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Organolithium reagent
Organolithium reagent
Organolithium reagent
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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.[1] Organolithium reagents are used in industry as an initiator for anionic polymerization, which leads to the production of various elastomers.[2]

A sec-butyllithium aggregate in which each of the four sec-butyl groups is associated with one face of the tetrahedron formed from four lithium atoms

History and development

[edit]

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.[3] Since then, organolithium reagents have overtaken Grignard reagents in common usage.[4]

Structure

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Although simple alkyllithium species are often represented as monomer RLi, they exist as aggregates (oligomers) or polymers.[5] The degree of aggregation depends on the organic substituent and the presence of other ligands.[6][7] These structures have been elucidated by a variety of methods, notably 6Li, 7Li, and 13C NMR spectroscopy and X-ray diffraction analysis.[1] Computational chemistry supports these assignments.[5]

Nature of carbon–lithium bond

[edit]
Delocalized electron density in allyllithium reagents

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.

Glass bottles containing butyllithium

The relative electronegativities of carbon and lithium suggest that the C−Li bond will be highly polar.[8][9][10] However, certain organolithium compounds possess properties such as solubility in nonpolar solvents that complicate the issue. [8] 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.[9][10] One estimate puts the percentage of ionic character of alkyllithium compounds at 80 to 88%.[11]

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.[6][12] In aryllithium complexes, the lithium cation coordinates to a single carbanion center through a Li−C σ type bond.[6][13]

Solid state structures of methyllithium tetramers, n-butyllithium hexamers and polymeric ladder of phenyllithium

Solid state structure

[edit]
Tetrahedron and octahedron metal cores formed by aggregation of the Li3 triangle - carbanion coordinate complex[5]

Like other species consisting of polar subunits, organolithium species aggregate.[7][14] Formation of aggregates is influenced by electrostatic interactions, the coordination between lithium and surrounding solvent molecules or polar additives, and steric effects.[7]

A basic building block toward constructing more complex structures is a carbanionic center interacting with a Li3 triangle in an η3- fashion.[5] 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.[5][7] 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.[5]

LDA dimer with THF coordinated to Li cations

Common lithium amides, e.g. lithium bis(trimethylsilyl)amide and lithium diisopropylamide, are also subject to aggregation.[15] 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. [16] For example, LDA exists primarily as dimers in THF.[15] 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.[17] Another important class of reagents is silyllithiums, extensively used in the synthesis of organometallic complexes and polysilane dendrimers.[7][18] 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.[7] 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.[7]

Solution structure

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It is possible for organolithium reagents adopt structures in solution that differ from the solid state.[6][19] 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.[6] Separate NMR signals can also differentiate the presence of multiple aggregates from a common monomeric unit.[20]

Organolithium compounds bind Lewis bases such as tetrahydrofuran (THF), diethyl ether (Et2O), tetramethylethylene diamine (TMEDA) or hexamethylphosphoramide (HMPA).[5] Methyllithium is a special case: its tetrameric structure is unaffected by ether or even HMPA.[7] 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.[21] TMEDA can also chelate to the lithium cations in n-butyllithium and form solvated dimers such as [(TMEDA) LiBu-n)]2.[5][6] 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.[6]

Solvated alkyllithium aggregate structures[6]
Alkyl group Solvent Structure
methyl THF tetramer
ether/HMPA tetramer
n‑butyl pentane hexamer
ether tetramer
THF tetramer-dimer
sec‑butyl pentane hexamer-tetramer
isopropyl pentane hexamer-tetramer
tert‑butyl pentane tetramer
THF monomer
phenyl ether tetramer-dimer
ether/HMPA dimer

Structure and reactivity

[edit]

As the structures of organolithium reagents change according to their chemical environment, so do their reactivity and selectivity.[7][22] 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.[23] However, reaction pathways in which dimer or other oligomers are the reactive species have also been discovered,[24] and for lithium amides such as LDA, dimer-based reactions are common.[25] A series of solution kinetics studies of LDA-mediated reactions suggest that lower aggregates of enolates do not necessarily lead to higher reactivity.[17]

Also, some Lewis bases increase reactivity of organolithium compounds.[26] [27] 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.[26][27] For example, TMEDA increases rates and efficiencies in many reactions involving organolithium reagents.[7] Toward alkyllithium reagents, TMEDA functions as a donor ligand, reduces the degree of aggregation,[5] and increases the nucleophilicity of these species.[28] 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.[29] 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.[30] Also, as opposed to simple alkyllithium compounds, TMEDA does not deaggregate lithio-acetophenolate in THF solution.[6][31] 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.[22]

Reactivity and applications

[edit]

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

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Carbolithiation reactions

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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.[32] 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.[33][34]

Anionic polymerization of styrene initiated by sec-butyllithium
Anionic polymerization of styrene initiated by sec-butyllithium

Another application that takes advantage of this reactivity is the formation of carbocyclic and heterocyclic compounds by intramolecular carbolithiation.[32] 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.[32] 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.[35]

A sample stereoselective intramolecular carbolithiation reaction
A sample stereoselective intramolecular carbolithiation reaction

Addition to carbonyl compounds

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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.[36] Addition of lithium salts such as LiClO4 can improve the stereoselectivity of the reaction.[37]

LiClO4 increase selectivity of t BuLi
LiClO4 increase selectivity of t BuLi

When the ketone is sterically hindered, using Grignard reagents often leads to reduction of the carbonyl group instead of addition.[36] However, alkyllithium reagents are less likely to reduce the ketone, and may be used to synthesize substituted alcohols.[38] Below is an example of ethyllithium addition to adamantone to produce tertiary alcohol.[39]

Li add to adamantone
Li add to adamantone

Organolithium reagents are also better than Grignard reagents in their ability to react with carboxylic acids to form ketones.[36] This reaction can be optimized by carefully controlling the amount of organolithium reagent addition, or using trimethylsilyl chloride to quench excess lithium reagent.[40] A more common way to synthesize ketones is through the addition of organolithium reagents to Weinreb amides (N-methoxy-N-methyl amides). This reaction provides ketones when the organolithium reagents is used in excess, due to chelation of the lithium ion between the N-methoxy oxygen and the carbonyl oxygen, which forms a tetrahedral intermediate that collapses upon acidic work up.[41]

Li add to weinreb
Li add to weinreb

Organolithium reagents also react with carbon dioxide to form, after workup, carboxylic acids.[42]

In the case of enone substrates, where two sites of nucleophilic addition are possible (1,2 addition to the carbonyl carbon or 1,4 conjugate addition to the β carbon), most highly reactive organolithium species favor the 1,2 addition, however, there are several ways to propel organolithium reagents to undergo conjugate addition. First, since the 1,4 adduct is the likely to be the more thermodynamically favorable species, conjugate addition can be achieved through equilibration (isomerization of the two product), especially when the lithium nucleophile is weak and 1,2 addition is reversible. Secondly, adding donor ligands to the reaction forms heteroatom-stabilized lithium species which favors 1,4 conjugate addition. In one example, addition of low-level of HMPA to the solvent favors the 1,4 addition. In the absence of donor ligand, lithium cation is closely coordinated to the oxygen atom, however, when the lithium cation is solvated by HMPA, the coordination between carbonyl oxygen and lithium ion is weakened. This method generally cannot be used to affect the regioselectivity of alkyl- and aryllithium reagents.[43][44]

1,4vs1,2 addition
1,4vs1,2 addition

Organolithium reagents can also perform enantioselective nucleophilic addition to carbonyl and its derivatives, often in the presence of chiral ligands. This reactivity is widely applied in the industrial syntheses of pharmaceutical compounds. An example is the Merck and Dupont synthesis of Efavirenz, a potent HIV reverse transcriptase inhibitor. Lithium acetylide is added to a prochiral ketone to yield a chiral alcohol product. The structure of the active reaction intermediate was determined by NMR spectroscopy studies in the solution state and X-ray crystallography of the solid state to be a cubic 2:2 tetramer.[45]

Merck synthesis of Efavirenz
Merck synthesis of Efavirenz

SN2 type reactions

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Organolithium reagents can serve as nucleophiles and carry out SN2 type reactions with alkyl or allylic halides.[46] Although they are considered more reactive than Grignard reagents in alkylation, their use is still limited due to competing side reactions such as radical reactions or metal–halogen exchange. Most organolithium reagents used in alkylations are more stabilized, less basic, and less aggregated, such as heteroatom stabilized, aryl- or allyllithium reagents.[6] HMPA has been shown to increase reaction rate and product yields, and the reactivity of aryllithium reagents is often enhanced by the addition of potassium alkoxides.[36] Organolithium reagents can also carry out nucleophilic attacks with epoxides to form alcohols.

SN2 inversion with benzyllithium
SN2 inversion with benzyllithium

As base

[edit]

Organolithium reagents provide a wide range of basicity. tert-Butyllithium, with three weakly electron donating alkyl groups, is the strongest base commercially available (pKa = 53). As a result, the acidic protons on −OH, −NH and −SH are often protected in the presence of organolithium reagents. Some commonly used lithium bases are alkyllithium species such as n-butyllithium and lithium dialkylamides (LiNR2). Reagents with bulky R groups such as lithium diisopropylamide (LDA) and lithium bis(trimethylsilyl)amide (LiHMDS) are often sterically hindered for nucleophilic addition, and are thus more selective toward deprotonation. Lithium dialkylamides (LiNR2) are widely used in enolate formation and aldol reaction.[47] The reactivity and selectivity of these bases are also influenced by solvents and other counter ions.

Metalation

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Metalation with organolithium reagents, also known as lithiation or lithium-hydrogen exchange, is achieved when an organolithium reagent, most commonly an alkyllithium, abstracts a proton and forms a new organolithium species.

Common metalation reagents are the butyllithiums. tert-Butyllithium and sec-butyllithium are generally more reactive and have better selectivity than n-butyllithium, however, they are also more expensive and difficult to handle.[47] Metalation is a common way of preparing versatile organolithium reagents. The position of metalation is mostly controlled by the acidity of the C–H bond. Lithiation often occurs at a position α to electron withdrawing groups, since they are good at stabilizing the electron-density of the anion. Directing groups on aromatic compounds and heterocycles provide regioselective sites of metalation; directed ortho metalation is an important class of metalation reactions. Metalated sulfones, acyl groups and α-metalated amides are important intermediates in chemistry synthesis. Metalation of allyl ether with alkyllithium or LDA forms an anion α to the oxygen, and can proceed to 2,3-Wittig rearrangement. Addition of donor ligands such as TMEDA and HMPA can increase metalation rate and broaden substrate scope.[48]

Directed ortho metalation
Directed ortho metalation

Directed ortho metalation is an important tool in the synthesis of regiospecific substituted aromatic compounds. This approach to lithiation and subsequent quenching of the intermediate lithium species with electrophile is often better than the electrophilic aromatic substitution due to its high regioselectivity. This reaction proceeds through deprotonation by organolithium reagents at the positions α to the direct metalation group (DMG) on the aromatic ring. The DMG is often a functional group containing a heteroatom that is Lewis basic, and can coordinate to the Lewis-acidic lithium cation. This generates a complex-induced proximity effect, which directs deprotonation at the α position to form an aryllithium species that can further react with electrophiles. Some of the most effective DMGs are amides, carbamates, sulfones and sulfonamides. They are strong electron-withdrawing groups that increase the acidity of alpha-protons on the aromatic ring. In the presence of two DMGs, metalation often occurs ortho to the stronger directing group, though mixed products are also observed. A number of heterocycles that contain acidic protons can also undergo ortho-metalation. However, for electron-poor heterocycles, lithium amide bases such as LDA are generally used, since alkyllithium has been observed to perform addition to the electron-poor heterocycles rather than deprotonation. In certain transition metal-arene complexes, such as ferrocene, the transition metal attracts electron density from the arene, thus rendering the aromatic protons more acidic, and ready for ortho-metalation.[49]

Superbases

[edit]
Main article: Superbase

Addition of potassium alkoxide to alkyllithium greatly increases the basicity of organolithium species.[50] The most common "superbase" can be formed by addition of KOtBu to butyllithium, often abbreviated as "LiCKOR" reagents. These "superbases" are highly reactive and often stereoselective reagents. In the example below, the LiCKOR base generates a stereospecific crotylboronate species through metalation and subsequent lithium-metalloid exchange.[51]

Superbase
Superbase

Organolithium reagents in asymmetric synthesis

[edit]

Chiral organolithium reagents can be accessed through asymmetric metalation.[52] They have also been applied in asymmetric synthesis in the pharmaceutical industry.[53] Asymmetric induction requires the presence of a chiral ligand such as (−)-sparteine.[52] The enantiomeric ratio of the chiral lithium species is often influenced by the differences in rates of deprotonation. In the example below, treatment of N-Boc-N-benzylamine with n-butyllithium in the presence of (−)-sparteine affords one enantiomer of the product with high enantiomeric excess. Transmetalation with trimethyltin chloride affords the opposite enantiomer.[54]

Asymmetric synthesis with nBuLi and (−)-sparteine
Asymmetric synthesis with nBuLi and (−)-sparteine

Enolate formation

[edit]

Lithium enolates are formed through deprotonation of a C−H bond α to the carbonyl group by an organolithium species. Lithium enolates are widely used as nucleophiles in carbon–carbon bond formation reactions such as aldol condensation and alkylation. They are also an important intermediate in the formation of silyl enol ether.

Sample aldol reaction with lithium enolate
Sample aldol reaction with lithium enolate

Lithium enolate formation can be generalized as an acid–base reaction, in which the relatively acidic proton α to the carbonyl group (pK =20-28 in DMSO) reacts with organolithium base. Generally, strong, non-nucleophilic bases, especially lithium amides such LDA, LiHMDS and LiTMP are used. THF and DMSO are common solvents in lithium enolate reactions.[55]

The stereochemistry and mechanism of enolate formation have gained much interest in the chemistry community. Many factors influence the outcome of enolate stereochemistry, such as steric effects, solvent, polar additives, and types of organolithium bases. Among the many models used to explain and predict the selectivity in stereochemistry of lithium enolates is the Ireland model.[56]

In this assumption, a monomeric LDA reacts with the carbonyl substrate and form a cyclic Zimmerman–Traxler type transition state. The (E)-enolate is favored due to an unfavorable syn-pentane interaction in the (Z)-enolate transition state.[55]

Ireland model for lithium enolate stereoselectivity. In this example, the (E) enolate is favored.
Ireland model for lithium enolate stereoselectivity. In this example, the (E) enolate is favored.

Addition of polar additives such as HMPA or DMPU favors the formation of (Z) enolates. The Ireland model argues that these donor ligands coordinate to the lithium cations, as a result, carbonyl oxygen and lithium interaction is reduced, and the transition state is not as tightly bound as a six-membered chair. The percentage of (Z) enolates also increases when lithium bases with bulkier side chains (such as LiHMDS) are used.[55] However, the mechanism of how these additives reverse stereoselectivity is still being debated.

There have been some challenges to the Ireland model, as it depicts the lithium species as a monomer in the transition state. In reality, a variety of lithium aggregates are often observed in solutions of lithium enolates, and depending on specific substrate, solvent and reaction conditions, it can be difficult to determine which aggregate is the actual reactive species in solution.[55]

Lithium–halogen exchange

[edit]
Main article: Metal-halogen exchange § Lithium-halogen exchange

Lithium–halogen exchange involves heteroatom exchange between an organohalide and organolithium species.

Lithium–halogen exchange is very useful in preparing new organolithium reagents. The application of lithium–halogen exchange is illustrated by the Parham cyclization.[57]

Parham cyclization in MitoSpin
Parham cyclization in MitoSpin

Transmetalation

[edit]

Organolithium reagents are often used to prepare other organometallic compounds by transmetalation. Organocopper, organotin, organosilicon, organoboron, organophosphorus, organocerium and organosulfur compounds are frequently prepared by reacting organolithium reagents with appropriate electrophiles.

Common types of transmetalation include Li/Sn, Li/Hg, and Li/Te exchange, which are fast at low temperature.[47] The advantage of Li/Sn exchange is that the tri-alkylstannane precursors undergo few side reactions, as the resulting n-Bu3Sn byproducts are unreactive toward alkyllithium reagents.[47] In the following example, vinylstannane, obtained by hydrostannylation of a terminal alkyne, forms vinyllithium through transmetalation with n-BuLi.[58]

Li Sn exchange
Li Sn exchange

Organolithium can also be used in to prepare organozinc compounds through transmetalation with zinc salts.[59]

Organozinc reagents from alkyllithium
Organozinc reagents from alkyllithium

Lithium diorganocuprates can be formed by reacting alkyl lithium species with copper(I) halide. The resulting organocuprates are generally less reactive toward aldehydes and ketones than organolithium reagents or Grignard reagents.[60]

1,4 cuprate addition
1,4 cuprate addition

Preparation

[edit]

Most simple alkyllithium reagents, and common lithium amides are commercially available in a variety of solvents and concentrations. Organolithium reagents can also be prepared in the laboratory. Below are some common methods for preparing organolithium reagents.

Displacement of a leaving group

[edit]

In lithium–halogen exchange, reduction of alkyl halide with metallic lithium can afford simple alkyl and aryl organolithium reagents.[36]

tert-Butyllithium or n-butyllithium are the most commonly used reagents for generating new organolithium species through lithium halogen exchange. Lithium–halogen exchange is mostly used to convert aryl and alkenyl iodides and bromides with sp2 carbons to the corresponding organolithium compounds. The reaction is extremely fast, and often proceed at −60 to −120 °C.[48]

Industrial preparation of organolithium reagents is achieved using this method by treating the alkyl chloride with metal lithium containing 0.5–2% sodium. The conversion is highly exothermic. The sodium initiates the radical pathway and increases the rate.[61] The reduction proceeds via a radical pathway. Below is an example of the preparation of a functionalized lithium reagent using reduction with lithium metal.[62] Sometimes, lithium metal in the form of fine powders are used in the reaction with certain catalysts such as naphthalene or 4,4’-di-t-butylbiphenyl (DTBB). Another substrate that can be reduced with lithium metal to generate alkyllithium reagents is sulfides. Reduction of sulfides is useful in the formation of functionalized organolithium reagents such as alpha-lithio ethers, sulfides, and silanes.[63]

Reduction with Li metal
Reduction with Li metal

Metalation

[edit]
Further information: Metalation § Reactivity and applications

A second method of preparing organolithium reagents is a metalation (lithium hydrogen exchange). The relative acidity of hydrogen atoms controls the position of lithiation.

This is the most common method for preparing alkynyllithium reagents, because the terminal hydrogen bound to the sp carbon is very acidic and easily deprotonated.[36] For aromatic compounds, the position of lithiation is also determined by the directing effect of substituent groups.[64] Some of the most effective directing substituent groups are alkoxy, amido, sulfoxide, sulfonyl. Metalation often occurs at the position ortho to these substituents. In heteroaromatic compounds, metalation usually occurs at the position ortho to the heteroatom.[36][64]

Transmetalation

[edit]
Further information: Transmetalation § Applications

The fourth method to prepare organolithium reagents is through transmetalation. This method can be used for preparing vinyllithium.

Shapiro reaction

[edit]

In the Shapiro reaction, two equivalents of strong alkyllithium base react with p-tosylhydrazone compounds to produce the vinyllithium, or upon quenching, the olefin product.

Handling

[edit]

Organolithium compounds are highly reactive species and require specialized handling techniques. They are often corrosive, flammable, and sometimes pyrophoric (spontaneous ignition when exposed to air or moisture).[65] Alkyllithium reagents can also undergo thermal decomposition to form the corresponding alkyl species and lithium hydride.[66] Organolithium reagents are typically stored below 10 °C. Reactions are conducted using air-free techniques.[65] The concentration of alkyllithium reagents is often determined by titration.[67][68][69]

Organolithium reagents react, often slowly, with ethers, which nonetheless are often used as solvents.[70]

Approximate half-lives of common lithium reagents in typical solvents
Solvent Temp n-BuLi s-BuLi t-BuLi MeLi CH2=C(OEt)-Li CH2=C(SiMe3)-Li
THF −40 °C 338 min
THF −20 °C 42 min
THF 0 °C 17 h
THF 20 °C 107 min >15 h 17 h
THF 35 °C 10 min
THF/TMEDA −20 °C 55 h
THF/TMEDA 0 °C 340 min
THF/TMEDA 20 °C 40 min
Ether −20 °C 480 min
Ether 0 °C 61 min
Ether 20 °C 153 h <30 min 17 d
Ether 35 °C 31 h
Ether/TMEDA 20 °C 603 min
DME −70 °C 120 min 11 min
DME −20 °C 110 min 2 min ≪2 min
DME 0 °C 6 min

See also

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Further reading

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Organolithium reagent

View on Grokipedia
from Grokipedia
Organolithium reagents are highly reactive organometallic compounds characterized by a direct carbon-lithium (C-Li) bond, typically represented by the general formula RLi where R is an alkyl, aryl, or alkenyl group, and they serve as powerful nucleophiles and strong bases in for forming carbon-carbon bonds and deprotonating substrates. These reagents exhibit exceptional reactivity, surpassing that of Grignard reagents, due to the high polarity of the C-Li bond, which imparts carbanionic character to the organic group, enabling nucleophilic additions to carbonyl compounds such as aldehydes, ketones, and esters to produce alcohols, as well as reactions with to yield carboxylic acids. Their basicity, with pKa values for conjugate acids ranging from 42 to 50, allows them to deprotonate weak acids like terminal alkynes or hydrocarbons, facilitating further synthetic transformations. Preparation of organolithium reagents commonly involves the reductive cleavage of alkyl or aryl (chlorides, bromides, or iodides) with metal in inert solvents such as , , or , producing the RLi and lithium as a , though the process requires strict conditions to prevent . Alternative methods include metal-halogen exchange or reactions for more complex variants. Structurally, they often exist as oligomeric aggregates—such as tetramers or hexamers—in the solid state or solution, featuring three-center, two-electron bridging bonds that influence their solubility and reactivity. Due to their extreme sensitivity to air, moisture, and protic solvents—reacting violently to form alkanes and —they demand rigorous handling protocols, including storage under inert atmospheres and use in specialized glassware, yet their commercial availability as solutions in hydrocarbons has made them indispensable in both academic research and industrial applications for pharmaceuticals, polymers, and fine chemicals. Common examples include (n-BuLi), (MeLi), and (PhLi), each tailored for specific synthetic roles based on steric and electronic properties.

History

Early Discovery

The discovery of organolithium reagents is credited to Wilhelm Schlenk and Johanna Holtz, who in 1917 reported the first synthesis of these compounds through a reaction involving metal and dialkylmercury derivatives. Specifically, they prepared ethyllithium (C₂H₅Li) as one of the initial examples by reacting diethylmercury with metal in an inert organic solvent, yielding the product alongside metallic mercury. The reaction can be represented as: C2H5HgC2H5+2Li→2C2H5Li+Hg\text{C}_2\text{H}_5\text{HgC}_2\text{H}_5 + 2\text{Li} \rightarrow 2\text{C}_2\text{H}_5\text{Li} + \text{Hg} This method marked a significant advancement in organometallic chemistry, though the use of highly toxic organomercury compounds limited its practicality. Early investigations revealed the extreme reactivity and instability of organolithium compounds, which contrasted sharply with the more robust Grignard reagents discovered by Victor Grignard in 1900 through the reaction of alkyl halides with magnesium in ether. Schlenk and Holtz observed that ethyllithium exhibited solubility in alkanes like petroleum ether, facilitating its isolation, but it was highly sensitive to air and moisture. The compounds were notably pyrophoric, with methyllithium—a related example—igniting spontaneously in air and burning with a characteristic red flame accompanied by golden sparks, underscoring the challenges in handling these air-sensitive species. These initial findings highlighted the potential of organolithium reagents as powerful nucleophiles, despite their handling difficulties, setting the stage for further exploration in the field.

Key Developments and Commercialization

In the 1930s, conducted pioneering studies on the polymerization of olefins using s and alkyl compounds, including alkyllithiums such as , which demonstrated their ability to initiate the polymerization of dienes like into oligomers and eventually stereoregular polymers. These investigations, beginning around 1937, revealed the potential of organolithium initiators to produce highly regular structures, paving the way for the development of stereospecific polymerization techniques that yielded isotactic and syndiotactic polybutadienes with controlled cis or trans configurations. Ziegler's early work built on the 1917 synthesis of the first organolithium compounds by Wilhelm Schlenk, transitioning from curiosities to tools for industrial synthesis. Alongside , Georg Wittig advanced organolithium chemistry through studies on metal-halogen exchange reactions, contributing to their expanded use in synthesis. During the and , Henry Gilman advanced the understanding of organolithium reactivity through extensive experimental studies, publishing extensively on organolithium reagents among other topics, with over 150 total papers in the and more than 300 in the . Gilman's research group at elucidated key reactivity patterns, such as metal-halogen exchanges and additions to functional groups, while applying these reagents to the synthesis of complex organic molecules, including organobismuth compounds and derivatives with anti-malarial potential. His contributions were instrumental in the post-World War II expansion of , where organolithiums facilitated innovative routes in pharmaceutical development, leading to numerous patents for their use in producing therapeutic agents and intermediates. Commercial production of organolithium reagents, particularly (n-BuLi) and sec-butyllithium (sec-BuLi), began in the early 1950s, driven by demand for polymerization initiators in manufacturing. Companies like the pioneered large-scale synthesis, achieving the first industrial production of n-BuLi in 1953 using as the solvent to stabilize the highly reactive compounds. This marked a shift from lab-scale preparations to economical, high-volume output, supporting the burgeoning and pharmaceutical industries amid the post-WWII economic boom. By the late 1950s, annual U.S. capacity for n-BuLi reached significant levels, underscoring organolithiums' role in enabling scalable synthetic processes.

Structure

Nature of the Carbon-Lithium Bond

The carbon-lithium bond in organolithium reagents is predominantly covalent yet highly polar, arising from the significant difference between (0.98) and carbon (2.55), which imparts substantial carbanion-like character to the carbon atom. This polarity results in a δ⁻ charge on carbon and δ⁺ on , enhancing the nucleophilicity of the organolithium species. Quantum chemical analyses describe the bond as a strongly polar interaction, with notable covalent contributions from mixing of lithium 2s orbitals into the carbon-lithium bonding orbital, and the carbon hybrid orbital exhibiting significant s-character that strengthens the bond relative to purely p-orbital involvement. Typical C-Li bond lengths range from 2.0 to 2.2 in monomeric forms, which is shorter than the C-Na bond (~2.6 ) in organosodium compounds but longer than the C-H bond (1.09 ), reflecting the intermediate ionic-covalent nature of the interaction. Evidence for partial ionic character is provided by the low C-Li stretching frequency observed in , typically around 500 cm⁻¹ (e.g., 417–550 cm⁻¹ across various alkyllithiums), indicative of weakened bond strength due to electrostatic contributions. Compared to Grignard reagents (R-MgX), organolithium compounds exhibit greater reactivity in nucleophilic additions and deprotonations, stemming from enhanced bond polarization; lithium's lower electronegativity (0.98) versus magnesium's (1.31) results in a more electron-rich carbon center. This heightened polarity facilitates faster reaction rates, particularly with electrophiles like carbonyls, though it also increases sensitivity to protic impurities. Aggregation in solution or solid states can modulate this polarity slightly through multicenter bonding, but the intrinsic bond characteristics dominate reactivity trends.

Solid-State Structures

Organolithium compounds exhibit diverse oligomeric structures in the solid state, primarily driven by the need to achieve tetracoordination around the cations through carbon-lithium bridging interactions. Simple alkyllithiums, such as and ethyllithium, typically form tetrameric clusters (Li₄R₄), where the alkyl groups act as bridges between lithium centers. For instance, adopts a cubic body-centered lattice composed of tetrameric units featuring a tetrahedral Li₄ core with μ₃-bridging methyl groups, as revealed by refinement from data. This structure provides each with a distorted tetrahedral coordination environment, stabilizing the highly polar C-Li bonds. In contrast, longer-chain alkyllithiums like favor hexameric aggregates (Li₆R₆) in the solid state, with the butyl groups bridging multiple atoms to form a more extended cluster. Single-crystal analysis of confirms this hexameric arrangement, where each is coordinated to four carbon atoms from different alkyl ligands, enhancing lattice stability through multicenter bonding. Ethyllithium, while tetrameric at , crystallizes in a centrosymmetric tetrameric form at low temperatures, highlighting temperature-dependent structural refinements that minimize steric strain in the ethyl bridges. Aryl- and vinyllithiums often display lower degrees of aggregation, forming monomeric or dimeric structures due to steric hindrance from the conjugated π-systems and substituents that limit bridging. For example, a sterically encumbered aryllithium exists as a rare monomeric σ-bonded species in the solid state, coordinated only by weak solvation, underscoring the role of bulkiness in preventing oligomerization. Similarly, β,β-shielded vinyllithiums are observed as dimers, with the vinyl groups providing sufficient steric to favor dimeric over higher-order clusters. These lattice energies are fundamentally influenced by the electrostatic coordination of Li⁺ ions to the lone pairs on carbanionic carbons, which imparts partial ionic character and contributes to the overall cohesion of the crystal packing.

Solution Structures and Aggregation

Organolithium reagents exhibit diverse aggregation states in solution, which are profoundly influenced by the solvent environment. In non-coordinating hydrocarbon solvents such as or , these compounds typically retain the oligomeric structures observed in the solid state, driven by lithium-carbon bridging interactions. For (n-BuLi), early cryoscopic measurements in indicated a tetrameric aggregate, though subsequent NMR investigations refined this understanding, revealing predominant hexameric forms at ambient temperatures and octameric at lower temperatures like -40 °C. These higher aggregates provide stability in apolar media by shielding the polar C-Li bonds. In contrast, ethereal solvents such as (Et₂O) and (THF) promote dissociation to lower-order aggregates through coordination of solvent oxygen atoms to centers, which competes with intramolecular bridging. n-BuLi, for example, exists primarily as a tetramer in Et₂O but equilibrates between tetramers and dimers in THF, reflecting the stronger donor ability of THF that further weakens aggregate cohesion. This solvent-dependent deaggregation is general for unhindered alkyllithiums, with bulkier variants like tert-butyllithium favoring dimers even in less coordinating ethers. Nuclear magnetic resonance (NMR) has been instrumental in elucidating these solution structures, particularly through ⁶Li, ¹³C, and ¹H techniques that detect distinct signals for different aggregate types. Variable-temperature NMR studies demonstrate fluxional behavior, where labile Li-C bridges break and reform rapidly, leading to signal coalescence at elevated temperatures and revealing dynamic interconversion between aggregates. For instance, in THF, the spectra of show separate resonances for monomeric and dimeric species that merge upon heating, confirming bridge-breaking processes. The addition of chelating ligands like N,N,N',N'-tetramethylethylenediamine (TMEDA) further modulates aggregation by providing bidentate coordination that stabilizes lower-order species. TMEDA effectively disrupts tetrameric or hexameric clusters of alkyllithiums in ethereal solvents, often yielding monomeric complexes, as evidenced by sharpened NMR signals and shifted chemical shifts indicative of isolated Li centers. This ligand-induced monomerization is particularly pronounced for hindered organolithiums, enhancing and structural definition in solution. Aggregation states are governed by concentration- and temperature-dependent equilibria, such as the tetramerization process: 4RLi⇌(RLi)44 \mathrm{RLi} \rightleftharpoons (\mathrm{RLi})_4 Theoretical and experimental analyses confirm that these equilibria exhibit dependence, with dissociation to dimers or monomers entropically favored at higher temperatures due to increased translational freedom of the separated units. Such behavior underscores the thermodynamic basis for and effects on solution structures.

Structure-Reactivity Relationships

The reactivity of organolithium reagents is profoundly influenced by their aggregation state, where higher-order aggregates such as dimers and tetramers reduce nucleophilicity compared to monomeric . In aggregates, the carbanionic charge is delocalized across multiple lithium-carbon interactions, effectively lowering the at the reactive carbon center and hindering nucleophilic attack on electrophiles. This delocalization stabilizes the reagent but diminishes its reactivity, with monomers exhibiting significantly higher nucleophilicity due to concentrated charge on the . In polar media, solvent-separated ion pairs further modulate reactivity by enhancing basicity relative to nucleophilicity. Solvents like (THF) or (HMPA) promote dissociation of contact ion pairs into separated ones, where the cation is solvated and less able to coordinate with the or substrate heteroatoms. This separation increases the availability of the naked for proton abstraction, favoring over reactions, while also boosting overall nucleophilicity in some contexts by reducing steric and electrostatic barriers. Steric bulk in the organic substituent plays a key role in favoring monomeric or less aggregated structures, leading to selective reactivity profiles. For instance, tert-butyllithium (t-BuLi) forms tetramers in solvents but favors dimers or monomers in ethereal solvents or with ligands, due to steric hindrance that inhibits higher aggregation and enhances reactivity toward hindered electrophiles or specific deprotonations compared to less bulky alkyllithiums. This contrasts with primary alkyllithiums like n-BuLi, allowing t-BuLi to exhibit unique selectivity in reactions where aggregation would otherwise suppress activity. Density functional theory (DFT) computations provide insights into these relationships by modeling charge distribution and frontier orbital interactions. Studies using functionals like M06-2X reveal that in aggregates, the highest occupied (HOMO) is more diffuse with lowered energy, reflecting charge delocalization and reduced reactivity, whereas monomeric forms show a higher, more localized HOMO conducive to nucleophilic orbital overlap. These models also highlight solvent effects on pair separation, correlating structural features with kinetic barriers in representative additions. An illustrative example is the general trend observed in nucleophilic additions: higher aggregates like the hexameric form of n-BuLi in hydrocarbons exhibit slower reaction rates due to charge delocalization, while lower aggregates such as the tetrameric form of sec-butyllithium (s-BuLi) in similar conditions proceed more rapidly, underscoring how degree of association directly impacts addition efficiency.

Preparation

Reaction with Lithium Metal

The classical preparation of organolithium reagents involves the direct insertion of lithium metal into the carbon-halogen bond of an organic halide, a method first demonstrated in the early 20th century and widely used for simple alkyl and aryl derivatives. The general reaction proceeds according to the stoichiometry: 2Li+RX→RLi+LiX2 \mathrm{Li} + \mathrm{RX} \rightarrow \mathrm{RLi} + \mathrm{LiX} where R is typically an alkyl or aryl group and X is a halogen, most commonly bromide or iodide, though chlorides are also employed industrially. This process requires strictly anhydrous conditions under an inert atmosphere, such as nitrogen, to prevent quenching by moisture or oxygen. The reaction is typically conducted in hydrocarbon solvents like , , or , or in ethers such as , with temperatures ranging from -10°C to 60°C depending on the substrate. Alkyl bromides and iodides react more readily than chlorides, while aryl bromides and iodides are suitable for aryllithium formation; fluorides generally do not react. To initiate and sustain the reaction, high-surface-area metal—often in the form of fine shavings, wire, or powder—is used, typically in 2-4 equivalents to account for surface passivation and ensure complete conversion. Vigorous agitation, such as stirring or shaking, is essential to maintain contact between the metal and . Yields generally range from 55% to 95%, influenced by the choice of and conditions. A prominent side reaction is Wurtz-type coupling, which forms the homodimer R-R via radical intermediates, following: 2RX+2Li→R−R+2LiX2 \mathrm{RX} + 2 \mathrm{Li} \rightarrow \mathrm{R-R} + 2 \mathrm{LiX} This competes with the desired insertion, particularly with iodides or at higher temperatures, but is minimized with compared to heavier metals due to lithium's lower . The extent of coupling can be reduced further by using solvents and low temperatures. Optimizations enhance initiation and yields, especially for less reactive substrates. Lithium dispersion with 0.02–2% sodium doping activates the metal surface, accelerating the reaction without significantly promoting side products. Ultrasonic irradiation disperses the lithium and cleans its surface, leading to faster reaction times and higher yields for alkyl bromides in ether solvents. Additives like 4,4'-di-tert-butylbiphenyl (DTBB) act as electron carriers, facilitating reductive insertion with lithium powder in THF at low temperatures, improving efficiency for certain aryl and alkyl halides. Industrially, this method is exemplified by the production of (n-BuLi), a key reagent, via the reaction of n-butyl chloride with metal in : 2Li+n−C4H9Cl→n−C4H9Li+LiCl2 \mathrm{Li} + n-\mathrm{C_4H_9Cl} \rightarrow n-\mathrm{C_4H_9Li} + \mathrm{LiCl} This process, developed in , uses sodium-activated and yields solutions suitable for direct use or . For substrates sensitive to strongly basic conditions, alternatives such as lithium-halogen exchange may be preferred.

Deprotonation and Direct Metalation

Organolithium reagents can be generated through of C-H bonds using strong bases such as alkyllithiums, which abstract a proton to form the carbanionic species and as a byproduct. This method is particularly effective for acidic protons, such as those at benzylic positions or ortho to electron-withdrawing directing groups on aromatic rings. The reaction typically proceeds in aprotic solvents like or (THF) at low temperatures to control reactivity and minimize side reactions like addition to carbonyls. Directed ortho metalation (DoM) is a key strategy for site-selective of aryl C-H bonds, where a directing metalation group (DMG) coordinates to the base, facilitating abstraction of the ortho proton. Common DMGs include tertiary amides and O-carbamates, which enhance the acidity of the adjacent C-H bond through coordination and inductive effects, allowing regioselective lithiation even in the presence of other positions. For instance, treatment of with (n-BuLi) in leads to ortho-lithioanisole, a reaction independently discovered by Gilman and Wittig in the late and early 1940s. Similarly, undergoes clean lithiation at one or both cyclopentadienyl rings with n-BuLi in the 1950s, enabling the synthesis of substituted ferrocenes used in and materials. For less acidic protons, superbases such as mixtures of n-BuLi and tert-butoxide (t-BuOK), known as Lochmann-Schlosser bases, provide enhanced basicity by forming more reactive potassium alkyl species, enabling at remote or sterically hindered sites. These mixtures are particularly useful for metalating hydrocarbons lacking strong directing groups, with the potassium component increasing the and reactivity of the base aggregate. Site selectivity in deprotonation often operates under kinetic control, where the directing group or inherent acidity dictates the fastest proton abstraction, as seen in DoM reactions at low temperatures. However, under thermodynamic conditions—such as higher temperatures or longer reaction times—equilibration can occur, favoring the most stable organolithium, as demonstrated in the metalation of where benzylic predominates. A representative example is the benzylic lithiation of : \mathrm{C_6H_5CH_3 + n\text{-BuLi \rightarrow C_6H_5CH_2Li + C_4H_{10}} This reaction proceeds slowly in toluene solvent, yielding benzyllithium selectively at the side chain under kinetic conditions.

Lithium-Halogen Exchange

Lithium-halogen exchange is a key method for preparing organolithium reagents through the rapid interconversion of an alkyl, aryl, or vinylic halide with an organolithium compound, typically at low temperatures to minimize side reactions. This process, first demonstrated in the late 1930s, allows selective generation of organolithiums that are unstable or difficult to access by other means, such as direct metalation. The reaction proceeds via a nucleophilic mechanism involving attack by the carbanion of the organolithium on the halogen-bearing carbon, forming a transient halogen "ate" complex that collapses to yield the new organolithium and the alkyl halide derived from the original organolithium. This pathway is favored for bromides and iodides over chlorides due to the weaker C-Br and C-I bonds, which facilitate faster exchange rates, while fluorides are generally unreactive. The exchange is highly kinetic in nature and occurs rapidly even at -78°C, often completing within minutes, which outpaces competing processes like or and thus preserves sensitive functional groups. For instance, tert-butyllithium (t-BuLi) is commonly employed as the exchanging agent with aryl bromides, as illustrated by the reaction t-BuLi + ArBr → ArLi + t-BuBr, where two equivalents of t-BuLi are typically used to drive the process forward by consuming the t-BuI through elimination. This method is particularly valuable for generating unstable organolithiums, such as vinylic lithium species from vinyl bromides or iodides, which can then be trapped in subsequent reactions. In vinylic cases, the exchange proceeds with stereospecific retention of configuration at the , enabling the synthesis of stereodefined intermediates for assembly. The equilibrium of the exchange favors the more stable carbanion, with sp-hybridized (alkynyl) > sp²-hybridized (vinylic, aryl) > sp³-hybridized (alkyl) organolithiums, allowing predictable selectivity in mixed systems. Low temperatures, such as -78°C in (THF) or , are standard to maintain kinetic control and prevent decomposition. Overall, this technique has become indispensable in synthetic for its speed, selectivity, and compatibility with a wide range of substrates.

Advanced and Modern Methods

The Shapiro reaction provides a valuable route to vinyllithium reagents through the treatment of tosylhydrazones derived from ketones or aldehydes with excess organolithium base. In this process, the tosylhydrazone undergoes sequential and elimination to generate the vinyllithium intermediate, which can be trapped with electrophiles before further decomposition to the occurs. This method is particularly useful for regioselective access to less substituted vinyllithiums, offering advantages over direct in cases where is challenging. Recent advances in mechanochemical techniques have enabled solvent-free preparation of organolithium reagents under air-tolerant conditions. In 2025, a method involving ball-milling of organic halides with metallic was reported, activating the lithium via mechanical force to facilitate direct C-Li bond formation without the need for solvents or inert atmospheres. This approach demonstrates high efficiency and scalability, producing organolithiums such as and in good yields, and has been applied to subsequent reactions like nucleophilic additions. Flow chemistry has emerged as a modern strategy for the safe and continuous generation of organolithium reagents, mitigating risks associated with their exothermic formation and high reactivity. Dedicated flow setups allow precise control of temperature, , and , enabling the production of concentrated solutions of alkyllithiums like butyllithium for immediate in-line reactions. This technique enhances scalability for synthetic applications, reducing waste and improving reproducibility compared to batch processes. Reductive lithiation using lithium naphthalenide offers a mild method for generating organolithium from sulfoxides or selenides. Treatment of alkyl aryl sulfoxides or phenyl selenides with dissolved in generates the corresponding alkyllithium by selective cleavage of the C-S or C-Se bond via single-electron transfer. This approach is effective for functionalized substrates sensitive to other preparative methods, providing clean access to organolithiums under aprotic conditions at low temperatures. In 2023, incorporation of organolithium reagents into organogels was developed as a stabilization strategy for precursors, allowing air-stable handling and storage. Sensitive species such as , , and sec-butyllithium are encapsulated within a hexatriacontane-based gel matrix, which prevents decomposition and enables portioned delivery for reactions. This innovation facilitates safer laboratory use and potential scale-up by maintaining reagent integrity under ambient conditions.

Reactivity

Nucleophilic Reactions

Organolithium reagents serve as highly reactive carbon nucleophiles, enabling the formation of new carbon-carbon bonds through addition to various electrophiles. Their nucleophilicity arises from the polarized carbon-lithium bond, where the carbon bears a partial negative charge, facilitating attack on electron-deficient centers. This reactivity is particularly pronounced in aprotic solvents like or (THF), where effects modulate the aggregation state and thus the nucleophilic power of the reagent. A primary mode of nucleophilic reactivity is the addition to carbonyl compounds, such as and ketones, generating lithium alkoxides as intermediates that yield secondary or tertiary alcohols upon aqueous . For instance, the reaction of an alkyllithium RLi with an R'CHO proceeds via nucleophilic attack at the carbonyl carbon, forming R'CH(OLi)R, which hydrolyzes to R'CH(OH)R. This transformation is a cornerstone of synthetic for constructing complex alcohol frameworks. A representative example is the addition of (MeLi) to , yielding the lithium alkoxide of 1-methylcyclohexanol: \ceMeLi+\bigcyclehexanone−>(1−methylcyclohexyl)OLi\ce{MeLi + \bigcyclehexanone -> (1-methylcyclohexyl)OLi} Upon hydrolysis, this affords 1-methylcyclohexanol in high yield. Such additions are generally fast and efficient, often requiring low temperatures to control exothermicity and side reactions. Organolithium reagents also participate in SN2 displacements with primary alkyl halides, displacing the halide to form new C-C bonds, as exemplified by n-BuLi reacting with 1-bromobutane to produce octane. However, these reactions are often limited in scope due to competing pathways, including rapid halogen-metal exchange and the high basicity of RLi leading to elimination or self-coupling (Wurtz-type reactions), which reduce selectivity and yield. Consequently, such substitutions are typically reserved for cases where exchange is minimized, such as with non-reactive halides or under controlled conditions. Carbolithiation represents another key nucleophilic process, involving the addition of the C-Li bond across carbon-carbon multiple bonds, particularly alkenes, to generate new organolithium species. For example, RLi adds to styrene (PhCH=CH₂), with the attacking the terminal carbon and the coordinating to the benzylic position, yielding PhCH(Li)CH₂R. This reaction is stereoselective and regioselective, often proceeding via a concerted or radical mechanism depending on the substrate and conditions, enabling the synthesis of functionalized organolithiums for further elaboration. Intermolecular carbolithiation is highly efficient for unactivated alkenes and has been applied in enantioselective variants using chiral ligands. With α,β-unsaturated carbonyl compounds, organolithium reagents exhibit a preference for 1,2-addition to the over 1,4-conjugate addition to the β-position, due to their hard nucleophilic character. However, the is solvent-dependent; in non-coordinating solvents like , 1,2-addition predominates, while coordinating solvents such as THF or additives like LiBr can enhance 1,4-addition by stabilizing intermediates. For instance, n-BuLi typically adds 1,4 to under certain conditions, but 1,2-selectivity can be tuned to over 95% with LiBr in ether. This tunability allows selective access to allylic alcohols (1,2) or β-substituted carbonyls (1,4), broadening synthetic utility.

Basic and Deprotonation Reactions

Organolithium reagents serve as exceptionally strong bases in , capable of C-H bonds with pKa values ranging from approximately 40 to 50, particularly for terminal alkanes like in . This basicity enables the formation of from carbonyl compounds such as ketones, where the pKa of the alpha-hydrogen (around 20 for acetone) is significantly lower, allowing irreversible under controlled conditions. A representative example is the reaction of with acetone to generate the lithium : n-BuLi+(CH3)2C=O→(CH3)2C=OLi+C4H10\mathrm{n\text{-}BuLi + (CH_3)_2C=O \rightarrow (CH_3)_2C=OLi + C_4H_{10}} This process is typically conducted at low temperatures to favor deprotonation over competing nucleophilic addition. To enhance kinetic deprotonation rates and selectivity, especially for less acidic substrates, organolithium reagents are often combined with potassium tert-butoxide to form so-called superbase mixtures, such as the Lochmann-Schlosser base (n-BuLi/KOtBu). These mixtures disrupt lithium aggregates, generating more reactive potassium organometallics that accelerate deprotonation while minimizing thermodynamic equilibration. Such suprabases are particularly useful for generating enolates from esters or amides, where standard organolithiums might be too aggressive. In polyfunctional molecules, organolithium bases enable site-selective metalation through (DoM) or complex-induced proximity effects, where coordinating groups like methoxy or direct to specific positions adjacent to the directing moiety. For instance, sec-butyllithium with TMEDA as a can selectively lithiate the ortho position of derivatives in the presence of other functional groups, allowing subsequent functionalization without affecting remote sites. This selectivity arises from the transient coordination of the base to the directing group, stabilizing the for at the desired C-H bond. The geometry of formed by organolithium deprotonation— versus —is profoundly influenced by the aggregation state of the in solution. often exist as dimers or higher aggregates in non-polar solvents like THF, where the is favored due to intramolecular coordination that minimizes steric repulsion in the cyclic ; addition of HMPA or crown ethers can disrupt aggregates, promoting . Seminal structural studies have shown that these aggregates dictate , with typically predominant under standard conditions for . Although is the primary mode, to the carbonyl can occur as a side reaction under warmer conditions or with excess .

Exchange and Transmetalation Reactions

Organolithium reagents participate in lithium- exchange reactions with organic halides, where the equilibrium position favors the formation of the less basic organolithium species due to differences in stability. This kinetic process is rapid and reversible, with the rate depending on the halogen type—I > Br > Cl—and the nature of the organic groups involved, allowing selective generation of desired organolithiums under controlled conditions. For instance, exchanging with aryl bromides shifts the equilibrium toward the aryl lithium because aryl are more stable than alkyl ones. These exchanges often proceed with retention of , particularly in vinyl halides, where the configuration of the is preserved through a concerted mechanism involving four-center transition states. This is crucial for synthesizing stereodefined organolithiums used in subsequent stereoselective transformations. reactions involve the transfer of organic groups from to other metals, yielding milder nucleophilic species suitable for selective reactivity. Organolithiums react with (I) salts to form lithium dialkylcuprates (Gilman reagents), which are less reactive than organolithiums and enable conjugate additions and substitutions without over-addition to carbonyls. A representative example is the formation of diphenylcuprate: 2 PhLi+CuI→Ph2CuLi+LiI2 \ PhLi + CuI \rightarrow Ph_2CuLi + LiI This ate complex exhibits enhanced stability and selectivity in carbon-carbon bond-forming reactions. Similarly, transmetalation with zinc halides produces organozinc reagents, which are even milder and compatible with sensitive functional groups, facilitating Negishi couplings and Reformatsky-type additions. These transmetalations preserve the stereochemistry of the original organolithium, maintaining chirality in asymmetric syntheses.

Applications

In Organic Synthesis

Organolithium reagents play a pivotal role in organic synthesis by facilitating carbon-carbon (C-C) bond formation, particularly through nucleophilic addition to carbonyl compounds, enabling the construction of complex scaffolds in natural product total syntheses. These highly reactive species are especially valuable for assembling intricate molecular architectures, such as in the total synthesis of steroids, where directed lithiation followed by addition to aldehydes or ketones introduces key carbon chains. For instance, in the synthesis of a functionalized steroid precursor, an α-lithiated organolithium intermediate was added to an aldehyde, yielding a tertiary alcohol that served as a critical intermediate for substituted testosterone analogs. This approach highlights their utility in building polycyclic frameworks essential to steroid chemistry. To enhance tolerance and minimize side reactions, such as over- or , synthetic strategies often employ controlled techniques. Inverse —wherein the is added to a solution of the organolithium reagent—prevents self-condensation or by ensuring stoichiometric delivery and reducing exposure to excess base, thereby improving yields in sensitive carbonyl additions. This method is particularly effective for substrates bearing acidic protons or coordinating groups that could otherwise quench the reagent prematurely. A notable pharmaceutical application involves the synthesis of an intermediate for , an antiretroviral drug, where ortho-lithiation of N-Boc-4-chloroaniline with , followed by addition to an , proceeds efficiently in flow reactors to afford the desired in 70% yield, surpassing batch conditions (28%). Similarly, in a telescoped flow process for itself, lithiation of an with n-BuLi and subsequent addition to a delivers the key alcohol intermediate in 73% yield over two steps, demonstrating scalability and safety for industrial routes. Compared to Grignard reagents, organolithiums exhibit superior reactivity toward hindered or acidic substrates due to their greater nucleophilicity and basicity, allowing additions to sterically demanding ketones that proceed sluggishly with magnesium counterparts. This enhanced potency stems from the more covalent C-Li bond, enabling access to polyfunctionalized targets where Grignards fail. Asymmetric variants of these additions, using chiral ligands, further extend their scope to stereocontrolled syntheses.

In Asymmetric Synthesis

Organolithium reagents are pivotal in asymmetric synthesis due to their ability to form configurationally stable chiral intermediates when coordinated with suitable chiral ligands, enabling enantioselective carbon-carbon bond formation. These processes often involve the generation of enantioenriched organolithium species via or directed metalation, followed by reaction with electrophiles to yield products with high enantiomeric excess (ee). Chiral auxiliaries or ligands, such as diamines and diols, play a critical role in inducing stereocontrol by influencing the aggregation state and reactivity of the organolithium species. A key strategy employs chiral ligands like (-)-sparteine or TADDOL for the formation of enantioenriched enolates from prochiral carbonyl compounds. For instance, TADDOL-derived chiral alkoxides catalyze the asymmetric benzylation of achiral ketone enolates, such as those derived from , delivering α-benzylated products with ee values exceeding 90% through selective coordination that directs the approach of the . Similarly, (-)-sparteine complexes with sec-butyllithium facilitate the asymmetric of epoxides or carbamates, generating chiral organolithium intermediates that react with aldehydes to form enantioenriched β-hydroxy esters with ee >95%. Asymmetric deprotonation represents a cornerstone application, particularly for lithiated amides and related substrates. Treatment of N-Boc-protected amides, such as N-Boc-indoline, with n-BuLi or s-BuLi in the presence of (-)- effects kinetic resolution or enantioselective at the α-position, producing chiral lithiated species that undergo electrophilic trapping—e.g., with —to afford enantioenriched α-substituted amides with ee up to 98%. This method relies on the diamine's ability to form a chiral mixed aggregate with the organolithium base, stabilizing the deprotonated intermediate and preventing . The subsequent addition of electrophiles like ketones or imines preserves the , enabling the synthesis of complex chiral motifs. Recent advances have expanded these protocols to remote deprotonations, including γ-selective processes in heterocyclic frameworks. For example, phosphoramide additives have been shown to disrupt contact ion pairs in tert-butyllithium, facilitating regioselective γ-deprotonation of chromanes at the 4-position under mild conditions, which can be adapted for asymmetric variants using chiral co-ligands to achieve enantioenriched functionalized chromanes with potential applications in synthesis. Such innovations enhance selectivity in polyfunctionalized substrates, building on earlier diamine-mediated methods. Enantioselective carbolithiation exemplifies the utility of chiral catalysts in organolithium-mediated cyclizations or additions. In the presence of (-)-sparteine or , alkyllithium reagents add across styrenyl or allylic systems to generate chiral benzylic organolithium intermediates, which are then trapped with electrophiles like CO2 to yield enantioenriched carboxylic acids with >90%. This process proceeds via a coordinated where the chiral enforces facial selectivity in the carbometalation step. Chiral organolithium reagents also enable direct enantioselective nucleophilic additions to carbonyls. The coordination of a chiral , such as a β-amino alcohol or derivative, to an organolithium species directs its addition to ketones, forming enantioenriched tertiary alcohols. A representative reaction is depicted below: \ceR−Li⋅L∗+R′R′′C=O−>R′R′′C(OH)−R\ce{R-Li \cdot L^* + R'R''C=O -> R'R''C(OH)-R} where \ceL∗\ce{L^*} denotes the chiral , yielding products with ee >90% through selective shielding of one enantioface. This approach has been particularly effective for aryl ketones, providing scalable access to chiral building blocks in pharmaceutical synthesis.

Industrial and Polymer Applications

Organolithium reagents play a pivotal role in , particularly as initiators for anionic to produce synthetic rubbers and . Sec-butyllithium (sec-BuLi) is widely employed to initiate the living anionic of styrene and , enabling the synthesis of solution styrene-butadiene rubber (S-SBR), a high-performance used in for improved traction and durability. This process allows precise control over molecular weight and microstructure, resulting in materials with enhanced mechanical properties compared to free-radical methods. Globally, (n-BuLi) production is estimated at 2,000–3,000 metric tons per year, with significant portions allocated to the industry and fine chemicals manufacturing. In pharmaceutical production, organolithium reagents facilitate scale-up through integration with continuous flow chemistry, addressing challenges like exothermic reactions and safety in batch processes. Recent advancements in 2024 have demonstrated pilot-scale implementation of organolithium-mediated couplings in flow reactors, such as the formation of intermediates for drugs like nemtabrutinib, enabling efficient kilogram-scale synthesis with reduced waste and improved heat management. A notable example is the commercial production of , an antiretroviral drug developed by Pharmaceuticals and first approved in 1998, where ortho-lithiation and subsequent addition of lithium cyclopropylacetylide to a provided a key stereoselective step in the synthesis. Emerging sustainable methods are enhancing industrial viability, including a 2025 mechanochemical approach for generating organolithium reagents directly from metallic and organic halides under solvent-free ball-milling conditions. This technique activates metal without traditional solvents or catalysts, offering a scalable, alternative for on-site preparation in and production, potentially reducing energy use and .

Handling and Safety

Laboratory Techniques

Organolithium reagents require manipulation under strictly inert conditions due to their high reactivity toward oxygen and moisture. In research laboratories, these operations are typically conducted using or gloveboxes filled with an inert atmosphere of or . A consists of a dual manifold system connected to a and inert gas supply, enabling the evacuation and backfilling of glassware to exclude air while allowing transfers and reactions. Gloveboxes, with their sealed enclosures and built-in manipulators, are particularly suited for handling neat or highly concentrated organolithiums, providing a controlled environment free of atmospheric contaminants. Transfer and addition of organolithium solutions employ or techniques to maintain inert conditions and control reaction rates. For volumes under 50 mL, a gas-tight is pressurized with from the reagent bottle, filled slowly to avoid bubbles or overfilling, and then injected through a into the reaction vessel. Slow addition via minimizes exotherms by allowing heat dissipation and preventing rapid, uncontrolled reactions. Larger transfers use cannulas under positive pressure, with the apparatus clamped to ensure stability during flow. Accurate determination of organolithium concentration is essential for synthetic reliability and is achieved through protocols. The Gilman double titration method, a standard procedure, involves adding a known volume of the reagent to in THF to form an organolithium intermediate, followed by titration with sec-butyl alcohol using phenanthroline as an indicator to quantify both active organolithium and basic impurities. Alternatively, a single titration with in THF, using 2,2'-bipyridine as a color indicator (colorless to red endpoint), provides a simpler assessment of the active concentration. These methods ensure precise dosing, with the double titration being particularly robust for commercial solutions containing potential contaminants. Quenching excess organolithium after reactions demands controlled conditions to mitigate vigorous gas evolution and heat release. The is first cooled to 0°C or lower in an ice or bath, then slowly treated with anhydrous isopropanol under vigorous stirring to initially decompose the reagent, followed by and finally water. This stepwise addition, performed in a with temperature monitoring to stay below 50°C, prevents splashing or pressure buildup. Commercial organolithium reagents are typically stored as 1.5–2.5 M solutions in non-coordinating solvents like or , refrigerated at 2–8 °C under to preserve reactivity and prevent . Bottles are sealed under , stored upright in dedicated refrigerators, and visually inspected for clarity before use, as discoloration indicates degradation.

Hazards and Precautions

Organolithium reagents are highly pyrophoric, igniting spontaneously upon exposure to air due to rapid oxidation, which can lead to fires or explosions. They also react violently with , generating gas and significant heat, potentially causing or bursts in confined spaces. These compounds pose risks, with lithium salts acting as irritants to skin, eyes, and , while the associated organic solvents or vapors, such as , are flammable and can cause hazards. For , the oral LD50 in rats exceeds 5,000 mg/kg, indicating low acute systemic toxicity but emphasizing the need for caution due to local corrosive effects. Laboratory incidents highlight these dangers; for instance, a 2008 fire at UCLA resulted from tert-butyllithium leaking from a during transfer, igniting on air contact and causing fatal burns due to inadequate and improper PPE. Improper of residues has also led to fires and explosions due to exothermic reactions and potential ignition, as seen in incidents with reactive metals where rapid addition of quenching agents like isopropanol in sealed vessels caused pressure buildup from gas evolution. The recommends handling organolithium reagents in a with flame-resistant lab coats, nitrile or gloves, and splash goggles or face shields to mitigate ignition and exposure risks. should involve slow addition of or isopropanol under inert conditions to avoid gas buildup, with emergency dry chemical (Class D) extinguishers nearby. Recent innovations include organogel encapsulation, developed in 2023, which stabilizes organolithium reagents like in a hexatriacontane matrix, enabling air-stable storage, portioning, and handling without inert atmospheres for up to several hours. Recent innovations include non-pyrophoric formulations of n- and t-BuLi, which maintain reactivity while reducing ignition risks during handling.

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