[CONTRIBUTION FROM THE
LABORATORIES OF GORDON A.
ALLES]
A CONVENIENT SYNTHESIS OF dl-SERINE C. ERNST REDEMANN
AND
ROLAND N. ICKE
Received November 30, 19@
The increased use of synthetic amino acids in biochemical, physiological and pharmacological investigations has stimulated the study of improved methods for their syntheses. While the synthesis of dl-serine has been considerably improved by several investigators (1,2, 3,4) within the last decade, each of these methods has certain undesirable features. The method of Dunn and co-workers (1) is inconvenient because of the low yield of ethoxyacetaldehyde obtained and of the necessity of using liquid hydrogen cyanide. The procedures of Schiltz and Carter (2), and Carter and West (3) require large quantities of mercury salts, which make the process expensive regardless of whether the mercury is recovered or discarded. This difficulty was overcome by Wood and du Vigneaud (4), but as a portion of their synthesis has to be carried out in a steel pressure vessel, the runs either have to be small or else some additional investment in equipment is necessary. The present method starts with the very inexpensive “Cellosolve” (6-ethoxyethanol) and arrives a t the desired dl-serine in what is essentially a two-step process, using only very inexpensive reagents and apparatus. While Drake and co-workers ( 5 )report that zinc chromite and copper chromite catalysts were unsatisfactory for the dehydrogenation of methoxy- and ethoxyethanols, in a patent issued to Drake (6) a year later, it is stated that the most satisfactory catalyst found for this dehydrogenation was one containing chromium oxide, prepared according to the method of Young (7). In a very recent patent granted Gresham (8), a copper-chromium oxide catalyst was employed for the dehydrogenation. The catalyst adopted by the authors is the standard copper chromite catalyst described by Lazier and Arnold (9). While this catalyst gives yields somewhat less than reported by Drake ( 5 , 6), it is a standard product, kept on hand a t all times by many laboratories, thus in many cases avoiding the preparation of a special catalyst. The catalyst was activated by passing isopropanol vapor over the hot catalyst prior to use in a manner similar to that of Young ( 7 ) . The presence of chromium in the catalyst greatly lessens the tendency of the catalyst to become inactive in use. The modified Strecker reaction, using sodium cyanide and ammonium chloride, has not been successfully applied t o ethoxyacetaldehyde before. By combining the modified Strecker reaction and a simplified method of isolation, the time yield of dl-serine has been greatly improved; the percentage yield, however, is not much superior to existing methods of preparation. The best alternate method, that of Wood and du Vigneaud (4), gives the excellent over-all yield of 47%. The somewhat older method of Carter and West (3) gives an over-all yield of 30-40%, but requires 7-10 granls of mercuric acetate to produce one gram of dl-serine. The present method gives a 51y0yield, based upon ethoxyacetaldehyde. 159
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C. E . REDEMANN AND R. N. ICKE
EXPERIMENTAL
Ethozyucetaldehyde. Cellosolve was vaporized through an electrically heated catalyst chamber containing copper chromite catalyst (9). Two styles of catalyst chambers were tried without significant difference in results; one was a horizontal Pyrex glass tube heated in a n electric furnace, the other was a vertical Pyrex glass column heated by a chromel resistance wire wrapped on asbestos paper. Only the latter will be described here. A side arm, diameter 11mm., and a bottom tube, diameter 16 mm., were sealed to a 60 cm. length of Pyrex glass tubing, inside diameter 28 mm., to form a large Hempel column. On the lower 45 cm. of the large tube was wound 28 feet of No. 24 B. & S. gauge chromel resistance wire over a single layer of asbestos paper moistened with a 2% solution of sodium silicate. The wire was then covered with three layers of asbestos paper in a similar manner, and the column was dried in a warm place overnight. The catalyst was made into a thick paste with water and smeared onto 25 mm. disks of copper wire screen (copper window screen). These disks were dried in an oven at 110" and were then placed in the Pyrex glass column, spaced by 20 mm. sections of 25 mm. thin-walled brass tubing, until a catalyst zone 40 cm. in length had been formed. A 360" thermometer extended 10 cm. into the heated zone through the top of the column. The temperature of the reaction zone was adjusted with a Variac transformer. The column was fitted to a 1-liter two-necked flask with a dropping-funnel in one neck. The vapors were condensed with a water-cooled condenser and the distillate colllected in a suitable receiver cooled by an ice-bath. About 50 g. of isopropanol was slowly distilled through the dehydrogenator while i t was being warmed t o the proper temperature, so that all the air was displaced and only vapor remained in the reaction zone. Hydrogen was evolved quite vigorously when the temperature reached 275-280'. When the temperature had risen to 310°, the last of the isopropanol was driven through the column and Cellosolve was then distilled a t the rate of 100 g. per hour while maintaining the temperature at 310330". The rate of gas evolution with Cellosolve was markedly less than with isopropanol, but this rate continued without diminution during a run lasting 7 hours. When the distillation of isopropanol was omitted, the catalyst rapidly lost its activity. The distillate from the above process was fractionally distilled through an 80 cm. Hempel column filled with 6 mm. glass Raschig rings and having a partial condenser a t the head to increase the reflux ratio. The fraction collected boiled a t 96-107" and showed 85% aldehyde content when analyzed by the method of Donnally (10). The yield was 3035% based upon unrecovered Cellosolve. dl-Serine. T o 80 cc. of an ice-cold saturated solution of ammonia in methanol was added 68 g. of %yoethoxyacetaldehyde, and the mixture was allowed to stand in the refrigerator for one-half hour or longer. I n the meantime, a solution of 38 g. of sodium cyanide in 80 cc. of water and a solution of 46 g. of ammonium chloride in 125 cc. of water were prepared and mixed just prior to using. The aldehyde-ammonia and ammonium cyanide solutions were then mixed. The dark-colored solution which was formed, gradually became lighter in color during the first half hour. After standing at room temperature for 18 hours the clear red solution was poured, while stirring, into 400 cc. of 48% hydrobromic acid (hood: hydrogen cyanide). The nearly black solution was slowly distilled until the vapor temperature reached 110". An additional 100 cc. of 48% hydrobromic acid was added and disdistillation was continued very slowly as long as any additional ethyl bromide was formed (4-6hrs.). The liquid in the boiler was cooled to room temperature, the salts which separated were removed by filtering, and the filter cake was washed with ethanol until nearly colorless. The combined filtrate was evaporated t o dryness under reduced pressure (boiling water-bath). An additional 100 cc. of water was added and the evaporation was repeated t o remove the excess hydrobromic acid as completely as possible. The residue was extracted with 400 cc. of 90% ethanol divided into three portions, the insoluble salts were removed by filtering and rinsed well with ethanol. The combined alcoholic solution was neutralized with concentrated aqueous ammonia until a faint permanent odor of ammonia was present, and the solution was placed in the refrigerator t o cool over-
SYNTHESIS OF &SERINE
161
night. The crystals which separated were filtered off, sucked dry, washed with methanol until nearly colorless, and dried. The dry product weighed 35.1 g. (51% of theory based upon 85% aldehyde content). This faintly colored product was rendered completely pure by dissolving in 150 cc. of boiling water, treating with 3 g. of decolorizing carbon and filtering while hot. The hot, crystal-clear, colorless solution was treated with an equal volume of ethanol and placed in the refrigerator t o cool for several hours. The colorless crystals, which were filtered off, washed with ethanol followed by ether, and dried, weighed 33.0 g. Anal. Calc'd for C ~ H I N ON, ~ : 13.33. Found: N, 13.4, 13.2 (Kjeldahl).' The product commenced to turn brown at 228" (corr.) and melted with gaseous decomposition a t 243-244' (corr.), which is in good agreement with the value reported by Wood and du Vigneaud (4). SUMMARY
Ethoxyacetaldehyde was prepared in 35% yield from inexpensive p-ethoxyethanol (Cellosolve) by catalytic dehydrogenation over a copper chromite catalyst at 310-330'. From this aldehyde dl-serine was obtained in 51% yield by the modiiied Strecker reaction. 770 S. ARROYO PARKWAY, PASADENA, CALIF. REFERENCES (1) DUNN,REDEMANN, AND SMITH,J. B i d . Chem., 104, 511 (1934). (2) SCHILTZAND CARTER,J . B i d . Chem., 116, 793 (1936). (3) CARTERAND WEST, Organic Syntheses, 20, 81 (1940). (4) WOOD,AND DU VIGNEAUD, J. B i d . Chem., 134, 413 (1940). THOMPSON, AND SONNICHSEN, J. Am. Chem. SOC.,60, 73 (5) DRAKE,DUVALL,JACOBS, (1938). (6) DRAKE,U. S. Patent 2,170,854. (7) YOUNG,U. S. Patent 1,977,750. (8) GRESHAM, U. S. Patent 2,286,034. Organic Syntheses, 19, 31 (1939). (9) LAZIERAND ARNOLD, (10) DONNALLY, Znd. Eng. Chem., Anal. Ed., 6, 91 (1933).
* The authors wish to thank Mr. Burnett B. Wisegarver for the Kjeldahl analyses reported in this paper.
