Syntheses of Organolithium Compounds：有机锂化合物的合成.doc

Organolithium CompoundsUmbreen MirCHM 331SProf. M. DenkApril 12th, 2000HistoryOver the years, organolithium compounds have gained an increasing value in chemical synthesis due to their high reactivity, relatively easy preparation and solubility in inert solvents.4The first attempt to synthesize an organolithium compound was with the reaction of lithium with diethyl mercury.10 Methyl-lithium was first prepared by Schlenk and Holtz in 1917.16 In 1930, the first successful synthesis of alkyllithiums was obtained from lithium metal and alkyl halides.10This fundamental method is still widely employed for the “direct” synthesis of organolithium compounds. However, this method has not been well understood in the past. New insights have unfolded over the years on the by-products, such as hydrocarbons (from coupling), alkanes, and alkenes, corresponding to the alkyl halides, which suggest that radicals may be involved.10 Figure 1: Mechanism of possible stereochemical pathways.10Metal-halogen exchange and transmetallation, as well as new procedures have been introduced to avoid producing racemic species.10 Structures of simple organolithium compoundsEfforts have been made in characterizing the structure of important reagents, both in solution and in the solid state. Several different forms of these reagents have been determined, because the degree of association is strongly dependent on the nature of the solvent used.3Table 1: Aggregation of Typical Organolithium Compounds 3,7SolventAggregationMethyl-lithiumX-ray crystallographyTHF, Et2OHydrocarbonsTMEDATetramericHexamericMonomericn-butyl-lithiumIR and NMRHydrocarbonsEtherHexamericTetramerics-butyl-lithium-To date, no crystal structures have been determined13t-butyl-lithiumMass spectroscopyHydrocarbonsPredominantly tetrameric, but some hexameric particles presentPhenyl-lithiumX-ray powder diffractionTHF, Et2ODimericIn 1964, Weiss and Lucken deduced that the structure of methyl-lithium, exists as a tetramer from its X-ray powder diffraction pattern.16 Today, X-ray crystallographic methods still confirm methyl-lithium to be a tetramer, but more specifically resembling a cubane, salt-like structure in the solid state.4, 10Figure 2: Tetrameric structure of methyl-lithium in the solid state.4, 10Early infrared studies up until 1957, indicated that methyl-lithium does not exist as a monomer, even in the gas phase.16 Recently, in 1997, the first unambiguous structural characterization of monomeric methyl-lithium was discovered. The structure was determined by millimeter/submillimeter spectroscopy.18 Figure 3: Monomeric structure of methyl-lithium18Ethyl-lithium also exists as tetrameric units of crystals in the solid phase (see Figure 4)Figure 4: Crystal structure of ethyl-lithium4, 10Infra-red and Raman spectra suggest that n-butyl-lithium is hexameric in benzene solution. Figure 5 proposes a structure, which involves carbon bridges, where hydrogen bridges would be expected.Figure 5: Suggested structure of n-butyl-lithium hexamer.4, 10The solid state structure of Lewis-base free phenyl-lithium has recently been confirmed through synchrotron X-ray powder diffraction.5 Figure 6 illustrates phenyl-lithium as consisting of dimeric Li2Ph2 molecules. These molecules interact with adjacent Li2Ph2 molecules, forming a polymeric ladder structure.Figure 6: Dimeric structure of unsolvated, Lewis-base free phenyl-lithium in the solid state.5Physical propertiesMany organolithium compounds are soluble in hydrocarbons, with a few exceptions, methyl-lithium and phenyl-lithium, which are associated in these solvents.7 Table 2: Comparison of Physical Properties of Typical Organolithium Compounds.4, 6, 7, 10, 14CompoundMW (g/mol)BP (°C)MP (°C)Density(g/ml)AppearanceSolubilityn-butyl-lithium64.0560-80 760mm Hg-950.68Solid/liquid mixture; clear yellowSoluble in ether, benzene and paraffinic hydrocarbonss-butyl-lithium64.05-0.75Solid/liquid mixture; clear light yellow-yellowish orangeSoluble in hydrocarbonst-butyl-lithium64.0536-40-0.66Colourless, crystallineSoluble in hydrocarbonsMethyl-lithium21.9734.600.70Clear liquid; crystal salt-like structure in solid stateSoluble in diethyl ether; insoluble in aliphatic hydrocarbonsPhenyl-lithium84.04-0.73Reddish brown liquidSoluble in diethyl ether; insoluble in hydrocarbonsSpectroscopic PropertiesNuclear magnetic resonance spectroscopy is an extremely useful tool in elucidating the structures of organolithium compounds in solution.4Table 3: Comparison of 13C-NMR Spectra of Alkyl-lithium Compounds and the Corresponding Hydrocarbons 4CompoundSolventd (13C) (ppm)J (13C-H) (Hz)n-C4H9LiHexane+182100(CH3)3CliCyclohexane+182-PhCH2LiBenzene+174.5116Ph2CLi-n-C5H11Benzene+115-In Figure 7, 7Li signals for more covalently organolithium compounds appear at the lower magnetic field and species with a large ionic character are shifted to the higher field. Figure 7: Li-NMR of organolithium compounds in cyclopentane solution.8Table 4: IR Spectroscopy of Methyl- and Ethyl-lithium in Benzene Solution 4CompoundBand Frequency (cm-1)CH3Li (mull)2840-2780aCHD3Li (mull)2150-2027a(But 6Li) and (But 7Li)2805 and 2725Ethyl-lithium2940,2840,2760a,ba unaffected by substitution of 6Li for 7Lib both in solution and in vapourSyntheses of Organolithium CompoundsSeveral organolithium compounds are industrially synthesized, but only some are produced on a considerable scale. For example, n- and s-butyl-lithium in hydrocarbons are produced in tonnage quantities.11 The cost is relatively low, and the unlimited storage period (under room temperature in a well-closed bottle) makes it is desirable to purchase cylinders of n-butyl-lithium in large quantities (25 litres or more), for laboratory purposes.2Some costs of the commercially available organolithium compounds are listed in Table 5.Table 5: Costs of Commercially Available Organolithium Compounds16CompoundConcentrationMSize(L)Cost(CDN $)Butyl-lithium1.62.010.00.18.018.00.10.80.10.88.034.70505.00928.6026.80129.8063.80378.501735.40sec-Butyl-lithium1.30.10.857.20101.00tert-Butyl-lithium1.70.10.88.040.40132.90939.60Iso-butyl-lithium1.60.1490.30Methyl-lithium1.01.40.10.10.88.053.8037.20162.701235.80(Trimethylsilyl)methyl-lithium1.00.10.2553.60199.80The fundamental process of synthesizing an organolithium compound is by lithium metal and an organic halide. 2, 6, 10, 11 Allyl and benzyl chlorides are avoided because they undergo Wurtz-type reactions. A more desired method requires the use of lithium halide (bromides and iodides may also be used). New methods often use organic chlorides, because they are less soluble in ether and thus produce high yields.11An inert atmosphere is required in order to perform organolithium procedures. The cheapest form is “white spot” nitrogen. This technique is sometimes replaced with argon for preparations with lithium metal, because the metal surface becomes tarnished by a nitride film in contact with nitrogen.11For small-scale work, the balloon method is ideal for maintaining an inert atmosphere. This simple method involves a balloon connected to a syringe needle and inflated by an inert gas. For larger scale processes, gas bubblers are preferred, as illustrated in Figure 8.Figure 8: Typical assembly for an organolithium reaction.11Lithium metal is now commercially available as a wire, shot and as a dispersion in mineral oil.11 The availablility of dispersions commercially, reduces the hazards involved in laboratory dispersion methods, in which molten metal is shaken or stirred vigorously in a high-boiling inert medium.11Syntheses of typical oranolithium compoundsThere are several ways in which an organolithium compound can be synthesized. Some general methods are outlined below.1. Direct Synthesis: This route involves the reaction between organic halides and lithium metal.10 The same reaction can be carried out with bromine, but it leads to lower yields.6,72. Metallation: This method involves the interaction of an acid, and the salt of a weaker acid.103. Metal-Halogen Exchange: This reaction was discovered by Gilman and Wittig,10 in which generalizations were made about this new intriguing method.10(a) The reaction is reversible(b) Lithium becomes attached to the organic group, which best stabilizes a negative charge(c) The reaction takes place readily with iodides and bromides(d) The reaction is faster in ethers than in hydrocarbonsThis process was introduced to synthesize desired organolithium compounds, which could not be produced directly from the corresponding alkyl halides and lithium metal.64. Lithium and hydrocarbon acids7Syntheses of Polyorganolithium Compounds1,1-Diltihio-Organyls1, 1-dilithio-organyls are obtained from alkynes in a two-step synthesis.17Halogen-Metal Exchange Reaction with Lithium Metal. The direct replacement of halogen in organic compounds with Li metal is limited in the synthesis of polyorganolithium compounds. After the first step, a, b, or gamma elimination of lithium halide is faster than the second halogen-metal exchange. As a result, only 1,4-dilithiobutane or higher 1,n-dilithioalkanes (n$4) can be prepared.16 n'1Br(CH2)nBr -LiBr :CH2 2 Li -LiBrBr(CH2)nLi n'2 -LiBr CH2=CH2 2 Li n$4-LiBr n'3 Li(CH2)nLi -LiBr There have been many attempts to obtain 1,2- and 1,3-dilithiocompounds from the preparation of 1,2-dilithioethane from 1,2-dichloro- or 1,2-dibromoethane, and 1,3-dilithiopropane from 1,3-dichloropropane with lithium metal. Both of these dilithium compounds are unstable, and decompose by lithium hydride elimination.16Safety PrecautionsGreat care must be taken when handling, storing or disposing organolithium compounds.Hazards: In general, organolithium compounds are pyrophoric, corrosive and air and water sensitive.Storage: should be kept away from heat, moisture, and any sources of ignition.14 They are packed under nitrogen in Sure/SealTM bottles15Disposal: must not be emptied in drains, but disposed in a manner consistent with the federal, state, and local regulations.ApplicationsThere are several organolithium compounds commercially available. They are normally sold as solutions in hydrocarbons or ethers. The list of organolithium compounds on sale as laboratory reagents differs from time to time,11 but some recent compounds are illustrated in Table 5.Table 6: Commercially Available Organolithium Compounds15CompoundSolventConcentration M*SupplierButyl-lithiumHexanesCyclohexanesPentanes1.6, 2.5, 10.02.02.0(a)Butyl-lithium-Lithium 1-butanide complexTolueneHexaneHeptane2.51.6, 10.02.7(b)s-Butyl-lithiumCyclohexane1.3(a,b)t-Butyl-lithiumPentane1.5, 1.7(b,a)Isobutyl-lithium-(Lithium 2-methyl-1-propanide complex)15% Heptane1.6(b)Methyl-lithium-(Lithium bromide complex)Diethyl ether1.0, 1.5(a,b)Methyl-lithium-(Lithium methanide)5% Diethyl ether1.4(a)(Trimethylsilyl)methyl-lithium complexPentane1.0(b)Phenyl-lithiumCyclohexane-ether1.6-1.8(a,b)*Concentrations are approximate(a) Aldrich Chemical Company(b) FlukaAlkyl-lithiums, in general, span from small-scale synthetic applications to large-scale industrial processes. They are frequently used for deprotonation2 and catalysts for polymerization of olefins.6n-Butyl-lithium is the most industrially important organolithium compound because of its use as an initiator in polymerization of dienes. It is the basic reagent used for most reactions proceeding via (polar) organometallic intermediates.2Methyl-lithium is important in organic synthesis as well as in the preparation of transition metal complexes.16Computational MethodsDimers are more common than trimers in the field of organolithium chemistry. However, 6Li-labeled lithioorganic dimers yield the same 13C-NMR patterns as trimers. Therefore a simple distinction between the two structures is not possible by the conventional 13C-NMR spectroscopy.1 New insights have developed towards the 6Li13C-HMQCSY method, which is now applied to distinguish a cyclic dimer from a cyclic trimer or higher aggregated species. Calculations confirm that a dimer reveals a pair of cross peaks located at the chemical shift in the f2 (6Li) domain, whereas the trimer is characterized by an extra cross peak at the chemical shift of the f1 (6Li) domain. 1 The data obtained by the 2D method reduces misinterpretations as compared to the 1D version, because the main signal is more sufficiently suppressed through careful pulse calibration and phase cycling.1Library ResourcesI initiated my research by consulting the handbook of organometallic chemistry. This book was particularly useful, since it outlined the basic methods, formulas, and structures of compounds. Furthermore, the journals available online, such as the Journal of the American Chemical Society, were excellent resources in researching new developments in organometallic chemistry. The MSDS databases were also easily accessible since they were available on the Internet. A large portion of books, which contained information on my topic, were located at Gerstein downtown. In general, recent articles that could be retrieved from the Internet were easily accessible,