[CONTRIBUTION FROM TEE RESEARCH LABORATORIES, SCHOOL OF PHARMACY, UNIVERSITY OF MARYLAND]

A NOTE ON THE HYDROGENATION OF @-PHENYL-(u-OXIMINO- PROPIONIC ACID

KENNETH L. WATERS' AND WALTER H. HARTUNG

Received J u l y 17, 194

In studying the catalytic hydrogenation of a number of a-oximino acids in these laboratories it has been observed (1) that approximately half of the,theo- retical amount of hydrogen needed to complete the reduction to the amino acid is taken up rapidly and that the second half is usually taken up a fifth to a fourth as rapidly (Fig. I). This decrease in the absorption of hydrogen suggested that the reaction proceeded step-wise and it was assumed that there might be formed first an intermediate product which is more difficult to hy- drogenate, for example:

RC(:NH)COOH HI

or -4 RCH(NH2)COOH RC(:NOH)COOH --?+ slow RCH (NH0H)COOH

Experiments have shown, however, that if the reduction is stopped a t the half-way stage, approximately equal molar. amounts of amino acid and un- reduced oximino acid are obtained. If the reduction is stopped when three- quarters of the calculated amount of hydrogen is taken up, the products consist of unchanged oximiio acid and amino acid in a molar ratio of about 1 to 3. These results suggest that if the postulated intermediary imine or hydroxylamine is formed, it is reduced more readily than the oxime and that the amino acid, as it is formed, acts as an inhibitor. The rate of hydrogenation of 8-phenyl-ol- oximinopropionic acid is shown graphically in Fig. I. That the decrease in rate of hydrogen up-take is not entirely a result of the decrease in concentration of the oximino acid is shown by Fig. 11, which represents a typical hydrogenation of the oximino acid in the presence of the amino acid that is formed from it.

In order to determine further whether the phenomenon is primarily due to a change in the concentration of the compound being reduced, the apparatus was modified to permit the addition of more oxime without interrupting the reaction or changing the internal gas pressure. If the change in rate were a function of the concentration of the oximino acid, then at the half-way or subsequent stages, there might reasonably be expected an increase in the rate of hydrogen up-take upon the addition of fresh oximino acid. The results of this experiment are shown in Fig. 111. It will be observed that there was no increase in the rate of hydrogenation when oximino acid was added a t the half- way stage or later (points a and b). This experiment indicates that the drop in the rate of hydrogenation is the result of inhibition and not due to the forma- tion of a more difficultly hydrogenated intermediate.

1 Present address: Mellon Institute, Pittsburgh 13, Pa. 524

0-PHENYL-a-OXIMINOPROPIONIC ACID 525

EXPERIMENTAL

Preparation of &phenyl-a-oximinopropionic acid. The 8-phenyl-a-oximinopropionic acid used in these experiments was prepared by either of two procedures: (a) From the substituted acetoacetic ester in 85% sulfuric acid by the action of alkyl nitrite as described

FIG.1 29. Oximino Acid

1 I I

40 80 I20 Time (in minutes)

FIG. I1 29. Oximino Acid

Pius I g. Phenylaloninr

FIG. I, 11, AND 111.

4"or

u 0 Y

Time (in minuter) F1G.m

29. Oximino Acid Plus Added Oxime At a And b

CATALYTIC HYDROGENATION OF &PHENYL-U-OXIMINO PROPIONIC ACID

by Hamlin and Hartung (1). (b) From the substituted malonic ester by the action of alkyl nitrite and hydrogen chloride using ether as the solvent as described by Barry (2).

Hydrogenatin of 8-phenyl-a-oximinopropionie acid. A mixture of 3 g. of palladinired charcoal, prepared by the method of Hertung (3), 96 cc. of 95% ethanol, 4 cc. of conc'd hydrochloric acid and 2 g. of 8-phenyl-a-oximinopropionic acid was placed in a 250-cc.

526 I(. L. WATERS AND W. €I. HARTUNG

hydrogenation flask and reduced a t atmospheric pressure and room temperature. A typical curve for this reduction is shown in Fig. I.

Hydrogenation of a mixture of &phenyl-a-oximinopropionic acid and phenykdanine. A mixture of 2 g. of 6-phenyl-a-oximinopropionic acid and 1 g. of phenylalanine was hydro- genated as described above. Fig. I1 is a typical curve for the reduction of this mixture.

Hydrogenation of 8-phenyl-a-oximinopropionic acid with the addition of fresh oximino acid at intervals. To the 250-cc. hydrogenation flask was attached a Claisen neck fitted with a burette so connected as to form a closed system which permitted no pressure change when additions were made to the flask from the burette. In the hydrogenation flask was placed the palladinized charcoal, 80 cc. of 95% ethanol, and 1 cc. of conc’d hydrochloric acid. In the burette was placed 37.5 cc. of a 10% solution of 6-phenyl-a-oximinopropionic acid, (3.75 g. oximino acid, 33.5 cc. ethanol, and 4 cc. of conc’d hydrochloric acid). Twenty cc. of the oxime solution (2 g. oximino acid) was run into the hydrogenation flask, previously filled with hydrogen, the shaker was started, and readings of the volume of hydrogen ab- sorbed were made at intervals. When approximately one-half of the theoretical amount of hydrogen had been taken up another 10 cc. (1 g. oximino acid) portion of the oxime solu- tion was added; it may be observed from Fig. 111, point a, that there was no increase in the rate a t which the hydrogen was taken up. After the lapse of a further thirty minutes the final 7.5 cc. of oxime solution (0.75 g. oximino acid) was added; again there was no increase in the rate a t which the hydrogen was taken up (Fig. 111, point b).

SUMMARY

1. It has been shown that the hydrogenation of a-oximino acids to a-amino acids does not proceed step-wise as had been assumed, but rather that any hypothetical intermediate imine or hydroxylamine, if it forms, is more readily reduced than is the original oximino acid.

2. It has been shown that the a-amino acid as it forms by catalytic hydro- genation from the a-oximino acid, causes an inhibitory effect on the rate of reduction of the unchanged oximino acid.

BALTIMORE, MD . REFERENCES

(1) c f . HAMLIN AND HABTUNQ, J . Biol. Chem., 146, 349 (1942). (2) BARRY, Thesis, University of Maryland, 1943. (3) HARTUNQ, J . Am. Chem. Soc., 60, 3370 (1928).