[CONTRIBUTION FROM
THE
CHEMICAL LABORATORIES OF THE UNIVERSITY OF
CALIFORNIA AND DARTMOUTH COLLEGE]
THE PREPARATION O F AMINONITRILES AND THEIR QUATERNARY AMMONIUM DERIVATIVES DANIEL B. LUTEN, JR.
Received November Y, 1998
The preparation of the series of aminonitriles and their derivatives, the betaine nitrile salts, which are described in this article was undertaken in connection with an investigation of the kinetics of the hydrolysis of the nitriles and the amides which are derived from them. The results of that investigation have been published in part1. The aminonitriles were prepared either by the method (I) of Knoevenagel and Mercklin2 which, according to Stewart and Li3, appears to involve the reactions :
+
(I) RR’CO HSO3- + RR’C(OH)S03RR’C(OH)S03R”2NH -+ RR’C(NR”2)OH RR’C(NR’’2)OH HSO3- + RR’C(NR”Z)S03RR’C(NR’’Z)S03CN- + RR’C(NR’’2)CN
+ + +
+ HS03+ HzO + so3=,
(1)
(2) (3) (4)
or by a frequently employed method (11) which has been shown by Stewart and Li3 to depend primarily upon the reactions:
+
(11) RR’CO R”2NH = RR’C(0H)NR”Z RR’C(0H)NR’’t HCN -+ RR’C(NR’’2)CN
+
+ H2O.
(5) (6)
While mutual neutralization of the secondary amine and hydrocyanic acid, together with the formation of cyanohydrin, occur to a considerable extent, neither of these reactions leads directly to the formation of the aminonitrile. The first method is the less satisfactory; by its use good yields of only the aminonitriles derived from formaldehyde and the simpler amines may be obtained. No product was obtained from formaldehyde and diisopropyl amine or dicaprylamine by this series of reactions. The method can be used to secure a-diethylaminopropionitrile (from acetaldehyde), (a) STEWART AND KORPI,J . A m . Chem. SOC., 64, 3977 (1932). ( b ) LUTENAND STEWART, i b i d . , 50, 2151 (1934). 2 KNOEVENAGEL AND MERCKLIN, Ber., 37, 4081 (1904). 8 STEWART AND LI, J . A m . Chem. SOC.,60,2782 (1938). 588 1
PREPARATION OF AMINONITRILES
589
and probably a-dimethylaminoisobutyronitrile (from acetone), but not t~-diethylaminoisobutyronitrile.~In cases where the method is unsuccessful the failure appears to be due to the low rate or adverse equilibrium of reaction 2. The second method, under the special conditions which were employed, gives a good yield in many cases where the first fails, but there are certain cases where it also fails to give any yield of product. Thus, no product was obtained from the interaction of diethylamine and methyl isopropyl l~etone~, or from dimethylamine and pinacolone. There seems to be little relation between the molecular weights of the reactants and the ultimate yield; however, diethylamine gives a much lower yield with each of the ketones employed than does dimethylamine. Some of the aldehydic derivatives were obtained in low yields owing to the destruction of the aldehydes by the competing aldol condensation reaction. Using this method it was noted that with the simpler derivatives considerable heat was evolved upon mixing the reagents, and that the reaction was quickly hished, whereas with the more complex derivatives there was no evolution of heat, and increased time of reaction appeared (although not unambiguously) to give increased yields of product. This is clearly shown in Table I under a-diethylamino-a-methylbutyronitrile. Although method I1 has been employed a number of times5 the experimental conditions used were not adapted to securing the highest yields of product. Stewart and Lia have been able, as a consequence of their kinetic investigation of the reactions, to show how better yields might be obtained by modification of the experimental conditions. Unfortunately, these modifications have not yet been employed in the more difficult preparations. The aminonitriles derived from formaldehyde and the ketones usually have pronounced camphor-like odors, but the aldehyde derivatives are similar to the parent aldehyde in odor, while derivatives of higher amines, such as dicaprylamine, resemble the parent amine. Dimethylaminoacetonitrile acquires a garlic-like odor on a few days' standing. The higher derivatives are more stable, but an odor of hydrogen cyanide appears in all cases on long standing. They are all clear, colorless liquids. The quaternary derivatives were prepared by adding the appropriate halide to the aminonitrile, or by adding iodoacetonitrile to the appropriate tertiary amine. The substitution of a radical, Rz, for a radical, RI, on 4 STEWART AND COOK[ J .A m . Chem. Soc., MI, 1980 (1928)] obtained this substance once by this method but were unable to repeat-the preparation. (a) BRUYLANTS, Bull. sci. acad. roy. Belg., [5] 10, 126 (1924); ( b ) [ 5 ] 11,261 (1925); (C) STEVENB, COWAN, AND MCKINNON, J . CheVZ. SOC., 1931, 2568; ( d ) THOMSON AND STEVBNB, ibid., 1Qa, 2607.
590
DANIEL B. LUTEN, JR.
TABLE NUM-
BER
I
BOILINGPOINTS AND YIELDSOF AMINONITRILES BOILINQ BUBBTANCE
POINTO,
OCpbm.)
26 27 29
138 4211 702s 5310 962s 789 78-7914 55-588 854 879 78-794 102-1044 93-944 146-1 50,
34 36
59-6140 5511
1
9 16 20 22 25
39 42 44 47 48 51 54
67-6828 75.516 572s 461a 5814 72-7414
56 58 60
7014 951s 784 6114 694 6312
62 64 66
781s 919 751o
__
METHOD OF PREPARATION AND YIELD, %
I, 45-79 I, 70-75 I, 72 I, 0 11, 52-65 (6 hr.) I, 75 I, 75 11, 45 (6 hr.) I, 84 I, 79 I, 0 11, 31(9 hr.) 11, 28 11, 68 11, 78 (8 hr.) I, 25 11, 52-69 (8 hr.) 11, 53 I, 0 11, 30-39 (24 hr.) I1 11, 44 I1 11, 39 11, 70 (3-8 hr.)
LITERATURE IO%INQ POINT"
Cp(mm.)
137-1 38' 139-1401' 1701° 70-71 141l 200-20210 89-901~'~
95-9611"
144" 6817'
47-4974 156-158" 1521' 75-7728' 7311~' 175-176"
171" 76-7716s
11, 18 (5 hr.) 11, 64 (6 hr.) 11, 49 (24 hr.)
If no figure for pressure is given the boiling point recorded is for atmospheric pressure (750-760 mm. Hg). ESCHWEILER, Ann., 279,44 (1894). 10 HENRY,Rec. trau. chim., 24, 173 (1905). l1 KLAQES, J. Prakt. Chem., ( 2 ) 66, 193 (1902). l2 YON BRAWN, Ber., 40, 3933 (1907). HENRY, Bull. sci. acad. roy. Belg., 1904, 741. I4 MCMEEKING AND STEVENS, J. Chem. Soe., 1935,347. l5 HENRY,Bull. sci. acad. T O Y . Belg., [31, 96, 241 (1898).
PREPARATION OF AMINONITRILES
591
TABLE I-Concluded NEYDER
68
I
BOILINQ
1
1
POINT^,
BUBBTANCE
~
OCp(mm. 1
(CzHs)zNC(CH,)(n-csHi)CN
80 81
(CHa)zNCH(CsHs)CN (CzHs)sNCH(CeHs)CN
82
/ CH2 \
UETHODOFPREPARATION A N D YIELD, %
11, 11.3 (15 hr.) 12.5 (24 hr.) 15.5 (48 hr.) 11, 42 (48 hr.) 63I 49 (24 hr.) 69-7310 11, 40 (5 hr.) 75 (26 hr.) 113-11518 11) 73 104-10510 11, 63 (21 hr.) 138-141 9 I, 70-76 10321 80-85s
90s 122-1240
I, 29 I, 56
830
I) 94
176-17716 176-1771' 125-12611' 26618 161-16321'' 1201p 120-13111' 112+
CHs.CHz
\
j\JCHZCN
210'0 99-1001617
CHa*CHz
\I"RUNIS I1
AND SACHS,
KLAGESAND
Ber., 37, 2636 (1904).
MARQOLINSKY,
ibid., 36, 4188 (1903).
the nitrogen atom influences the rate of quaternization to a degree similar to that found if the same substitution is made in simple amines. If I12 is substituted for RI on the carbon atom adjacent to the nitrile group the rate of the reaction is altered to a similar degree; the effect is not, as might be expected, of a magnitude several-fold smaller. The rates of quaternization of the aminonitriles are much slower than are those of similarly N-substituted alkyl amines. The quaternary derivatives are colorless salts; they vary remarkably in the ease with which they crystallize. While many of the derivatives are strongly crystalline, in other cases the reaction mixtures stood for over a year before any crystals appeared. In a number of cases crystals never were obtained, even though it was obvious that the amine and halide had reacted to a considerable extent. The melting points of the salts range from 85" to 268". The results of the preparations are summarized in Tables I and 11. The general methods of preparation, the yields and boiling points of the aminonitriles, and the analyses and melting points of the quaternary derivatives are given. In some cases with aminonitriles prepared by method I1 the time allowed for the reaction is also given. The boiling points and melting points which are recorded in the literature are included.
592
DANIEL B. LUTEN, JR.
TABLE I1
NUY-
MELTINGPOINTS
AXD
ANALYSES OF
&UATEF&NARY SALTS
BUBBTANCII
BER
-__-____ 2
(CHa)sW+CHzCN I-
3
(CzHs) (CHs)zN+CHzCN I-
4
( ~ - C ~ H ~ ) ( C H ~ ) & C H IZCN
5
(i-CsH7)(CHs)zfiCHrCNI-
6
(n-CdH9) (CH&fiCHzCN I-
7 8
(n-C~Hsa)(CH+a)zfiCHzCNI(CH3) (CzHs)zNCHzCONH2 I-
10
(CH3)(CzHs)2fiCH2CNI-
11
(CzHs)3fiCHzCNI-
lla
(CZHS)&CHZCN Br-
12
( ~ - c ~ H , ) ( c ~ H ~ ) ~ ~ ~I-c H ~ c N
13
( ~ - c , H ~ ) ( c ~ H ~ ) ~ ~ ~I-c H ~ c N
14
( ~ - C S H ~ ~ ) ( C Z H ~ ) ~ SI-~ C H ~ C N
15
( c H ~CH. : C H ~() c ~ H ~ ) ~ ~ ~ c I-H ~ c N
17
(CH3)(n-CsH7)zfiCH~CNI-
18 19
( C Z H S ) ( ~ - F ~ H ~ ) Z S ~ CI-H Z C N (n-CsHr)aNCHzCN I-
21
(CH3)(i-CsH7)2fiCHzCNI-
23 24 28
(CHs) ( ~ - C ~ H ~ ) , S ~ C H I- ~ C N (n-CdH p)aNCHzC+NI(CH3)(i-CsHi1)2NCHzCN I-
30
(HOCHzCHz)(CzHs)2fiCHzCNI-
56.1556.16 19618 5 6 19 209 52.8852.59 52.59 95 49.9649.82 49.90 219 49.9649.82 49.81 86.5 47.3547.36 47.38 30.0728.7 118 46.6546.16 46.15 199 49.96 49.92 190-19117 49.91 18619 187 47.35 47.17 18417 47.20 209 36.1535.92 20200 35.93 195 45.0044.73 44.91 1% 42.8742.78 43.01 125 40.9440.76 40.78 157 45.3244.98 45.09 162 45.0044.72 15011 44.96 176 42.8742.77 179 40.9440.97 40.87 196 45.0044.87 44.87 104 40.9440.94 131 36.05 35.88 109 37.5437.34 37 * 44 44.6843.97 228
BRAUN,DEUTSCH, AND SCHMATLOCH, ibid., 46, 1262 (1912). KNOEVENAQEL, ibid., 37, 4073 (1904). M VON BRAUN, ibid., 41, 2113 (1908). 18
19
VON
593
PREPARATION OF AMINONITRILES
-
TABLE 11-Continued HALOGEN LITERA-
NUMBER
BUBSTANCE
128
31
(CzH&(CHzCN)h'CHzCOOC.Hs Br-
32
102 (CH,)Z(CHZCN)~~CHZCH,COOC~H~ Br-
33
122 (CH,)Z(CHZCN)~'CHZCHZCOOCZH~ I-
35
(CH&fiCH(CH,)CN I-
204
37
(CH3)(C2Hs)zl;jCH(CHs)CN I-
202
38 40
(CHa)a$CHzCHzCIS'C1(CHs)aNCH(CzHs)CN I-
230 176
41
( C Z H S ) ( C H ~ ) Z ~ ~ C H ( C ZI-H ~ ) C N
135
43
(CHI)(CZHS)Z&CH(CZH~)CN I-
184
45
(CH&fiC(CHa),CN I-
268
46
(C2H6)(CH3)2fiC(CHa)2CN I-
a. 250
49
(CHJ (C2Hs)2fiC(CH3)2CN I-
241
50
( C H a ) 3 f i C H ~ C H ~ C H ~BrCN
226
52
(CHs)3h'CH(n-CsH7)CN I-
163
53
(C2Hs)(CH&fiCH(n-CsH7)CN I-
121
55
(CHa)(C2H&&CH(n-CsH7)CN I-
132
57
(CHa)&CH (i-CaH 7)CN I-
177
59
(CHs)(CzHs)2fiCH(i-CsH7)CN I-
150
61
( c H ~ ) ~ ~ c ( c H ~ ) ( c ~ H ~I-) c N
216
63
(CH3)(CzHs)zfiC(CHs)(C2Hs)CN 1-
65
(CHa) ( C ~ H S ) Z ~ ~ C H ( ~ - C I HI-Q ) C N
21
EWINS,Biochem. J . , 8, 369 (1914).
a. 220
116
-
28.63 28.63 28.58 30.15 30.23 30.17 40.6740.60 40.56 52.88 52.53 52.52 47.35 47.16 195-1961' 47.17 1922 23.86 23.88 228-2292' 49.96 49.89 49.82 47.35 47.41 47.42 45.00 44.86 45.02 49.96 50.01 49.95 47.35 47.32 47.30 45.00 44.96 44.98 38.60 38.42 38.38 47.35 47.46 47.34 45.0045.06 44.91 42.8742.91 42.94 47.35 47 33 47.39 42.87 42.77 42.67 47.35 47.34 47.32 42.8742.74 42.90 40.94 40.90 40.861 ~
~
594
__
DANIEL B. LUTEN, JR.
TABLE 11-Concluded ~
BALYEN
j LITERA-
NUM-
BER
SUBETANCE
67
165
69
119
71
188
73
191
76
199
78 79
158
83
206
84
183
85
152
S6
154
__
45 .OO 45.09 45.09 40.94 41.15 41.14 45.00 45.30 45.37 45.00 45.26 45.23 40.94 41.00 40.92 42.02 41.81 1008 41.69 31.33 31.28 31.32 47.71 47.43 192-1931' 47.48 45.32 44.93 45.04 43.16 43.08 42.99 27.45 27.12 27.23
For the sake of convenience the aminonitriles and the quaternary salts are tabulated separately, but they are numbered as if they were tabulated in one series. Specific exceptions to the general methods are described in detail in the experimental section. EXPERIMENTAL
The general methods for the preparations of the aminonitriles are outlined below. Method I.-A concentrated aqueous solution of the aldehyde bisulfite is prepared by the addition, with cooling, of a slight (5%) excess of solid sodium metabisulfite to a concentrated aqueous solution of the deeired aldehyde. After the completion of this reaction as evidenced by the cessation of evolution of heat one equivalent of amine is added t o the solution a t room temperature, with stirring. In many cases the sodium salt of the aminosulphonic acid precipitates from the solution as a gelatinous mush. The addition of saturated aqueous potassium cyanide dissolves the precipitate (heating is necessary in certain cases) and reeults in the rapid formation of the aminonitrile as a n upper, oily, layer. This is separated, dried over potassium carbonate, and vacuum-distilled.
PREPARATION OF AMINONITRILES
595
Method II.-The directions of ImmendorferBwere adhered to in most cases. To a concentrated aqueous solution of the desired amine hydrochloride an equivalent amount of potassium cyanide was added, following which the desired ketone or aldehyde was added in about 30% excess. The resulting mixture was left on a shaker for a period varying from two to forty-eight hours as indicated in Table I. The appearance of an oily phase in the mixture, and the odor of the mixture indicate roughly the extent t o which the reaction has proceeded. The aminonitrile was removed and treated as described above. KO great pains were taken t o obtain the aminonitriles in high purity since they served only as intermediates in the preparation of the quaternary derivatives. However, Dr. C. H. Li7 has prepared a number of the aminonitriles in highly purified form, and has obtained the same values for the boiling points as were obtained by distillation of the crude materials. The yields obtained and boiling points of the aminonitriles are given in Table I. The quaternization reactions were carried out in dry acetone or n-propyl alcohol solution. The simpler derivatives reacted rapidly at room temperature, dilution with solvent being necessary t o keep them under control. The slow reactions were carried out in a thermostat at 60"; higher temperatures appeared to favor too much the formation of resinous substances. Well over a month's reaction time was required for a number of the preparations under these conditions. The yields were nearly quantitative for the more rapid reactions, but diminished regularly as the rates decreased. In a number of cases the quaternary salts were most easily obtained by the reaction of iodoacetonitrile with the desired tertiary amine. This is especially true, owing to the great reactivity of the iodoacetonitrile, when one of the higher alkyl halides must be treated with an aminonitrile. The iodoacetonitrile was prepared by the method described by von Braun.8 Two preparations of iodoacetonitrile gave yields of 443 grams and 130 grams, 78% and 73%, respectively, boiling from 73" to 78" at 6-9 mm. pressure. Von Braun observed a boiling point of 73-76' at 7 mm. and obtained a yield of 70-75% of a somewhat more carefully purified product. The crude salts were recrystallized from n-propyl alcohol. In this process high yield8 of the quaternary salts were sacrificed to obtain greater purity. Ordinarily, one recrystallization was sufficient to give a product of more than 99.5% purity, but in a few cases three or four recrystallizations were necessary. Most of the salts are very rioluble in hot n-propyl alcohol, but some of the ketone derivatives will not dissolve until water t o the extent of a few per cent. is added t o the alcohol. The temperature coefficient of solubility is high as is usual with iodides. The solubilities of the sdts in water may be qualitatively correlated with the melting points and weight of the alkyl radicals; high melting point and high molecular weight both result in diminished solubility. The iodine content of the salts was determined by titration with silver nitrate, using a chromate indicator. The melting points were determined as described by Luten and Stewart1b. They are easily reproducible t o within four or five degrees. The analyses and melting points of the quaternary salts are given in Table 11. In the following paragraphs specific points with regard t o the preparation or propIMMENDORFER, Ber., 48, 606 (1915). Private communication. 8 VON BRAUN, Ber., Pi, 2134 (1908).
596
DANIEL B. LUTEN, JR.
erties of certain of the substances described are presented. The italicized number at the beginning of each paragraph refers t o the number of the substance used in Tables I and 11. (4, 6) Extremely soluble in n-propyl alcohol. (6) Slightly soluble in n-propyl alcohol. ( 7 ) Obtained as an apparently non-crystalline wax. Very slightly soluble in water. ( 8 ) Obtained from the corresponding nitrile by the method described by Luten and Stewartlb. (14) The yield on quaternization was in the neighborhood of 5%. (19) Prepared from the aminonitrile and n-propyl iodide and also from tri-npropylamine and iodoacetonitrile. J. von BraunZ0 prepared the bromide but not the iodide. (24) Prepared only from the tertiary amine and iodoacetonitrile. (90) This material decomposed slowly on storage; it probably was never obtained in a very pure condition. It was prepared from iodoacetonitrile and ,%diethylaminoet hanol. (SI) Prepared from the aminonitrile and ethyl bromoacetate. (32, 33) The iodide was prepared from the aminonitrile and ethyl P-iodopropionate. No difficulties were encountered. In the preparation of the bromide using ethyl p-bromopropionate considerable olefin formation occurred, judging from the fact that a large part of the product was trimethylamine hydrobromide. Repeated crystallization from n-propyl alcohol gave a product free of the hydrobromide. ($4) The small yield in this reaction is probably due to the removal of acetaldehyde by the competitive aldol condensation reaction. (38) The chloride was prepared without difficulty from trimethylamine and 8-chloropropionitrile, as described by Ewins.21 An attempt was made t o prepare the corresponding bromide from 8-bromopropionitrile (b.p., 58-61", 15% yield) which in turn was prepared from ethylene cyanohydrin and phosphorus tribromide. The reaction of this substance with trimethylamine was very rapid, although carried out below zero degrees, and gave a product which was 75% trimethylamine hydrobromide and only 25% quaternary salt; the latter substance was never recovered pure from the mixture. (46) This substance decomposes a t about 250" without melting. (60) This substance melts at 226' without perceptible decomposition. I t was prepared from trimethylamine and y-bromobutyronitrile. The latter Substance was prepared from trimethylene bromide and potassium cyanide by the method described by Derick and Hess.22 (67) One preparation of this material was impure after the first recrystallization and became more so upon repeated recrystallization; a second preparation, however, was satisfactory after the first recrystallization. (68) Decomposes without melting a t about 220". (71, 75, and 76) Considerable difficulty was encountered in the purification of these substances. For recrystallization, dilution of the alcoholic solvent with water gives more satisfactory results. (78) The method of preparation described by J. von Braun6 (iodoacetonitrile and dimethyl-p-toluidine) was employed. This and similar aryl derivatives are unstable under ordinary conditions of storage. The related phenyl derivative becomes 22
DERICKAND HESS,J . Am. Chem. SOC.,40,546 (1918)
PREPARATION OF AMINONITRILES
597
largely decomposed within two months; the p-tolyl derivative requires about ten times as long t o reach the same condition. (79) This substance was prepared from the aminonitrile and benzyl bromide. The quaternization reaction was rapid and unmarred by resin-forming side reactions. A crystalline product was easily obtained but on analysis i t was found to give an acid reaction which was due t o contamination by a n amine hydrobromide. It could not be purified by recrystallization from n-propyl alcohol owing to the fact that the acidic impurity was generated during the process. A satisfactory product was obtained by twice dissolving the salt in cold alcohol and precipitating i t with ether. (26, 25, 74, 29, and 47). The methiodides of the first three of these substances were never obtained in a crystalline form, although i t was clear that the quaternization reaction proceeded at a fairly high velocity. In view of the lack of success with these substances no attempt was made to quaterniae (n-CsHlr)ZNCHzCN (19). Similarly, in view of the fact that i t was much more difficult to prepare the ethiodides than the methiodides of the higher aldehyde and ketone derivatives, no attempt was made t o prepare the propiodide of (CHa) (CzHs)NC(CHa)zCN (47),its methiodide and ethiodide already having been prepared by different routes. Four other compounds were conspicuous in their failure to crystallize : (i-CdHo)a4NCHzC!N I-, (n-CbHii)aNCH&N I-, (i-C6Hii)3NCHzCN I-, and (CaH6CHz)a4XCHzCIK I-. In each case the attempt at the preparation was made with iodoacetonitrile and the appropriate tertiary amine, and there was no doubt that the quaternization reaction took place.
+
+
I am indebted to Dr. Bernhardt Weidenbaum and Mr. Karl Polifka for the preparation of several of the aminonitriles. SUMMARY
A series of thirty-three aminonitriles, largely aliphatic derivatives, and Uty-two betaine nitrile salts, most of which are dervived from the aminonitriles, have been prepared. The limitations of two general methods of preparation of the aminonitriles are outlined.
