Claims
- 1. A process for producing organometallic compositions comprising reacting at a temperature between 20.degree. C. and 50.degree. C. an organic halide of the formula RX in which X is selected from the group of chloride, bromide and iodide and R is selected from alkyl, cycloalkyl, .alpha.,.alpha.-alkylene, alkenyl, and aryl groups with a mixture of two different metals, in finely divided form, one metal being selected from lithium, sodium and potassium and the other metal being selected from magnesium, calcium, barium, aluminum and zinc in a hydrocarbon solvent containing 0.05 to 2.0 moles of a Lewis Base per mole of organic halide.
- 2. The process of claim 1 in which the two different metals are lithium and magnesium.
- 3. The process of claim 1 in which the hydrocarbon solvent contains 1.2 to 1.5 moles of Lewis Base per mole of the organometallic composition.
- 4. The process of claim 1 wherein the Lewis Base is selected from tetrahydrofuran and methyltetrahydrofuran.
- 5. The process of claim 1 in which the organic halide is slowly added to the two metals slurried in the hydrocarbon solvent over a period of one to two hours.
- 6. The process of claim 1 in which the process temperature is maintained between 30.degree. C. and 40.degree. C.
- 7. The process of claim 1 in which the liquid hydrocarbon solvent is selected from aliphatic and alicyclic hydrocarbons containing 5 to 10 carbon atoms, and aromatic hydrocarbons.
- 8. The process of claim 2 in which the lithium metal contains at least 0.7 weight percent sodium and RX is an organic chloride.
- 9. The process of claim 1 in which the two different metals are lithium and magnesium, the organic halide is methyl chloride and the ratio of lithium to magnesium does not exceed 2 to 1; the hydrocarbon is selected from cumene and toluene and the reaction temperature is between 30.degree. C. and 40.degree. C.
- 10. The process of claim 1 in which the two different metals are lithium and magnesium, the organic halide is methyl chloride and the ratio of lithium to magnesium is not less than two to one; the hydrocarbon selected from cumene, ethylbenzene and toluene, and the reaction temperature is between 30.degree. and 40.degree. C.
- 11. A method of preparing a stable methyllithium solution comprising adding a methyl halide to a mixture of lithium metal and an aromatic hydrocarbon containing tetrahydrofuran in an amount not exceeding 2 moles of tetrahydrofuran per mole of methyl halide while maintaining the mixture at a temperature not exceeding 50.degree. C. to thereby react in an inert atmosphere the lithium metal and methyl halide to produce methyllithium and by-product lithium halide.
- 12. The method according to claim 11 wherein the methyl halide is methyl chloride and the lithium metal contains sodium in an amount of 0.7% and higher by-weight based on the weight of the lithium metal.
- 13. The method according to claim 11 wherein the mole ratio of tetrahydrofuran to methyl halide is from 1.1:1 to 1.5:1.
- 14. The method according to claim 11 wherein the methyl halide is selected from methyl chloride, methyl bromide and methyl iodide.
Parent Case Info
This application is a division of application Ser. No. 160,388, filed Feb. 25, 1988, now U.S. Pat. No. 4,976,886.
This invention concerns a high-yield, economical process for producing novel, hydrocarbon soluble organo metallic compositions such as alkyllithium compounds, in a hydrocarbon solvent containing a limited amount of tetrahydrofuran (THF), other ethereal compounds or Lewis bases.
Alkyllithium compounds, particularly methyllithium (MeLi), are used as reagents in the preparation of pharmaceuticals and special chemicals. MeLi has been available commercially in diethyl ether solutions in the presence of an equivalent of lithium bromide (LiBr) formed as a by-product and remaining in solution as a complex with the methyllithium. A principle deficiency of this product is its high flammability due in part to the diethyl ether which is highly flammable and explosive in combination with oxygen and which contributes highly to the pyrophoric nature of the contained methyllithium. Although the presence of lithium bromide reduces the pyrophoric nature of methyllithium itself, the presence of lithium bromide interferes with certain applications of the methyllithium. There is evidence that the presence of lithium bromide may influence significantly the stereochemistry during the addition of methyllithium to carbonyl compounds. For these reasons it is often desirable to use an essentially halide-free methyllithium. However, the MeLi.LiBr complex has found in the past, and will in the future, many uses in organic syntheses, especially for those applications where stereochemistry is unimportant.
The pyrophoric nature of methyllithium taken together with the presence of diethyl ether has resulted in limited use of MeLi in diethyl ether. Moreover, other chemical routes or methyl Grignards are used.
Attempts were made in the 1970's to commercially market ethereal solutions of halide-free methyllithium prepared from methyl chloride and lithium shot. This resulted in the desired product containing not more than 5 mole percent lithium chloride based on contained methyllithium because the lithium chloride by-product has low solubility in diethyl ether. The slow reaction of methyl chloride with lithium shot resulted in incomplete reaction before filtration which resulted in poor product shelf life due to the post reaction Wurtz coupling of methyllithium and residual methyl chloride to form ethane and lithium chloride (LiCl). These diethyl ether solutions of methyllithium are marketed commercially even though they often degrade badly before use. Gilman and Gaj in Journal of Organic Chemistry, 22, 1164 (1957) disclose preparing methyllithium from methyl chloride and lithium metal in THF. The THF/Li mole ratio was 9.8 indicating use of a large excess of THF. Thermal stability of these products was found to be poor even at 0.degree. C. So in view of the thermal decomposition and the high cost of THF these products are not commercially feasible. There remains a need for a halide-free, thermally stable methyllithium solution in a relatively non-volatile solvent system and a process for producing such a product.
Using proton and lithium NMR analysis House, H. O. et al., J. Oro. Chem., 32, 2481 (1967) and L. M. Seitz et al., J. Amer. Chem. Soc., 88, 4140 (1966) found that in diethyl ether methyllithium (MeLi) and dimethylmagnesium (Me.sub.2 Mg) form Li.sub.2 MgMe.sub.4 and Li.sub.3 MgMe.sub.5 complexes. L. M. Seitz et al. J. Orqanometallic Chem., 18, 227 (1969) disclose that in tetrahydrofuran only the 2:1 (Li:Mg) complex was observed. These workers prepared halide-free dimethylmagnesium via two methods: (1) &:he long, tedious Schlenk reaction which involves first the synthesis of methylmagnesiumbromide, the addition of dioxane to precipitate magnesium bromide followed by vacuum removal of the dioxane; (2) the process in which highly toxic and expensive dimethylmercury was stirred with excess magnesium to generate dimethylmagnesium.
Kamienski and Eastham in J. Oroanometallic Chem., 8, 542 (1967) disclose the reaction of an alkyllithium with a special activated magnesium chloride in diethyl ether which was not and is not commercially available as a route to dimethylmagnesium. Kamienski and Eastham in J. Org. Chem., 34 1116 (1969) disclose reaction of RLi with RMgX in diethyl ether to prepare dialkylmagnesium.
Most of the processes of the prior art are expensive, require handling of highly toxic reagents, employ commercially unavailable reagents and use highly flammable diethyl ether and thus are not commercially feasible processes. Unfortunately diethyl ether solutions of halide-free methyllithium are undesirably pyrophoric. The need remains for an inexpensive, commercial synthesis of halide-free dimethylmagnesium and halide-free, stable alkyllithium compositions.
The present invention provides stable hydrocarbon solvent-Lewis base, such as hydrocarbon-tetrathydrofuran, solutions of alkali metal alkyls and a method for producing stable hydrocarbon Lewis Base compositions of alkali metal alkyls containing not more than 5 mole percent lithium chloride based on the alkali metal alkyl content in which compositions the ratio of tetrahydrofuran to alkali metal alkyl is within the range of 0.05:1 and 2:1 and the hydrocarbon is a liquid aliphatic, alicyclic or aromatic hydrocarbon. These compositions are further stabilized by the presence of a small amount of an organometallic compound containing an alkyl group and a metal selected from group 2A, aluminum and zinc in the solutions. The method reacts an alkyl halide with an alkali metal in a hydrocarbon solvent containing not more than 2 moles of a Lewis Base, such as tetrahydrofuran, per mole of alkyl halide. When it is desired to produce these stabilized alkyl alkali metal compounds, mixtures of metals, one an alkali metal the other selected from group 2A, aluminum and zinc are reacted with an alkyl halide to produce compositions of variable metal content. For example, methyllithium stabilized with dimethylmagnesium can be varied from ratios of 1:99 to 99:1. Of course the dialkylmagnesium and alkyllithium can be separately produced and simply mixed together in the desired ratios. The preferred methyl halide, methyl chloride (MeCl) when reacted with an alkali metal produces a by-product which is essentially insoluble. When organic bromides or organic iodides such as methyl bromide (MeBr) or methyl iodide (MeI) are employed, higher levels of by-product inorganic halide go into solution and actually improve the thermal stability of the complexed organo-metallic which is dissolved in a limited amount of Lewis Base and an aromatic solvent. For example, a MeLi.sub.1.0 .multidot.LiBr.sub.0.69 complex dissolved in a limited amount of THF (THF/MeLi=1.65 mole ratio) and toluene was found significantly more thermally stable (about 8 times) at 40.degree. C. than a comparable halide-free methyl-lithium solution in limited THF/toluene. As the number of carbon atoms in the alkyl group increases the amount of THF required to solubilize the organometallic compounds decreases. The solubility of methyllithium, even when stabilized with dimethylmagnesium or an inorganic halide is such that at least some of the solvent must be an aromatic solvent.
The process of the invention when producing alkali metal alkyls reacts an alkali metal preferably lithium metal, most preferably containing some sodium with an alkyl halide in a hydrocarbon solvent containing a small amount of a Lewis Base such as THF. The alkali metal is preferably finely divided and dispersed or slurried in an aromatic hydrocarbon containing tetrahydrofuran. The alkyl halide, preferably methyl or ethyl halide is added to the slurried lithium metal while the temperature is maintained below about 50.degree. C; preferably the temperature is maintained between 30.degree. C. and 40.degree. C. It is preferred to activate or condition the finely divided alkali metal, such as lithium metal and, if desired, magnesium metal, by stirring it or them together with a small amount of alkyl lithium in the selected solvent for a short period before reaction with the alkyl halide. This appears to increase the reactivity of the lithium and magnesium metals. Typically the alkyl halide is added slowly to the alkali metal slurry with agitation as this facilitates control of the reaction temperature. The reactions involving an alkali metal are done under an inert atmosphere, preferably argon. The product is a tetrahydrofuran complex of alkyllithium, which may contain a corresponding dialkylmagnesium, in a hydrocarbon solvent.
A method or process variable having a great influence on yield is the amount of Lewis Base (THF) present during the reaction. While the ratio of Lewis Base (THF) to alkyl halide may vary between about 0.05 and about 2.0 moles of Lewis Base (THF) per mole of alkyl halide, the preferred range is about 1.2 to 1.5 moles of Lewis Base (THF) per mole of methyl halide when there is no magnesium present in the reaction. Surprisingly higher and lower levels of Lewis Base (THF) tend to result in lower yields.
Organic halides useful in practicing this invention may be represented by the formula RX in which X is selected from the group of chloride, bromide and iodide and R is selected from the group of alkyl, cycloalkyl, .alpha.,.alpha.-alkylene, alkenyl and aryl groups. More specifically, R can be selected from the group of methyl, ethyl, n-butyl, sec-butyl, 2-ethylhexyl, n-octyl, cyclohexyl, 1,4-butylene, phenyl, cumyl, benzyl, tolyl, vinyl and crotyl groups. When desired mixtures of different organohalides can be employed to produce mixed organic groups in the products of this invention.
The liquid hydrocarbon solvents used in practicing this invention are typically selected from aliphatic hydrocarbons containing five to ten carbon atoms, alicyclics containing six to ten carbon atoms ant aromatic hydrocarbons such as benzene, toluene, ethylbenzene, cumene and so forth.
Products of this invention of particular interest include solutions of lower alkyllithium compounds which if desired can contain stabilizing amounts of diorgano-metallic compounds such as dialkylmagnesium products or inorganic halides such as lithium bromide or lithium iodide. Thus, such compounds as methyl or ethyllithium are stabilized by small amounts of dimethyl- or diethyl-magnesium, respectively. These compounds are useful as alkylating agents in the synthesis of pharmaceuticals and in other complex organic synthesis reaction sequences. These alkyllithium solutions containing a diorganometallic compound have improved stability, that is compounds such as methyllithium containing a stabilizing amount of dimethylmagnesium have a reduced tendency to precipitate methyllithium from solution and have a reduced tendency to metallate the aromatic solvents and thus do not release methane with accompanying increased pressure, which is undesirable.
The dialkylmagnesium/alkylmagnesium halides compositions of this invention have characteristics similar to the corresponding dialkylmagnesium compounds and are used for similar purposes such as alkylations and the like where Grignard agents are often used. In this respect these compounds, such as Me.sub.2 Mg/MeMgCl, react more completely than Me.sub.2 Mg as the presence of the chloride is believed to promote reaction of the alkyl groups and so, more completely reacting such alkyl groups in the Me.sub.2 Mg/MeMgCl compounds.
Methyllithium and dimethylmagnesium (Me.sub.2 Mg) are not hydrocarbon soluble. While the use of a limited amount of a Lewis Base, such as THF, solubilizes these organo-metallic compounds in hydrocarbon solvents, preferably aromatic solvents, the solutions containing only methyllithium tend to be unstable; methyllithium precipitates in certain cases, such as when cumene is the aromatic solvent, upon storage at low or elevated temperatures and metallates aromatic solvents under some storage conditions such as, at elevated temperatures. Surprisingly, inclusion of dimethylmagnesium in small amounts in the methyllithium solutions in a hydrocarbon solvent containing limited THF both stabilizes the methyllithium and increases its solubility thus, making possible more concentrated, stabilized solutions. It is possible to separately prepare dimethylmagnesium and methyllithium solutions and mix them together to obtain the stabilized compositions of this invention. However, it is much easier and simpler to prepare methyllithium solutions stabilized with dimethylmagnesium by using the mixed-two metal process of the present invention.
The present process employs a hydrocarbon solvent containing a limited amount of tetrahydrofuran (THF), other ethereal compound or Lewis Base. The novel organometallic products of the process are dissolved in these hydrocarbon solvents containing a limited amount of a Lewis Base such as tetrahydrofuran, methyltetrahydrofuran and so forth. The amount of THF varies from 0.05 to 2.0 depending on the alkyl group selected. Slightly more than one (1) equivalent of THF per alkyl group is used when the alkyl group is methyl with 1.2 to 1.5 THF equivalents being preferred. However, as the carbon content of the alkyl group increases less THF is required to solubilize the organometallic compound; when the alkyl group is ethyl only 0.5 to 0.7 equivalents of THF are required to solubilize ethyllithium and it is known that diamylmagnesium is hydrocarbon soluble without THF. Moreover n-propyllithium is known to be hydrocarbon soluble. Compositions of particular interest in pharmaceutical synthesis work are solutions of methyl-lithium; methyllithium hydrocarbon solutions solubilized by 1.2 to 1.5 equivalents of THF and stabilized by 7 to 8 mole percent or more of dimethylmagnesium are also useful in such complex organic synthesis operations.
A particular advantage of the present invention is that the compounds of the invention have been synthesized in high yield by way of a novel reaction sequence in a single reactor which involves gradual addition of an organic halide to a mixture of an alkali metal and a metal selected from magnesium, calcium, bariux, aluminum and zinc in a hydrocarbon solvent containing a limited amount of tetrahydrofuran. The final product is obtained by filtration to remove unreacted metal and inorganic metal halide. The most important novel compositions synthesized via this general process are dimethylmagnesium and methyllithium/dimethylmagnesium compositions in which the ratios of the components in the latter product range from 1:99 to 99:1.
MeLi/Me.sub.2 Mg compositions in solution in limited THF/Toluene containing 50 or more mole % Me.sub.2 Mg are stable and need not be refrigerated. Compositions in toluene containing less than 50 mole % Me.sub.2 Mg are more stable than MeLi alone, however they will require refrigeration to avoid thermal degradation. At higher temperatures degradation occurs via metallation of toluene to form benzyllithium and methane gas. MeLi/Me.sub.2 Mg compositions prepared in cumene are even further improved as shown by the fact that solutions of MeLi with as little as 5 mole percent Me.sub.2 Mg show no decomposition after storage at 40.degree. C. for a 30 day period.
The process of this invention employs an alkali metal, preferably lithium, sodium or potassium. When preparing bimetallic compounds a mixture of two metals are employed. One metal is an alkali metal, preferably lithium and the other metal is selected from metals listed in group 2A of the Periodic Chart of Elements, aluminum and zinc preferably magnesium. The organic halide, which is typically selected from lower alkyl halides and aromatic halides, such as methyl or ethyl chloride is reacted with the mixed metals in a hydrocarbon solvent containing a limited amount of tetrahydrofuran, other ethereal compound or appropriate Lewis Base. The hydrocarbon solvent may be a liquid, lower aliphatic hydrocarbon solvent containing five to ten carbon atoms, an alicyclic hydrocarbon of six to ten carbon atoms or an aromatic hydrocarbon, preferably cumene and a limited amount of tetrahydrofuran.
The usual synthesis of the bimetallic compositions involves the slow addition, generally over one to two hours, of an organic chloride such as methyl chloride to a mixture of finely divided lithium particles and magnesium powder slurried in a hydrocarbon reaction medium containing a limited amount of tetrahydrofuran. In typical examples varying amounts of these metals are used and the reaction directly produces the desired soluble MeLi/Me.sub.2 Mg composition from which by-product lithium chloride and excess metals are separated by filtration. Characterization of the products was done by titrimetric, nuclear magnetic resonance and atomic absorption spectroscopy methods.
The reactivity of the finely divided lithium in producing mono-metallic or bimetallic compositions is increased by the presence of a small amount of sodium. H. O. House and M. Call in Organic Synthesis (1972), 52, 39 showed that a minimum 0.7 wt % preferably 1 to 2 weight percent sodium in the finely divided lithium is necessary for efficient and complete reaction with methyl chloride in diethyl ether.
The general procedure of the bimetallic process aspect of this invention is further described with respect to the reaction of the methyl chloride with lithium and magnesium metals in cumene containing limited amounts of tetrahydrofuran. MeLi/Me.sub.2 Mg of various compositions are predictably synthesized via the simultaneous reaction of methyl chloride with a mixture of washed lithium metal particles (minimum 0.7% Na) and magnesium powder slurried in toluene containing slightly more than one equivalent of tetrahydrofuran per equivalent of methyl chloride employed.
In one aspect of this invention lithium and magnesium metals are reacted with an alkyl halide such as methyl, ethyl, or butyl chloride or an aromatic halide such as phenyl chloride. Surprisingly when the reactant ratios are selected so as to provide at least 1 mole percent and preferably 5 to 10 mole percent of magnesium per mole of lithium and the alkylhalide is methyl-chloride a highly stable methyllithium/dimethylmagnesium solution is produced. Likewise, the reactant metal ratios can be chosen such that product ratios of alkyl-lithium to dialkylmagnesium may vary from 0.01 to 0.99. This aspect of this invention may be illustrated by the following equation:
When x=2 and y=1 in the above equation the product will be a dialkylmagnesium only. The reaction is conducted in an aliphatic hydrocarbon of five to ten carbon atoms or an aromatic hydrocarbon, containing in all cases a limited amount of tetrahydrofuran or other Lewis Base.
Dialkylmagnesium/alkylmagnesium halides of various compositions are synthesized via the process of this invention. This aspect of this invention can be represented by the following equation:
Following the general procedure of the invention the two metals are slurried in an aromatic solvent, preferably cumene and the metals preconditioned (activated) by contact (stirring) with a small amount of a methyl-metallic (1 to 3 mole percent based on methyl chloride used) such as MeLi, Me.sub.2 Mg, MeLi/Me.sub.2 Mg or Me.sub.2 Mg/MeMgCl or the like for 2 to 4 hours. Generally, for predictability not more than 20 mole % excess metals (M=Li+Mg=20% excess) should be used (based on methyl chloride), and desired MeLi/Me.sub.2 Mg compositions can be prepared by simply varying the relative amounts of metals employed (see equation 1 above). Dry THF is added just prior to starting the reaction. After initiation with a small amount of gaseous methyl chloride, the remaining methyl chloride is slowly added to the metal slurry over 1 to 2 hours while maintaining the reaction temperature between about 30.degree. C. and about 50.degree. C. but preferably between 30.degree. C. and 40.degree. C. generally at about 35.degree. C. Generally, one to two hours post reaction time, with agitation assures reaction of all the methyl chloride. After the reaction, the mass is stirred until no methyl chloride is present in solution (based on NMR analysis). The reaction product is filtered to remove solids and a light yellow to water white solution of MeLi/Me.sub.2 Mg is recovered. The product is assayed by the methods disclosed herein.
The process of this invention for producing bimetallic compositions can be operated at temperatures from ambient up to about 50.degree. C, but preferably 30.degree. C. to 40.degree. C. The reactants participate in exothermic reactions and while a reaction may nitrate at ambient temperature the resultant temperature can go up to as high as 30.degree. to 35.degree. C. or even higher. While high temperatures are possible it is preferred to operate in the temperature range of ambient to 50.degree. C. and typically with methyl chloride, lithium and magnesium the temperature is maintained at 30.degree. to 35.degree. C. While pressure reactions are possible, it is preferred to run the reaction at atmospheric pressure. The reactions should be carried out under an inert gas, preferably argon. Materials of construction of the reactors and condensers are not critical so long as they are inert to the reaction. Glass lined, stainless steel, Hastelloy, carbon steel and other quality materials of construction are suitable.
US Referenced Citations (10)
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 0040141 |
Nov 1981 |
EPX |
| 2183650 |
Jun 1987 |
GBX |
Non-Patent Literature Citations (2)
| Entry |
| Lithium-7 and Proton Nuclear Magnetic Resonance Spectra of Methyllithium/Dimethylmagnesium (Zinc, Cadmium) in Tetrahydrofuran and Methyllithium/Dimethylcadmium in Ether; L. M. Seitz & B. F. Little, J. Organometal. Chem., 18 (1969) 227-241. |
| Wakefield, "The Chemistry of Organolithium Compounds", pp. 198-199, Pergamon Press. |
Divisions (1)
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Number |
Date |
Country |
| Parent |
160388 |
Feb 1988 |
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Patent Grant
5141667
