Organolithium reagents are a collection of organolithium compounds that are widely used in organic synthesis and polymer chemistry. These reagents are used to transfer the organic group or the lithium atom to diverse substrates, usually through nucleophilic addition or simple deprotonation. Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers.
History and development Studies of organolithium reagents began in the 1930s and were pioneered by Karl Ziegler, Georg Wittig, and Henry Gilman. In comparison with Grignard (magnesium) reagents, organolithium reagents can often perform the same reactions with increased rates and higher yields, such as in the case of metalation. Since then, organolithium reagents have overtaken Grignard reagents in common usage.
Structure Although simple alkyllithium species are often represented as monomer RLi, they exist as aggregates (oligomers) or polymers. The degree of aggregation depends on the organic substituent and the presence of other ligands. These structures have been elucidated by a variety of methods, notably 6Li, 7Li, and 13C NMR spectroscopy and X-ray diffraction analysis. Computational chemistry supports these assignments.
Nature of carbon–lithium bond
Due to the large difference in electronegativity between the carbon atom and the lithium atom, the C−Li bond is highly ionic. Owing to the polar nature of the C−Li bond, organolithium reagents are good nucleophiles and strong bases. For laboratory organic synthesis, many organolithium reagents are commercially available in solution form. These reagents are highly reactive, and are sometimes pyrophoric. The relative electronegativities of carbon and lithium suggest that the C−Li bond will be highly polar. However, certain organolithium compounds possess properties such as solubility in nonpolar solvents that complicate the issue. While most data suggest the C−Li bond to be essentially ionic, there has been debate as to how much covalent character exists in it. One estimate puts the percentage of ionic character of alkyllithium compounds at 80 to 88%.
In allyl lithium compounds, the lithium cation coordinates to the face of the carbon π bond in an η3 fashion instead of a localized, carbanionic center, thus, allyllithiums are often less aggregated than alkyllithiums. In aryllithium complexes, the lithium cation coordinates to a single carbanion center through a Li−C σ type bond.
Solid state structure
Like other species consisting of polar subunits, organolithium species aggregate. Formation of aggregates is influenced by electrostatic interactions, the coordination between lithium and surrounding solvent molecules or polar additives, and steric effects.
A basic building block toward constructing more complex structures is a carbanionic center interacting with a Li3 triangle in an η3- fashion. In simple alkyllithium reagents, these triangles aggregate to form tetrahedron or octahedron structures. For example, methyllithium, ethyllithium and tert-butyllithium all exist in the tetramer [RLi]4. Methyllithium exists as tetramers in a cubane-type cluster in the solid state, with four lithium centers forming a tetrahedron. Each methanide in the tetramer in methyllithium can have agostic interaction with lithium cations in adjacent tetramers. Ethyllithium and tert-butyllithium, on the other hand, do not exhibit this interaction, and are thus soluble in non-polar hydrocarbon solvents. Another class of alkyllithium adopts hexameric structures, such as n-butyllithium, isopropyllithium, and cyclohexanyllithium.
Common lithium amides, e.g. lithium bis(trimethylsilyl)amide and lithium diisopropylamide, are also subject to aggregation. Lithium amides adopt polymeric-ladder type structures in non-coordinating solvent in the solid state, and they generally exist as dimers in ethereal solvents. In the presence of strongly donating ligands, tri- or tetrameric lithium centers are formed.
For example, LDA exists primarily as dimers in THF. The structures of common lithium amides, such as lithium diisopropylamide (LDA) and lithium hexamethyldisilazide (LiHMDS) have been extensively studied by Collum and coworkers using NMR spectroscopy. Another important class of reagents is silyllithiums, extensively used in the synthesis of organometallic complexes and polysilane dendrimers. In the solid state, in contrast with alkyllithium reagents, most silyllithiums tend to form monomeric structures coordinated with solvent molecules such as THF, and only a few silyllithiums have been characterized as higher aggregates. This difference can arise from the method of preparation of silyllithiums, the steric hindrance caused by the bulky alkyl substituents on silicon, and the less polarized nature of Si−Li bonds. The addition of strongly donating ligands, such as TMEDA and (−)-sparteine, can displace coordinating solvent molecules in silyllithiums.
Solution structure It is possible for organolithium reagents adopt structures in solution that differ from the solid state. NMR spectroscopy has emerged as a powerful tool for the studies of organolithium aggregates in solution. For alkyllithium species, C−Li J coupling can often used to determine the number of lithium interacting with a carbanion center, and whether these interactions are static or dynamic. Separate NMR signals can also differentiate the presence of multiple aggregates from a common monomeric unit.
Organolithium compounds bind Lewis bases such as tetrahydrofuran (THF), diethyl ether (Et2O), tetramethylethylene diamine (TMEDA) or hexamethylphosphoramide (HMPA). Methyllithium is a special case: its tetrameric structure is unaffected by ether or even HMPA. On the other hand, THF deaggregates hexameric butyl lithium: the tetramer is the main species, and ΔG for interconversion between tetramer and dimer is around 11 kcal/mol. TMEDA can also chelate to the lithium cations in n-butyllithium and form solvated dimers such as [(TMEDA) LiBu-n)]2. Phenyllithium has been shown to exist as a distorted tetramer in the crystallized ether solvate, and as a mixture of dimer and tetramer in ether solution.
+ Solvated alkyllithium aggregate structures Alkyl group Solvent Structure methyl THF tetramer ether/HMPA tetramer nbutyl pentane hexamer ether tetramer THF tetramer-dimer secbutyl pentane hexamer-tetramer isopropyl pentane hexamer-tetramer tertbutyl pentane tetramer THF monomer phenyl ether tetramer-dimer ether/HMPA dimer
Structure and reactivity As the structures of organolithium reagents change according to their chemical environment, so do their reactivity and selectivity. One question surrounding the structure-reactivity relationship is whether there exists a correlation between the degree of aggregation and the reactivity of organolithium reagents. It was originally proposed that lower aggregates such as monomers are more reactive in alkyllithiums. However, reaction pathways in which dimer or other oligomers are the reactive species have also been discovered, and for lithium amides such as LDA, dimer-based reactions are common. A series of solution kinetics studies of LDA-mediated reactions suggest that lower aggregates of enolates do not necessarily lead to higher reactivity.
Also, some Lewis bases increase reactivity of organolithium compounds.
However, whether these additives function as strong chelating ligands, and how the observed increase in reactivity relates to structural changes in aggregates caused by these additives are not always clear. For example, TMEDA increases rates and efficiencies in many reactions involving organolithium reagents. Toward alkyllithium reagents, TMEDA functions as a donor ligand, reduces the degree of aggregation, and increases the nucleophilicity of these species. However, TMEDA does not always function as a donor ligand to lithium cation, especially in the presence of anionic oxygen and nitrogen centers. For example, it only weakly interacts with LDA and LiHMDS even in hydrocarbon solvents with no competing donor ligands. In imine lithiation, while THF acts as a strong donating ligand to LiHMDS, the weakly coordinating TMEDA readily dissociates from LiHMDS, leading to the formation of LiHMDS dimers that is the more reactive species. Thus, in the case of LiHMDS, TMEDA does not increase reactivity by reducing aggregation state. Also, as opposed to simple alkyllithium compounds, TMEDA does not deaggregate lithio-acetophenolate in THF solution. The addition of HMPA to lithium amides such as LiHMDS and LDA often results in a mixture of dimer/monomer aggregates in THF. However, the ratio of dimer/monomer species does not change with increased concentration of HMPA, thus, the observed increase in reactivity is not the result of deaggregation. The mechanism of how these additives increase reactivity is still being researched.
Reactivity and applications The C−Li bond in organolithium reagents is highly polarized. As a result, the carbon attracts most of the electron density in the bond and resembles a carbanion. Thus, organolithium reagents are strongly basic and nucleophilic. Some of the most common applications of organolithium reagents in synthesis include their use as nucleophiles, strong bases for deprotonation, initiator for polymerization, and starting material for the preparation of other organometallic compounds.
As nucleophile
Carbolithiation reactions As nucleophiles, organolithium reagents undergo carbolithiation reactions, whereby the carbon–lithium bond adds across a carbon–carbon double or triple bond, forming new organolithium species. This reaction is the most widely employed reaction of organolithium compounds. Carbolithiation is key in anionic polymerization processes, and n-butyllithium is used as a catalyst to initiate the polymerization of styrene, butadiene, or isoprene or mixtures thereof.Heinz-Dieter Brandt, Wolfgang Nentwig1, Nicola Rooney, Ronald T. LaFlair, Ute U. Wolf, John Duffy, Judit E. Puskas, Gabor Kaszas, Mark Drewitt, Stephan Glander "Rubber, 5. Solution Rubbers" in Ullmann's Encyclopedia of Industrial Chemistry, 2011, Wiley-VCH, Weinheim.
Another application that takes advantage of this reactivity is the formation of carbocyclic and heterocyclic compounds by intramolecular carbolithiation. As a form of anionic cyclization, intramolecular carbolithiation reactions offer several advantages over radical cyclization. First, it is possible for the product cyclic organolithium species to react with electrophiles, whereas it is often difficult to trap a radical intermediate of the corresponding structure. Secondly, anionic cyclizations are often more regio- and stereospecific than radical cyclization, particularly in the case of 5-hexenyllithiums. Intramolecular carbolithiation allows addition of the alkyl-, vinyllithium to triple bonds and mono-alkyl substituted double bonds. Aryllithiums can also undergo addition if a 5-membered ring is formed. The limitations of intramolecular carbolithiation include difficulty of forming 3 or 4-membered rings, as the intermediate cyclic organolithium species often tend to undergo ring-openings. Below is an example of intramolecular carbolithiation reaction. The lithium species derived from the lithium–halogen exchange cyclized to form the vinyllithium through 5-exo-trig ring closure. The vinyllithium species further reacts with electrophiles and produce functionalized cyclopentylidene compounds.
Addition to carbonyl compounds Nucleophilic organolithium reagents can add to electrophilic carbonyl double bonds to form carbon–carbon bonds. They can react with aldehydes and ketones to produce alcohols. The addition proceeds mainly via polar addition, in which the nucleophilic organolithium species attacks from the equatorial direction, and produces the axial alcohol. Addition of lithium salts such as LiClO4 can improve the stereoselectivity of the reaction.