Lithium diisopropylamide

Lithium diisopropylamide

Overview
Lithium diisopropylamide is the chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

 with the formula [(CH3)2CH]2NLi. Generally abbreviated LDA, it is a strong base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 used in organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 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.
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Encyclopedia
Lithium diisopropylamide is the chemical compound
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

 with the formula [(CH3)2CH]2NLi. Generally abbreviated LDA, it is a strong base
Base (chemistry)
For the term in genetics, see base A base in chemistry is a substance that can accept hydrogen ions or more generally, donate electron pairs. A soluble base is referred to as an alkali if it contains and releases hydroxide ions quantitatively...

 used in organic chemistry
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 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 and structure



LDA is commonly formed by treating a cooled (0 to −78 °C) tetrahydrofuran
Tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...

 (THF) solution of diisopropylamine
Diisopropylamine
Diisopropylamine is a secondary amine with the chemical formula 2HC-NH-CH2. It is best known as its lithium salt, lithium diisopropylamide, known as "LDA"...

 with n-butyllithium
N-Butyllithium
n-Butyllithium is an organolithium reagent. It is widely used as a polymerization initiator in the production of elastomers such as polybutadiene or styrene-butadiene-styrene...

.

Diisopropylamine has pKa
PKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...

 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 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 more cost effective to prepare LDA in situ.

Kinetic vs thermodynamic bases


The deprotonation of carbon acids can proceed with either kinetic or thermodynamic reaction control
Thermodynamic reaction control
Thermodynamic reaction control or kinetic reaction control in a chemical reaction can decide the composition in a reaction product mixture when competing pathways lead to different products and the reaction conditions influence the selectivity...

. Kinetic controlled deprotonation requires a base that is sterically hindered. For example, in the case of phenylacetone
Phenylacetone
Phenylacetone , is an organic compound. It is a clear oil with a refractive index of 1.5168. This substance is used in the manufacture of methamphetamine and amphetamine as a starting material or intermediate, where it is commonly known as P2P...

, 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
Alkoxide
An alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They can be written as RO−, where R is the organic substituent. Alkoxides are strong bases and, when R is not bulky, good nucleophiles and good ligands...

, 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, with a slurry
Slurry
A slurry is, in general, a thick suspension of solids in a liquid.-Examples of slurries:Examples of slurries include:* Lahars* A mixture of water and cement to form concrete* A mixture of water, gelling agent, and oxidizers used as an explosive...

 of sodium hydride
Sodium hydride
Sodium hydride is the chemical compound with the empirical formula NaH. It is primarily used as a strong base in organic synthesis. NaH is representative of the saline hydrides, meaning it is a salt-like hydride, composed of Na+ and H− ions, in contrast to the more molecular hydrides such as...

 in THF or dimethylformamide
Dimethylformamide
Dimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...

 (DMF), the base only reacts at the solution-solid interface. A ketone molecule might be deprotonated at the kinetic site. This enolate may then encounter other ketone
Ketone
In organic chemistry, a ketone is an organic compound with the structure RCR', where R and R' can be a variety of atoms and groups of atoms. It features a carbonyl group bonded to two other carbon atoms. Many ketones are known and many are of great importance in industry and in biology...

s and the thermodynamic enolate will form through the exchange of protons, even in an aprotic solvent which does not contain hydronium ions.

LDA can, however, act as a nucleophile under certain conditions. For instance, it can react with tungsten hexacarbonyl
Tungsten hexacarbonyl
Tungsten hexacarbonyl is the chemical compound with the formula W6. This complex gave rise to the first example of a dihydrogen complex....

 as part of the synthesis of a diisopropylaminocarbyne. 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]-).

Reactions


Owing to its high basicity, LDA is capable, for example, of deprotonating alkenyl halides and even enol ether
Enol ether
An enol ether is an alkene with an alkoxy substituent. The general structure is R_1R_2C=CR_3-O-R_4 with R an alkyl or an aryl group. Enol ethers and enamines are so-called activated alkenes or electron rich alkenes because the oxygen atom donates electrons to the double bond by forming a resonance...

s, giving a mixture of allene and alkyne products.