WO1992019622A1

WO1992019622A1 - Aryllithium process

Info

Publication number: WO1992019622A1
Application number: PCT/US1992/001208
Authority: WO
Inventors: Robert Charles Morrison
Original assignee: Fmc Corporation
Priority date: 1991-04-29
Filing date: 1992-02-14
Publication date: 1992-11-12
Also published as: AU1926292A

Abstract

A process for producing high purity stable etherical solutions of aryllithium compounds by reacting lithium metal, in the form of a dispersion, with a monohaloaryl compound in an ether of the formula ROR' wherein R and R' are independently selected from alkyl radicals containing three to eight carbon atoms, the mole ratio of ether to monohaloaryl compound is at least 1.0 and the reaction temperature is maintained below 65 °C.

Description

ARYLLITHIUM PROCESS

This invention concerns a process for producing aryllithium compounds and certain novel aryllithium compositions.

The preparation of aryllithium compounds by the direct reaction of an organic halide with lithium metal in an ethereal solvent has long been known. Ethereal solvents are employed due to the insolubility of aryl- lithium compounds in hydrocarbon solvents. It is well known that aryllithium compounds react with ethers, resulting in cleavage of the ether linkage and destruction of the aryllithium compound [Gil an, Haubein and Hartzfield, J. Orσ. Chem. 19. 1034 (1954); Gilman and Gaj, J. Orσ. Chem. 22. 1167 (1954); and Barwell, R.L. Chem. Revs.. 54. 615 (1954)]. Ether cleavage is reduced or stopped by preparing and/or storing the aryllithium solutions at low temperatures of -35° to -60°C. U.S. Patent 3,197,516 advises that "Solutions of aryllithium compounds, such as diethyl ether solutions of phenyllithium, are not stable under conditions of ordinary storage due to the reaction of phenyllithium with ether." This U.S. Patent overcomes these problems of lack of hydrocarbon solubility and stability in ether solutions by using mixed ether/hydrocarbon solvent reaction mediums that contain at least enough ether to solubilize the aryllithium. A slightly different solution to this process problem is disclosed in U.S. Patent 3,446,860 which discloses reacting an ether solution of an arylhalide with a hydrocarbon dispersion of lithium metal to produce stable ether/hydrocarbon solutions of aryllithium compounds. While these mixed ether/hydrocarbon solutions of aryllithium compounds are useful and produced and sold in commercial quantities, highly stable solutions of aryllithium compounds are very desirable for many uses.

The present invention provides a process for producing high purity, thermally stable ether solutions of aryllithium compounds by reacting a dispersion of lithium metal with a monohaloaryl compound in an ether of the formula ROR¹ wherein R and R¹ are independently selected from alkyl radicals containing three to five carbon atoms. R and R^ may be the same or different alkyl radicals. The ratio of ether to monohaloaryl compound is at least 1.5 to 1, and the reaction temperature is maintained between 5°C and 65°C, preferably 15°C to 40°C and most preferably in the range of about 30°C to 35°C. The preferred mole ratio of ether to monohaloaryl compound is 1.7-2.0 to 1. For example, when using di-n-propyl ether, di-n-butyl ether or di-n-pentyl ether and monochlorobenzene the preferred mole ratio of ether to aryl compound is at least 1.5 and the most preferred ratio is about 1.7. Very high ratios of ether to monohaloaryl compound, such as 6 to 1 or higher, can be used but the product can thereby become rather diluted.

Ethers used in the practice of this invention are of the formula ROR¹ wherein R and R¹ are generally independently selected from alkyl groups containing at least 3 carbon atoms; R and R¹ can be the same or they can be different. Mixtures of ethers can, of course, be employed. Typical ethers useful in practicing this invention include, but are not limited to di-n-butyl ether, di-n-pentyl ether, di-n-propyl ether, and the like. Preferred ethers include di-n-butyl ether, di-n- pentyl ether and di-n-propyl ether.

It is an advantage of the present invention to provide a process which produces aryllithium compounds of high purity and in a high yield process that can be conducted at temperatures up to about 65°C, preferably at temperatures of 15° to 40°C. Higher reaction temperatures can be employed with the higher carbon content ethers. When di-n-hexyl ether was employed the reaction at 35-40°C was extremely slow compared to ethers with a lower carbon content. Lower temperatures of 0° to -60°C as disclosed by Gilman, et al., can be employed, but such low temperatures are not desirable due to the cooling costs and low rate of reaction. The process is conducted in an inert atmosphere to protect the aryllithium products which are degraded by contact with a reactive atmosphere such as air contain¬ ing any appreciable amounts of water vapor. The inert atmosphere is typically a noble gas and preferably argon or helium.

The reactants are employed in about stoichiometric amounts with a slight excess of lithium dispersion being preferred to ensure the reaction proceeds to completion; the excess lithium is easily removed and recovered by conventional means. The desired final aryllithium concentration is dependent on the amounts of reactants used. The concentration of the aryl¬ lithium compounds in the recovered solutions will range in general from about 1 up to about 35 weight percent depending on the solubility of each aryllithium compound. Solutions of 5 to 24 weight percent are preferred. Higher concentrations are possible but they may not be stable at low temperatures often encountered in shipping products in cold climates. Surprisingly, compositions containing 5 to 14 weight percent phenyllithium dissolved in di-n-butyl ether are not pyrophoric. Concentrations of about 14 weight percent and less are not pyrophoric, while con¬ centrations of 24 weight percent and above are pyrophoric. While, in the most preferred embodiment of the present invention the aryllithium compound is phenyl- lithium, various other aryllithium compounds , for instance biphenyllithiums , such as 2 biphenyllithium, 3 -biphenyllithium and 4-biphenyllithium; alpha- naphthyllithium; are definitely contemplated and encompassed by this invention.

Therefore included, by way of further example, are the group of aryllithium compounds which result from the utilization, in the practice of the methods disclosed herein, of monohaloaryl compounds such as monohalobenzenes, exemplified by chlorobenzene and bro obenzene; monohaloalkylbenzene compounds, exemplified by o,m,p-bromotoluene, and p-bromoisobutyl- benzene, and polynuclear haloaryl compounds exemplified by α-bromonaphthalene, 4-bromobiphenyl, and 9- bromoanthracene. Other haloaryl compounds with functional groups which can be used are alkoxyaryl halides exemplified by o-anisylbromide, 3-isobutoxy-4- bromotoluene, and 2-chloro-3-methyl-4-ethoxytoluene; dialkylaminoarylhalides exemplified by p- bromodimethylaniline , and 2 -bromo-3 , 4 -dimethy 1-N , N- diethylaniline; heterocyclic aryl halides, exemplified by 4-bromo-10-ethyl-phenothiazine; o-bromodiphenyl- sulfone, and 4-bromobenzothiophene; and aryl halides containing other metallic or metalloidal groups, exemplified by p-bromophenyl di-n-propylarsine, and p- bromophenyl trimethylsilane.

Aryllithium compounds, for example, phenyllithium, are synthesized in a single-pot via the the reaction of monochlorobenzene with lithium dispersion in di-n-butyl ether (DBE) as shown by the following chemical equation: Equation 1

1.8 DBE

Li + PhCl > PhLi + LiCl

30 to 35RC

In order to control the exothermic reaction the mono¬ chlorobenzene is added dropwise to the stirred lithium slurry in DBE. After reaction and a minimum of two hour post-reaction time (preferably overnight) , the reaction mass is filtered to remove lithium chloride and excess lithium metal. A light amber colored solu¬ tion of phenyllithium (-25 wt. %) in DBE is obtained. The phenyllithium is stable at room temperature (20-22°C) and at elevated temperature (40°C) for at least 40 and 30 days, respectively. The final product is assayed by total alkalinity titration, Watson Eastham titration for active carbon-bound lithium, GLC for purity and by NMR analysis to determine the mole ratio of ether to phenyllithium.

The following examples further illustrate the invention. In the examples all proportions are by weight, all temperatures are in degrees Celcius (°C), and pressures are atmospheric, unless indicated otherwise.

Exemplary Run (361-72) The following materials and equipment were employed: 27.8 g lithium dispersion, 30 wt.% in mineral oil containing 0.75 wt.% Na (based on lithium content) lithium = 1.2 moles; 58.6 g monochlorobenzene (0.52 moles); 117.2 g di-n-butyl ether (0.90 moles); 10 ml phenyllithium in di-n-butyl ether (DBE) (0.021 Moles) used as lithium metal conditioner, and the following laboratory equipment: round bottom, 3 neck reaction flask (500 ml.) with a gas inlet; thermometer, filter funnel, fine porosity (500 ml) ; mechanical stirrer with associated equipment; and cooling bath (dry- ice/hexane) . All glassware was baked in an oven (-150°C) for several hours, then assembled and purged with argon until cool. To protect the final product an argon atmosphere was maintained throughout the reaction, the filtration, and packaging. Lithium dispersion (1.2 moles) was washed in the filter funnel with aliquots of hexane followed by DBE (100 ml each) and then transferred to the reaction flask along with di-n-butyl ether (117.2 g) . Next 10 ml phenyllithium solution was added to the slurry which was then stirred for ~1 hour in order to condition (activate) the lithium. The metal/organic halide reaction was then initiated by the addition of 2 ml of monochlorobenzene. The initiation was rapid as evidenced by a 6 degree rise in temperature. The remaining organic halide was added dropwise over the next 42 minutes while controlling the reaction temperature between 30 and 35^βC. The reaction mass gradually cooled to ambient during the next hour indicating some post reaction was occurring. The reaction mass was slowly stirred overnight to ensure complete reaction of the chlorobenzene.

Filtration of the final product to remove by¬ product lithium chloride and residual lithium metal was very rapid (-5 minutes) . The filter cake was stirred with an additional 50 ml of DBE which was also filtered. The DBE/filter cake wash was combined with the main filtrate to yield 182 g of a clear light amber solution of phenyllithium in DBE. Analytical Results:

Total Base = 2.32 M (24.1 wt. %) W.E. Titration = 2.28 M NMR = 2.34 M (24.2 t. %) = 2.0 mole ratio DBE/PhLi

GLC = 0% residual monochlorobenzene

Density = 0.81 g/cc Yield = 96.1 %

The procedure of this Exemplary run 361-72 was repeated a number of times in further experiments discussed herein; the experimental details are reported in the tables.

Phenyllithium was synthesized in this new process via the reaction of monochlorobenzene and lithium dispersion in a high boiling ether, di-n-butyl ether (DBE - see Equation 1) . Equation 1 shows the use of 1.8 equivalents of DBE/chlorobenzene which resulted in extremely high yields of phenyllithium (see Table III, Exp. No. 6778 - yield = 93.4%, and Exp. No. 361-72 - yield = 96.1%). Filtration of these light amber colored solutions of phenyllithium was very rapid.

The use of less ether (DBE/chlorobenzene = 0.9 mole ratio) in an attempt to produce a more concentrated phenyllithium solution (-35 wt. %) resulted in a lower yield (50.6%) indicating that more DBE was needed to obtain high yields (see Table III, Exp. No. 361-68) . Two other duplicate experiments utilizing a mole ratio of DBE/chlorobenzene = 1 and cyclohexane as co-solvent resulted in slow initiation, sluggish reaction and essentially no yield (see Table III, Exp. No. 6776 and 6777) .

Thus, to achieve high yields and sufficient con¬ centration of phenyllithium (25 wt. %) a mole ratio of at least 1.8 DBE/chlorobenzene is required. The reaction should be carried out in pure DBE containing no hydrocarbon co-solvent. Also, to avoid deactivation of the lithium the reaction should be conducted on the same day that the lithium and DBE are brought into contact. Because less fine lithium chloride is produced in the new process due to fewer side- reactions, filtration of the final product was extremely fast.

Due to fewer side-reactions phenyllithium synthesized in DBE was of very high purity. Samples of phenyllithium in DBE (see Table II, Exp. No. 6878) and a commercially available phenyllithium in ethyl ether/cyclohexane (FMC Corporation, Lithium Chemical Division Plant) were analyzed by gas liquid chromatography (GLC also termed GC) employing "active" and "hydrolyzed" injection techniques. This method differentiates between lithium bearing and non-lithium bearing species. First, an active (non-hydrolyzed) sample of phenyllithium was injected into the cool (50°C) injection port of the GLC and the volatile compounds measured were essentially zero. This GC scan was compared to a GC scan of a hydrolyzed sample of phenyllithium run under the same GC conditions to determine which compounds were non-volatile or lithium bearing species. Hydrolysis converts phenyllithium into benzene and lithium hydroxide. The results of the comparison study are shown in the following Table I. TABLE I

GLC COMPARISON PHENYLLITHIUM

SYNTHESIZED IN DBE AND IN ET₂0/CYCLOHEXANE

Compounds Detected DBE Diethyl ether/ Cyclohexane

Phenyllithium (% purity) >99 >95

Biphenyl (mole %) 0.63

Lithiated Biphenyl (mole %) 5.5

Chlorobenzene (mole %) 0(a) 0(b)

Free benzene (GLC %) 0.5 (c)

Color of solutions light black amber

a. Phenyllithium freshly prepared b. Aged phenyllithium (7 mos) c. Under these GC conditions benzene could not be separated from cyclohexane. The above Table shows that the new process produced high purity phenyllithium which contained only a small amount of non-lithiated biphenyl (0.63 mole % based on contained PhLi) . On the other hand, the commercially available phenyllithium in diethyl ether/cyclohexane solvent contained a significant amount of lithiated biphenyl and/or the lithium adduct of biphenyl (5.5 mole %) either of which, as organometallics, would enter into subsequent synthesis reactions along with phenyllithium. These lithium bearing impurities compete with desired aryllithium compounds in reactions and form unwanted products.

These impurities are present because of side reactions which occur during and after the organic halide/metal reaction. The side reactions include the following:

1. Wurtz coupling o°

cr biphenyl

2. Adduction with Lithium Metal

LI adduct

3. Metalatlon of chlorobenzeπe to form a "Benzyne" Intermediate

"Benzyne"

This coupling reaction, which not only generates both biphenyl and extremely fine lithium chloride, can be controlled by temperature of reaction, halide feed rate and use of excess lithium. Also, coupling can be affected by the polarity of the ether employed as solvent. For example, the synthesis of phenyllithium in limited THF/cyclohexane (THF/PhCl = 0.96 mole ratio) resulted in a low yield (43.9%) when all the THF was in the reaction flask at the beginning of reaction (see Table III, Exp. No. 6694). In .a duplicate experiment coupling was controlled by placing 80% of the THF in the addition funnel along with the chlorobenzene to achieve a high yield (96.4%). However, the product precipitated from solution as the l:l phenyllithium/ etherate (see Table III, Exp. No 6702) . In ethyl ether employing no co-solvent a low yield of phenyllithium (72%) was recorded (see Table III, Exp. No 4196). In pure THF Gilman(4) reported that low temperatures (-60°C) controlled coupling and obtained high yields (92%) . At higher temperatures yields were progressively worse (e.g., yield = 77% at -35°C) . Now, it has been discovered that phenyllithium can be synthesized in high yield in a totally ether solvent (DBE) . In the less labile ether (DBE) , Wurtz coupling was essentially inhibited as evidenced by the fact that only a trace of biphenyl (0.63 mole % based on PhLi content) was found in the new phenyllithium (see Table I above) .

Adduction with lithium metal can generate a biphenyl lithium adduct. In more labile ethers such as THF and ethyl ether adduction readily occurs causing the characteristic black coloration of phenyllithium. Adduction does not occur in the synthesis of phenyl¬ lithium in DBE as no lithiated aromatic species was found in the final product (see Table I, above) . Metalation of chlorobenzene to form a "benzyne" intermediate may occur. The formation of lithiated biphenyl may occur during reaction or after filtration if residual (unreacted) chlorobenzene is in the final solution. This side-reaction is slow and can be controlled by employing excess lithium metal (10 to 20%) to ensure complete reaction and sufficient post- reaction time. In DBE, this side-reaction was avoided because no lithiated biphenyl or residual chlorobenzene was found in the final filtered product (see Table I, above) . To show that side-reaction does occur 0.1 equivalents of chlorobenzene was added to 50 ml phe¬ nyllithium solution (Exp. 6778 - 2.38M.). After 36 hours no precipitation of lithium chloride was noted indicating this reaction to be slow in DBE. However, during the course of 8 days a white precipitate (LiCl) appeared on the walls of the bottle. GLC analysis using the previously described "active" and "hydrolyzed" injection techniques indicated the phenyl- lithium to contain a near quantitative amount of lithiated biphenyl.

In summary, high yields of phenyllithium can be synthesized in DBE because the known side-reactions are virtually eliminated. The final product was extremely pure containing no lithiated impurities or residual chlorobenzene.

TABLE II

THERMAL STABILITY OF PHENYLLITHIUM

IN DBE (EXP. NO.6778)

Number Temp. Total Active(1) DBE/PHLi(2) Date Days °C Base M. C-Li M. mole ratio

1/15/90 0 Start 2.38 2.35 1.90 Remarks: Solution Clear/Light Amber

1/22/90 7 40(3) 2.38 2.42 1.86 Remarks: No change in appearance

1/29/90 14 40(3) 2.40 2.32 1.88

Remarks: Solution Light Amber; Slight Amount of Solids

2/5/90 21 40(3) 2.39 2.36 1.82

Remarks: Solution Light Amber; Slight Amount of Solids

2/12/90 30 40(3) 2.38 2.42 1.82

Remarks: Solution Light Amber; Slight Amount of Solids

2/22/90 40 RT(4) 2.39 2.36 1.86

Remarks: Solution Clear, Light Amber, Slight Amount of Solids

1. Determined by W.E. titration: Watson, S.C. and Eastman, J.F., J. Organomet. Chem. 9, 165, (1967).

2. Determined by NMR analysis.

3. Sample bottles of phenyllithium were placed in a constant temperature bath (40 + 0.5°C) for the tests.

4. RT = room temperature. (20-21^βC) As Table II shows phenyllithium in DBE (24.7 wt.%) was found to be stable at an elevated temperature (40^βC) and at room temperature (20-2l°C) for 30 days and 40 days, respectively. This was shown by total bas and active carbon-lithium analyses and, also, confirme by NMR which quantitatively measured phenyllithium and di-n-butyl ether during the testing period which demonstrated that there was no cleavage of the ether o degradation of the phenyllithium. For the first time phenyllithium has been shown to be stable in a totally ether solvent.

TABLE III SYNTHESIS OF PHENYLLITHIUM IN VARIOUS SOLVENTS

TABLE III - Continued SYNTHESIS OF PHENYLLITHIUH IN VARIOUS SOLVENTS

1 Employed lithium dispersion containing 0.5 to 0.75 wt. X sodiun

2 PhCl - monoc lorobenzene

3 Active carbon-bound lithium analysis; Watson S.C. and Eastman J.F., J. Organomet Chem., 9, 165, (1976)

4 Determined by NHR

5 THF - tetrahydrofuran

6 Et₂0 - ethyl ether

7 DBE - di-n-butyl ether

8 Comparison example

9 DPE - di-n-propyl ether

10 DAE - di-n-pentyl ether

Rx flask - reaction flask

Claims

Claims;

1. A process for producing high purity thermally stable solutions of aryllithium compounds by reacting lithium metal with a monohaloaryl compound in an ethereal solvent characterized by reacting a dispersion of lithium metal with a monohaloaryl compound in an ether of the formula ROR' wherein R and R' are independently selected from alkyl radicals containing three to eight carbon atoms and the mole ratio of ether to monohaloaryl compound of at least 1.5 and the reaction temperature is maintained between 5°C and 65°C, with the proviso that the ether contains at least six carbon atoms.

2. The process of claim 1 characterized in that the monohaloaryl compound is selected from monohalobenzene, monohalbiphenylbenzene, monohalonaphthalene, monohalophenanthrene , ortho- halotoluene, meta-halotoluene and para-halotoluene.

3. The process of claim 1 or 2 characterized in that the monohaloaryl compound is selected from monochlorobenzene and monobromobenzene.

4. The process of claim 1 or 2 characterized in that the halo radical is selected from bromo and chloro. 5. The process of claim 1 characterized in that the ratio of ether to monohaloaryl compound is in the range of 1.

5-2.0 to 1.

6. The process of claim 4 characterized in that the ratio of ether to monohaloaryl compound is 1.7 to 1.

7. The process of claim 1 characterized in that the temperature is maintained between 30° and 35°C.

8. A process for producing high purity phenyl¬ lithium by reacting lithium metal with a mono- halobenzene in a liquid ether characterized by reacting a dispersion of lithium metal with a monohalobenzene selected from monochlorobenzene and monobromobenzene, the ether is selected from di-n-butyl ether, di-n- pentyl ether and di-n-propyl ether and there is a mole ratio of ether to monohalobenzene of at least 1.5 and the reaction temperature is maintained below 65^βC.

9. The process of claim 8 characterized in that the ether is di-n-butyl ether and the ratio of ether to monohalobenzene is in the range of 1.5-2.0 to l.

10. The process of claim 8 characterized in that the ratio of di-n-butyl ether to monohalobenzene is 1.7 to 1.

11. The process of claim 8 characterized in that the temperature is maintained between 30° and 35°C.

12. The process of claim 1 or 8 characterized in that the ether is di-n-propyl ether.

13. The process of claim 1 or 8 characterized in that the ether is di-n-pentyl ether.

14. The process of claim 1 or 6 characterized in that the monohaloaryl compound is selected from the group consisting of monochlorobenzene and monobromobenzene.