Because of the practical limitations inherent in the equilibria represented by Equation 2, the higher aluminum alkyls obtained by the present procedure contain small amounts of ethylaluminum groups, as shown in Table I. Aluminum alkyls prepared by the present method have been air-oxidized according to the procedure of Ziegler ( 3 ) . Hydrolysis of the resulting aluminum alkoxides gave the corresponding alcohols in excellent yields, based on starting olefin.
realized with the diisobutylaluminum hydride method. In commercial use this problem may be minimized by regeneration of diethylaluminum hydride from triethylaluminurn by the Ziegler synthesis ( 5 ) ,
4 Al(C2Hs)a
+ 2 A1 + 3 Hz
+6
Al(CzHs)?H
(6)
+ CZHB
(7)
or by hydrogenation ( 7 ) .
Al(CzHs)s
+ Hz
+
(CzH6)zAlH
Conclusions Discussion The present method for the preparation of higher aluminum alkyls has the advantage of a mild temperature and short reaction time. Under these conditions alkyl dimerization (Equation 4) is prevented. (RCHzCHz)sAl*
RCHCHz-AI-H
I
I
(4)
RCHzCHz CHzCHzR This is in contrast to the diisobutylaluminum hydride method ( 6 ) ,
3 RCH=CH?
+ [(CH~)ZCHCH~]~AIH
Higher aluminum alkyls may be rapidly and conveniently prepared from higher olefins and diethylaluminum hydride, although the aluminum alkyl product is contaminated with ca. 15 to 25 mole % ethylaluminum groups. The diisobutylaluminum hydride method for the preparation of higher aluminum alkyls requires about three times as much processing time but gives a product substantially free of lower alkyl groups. The economic feasibility of the diethyIaluminum hydride method is critically dependent on the extent to which ethylaluminum groups in the product may be tolerated and the availability of facilities for the use or re-use of by-product trie thylaluminum.
+
(RCHzCH2)aAl
+ 2 (CHJzC=CHz
(5)
which we have often observed to give ca. 5 to 10 mole % of alkyl dimer. Two primary disadvantages are inherent in the present method. The retention of ethylaluminum groups in the product precludes the preparation of pure higher aluminum alkyls. Secondly, the present method uses directly only one third of the available organoaluminum groups, while the other two thirds are recovered as triethylaluminum. In contrast, almost complete utilization of all organoaluminum groups is
literature Cited (1) Podall, H. E., Petree, H. E., Zietz, J. R., J. Org. Chem. 24, 1222 (1959). ( 2 ) Wanninen, E., Ringbom, A., Anal. Chim. Acta 12, 308 (1955). (3) Ziegler, K., Experientia, Suppl. 2, 14‘ Congr. intern. chim. pure appl., Zurich, 274 (1955). (4) Ziegler, K., “Organometallic Chemistry,” H. Zeiss, ed., pp. 194-269, Reinhold, New York, 1960. (5) Ziegler, K., Gellert, H.-G., Lehmkuhl, H., Pfohl, W., Zosel, K., Ann. 629, 1 (1960). (6) Ziegler, K., Martin, H., Krupp, F., Ibid., p. 14. RECEIVED for review September 20, 1963 ACCEPTED December 23, 1963
RECYCLING PROCESS FOR THE COMMERCIAL PREPARATION OF 1=METHY LPY RI D I N I U M= 2-ALDOXIME CHLORIDE R 0 B E R T I . E L L I N , Physiological Chemistry Branch, Physiology Division, Edgewood Arsenal, M d . A process has been developed for the preparation of 1 -methylpyridinium-2-aldoxime chloride (2-PAM-CI) b y simply heating the corresponding iodide salt (2-PAM-I) with methanolic hydrogen chloride. The yields are high, and the resulting product is white and does not require recrystallization. Methyl iodide, recovered as a by-product in 80y0 yields, may be made to react with pyridine-2-aldoxime to prepare additional starting product for the reaction.
of 1-methylpyridinium-2-aldoxime chloride be effective as antidotes when administered to animals and humans exposed to organophosphorus cholinesterase inhibitors. If the oxime is to be stockpiled for service or civilian use, a process for its large scale manufacture is required. Three procedures are known for the preparation of 2PAM-Cl : (A) 1-methylpyridinium-2-aldoximeiodide (2OmmATIoNs
C (2-PAM-C1) and atropine have proved to
20
I & E C PRODUCT RESEARCH A N D DEVELOPMENT
PAM-I) is made to react with a suspension of silver chloride in water ( 6 ) ; (B) 2-PAM-I may be passed over a chloride exchange resin (6) ; (C) pyridine-2-aldoxime (P-2-A) is made to react with methyl chloride in dimethylformamide (DMF) in a closed reaction vessel ( 3 ) . The cost of the silver chloride makes Procedure A expensive. Furthermore, the resulting white 2-PAM41 crystals turn gray on storage, probably because of traces of silver ion. Because
2-PAM-I is only slightly soluble in water, about 3% a t 25’ C., high ion exchange columns would be required in Procedure B, and large volumes of water would have to be evaporated to recover the more soluble 2-PAM-C1. Procedure C may have commercial application. However, the reaction must be run under pressure and a yield of only SOY0 is obtained after 22 hours. The resulting product is dark gray and must be recrystallized. The solvent, DMF, has been reported to have toxic properties ( 7 ) and removal of the solvent would be a necessary precaution. In the method presented below, 2-PAM-I is added to methanolic HC1 and the resulting mixture heated for 45 minutes. The corresponding chloride salt is isolated in yields of about 90%. A by-product of this reaction is methyl iodide, which probably forms by the displacement of iodide ion of 2-PAM-I by chloride ion and the subsequent reaction of hydrogen iodide with methanol. C-cH=NoH
c-
6y
CH,
t
Hci
t
cH,OH
-
QcH=NoH
+
CH,t
t
H,o
&
(“3
obtained, having a melting point of 235-7’ C. (decomposition). Analysis: C7H9ClN20. Calculated : carbon, 48.7; hydrogen, 5.3; chlorine, 20.6. Found: carbon, 48.8; hydrogen, 5.3; chlorine, 20.6.
Quantitative Determination of Methyl Iodide Evolved from Reaction. The Zeisel method for the determination of methoxy groups was used to assay the quantity of methyl iodide evolved from the previous reaction. A modified Clark alkoxy apparatus, volumetric assembly, was used (7). The scrubber was filled with about 8 ml. of a sodium bicarbonate-sodium thiosulfate solution and the volumetric receiver was filled with an acetic acid-potassium acetate-bromine solution. The methyl iodide evolved into the receiver could then be estimated by titration with sodium thiosulfate. Approximately 150 mg. of 2-PAM-I were added to the reaction flask containing 20 ml. of methanol. Carbon dioxide was passed through the apparatus via the side arm of the flask. The mixture was then heated on an oil bath at temperatures ranging from 80’ to 90’ C. By using a series of such experiments, knowledge of the rate and extent of formation of methyl iodide was obtained. At 80’ C., recovery of methyl iodide was 71y0; at 90’: 79.5% of the total calculated methyl iodide was recovered.
The methyl iodide can then react with additional P-2-A to form 2-PAM-I, the starting product of the reaction. Advantages to be gained from the process are: Specially designed pressure equipment is not needed. The procedure can be scaled for the production of large quantities of 2-PAMC1. T h e product which forms is white and requires no further recrystallization. It is approximately 1007, pure, based on an analytical assay of carbon and hydrogen. This procedure would not only eliminate the disadvantages inherent in the above-mentioned reports but may be adapted into a large scale recycling process, which might further be developed into a continuous one.
Recycle Process for Synthesis of 2-PAM-Cl. Three 250ml. round-bottomed flasks were connected in series with glass tubing. Flask A contained 2.6 grams of 2-PAM-I, 50 ml. of methanol. and 2.7 grams of hydrogen chloride; flask B, immersed in an ice-salt bath, contained a n excess of 20% sodium hydroxide in order to absorb acids evolved from the reaction; flask C, in a solid carbon dioxide-acetone bath, contained acetone and 1.2 grams of P-2-A. After flask A was heated to boiling for 1 hour, flask C was disconnected, fitted with a reflux condenser, and heated for 16 hours. Ether was then added to flask C to dissolve the excess P-2-A and to precipitate 2-PAM-I which formed during the reaction. The resulting precipitate \vas identified as the quaternary salt by paper chromatography (2) and ultraviolet analysis ( 4 ) .
Experimental
Acknowledgment
Preparation of 2-PAM-CI from 2-PAM-I. The synthesis of 2-PAM-I has been reported ( 5 ) . However, in order to obtain kinetic data, pyridine-2-aldoxime (P-2-A) was refluxed with a threefold excess of methyl iodide in acetone. After 4, 6, 8, and 16 hours, 2-PAh4-I precipitated in the reaction flask in yields of 50, 65, 75, and 947& respectively. The firstorder rate constant based on the disappearance of P-2-A was calculated to be 1.73 X IO-’ per hour.
The author gratefully acknowledges the assistance of Cecil Rush in performing the elemental analyses and John Kierzkoivski in the methyl iodide determinations.
T o 2.65 grams (0.01hl)of 2-PAM-I in a 150-ml. Erlenmeyer flask, 50 ml. of methanol containing 2.7 grams of dry hydrogen chloride were added. The contents of the flask were evaporated on a steam bath to a volume of approximately 10 ml. Upon cooling. a gel-like solid formed. Upon addition of acetone, a finely divided ivhite precipitate appeared. The solid was filtered, washed with ether, and dried in a desiccator; 1.5 grams of crystals (887, yield based on 2-PAM-I) were
literature Cited (1) Davis, K. J., Jenner, P. M., Toxicol. Appl. Pharmacol. 1, 576 (1959). f2\ Ellin. R. I.. Easterdav. D.. J . Pharm. Pharmacol. 13. 370 (1961). (3j Ellin; R. I.; Easterday, D:, Kondritzer, A. A., J . ’Med. ‘Pharm. Chem. 5, 404 (1962). (4) Ellin? R. I., Kondritzer, A. A., Anal. Chem. 31, 200 (1959). 79, 481 (1957). (5) Ginsburg. S., LYilson, I. B., J . Am. Chem. SOC. (6) Kondritzer, A. A , , Ellin. R. I.. Edberg. J. J.. J . Pharm. Sci. v, ‘ ’50, 109 (1961). (7) Steyermark, A , “Quantitative Organic Microanalysis,” pp. 422-32, Academic Press, New York, 1961.
RECEIVED for review September 13, 1963 ACCEPTED January 6, 1964
VOL. 3
NO. 1
MARCH 1964
21
