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Europâisches Patentamt è European Patent Office @ Publication number: 0 092 998 B1 Office européen des brevets

EUROPEAN PATENT SPECIFICATION

© Date of publication of the patent spécification : © mt. ci.*: C 07 C 41/16, C 07 C 43/10, 12.03.86 C 07 D 307/12, C 07 D 493/04 @ Application number: 83302312.0 @ Date of f iling : 22.04.83

H> Etherification process for hexitols and anhydrohexitols.

© Priority: 28.04.82 US 372623 Proprietor: ICI AMERICAS INC, Concord Pike & New Murphy Road, Wilmington Delaware 19897 (US) Date of publication of application: 02.11.83 Bulletin 83/44 Inventor: Kruse, Walter Max, 1 Woodbury Court, Wilmington Delaware 19805 (US) Inventor: Stephen, John Fergus, 200 William Penn Blvd., Publication of the grant of the patent : West Chester, PA 19380 (US) 12.03.86 Bulletin 86/11 (74) Représentative: Colens, Alain M. G. M. et al, Impérial @ Designated Contracting States: Chemical Industries PLC Légal Department: Patents AT BE CH DE FR GB IT Ll LU NL SE P.O. Box 6 Bessemer Road, Welwyn Garden City Hertfordshire AL7 1 HD (GB)

(§§) Références cited: AT- B- 258 870 DE-A-3038 996 DE -C -510423 GB -A- 988 123 ^ US-A-3840605 10

00 O) 0) CI o © Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be f iled in a written reasoned A statement. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) European patent JJj convention). ACTORUM AG , water and alkali in excess and thereafter ad- ding all at once an alkyl halide dissolved in an organic This invention is related to an improved high solvent along with a phase transfer agent. The reac- yield/low pressure process for polyetherification of tion is carried out by agitating the entire mixture until hexitol C6H8(OH)6; hexitan C6H$(OH)4 and hexide the reaction is complete. This process however re- CεHε(OH)z by the reaction of monoalkali metal quires the formation of polyalkali metal alkoxide. It alkoxides of these compounds with low molecular has now been found that the latter feature may be weight alkyl halides in aqueous solutions dispersed in detrimental for the polyalkoxylation of hexitols. organic solvents. It includes conducting the reaction It is an object therefore of the present invention to in a mixture with organic solvents and phase transfer provide for a high yield process for the polyalkylation catalysts. of hexitols and inner ethers of hexitols such as hexi- In general the method of the invention can be con- tans and hexides or isohexides to form polyalkyl sidered an improved process for conducting the inter- ethers by displacing the hydrogen on the hydroxyl action of alkaline metal alkoxide with an alkyl halide groups of these materials with alkyl groups having which is traditionally referred to as the Williamson from 1-4 carbon atoms by (a) forming an aqueous so- ether synthesis. Completely etherified anhydro- lution of the hexitol dispersed in organic solvent (b) hexitol derivatives have been described in U.S. forming a monoalkali metal alkoxide by the addition 2 234 200 and 2 420 519. The earlier patent of substantially stoicheometric amounts of sodium describes a technique for carrying out the synthesis or alkali, (c) forming a monoalkyl ether by in liquid ammonia while the latter case is directed to the addition of an alkylmonohalide having 1-4 carbon the treatment of alkali solutions of sorbide (isosor- atoms to the solution, (d) completing the polyalkyla- bide) (dianhydro-) with dimethyl sulfate. In tion by adding more alkylmonohalide with the addi- traditional commercial procedures the polyhydroxy tion of substantially stoicheometric amounts of derivatives have been treated with excess sodium hydroxide such that no more than a monoalkali metal hydroxide and thereafter reacted with alkyl chloride at alkoxide derivative is present in the solution, and (e) temperatures of 120°C and at pressures above 5,170 separating the polyalkyl ether from the reaction mix- mm Hg (100 pounds per square inch). Such high tem- ture. It is a further object to provide for a process perature reactions require special equipment, involve wherein steps (a) thru (d) is carried out in the a sizeable amount of decomposition, form products presence of a reaction promoter such as a phase which are off color and offer poor yields because of transfer catalyst. Another object includes a process incomplete alkylation and the difficulty of separating for performing steps (a) thru (c) sequentially. pure products from the reaction mixture. The process of the invention is particularly useful The present invention is directed to the stepwise in preparing fully methylated, ethylated, propylated alkylation of hexitol and anhydrohexitol derivatives in and butylated polyethers of hexitols such as sorbitol aqueous media dispersed in organic solvent. The and . In particular it is useful in preparing description of an anhydrous procedure for conduct- hexamethyl hexitols and dimethylisosorbide. The an- ing the Williamson ether synthesis in dimethylsulf- hydrohexitols are inner ethers resulting from splitting oxide has. been described by Smith, Vanderpool and off one or two moles of water from hexitol, a six car- Culak, Canadian J. Chem., 47, 1969, pages bon straight chain hexahydric . The removal of 2015-2019. When their anhydrous technique is car- one molecule of water results in the formation of a ried out in the presence of a slight excess of solid so- hexitan such as or mannitan which are use- dium hydroxide, a large amount of dimethylsulfoxide ful starting materials in the preparations of the and applied to hexitols and hexitol anhydrides, the tetralkyl ether of sorbitan and mannitan such as reaction is very slow and does not go to completion. tetramethyl and tetraethyl sorbitan. The tetramethyl An anhydrous synthesis of aliphatic ethers in dime- sorbitan has specific solvent. properties and can be thylsulfoxide employing potassium hydroxide and used as a solvent in the preparation of certain phar- alkyl bromide or sulfate is described by Benedict, Bi- maceutical bases. The removal of two molecules of anchi, and Cate in Synthesis, June 1979, page 428 water from a hexitol results in the formation of a and 429. Alkylation of primary has been hexide or iso-hexide which are dinnerethers such as demonstrated using potassium hydroxide powder sorbide or , mannide or isomannide. In par- and alkyl bromides and iodides in anhydrous ticularthe process can be applied to the manufacture dimethylsulfoxide at room temperature by Johnstone of dimethyl, diethyl, dipropyl, diisopropyl, diisobutyl, and Rose in Tetrahedron, 35, (1979), pages 2169- dibutyl, isosorbide. Such derivatives are particu- 2172. Reactions conducted with bromides and io- larly useful as solvents with special attention drawn dides are too expensive for commercial synthesis. to dimethyl isosorbide which has application in A recently issued patent U.S. 4 322 359 is direct- the preparation of pharmaceutical ointment and . ed to adding an excess of dimethyl sulfate to inner Less common hexitol such as dulcitol, ethers of sorbitol in organic solvent at low tempera- , talitol and their inner ethers can be used as ture. Another process for alkylating primary alcohols starting materials in proportions similar to those in organic solvent using a phase transfer catalyst em- described for sorbitol and mannitol and their cor- ploying excess aqueous alkali, alkyl chloride in organ- responding anhydro and dianhydro inner ethers to ic solvent is described by Freedman and Dubois. provide polyalkylated derivatives. Tetrahedron Letters No. 38, pp. 3251-3254 (1975). As alkylating agent may be employed a monoalkyl German patent application 3 038 996 directed to a chloride selected from methyl, ethyl, propyl, iso- process which requires first forming a mixture of propyl, butyl, and isobutyl chloride. The equivalent bromide and iodide may also be used if economical. ratio of dimethylsulfoxide to isosorbide in the starting The term alkyl halide refers to these compounds. mixture ranges from 0.2-1. A most preferred ratio is Polar aprotic solvents such as dimethyl formamide, 0.4-0.8. dimethylacetamide, and dimethylsuloxide may be When the reaction is run in a dispersion of an aro- used as dispersing agent for carrying out the reaction matic solvent such as toluene it is advantageous to provided that the water concentration does not ex- employ a phase transfer catalyst. The use of phase ceed about 50%. transfer catalyst in promoting the Williamson synthe- For example, dimethyl sulfoxide (CH3)2S0 (DMSO) sis is known for hydrophilic alcohols at a temperature is available commerically and may be used as the sol- below 60°C. Such catalytic materials include quar- vent when aqueous alkali is added thereto or as an ternary ammonium and phosphonium , tertiary aqueous mixture when the mol ratio of water to amines which are transformed into quarternary am- dimethyl sulfoxide does not exceed 10/1. monium salts during the reaction, strongly basic Sodium hydroxide or potassium hydroxide may be quarternary ammonium polystyrene type ion ex- added as alkali in , dry powder or change resins, and polyethylene glycols or their granules. In place of the hydroxide may be used the mono and dialkyl ethers. When the reaction is carried equivalent carbonates with somewhat lower activity. out at temperatures below 85°, quarternary ammoni- In the practice of this invention it is preferred to use um salts such as tetrabutyl ammonium sulfate, tri- a concentrated aqueous solution of potassium or so- butylhexadecyl phosphonium bromide, tetraethyl dium hydroxide and most preferred is a 50% aqueous ammonium bromide, methyltrioctyl ammonium chlo- solution thereof. ride, cetyltrimethyl ammonium bromide, ben- In general the invention is carried out by first form- zyltrimethyl , cetylpyridinium ing an aqueous solution of the hexitol or hexitol inner chloride can be useful. A certain media ether dispersed in an organic solvent such as such as Amberlite IRA-400 C.P. a strongly basic, dimethyl formamide, dimethyl acetamide, dimethyl- quarternary ammonium (polystyrene) type (aminat- sulfoxide, toluene, xylene, diethyl- ed with trimethylamine) anion exchange resin of ether, bis(2-methoxyethyl)ether and the like. This so- medium porosity is also effective as catalyst. lution is heated to a temperature of at least about Poly(ethylene glycols) and their dimethyl ethers are 60°C and most preferably 80-90°C and thereafter also useful catalysts. These catalysts are employed agitated employing efficient mixing during the addi- based on the weight of the hexitol or hexitol inner tion of the alkali such that a homogeneous mixture is ether in concentrations ranging from 1-10 mol %. maintained. The addition of alkali is controlled such The solvent which contains the alkylated hexitol that the temperature of the reaction mix does not ex- derivative may be then distilled under low pressure ceed 100 OC. Alkyl halide may be added after or simul- conditions to recover the pure derivative. It is for this taneously with the addition of alkali. reason that solvents having a boiling point in the The rate of addition of alkali to the reaction mix- range of 100-1900C be employed such that they may ture is carried out such that no more than a mono- be separated from the product by vacuum distillation. alkali metal alkoxide of the hexitol or hexitol ether is Suitable solvents such as ethylene glycol diethyl formed in the reaction mixture. This is a critical ether (b.p. 121°C), bis(2-methoxyethyl) ether (b.p. feature of the invention in that the formation of 160-163°C) and toluene (b.p. 110°C). the dialkali metal alkoxide may result in the formation The following examples are carried out in a four- of an insoluble derivative which separates from the neck, 2-literflask provided with a gas sparger a three reaction mix. inch Teflon stirrer (driven by an electric motor regulat- Upon completion of the reaction to form the fully ed by a Variac), a thermocouple connected to a tem- alkylated hexitol or hexitol inner ether derivatives the perature controller which regulates the heat input reaction mix is cooled and extracted with aromatic into the heating mantle, a dropping funnel and a con- hydrocarbons, ethers, esters, ketones or nitriles and denser (equipped with a water separator for Example in the case of dimethyl isosorbide most preferably 2) which is connected via a mercury bubbler to a dry toluene or ethyl benzene to remove the alkylated ice trap for condensing unreacted methyl chloride product from the aqueous alkali metal solution. when it is used as a methylating agent. Careful con- The pure derivative is then separated from the sol- trol of methyl chloride flow allows only a small vent extract by distillation. amount of methyl chloride to espace the reactor. It has been found that the reaction is more effec- Controling the gas flow is also achieved by placing tively carried out in a dispersion of an aromatic sol- the methyl chloride cylinder in a controllable cold vent such as toluene or aprotic solvent such as bath. The boiling point of methyl chloride is -24°C dimethylsulfoxide. An unexpected advantage offered and has a vapor pressure at 0°C of 36.6 psi (1,892 by carrying out the reaction with isosorbide to form millimeters Hg). Of course in commercial equipment dimethyl isosorbide in DMSO is that two phases are the reaction may be carried out at pressures higher formed after cooling and the addition of toluene than atmospheric pressure and corresponding higher produces an immiscible toluene/dimethyl isosorbide temperatures of 120°C or thereabouts. layer and dimethyl sulfoxide/water/alkali chloride salt layer. Example 1 The reaction be carried out in relatively small may Hexamethyl sorbitol amounts of solvent. For example, when dimethylsulf- oxide is used in the preparation of dimethyl isosor- 182 g sorbitol (1 ) and 300 milliliters dimethyl bide excellent results are obtained when the molar sulfoxide (DMSO) were charged to the flask de- scribed above. The Variac was set such that the stir- yield a 185 g portion (43%) tetramethyl 1,4 sorbitan rerturned at about 650 rpm. The mixture was heated by distillation at 120°C at 6 mm Hg. to a temperature of 80°C at which time methyl chlo- 1.44543 (20°C); viscosity 7.4768 centipoise ride was slowly added and 50% aqueous sodium (20°C). hydroxide solution was permitted to drop into the so- lution. The temperature was permitted to rise to Example 3 85°C and held at that temperature as near as possi- Dimethyl Isosorbide ble throughout. The addition of 160 g 50% sodium hydroxide solution (2 moles) was completed after 300 g isosorbide (2 moles) and 165 g DMSO were one hour. 160 g (4 moles) sodium hydroxide pellets in charged into the equipment described above and portions of about 20 g were added over a period of heated to 80°C. Methylchloride gas was passed into two hours. The reaction mixture was then cooled to the reaction mixture through the sparger and 480 g room temperature and filtered to remove sodium of 50% sodium hydroxyde solution (6 moles) was ad- chloride precipitate. The filtrate was returned to the ded dropwise. The temperature went to 85°C and reactor and heated again to 8 5 ° C after which two 20 was controlled at that temperature by control of the g portions of sodium hydroxide pellets were added sodium hydroxide addition. The agitator was operat- and stirred for an additional four hours under continu- ed at 650 rpm to achieve good liquid gas mixing. The ous methyl chloride sparging. Analysis indicated the addition of sodium hydroxide solution was complete formation of penta and tetramethyl sorbitol. The within two hours. The reaction was terminated after reaction mixture again was filtered and the filtrate an additional two hours, cooled and filtered to remove was concentrated to remove water. The concentrat- precipitate. The filtercake was ed filtrate was placed back into the reactor with an washed with 300 ml of toluene which was added to additional 100 ml DMSO added and after the temper- the filtrate which was placed in a 2 liter separatory ature had reached 85°C 80 grams of 50% sodium funnel. After a brief intensive shaking two phases hydroxide was added and methyl chloride sparging separated within minutes. The aqueous layer was continued. After 1.5 hours the reaction was complete again extracted with 300 ml toluene for the second with the formation of hexamethyl sorbitol. The salt extraction and again with 200 ml tolueneforthethird was removed by filtration and the filtrate was three extraction. To avoid the filtration of sodium chloride times extracted with 300 ml portions of toluene in a 300 ml of toluene can be added to the vigorously two liter separatory funnel. After intensive shaking stirred reaction mixture. After the stirring was two phases separated within a few minutes after stopped the toluene phase was syphoned off to which the toluene layer was removed and collected. remove the produced dimethyl isosorbide from the The toluene was removed by distillation in a rotary aqueous DMSO/sodium chloride salt phase. The evaporater whereupon hexamethyl sorbitol contain- phase separation can be speeded up by addition of a ing less than about 0.5% DMSO and toluene re- minor amount of acid to the aqueous phase. After mained. The hexamethyl sorbitol is distilled at 121 ° C removal of toluene in the rotary evaporator 180 g under 5 mm Hg pressure, 175 g of hexamethyl sor- dimethyl isosorbide was distilled at 21 mm Hg pres- bitol (67% yield) having a refractive index 1.43564 sure at 125°C for a yield of about 83.5%. (20°C) and a viscosity of 10.3654 centipoises (20°C). Example 4 Dimethyl lsosorbide Example 2 In described above 400 ml Tetramethyl 1,4 Sorbitan equipment was placed toluene 20.4 g (60 millimoles, 3 mole percent) 364 g sorbitol (2 moles), 600 ml toluene and 1 g tetrabutyl ammonium hydrogen sulfate, 300 grams concentrated sulfuric acid were placed into the isosorbide (2 moles) which was heated under stirring equipment described above. The reaction mixture (at least 650 rpm) to 85°C. Methyl chloride gas was was heated to reflux temperature and 40 ml water added and the addition of 480 g sodium hydroxide (2.2 moles) was collected by azeotropic distillation (50% solution) was added over a period of two hours. within 6 hours. The toluene phase was decanted and The reaction dispersion was permitted to agitate for the sorbitan formed was dissolved in 300 ml DMSO an additional five hours after which it was cooled and and placed into the reactor together with 3 ml 50% filtered to remove sodium chloride. The filtrate was sodium hydroxide. placed in a 2 liter separatory funnel and the layers per- The reaction mixture was brought to 85°C. Methyl mitted to separate. The aqueous phase was separat- chloride was added through the sparger system and ed and extracted with 2 portions of 200 ml of toluene. 480 g of 50% sodium hydroxide (6 mole) solution The organic phase and toluene washes were com- was added aver a period of two hours. An additional bined and washed with 200 ml of 50% sulfuric aicd. 80 g of hydroxide pellets were added in 10 g portions The toluene phase after separation was placed in a over the next two hours. The mixture was cooled and rotary evaporator after which the residue was dis- filtered to remove sodium chloride after which the tilled to remove dimethyl isosorbide in a yield of about filtrate was added to the flask and heated to 85°C 80.5%. with an additional 80 g of sodium hydroxide (2 moles) Examples 3 and 4 were repeated for Examples 5-18 pellets added at 85°C aver a period of one hour. using varying amounts of ingredients and are listed in The reaction mixture was cooled extracted with Tables 1 and 2. Total yields as reported in Column 6 toluene and distilled as described in Example 1 to were determined by gas-liquid chromatographic (GLC) techniques from samples of the reaction mix. starting with sorbitol to produce isosorbide which is Recovered yields are reported in the Table. Examples then methylated and recovered from the pot by direct 19-24 listed in Table 3 describe a one pot technique distillation therefrom. 1. A process forthe polyalkylation of a hexitol and 1. Verfahren für die Polyalkylierung eines Hexits inner ether derivatives thereof to form polyalkyl ether und innerer Etherderivate davon zur Bildung von Poly- derivatives by addition of alkyl monohalide having 1 alkyletherderivaten durch Addition von Alkylmono- to 4 carbon atoms to said hexitols in the presence of halogenid mit 1 bis 4 Kohlenstoffatomen an die Hexi- sodium or potassium alkali in an aqueous solution te in Gegenwart von Natrium- oder Kaliumalkali in ei- said hexitols being present in said aqueous solution ner wässrigen Lösung, wobei die Hexite in der wässri- dispersed in an organic solvent such as dimethylsulf- gen Lösung in einem organischen Lösungsmittel wie oxide, dimethylformamide, toluene, xylene, bis(2- z.B. Dimethylsulfoxid, Dimethylformamid, Toluol, Xy- methoxyethyl)ether or ethyleneglycoldiethyl ether lol, Bis(2-methoxyethyl)ether oder Ethylenglykoldi- characterised in that said alkyl halide and said alkali ethylether dispergiert vorhanden sind, dadurch ge- is added in subsantially stoechiometric amounts kennzeichnet, dass das Alkylhalogenid und das Alkali such that no more than a mono-alkali metal alkox- in im wesentlichen stöchiometrischen Mengen der- ide derivative is present at any time in said disper- art zugegeben werden, dass in der Dispersion zu kei- sion. ner Zeit mehr vorhanden ist als ein Monoalkalimetall- 2. The process of claim 1 wherein the addition is alkoxidderivat. carried out at a temperature of 60-120°C. 2. Verfahren nach Anspruch 1, bei dem die Zugabe 3. The process of claim 1 wherein the addition is bei einer Temperatur von 60 bis 120°C durchgeführt carried out at 80-90°C. wird. 4. The process of claim 1 wherein said hexitol and 3. Verfahren nach Anspruch 1, bei dem die Zugabe inner ethers thereof are selected from sorbitol, bei 80 bis 90°C durchgeführt wird. mannitol, sorbitan, mannitan, isosorbide and iso- 4. Verfahren nach Anspruch 1, bei dem der Hexit mannide. und seine inneren Ether aus Sorbit, Mannit, Sorbitan, 5. The process of claim 1 wherein said inner ether Mannitan, Isosorbid und Isomannid ausgewählt sind. is isosorbide, said alkyl halide is methyl chloride and 5. Verfahren nach Anspruch 1, bei dem der innere said organic solvent is selected from dimethyl sulf- Ether Isosorbid ist, das Alkylhalogenid Methylchlorid oxide, toluene and mixtures thereof. ist und das organische Lösungsmittel aus Dimethyl- 6. The process of claim 1 wherein the organic sol- sulfoxid, Toluol und Mischungen davon ausgewählt vent is dimethylsulfoxide and there is further carried ist. out a solvent extraction using a non polar aromatic 6. Verfahren nach Anspruch 1, bei dem das organi- solvent to remove the completely alkylated product sche Lösungsmittel Dimethylsulfoxid ist und bei dem from the dimethyl sulfoxide-water-chloride salt ferner eine Lösungsmittelextraktion unter Verwen- residue. dung eines nichtpolaren aromatischen Lösungsmit- 7. The process of claim 6 wherein said aromatic tels durchgeführt wird, um das vollständig alkylierte solvent is toluene. Produkt aus dem Dimethylsulfoxid/Wasser/Chlorid- 8. The process of claim 1 wherein the reaction is salz-Rückstand zu entfernen. carried out using an aromatic solvent and a phase 7. Verfahren nach Anspruch 6, bei dem das aro- transfer catalyst. matische Lösungsmittel Toluol ist. 9. The Process of claim 9 wherein said phase 8. Verfahren nach Anspruch 1, bei dem die Umset- transfer catalyst is selcted from the group consisting zung unter Verwendung eines aromatischen Lö- of tetrabutyl ammonium bromide and tetrabutyl am- sungsmittels und eines Phasenübergangskatalysa- monium sulfate. tors durchgeführt wird. 9. Verfahren nach Anspruch 8, bei dem der Pha- 3. Procédé suivant la revendication 1, dans lequel senübergangskatalysators aus der Gruppe ausge- l'addition est exécutée à 80-90 °C. wählt ist, die aus Tetrabutylammoniumbromid und 4. Procédé suivant la revendication 1, dans lequel Tetrabutylammoniumsulfat besteht. l'hexitol et ses éthers internes sont choisis parmi le sorbitol, le mannitol, le sorbitane, le mannitane, l'iso- sorbide et l'isomannide. 5. Procédé suivant la revendication 1, dans lequel l'éther interne est l'isosorbide, l'halogénure d'alcoyle 1. Procédé de polyalcoylation d'un hexitol et d'un est le chlorure de méthyle et le solvant organique est éther interne de celui-ci pour la formation d'éthers choisi entre le diméthylsulfoxyde, le toluène et leurs polyalcoyliques par addition d'un monohalogénure mélanges. d'alcoyle de 1 à 4 atomes de carbone à ces hexitols 6. Procédé suivant la revendication 1, dans lequel en présence d'alcali sodique ou potassique dans une le solvant organique est le diméthylsulfoxide et on solution aqueuse, ces hexitols étant présents dans la exécute en outre une extraction en solvant à l'aide solution aqueuse en dispersion dans un solvant orga- d'un solvant organique non polaire pour séparer le nique tel que le diméthylsulfoxyde, le diméthylform- produit complètement alcoylé du résidu de chlorure amide, le toluène, le xylène, l'éther bis(2-méth- de sodium, d'eau et de diméthylsulfoxyde. oxyéthylique) ou l'éther diéthylique d'éthylèneglycol, 7. Procédé suivant la revendication 6, dans lequel caractérisé en ce que l'halogénure d'alcoyle et l'alcali le solvant aromatique est le toluène. sont ajoutés en quantités sensiblement stoechiomé- 8. Procédé suivant la revendication 1, dans lequel triques de façon qu'il n'y ait à tout moment dans la la réaction est exécutée à l'aide d'un solvant aromati- dispersion pas plus qu'un alcoolate de monométal que et d'un catalyseur de transfert de phase. alcalin en présence. 9. Procédé suivant la revendication 8, dans lequel 2. Procédé suivant la revendication 1, dans lequel le catalyseur de transfert de phase est choisi dans la l'addition est exécutée à une température de 60 à classe formée par le bromure de tétrabutylammo- 120°C. nium et le sulfate de tétrabutylammonium.