[CONTRIBUTION FROM
THE
CHEMISTRY DEPARTMENT, PURDUE UNIVERSITY]
THE PREPARATION AND PROPERTIES OF 2,3,4,6-TETRAETHYL-cL-METHYL-~-GLUCOSIDEAND OF
2,3,4,6-TETRAETHYL-d-GLUCOSE* ALGIE R. PADGETT
WITH
ED. F. DEGERING
Received August 18, 1936
Methylated derivatives of d-glucose have been known for many years but very few references to ethylated derivatives occur in the literature. In his bibliography on the alkylation of d-glucose,' Coles states that the 2,3,6-triethylethylgluco~ide~ has been prepared from triethylcellulose. This glucose derivative is a colorless, mobile oil (b.p. 120-5"/0.2 mm.), strongly refractive and soluble in water and most organic solvents. Triethylglucose has been studied by means of X-ray diagram^,^ and other references to it occur in the l i t e r a t ~ r e . ~Reference is made to 2,3,5,6tetraethylglucose, but it has not been obtained in a pure form.2 X o other ethylated products of d-glucose are mentioned in this bibliography,' but Muskat reports the preparation and identification of 3-ethyldiacetoneglucose.6 With a view to a forward step in the study of such higher alkyl derivatives as well as to establish an additional reference compound for work upon more complicated carbohydrate materials, the preparation of 2,3,4,6-tetraethyl-d-glucosewas undertaken. Of particular importance in the successful termination of the research was the application to carbohydrate chemistry of low-pressure fractionation of the intermediate glucosides by means of a modified Podbielniak column. There are, in general, three procedures that have been used for the methylation of the carbohydrates. Purdie and Irvinec introduced the use of methyl iodide in the presence of silver oxide as a methylating agent for the glucosides. Somewhat later this procedure was largely re-
* Abstract of a Master's Thesis presented to the Faculty of the Graduate School of Purdue University by Algie R. Padgett. This paper was presented before the Organic Division a t the ninety-first meeting of the American Chemical Society, Kansas City, April 14, 1936. 1 COLES,Iowa State Call. J . Science, 6 , 33-42, 43-64 (1932). HESS A N D TROGENS, Ber., 61, 1982-96 (1928); HESS AND MULLER,Ann. 4SG, 94-9 (1928). HEW AND SALZMANN, Ann., 446, 111-22 (1925). HESSAND MULLER,ibid., 466,205-14 (1927); HESS,WITTLESBACH AND MESSNER, 2. a n g m . Chew., 34, 448-54 (1921). MUSICAT, J. Am. Chein. SOC.,lis, 693-5, 2449-3 (1934). 6 PURDIE AND IRVINE, J . Chem. Sot-., 83, 1021 (1903); 8G, 1049 (1904). 336
2 3,4
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~-TETRAETHYL-~-GLUCOSE
placed by the use of methyl sulfate in the presence of sodium hydroxide.' The mLethyl sulfate procedure has recently been modified so that it is now possible t o methylate sugars directly by using carbon tetrachloride as a A more recent method consists in the use of methyl iodide or methyl sulfate in the presence of liquid ammonia as the solvent.6 By this means the direct methylation of d-glucose has been effected and the possibility of the preparation of higher alkyl derivatives is indicated. ,4 suitable modification of certain of these methylation procedures made possible the preparation of the desired compounds. EXPERIMENTAL Preparation of 2,3,4,6-Tetraethyl-a-rnethyl-d-glucoside.-The 2,3,4,6-tetraethylwmethyl-d-glucoside was prepared from a-methyl-d-glucoside by the procedure of Haworth,' with certain modifications by Greene and others,* followed by a final ethylation by the procedure of Purdie and The a-methyl-d-glucoside 'cvas prepared according to Organic Syntheses.10 The first four ethylations were carried out in a five-liter three-necked flask fitted with a mechanical stirrer, thermometer, reflux condenser, and two burets: one for the introduction of the ethyl sulfate and the other for aqueous sodium hydroxide. The flask was heated by means of a water bath. A 240-g. portion of a-methyl-dglucos,de, dissolved in 500 cc. of water, was placed in the ethylation flask. The temperature was raised to 80°, and 2100 cc. of ethyl sulfate and 1350 cc. of 50% sodium hydroxide (50 g. NaOH in 100 cc. of solution) were added dropwise over a period of six hours, the addition being so adjusted that the solution was a t all times slightly alkaline to phenolphthalein (a drop of which was added every few minutes). The bath was then raised to boiling, maintained a t that temperature for about thirty minuhs, and allowed to cool. A yellowish-red oil separated. The solution was then extracted with four 300-cc. portions of chloroform; the chloroform extract was dried and filtered, and the solvent was removed by distillation up to 60" on a water bath under a pressure of 25 mm. About 200 cc. of a yellow sirup was obtained. An analogous procedure was followed in the second and third ethylations except that 200 cc. and 50 cc., respectively, of carbon tetrachloride were used to dissolve the partially ethylated glucoside. In the fourth ethylation no solvent m-as used, the concentration of the alkali was increased to 60%, and one-half amounts of ethyl sulfate and alkali were used.i The chloroform extract from the final ethylation was treated with Norite, filtered, and dried over sodium sulfate, and the solvent was removed by evaporation to give a residue of 150 cc. of crude ethylated glucoside. This product was then subjected to a fifth ethylation by permitting i t t o reflux for six days with 150 g. of ethyl iodide and 90 g. of silver oxide. The mixture was extracted with chloroform, and the extract was dried and fractionated through a distilling flask to give a colorless, thin sirup (b.p. 95-100"/0.1 mm.). Then, 108 cc. z9
HAWORTH, ibid., 107,8 (1915); HAWORTH AND LEITCH,ibid., 113, 188 (1918). WESTAND HOLDEN, J . Am. Chern. SOC.,66, 930-2 (1934). GREENEAND LEWIS,ibid., 60, 2813-25 (1928). l o HELFERICH AND SCHAFER, Organic Syntheses, 6, 64 (1926); Collective Volume I, pp. 3(56-7. t 8ubsequent work in this laboratory raises some doubt as to the advisability of re-ethylation. 8
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ALGfE 8. PADGE'B' WITH ED. F. DEGERING
of sirup was fractionated and refractionated through a modified Podbielniak column of 10-mm. glass tubing containing a twenty-inch spiral of tantalum wire. The distillate was tested hourly with an Abbe refractometer, and a fraction of 79 cc. which showed no variation in refractive index was obtained. Four carbon determinations on this product by the wet method" gave 58.7 f 0.1% as compared with a theoretical value of 58.787,. Molecular weight determinations in nitrobenzene showed an average of 299 g. per mole as compared with the theoretical value of 306.24 g. per mole. The glucoside is a colorless, rather sirupy liquid [b.p. 94-6"/0.15 mm., 97-100"/0.2 mm.; [a]: +76.5" (c = 5 in ethyl alcohol)], which is quite soluble in chloroform, alcohol, ether, petroleum ether, ethylene bromide, and nitrobenzene but only slightly soluble in water. Maintenance of the glucoside in a solid carbon dioxide-alcohol mixture for 24 hours with frequent scratching failed to produce crystallization. Preparation of I,$ ,4,6-Tetraethyl-d-glucose.-2,3,4,6-Tetraethyl-d-glucose was prepared by the hydrolysis of the corresponding methylglucoside (40 9.) by digesting it in an aqueous solution (8% HCI, 9.9% glucoside), under vigorous stirring, on a water bath for a period of four hours.9.12 The solution was then allowed to cool, and was extracted with four 50-cc. portions of chloroform. The chloroform extract was decolorized with two grams of Norite, filtered, and dried with calcium chloride, and the solvent was removed by evaporation. The light yellow residue, amounting to about 35 cc., was dissolved in an equal volume of low-boiling petroleum ether and allowed to stand in the ice-box with frequent scratching for two days to give about 2 g. of small, very slender needles. Continued crystallization for ten days, yielded about 10 g. of crude tetraethyl-d-glucose (m.p. 70-7") and about 20 cc. of viscous sirup which continued to yield crystals. The 10 g. of crude product, upon two recrystallizations from petroleum ether, yielded 8 g. of slender, white, lustrous, fluffy needles of 2,3,4,6-tetraethyl-d-glucose (m.p. 80-2'). Carbon determination by the wet methodll gave 57.6 f O.l%, as compared with a theoretical value of 57.49%. Molecular weight determinations in nitrobenzene gave 289 g. per mole, as compared with a theoretical value of 292.224 g. per mole. +95.9" (c = 2). The 2,3,4,6Measurement of the rotation in ethyl alcohol gave [a]," tetraethyl-d-glucose is soluble in water, chloroform, alcohol, ether, ethylene bromide, and nitrobenzene. It is soluble in warm low-boiling petroleum ether but only slightly soluble a t 0". In assigning the structures to the derivatives obtained in this work i t was assumed, in accordance with the work of previous investigators, that the pyranoid ring structure of a-methyl-d-glucoside is stable to subsequent alkylation. If this assumption is correct, the delta hydroxyl group would be linked up in the pyranoid ring structure and would not be subject to ethylation. The product obtained, in which four ethyl groups had been introduced, therefore, must be the 2,3,4,6-tetraethyl-a-methyl-d-glucoside, and the hydrolytic product must be 2,3,4,6-tetraethyld-glucose. BUMMARY
2,3,4,6-Tetraethyl-a-methyl-d-glucosideand 2,3,4,6-tetraethyl-d-glucose have been prepared, and some of their properties are described. The use of a modified Podbielniak column made possible the successful fractionation of the ethylated methylglucosides. l1 12
POLLARD AND FORSEE, Ind. Eng. Chem., Anal. Ed., 7,77 (1935). IRVINEAND MOODIE,J . Chem. SOC.,87, 1465 (1905).
