[CONTRIBUTION FROM TEE CHEMICAL
LABORATORY O F BOSTON UNIVERSITY]
REACTIONS OF MORPHOLIXEMETHAKOL WITH COMPOUNDS CONTAINING ACTIVE HYDROGEN ATOMS MORRIS ZIEF
WITH
J. PHILIP MASON
Received July 10, 1942
It has been shown by Henry (1) that the substituted aminomethanol formed by the interaction of a secondary amine and formaldehyde will react with nitroethane to replace both of the alpha hydrogen atoms of nitroethane with dialkylaminomethyl groups (I). (I) RzNH - HCH% R2NCHzOH
c 9 H 5 N 0 ~
( R ~ N c H ~C(CH,)K02 )~
Henry (1) and also Duden, Bock, and Reid (2) obtained similar results with substituted aminomethanols and nitromethane. More recently, Cerf de Mauny (3) studied the reaction of secondary amines and formaldehyde with certain nitroparaffins. He postulated the rule that the number of hydroxymethylamine groups that would react with a nitroparaffin is one less than the number of hydrogen atoms linked to the carbon atom to which the nitro group is attached. According to this rule, nitroethane should react with only one molecule of hydroxymethylamine. Our results show that two molecules of morpholinemethanol react with one molecule of nitroethane, thus confirming the observations of Henry (1). It should be noted that Cerf de Mauny postulated his rule on the basis of experiments with nitromethane, 1-nitropropane, and l-nitrooctane. Apparently, nitroethane must be considered an exception to Cerf de Mauny's rule. We have isolated the morpholinonitroalkanes obtained by the reaction of morpholinemethanol with (a) nitromethane, (b) nitroethane, and (c) l-nitropropane.' In view of the fact that our results with nitroethane were contrary to those predicted by Cerf de Mauny's rule, this reaction was carried out using one equivalent of nitroethane with one equivalent of morpholinemethanol as well as by using one equivalent of nitroethane with two equivalents of morpholinemethanol. The same product was formed in each experiment. In the reaction with 1-nitropropane, even though the proportion of morpholinemethanol was increased, only one morpholinomethyl group could be introduced. The morpholinonitroalkanes were reduced readily in a Parr hydrogenation apparatus of the low-pressure type, using a Raney nickel catalyst activated by the method of Covert and Adkins (4). Several attempts were made to reduce these nitro compounds with tin and hydrochloric acid, but only the l-morpholino-2-nitrobutane was reduced by this method. Although 1,3-dirnorpholino-2-arninopropane and 1,3-dimorpholino-2-amino2-methylpropane formed solid ureas readily with phenyl isocyanate, a thick gum was the product of the interaction of 1-morpholino-2-aminobutane and 1 We are grateful t o the Commercial Solvents Corporation for giving us these nitroparaffins. 1
phenyl isocyanate. a-Saphthpl isocyanate also yielded a gum with this amine. Attempts to make the acetyl and the p-broniobenzenesulfonyl derivatives were also unsuccessful. A benzoyl derimtil-e was obtained as a soft waxy solid. The hydrochloride was found to be gelatinous and sticky. A satisfactory solid derivative was finally obtained as a salt formed by the reaction with 3 , s dinitrobenzoic acid ( 5 ) . It is interesting to note that the two amines which contained two morpholine rings formed solid ureas with phenyl isocyanate, while the amine with only one morpholine ring formed a gum. This obserration confirms that made by Harradence and Lions (6) that the presence of the morpholine ring in a molecule improves the crystallizing ability of the molecule. According to the principle of vinylogp (7) it would be reasonable to espect that o- and p-nitrotoluenes vould resemble nitroinethane in the reaction with morpholinemethanol. Both compounds were tried, but there was no evidence of any reaction. Whcn 2,4-clinitrotoluene was used, an explosive decomposition occurred during an attempted distillation of the reaction mixture under reduced pressure. Henry (S) observed that dialkylaminomethanols reacted readily with secondary aliphatic and heterocyclic amincs. We have found that morpholinemethanol reacts similarly with diethylamine, dibutylamine, dicyclohesylamine, piperidine, and morpholine. Methylaniline yielded a mixture from which no pure compound, other than dimorpholinomethane, was isolated. Three primary amines, n-butylamine, aniline, and o-toluidine, were allowed to react with morpholinemethanol. The products obtained were those expected hy the reaction of one equivalent of morpholinemethanol with one equivalent of primary amine. Several unsuccessful attempts were made to cause a reaction betwecn dimethylaniline and morpholinemethanol. I t vas found impossible to form picrates of these methylene diamines, because the diamines were readily hydrolyzed in the 95% alcohol used as a solvent for picric acid. In this solvent, dimorpholinomethane yielded a precipitate of morpholine picrate on standing overnight. When an anhydrous benzene solution of picric acid was used in a glass-stoppered bottle, the precipitate of morpholine picrate came down slowly over a period of several days, along with some gummy material. Replacement of one of the methylene hydrogen atoms with a phenyl group did not prevent hydrolysis during attempted picrate formation. This was shown by the fact that when phenyldimorpholinomethane was treated with alcoholic picric acid solution, morpholine picrate was the product obtained. Since the cyanide group is known to have an activating effect on hydrogen atoms linked to an adjacent carbon atom, morpholinemethanol was allowed to react with methyl, ethyl, propyl, and benzyl cyanides. The only one of these to react was benzyl cyanidc which formed a-morpholinomethyl-a-toluonitrile. This compound did not form a picrate with alcoholic picric acid solution, as hydrolysis occurred and morpholine picrate was obtained. This was unexpected because 0-phenethylmorpholine (9) formed a stable picrate. The ready hydrolysis of a-morpholinomethyl-a-toluonitrilc map be due to two factors, (a) the electron-attracting character of the cyanide group and (b) the tendency of
thc amine nitrogen to assume an onium structure. The molecule is believed to separate according to cquation 11.
The positive iminium ion (10) would then combine with the hydroxyl ion from the water to form morpholinernethanol which would decompose readily in the presence of picric acid to form morpholine picrate. I n view of the fact that both a phenyl group and a cyanide group are necessary in order to have a reactive methylene group and also in view of the fact that simple aliphatic ketones, e.g., acetone, react with morpholinernethanol ( 6 ) , we were interested in determining whether phenylacetone would react with one or with two moles of morpholinemethanol. It was found that two molecules of morpholinemethanol reacted with one molecule of phenylacetone. EXPERIMEXTAL
i?.lorpholinonilroaZkanes. These compounds were made by the method of Cerf de Mauny (3) using 17 cc. of 37% formalin and 17 cc. of morpholine. After cooling t o 0", 0.1 mole of the nitro parafin (0.2 mole was used in the experiment with 1-nitropropane) was added. The mixture was shaken and allowed t o stand. I n the experiment with nitromethane, the entire mass solidified in thirty minutes; with nitroethane, a solid separated on standing overnight; with I-nitropropane, the mixture was allowed t o stand for two days, when two layers had separated. The solids were recrystallized from absolute ethyl alcohol. I n the experiment with 1-nitropropane, the lower, non-aqueous layer was fractionally distilled under reduced pressure. The results are given in Table I. Morpholinoaminoalkanes. Each morpholinonitroalkane was dissolved in 176 cc. of 9570 alcohol and eight grams of activated (4) Raney nickel was added. The reduction was continued until the pressure remained constant, and was complete within an hour. The mixture was filtered, the alcohol removed by distillation, and the residue distilled under reduced pressure. The results are given in Table 11, togetlm Kith the melting points and analyses of solid derivatives of the thrce anines. Reduction o j 1-morpholino-2-nitrobutanewith tin and hydrochloric acid. Twenty-eight grams of 1-morpholino-2-nitrobutanewas mixed k i t h 30 g. of mossy tin, and 70 cc. of concentrated hydrochloric acid was added slo~vly. The mixture was heated on the steam-bath for two hours, diluted with 600 cc. oi*water and saturated with hydrogen sulfide. The tin sulfide was removed by filtration and the filtrate was concentrated on the steam-bath t o approximately 100 cc. The solution was made alkaline and estrscted with four BO-cc. portions of ether. The ether estracts were dried over solid sodium hydroxide pellets. ilfter filtration, the ether was removed by distillation and the residue was distilled under reduced pressure. Fourteen grams of colorless oil distilled a t 102-104" a t 15 min. Yield 60%. Jiorpholinemethanol (11). To 18 cc. of 37% formaldehyde solutio2 was added 17.4 g. (0.2 mole) of morpholine. The mixture was cooled in an ice-bath. Five grams of potassium carbonate was added, the mixture was shaken and allowed t o stand for thirty minutes. The uppcr layer, consisting of a n aqueous solution of morpholinemethanol, was separated and titrated with hydrochloric acid, using methyl orangc as an indicator. The results indicated t h a t a 95% yield of morpholinernethanol was obtained. Since the niorpholinemethanol was made in this way for all subsequent experiments, only the upper layer
4
MORRIS ZIEF B f i D J. PHILIP YASOS
being used, all yields were based upon the amount of morpholinemethanol present in this upper layer. Reaction of morpholinemelhanol with primary and secondary amines. T o the ice-cold solution of morpholinemethanol obtained from 17.4 g. (0.2 mole) of morpholine was added 0.2 mole of the secondary amine. After thorough mixing, 5 g. of anhydrous potassium carbonate was added and the mixture was allowed to stand a t room temperature for twentyfour hours. The two layers were separated and the upper, non-aqueous layer was distilled fractionally under reduccd pressure. The results, including analyses, are given in Table 111. TABLE I hfORPHOLINOXITRO.%LKANES
COMPOUND
YIELD,
I
$;
I1
-__
M.P.,"C.
Calc'd
!
1,3-Dlmorpholino-2-nitropropane. .......... 1,3-Dimorpholino-2-nitro-2-methylpropane. . l-hlorpholin0-2-nitrobutane~. ...............
I
16.22 15.38 14.89
124-125
Found
16.24, 16.10 15.00, 14.95 14.68, 14.69
Anal. Calc'd for CaHleN203: Xeut. equiv., 188. Found: 195, 201. R1.p. of picrate, 120-122'. Anal. Calc'd for claH~sT\;&: N , 16.79. Found: T\;, 16.53, 16.59. Ir B.p. at 15 mm. TABLE I1 MORPHOLINOAMIXOALI~ANES COYPOUND
I i
1,3-Dimorpholino-2-aminopropane ........................ 1,3-Dimorpholino-2-amino-2methylpropanec . . . . . . . . . . . . . . I-hlorpholino-2-aminobutaned,'. . . . . . . . . . . . . . . . . . . . .
WT. OF NITRO
PRESSURE,
co4LpouND USED, G.
14
1 ~
80
~
67-6Sb
i
I
NITROGEN,%
Calc'd
Found
18.34 , 17.90, 17.68
15 18.8
a M.p. of phenylurea, recrystallized from 95% alcohol, 233-234". Anal. Calc'd for C18H28?;103: N, 1609. Found: S , 15.61, 15.70. 31.p. A1.p. of phenylurea, recrystallized from 95% alcohol, 177-178". Anal. Calc'd for clsII30x403: N , 15.47. Found: S , 15.21, 15.17. d Calc'd for CsH18;"\Tz0:mol. wt., 158. Found: Mol. wt. in benzene,l60.9, 161.4. e il1.p. of substituted ammonium 3,5-dinitrobenzoate, recrystallized from absolute ethyl alcohol, 162-163". Anal. Calc'd for Cl&?X40,: S,15.14. Found: X , 14.80, 14.81.
I n the experiment with n-butylamine, a 59% yield of dimorpholinomethane was obtained. The only other experiment which yielded an appreciable quantity of dimorpholinomethane as a by-product was the experiment with diethylamine, where the yield of dimorpholinomethane was 22%. Hydrolysis of morpholinomethylaniline. This compound was hydrolyzed with 20% sodium hydroxide solution in the presence of benzenesulfonyl chloride, and the well-known Hinsberg method (12) of separating primary amines from secondary amines was follomd. The benzenesulfonyl derivative of morpholine, m.p. 118-120°, and benzene-sulfonanilide, m.p. 110-112", were obtained.
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REACTIOXS OF MORPHOLINEMETHAKOL
a-Morpholinomethyl-a-toluonitrile. This compound was made by the procedure used for the reaction of morpholinemethanol with secondary amines. The product distilled a t 103-105" a t 7 mm. and the yield was 51%. Anal. Calc'd for C13H&20: Neut. equiv., 216; N, 12.96. Found: Neut. equiv., 214; N, 12.75, 12.77. Reaction between morpholinemethanol and phenylacetone. This reaction was carried out according t o the usual procedure, except t h a t 5 g. of morpholine, 5 cc. of 37% formaldehyde solution, 3 g. of potassium carbonate, and 6.7 g. (0.05 mole) of phenylacetone were used. Five grams of a colorless oil distilled a t 109-111" a t 11 mm.; yield 60%. Anal. Calc'd for C1gH28N203: Xeut. equiv., 166; N, 8.43. Found: Neut. equiv., 175; N, 8.00, 7.96. An attempt t o make a picrate of this compound resulted in the formation of morpholine picrate. The hydrolysis of this compound indicated t h a t i t would be impossible t o determine definitely t o which of the carbon atoms the two morpholinomethyl groups were linked. I t is highly probable that they are both linked t o the carbon atom t o which the phenyl group is attached and that the compound is 1-phenyl-1, 1-di(morpholinomethy1)acetone. TABLE I11 hlORPHOLINOMETHYLAMINES NORPHOLINOMETHYL
I
"C B.P.
Butylamine... . . . . . . . . . . . . . . 58-62 Aniline". . . . . . . . . . . . . . . . . . . . 108-112
PRESSURE,
MY.
13 10 10 13 14 8
12 12 a
YIELD,
%
20 52 39 64 58 64 66 63
Found
14.58 14.37, 14.40 13.59 13.40, 13.42 84.1 16.28 16.50, 16.52 114 112.0 12.28 11.92, 12.11 140 138.6 10.00 10.12, 9.61 92 1 91.6 15.22 15.32, 15.29
'
!'
Calc'd for C11HlsX20:mol. wt., 192. Found: mol. wt. in benzene 194. (1939).
* Harradence and Lions, J . Proc. Roy. SOC.N.S. Wales, 73, 22-28
Phenyldimorpholinomeihane. To 21.2 g. (0.2 mole) of benzaldehyde was added, with cooling, 17.4 g. (0.2 mole) of morpholine. The clear solution gradually became turbid, and in about an hour a white solid appeared. The mixture was allowed t o stand overnight and filtered. The filtrate consisted of 10 cc. of unreacted benzaldehyde. The dry, crude product weighed 20.4 g., representing a yield of 77%. Recrystallization from 95% alcohol gave white crystals, m.p. 101-101.5". Anal. Calc'd for C15H22KL02: K, 10.69. Found: E,10.58, 10.64. SUMMARY
Morpholinemethanol has been found to react with nitromethane, nitroethane, 1-nitropropane, n-butylamine, aniline, o-toluidine, diethylamine, dibutylamine, dicyclohexylamine, piperidine, morpholine, benzyl cyanide, and phenylacetone. The morpholinonitroalkanes have been reduced to the corresponding morpholinoalkyl amines. The methylenediamines, phenyldimorpholinomethane, a-morpholinomethyla-t oluonitrile, and 1-phenyl-1 ,1-di(morpho1inomethyl)acetone were found to hydrolyze so readily that picrates could not be formed. BOSTON,MASS.
6
MORRIS ZIEF AXD J. PHILIP MASOX
REFERESCES
(1) HENRY,Ber., 38, 2027 (1905). (2) DUDEN,BOCKAND REID,Ber., 41, 2036 (1905). (3) CERFDE MAUNY, Bull. SOC. chim., (5) 4, 1460 (1937). (4) COVERT AND ADBINS, J . A m . Chem. soc., 54, 4116 (1932). (5) BUEHLER, CURRIER, AKD LAWRENCE, Ind. Eng. Chem., Anal. Ed., 6, 277 (1933). (6) HARRADENCE AND LIONS,J . Proc. Roy. soc. ?i.s.Wales, 72, 233-248 (1939). (7) FUSON,Chem. Rev., 16, 12 (1935). (8) HENRY,Bull. SOC. chim.,13, 157 (1895). (9) MASONAND ZIEF, J . A m . Chem. Soc., 62, 1450 (1940). (10) STEWART AND BRADLEY, J . Am. Chem. SOC.,64,4172 (1932). (11) BINZAND PENCE, J. Am. Chem. Soc., 61,3134 (1939). (12) SHRINER AND FUSON,“Systematic Identification of Organic Compounds”, second edition, J. Wiley and Sons, S e n York, 1940,pp. 49-50.
