Lithium diisopropylamide
[CAS# 4111-54-0]

Identification

• Classification: Organic raw materials >> Organometallic compound >> Organic lithium
• Name: Lithium diisopropylamide
• Molecular Formula: C₆H₁₄LiN
• Molecular Weight: 107.12
• CAS Registry Number: 4111-54-0
• EC Number: 223-893-0
• SMILES: [Li+].CC(C)[N-]C(C)C

Properties

• Density: 0.812 g/mL (25 °C) (Expl.)
• Flash point: 2 °C (closed cup) (Expl.)
• Water solubility: decomposes (Expl.)

Safety Data

• Hazard Symbols: GHS02;GHS05 Danger
• Risk Statements: H228-H250-H314-H318
• Safety Statements: P210-P222-P231-P233-P240-P241-P260-P264-P264+P265-P280-P301+P330+P331-P302+P335+P334-P302+P361+P354-P304+P340-P305+P354+P338-P316-P317-P321-P363-P370+P378-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin corrosion	Skin Corr.	1B	H314
Pyrophoric solids	Pyr. Sol.	1	H250
Serious eye damage	Eye Dam.	1	H318
Flammable solids	Flam. Sol.	1	H228
Skin corrosion	Skin Corr.	1A	H314
Flammable liquids	Flam. Liq.	1	H224

• Transport Information: UN 3393

Discovery and Applications

Lithium diisopropylamide (LDA) is a highly versatile and strong organometallic base widely used in organic synthesis. It was first introduced in the early 1960s as a powerful tool for inducing deprotonation in a variety of organic compounds, enabling the formation of highly reactive intermediates such as enolates, which are essential for a range of organic reactions. LDA consists of a lithium cation (Li+) and a diisopropylamide anion ([(CH3)2CH]2N−), and it is typically prepared by reacting lithium metal with diisopropylamine in anhydrous conditions, usually in the presence of a non-polar solvent like tetrahydrofuran (THF).

The discovery of LDA arose from the need for stronger and more selective bases in synthetic chemistry. Diisopropylamine, being a relatively weak base by itself, when combined with lithium metal, creates a much stronger base, with the ability to deprotonate even less acidic compounds. This increased reactivity and selectivity have made LDA an indispensable reagent in organic laboratories and industries alike.

One of the key applications of LDA is in the generation of enolates. Enolates are highly reactive intermediates formed by the deprotonation of carbonyl compounds, such as aldehydes and ketones. These intermediates can then undergo nucleophilic addition reactions with electrophiles to form carbon-carbon bonds, which is crucial in a wide variety of organic transformations, including aldol condensations, Michael additions, and the synthesis of β-hydroxy ketones and aldehydes. LDA is particularly effective in generating enolates from sterically hindered ketones, which are otherwise difficult to deprotonate with weaker bases.

LDA is also employed in the synthesis of complex molecules and natural products. In particular, it is used in the preparation of organometallic intermediates, which can participate in various cross-coupling reactions such as the Aldol reaction, Suzuki coupling, and Negishi coupling. These reactions are crucial in the development of pharmaceuticals, agrochemicals, and functional materials. LDA's ability to generate reactive intermediates with high regioselectivity makes it an essential tool for creating molecular diversity.

Another notable application of LDA is in the deprotonation of heteroatom-containing compounds, such as amides and imides. LDA has been shown to effectively induce deprotonation in these compounds, enabling the formation of heterocyclic intermediates, which are important in the synthesis of biologically active compounds. Moreover, LDA is used in reactions that require the selective removal of hydrogen atoms from specific positions in molecules, making it a valuable reagent in asymmetric synthesis and stereoselective reactions.

The high basicity and reactivity of LDA, however, require careful handling and storage. The reagent is highly sensitive to moisture and must be kept under dry, inert conditions to prevent decomposition. Additionally, LDA reacts violently with water, forming diisopropylamine and lithium hydroxide, which can be hazardous. Thus, it is essential for users to work with LDA in an anhydrous, controlled environment, typically under an inert atmosphere such as nitrogen or argon.

Despite these safety precautions, LDA remains one of the most widely used reagents in synthetic chemistry due to its effectiveness and versatility. Its ability to facilitate the formation of reactive intermediates in a highly controlled and selective manner has made it indispensable in the synthesis of complex organic molecules, particularly in the fields of medicinal chemistry, materials science, and fine chemical production.

References

2008. Autocatalysis in Lithium Diisopropylamide-Mediated Ortholithiations. Journal of the American Chemical Society, 130(48).
DOI: 10.1021/ja807331k

2020. Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists. Nature Chemistry, 12(3).
DOI: 10.1038/s41557-019-0413-8

2016. Advances in the synthesis of α-quaternary α-ethynyl α-amino acids. Amino Acids, 48(10).
DOI: 10.1007/s00726-016-2276-2