[CONTRIBUTION FROM
TBE
CHEMISTRY DEPARTMENT OF DUKEUNIVERSITY
ACYLATION OF ALDOXIMES. 111. T H E CONFIGURATION OF DIPHENYLCARBAMYL AND PICRYL ETHER DERIVATIVES PREPARED FROM syn ALDOXIMES' GERTRUDE VERMILLION, A. E. RAINSFORD
AND
CHARLES R. HAUSER
Received September 86, 1989
Diphenylcarbamyl aldoximes may be represented in geometrically isomeric forms by (I) and (11), while picryl ether derivatives (which react like acyl derivatives) may be represented by (111) and (IV). Among acyl aldoximes, the more stable a-isomers are assigned the syn configuration, while the relatively unstable 8-isomers are assigned the anti configuration. syn Derivatives (a) R-C+H 0
II
II
N-0-C-:N
I
I11
(CeHs)2
anti Derivatives (8) 0 R-C-H
II
(C~HS)~N-C-O-N
II
I1
IV
Actually, diphenylcarbamyl and picryl ether derivatives have been isolated in but one form. Brady and co-workers (1) have prepared the former by heating a suspension of the sodium salts of syn aldoximes in chloroform with diphenylcarbamyl chloride. These workers reported that the same derivatives were obtained from the sodium salts of the corresponding anti aldoximes and diphenylcarbamyl chloride. Picryl ether derivatives (2) have been prepared by treating syn aldoximes in alcoholic alkali with picryl chloride; anti aldoximes under the same conditions give the corresponding nitrile and aldehyde directly. Although one should expect to obtain the more stable syn isomers under these conditions, the earlier workers considered that the diphenylcarbamyl and picryl ether derivatives prepared as described above were the rela1
Paper I1 of this series, Rainsford and Hauser, J . Org. Chem., 4, 480 (1939). 68
ACYLATION OF ALDOXIMES
69
tively unstable anti isomers, because, when they were heated with alkali, a nitrile or the corresponding acid was obtained. Hence, the preparation of these derivatives from syn aldoximes was considered to involve an inversion of configuration. This view seemed reasonable a t the time, since in the two cases in which acyl derivatives have been isolated in two geometrically isomeric forms, namely, the acetyl, and carbanilino aldoximes, only the anti isomers with alkali give mainly nitrile; the syn isomers with this reagent give almost entirely the corresponding syn aldoxime. Evidence is presented in this paper, however, that the diphenylcarbamyl, and picryl ether derivatives actually have the syn configuration and not the anti configuration as was formerly assumed. We have found that the diphenylcarbamyl derivatives prepared by Brady and co-workers (1) from the sodium salts of syn aldoximes and diphen:ylcarbamyl chloride in chloroform may be prepared equally well by carrying out the reaction in warm alcoholic alkali solution; in certain cases, a little nitrile also was obtained, but this was avoided by carrying out the reaction a t lower temperatures. Under the same conditions anti aldoximes give nitrile directly. These results are best explained as follows: The syn aldoximes (as sodium salts) react with diphenylcarbamyl chloride to give the corresponding syn derivative, which in the presence of warm alkali is slowly decomposed to give nitrile. The anti aldoximes (as sodium salts) with diphenylcarbamyl chloride under the same conditions give the corresponding anti derivative, which in the presence of the alkali is immediately decomposed to nitrile. It should be expect,ed that the anti derivatives would give nitrile more readily than the syn isomers. Therefore, on the basis of these results alone, one may conclude that no inversion of configuration occurs in the reaction of the sodium salts of syn aldoximes with diphenylcarbamyl chloride. How these diphenylcarbamyl derivatives can have the syri configuration and yet give nitrile with hot alkali becomes more understandable on the basis of the following considerations. It has been pointed out previously (3) that the reactions of a pair of geometrically isomeric acyl aldoximes differ only in degree, not in kind. While the anti isomers probably always eliminate HOOCR' to form nitrile inuch more readily than the syn isomers, certain of the latter also, under certain conditions, may give mainly nitrile. Moreover, both the syn, and anti isomers may undergo hydrolysis to form the corresponding syn, or anti aldoxime. The relative yields of nitrile and aldoxime formed in any case depend upon the relative rates of these two competing reactions. Apparently, an elevation of temperature accelerates the elimination reiiction more than the hydrolysis, since for example, acetyl anti aldoximes give mainly the corresponding anti aldoxime with cold alkali (at O"), but mainly the nitrile with hot alkali (at 30" or above) (3).
70
G. VERMILLION, A. E. RAINSFORD AND C. R. HAUSER
Although acetyl syn aldoximes with hot alkali undergo mainly hydrolysis giving syn aldoxime, this is not so with certain other acyl syn derivatives. Thus, carbethoxy syn aldoximes with hot alkali give considerable or even largely nitrile (4). There is little doubt that these carbethoxy derivatives have the syn configuration, since (similar to acetyl syn aldoximes) they give practically entirely the corresponding syn aldoxime (4) with cold alkali. The fact that a carbethoxy syn derivative with hot alkali gives a higher yield of nitrile, and a correspondingly lower yield of syn aldoxime, than the analogous acetyl syn aldoxime is explained on the basis that the former undergoes hydrolysis less readily, and/or the elimination reaction, more readily than the acetyl derivative. The diphenylcarbamyl derivatives are regarded as examples of acyl syn aldoximes which undergo hydrolysis only with great difficulty ; consequently, the elimination reaction predominates on heating with alkali. Attempts to hydrolyze 1;hese derivatives with hot or cold alkali or with alcoholic ammonia resulted in the formation of only traces of aldoximes. It should be pointed out that the resemblance of the diphenylcarbamyl derivatives to authentic anti derivatives in giving nitrile with hot alkali is not as close as might a t first appear. The acetyl anti aldoximes are readily decomposed by alkali even at room temperatures, whereas hot alkali is required to decompose the diphenylcarbamyl derivatives at an appreciable rate; in fact, diphenylcarbamyl derivatives may be prepared even in the presence of warm alcoholic alkali with only slight decomposition to nitrile (see experimental). It would probably be very difficult or impossible to prepare acetyl anti derivatives in the presence of alkali. On the other hand, the diphenylcarbamyl derivatives resemble acetyl syn aldoximes (as well as other acyl syn derivatives) in their reactions with certain bases. At room temperature, acetyl syn derivatives are stable in pyridine solution, whereas acetyl anti derivatives are decomposed readily by this base, giving nitrile ( 5 ) . Like an acetyl syn aldoxime, a diphenylcarbamyl derivative is stable in pyridine solution and may be recovered unchanged even after standing in pyridine solution a t room temperatures for several days. When treated with n-butylamine, acetyl syn aldoximes react without noticeable rise of temperature, giving the corresponding syn aldoxime, whereas acetyl anti aldoximes react vigorously, generating considerable heat and giving mainly nitrile. Like an acetyl syn aldoxime, a diphenylcarbamyl derivative, when treated with n-butylamine generates no appreciable amount of heat and on standing with this base (using pyridine as solvent) gives some (10-15ojO yield) of the corresponding syn aldoxime. In order to show that anti aldoximes were not first formed in this aminolysis and then converted to the s y n isomers, anti aldoximes were treated with n-butylamine (and pyridine) under the same conditions;
ACYLATION OF ALDOXIMES
71
the original anti aldoximes were recovered practically unchanged from the amine solutions. Although only low yields of syn aldoxime were obtained from diphenylcarbamyl derivatives, the result may be taken as evidence supporting the view that the derivatives have the syn configuration. These results show that the diphenylcarbamyl derivatives have the syn configuration; therefore, their preparation from syn aldoximes involves no inversion of configuration as was formerly assumed. The reactions of syn, a,nd anti aldoximes with diphenylcarbamyl chloride in alkaline solution and the reactions of the derivatives with certain bases may be represented as follows.
not isolated Picryl ether derivatives have been prepared from certain representative syn aldoximes, picryl chloride and alcoholic alkali according to the method of Bmdy and co-workers (2). It seems likely that these derivatives have the syn configuration, since under the same conditions, anti aldoximes react with picryl chloride to give nitrile and aldehyde. The nitrile is obtained presumably by the decomposition of intermediate picryl ether anti derivatives. The formation of the aldehyde apparently involves the hydrolysis of the carbon-nitrogen double bond. Brady and Klein (2) have suggested that the formation of aldehyde in the similar reaction of 2,4-dinitrochlorobenzene with the sodium salt of an anti aldoxime involves the intermediate formation of a N-substituted derivative. Similar to the diphenylcarbamyl derivatives, the picryl ether derivatives appear to be very difficult to hydrolyze. Nevertheless, it has been found that a t least the picryl ether derivative of syn-3,4-methylenedioxybenzaldoxime undergoes some hydrolysis in the presence of alkali (at room temperature or below) giving the corresponding syn aldoxime. It has
72
G. VERMILLION, A. E. RAINSFORD AND C. R. HAUSER
been shown that under the same conditions, the isomeric anti-3 ,bmethylenedioxybenzaldoxime may be recovered practically unchanged ; consequently, the anti aldoxime was not first formed and then isomerized, but the syn aldoxime was formed directly. Although the yield of syn aldoxime obtained from the picryl ether derivative was low (10-150j0), this result supports the view that the derivative has the syn configuration. The pyridine-n-butylamine test for configuration was not applicable to the picryl ether derivatives. In connection with this work it has been shown that anti-3,4-methylenedioxy-, and anti-4-methoxy- benzaldoximes are relatively stable in solutions of pyridine and n-bu tylamine, alcoholic alkali and alcoholic ammonia. After standing for some time, the anti aldoximes were recovered practically unchanged from these basic solutions. The results are given in Table I. TABLE I MELTINGPOINTS OF anti :BENZALDOXIMES RECOVERED FROM BASICSOLCTIOKS SUBSTITUENT
3 4-CH102 ~
3,4-CHz02 3,4-CH202 4-CHsO
Pyridine-n-butylamine 5% alc. NaOH 4 N alc. NHs Pyridine-n-butylamine 5% alc. XaOH 4 N ale. NH3
~
I
8
144-145
110
146
50 50 8
140-143 142-143 129-131
110 110 64
146 146 133
130-132 130-132
64 64
133 133
EXPERIMENTAL
Diphenylcarbamyl derivatives were obtained when the sodium salts of syn-4methoxybenzaldoxime and syn-3,4-methylenedioxybenzaldoximewere refluxed Kith chloroform solutions of diphenylcarbamyl chloride according to the method of Brady and Dunn (la); the melting points of our products agreed with those reported by these earlier workers. Attempts to prepare these derivatives from the corresponding anti aldoximes, however, were unsuccessful. Reactions of syn, and anti aldoximes with diphenylcarbamyl chloride in alkaline solution.-When syn-3,4-met,hylenedioxy-, syn-4-methoxy-, syn-3-nitro-, and syn-4dimethylamino- benzaldoxinies dissolved in alcoholic alkali (prepared from sodium and 95% alcohol) were treated with warm alcoholic solutions of diphenylcarbamyl chloride, the corresponding carbamyl derivatives were obtained in yields of 65-75Yo. I n the reaction of syn-3,4-methylenedioxybenzaldoxime,a small yield of the corresponding nitrile was also obtained. No nitrile could be isolated, however, and a good yield of the diphenylcarbamyl derivative was obtained, when syn-3,4-methylene dioxybenzaldoxime was allowed t o react with diphenylcarbamyl chloride and
ACYLATION OF ALDOXIMES
73
alkali ,at 0-lo", using acetone and alcohol as solvents. It was shown that the diphenylcarbamyl derivative of syn-3,4-methylenedioxybenzaldoximeon standing with warm alcoholic alkali slowly formed the corresponding nitrile. The reactions of anti-3,4-methylenedioxy-, anti-4-methoxy-, and anti-3-nitrobenzaldoximes with diphenylcarbamyl chloride and alcoholic alkali under similar conditions gave the corresponding nitrile and diphenylamine; no diphenylcarbamyl derivative was obtained. Treatment of diphenylcarbamyl derivatives with pyridine and n-butylamine.-Onegram samples of the diphenylcarbamyl derivatives prepared from syn-3,4-methylenedioxy-, syn-4-methoxy-, and syn-3-nitro- benzaldoximes were shaken with 20 cc. of pyridine and the mixture allowed t o stand a t room temperature. Most of the solid derivative dissolved in the pyridine. After standing eight days, the mixture was poured on t o ice and water. The diphenylcarbamyl derivatives were recovered in almost quantitative yields. The three diphenylcarbamyl derivatives mentioned above were apparently unaffected when shaken with n-butylamine; they appeared t o be practically insoluble in this amine. One-gram samples of the derivatives were shaken with a mixture of 10 cc. of n-butylamine and 10 cc. of pyridine. After standing for eight days a t room temperature, the mixture was poured on 100 cc. of ice and water. The aqueous mixture was filtered and the precipitate washed with 2 N sodium hydroxide. From the filtrates and washings were isolated 10-15% yields of the syn aldoxime corresponding to the diphenylcarbamyl derivative used. I n order to avoid the conversion of any anti aldoxime t h a t might possibly have been present, no strong acids were used during the isolation of the aldoximes. The procedure was as follows. The mixture was saturated with carbon dioxide. A rapid stream of carbon dioxide served to remove some of the butylamine. The mixture was extracted with ether and the ether solution extracted with 2 N sodium hydroxide. The aldoxime was precipitated from the alkaline layer by means of carbon dioxide in the usual manner. Stabilities of anti aldoximes in basic solutions.-It is well known that anti aldox imes readily revert t o their syn isomers in the presence of acids (especially strong acids) ; however, anti aldoximes are much more stable in basic solutions. I n Table I are given the melting points of anti-3,4-methylenedioxy-,and anti-4-methoxybenxaldoximes recovered from basic solutions after standing at room temperatures for various lengths of time. The alcoholic solutions were evaporated in a current of air a t room temperature, the residue dissolved in alkali, and the oxime precipitated with carbon dioxide in the usual manner. The amine solutions were poured onto ice and water and the anti aldoximes isolated according to the procedure described in the preceding section. It can be seen that the anti aldoximes were recovered practically unchanged from the basic solutions. Results with picryl ether derivatives.-Picryl ether derivatives were prepared from syn-3,4-methylenedioxy-,and syn-4-methoxy- benzaldoximes with picryl chloride in alcoholic alkali according to the method of Brady and co-workers (2). Samples of these derivatives were allowed t o stand with 5% alcoholic sodium hydroxide a t 0" and a t room temperature. After 40 days, the alcohol was evaporated and the residue stirred with alkali and the mixture filtered. The filtrate was saturated with carbon dioxide. From the derivative of 3,4-methylenedioxybenzaldoxime, the corresponding syn aldoxime was obtained (a yield of 10% a t room temperature, and a yield of 15% a t O " ) , but only a trace of oxime could be isolated from the picryl ether derivative of 4-methoxybenzaldoxime.
74
G. VERMILLION,
A.
E. RAINSFORD AND C. R . HAWSER SUMMARY
1. Evidence is presented that the diphenylcarbamyl derivatives obtained from the sodium salts of syn aldoximes and diphenylcarbamyl chloride have the syn configuration, not the a n t i configuration as was formerly assumed. 2. It seems likely thar, the corresponding picryl ether derivatives prepared from the sodium salts of syn aldoximes and picryl chloride likewise have the s y n configuration. 3. These results are jn agreement with the hypothesis held in this laboratory that the acylation of syn aldoximes in the presence of a sufficiently strong base involves no change in configuration. 4. A method for preparing diphenylcarbamyl syn aldoximes from the sodium salts of syn aldoximes and diphenylcarbamyl chloride in alcoholic solution is described. DURHAM, NORTHCAROLINA.
REFERENCES (1) (a) BRADYAND DUNN,J . Chem. SOC.,103,1613 (1913); (b) BRADY AND MCHUGE, ibid., 127, 2414 (1925). (2) BRADYAND KLEIN,ibid., 127,844 (1925);also see ref. lb. (3) See HAUSER AND JORDAN, J . Am. Chem. SOC.,67,2450 (1935). (4) HAUSER,JORDAN AND O’CONNOR, ibid., 67,2456 (1935). J . Am. Chem. Soc., 68, 1772 (1936). (5) HAUSERAND JORDAN,
