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Phenyllithium

Phenyllithium (C₆H₅Li) is a highly reactive organolithium compound that serves as a versatile reagent in organic synthesis, primarily functioning as a strong nucleophile and base to introduce phenyl groups via nucleophilic addition or substitution reactions.^[1]^[2] With a molecular weight of 84.05 g/mol and CAS number 591-51-5, it is particularly valued for reactions with hindered ketones and as a substitute for Grignard reagents in cases requiring greater reactivity.^[3]^[4] The compound is synthesized by the direct reaction of bromobenzene (or chlorobenzene) with lithium metal in an anhydrous ether solvent, such as diethyl ether, under inert atmosphere conditions to prevent decomposition.^[5]^[6]^[1] This direct reaction typically yields a solution of phenyllithium, as the pure solid is challenging to isolate due to its extreme sensitivity to air and moisture; yields can reach approximately 75% under optimized conditions.^[7]^[8] In terms of physical properties, pure phenyllithium appears as a colorless crystalline solid, but it is most often encountered as a dark brown to black solution in ether or hydrocarbon solvents.^[1] It exhibits high solubility in polar solvents like ethers and tertiary amines, while remaining insoluble in non-polar hydrocarbons unless donor additives such as tetrahydrofuran (THF) are present to facilitate solvation and modify its aggregation state from tetramers to dimers.^[4]^[9] Due to its pyrophoric nature and strong reducing properties, phenyllithium must be handled under strictly anhydrous and oxygen-free conditions, often in solutions stabilized at low temperatures for storage.^[10]^[11] Key applications of phenyllithium include carbon-carbon bond formation, such as in the synthesis of triarylmethanes or phosphine ligands, and metalation reactions to generate other organometallics.^[3]^[1] It also finds use in polymer chemistry as an initiator for anionic polymerization and in the preparation of isotopically labeled compounds for research.^[12]^[13] Its reactivity profile, including aggregation-dependent behavior in solution, has been extensively studied to optimize its performance in synthetic protocols.^[9]

General Information

Nomenclature and Formula

Phenyllithium is an organometallic compound with the empirical and molecular formula C₆H₅Li and a molar mass of 84.045 g/mol.^[14] The systematic names for this compound are lithium phenyl or phenyllithium, while a systematic IUPAC name is lithium;benzene (also known as lithium benzenide).^[15] The basic structure consists of a phenyl group (C₆H₅) directly bonded to a lithium atom, represented as:

\chemfig{**6(-=-=-=)-Li}

This Kekulé depiction shows the benzene ring with alternating double bonds and the C–Li bond.^[16] Phenyllithium exemplifies an organolithium reagent, characterized by the general formula RLi, in contrast to Grignard reagents which incorporate magnesium and a halide (RMgX).

History

The development of organolithium chemistry began with the pioneering efforts of Wilhelm Schlenk, who in 1917 first synthesized phenyllithium through the reaction of diphenylmercury with lithium metal, marking the initial entry into alkyl- and aryllithium compounds and establishing techniques for handling air-sensitive organometallics.^[17] This transmetalation method, though effective, relied on mercury intermediates and limited scalability for practical applications. In 1930, Karl Ziegler advanced the field by introducing the direct synthesis of phenyllithium from phenyl halides and lithium metal, such as bromobenzene in benzene solution yielding 68% phenyllithium, which simplified preparation and highlighted the compounds' stability toward certain organic halides compared to heavier alkali analogs.^[18] Ziegler's work built on his earlier 1929 observations of organolithium reactivity, shifting focus from mercury-based routes to more direct metal-halide reactions and laying groundwork for broader organolithium exploration. The 1930s saw further milestones through contributions from Georg Wittig and Henry Gilman, who independently developed halogen-metal exchange as a versatile route to phenyllithium and related species; Wittig in 1938 demonstrated exchange using phenyllithium with aryl bromides like o-bromoanisole, while Gilman in 1939 extended it to alkyl systems and emphasized applications in directed metalation.^[19] These innovations evolved synthesis from cumbersome early methods to efficient exchanges, with Gilman's subsequent publications in the 1940s and beyond promoting organolithium reagents in synthetic organic chemistry for carbon-carbon bond formation and functional group transformations.

Physical Properties

Appearance and Phase Behavior

Phenyllithium in its pure form consists of colorless crystals. Solutions of the compound, which are the typical form in which it is handled, appear brown or red, a coloration attributed to impurities or interactions with the solvent.^[20]^[1] The benzene solvate of phenyllithium has a melting point of 160–163 °C.^[21] Solutions in diethyl ether exhibit a boiling point of 140–143 °C. The density of liquid solutions, such as those in dibutyl ether, is 0.835 g/cm³ at 25 °C.^[21]^[22] Phenyllithium displays good solubility in ether-based solvents, including diethyl ether and tetrahydrofuran (THF), facilitating its use in synthetic applications. It is generally insoluble in hydrocarbons unless donor additives like TMEDA are incorporated to enhance solubility. The compound decomposes rapidly in protic solvents such as water or alcohols.^[12]^[23] Due to its high reactivity, phenyllithium is pyrophoric upon exposure to air and extremely sensitive to moisture, necessitating handling under an inert atmosphere to prevent ignition or decomposition.^[22]^[4]

Spectroscopic Properties

Phenyllithium is characterized by a range of spectroscopic techniques that provide insights into its structure, aggregation, and bonding. These methods reveal the influence of solvation and aggregation on its properties in solution and the solid state. Nuclear magnetic resonance (NMR) spectroscopy is particularly valuable for elucidating the solution behavior of phenyllithium, including its aggregation states as monomer, dimer, or tetramer. The ¹H NMR spectrum exhibits signals for the phenyl ring protons, typically appearing as multiplets between 6.8 and 7.5 ppm in ethereal solvents, with the ortho protons closest to the lithium showing deshielding due to the electron-withdrawing effect of the C-Li bond. The ⁷Li NMR spectrum is sensitive to the coordination environment of lithium, displaying chemical shifts that vary with solvation and aggregation; for instance, the dimeric form in tetrahydrofuran (THF) shows a ⁷Li resonance around -1.5 ppm, while higher aggregates exhibit broader or shifted signals indicative of multiple lithium environments. The ¹³C NMR spectrum offers direct evidence of the ipso carbon (directly attached to lithium), where chemical shifts correlate with aggregation degree: the tetramer in diethyl ether displays an ipso signal at 174.0 ppm (with J_{C-Li} = 5.1 Hz, appearing as a septet due to coupling with four equivalent lithium atoms), the dimer at 187.0 ppm (J_{C-Li} = 7.6 Hz, quintet for two lithiums), and the monomer in THF with polydentate ligands like PMDTA at 196.4 ppm (J_{C-Li} = 15.6 Hz, doublet). These downfield shifts and coupling patterns reflect increased s-character in the C-Li bond and reduced aggregation upon solvation, aiding in structural confirmation.^[24] Infrared (IR) spectroscopy highlights the vibrational signatures of the C-Li bond and phenyl moiety. The characteristic C-Li stretching mode appears as a weak absorption in the 500–600 cm⁻¹ region, owing to the low polarity and mass of the bond, distinguishing it from C-H or other stretches. Phenyl ring vibrations, including C=C stretches, are observed at 1400–1600 cm⁻¹, with aromatic C-H stretches near 3000–3100 cm⁻¹, providing confirmation of the intact phenyl group in synthetic intermediates or adducts. These low-frequency bands are crucial for monitoring reactions involving phenyllithium, as they persist in aggregated forms.^[25] Ultraviolet-visible (UV-Vis) spectroscopy of phenyllithium in solution shows absorptions attributed to charge-transfer transitions between the phenyl ring and lithium, often appearing as broad bands in the 240–260 nm range in ethereal solvents. These features arise from the partial ionic character of the C-Li bond, leading to π → σ* or similar excitations, and are sensitive to solvation effects that alter aggregation and thus the effective chromophore. Such spectra are used to track the reagent's concentration and purity during synthesis.^[25] Mass spectrometry of phenyllithium typically reveals the molecular ion at m/z 84 ([C₆H₅Li]⁺), though the ionic nature of the compound often leads to fragmentation; common fragments include loss of lithium (m/z 77 for C₆H₅⁺) or phenyl (m/z 7 for Li⁺). In electrospray ionization (ESI) modes, solvated or aggregated species may appear, but vapor-phase studies are challenging due to thermal instability, making this technique less routine than NMR for characterization.^[26] Raman spectroscopy complements IR by providing evidence for the Li-C bond through symmetric stretching modes, often observed around 500–550 cm⁻¹ in the solid state or frozen solutions, where the weak Raman activity of the polar C-Li bond becomes detectable. Phenyl ring modes, such as the ν₈a vibration at ~1600 cm⁻¹, are enhanced in resonance Raman setups, confirming the planarity and conjugation in the molecule. This technique is particularly useful for in situ monitoring of aggregation in non-polar media.^[27]

Chemical Structure

Solid-State Structure

The solid-state structure of unsolvated phenyllithium (PhLi) consists of infinite, ladder-like polymeric chains formed by edge-sharing Li₂Ph₂ dimer units, as determined by high-resolution synchrotron X-ray powder diffraction.^[28] These chains extend along the b-axis of the unit cell, with each dimer featuring a central, nearly planar Li₂C₂ four-membered ring where the two lithium atoms are bridged by the ipso carbon atoms of two phenyl groups.^[28] The phenyl rings are oriented nearly perpendicular to the plane of the Li₂C₂ ring, and adjacent dimers are linked through additional Li–C interactions involving the ortho and meta carbons of neighboring phenyl groups, resulting in a zigzag ladder motif stabilized by both σ- and π-bonding.^[28] Each lithium atom in the structure adopts a distorted tetrahedral coordination geometry, bonded to two ipso carbon atoms from the bridging phenyl groups (forming three-center, two-electron bonds) and additionally interacting with the π-electron density of adjacent phenyl rings from neighboring dimers.^[28] The Li–C(ipso) bond lengths within the dimer bridges are 2.24(1) Å and 2.32(1) Å, reflecting the asymmetric nature of the coordination, while the Li–Li separation across the ring is approximately 2.52 Å.^[28] The Li–C–Li bridge angle measures 63.2(7)°.^[28] Crystallographically, unsolvated PhLi crystallizes in the monoclinic space group P2₁/n, with unit cell parameters a = 11.528(1) Å, b = 4.555(1) Å, c = 10.406(1) Å, β = 114.24(1)°, and V = 498.22(2) Å³ (Z = 4).^[28] This structure was refined from powder diffraction data collected at 293 K, yielding agreement factors R_p = 0.0322 and R = 0.0468.^[28] In contrast, solvated forms of PhLi, such as those with diethyl ether or THF, typically exhibit discrete tetrameric aggregates rather than extended polymeric chains, with lithium coordination completed by oxygen donors from the solvent molecules.^[28]

Solution Structure

In solutions of diethyl ether, phenyllithium predominantly exists as a tetrameric cluster, often described as a cubane-type (Li₄Ph₄) structure where lithium and ipso-carbon atoms alternate at the vertices, with some evidence for a mixture including dimeric species depending on conditions.^[9] In tetrahydrofuran (THF), phenyllithium is primarily monomeric or dimeric, with each lithium atom coordinated by solvent molecules through their oxygen atoms to achieve tetrahedral geometry.^[9]^[12] The degree of aggregation for phenyllithium in ethereal solvents is governed by an equilibrium that shifts with concentration and temperature; for instance, cryoscopic measurements in THF reveal a monomer-dimer equilibrium, with lower concentrations and higher temperatures favoring the monomeric form.^[29]^[12] Solvate structures typically feature ether molecules coordinating to lithium centers, often in a bridging manner between Li atoms within clusters, enhancing stability through additional Li-O interactions.^[30] Density functional theory (DFT) calculations on phenyllithium oligomers confirm the relative stability of tetrameric clusters in less coordinating solvents like diethyl ether compared to dimeric or monomeric forms in THF, attributing this to optimized Li-C and Li-O bonding energies.^[31] Nuclear magnetic resonance (NMR) spectroscopy provides evidence for fluxional behavior in solution, including rapid intra-aggregate lithium-lithium exchanges in tetramers and dynamic solvent coordination in lower aggregates, as observed through variable-temperature ⁶Li and ¹³C NMR spectra.^[32]^[33]

Synthesis

Direct Synthesis from Metals

The direct synthesis of phenyllithium primarily involves the reaction of elemental lithium with an aryl halide precursor, such as bromobenzene, in an anhydrous ether solvent. This method, introduced by Karl Ziegler in 1930, proceeds via the reductive cleavage of the carbon-halogen bond, producing phenyllithium and lithium halide as a byproduct. The reaction is typically carried out under reflux to ensure complete conversion, with the general equation represented as: $2 \mathrm{Li} + \mathrm{C_6H_5Br} \rightarrow \mathrm{C_6H_5Li} + \mathrm{LiBr} Yields for this process generally range from 70% to 90%, depending on the purity of reagents and reaction control.^[34]^[35] A historical precursor to this approach was developed in 1917 by Wilhelm Schlenk, who prepared phenyllithium via transmetalation of diphenylmercury with lithium metal in an inert organic solvent: (\mathrm{C_6H_5})_2\mathrm{Hg} + 2 \mathrm{Li} \rightarrow 2 \mathrm{C_6H_5Li} + \mathrm{Hg} This method avoided halide byproducts but was largely supplanted by the more accessible halide-based synthesis due to the availability of phenyl halides.^[36] In practice, the reaction requires strictly anhydrous diethyl ether as the solvent to prevent quenching by moisture or protic impurities. Lithium is typically used in slight excess (e.g., a 2:1 molar ratio to the halide) and cut into small pieces or activated (e.g., via dispersion or ultrasonic treatment) to initiate the vigorous, exothermic process. A small portion of the phenyl bromide in ether is added first to start the reaction, followed by dropwise addition of the remainder over 30–60 minutes while maintaining reflux. The mixture is then stirred for several hours to ensure completion.^[35]^[36] Key challenges include side reactions such as Wurtz coupling, where two phenyl groups couple to form biphenyl (C₆H₅–C₆H₅), reducing yields; this is mitigated by controlled addition rates, excess lithium, and high-purity starting materials. The lithium halide forms an insoluble precipitate, which is removed by filtration under inert atmosphere post-reaction. For isolation of pure, solvent-free phenyllithium, the ether solution can be concentrated and distilled under reduced pressure, though the reagent is often used directly in solution due to its air- and moisture-sensitivity.^[36]^[6] A recent development as of 2025 involves mechanochemical activation of metallic lithium using ball milling to generate phenyllithium from bromobenzene or chlorobenzene in a solvent-free manner. This method enables preparation on scales up to 15 mmol with high efficiency and reduces risks associated with solvents and heat, offering advantages for safer synthesis.^[37] While highly effective for laboratory-scale preparations (up to several moles), scalability to industrial levels is limited by the pyrophoric nature of lithium metal, explosion risks from ether peroxides, and the need for specialized inert-atmosphere equipment; consequently, halogen-metal exchange methods are preferred for large-scale production.^[36]^[12]

Halogen-Metal Exchange

Phenyllithium is commonly synthesized via halogen-metal exchange, a process in which an alkyllithium reagent, such as n-butyllithium (n-BuLi), reacts with an aryl halide like bromobenzene to selectively transfer the lithium atom. The representative reaction is:

\mathrm{C_6H_5Br + n\text{-BuLi \rightarrow C_6H_5Li + n\text{-BuBr}}

This exchange is typically performed in tetrahydrofuran (THF) or diethyl ether as the solvent, with temperatures ranging from -78 °C to room temperature to control reactivity and minimize side reactions.^[38]^[39] The mechanism of this reaction is rapid and equilibrium-driven, proceeding through a four-center transition state or ate-complex intermediate, with the position of equilibrium favoring the formation of the more stable aryl organolithium over the alkyl variant due to differences in carbanion stability (sp² > sp³). It is particularly favored for bromides and iodides, while chlorides react more slowly and less selectively. Kinetic studies indicate the process is first-order in both the aryl halide and alkyllithium, with a Hammett ρ value of approximately +2, supporting the development of negative charge on the aryl ring in the rate-determining step. Solvent polarity influences selectivity, as coordinating solvents like THF enhance the solubility and reactivity of the organolithiums.^[40]^[39] This method offers significant advantages over direct metallation with lithium metal, providing higher purity products by avoiding heterogeneous conditions and reducing impurities from over-reduction. Yields typically exceed 95%, with side products such as deprotonation or elimination minimized under optimized low-temperature conditions. Variations include the use of iodoarenes, which undergo exchange even more readily due to weaker C-I bonds, or tert-butyllithium (t-BuLi) for faster reactions, often requiring only stoichiometric amounts but proceeding at higher rates to achieve near-quantitative conversion in minutes.^[39]^[38]

Reactions and Reactivity

Nucleophilic Additions

Phenyllithium acts as a strong nucleophile, readily adding to the electrophilic carbon of carbonyl compounds to form carbon-carbon bonds, yielding lithium alkoxides that are subsequently hydrolyzed to tertiary alcohols upon aqueous workup. The general reaction proceeds as follows:

\mathrm{C_6H_5Li + R_2C=O \rightarrow C_6H_5C(R_2)OLi}

followed by protonation with water or acid to give the alcohol \mathrm{C_6H_5C(R_2)OH}.^[37] This addition is highly efficient for both aldehydes and ketones, often occurring at low temperatures in ethereal solvents like diethyl ether or THF to control reactivity and minimize side reactions. A classic example is the addition of phenyllithium to benzophenone, which produces the corresponding lithium alkoxide and, after hydrolysis, triphenylmethanol in high yield. This reaction demonstrates the utility of phenyllithium in constructing sterically hindered tertiary alcohols from diaryl ketones. Similarly, the reaction with acetone illustrates the process with a simple dialkyl ketone:

\mathrm{C_6H_5Li + (CH_3)_2C=O \rightarrow (CH_3)_2C(C_6H_5)OLi}

hydrolyzing to 2-phenylpropan-2-ol, typically in yields exceeding 90% under standard conditions.^[37] Phenyllithium also undergoes nucleophilic addition to carbon dioxide, forming lithium benzoate as the initial product, which upon acidification yields benzoic acid. This carboxylation reaction is a key method for introducing carboxylic acid functionality from aryl organometallics, though it requires careful control due to the high reactivity of phenyllithium, which can lead to side products.^[41] In addition to carbonyls, phenyllithium adds to the C=N bond of imines, generating lithium amides, which upon hydrolysis provide a route to secondary amine synthesis. These additions are particularly valuable for constructing chiral amines when using enantiopure imines or ligands, with enantioselectivities up to 98% reported in asymmetric variants.^[42] Regarding stereochemistry, additions of phenyllithium to cyclic ketones often proceed with high diastereoselectivity, favoring axial approach of the nucleophile in chair-like conformations, leading to equatorial alcohols in products like those from cyclohexanone derivatives. For instance, reaction with (-)-menthone yields the trans alcohol stereospecifically due to this axial addition mode.^[43]

Metalations and Deprotonations

Phenyllithium acts as a strong, non-nucleophilic base in deprotonation reactions, enabling the formation of carbanions from weak C-H acids with pKa values around 25–43. The general deprotonation process follows the equation:

\ce{PhLi + RH -> PhH + RLi}

where Ph represents phenyl and R is the deprotonated substrate. This reactivity stems from the high basicity of phenyllithium, with the conjugate acid benzene having a pKa of approximately 43, allowing it to abstract protons from more acidic sites.^[34] A representative example is the deprotonation of terminal alkynes, where phenyllithium cleanly generates alkynyllithium species under mild conditions, as demonstrated in the synthesis of complex natural products like phomactin B2. In this case, phenyllithium deprotonates the terminal alkyne prior to subsequent metal-halogen exchange, avoiding side reactions common with stronger alkyl bases. In directed ortho-metalation (DoM), phenyllithium selectively deprotonates aromatic C-H bonds ortho to a coordinating directing metalation group (DMG), such as the methoxy substituent in anisole. The reaction with anisole proceeds at low temperatures in ether solvents to yield 2-methoxyphenyllithium, with the DMG coordinating to the lithium cation to stabilize the developing carbanion and enhance regioselectivity. Unlike more aggressive bases like n-butyllithium, phenyllithium's milder basicity minimizes over-lithiation or competing nucleophilic additions, achieving isolated yields up to 33% for the ortho-lithiated product. The general equation for this transformation is:

\ce{PhLi + C6H5OCH3 -> PhH + [o-(Li)C6H4OCH3]}

The mechanism of phenyllithium-mediated DoM primarily involves a polar pathway, initiated by coordination of the organolithium to the DMG heteroatom, forming a prelithiation complex that positions the ortho C-H bond for deprotonation. This coordination-directed process lowers the activation barrier for proton abstraction compared to undirected lithiation. Although single-electron transfer (SET) pathways have been observed in some arene systems, experimental evidence from kinetic studies and trapping experiments supports the dominance of polar mechanisms for DMG-directed reactions with phenyllithium. Phenyllithium also facilitates metalation of heteroaromatic systems. Compared to Grignard reagents, phenyllithium exhibits faster deprotonation kinetics due to its greater basicity and the more ionic character of the C-Li bond, which enhances nucleophilicity and reactivity toward C-H bonds. Rate studies indicate that organolithium deprotonations proceed orders of magnitude quicker than analogous Grignard processes under similar conditions, attributed to the lower solvation energy and higher charge separation in lithium species.^[34] This kinetic advantage makes phenyllithium particularly suitable for selective metalations where rapid, clean proton abstraction is required.

Applications

In Organic Synthesis

Phenyllithium serves as a versatile nucleophile and base in laboratory organic synthesis, particularly for introducing phenyl groups into complex molecules where Grignard reagents may be insufficient due to their lower reactivity. Its higher nucleophilicity enables reactions with sensitive or hindered electrophiles, such as sterically demanding ketones, that proceed sluggishly or not at all with phenylmagnesium halides. For instance, phenyllithium adds efficiently to hindered carbonyls to form tertiary alcohols, offering a practical alternative in syntheses requiring clean phenyl transfer without over-addition.^[34] This enhanced reactivity stems from the more ionic carbon-lithium bond compared to the covalent carbon-magnesium bond, allowing phenyllithium to function effectively in low-temperature conditions to minimize side reactions with labile substrates.^[44] Phenyllithium also plays a key role in pharmaceutical synthesis, particularly as an intermediate precursor for antiestrogenic agents. In the preparation of tamoxifen analogues, phenyllithium in di-n-butyl ether adds to protected ketone intermediates, facilitating the construction of the triarylethylene core with high stereoselectivity.^[45] For ketone synthesis from esters, phenyllithium reacts with Weinreb amides (N-methoxy-N-methylamides) to deliver ketones selectively, avoiding over-addition to tertiary alcohols. A typical sequence involves treating an ester-derived Weinreb amide with phenyllithium at low temperature, yielding the phenyl ketone in 80-95% efficiency, as the chelated tetrahedral intermediate prevents further nucleophilic attack.^[46] As a polymerization initiator, phenyllithium enables living anionic polymerization of styrene and dienes, producing polymers with narrow molecular weight distributions and controlled end-group functionality. In benzene or THF solvents, phenyllithium initiates styrene polymerization at room temperature, yielding polystyrene with molecular weights tunable by monomer-to-initiator ratio, often achieving polydispersity indices below 1.1.^[47] Similar initiation applies to dienes like butadiene, forming polybutadienes with 1,4-microstructures suitable for elastomer precursors. Phenyllithium's advantages include tolerance for polar functional groups like ethers and amines in the monomer backbone, which Grignard initiators often disrupt due to premature quenching.^[34]

Commercial and Industrial Uses

Phenyllithium is commercially available primarily as solutions in organic solvents, with typical concentrations ranging from 1.0 to 1.9 M. Common formulations include 1.9 M in dibutyl ether, 1.5 M in diethyl ether, and 1.8 M in a cyclohexane/ether mixture, which facilitate safe handling and storage under inert atmospheres.^[3]^[48] Major suppliers such as MilliporeSigma (formerly Sigma-Aldrich) and American Elements offer these products for research and industrial applications, with packaging options from 50 mL to 800 mL bottles.^[3]^[49] Industrial production of phenyllithium occurs on a large scale through methods like halogen-metal exchange, often adapted to continuous flow processes to enhance safety and efficiency for organolithium reagents. Companies such as FMC Corporation, a key player in organolithium manufacturing, have developed patented processes for its synthesis, enabling production up to manufacturing volumes for fine chemicals and specialty applications.^[6]^[34] Continuous flow techniques, including lithium-halogen exchange in hydrocarbon media, allow for scalable generation of phenyllithium intermediates, minimizing risks associated with batch reactions.^[50]^[51] In the fine chemicals sector, phenyllithium serves as a versatile reagent for synthesizing pharmaceuticals and intermediates, such as sulfonamides and acetyl-diphenylphosphinoferrocene derivatives used in medicinal chemistry. It also acts as a precursor for organometallic complexes employed in electronics, including thin-film deposition materials for LEDs and semiconductors.^[4]^[49] The organolithium market, of which phenyllithium is a component, exceeded $2 billion in 2024 and is projected to reach $3.21 billion by 2031, driven by a 6.1% CAGR linked to demand in battery technologies and advanced materials. Phenyllithium contributes to this growth through its role in producing high-performance polymers and lithium-based compounds for energy storage.^[52]^[53] Purity grades for phenyllithium vary by application, with research-grade products typically exceeding 99% purity to ensure precision in synthetic transformations, while industrial technical grades around 95% suffice for bulk processes in materials production.^[34]^[54]

Safety Considerations

Hazards

Phenyllithium is highly reactive and poses significant chemical and physical hazards due to its organometallic nature. Under the Globally Harmonized System (GHS), it is classified as pyrophoric (H250: Catches fire spontaneously if exposed to air) and corrosive to skin and eyes (H314: Causes severe skin burns and eye damage).^[55] The compound ignites spontaneously upon exposure to air, presenting an extreme fire risk even in trace amounts of oxygen. It reacts violently with water, protic solvents, or any source of protons, liberating hydrogen gas that can self-ignite and lead to explosions.^[22]^[4] Health effects from exposure are severe; contact with skin or eyes results in chemical burns and potential permanent damage, including blindness. Inhalation or ingestion can cause respiratory irritation, lithium toxicity affecting the central nervous system, kidneys, thyroid, and other organs, with symptoms including nausea, tremors, and long-term neurological impairment.^[22]^[49] Environmentally, phenyllithium is toxic to aquatic organisms (H402) and harmful to aquatic life with long-lasting effects (H412), necessitating prevention of release into waterways or soil where it may contribute to persistent contamination.^[55]^[22] Regarding flammability, phenyllithium has a flash point below 0 °C in typical solvent solutions and autoignites in air at ambient temperatures. Specific toxicity metrics such as LD50 values are not established for phenyllithium, though it exhibits hazards analogous to other alkyllithium compounds, which are highly toxic by ingestion, inhalation, and dermal routes.^[22]^[56]

Handling and Storage

Phenyllithium, being highly air- and moisture-sensitive, must be handled exclusively under an inert atmosphere to prevent ignition or violent reactions.^[11] Standard techniques include the use of a Schlenk line or inert atmosphere glovebox, with nitrogen (N₂) or argon (Ar) as the blanketing gas to exclude oxygen and water vapor.^[57] All glassware and equipment should be oven-dried (typically at 120°C for 2 hours) and purged with inert gas prior to use.^[58] For manipulation, syringe transfers are recommended for volumes under 50 mL, using gas-tight syringes equipped with PTFE seals to minimize leaks; larger volumes may employ cannula techniques under positive inert gas pressure.^[59] Transfers should occur within a metal bowl or secondary containment to catch potential spills.^[58] Quenching of residues or excess reagent begins with dilution to less than 5 wt.% using an inert solvent like heptane, followed by slow addition to 2 M isopropanol in heptane at or below 50°C (using a cooling bath such as dry ice/heptane), and final hydrolysis with water under inert conditions.^[57] Personal protective equipment (PPE) is essential and includes flame-retardant antistatic clothing (e.g., Nomex lab coat), tightly fitting safety goggles or a face shield, and chemical-resistant gloves such as fluorinated rubber (0.7 mm thickness) or Viton over nitrile for added protection.^[11] Closed-toe leather shoes and, if vapors are present, a respirator with ABEK filters are also advised.^[58] Storage requires sealed containers under inert gas (N₂ or Ar) in a cool, dry, well-ventilated location, ideally an explosion-proof refrigerator at 2-8°C, away from water, acids, heat sources, and ignition points.^[11] Bottles should be dated upon receipt and disposed of after 6 months or 8 uses to avoid degradation; secondary containment is mandatory.^[57] In the event of a spill, evacuate the area immediately, ensure adequate ventilation, and avoid ignition sources.^[11] Cover the spill with a dry inert absorbent such as sand or powdered lime to smother it, then purge the area with inert gas before cleanup using non-sparking tools; collect residues for disposal as hazardous waste.^[57] Small fires from spills can be extinguished with a Class B extinguisher like dry chemical (e.g., Purple K), but water must never be used.^[58] Disposal involves quenching unreacted phenyllithium under inert atmosphere by slow addition to a mixture of alcohol (e.g., isopropanol) and water in a fume hood, maintaining temperatures below 50°C to control the exothermic reaction.^[59] The resulting solutions should be collected as flammable hazardous waste and disposed of at an approved facility in accordance with local regulations; containers must be triple-rinsed with inert solvent and left open in a hood for solvent evaporation prior to standard disposal.^[57]

References

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Phenyllithium CAS#: 591-51-5 - ChemicalBook
Phenyllithium is a colorless crystalline solid or dark brown to black solution, It is soluble in polar solvents such as ethers and tertiary amines but insoluble ...
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Phenyllithium (PhLi) is a highly reactive organolithium reagent widely used in organic synthesis for nucleophilic additions, particularly to hindered ketones.
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Phenyllithium | 591-51-5 - ChemicalBook
Jul 4, 2025 · Phenyllithium is soluble in ether solvents; it is soluble in hydrocarbon solvents especially through the addition of donor additives/solvents.
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Preparation of phenyllithium (PhLi · LiBr) - PrepChem.com
Phenyllithium is prepared by reacting bromobenzene with elemental lithium. The obtained products is dissolved in ether.
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US3446860A - Method of making phenyllithium - Google Patents
The preparation of phenyllithium by reacting lithium with a monohalobenzene according to the equation: where X is a halogen, usually chlorine or bromine, is ...
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2-phenylpyridine - Organic Syntheses Procedure
The yield of phenyllithium is approximately 75 per cent. It can be determined by allowing the phenyllithium to react with an excess of benzophenone and weighing ...
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How to Synthesize Phenyllithium? - FAQ - Guidechem
Jan 1, 2023 · In current techniques, it is typically prepared by the reaction of bromobenzene or chlorobenzene with lithium metal in diethyl ether or a ...
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Aggregation and Reactivity of Phenyllithium Solutions
Phenyllithium forms a mixture of tetramer and dimer in ether. Complete conversion to dimeric solvates is achieved by the addition of THF, dioxolane, DME, ...
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Apr 15, 2001 · Several procedures have been used to prepare solid, salt-free PhLi. The synthesis of 13C-labeled PhLi (ipso carbon only) has been described.
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Lithiation and Organolithium Reactions - Mettler Toledo
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Formula: C6H5Li · Molecular weight: 84.045 · CAS Registry Number: 591-51-5 · Information on this page: Condensed phase thermochemistry data; References; Notes.
[15]
Phenyl lithium | C6H5Li | CID 637932 - PubChem - NIH
Molecular Formula. C6H5Li ; Synonyms. lithium;benzene; phenyl lithium; lithium benzenide; Lithium, diphenyldi-; PhLi ; Molecular Weight. 84.1 g/mol. Computed by ...
[16]
Phenyllithium | C6H5Li - ChemSpider
Molecular formula: C6H5Li. Average mass: 84.047. Monoisotopic mass: 84.055130 ... [IUPAC index name – generated by ACD/Name]. MFCD00014254. [MDL number].
[17]
https://doi.org/10.1002/cber.19170500144
[18]
https://doi.org/10.1002/jlac.19304790112
[19]
https://doi.org/10.1002/cber.19380710911
[20]
591-51-5, Phenyllithium Formula - ECHEMI
Phenyllithium is a colorless crystalline solid or dark brown to black solution ... Boiling Point: 140-143 °C. Flash Point: 20 °C. Water Solubility: H2O: Severe ...<|separator|>
[21]
591-51-5(Phenyllithium) Product Description - ChemicalBook
591-51-5 CAS No. 591-51-5 Chemical Name: Phenyllithium CBNumber: CB4853905 Molecular Formula: C6H5Li Formula Weight: 84.05
[22]
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### Summary of Section 9: Physical and Chemical Properties (Aldrich - 593230)
[23]
Phenyllithium | 591-51-5 - ChemicalBook
Jun 14, 2022 · Properties Phenyllithium has a molecular weight of 84.046 g/mol, a monoisotopic mass of 84.055 g/mol and an exact mass of 84.055 g/mol. It ...
[24]
https://pubs.acs.org/doi/10.1021/ja980684z
[25]
Nuclear magnetic resonance and ultraviolet spectroscopy of ...
Nuclear magnetic resonance and ultraviolet spectroscopy of phenylmagnesium bromide, phenyllithium, andpyridine | The Journal of Physical Chemistry.
[26]
Phenyllithium
**Summary of Phenyllithium (CID 53629015) from PubChem:**
[27]
A solid state 7Li NMR study of phenyllithium aggregates
A 7Li MAS and static NMR study of mono-, di-, and tetra-meric phenyllithium aggregates was performed. The chemical shifts and quadrupolar coupling constants ...
[28]
https://doi.org/10.1021/ja972816e
[29]
Bestimmung des Aggregationsgrads lithiumorganischer ...
Nov 7, 1984 · Abstract. Degree of Aggregation of Organolithium Compounds by Means of Cryoscopy in Tetrahydrofuran. The association behaviour of alkyl-, aryl ...
[30]
Studies of Complexes between Phenyllithium and (−)-Sparteine in ...
It is found that PhLi forms a tetrameric ladder complex in diethyl ether (Et2O) solution complexed by (−)-sparteine. The tetrameric ladder core is terminated by ...
[31]
Density Functional Calculations of Methyllithium, t-Butyllithium, and ...
Atomic charges from natural population analysis (NPA) indicate that Li−C bonds show dominant ionic character for methyl, tert-butyl, and phenyllithium oligomers ...Missing: solution | Show results with:solution
[32]
Selected topics from recent NMR studies of organolithium compounds
After a short introduction to NMR spectroscopy of alkali and alkaline earth metals the review concentrates on NMR investigations of organolithium compounds.
[33]
Intraaggregate Fluxional Lithium and Carbanion Exchanges in a ...
Apr 1, 1999 · Direct observation of fluxional lithium–lithium exchange in a cubic tetramer has been made possible for the first time by a novel type of ...
[34]
Alkyllithiums, Lithium sec-Organoamides, and Lithium Alkoxides
The interdependent properties, such as pyrophoricity, solubility, stability, and aggregation, are tabulated and discussed. These properties have a direct ...
[35]
https://www.orgsyn.org/demo.aspx?prep=cv2p0517
[36]
https://doi.org/10.1002/zaac.201700394
[37]
[PDF] Electronic Supplementary Information
The detection of significant absorptions of phenyllithium is demonstrated in figure 4.1. The organolithium compound is formed in a metal halogen exchange ...<|separator|>
[38]
[PDF] The Mechanism of Lithium-Halogen Exchange - Macmillan Group
Feb 22, 2007 · Ziegler, K.; Crössman, F.; Kleiner, H.; Schäfer, O. Liebigs Ann. Chem. 1929, 473, 1. Page 4. ü. The First Lithium–Halogen Exchange Reaction.
[39]
Preliminary studies of the mechanism of metal-halogen exchange ...
Preliminary studies of the mechanism of metal-halogen exchange. The kinetics of reaction of n-butyllithium with substituted bromobenzenes in hexane solution.
[40]
Mechanochemical activation of metallic lithium for the generation ...
Feb 21, 2025 · Here we report a mechanochemical method for the direct generation of organolithium reagents from readily available organic halides and unactivated lithium ...
[41]
Fixation of carbon dioxide to aryl/aromatic carboxylic acids
For instance, Nagaki and co-workers showed the synthesis of benzoic acid from highly reactive phenyllithium with CO2 along with the formation of other side ...
[42]
Asymmetric Addition of Organolithium Reagents to Imines
... Methyllithium and Phenyllithium ... Effect of Ligand Structure in the Bisoxazoline Mediated Asymmetric Addition of Methyllithium to Imines.
[43]
[PDF] TITLE (Word Style “A_Title”) - Arkivoc
reported for the addition of phenyllithium to (-)-menthone and other hindered cyclic ketones.7. These reactions occur stereospecifically, leading in all ...
[44]
Mechanistic evidence for ortho-directed lithiations from one
Role of Organolithium Aggregates and Mixed Aggregates in Organolithium Mechanisms. ... On the Mechanism of the Ortho-Directed Metalation of Anisole by n- ...
[45]
lithiation of α-N,N-deimethylaminoethylferrocene and the single ...
The documented lithiation reactions of ferrocene and α-N,N ... phenyllithium exemplifies bridging between sp2 carbon atoms. A few organolithium ...
[46]
Grignard and Organolithium Reagents - Chemistry LibreTexts
Jan 22, 2023 · Although not usually done with Grignard reagents, organolithium reagents can be used as strong bases.
[47]
The Versatile and Strategic O-Carbamate Directed Metalation Group ...
Jun 12, 2024 · The aryl O-carbamate (ArOAm) group is among the strongest of the directed metalation groups (DMGs) in directed ortho metalation (DoM) chemistry.
[48]
Influence of the Length and Positioning of the Antiestrogenic Side ...
Phenyllithium in di-n-butyl ether (1.8 mL of 1.8 M solution) and THF (10 mL) ... Synthesis of novel flexible tamoxifen analogues to overcome CYP2D6 ...<|separator|>
[49]
Weinreb Ketone Synthesis - Major Reference Works
Sep 15, 2010 · The synthesis of ketones by the treatment of the Weinreb amides (ie, amides of N-methyl-N-methoxy hydroxylamine) with a variety of carbanions.
[50]
Effect of solvents on the anionic polymerization of styrene by ...
The anionic polymerization of styrene by phenyllithium was studied in various solvents The order of the decreasing molecular weights obtained depending on ...Missing: initiator | Show results with:initiator
[51]
https://pubs.acs.org/doi/10.1021/acs.oprd.2c00007
[52]
Phenyllithium | AMERICAN ELEMENTS ®
0. Lithium benzenide; PhLi; Lithium, phenyl-; Phenyllithium Solution, 16-20% in di-n-butyl ether, (1.6 M-2.0 M). Signal Word, Danger. Hazard Statements, H340 ...
[53]
Halogen/lithium exchange in hydrocarbon media - ScienceDirect.com
Our initial study explored the 1:1 exchange by the addition of bromobenzene in cyclohexane to n-BuLi at ambient temperature with analysis performed by treating ...
[54]
Continuous Processing of Concentrated Organolithiums in Flow ...
Apr 19, 2022 · In this study, we compare static and dynamic flow reactor technologies for two important organolithium (butyllithium and hexyllithium)-enabled ...Missing: phenyllithium | Show results with:phenyllithium
[55]
Organolithium Market Size, Growth, Forecast Till 2031 - Report Prime
The Organolithium Market is expected to grow from USD 2.12 Billion in 2024 to USD 3.21 Billion by 2031, at a CAGR of 6.10% during the forecast period.
[56]
Organolithium Market Poised for Growth as Industrial and Chemical ...
Nov 6, 2024 · Key growth drivers include increasing demand for specialty chemicals, pharmaceuticals, and lithium-ion batteries, along with advancements in ...
[57]
Phenyl Lithium Market: Future Outlook and Trends 2035
The High Purity Grade is becoming increasingly important, particularly in research and development settings, where precise chemical properties are critical ...
[58]
Phenyllithium | C6H5Li | CID 53629015 - PubChem - NIH
Phenyllithium ; Molecular Weight. 84.1 g/mol. Computed by PubChem 2.1 (PubChem release 2021.05.07) ; Parent Compound. CID 123159 (Phenyl) ; Component Compounds.
[59]
[PDF] Safety Data Sheet
May 12, 2010 · Product name: Phenyllithium, 1.7-1.8M in dibutyl ether Spontaneously flammable in air. Reacts violently with water Conditions to avoid No ...
[60]
[PDF] Techniques for Handling Air- and Moisture-Sensitive Compounds
Feb 22, 2014 · An inert atmosphere glove box may also be used. 6. Minimising the amount of organolithium reagent used and ensuring proper controls for storage ...
[61]
None
### Summary of Safe Handling of Organolithium Compounds
[62]
Safe handling of organolithium compounds in the laboratory
Pyrophoric materials should be diluted to less than 5 wt.% with an inert solvent, such as heptane. This solution should then be added slowly (via an ...Missing: stability | Show results with:stability