diisopropylamide

Diisopropylamide most often refers to the lithium salt of diisopropylamine, lithium diisopropylamide (LDA). It is a strong, non-nucleophilic base widely used in organic synthesis to deprotonate carbonyl compounds and related substrates to form enolates.

Preparation and structure: LDA is typically prepared in situ by treating diisopropylamine with n- or sec-butyllithium in anhydrous tetrahydrofuran (THF) or diethyl ether at very low temperature, commonly around -70 to -78 °C. The resulting solution contains LiN(i-Pr)2, usually as a coordination complex with solvent and lithium alkyls. The reagent is moisture sensitive and is used under inert conditions.

Properties and use: The diisopropylamido anion is bulky and highly basic, yet its nucleophilicity is suppressed by steric hindrance. It is used to generate enolates by deprotonating ketones, esters, and other carbonyl substrates, favoring the kinetic enolate at low temperature. The resulting enolate can be alkylated, acylated, or trapped with electrophiles such as alkyl halides or aldehydes, enabling alpha-substitution of carbonyl compounds after hydrolysis or further transformation.

Alternatives and variations: Sodium diisopropylamide and potassium diisopropylamide are analogous bases using Na+ or K+ instead of Li+. LDA remains the most widely used due to its solubility in common organic solvents and its well-characterized behavior in enolate chemistry. Variations include different solvent systems and temperatures to optimize kinetic versus thermodynamic control.

Safety: LDA is a strong base and moisture sensitive, reacting vigorously with water and air. It should be handled under inert atmosphere in dry solvents, with appropriate personal protective equipment. Solvents and reagents are often flammable and corrosive, requiring careful handling and proper storage.

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