Preparation, Properties, and Safe Handling of Commercial Organolithiums: Alkyllithiums, Lithium sec-Organoamides, and Lithium Alkoxides

This review includes the preparation and properties of various organolithiums, which are commercially available, up to manufacturing scale. The interdependent properties, such as pyrophoricity, solubility, stability, and aggregation, are tabulated and discussed. These properties have a direct bearing on their chemical reactivity and requirements for safe handling and storage. Extensive guidance for storage, use, analysis, and disposal of these organolithium solutions is also provided.

[1]  R. Luisi,et al.  Lithium Compounds in Organic Synthesis: Luisi/Lithium Compounds in Organic Synthesis , 2014 .

[2]  Paul M. Witt,et al.  Investigation of a lithium-halogen exchange flow process for the preparation of boronates by using a cryo-flow reactor. , 2014, Chemistry.

[3]  R. Mulvey,et al.  Synthetically important alkali-metal utility amides: lithium, sodium, and potassium hexamethyldisilazides, diisopropylamides, and tetramethylpiperidides. , 2013, Angewandte Chemie.

[4]  A. Kennedy,et al.  Concealed cyclotrimeric polymorph of lithium 2,2,6,6-tetramethylpiperidide unconcealed: X-ray crystallographic and NMR spectroscopic studies. , 2013, Chemistry.

[5]  D. Stalke,et al.  Toluene and lithium amide diffusion into polystyrene: a slice-selective NMR-spectroscopic study. , 2013, Chemphyschem : a European journal of chemical physics and physical chemistry.

[6]  H. Reich.  Role of organolithium aggregates and mixed aggregates in organolithium mechanisms. , 2013, Chemical reviews.

[7]  D. Stalke,et al.  7Li‐quadrupolare Restkopplungen zur Bestimmung des Aggregationsgrades von Organolithiumverbindungen , 2012 .

[8]  D. Stalke,et al.  7Li residual quadrupolar couplings as a powerful tool to identify the degree of organolithium aggregation. , 2012, Angewandte Chemie.

[9]  D. Stalke,et al.  Aggregation of donor base stabilized 2-thienyllithium in a single crystal and in solution: distances from X-ray diffraction and the nuclear Overhauser effect. , 2012, Journal of the American Chemical Society.

[10]  D. Stalke,et al.  Mixed crystalline lithium organics and interconversion in solution. , 2012 .

[11]  Dilani A. Jayawardhana,et al.  Rapid, efficient quantification of water in solvents and solvents in water using an ionic liquid-based GC column , 2011 .

[12]  D. Stalke,et al.  Pure α-metallated benzyllithium from a single-crystal-to-single-crystal transition. , 2011, Angewandte Chemie.

[13]  M. J. Jorgenson.  Preparation of Ketones from the Reaction of Organolithium Reagents with Carboxylic Acids , 2011 .

[14]  W. Bailey,et al.  Optimization of Organolithium Reactions , 2009 .

[15]  Y. Kondo,et al.  Deprotonative metalation using ate compounds: synergy, synthesis, and structure building. , 2007, Angewandte Chemie.

[16]  David F. Aycock,et al.  Solvent Applications of 2-Methyltetrahydrofuran in Organometallic and Biphasic Reactions , 2007 .

[17]  Mingsheng Huang,et al.  Organolithium reagents in pharmaceutical asymmetric processes. , 2006, Chemical reviews.

[18]  J. Nolan.  Regioselective Lithium-Halogen Exchange and Palladium-Catalyzed Cross-Coupling Reactions of 2,4-Dihaloquinolines , 2005 .

[19]  E. Grabowski.  Enantiopure drug synthesis: from methyldopa to imipenem to efavirenz. , 2005, Chirality.

[20]  H. Günther,et al.  NMR spectroscopy of organolithium compounds. XXVI —The aggregation behaviour of methyllithium in the presence of LiBr and LiI in diethyl ether and tetrahydrofuran , 2004, Magnetic resonance in chemistry : MRC.

[21]  T. Hoye,et al.  No-D NMR spectroscopy as a convenient method for titering organolithium (RLi), RMgX, and LDA solutions. , 2004, Organic letters.

[22]  Z. Rappoport,et al.  The chemistry of organolithium compounds , 2004 .

[23]  A. Beatty,et al.  Characterization of a kinetically stable, highly ordered, octameric form of lithium tert-butoxide and its implications regarding aggregate formation. , 2004, Journal of the American Chemical Society.

[24]  C. Woltermann,et al.  Safe handling of organolithium compounds in the laboratory , 2002 .

[25]  John A. Ragan,et al.  From bench to pilot plant : process research in the pharmaceutical industry , 2002 .

[26]  P. Gros,et al.  Ring Selective Lithiation of 3,5-Lutidine. A New Route to Heterocyclic Building Blocks. , 2002 .

[27]  D. Stalke,et al.  [{(MeLi)4(dem)1.5}∞] and [(thf)3Li3Me{(NtBu)3S}]—How to Reduce Aggregation of Parent Methyllithium , 2001 .

[28]  J. Palmer,et al.  Synthesis of 2,4-Di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indoles, Including Antiasthma Clinical Candidate PNU-142731A , 2001 .

[29]  Jerry March,et al.  March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 2001 .

[30]  J. Cummins,et al.  Highly Enantioselective 1,2-Addition of Lithium Acetylide-Ephedrate Complexes: Spectroscopic Evidence for Reaction Proceeding via a 2:2 Tetramer, and X-ray Characterization of Related Complexes , 2000 .

[31]  D. B. Collum,et al.  Lithium Diisopropylamide-Mediated Enolizations: Solvent-Independent Rates, Solvent-Dependent Mechanisms , 2000 .

[32]  Choppin,et al.  Unusual C-6 Lithiation of 2-Chloropyridine-Mediated by BuLi-Me(2)N(CH(2))(2)OLi. New Access to 6-Functional-2-chloropyridines and Chloro-bis-heterocycles. , 2000, Organic letters.

[33]  B. Lucht,et al.  Lithium Hexamethyldisilazide: A View of Lithium Ion Solvation Through a Glass-Bottom Boat , 1999 .

[34]  A. J. Thompson,et al.  Lithium Ephedrate-Mediated Addition of a Lithium Acetylide to a Ketone: Solution Structures and Relative Reactivities of Mixed Aggregates Underlying the High Enantioselectivities , 1998 .

[35]  C. Ogle,et al.  BENZYLLITHIUM: PREPARATION, REACTIONS AND X-RAY CRYSTAL STRUCTURE OF BENZYLLITHIUM·2THF , 1998 .

[36]  A. Navrotsky,et al.  Energetics of Ternary Nitrides: Li−Ca−Zn−N and Ca−Ta−N Systems , 1997 .

[37]  B. Lucht,et al.  Lithium Diisopropylamide Solvated by Monodentate and Bidentate Ligands: Solution Structures and Ligand Binding Constants , 1997 .

[38]  M. Mihovilovic,et al.  HALF-LIVES OF ORGANOLITHIUM REAGENTS IN COMMON ETHEREAL SOLVENTS , 1997 .

[39]  R. Lagow,et al.  Isolation and Structure Analysis of Neohexyllithium Generated by Ether Cleavage: Primary and Secondary Coordination in Alkyllithium Aggregates , 1997 .

[40]  P. Gros,et al.  Aggregative activation in heterocyclic chemistry. Part 4. Metallation of 2-methoxypyridine: unusual behaviour of the new unimetal superbase BuLi–Me2N(CH2)2OLi (BuLi–LiDMAE) , 1997 .

[41]  P. Gros,et al.  Aggregative activation in heterocyclic chemistry. Part 5.† Lithiation of pyridine and quinoline with the complex base BuLi·Me2N(CH2)2OLi (BuLi·LiDMAE) , 1997 .

[42]  J. V. Vusse,et al.  Unique and Efficient Synthesis of [2S-(2R*,3S*,4R*)]-2-Amino-1-cyclohexyl- 6-methyl-3,4-heptanediol, a Popular C-Terminal Component of Many Renin Inhibitors , 1996 .

[43]  B. Lucht,et al.  Structure of Lithium 2,2,6,6-Tetramethylpiperidine (LiTMP) and Lithium 2,2,4,6,6-Pentamethylpiperidide (LiPMP) in Hydrocarbon Solution: Assignment of Cyclic Trimer and Tetramer Conformational Isomers , 1994 .

[44]  P. Schleyer,et al.  Are Polar Organometallic Compounds “Carbanions”? The Gegenion Effect on Structure and Energies of Alkali‐Metal Compounds , 1994 .

[45]  K. Bergander,et al.  NMR spectroscopy of organolithium compounds, Part XVI , 1994 .

[46]  V. Mani,et al.  Enantioselective addition of alkyllithium reagents to aldehydes induced by chiral lithium alkoxides , 1994 .

[47]  C. Ogle,et al.  Isolation, characterization, and crystal structure of [MeLi.THF]4 , 1993 .

[48]  D. Stalke,et al.  Structures of Classical Reagents in Chemical Synthesis: (nBuLi)6, (tBuLi)4, and the Metastable (tBuLi · Et2O)2 , 1993 .

[49]  D. B. Collum,et al.  Distinction of symmetric lithium dialkylamide dimers from higher oligomers by inverse-detected nitrogen-15 homonuclear zero-quantum NMR spectroscopy , 1992 .

[50]  D. B. Collum,et al.  Mixed aggregation of lithium enolates and lithium halides with lithium 2,2,6,6-tetramethylpiperidide (LiTMP) , 1991 .

[51]  M. Mallet.  Le phnyl-lithium: nouvel agent de mtallation du cycle pyridinique , 1991 .

[52]  E. Weiss,et al.  Über Metallalkyl‐ und ‐aryl‐Verbindungen, 40 Strukturverfeinerung von Methyllithium durch Neutronenbeugung von (LiCD3)4 bei 1.5 und 290 K , 1990 .

[53]  Stanley G. Smith,et al.  Complex-induced proximity effects and dipole-stabilized carbanions: kinetic evidence for the role of complexes in the .alpha.'-lithiations of carboxamides , 1988 .

[54]  Ruthanne D. Thomas,et al.  Unusual stability of an alkyllithium dimer. Preparation, properties, and decomposition mechanism of tert-butyllithium dietherate dimer , 1988 .

[55]  W. Bauer,et al.  Monomeric organolithium compounds in tetrahydrofuran: tert-butyllithium, sec-butyllithium, supermesityllithium, mesityllithium, and phenyllithium. Carbon-lithium coupling constants and the nature of carbon-lithium bonding , 1987 .

[56]  R. Jensen,et al.  Aggregation states and exchange properties of alkyllithium compounds in hydrocarbon solvent from carbon-13-lithium-6 coupling , 1987 .

[57]  L. Brandsma,et al.  Preparative polar organometallic chemistry , 1987 .

[58]  R. Jensen,et al.  Fluxional exchange of tert-butyllithium tetramers from temperature-dependent carbon-13-lithium-6 coupling , 1986 .

[59]  C. Ogle,et al.  High-field proton NMR study of the aggregation and complexation of n-butyllithium in tetrahydrofuran , 1985 .

[60]  M. Hewitt,et al.  Structure and dynamic behavior of a chiral alkyllithium compound: carbon-13 and lithium-6 NMR of sec-butyllithium , 2002 .

[61]  D. Seebach,et al.  Bestimmung des Aggregationsgrads lithiumorganischer Verbindungen durch Kryoskopie in Tetrahydrofuran , 1984 .

[62]  M. Reetz,et al.  An Economical Large-Scale Synthesis of Titanium Tetrakis[diethylamide] and Chlorotitanium Tris[diethylamide] , 1983 .

[63]  D. Seebach,et al.  13C‐NMR.‐Spektroskopie von Organolithiumverbindungen bei tiefen Temperaturen. Strukturinformation aus der 13C, 6Li‐Kopplung , 1983 .

[64]  G. Boche,et al.  The reaction of n-butyllithium/sodium(potassium) tert.-butoxide (Lochmann-Schlosser base) with a ch-acid leads to organo-sodium(potassium) compounds. An NMR spectroscopical study of several organo-lithium, -sodium and -potassium compounds in tetrahydrofuran-D8 , 1983 .

[65]  W. F. Maier,et al.  Einfache Darstellung von Lithiumdiisopropylamid in molarem Maßstab , 1980 .

[66]  M. Geckle,et al.  Structure and dynamic behavior of propyllithium from carbon-13, lithium-7, and lithium-6 NMR , 1979 .

[67]  E. Weiss,et al.  Über metallalkyl- und -arylverbindungen : XXIII. Darstellung und kristallstruktur des (methyllithium)4(N,N,N′,N′-tetramethylethylendiamin)2 , 1978 .

[68]  E. C. Ashby,et al.  Preparation and characterization of lithium magnesium trihydride, lithium dimagnesium pentahydride, LiMgRH2, LiMgR2H and LiMg2H3R2 compounds , 1978 .

[69]  R. Quirk,et al.  Solvation of alkyllithium compounds. Steric effects on heats of interaction of bases with hexameric versus tetrameric alkyllithiums , 1977 .

[70]  B. Wakefield.  The Chemistry of Organolithium Compounds , 1974 .

[71]  R. Bates,et al.  Cycloreversions of anions from tetrahydrofurans. Convenient synthesis of lithium enolates of aldehydes , 1972 .

[72]  S. C. Honeycutt.  Kinetics of the cleavage of tetrahydrofuran by n-butyllithium in hydrocarbon solvent , 1971 .

[73]  D. Margerison,et al.  Degrees of association of n-pentyl lithium and n-octyl lithium in benzene , 1971 .

[74]  H. Lewis,et al.  Association of alkyllithium compounds in hydrocarbon media. Alkyllithium-base interactions , 1970 .

[75]  E. B. Baker,et al.  Carbon-13-lithium-7 spin-spin coupling in alkyllithium compounds , 1968 .

[76]  D. Lim,et al.  Association degree of t-butoxides of alkali metals in aprotic solvents , 1968 .

[77]  D. Worsfold,et al.  Alkyllithium anionic polymerization initiators in hydrocarbon solvents , 1967 .

[78]  R. Waack,et al.  Colligative property measurements on oxygen- and moisture-sensitive compounds. I. Organolithium reagents in donor solvents at 25.degree. , 1967 .

[79]  J. Eastham,et al.  Colored indicators for simple direct titration of magnesium and lithium reagents , 1967 .

[80]  T. L. Brown,et al.  The Mass Spectra of Lithiomethyltrimethylsilane and Lithium t-Butoxide , 1966 .

[81]  C. Kamienski,et al.  Relationship between Structure and Solubility of Organic Lithium Compounds , 1965 .

[82]  E. Weiss,et al.  Die kristall- und elektronenstruktur des methyllithiums , 1964 .

[83]  R. West,et al.  The Physical Properties and Structure of t-Butyllithium , 1962 .

[84]  D. C. Bradley,et al.  765. Metallo-organic compounds containing metal–nitrogen bonds. Part I. Some dialkylamino-derivatives of titanium and zirconium , 1960 .

[85]  H. Gilman,et al.  The Quantitative Analysis of Alkyllithium Compounds1 , 1944 .