[CONTRIBUTION FROM THE CHEMICAL LABORATORY OF THE UNIVERSITY OF ILLINOIS]
ACID CATALYSIS IN LIQUID AMMONIA. 111. EFFECT OF CY-SUBSTITUENTSON THE AMMONOLYSIS OF ESTERS L. F. AUDRIETH AND J. KLEINBERG Received July $6, 1838
Sinoe ammonium salts behave as acids in liquid ammonia it was to have been expected that the presence of compounds yielding the ammonium ion would accelerate ammonolytic reactions. This theoretical premise has been confirmed experimentally in a number of studies on the ammonolysis of esters, not only by Shatenshteinl in the case of diethyl tartrate, but also in this laboratory in the case of ethyl benzoate2 and of diethylmalonate.* This concept has also been extended to apply to the ammonolysis of esters derived from polyhydric alcohols and long-chain saturated or unsaturated fatty acids.' In all of these instances the addition of ammonium salt has caused a tremendous increase in the velocity of the reaction between esters and liquid ammonia. An increase in the concentration of ammonium salt has also been found to give proportionately greater yields of the oorresponding acid amides over comparable time intervals. These reactions presumably represent examples of acid catalysis in liquid ammonia. Experimental work now in progress in this laboratory indicates that solvolytic reactions are in general, susceptible to catalysis by the corresponding onium ion, id est, the solvated proton. The concept of onium-ion catalysis is therefore applicable to a wide variety of protophyllic solvents. It is well-known that the ease of hydrolysis of esters varies considerably with the qature of,the a-substituent. It was therefore considered to be of distinct theoretical interest to determine if this same order of reactivity held qualitatively for the corresponding ammonolytic reactions. The experimental results of a study of the ammonolysis of the ethyl esters of acetic, cyanoacetic, malonic, malonamic, lactic, mandelic, phenylacetic and ethoxyacetic acids at 0' are presented in the first part of this paper. The catalytic effect of the addition of ammonium chloride was also deterSHATENSHTEIN, J . Am. Chem. Soc., 69,432 (1937). FELLINQER AND AUDBIETH, ibid., 60,579 (1938). ~SLOBUTSKY AND AUDRIETH,Trans. Ill. Acad. A%{., m, 104 (1936); PTOC. Nut. Acad. Sci., 23,611 (1937). 4 BALATY, FELLINQEB, AND AUDRIETH,In press (Ind. Eng. Chem.) 312 1
2
3 13
ACID CATALYSIS I N LIQUID AMMONIA
mined in each case. I n the course of this investigation it was found that the treatment of certain classes of esters with liquid ammonia afforded a very simple and convenient method for the preparation of the corresponding acid amides. Consequently, reactions between ammonia and the ethyl esters of lactic and of mandelic acids were carried out at higher temperatures and pressures in order to investigate in more detail, than previously reported by Glattfeld and MacMillan6, the usefulness of this method for the preparation of a-hydroxy acid amides. EXPERIMENTAL
I. Efect of a-Substituents on the Ammonolysis of Esters Preparation of materials.-All liquid esters were carefully dried over anhydrous sodium carbonate and then distilled fractionally under reduced pressure. Especial care was taken to remove any free acid contaminating the esters, in view of the fact TABLE I AMMONOLYSIS OF ESTERS AT 0" (XCH~COOC~HS = 0.025 mole in 25 cc. NHa)
ESTER
RELATIVE 3APONIFICATIOl CONSTANTS (OWON)
PERCENTAQE YIELDS OF AXIDES
24 hours
48 hours
No catalyst
No catalyst
8.2 g. NH4Cl
~
CNCHzCOOEt /CONHz CHz \COOEt C'Ht(COOEt)* C&H6CHOHCOOEt CHsCHOHCOOEt C2HsOCHzCOOEt CeHsCHzCOOEt C!HaCOOEt
2070 1015 968 985 191 100
97
96
99
100
67
91
93
98
9 44 26 5 0.6 0
79 63 53 53 2 1
63 62 .38 12 1.2 0
95 79 77 86 4.7 3
that the acids would be converted into.the ammonium salts by liquid ammonia and by their presence exert a catalytic effect on the reaction. Ethyl malonamate was purified by recrystallization from benzene. Procedure.-Pyrex tubes (16 X 350 mm.) were sealed a t one end to form elongated test-tubes. A definite quantity of pure ester (0.025 mole) was placed in each reaction tube. Where the experiments were carried out in the presence of catalyst, a weighed amount (0.2 9.) of ammonium chloride was next added. The tubes were then cooled thoroughly in a solid carbon dioxide-acetone bath, and liquid ammonia was siphoned into each tube to give a total volume of 25 cc. With the contents of the tube entirely below the surface of the cooling bath, the upper end was sealed off. The sealed tubes were allowed t o warm slowly to 0" and the contents mixed thoroughly t o produce a 6
GLATTFELD AND MACMILLAN, J . Am. Chem. Soc., 68,898 (1936).
314
L. F. AUDRIETH AND J. KLEINBERG
homogeneous solution. The starting time of the reactions was taken as the time of mixing. After 24- or 48-hour interval tubes were removed from the ice-water bath and immediately cooled in a carbon dioxide-acetone bath. After the seals had been broken, the tubes were inserted through closely fitting rubber stoppers into filter flasks, and the contents were allowed to drain into the containers. The ammonia was allowed to evaporate spontaneously, and the alcohol was removed by drawing warm dry air through the container. A suitable solvent, either low-boiling petroleum ether or absolute ether, was added to extract the unreacted ester. The residues were filtered through tared sintered-glass crucibles, washed with the solvent used in extracting the unreacted ester, dried and weighed. The known weights of catalyst were deducted to determine the net yields of amides. The identity of the ammonolytic products was verified in each case either by a check of the physical properties as recorded in the literature or by analysis. Typical experimental results are recorded in Table I. Percentage yields of amides are given for runs with and without ammonium chloride for 24- and 48-hour reaction periods. The error in these determinations is, on the average, not greater than &5 per cent., except in those cases where relatively small quantities of amide were isolated and weighed. Here the slight, but definite solubility of the amides in the solvent mixture containing the unreacted ester, introduced an appreciable error. Discussion.-The relative saponification constants for these same esters, as calculated by 01sson8, taking the reactivity of ethyl acetate as equal to 100, are given in the second column of Table I. It may seem illogical to compare the reactivity of esters towards alkaline hydrolysis with findings based upon their susceptibility to ammonolysis. However, both types of reactions are solvolytic, and i t is apparent from our results (1) that the nature of thea-substituent exerts a profound effect upon the reactivity of esters towards ammonia, and (2) that this effect is qualitatively in the same order as in the case of water. The one apparent exception to this generalization, among the uncatalyzed reactions, is diethyl malonate. Previous study in this laboratory had shown that the reaction between ammonia and diethyl malonate3 is autocatalytic in nature. Both the intermediate product, ethyl malonamate, and the end product, malonamide, behave as acids in liquid ammonia. A relatively long induction period is necessary in order to build up a sufficiently high concentration of these products t o give enough ammonium ions (from RCONHs NH3 e NHr+ RCONH-) to catalyze the reaction. While the yields of malonamide under the given experimental conditions, in the absence of catalyst, are slight after 24 hours, they become appreciable after a 48-hour reaction period. All of the esters listed in Table I are quite soluble in liquid ammonia a t 0". This may in part account for the fact that the ammonolysis of esters, even in the absence of catalyst, proceeds more rapidly than the corresponding uncatalyzed hydrolytic reactions. Furthermore, liquid ammonia is recognized as a strongly basic solvent and as such enhances the acid strength of weak acids. The reaction products, as pointed out above in the case of diethyl malonate, serve to catalyze ammonolytic reactions of this type. In addition, i t is possible t h a t the acidity of a methylenic hydrogen is enhanced in liquid ammonia-and this factor may serve to increase the rate of ammonolysis. In line with these considerations i t is also apparent why the a-hydroxy esters are ammonolyzed so readily. Compounds of the type ROH are
+
6
OLSSON, Z. physik. Chem., 133, 233 (1928).
+
315
ACID CATALYSIS I N LIQUID AMMONIA
more itcidic in ammonia than in water, due t o the greater basicity of the solvent and because of the fact t h a t competition for the proton is displaced in the direction of NH,+). formation of the ammonium ion (ROH NHI e ROThe effect of a-substituents upon the reactivity of the ethyl esters of acetic and related acids may be given by the following series:
+
CN-C
+
CeH6
CH,
HO
HO
> HZNOC-C > C2HaOOC-C >
C2H60-C
\ C> /
\ C> /
> C6Hs-C > H-C
The magnitude of the catalytic effect of addition of ammonium chloride varies with different esters. I n every case, however, addition of ammonium salt, brings about a marked increase in yields of the corresponding acid amides. Since ammonium chloride is the ammonia analogue of hydrochloric acid our results may be considered as further confirmation of the original premise that ammonolytic reactions of this type are susceptible t o catalysis by ammono acids.
I I . Preparation of a-Hydroxy Acid Amides The data given in Table I indicate that many amides may be prepared readily and in good yields by reaction with liquid ammonia. However, only in the case of the a-hydroxy acid amides does this method possess particular advantages over acceptfed procedures. Mc’Kenzie and Wren’, prepared dl-mandelamide by reaction of the methyl ester with alcoholic ammonia. They point out that the reaction is a very slow one. aedas prepared a number of a-hydroxy amides in 85-90% yields by treating the acetone derivatives of the corresponding acids with liquid ammonia. Twenty-five to thirty moles of liquid ammonia per mole of acetone compound was employed. This latter method involves the intermediate preparation of the acetone derivatives from the respective acids. Glattfeld and MacMillan6 studied the action of liquid ammonia a t its boiling point upon various lactates and mandelate8 and found these esters to undergo ammonolysis readily. They give no specific details. In ;studying this method for preparation of the amides of lactic and mandelic acids use was made of a steel autoclave to enable the synthesis of larger quantities and permit operation a t room temperature. It is interesting to note that the addition of catalyst does not cause enough of an increase in yield of these amides over a 24-hour period a t room temperature to warrant its use. Preparation of mandelamide. *-Forty grams (0.22 mole) of ethyl mandelate was placed in a large Pyrex tube and cooled in a solid carbon dioxide-acetone bath. One
MCKENZIE AND WREN, J . Chem. SOC., 93,311 (1908). D A Bull. , Chem. SOC.(Japan), 11, 385 (1936). * Through the courtesy of H. A. Shonle of the Lilly Research Laboratories samples of the amide were subjected t o pharmacological study. An abstract of his report follow,s: “Mandelamide was tested for toxicity by intravenous injection on mice and for rate of excretion on a single dog. The doses for the excretion experiments 7
*~
316
L. F. AUDRIETH AND J. KLEINBERG
hundred cc. of liquid ammonia was added, and the mixture was stirred to effect solution. The solution was placed in the steel bomb and allowed to remain in the autoclave for 24 hours. The excess ammonia was then allowed t o escape from the bomb, and the reaction product was treated with 100 cc. of absolute ether t o remove unchanged ester. The product was filtered, washed with ether, and dried. The yield of mandelamide was 27 g. (80.5% theoretical). Preparation of lactamide.-Fifty-nine grams (0.5 mole) of ethyl lactate and 200 cc. of liquid ammonia were allowed to react as described above. The yield of lactamide was 31.5 g. (70.8 % theoretical). Similar experiments with 4 g. ammonium chloride gave slight increases in yield (74 and 7601, theoretical), indicating that under the given conditions a catalyst is not desirable, since i t necessitates additional purification of the reaction product. SUMMARY
1. The concept of acid catalysis has been shown to be generally applicable to the ammonolysis of esters in liquid ammonia. 2. The reactivities of esters toward ammonolysis in liquid ammonia parallel, qualitatively, the reactivities of esters toward alkaline hydrolysis in aqueous solution. 3. The relative influence of various a-substituents on the reactivity of the ester toward ammonolysis in liquid ammonia is given by the following series:
CN-C
> HzNOC-C > CeH600C-C >
CaH5
CHI
HO
HO
\ C> /
\ >
4. A convenient method for the preparation of a-hydroxy amides, by the action of anhydrous liquid ammonia on the esters, has been developed. were made proportional to twice the equivalent of a dose of 12 g. of mandelic acid for a 70 kg. man. Mandelic acid was tested in a similar way and a t the same time. Both the amide and the acid were found t o have aM.L.D. of 610 mg. per kg. of body weight. The urine had neither bactericidal or bacteriostatic action on cultures of Staphylococcus aureus and Bacillus coli. With a dose equivalent t o twice the effective dose of mandelic acid for man, mandelamide in dogs showed less than 50% recovery and no appreciable decrease in the pH of the urine from these treated dogs.”
