FEATURE Safe handling of organolithium compounds in the laboratory

Organolithium compounds are extremely useful reagents in organic synthesis and as initiators in anionic polymerizations. These reagents are corrosive, flammable, and in certain cases, pyrophoric. Careful planning prior to execution of the experiment will minimize hazards to personnel and the physical plant. The proper personal protective equipment (PPE) for handling organolithium compounds will be identified. Procedures to minimize contact with air and moisture will be presented. Solutions of organolithium compounds can be safely transferred from the storage bottles to the reaction flask with either a syringe or a cannula. With the utilization of these basic techniques, organolithium compounds can be safely handled in the laboratory.

By James A. Schwindeman, oxides (typi®ed by lithium t-butoxide). various classes of organolithium com-

Chris J. Woltermann, and These organolithium compounds have pounds, with pKa from 15.2 (lithium Robert J. Letchford found wide utility as reagents for methoxide) to 53 (t-butyllithium).5 organic synthesis in a variety of appli- Fourth, organolithium reagents demon- cations. For example, they can be strate enhanced nucleophilicity com- INTRODUCTION employed as strong bases (alkyl- pared to the corresponding organo- When properly handled, organo- lithiums, aryllithiums, lithium amides magnesium compound. Finally, they lithiums provide unique properties and lithium alkoxides), nucleophiles are convenient, as a variety of organo- that allow for more precise control (alkyllithium and aryllithium com- lithium compounds from all four cate- and greater performance features. pounds) and reagents for metal±halo- gories are commercially available. With proper care and attention, orga- gen exchange (alkyllithium and arylli- Thus, the experimentalist can select nolithiums can be safely and effectively thium compounds).1 Alkyllithium com- and purchase the appropriate reagent utilized in both laboratory and physi- pounds have also found extensive needed for the desired transformation. cal plant environments, while being application as initiators for anionic the effective choice for many synthesis polymerization. The unique properties applications. Organolithium com- of the carbon±lithium bond in poly- HAZARDS OF ORGANOLITHIUM pounds fall into four broad categories: merization processes allow the precise COMPOUNDS alkyllithiums (exempli®ed by n-butyl- control of the polymer's molecular Organolithium compounds, which lithium), aryllithiums (such as phenyl- architecture.2 exhibit outstanding performance in a lithium), lithium amides (for example, variety of applications, are highly reac- lithium diisopropylamide and lithium tive materials. There are three princi- hexamethyldisilazide) and lithium alk- CHARACTERISTICS OF pal hazards associated with these ORGANOLITHIUM COMPOUNDS compounds: corrosivity, ¯ammability James A. Schwindeman received his Several characteristics of organo- and, in certain instances, pyrophori- B.S. degree in Chemistry from Miami lithium compounds have enhanced city. The inherent corrosive nature of University and his Ph.D. in Organic their utilization in the laboratory. First, all four classes of organolithiums can Chemistry from the Ohio State organolithium compounds exhibit cause chemical and thermal burns University, has over 10 years experience excellent solubility in organic solvents. upon operator exposure. The organo- in the synthesis of organometallic As an example, n-butyllithium is avail- lithium compounds themselves are compounds at FMC Lithium. able commercially as a solution in hex- ¯ammable. Typically, they are supplied E-mail: [email protected]. anes from 1.5 M (15 wt.%) to 10 M in an organic solvent, which exacer- Chris J. Woltermann received his B.S. in (85 wt.%). One caveat is that alkyl- bates the ¯ammability. Pyrophoricity6 Chemistry from the University of lithium compounds do react with ethe- is de®ned as the property of a material Dayton in 1990 and his Ph.D. in real solvents.3 Second, in contrast to to spontaneously ignite on exposure to Organic Chemistry from the Ohio State alkylorganometallics derived from air, oxygen or moisture. In particular, University in 1996. other alkali metals, alkyllithium com- all formulations of n-butyllithium, s- Robert J. Letchford received his B.S. pounds have enhanced stability.4 The butyllithium and t-butyllithium are pyr- degree in ChemicalEngineering from alkyllithium compounds exhibit suf®- ophoric, as determined by the of®cial Youngstown State University and a cient stability to be prepared, stored Department of Transportation (DOT) M.S. degree in Polymer Chemistry from and transported. Third, a wide range protocol.7 Before any laboratory work the University of Akron. of base strength is available from the with an organolithium is conducted,

6 ß Division of Chemical Health and Safety of the American Chemical Society 1074-9098/02/$22.00 Elsevier Science Inc.All rights reserved. PII S1074-9098(02)00295-2 appropriate planning should be con- ducted to safeguard personnel and property against these hazards. There are a number of factors that in¯uence the pyrophoric nature of the alkyllithium compound. For the same concentration of alkyllithium, the pyr- ophoricity increases in the order n- butyllithiumhydride is pyro- ef®cient fume hood. The fume hood increases in the formulation. The sol- phoric. To maximize the shelf-life of should be free of clutter. The hood vent in the formulation also in¯uences these materials, it is recommended that should not be used as a storage area pyrophoricity. The lower the ¯ash they be stored in an explosion-proof for out of service equipment and sup- point of the solvent the greater the refrigerator at <108C. Further, since plies. Less clutter makes it easier to pyrophoricity. Pyrophoricity is also the assay of these reagents can decline clean up a spill or extinguish a ®re in impacted by environmental factors in with storage, it is good practice to ver- the event of a release of an organo- the laboratory. Higher relative humid- ify the assay prior to utilization in an lithium. The fume hood will also sweep ity and higher ambient temperature experiment.11 fumes away more effectively with less result in greater pyrophoricity.8 clutter present. Combustible materials, The stability of two classes of orga- such as solvents, ¯ammable chemicals nolithium compounds must also be PLANNING THE EXPERIMENT (reagents or samples), paper or cloth considered. Alkyllithium compounds In spite of these hazards, the reactivity should be removed from the hood undergo thermal decomposition via of organolithium compounds has been prior to the experiment. These are all loss of lithium hydride, with formation successfully harnessed. Indeed, with potential fuel sources that can contri- of the corresponding alkene. The proper planning on the part of the bute to a ®re in the event of spill of an decomposition of n-butyllithium is il- experimenter, organolithium com- organolithium. The fume hood must be lustrated in Figure 1. pounds can be safely handled in the equipped with a source of inert gas, Several factors in¯uence the rate laboratory. These same techniques can such as nitrogen or argon. A delivery of this decomposition. The thermal also be employed in large-scale appli- system to distribute the inert gas to the stability of alkyllithiums increases cations, from kilo laboratory up to reactor, such as manifold or plastic in the series s-butyllithium < n- commercial-scale production. Proper lines, and a bubbler system are also butyllithium < t-butyllithium, at the precautions must be taken against required. The delivery system will be same concentration.9 For a given alkyl- the principle hazards of organolithium described in more detail in the next lithium, the stability increases with compounds: corrosivity, ¯ammability section. Equipment is also required decreasing concentration in the formu- and in certain instances, pyrophoricity. to dry the glassware prior to the experi- lation.9 A lower storage temperature There are a number of circumstances ment. lowers the decomposition rate. The that must be avoided in dealing with Nitrogen or argon can be employed presence of alkoxide impurities, gen- organolithium compounds in the labo- as the inert gas in reactions that erated from admission of adventious ratory: personnel exposure, air, oxygen, employ organolithium reagents. Typi- oxygen, accelerates the rate of decom- moisture, water, heat, clutter, source of cally, nitrogen is available in several position.10 Lithium dialkylamides also ignition (spark) and fuel. Prior to the grades from the supplier. Select the undergo decomposition via loss of commencement of an experiment that grade with the lowest moisture and lithium hydride, to afford the corre- utilizes an organolithium, it is strongly oxygen content. Argon must be utilized sponding imine. The decomposition recommended to consult the Material in reactions where lithium metal is a of lithium diisopropylamide is illu- Safety Data Sheet (MSDS) supplied by reactant. Nitrogen reacts exothermi- strated in Figure 2. The rate of this the vendor. The MSDS will contain cally with lithium metal to afford decomposition is primarily impacted recommendations for handling and lithium nitride (Li3N). Further, this by the storage temperature. Higher storage of the speci®c organolithium reaction is catalyzed by moisture. temperature accelerates the decompo- compound of interest. The glassware employed in the reac- sition. The lithium hydride that is pro- The ®rst consideration in planning tion must be free of moisture and duced in the decomposition of the experiment is locationÐwhere to oxygen before introducing the organo- alkyllithium compounds and lithium conduct the experiment. To minimize lithium compound. There are several dialkylamides precipitates from the personnel exposure, it is highly advi- techniques routinely employed to dry and inert a reaction apparatus. One technique is to assemble the glassware in the hood, attach the inert gas line, Figure 1. Thermal decomposition of n-butyllithium. evacuate the apparatus with a vacuum

Chemical Health & Safety, May/June 2002 7 source, heat the apparatus with a heat mended ®re extinguisher is a Class B in a metal bowl. This serves as a catch gun for several minutes, isolate the ®re extinguisher.15 It is imperative pan for the organolithium solution in vacuum, then re®ll the apparatus with NOT to use ®re extinguishers that con- the event either breaks. In addition, the the inert gas. This vacuum/inert gas tain water, carbon dioxide or haloge- metal bowl surrounding the reaction cycle should be repeated several times. nated hydrocarbons for organolithium vessel can be employed to hold the A popular alternative is to assemble ®res. Alkyllithiums react violently with cooling medium for a cryogenic reac- the glassware in the hood, attach the these three classes of extinguishing tion. This cooling medium should be inert gas line, start the ¯ow of the gas, agents. The use of these improper heat the apparatus with a heat gun for extinguishers will exacerbate, rather There are two basic several minutes and then let it cool to than mitigate, the ®re scenario. room temperature in a stream of the techniques for the inert gas. One additional technique for transfer of organoli- glassware drying/inerting is to place LABORATORY SET-UP the individual glassware pieces in an A typical organolithium reaction appa- thium solutions in the oven to dry. The glassware should ratus, out®tted for cannula transfer, is remain in the oven for at least several illustrated schematically in Figure 3. laboratory, the syringe hours at 1208C, assembled hot in the The reactor is equipped with a technique and the hood, and allowed to cool to room mechanical stirrer, a pressure-equaliz- temperature in a stream of inert gas. ing addition funnel equipped with a cannula technique. Alternatively, the glassware can be septum, and a Claisen adapter ®tted removed from the oven, placed in a with a thermometer to measure inter- an inert hydrocarbon solvent, such as desiccator to cool to room tempera- nal temperature and a dry ice conden- hexane or heptane, mixed with solid ture, assembled in the hood then ser. The inert gas line is attached to the carbon dioxide, ``dry ice.'' The more purged with the inert gas. outlet of the condenser, which is con- traditional cooling bath solvents, acet- The proper personal protective nected via a ``T'' ®tting to a bubbler one or 2-propanol, react vigorously equipment (PPE) for handling organo- ®lled with mineral oil. This bubbler16 with organolithium solutions and lithium compounds should also be monitors the positive ¯ow of inert gas should be avoided. Similarly, a water secured prior to experimentation. To through the system and prevents the condenser should not be used, due to protect the eyes from the corrosivity of in¯ow of air into the reactor in the potential for leaks, which could enter organolithium compounds, eye protec- event of partial vacuum. A second inert the reaction vessel. tion in the form of safety glasses or gas line is employed for the reagent goggles should always be worn. Addi- bottle of organolithium. The mineral tional eye protection, provided by a oil bubbler on this side has a clamp on TRANSFER TECHNIQUES face shield, is recommended in experi- the outlet to facilitate transfer via the There are two basic techniques for the ments where higher volumes of orga- cannula. The reaction vessel and the transfer of organolithium solutions in nolithium reagents (greater than 1 L) organolithium should each be placed the laboratory, the syringe technique are employed. The ¯ammability and pyrophoricity hazards are mitigated by the use of a ¯ame-resistant lab coat or coveralls.12 Proper glove selection will provide protection for hands potentially exposed to the corrosive nature of the organolithium com- pounds and the organic solvents in which they are formulated. Gloves made of Viton1 afford the best overall protection; however, they are expen- sive.13 Nitrile gloves offer a good com- promise between chemical protection and affordability.14 Proper footwear, leather, closed-toe shoes, protect the feet from spills. In the event of a spill, another important element to protection of personnel and equipment is a ®re extinguisher. It is important to secure the appropriate ®re extinguisher for organolithium reagents prior to initia- tion of the experiment. The recom- Figure 3. Laboratory apparatus for cannula transfer.

8 Chemical Health & Safety, May/June 2002 and the cannula technique. The two down on the syringe plunger. The solid bottle. The other tip of the cannula is techniques are very similar. The syr- cap is replaced on the sample bottle inserted into the septum in the addi- inge technique is preferred when rela- and it is returned to the refrigerator. tion funnel. The tip of the cannula is tively small volumes of organolithium The amount of the organolithium dis- lowered into the liquid of the organo- solutions are required (less than pensed can be calculated by noting the lithium solution. The clamp on the exit 50 mL). The transfer of larger volumes ®nal volume in the addition funnel. A of the mineral oil bubbler attached to is most easily accomplished with the more accurate technique for determin- the reagent bottle is slowly closed. This cannula technique. The laboratory ing the amount of organolithium trans- causes pressure to build in the reagent apparatus for a cannula transfer is illu- ferred is by weight. This is bottle and the organolithium solution strated in Figure 3.17 accomplished by weighing the sample will transfer to the addition funnel. bottle before and after the reagent has Inert gas pressure should never exceed Syringe Technique been dispensed. It is advisable to clean 5 psi (0.3 bar). When the desired Clutter and combustibles are removed the syringe soon after the transfer is volume has been transferred, the from the hood where the reaction will complete, to minimize the chance of clamp on the bubbler is released and be conducted. The reaction apparatus the plunger sticking and ``freezing'' in the tip of the cannula is raised above is dried, purged with an inert gas and the barrel. For pyrophoric solutions, the liquid level in the bottle. This latter assembled in the hood using one of the any residue in the syringe should be action will prevent siphoning of the techniques detailed previously. The diluted to less than 5 wt.% with an organolithium solution. Let any excess reaction ¯ask is placed in a metal bowl. inert solvent, such as heptane. This organolithium solution drain back into The bottle of the organolithium com- rinse solution can then be quenched the reagent bottle by gravity. The can- pound is removed from the refrigerator by slowly mixing with an equal volume nula is removed from the reagent bottle and is clamped in the hood in a metal of cold water. and then from the addition funnel. The bowl. This minimizes the chance of a solid cap is replaced on the sample spill if the bottle is accidentally Cannula Technique bottle and it is returned to the refrig- bumped during the transfer. It is Clutter and combustibles are removed erator. The amount of the organo- recommended that the syringe be at from the hood where the reaction will lithium dispensed can be calculated least twice the volume of the organo- be conducted. The reaction apparatus by noting the ®nal volume in the addi- lithium to be dispensed. The syringe is dried, purged with an inert gas and tion funnel. A more accurate technique that will be employed in transfer must assembled in the hood using one of the for determining the amount of organo- also be dried before it is employed. The techniques detailed previously. The lithium transferred is by weight. This is syringe should be dried in an oven for reaction ¯ask is placed in a metal bowl. accomplished by weighing the sample at least 2 hr at 1208C, placed in a The bottle of the organolithium com- bottle before and after the reagent has desiccator to cool to ambient tempera- pound is removed from the refrigerator been dispensed. It is advisable to clean ture, then purged with a stream of inert and is clamped in the hood in a metal the cannula soon after the transfer is gas. Don all the recommended PPE. If bowl. This minimizes the chance of a complete, to minimize the chance of the reagent bottle for the organo- spill if the bottle is accidentally cannula plugging. For pyrophoric solu- lithium compound was shipped with bumped during the transfer. The can- tions, any residue in the cannula a solid cap from the supplier, it should nula is a long syringe needle with a should be diluted to less than 5 wt.% be replaced with a cap with a septum. sharpened tip at each end. The cannula with an inert solvent, such as heptane. The inert gas ¯ow is started on the that will be employed in transfer must This rinse solution can then be reagent line. A standard syringe needle also be dried before it is employed. The quenched by slowly mixing with an is inserted into the end of the inert gas cannula should be dried in an oven for equal volume of cold water. line. The tip of this needle is then at least 2 hr at 1208C, placed in a inserted into the septum of the reagent desiccator to cool to ambient tempera- bottle. Observe the inert gas ¯ow at the ture, then purged with a stream of inert DISPOSAL OF ORGANOLITHIUM bubbler and adjust the ¯ow accord- gas. Don all the recommended PPE. If COMPOUNDS ingly. The syringe is then employed the reagent bottle for the organo- Small residues of organolithium com- to withdraw the required amount of lithium compound was shipped with pounds can be safely quenched in a organolithium from the sample bottle. a solid cap from the supplier, it should hood. Pyrophoric materials should be Care must be taken not to withdraw be replaced with a cap with a septum. diluted to less than 5 wt.% with an the organolithium solution faster than The inert gas ¯ow is started on the inert solvent, such as heptane. This the inert gas ¯ow can re®ll the void. reagent line. A standard syringe needle solution should then be added slowly This would allow air to enter the inert is inserted into the end of the inert gas (via an addition funnel) to well-stirred gas line and possibly contaminate the line. The tip of this needle is then solution 2 M of 2-propanol in heptane. organolithium solution. The tip of the inserted into the septum of the sample Monitor the temperature of this syringe needle is then inserted into the bottle. Observe the inert gas ¯ow at the quench solution with an internal ther- septum of the addition funnel. The bubbler and adjust the ¯ow accord- mometer. Maintain the temperature at organolithium solution is then dis- ingly. One tip of the cannula is then 508C or below by controlling the feed pensed into the funnel by pushing inserted into the septum of the reagent rate of the organolithium solution or

Chemical Health & Safety, May/June 2002 9 by application of an external cooling ane, a liquid with a boiling point of corrosive, ¯ammable and in certain bath of dry ice/heptane. The resultant 678C. A similar reaction with n-butyl- cases, pyrophoric. However, these solution of lithium isopropoxide in lithium would afford butane (boiling hazards can be minimized. The experi- heptane can then be disposed of as point ˆÀ0:58C) as the co-product. n- ment should be carefully planned prior ¯ammable, hazardous waste. Contain- Hexane is much easier to contain than to its execution to minimize hazards to ers of organolithium reagents that have butane, particularly on an industrial personnel and the physical plant. developed signi®cant quantities of scale. Another innovation is the com- Proper PPEto mitigate the hazards solids should be discarded. These lar- mercial availability of preformed solu- of organolithium compounds should ger volumes of organolithium reagents tions of lithium diisopropylamide be secured and worn at all times. All that are no longer needed should be (LDA). These formulations of LDA are equipment that is employed for the sent out for disposal as a lab pack. non-pyrophoric.7 In addition, when experiment must be free of moisture. This minimizes laboratory personnel the preformed solution of LDA is An inert atmosphere of nitrogen or exposure to the hazards of quenching employed, the experimenter does not argon is also critical in minimizing large volumes of organolithium com- have to handle pyrophoric n-butyl- the hazards of organolithium com- pounds and their decomposition lithium traditionally employed. A pounds. Solutions of organolithium products. further advantage of the preformed compounds can be safely transferred LDA formulation is that again, the from the storage bottles to the reaction experimenter does not have to deal ¯ask with either a syringe or a cannula. NEW DEVELOPMENTS with the emission of the co-product With the utilization of these basic tech- Several innovative organolithium com- butane. A third innovation is the newly niques, organolithium compounds can pounds and formulations have recently commercialized formulation of t-butyl- be safely handled in the laboratory. been commercialized. These innova- lithium in heptane.18 While this new When properly handled, organoli- tions have improved safety character- formulation is still pyrophoric, it is thiums provide unique properties that istics over the older, more traditional much safer to handle than the tradi- allow for precise control of a molecular organolithium reagents. The ®rst is tional pentane formulation of t-butyl- architecture, while also demonstrating 33 wt.% n-hexyllithium in hexanes. lithium.19 This is due to the much enhanced nucleophilicity, stability, and This 2.5 M solution of n-hexyllithium higher ¯ash point of heptane (Fp ˆ excellent solubility in organic solvents. has similar reactivity to the analogous À18C) versus pentane (Fp ˆÀ49C). With proper care and attention, orga- nolithiums can be safely and effectively utilized in both laboratory and physical Severalinnovative CONCLUSIONS plant environments. organolithium Organolithium compounds are extre- compounds and mely useful reagents in organic synth- Acknowledgements formulations have The authors would like to thank Organolithium Doug Sutton for his practical sugges- recently been com- compounds are tions on transfer techniques. mercialized. These extremely useful innovations have reagents in organic References improved safety 1. Wake®eld, B. J. The Chemistry of synthesis and as Organolithium Compounds; Perga- characteristics over mon: Oxford, 1974; initiators in anionic Wake®eld, B. J. Organolithium Meth- the older, more tradi- ods, Academic Press: London, 1988; polymerizations. Brandsma, L.; Verkruijsse, H. Pre- tionalorganolithium These reagents are parative Polar Organometallic Chem- reagents. istry I; Springer-Verlag: Berlin, 1987; corrosive, ¯ammable Brandsma, L. Preparative Polar Orga- nometallic Chemistry II; Springer- concentration of n-butyllithium in and in certain cases, Verlag: Berlin, 1990; typical applications. Furthermore, it pyrophoric. However, Stowell, J. C. Carbanions in Organic exhibits two signi®cant safety advan- Synthesis; Wiley: New York, NY, tages over n-butyllithium.First, this for- 1979. (For the application of or- these hazards can be ganolithium reagents in organic mulation of n-hexyllithium in hexanes minimized. synthesis.) tested as non-pyrophoric, even at con- 2. Hsieh, H. L.; Quirk, R. P. Anionic 7 centrations up to 85 wt.%. The second Polymerization; Marcel Dekker: New advantage is that in deprotonation esis and as initiators in anionic York, NY, 1996. (For an excellent experiments, the co-product is n-hex- polymerizations. These reagents are overview of anionic polymerization.)

10 Chemical Health & Safety, May/June 2002 3. Stanetty, P.; Mihovilovic, M. D. J. Org. 8. Wake®eld, B. J. Organolithium Meth- 13. One pair of Viton1 gloves, size 9, is Chem., 1997, 62, 1514. (For example, ods; Academic Press: London, 1988, listed in the 2000±2001 Aldrich catalog the half-life of n-butyllithium in THF p. 12. for $57.60. at 208C is 1.78 hr. The half-lives of 9. Totter, F.; Rittmeyer, P. Organometal- 14. One pair of nitrile gloves, size L, is various alkyllithiums in ethereal sol- lics in Synthesis: A Manual; Schlosser, listed in the 2000±2001 Aldrich cata- vents as a function of temperature.). M., Ed.; Wiley: Chichester, 1994, log for $7.20. 4. Malpass, D. B.; Fannin, L. W.; Ligi, J. J. pp. 171±2. 15. Ansul1 Purple K is one popular choice Kirk-Othmer Encyclopedia of Chemi- 10. Kamienski, C. W.; McDonald, D. P.; for a Class B ®re extinguisher. calTechnology , 3rd ed.; Grayson, M., Stark, M. W. Kirk-Othmer Encyclope- 16. A number of bubbler designs are Ed.; Wiley: New York, NY, 1981, Vol. dia of ChemicalTechnology , 4th ed.; commercially available from labora- 16, pp. 557±8. Kroschwitz, J. I., Ed.; Wiley: New tory glassware suppliers. A versatile 5. March, J. Advanced Organic Chemistry, York, NY, 1995, Vol. 15, pp. 453±4. bubbler design is Chemglass catalog 5th ed.; Wiley: New York, NY, 2001, 11. Kamienski, C. W. Lithium Link, 1994 number AF-0513-20. p. 330. (Winter). (For an excellent review of 17. Butyllithium: Guidelines for Safe 6. Pyrophoric is derived from the Greek the various methods of analysis of Handling, a brochure available at no word pyrophoros, which is a combina- organolithium compounds.) charge from FMC Lithium. (For a tion of pyr (®re) and pherein (to bear), 12. One brand of ¯ame resistant fabric is more extensive discussion of these in Webster's New World Dictionary of Nomex1. A variety of clothing styles, transfer techniques.) American English, 3rd College ed.; including lab coats, coveralls, shirts 18. Commercially available from FMC Prentice Hall: New York, NY, 1994, and pants, is commercially available. Lithium, 449 N. Cox Road, Gastonia, p. 1096. Flame-resistant clothing is available NC 28054. 7. The of®cial test for pyrophoricity is from a number of laboratory supply 19. Bailey, B.; Longstaff, S. Lithium Link, detailed in the Department of Trans- vendors, including Aldrich, Fisher and 2000 (Fall). (For an excellent review of portation (DOT) regulations (49 CFR VWR. t-butyllithium chemistry.) 173, Appendix E).

Chemical Health & Safety, May/June 2002 11