Organolithium reagent

An organolithium reagent is an organometallic compound with a direct bond between a carbon and a lithium atom. As the electropositive nature of lithium puts most of the charge density of the bond on the carbon atom, effectively creating a carbanion, organolithium compounds are extremely powerful bases and nucleophiles.

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Production

Organolithium reagents are industrially prepared by the reaction of an halocarbon with lithium metal, i.e. R-X + 2 Li → R-Li + LiX.^[1] A side reaction of this synthesis, especially with alkyl iodides, is the Wurtz reaction, in which an R-Li species reacts with an R-X species forming an R-R coupled product. This side reaction can be almost completely avoided by using alkyl chlorides or bromides.

A second method is the reaction of an alkyl halide with a radical anion lithium salt, such as lithium naphthalide. These radical anions can be prepared by the reduction of an aromatic system such as naphthalene with metallic lithium. As the organic reduction of alkyl halides is much faster with radical anions than it is with direct reaction with lithium metal, this reactions enables a number of more exotic organolithium compounds to be prepared.

A third method involves the metal-halogen exchange between an organic halide compound and an organolithium species. As this is an equilibrium reaction, the equilibrium lies towards the most electronegative organometallic compound, which stabilizes the carbanion the best. This method is usually used with halide compounds that are generally unreactive towards metallic lithium, such as aryl-, vinyl- and ethynyl halides. The only prerequisite is that the halide compound is substantially more electronegative than butyllithium.

A fourth method is another exchange, this time between an organolithium compound and another organometallic compound. This is again an equilibrium reaction, where the most electropositive metal (lithium) will end up attached to the most electronegative organic group. An example is the synthesis of vinyllithium out of tetravinyltin and phenyllithium. Vinyllithium is very difficult to prepare with other methods.

A fifth method is the deprotonation of organic compound with an organolithium species, an acid-base reaction.

Structure

In solution organolithium reagents are aggregated with lithium coordinating to more than one carbon atom. For instance methyllithium in THF at 1M is a tetramer, n-butyllithium in benzene at 3M is a hexamer and in THF at 1M a tetramer. t-BuLi in THF is a dimer. Isopropyllithium in cyclopentane is a mixture of hexamer, oktamer and nonamer.

Different organolithium aggregation states are encountered in the simple deprotonation of the terminal alkyne (phenylthio)acetylene by n-butyllithium in THF at -135°C, a process that can be followed by ⁷Li NMR spectroscopy ^[2]:

The cubane-like tetramer A is hardly reactive compared to the dimer B which forms first mixed-dimer species C and ultimately homodimer D. In fact the dimer is more reactive than the tetramer by a factor 3.2x10⁸.

Uses

Organolithium compounds are strongly polarised by the electropositive character of lithium. They are therefore highly reactive nucleophiles and react with almost all types of electrophiles. They are comparable to Grignard reagents, but are much more reactive. Due to this reactivity they are incompatible with water, oxygen, and carbon dioxide, and must be handled under a protective atmosphere such as nitrogen or, preferably, argon.

A common use of simple commercially available organolithium compounds (like n-BuLi, sec-BuLi, t-BuLi, MeLi, PhLi) is as very strong bases. Organolithium compounds can deprotonate almost all hydrogen-containing compounds (the metalation or Li/H exchange reaction), with the exception of alkanes. In principle, a deprotonation can go to completion if the acidic compound is 2 pK_A units stronger than the lithium species, although in practice a larger pK_A difference is required for useful rates of deprotonation of weakly acidic C-H acids. As alkyl groups are weakly electron donating, the basicity of the organolithium compound increases with the number of alkyl substituents on the charge-bearing carbon atom. This makes tert-butyllithium the single strongest base that is commercially available, with a pKa greater than 53. The metalation reaction is an important synthetic method for the preparation of many organolithium compounds. Some examples are shown below:

Organolithium compounds are also commonly used for nucleophilic addition reactions to carbonyl compounds and other carbon electrophiles. Deprotonation can be a side reaction with enolizable carbonyl compounds, especially with hindered organolithium reagents such as t-butyllithium. Grignard reagents, although much less reactive, are an alternative in addition reactions, with less problems with deprotonation.

An important use of organolithium reagents is in the preparation or other organometallic compounds, usually by reaction with metal halides. Especially important in synthetic organic chemistry is the formation of organocopper reagents (including Gilman reagents) by reaction of RLi with CuI or CuBr, and the preparation of organozinc reagents by reaction with ZnCl₂. Even Grignard reagents are sometimes prepared by reaction of RLi with MgBr₂, in situations where the lithium reagent (but not the Grignard) can be easily prepared by a metalation reaction. Organotin, organosilicon, organoboron, organophosphorus, and organosulfur compounds are also frequently prepared by reaction of RLi with appropriate electrophiles.

The most commonly used organolithium reagents are methyllithium (CH₃Li), n-butyllithium and tert-butyllithium ((CH₃)₃CLi). A recent review of process chemistry indicates that the following are the most commonly used organolithium reagents: butyllithium, hexyllithium, sec-butyllithium, and phenylithium.^[3] Two very commonly used strong bases prepared using butyllithium are lithium diisopropylamide (LDA), and lithium hexamethyldisilazide (LiHMDS).

Aryllithium derivatives are intermediates in directed ortho metalation such as Me₂NCH₂C₆H₄-2-Li obtained from dimethylbenzylamine and butyllithium.

Reactivity

Some general reactions of organolithium compounds are:

• Protonation in reaction with any compound containing acidic protons
• Reaction with ketones and aldehydes to alcohols ^[4].
• Reaction with carboxylic acid salts and acid chlorides to the corresponding ketone ^[5]
• Reaction with oximes to the corresponding amines ^[4].
• Reaction with isonitriles to the corresponding lithium aldimine. Subsequent hydrolysis effectively converts the organolithium compound to its aldehyde ^[6]
• Reaction with certain epoxides to the corresponding alkenes. ^[7]

References

See also

• HSAB concept
• Grignard reagent
• The chemistry of carbon bonded to other elements in the periodic table: