility in THF, LDA is a widely used base for enolate anion formation. In this application one equivalent of diisopropylamine is produced along with the lithium enolate, but this normally does not interfere with the enolate reactions and is easily removed from the products by washing with aqueous acid.

                

(2R,5S)-2-tert-Butyl-5-methyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one: In a 250-mL, round-bottomed flask equipped with a magnetic stirrer, 18.3 mL (0.131 mol) of diisopropylamine is mixed with 120 mL of dry tetrahydrofuran (THF) under argon. At −78 °C bath temperature, 88.6 mL of a 1.6 M solution of butyllithium (0.142 mol) in hexane is added and the mixture is allowed to warm to room temperature for 20 min. After the mixture is recooled to −78 °C, the lithium diisopropylamide (LDA) solution is added over a period of 20 min to a solution of 20.0 g (0.109 mol) of (2R,5S)-2-tert-butyl-1-aza-3-oxabicyclo[3.3.0]octan-4-one in 600 mL of dry THF in a 1-L, round-bottomed flask, precooled to −78 °C. Tetrahydrofuran (20 mL) is used to rinse the 250-mL flask. After keeping the resulting solution at −78 °C for 45 min, 8.8 mL (0.142 mol) of iodomethane   is added over a period of 10 min. The resulting mixture is allowed to warm to 0 °C over a period of 3 hr, and 300 mL of a saturated aqueous solution of ammonium chloride is added. After separation, the organic layer is washed with 300 mL each of saturated aqueous solutions of sodium carbonate and brine. Each aqueous layer is extracted twice with 200 mL of ethyl acetate. The combined organic layers are dried over magnesium sulfate and the solvent is removed in a rotary evaporator at ca. 15 mm. Traces of solvent are removed by drying the residue at 60 °C/0.05 mm for 2 hr under an oil pump vacuum to yield19.8–20.5 g (0.100–0.104 mol, 93–95%) of the desired product. It is used directly in the next step.

Reference: Organic Syntheses, Coll. Vol. 9, p.626 (1998); Vol. 72, p.62 (1995)

Stability:

Since i-Pr₂NLi is a sufficiently strong base to deprotonate and cleave solvents such as Et₂O, THF, and especially DME and HMP [(Me₂N)₃PO] at temperatures above 0 ^oC, it is not practical to prepare stock solutions of i-Pr₂NLi in these solvents. However, we have found that if commercial solutions of n-BuLi in hexane are diluted with additional hexane or pentane and then treated with 1 molar equiv of i-Pr₂NH, stable solutions of i-Pr₂NLi (0.5-0.6 M) in hexane or hexane-pentane mixtures are formed. Provided that these hexane solutions are not cooled or concentrated to induce the irreversible separation of solid i-Pr₂NLi, they may be standardized (titration with 2,2'-bipyridyl indicator) and stored at 25 ^oC without deterioration for weeks. Thus, it is especially convenient to prepare solutions of i-Pr₂NLi for reactions by adding a known volume of the stable hexane solution to the desired volume of cold (<O ^oC) ethereal solvent such as Et₂0 or THF.