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Lithium diisopropylamide

Lithium diisopropylamide (LDA), also known as lithium N,N-diisopropylazanide, is an organolithium compound with the LiN(iPr)2 (where iPr denotes isopropyl), widely recognized as a strong, in . This colorless, pyrophoric solid, typically employed as a solution in (THF) or other ethers, has a molecular weight of 107.12 g/mol and a of approximately 0.79 g/cm³ for its solutions. LDA is prepared by treating with * in an like THF at low temperature, usually −78 °C, to generate the via while minimizing side reactions. In solution, LDA predominantly exists as a disolvated dimer, [LDA·2THF]2, whose aggregation state and profoundly affect its kinetics and selectivity in reactions, often exhibiting half-order dependence on LDA concentration indicative of monomer-dimer equilibria. The compound's primary applications stem from its high basicity (pKa ≈ 36 in THF) and steric bulk, which allow selective of carbon acids—such as ketones, esters, and amides—at the α-position to form lithium under kinetic control, avoiding unwanted nucleophilic additions or thermodynamic equilibration. This capability has made LDA indispensable in , with surveys of over 500 syntheses identifying it as the most frequently used for enolization and metalation steps in constructing complex molecules like pharmaceuticals and natural products. Recent advancements include its adaptation to continuous-flow processes for safer, scalable enolate alkylations and other transformations. Due to its extreme reactivity, LDA poses significant safety hazards: it is highly flammable, ignites spontaneously in air (pyrophoric), reacts violently with water or protic solvents to release flammable gases, and causes severe skin burns, eye damage, and respiratory irritation upon exposure. Handling requires inert atmospheres, low temperatures, and specialized equipment, underscoring its role as a powerful yet demanding tool in modern synthetic chemistry.

Properties

Physical properties

Lithium diisopropylamide possesses the molecular formula \ce{LiN(CH(CH3)2)2} (or \ce{C6H14LiN}) and a of 107.12 g/mol. It exists as a colorless to white solid, often described as a or chunks, and is highly air- and moisture-sensitive, rendering it pyrophoric upon exposure to oxygen. LDA exhibits good solubility in nonpolar organic solvents such as (THF) and , which facilitates its common use in solution form, while showing limited solubility (approximately 10% in ) in hydrocarbons and reacting violently with , precluding solubility therein. It lacks a defined or , decomposing upon heating rather than melting, which underscores its thermal instability above low temperatures (typically stored at 2–8°C). The pKa of its conjugate acid, , is 36 in THF, indicating the strong basicity of LDA in this solvent.

Chemical properties

Lithium diisopropylamide (LDA) serves as a strong, , characterized by the high acidity of its conjugate acid (pKa ≈ 36 in ), enabling selective of weakly acidic C–H bonds while minimizing unwanted due to steric bulk from the diisopropyl groups. This property favors kinetic deprotonation pathways, where less substituted protons are abstracted preferentially under low-temperature conditions. LDA exhibits high reactivity toward protic species, decomposing violently upon contact with water or protic solvents to liberate diisopropylamine and lithium hydroxide; may evolve flammable gases. The solid form is pyrophoric, igniting spontaneously in moist air, whereas solutions in anhydrous tetrahydrofuran (THF) or diethyl ether are stable and non-pyrophoric when handled under inert atmospheres. In aprotic solvents, LDA's reactivity is modulated by aggregation, predominantly forming cyclic dimers that reduce the concentration of monomeric, highly reactive species and thereby influence rates and selectivity. Safety data sheets highlight its corrosivity, noting severe burns, eye , and respiratory upon , along with high flammability. Proper handling requires inert conditions, moisture exclusion, and protective equipment to mitigate these hazards.

Preparation and Structure

Synthesis

Lithium diisopropylamide (LDA) is most commonly prepared in the laboratory by the of with (n-BuLi) in anhydrous (THF) under an inert atmosphere. The procedure involves dissolving (typically 0.51 mol, 51.6 g) in THF (400 mL) in a dry, nitrogen-flushed flask, cooling the to 0 °C using an , and adding n-BuLi (1.7 M in , 0.49 mol, 288 mL) dropwise over 30 minutes with stirring. The resulting LDA is then cooled to -78 °C in a dry ice-acetone bath for 1 hour prior to use. The reaction proceeds according to the equation: (CH_3)_2CHNHCH(CH_3)_2 + n\text{-BuLi} \rightarrow LiN[CH(CH_3)_2]_2 + n\text{-BuH} This method yields LDA as a suitable for immediate application, with the byproduct gas evolving during . For small-scale reactions, LDA is frequently generated in situ by adding n-BuLi to directly in the reaction vessel at -78 °C to ensure kinetic control and minimize side reactions; all operations must exclude air and to prevent or ignition, as LDA is highly reactive toward protic impurities. Alternative alkyllithiums, such as sec-BuLi, can be employed in place of n-BuLi for , though n-BuLi remains the standard due to its availability and milder reactivity. To isolate solid LDA, the THF solution is concentrated under reduced pressure at low temperature, followed by or under inert conditions; a THF-solvated can be crystallized from the concentrated solution and purified by recrystallization from THF or by , yielding a colorless, pyrophoric solid. On an industrial scale, a nonpyrophoric solid form of LDA is produced by reacting metal dispersion with and an electron carrier like styrene in THF at 30–45 °C, followed by to remove excess and insolubles, resulting in a stable, pale yellow solution that can be isolated as a solid.

Molecular structure

Lithium diisopropylamide (LDA) in (THF) predominantly adopts a solvated dimer structure, in which each lithium cation is coordinated to two nitrogen atoms—one from each diisopropylamide —and to oxygen atoms from two THF molecules, forming a tetrahedral coordination environment around . This disolvated dimer is the dominant species observed in THF solutions at typical concentrations used in synthesis. In nonpolar solvents such as , LDA forms higher-order oligomeric structures, including trimers and tetramers, with the aggregation state exhibiting temperature dependence; for instance, at , trimers and tetramers coexist in a 2:1 ratio. These oligomeric forms feature centers bridged by atoms from multiple units, leading to varied coordination geometries. The solid-state crystal structure of LDA, determined in 1991, consists of an infinite helical chain with four diisopropylamide units per helical turn, constructed from near-linear nitrogen-lithium-nitrogen (N-Li-N) linkages that form the backbone. In this arrangement, each lithium is two-coordinate, with unsymmetrical Li-N bonds averaging 1.937 Å (shorter) and 1.957 Å (longer), and average N-Li-N angles of approximately 172.5°, indicating nearly linear at . The nitrogen atoms exhibit near-sp² hybridization, with C-N-Li angles close to 120° in the Li-N-C framework, consistent with partial double-bond character in the N-C bonds due to resonance. Solvation significantly influences LDA's reactivity by modulating its aggregation state; for example, THF solvation stabilizes the reactive dimeric form, while weaker solvation in promotes less reactive higher oligomers, affecting rates and selectivity in transformations.

Applications

Deprotonation reactions

Lithium diisopropylamide (LDA) serves as a key for the selective kinetic of carbonyl compounds, enabling the formation of lithium enolates that are crucial intermediates in . This process exploits LDA's high basicity and steric bulk to target α-hydrogens without competing to the electrophilic . The utility of LDA in deprotonation traces back to its initial synthesis by Hamell and in 1950, who developed hindered lithium amides specifically to achieve α-deprotonation of esters while avoiding carbonyl attack. In their work, LDA effectively generated anions from and related esters, demonstrating its potential for Claisen-type condensations under controlled conditions. For optimal selectivity, deprotonation reactions are typically performed at low temperatures, such as -78 °C, in aprotic solvents like tetrahydrofuran (THF), using 1.1 equivalents of LDA to fully convert the substrate to the kinetic enolate. These conditions minimize equilibration to thermodynamic enolates and suppress side reactions, ensuring the less substituted α-proton is preferentially removed in unsymmetrical substrates. Representative examples include the α-deprotonation of ketones, esters, and nitriles of the general structure HC(Z)R₂, where Z represents C(O)R' for ketones, C(O)OR' for , or CN for nitriles. For instance, undergoes clean at the α-position to form the corresponding lithium , which resists addition to the carbonyl due to LDA's bulkiness. Similarly, is deprotonated at the without ester or addition, yielding a stable suitable for further manipulation. In nitriles like phenylacetonitrile, LDA selectively removes the α-proton adjacent to the cyano group, forming an that avoids nucleophilic attack on the electron-withdrawing CN functionality. The lithium enolates generated by LDA-mediated deprotonation are highly reactive nucleophiles that can be subsequently quenched with electrophiles such as alkyl halides, carbonyl compounds, or aldehydes to produce α-functionalized derivatives. This quenching step, often conducted by warming from -78 °C to after electrophile addition, allows for efficient C-C bond formation while preserving stereochemical control from the kinetic enolate.

Other synthetic uses

Lithium diisopropylamide (LDA) plays a key role in (DoM) reactions, where it selectively deprotonates aromatic compounds at the position relative to a directing group, such as carbamates, amides, or , enabling the formation of organolithium intermediates for subsequent functionalization. For instance, in the ortholithiation of 1-chloro-3-(trifluoromethyl) at -78 °C in , LDA achieves high , allowing with electrophiles to introduce substituents to the . Similarly, regioselective lithiation of halopyridines with LDA under the same conditions provides access to 2-, 3-, and 4-substituted pyridyl lithium species, which are versatile for cross-coupling or addition reactions. Beyond , LDA occasionally participates in under non-standard conditions, particularly when initial metalation is reversed, leading to attack by the anion on electrophiles like activated heterocycles. In the of 2-silylbenzothiazoles, for example, LDA first lithiates the , but autocatalytic reversal promotes nucleophilic attack by LDA itself, yielding products rather than simple deprotonation outcomes. Such behavior is rare due to LDA's steric bulk, which generally suppresses nucleophilicity, but it highlights LDA's dual role in certain kinetic regimes. LDA also facilitates the generation of organolithium from non-acidic precursors, which then undergo further transformations in synthetic sequences. In the lateral metalation of o-tolyl carbamates, LDA directs lithiation to the benzylic position, enabling cyclization to benzofuran-2(3H)-ones upon electrophilic . This approach has been applied in total syntheses, such as the enantioselective construction of cassane-type furanoditerpenoids, where LDA-mediated lithiation installs key units for subsequent ring formation. Additionally, in chemistry, LDA with promotes lithiation followed by addition to carbonyls, contributing to frameworks. Recent advancements include the use of LDA in continuous-flow processes, which allow safer and more scalable formations and alkylations by maintaining low temperatures and precise reagent addition, reducing risks associated with its pyrophoric nature. Despite these utilities, LDA's bulky diisopropyl groups limit its nucleophilic character, favoring over addition in most cases and restricting its use to sterically accessible sites. A comprehensive survey of over 500 total syntheses underscores LDA's prevalence in such niche applications, yet emphasizes the need for low temperatures and aprotic solvents to maintain selectivity.

Comparisons and Alternatives

Kinetic versus thermodynamic bases

In , the choice of base for of carbonyl compounds allows for control over the of enolate formation, distinguishing between kinetic and thermodynamic products. Kinetic bases, such as lithium diisopropylamide (LDA), are strong, sterically hindered non-nucleophilic bases that preferentially deprotonate the less substituted α-carbon of unsymmetrical ketones. This selectivity arises from the lower for proton abstraction at the less hindered site and is typically achieved by conducting the reaction at low temperatures (e.g., -78 °C in THF) to prevent equilibration. Kinetic can be trapped as trimethylsilyl ethers with high regioselectivity. In contrast, thermodynamic bases are weaker and less sterically demanding, such as alkoxides (e.g., sodium ethoxide) or sodium hydride (NaH) in polar aprotic solvents like DMF, leading to the formation of the more stable, more substituted enolate under conditions that allow equilibration. These conditions often involve higher temperatures or protic solvents that facilitate proton transfer, shifting the equilibrium toward the thermodynamically favored product due to greater conjugation and hyperconjugation in the more substituted enolate. Base strength plays a key role, as weaker bases do not fully deprotonate the carbonyl, allowing reversible proton exchange. A representative example is the deprotonation of phenylacetone (1-phenylpropan-2-one), which has α-protons at both the methyl (less substituted) and methylene (more substituted) groups. With LDA at -78 °C, the kinetic enolate forms predominantly at the methyl group with high selectivity, while NaH at room temperature yields the thermodynamic enolate at the methylene group with high selectivity. The interconversion between kinetic and thermodynamic enolates occurs via proton transfer, typically between the enolate and an unreacted ketone molecule. For phenylacetone, this equilibration can be represented as: \text{Kinetic enolate (methyl deprotonated)} + \ce{PhCH2C(O)CH3} \rightleftharpoons \text{Thermodynamic enolate (methylene deprotonated)} + \ce{PhCH2C(O)CH3} Concentration effects influence this process; dilute conditions favor kinetic control by reducing intermolecular proton transfers, while higher concentrations or added proton sources promote equilibration toward the thermodynamic product. Temperature is critical, as raising it (e.g., from -78 °C to 25 °C) accelerates reversibility, and solvent polarity can modulate aggregation of the lithium enolate, further tuning selectivity.

Related organolithium reagents

Lithium diisopropylamide (LDA) is less nucleophilic than (n-BuLi) primarily due to the steric bulk imparted by its diisopropylamide , which hinders approach to electrophilic centers like carbonyl groups. This bulkiness reduces side reactions such as , a common issue with n-BuLi, which has a conjugate acid of approximately 50 and acts more aggressively as both a and . In contrast, LDA's of 36 provides sufficient basicity for selective deprotonations while favoring kinetic control over thermodynamic equilibration. Related organolithium bases include lithium hexamethyldisilazide (LiHMDS) and lithium 2,2,6,6-tetramethylpiperidide (LTMP), both of which function in kinetic deprotonations but offer tuned steric and basicity profiles. LiHMDS, with a of 30, exhibits lower basicity than LDA but greater steric hindrance from its bis(trimethylsilyl)amide structure, rendering it less nucleophilic and ideal for prone to hydride reduction with LDA. LTMP, featuring a of 37, is slightly more basic and the most sterically demanding due to its tetramethylpiperidide ring, resulting in the lowest nucleophilicity and accelerated rates for deprotonating hindered positions—often 5–500 times faster than LDA under comparable conditions. LDA is preferentially chosen over n-BuLi or bulkier alternatives like LTMP for ester deprotonations, where its moderate steric bulk enables quantitative formation of kinetic enolates at the less substituted alpha position without nucleophilic side reactions or over-hindrance that could slow reactivity. For instance, in generating enolates for , LDA's ensures complete of the typically less acidic alpha protons ( ~25) while its bulk promotes . Structurally, LDA, LiHMDS, and LTMP share features as amide-based organolithiums, consisting of a lithium cation coordinated to a deprotonated secondary anion (LiN(R)2), often forming solvated dimers or monomers in ethereal solvents with aggregation influenced by donor ligands like THF or HMPA. This common motif contributes to their strong Lewis acidity and solution behavior, distinguishing them from simpler alkyllithiums like n-BuLi, which aggregate into higher-order clusters.

History and Commercial Aspects

Discovery

Lithium diisopropylamide (LDA) was first prepared in 1950 by Matthew Hamell and Robert Levine at the as part of their investigations into substituted lithium for selective reactions. In their seminal work, they synthesized LDA along with other sterically hindered lithium diorganylamides by reacting with , demonstrating its utility in deprotonating esters at the α-position without promoting competing Claisen condensations. This preparation marked an early example of tailoring bases to minimize nucleophilicity while maintaining strong basicity, addressing limitations of simpler lithium like lithium amide itself. The development of LDA emerged within the broader evolution of organolithium chemistry during the mid-20th century, building on foundational advances in alkyllithium pioneered by researchers such as Henry Gilman in and . Levine's group, active in the late and early 1950s, systematically explored amides as for carbon-carbon bond formation and , recognizing the need for hindered variants to achieve in carbonyl compounds. LDA's steric bulk from the diisopropyl groups rendered it less prone to addition reactions compared to unhindered bases, positioning it as a key innovation in the quest for selective synthetic tools. This context reflected the growing emphasis on non-nucleophilic bases to enable precise control in organic transformations. LDA gained widespread adoption in during the 1970s and 1980s, particularly for generating kinetic enolates under low-temperature conditions in . Chemists like Robert E. Ireland highlighted its role in stereoselective enolizations, as detailed in his 1976 mechanistic proposals, which underscored LDA's monomeric behavior and efficiency in aprotic solvents. By the 1980s, LDA had become a staple reagent in , facilitating directed aldol reactions and alkylations with high . LDA has served as the premier for over 50 years due to its solubility and reactivity profile. A significant milestone in understanding LDA's structure came in 1991 with the first crystallographic analysis, revealing an infinite helical in the solid state composed of near-linear N-Li-N units coordinated by four diisopropylamide ligands per helical turn. This study by William Clegg and Paul A. O'Neil provided of LDA's aggregated , influencing interpretations of its solution behavior and reactivity in synthetic applications.

Availability and production

Lithium diisopropylamide (LDA) is commercially available primarily as solutions to ensure stability and safe handling, with common formulations including 2.0 M concentrations in (THF) mixed with or from suppliers such as and . Other major producers like and Zibo Weiqiang Chemical offer bulk quantities for industrial applications, often customized for pharmaceutical and sectors. These solutions are preferred over solid forms due to the compound's inherent instability outside of solvent environments. Large-scale production of LDA typically employs batch processes, where diisopropylamine is deprotonated by in solvents under inert atmospheres, allowing for controlled reaction conditions in specialized reactors. Emerging continuous flow methodologies are gaining traction for enhanced safety and efficiency, particularly in integrated manufacturing setups that minimize exposure risks during scale-up. Key manufacturers utilize these approaches to meet growing demands from industries. Production faces significant challenges related to the compound's , especially when handling solid intermediates or during , necessitating rigorous exclusion of air and moisture to prevent ignition. Achieving high purity—often exceeding 97%—is critical for downstream applications, as impurities like residual amines or salts can compromise reaction selectivity, requiring advanced and analytical quality controls in manufacturing. As of , the global LDA market is valued at approximately USD 150 million, driven by pharmaceutical , with solution prices ranging from USD 200–500 per liter for standard lab quantities and lower for bulk industrial orders. Market trends indicate an 8.5% through 2033, fueled by expanded use in complex molecule synthesis, though bulk users increasingly opt for on-site generation from precursors to mitigate costs and logistics. Regulatory frameworks for LDA handling emphasize its classification as a hazardous, pyrophoric, and corrosive material. In laboratory settings, OSHA guidelines mandate use in fume hoods with and purging, while industrial operations comply with EPA and REACH requirements for and environmental impact assessments. Transportation falls under regulations as a (UN 2924), requiring UN-approved containers and labeling to ensure safe global distribution.