Organolithium reagent
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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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[edit] Production
Organolithium reagents are industrially prepared by the reaction of an organohalogen with lithium metal, i.e. R-X + 2 Li → R-Li + LiX. 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 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.
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.
[edit] Reactivity and 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 organolithium compounds is as a very strong base. 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 pKA units stronger than the lithium species, although in practice a larger pKA difference is required for useful rates of deprotonation of 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 t-butyllithium, or tert-butyllithium, the single strongest base that is commercially available, with a pKa greater than 53. The metalation reaction is mainly used to synthesize other organolithium compounds. Some examples are shown below:
Organolithium compounds are also commonly used for nucleophilic addition reactions to carbonyl compounds and other electrophiles, although deprotonation can be a side reaction, 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.
The most commonly used organolithium reagents are methyllithium (CH3Li), n-butyllithium and t-butyllithium ((CH3)3CLi). A recent review of process chemistry, indicates that the following are the most common organolithium reagents: butyllithium, hexyllithium and phenylithium.[1] Two very commonly used strong bases prepared using butyllithium are lithium diisopropylamide (LDA), and lithium hexamethyldisilazide (LiHMDS).
Another organolithium reagent is phenyllithium C6H5Li. Phenyllithium derivatives are intermediates in directed ortho metalation such as Me2NCH2C6H4-2-Li obtained from dimethylbenzylamine and butyllithium.
[edit] References
- ^ Wu, G. Huang, M. (2006). "Organolithium Reagents in Pharmaceutical Asymmetric Processes". Chemical Reviews 106: 2596 -2616. DOI:10.1021/cr040694k. .
