May 1948
INDUSTRIAL AND ENGINEERING CHEMISTRY
Gunther, F., and Hetzer, J., U. S. Patent 1,737,792 (1929). Gurwitch, L., "Scientific Principles of Petroleum Technology," p. 415, London, Chapman & Hall, 1926. Hilmann, E. S., and Barnett, B., Proc. Am. SOC.Testing M a t e -
897
Menschutkin, B. N., and Wolf, M. B., Neftyanoe Khoz., 13, -340 (1927).
Mikeska, L. A , , IND. ENG.CHEM.,2 8 , 9 7 0 (1936). Murphy, B. A., J . I n s t . Petroleum, 31 (264), 475 (1945). Neyman-Pilat, E., and Pilat, S. von, IND. ENG.CHEM.,33, 1382
rials, 37,558-66 (1937).
Institute of Petroleum, Standard Methods, p. 10, Method A, London, 1945. Ibid., p. 318, London, 1945. Konovalow, M., Chem.-Ztg., 14,113, 145 (1890). McIlhiney, P. C., J. SOC.Chem. I n d . , 13, 668 (1894). Marcusson, J., Burchartz, H., and Wilke, P., "Die natnrlichen and kilnstlichen Asphalte," 2nd ed., Leipzig, Wilhelm Engelmann, 1931. Markownikov, W. W., J . Russ. Phys. C h e m . SOC., 24,141 (1892). Markownikov, W. W., and Rudevitsch, W., Ibid., 30, 586
(1941):
Otto, R., Ber., 19, 1832 (1886). Petroff, G. S., German Patent 264,785 (1911). Pilat, S. von, Sereda, J., and Szankowski, W., Petroleum Z . , 29 (3), 1 (1933).
Pilat. S. von. and Szankowski,W.. Ibid..31, 10 (1935) Rudevitsch, W., J . Russ. Phys. Ohem. Sac., 25, 385 (1893). Schestakoff, P. I., and Robinowitsch, A. R., Ibid., 45, 664 (1913).
Tilicheev, M. D., and Kuruindin, K. S.,C h e m . Zentr., 1931 I, 2559.
(1898).
Vlugter, J. C., Waterman, H. I., and Van Western, H. A , , J . Inst. Petroleum, 18, 735 (1932) ; 21, 661, 701 (1935).
Markownikov, W. W., and Spady, J., Ber., 20, 1850 (1887). Marx, K., Brodersen, K., and Quaedvlieg, M., U. S. Patent 2,014,502 (1935).
RECEWED Febmsry'l2, 1947.
Application of Cinchona Alkaloids in the Rubber Industry d
R . F. A. ALTMAN' AND G. J. VAN DER BIE Rubber Research Institute, Buitenzcorg, Java I n an attempt to find new applications for the cinchona by-product alkaloids which are qbtained in considerable quantities as waste in the quinine industry, the alkaloids originally present in cinchona bark as well as different quinine variants, specially prepared for the purpose, have been tested as vulcanization accelerators and antioxidants for rubber. The results are summarized in tables and graphs. Sofne of the compounds appear to be equal in activity to certain widely used commercial accelerators and antioxidants.
One of the present authors ( I ) , while agreeing with this contention, suggested some alterations in Rabe's specific proposals to bring them into line with international rules for the nomenclature and numbering of organic ring systems (7'). Theoretically speaking, all quinine variants may be considered as derivatives of the following systems, which have been named rubiacine and rubatoxine: H C
H
N
//"\c/">cH
"CH
1
0
NE of the most important problems in cinchona research
has been and still is to find practical and economical uses for the by-products of quinine production-that is, the nonquinine alkaloids of cinchona bark. At a prewar production of half a million kilograms of quinine a year, not less than I61,OOO kg. alkaloids were obtained yearly as a waste product (9) which has, perhaps with the exception of quinidine, far less value than quinine itself. The quantity of these by-products used in drugs constituted only a minute fraction of the quantity produced. Results are described here of a n attempt to apply cinchona alkaloids and some of their derivatives as accelerators and antioxidants for rubber. The idea is not new, as in 1922 Eaton and Bishop ( 4 ) investigated the accelerating activity of a limited number of cinchona products in rubber vulcanization. The literature on the chemical constitution of known accelerators and antioxidants indicated t h a t some of the cinchona alkaloids and certainsof their derivatives would be active accelerators and antioxidants. As will be seen from the experimental section of this paper the alkaloids can be converted relatively easily into derivatives containing groups favorable t o accelerating activity, such as amino groups and dithiocarbamic, thiourea, and thiazole residues.
b 3fhH \if/ \ ; /
B'CH €€
9
8,'
CHz-CH
I
CH2
\
Rubiacine
"H,
;CHz
\ 4 /
' Rubatoxine
Thus, quitenine, for example, may be called 3-carboxyl-9hydroxy-6'-methoxyrubiacine, and cinchotoxine, 3-vinyl-9hydroxyrubatoxine. Trivial names, however, such as quinine, cinchonine, etc., which have long been in use and cannot lead t o confusion, are retained. TEST METHODS
NOMENCLATURE
About 25 years ago Rabe (8)called attention to the desirability -of adopting a systematic nomenclature for the cinchona alkaloids. 1
Present address, Laan van Meerdervoort 52 H, The Hague, Holland.
The accelerating'activity of the different cinchona preparations have been estimated by curing in the following stocks, in parts by weight: (a) A.C.S. compound: 100 rubber, 3.5 sulfur, 6 zinc oxide, 0.5 stearic acid, 0.5 accelerator; ( b ) a compound of the Govern-
898
Vol. 40, No. 5
INDUSTRIAL AND ENGINEERING CHEMISTRY
ARB( DIPHENYLGUANIDINE HY DROPUlNlDlNE
15
T
I
t
I
%m'.
I I
HYDROCINCHONINE PUlNlDlNE HYDROCINCHONIDINE HYDRO UlNlNE CAPTAF: WINATOX INE CINCHOTOXINE HYDROPUINATOXINE
.
the various vulcanizates mere aged as follom and tested after 24 hours' rest: (a)heated in a Geer oven a t 70" C. for 4 weeks; ( b ) submitted to the action of oxygen under a pressure of 20 atmospheres and a t 70" C.; (c) 3 hours a t 127"C. under 5 atmospheres air pressure.
C CINCHONIDINE
100-
v3NCHONINE
DISCUSSION OF RESULTS
From the results obtained the following preliminary conclusions may be drawn. 1. I n general, the hydrogenated quinine variants I (hydrogenated in the 3-vinyl I group) are better accelerators i than the unhydrogenated compounds. 2. Introduction of a C1-, NO ACCELERATOR YO,-, or "2into the quinoline nucleus does not influence perceptibly the acII 1 1 celerating capacity. 040 45 50 55 $0 3. Oxidation of the vinyl MINUTES A T 147'C. group t o a carboxyl group has Figure 1. Accelerating Activity of Cinchona Alkaloids and Derivatives in Stock of an unfavorable influence. Rubber 100, Sulfur 5, Zinc Oxide 3, Accelerator 1, Cured at 147' C. 4. The toxines and thcir phenylhydrazones and oximes show only little difference in activity from that of the unchanged cinchona alkaloids. merit Rubber Service, Delft. Holland: 100 rubber, 5 sulfur. 3 0
50
1
I
i
F
captax (m~ercaptobenzothiazo~e) or DPG (diphenylguanidine)
t
-
6. Dithiocarbamic acid derivatives of some of the cinchona materials are equal t o Captax in accelerating action and, in view were used as controls in each of the three stocks. The tensile of the ease M,ith>,,-hichthey can be prepared, shouid be of pracstrength ( T ) , elongation a t break ( E ) , and modulus at 600% ticalvalue. (T-BOO)weremeasured on the Schopper machine, and the hardness ( H ) by the Shore duromINCHOTOXINE -CAPTAX UINATOXINE CAPTAX eter. The results obtained are summarized in Tables I to I V and Figures 1 to 4. In the tables the optimum cures have been indicated. I n testing the cinchona preparations as antioxidants, account is taken of their possible accelerating effect. Stocks are compared a t equal statesof cure, preferably a little short of the optimum cures, because overcured samples quiclcly liquefy when subjected t o accelerated aging. Figure 2 . Accelerating Aotivity of Cinchona Alkaloids and Derivatives in Stock of Rubber 100, Sulfur 5, Zinc Oxide 3, Accelerator 1, Cured at 127" C. Rings cut from
-
May 1948
I N D U S T R I A L A N D E N G I N E E R I N G CHEMISTRY
7. Unlike most of the common vulcanization accelerators, the quinine variants are active without zinc oxide.
*
In brief, the present investigation, although far from exhaustive, is not discouraging but indicates the possibility of developing worth-while accelerators and antioxidants from the by-product cinchona alkaloids. The possibilities of modifying these alkaloids are numerous. Besides the modifications of the quinoline nucleus, the quinuclidine nucleus, and the bridge chain, alone or in combination with one another, the coupling of basic quinine variants with all kinds of acid products, or the' combination of acidic variants with bases, or again, the decomposition of the alkaloids into quinoline and piperidine derivatives, may yield useful accelerators or antioxidants. The authors' colleague, W. B. Deys (s), prepared the sodium, lead, and zinc salts of cinchotoxine dithiocarbamic acid (l-dithiocarbamic acid-3-vinyl-9-hydroxyrubatoxine). The two latter salts (designated by Deys as PbX and ZnX) and also certain alkaloid-Captax double salts (ARB,, ARB2, and ARBB) prepared by one of the present authors (IO)were found to have an accelerating action in rubber vulcanization, and this led to the present more extended investigation. In the following sections the preparation of the quinine variants under investigation is given only when the compound has not been previously described in the literature or when significant improvements were made in procedure or yield. New compounds have been numbered ARI, AR2, AR3, etc.
TABLE I. ACCELERATINGACTIVITYOF CINCHONA ALKALOIDS AND DERIVATIVES FOR STOCK CUREDAT 147' C. (FIGURE 1) Stock: rubber 100, sulfur 5, zinc oxide.3 accelerator 1; t = time of cure minutes; T = tensile strength, kg./sq. c&.: E = ultimate elongation, %; T-600 = modulus a t 600% elongation: H = Shore hardness
H
T
E
None (control)
30 45 60 75
3 21 19 32
761 961 867 915
Csptax
20 30 40 50 60
115 124 133a 131 132
882 841 830 842 820
20 80 40 50 60
138 153 166 174a 161
979 919 803 774 755
30 45 60 75
26 89 103= 60
1030 925 925 830
11
28 36 36 36
20 30 40 50. 60 2n -_ 30 40 50 60
74 95 146" 141 147
1063 1029 958 895 860
15
33 29 39 40 41
(17
103 141a 136 135
1019 986 934 880 860
16 1
33 40 40 40 43
30 40 50 60 80
36 57 67 79 93
947 926 892 863 857
30 45 60 75
76 89 143a 131
20 30 40 50 80
t
Accelerator
DPG
Cinchonidine
Hydrocinchonine
Hydrocinchonidine
Quinine
RUBIACINE DERIVATIVES
5'-A~flNOHYDROQUININE (3-ETHYL-9-HYDROXY-5'-AMlNO-6'METHOXYRUBIACINE). Contrary t o the description given by Jacobs and Heidelberger ( B ) , this compound can be easily prepared in the following way: A solution of 37,5 grams of 5'nitrohydroquinine in 50 ml. of hydrochloric acid (density = 1.19) and 200 ml. of water is slowly added to a solution of 125 grams of SnCl2.2Hz0in 300 ml. of hydrochloric acid (d = 1.19), t o which 75 ml. of water had been added after the complete dissolution of the stannous chloride in the strong acid. The temperature is held a t 40" t o 45" C. After the mixture is left for half a n hour, a bright red solution is obtained containing a considerable quantity of the orange-colored double salt of stannous chloride and 5'-aminohydroquinine. The free base is obtained by diluting the mixture with water enough t o dissolve the orange crystals completely, adding an excess of 2570 sodium hydroxide, and filtering off the yellow precipitate. The latter, originally amorphous, turns t o a crystalline product when digested with ether. Recrystallization from dilute alcohol yields yellow needles combined instars. Melting point (m.p.), 223" C.; N: found, 12.3%; calculated for C2~H2~OZN3, 12.32%. AR14 (DOUBLE COMPOUND O F 1 MOLE5'-AMINOHYDROQUININ~ AND 1 MOLE 3-ETHYL9-HYDROXY-5'-DITHIOCARBAMIC ACID-6 METHOXYRUBIACINE). This is easily obtained in quantitative yield by adding an excess of carbon disulfide t o a saturated benzene solution of aminohydroquinine. Almost immediately a voluminous mass separates, apparently consisting of colorless needles which decompose a t 115" C. with evolution of hydrogen sulfide. The compound is very soluble in chloroform, methanol, ethanol, and carbon disulfide; slightly soluble in benzene, acetone, and ethyl acetate; and insoluble in water, ether, and ligroin. ARI4 is cpmpletely soluble in dilute hydrochloric acid with a speci.fic red color indicating the presence of 5'-aminohydroquinine. I n diluted caustic alkali the preparation only partly dissolves; the insoluble part, isolated by means of a n ether extraction, was identified as 5'-aminohydroquinine. Since A R I ~ decomposes a t ordinary temperature it could not be analyzed; its identification follows from the analysis of its decomposition product ARI5. ARlj [SYMMETRICAL BIS(5'-AMINOHYDROQUINYL)THlOUREA]. This compound is obtained in 80% yield by boiling the alcoholic solution of ARI4 under reflux in the presence of carbon disulfide for several hours, until no more hydrogen sulfide is formed. The brown mass thus obtained is evaporated t o dryness and the dark colored residue taken up with dilute hydrochloric acid. From this solution, filtered, if necessary, the base is precipitated with ammonia and extracted with ethyl acetate. Thereupon the solution is dried over anhydrous sodium sulfate, boiled for a short time with charcoal, and concentrated t o a small volume. On cooling, ARls separates in rhomboidal leaflets of a light brown color. By recrystallization from dilute alcohol, colorless leaf-
899
Quinidine
Hydroquinine
Hydroquinidine
Cinchotoxine
Quinatoxine
-
'
Hydroquinatoxine
ARBl (quinine-Captax)
a
,
T-600
5 28
53
.. ... ... 36 39 40 41 41 38 44 44 46 46
28 33 16
36 37
1000 995 904 897
15
32 33 38 38
58 80 137a 132 134
1043 984 951 904 856
14
20 30 40 50
83 103 157''
1029 991 952 900 854
16 7
33 40 40 42 41
20 30 40 50 60
72 100 120a 116 120
1053 1043 983 934 914
11 2
32 33 40 40 39
61 77 ll9Q 120 123
1008 982 967 92 1 903
12 2
32 35 38 40 40
20 30 40 '50 60
94 113 l66a 135 118
1042 948 925 877 878
19.2
35 37 37 41 40
30 40 50 60
155 161a 164 165
773 805 763 760
39
43 40 44 44
20 30 40 50 60
160
'
33
35
39 41 41
Optimum cure.
lets are obtained. M.P., 192" C. Found: N, 11.3%; F, 3.1y0; calculated for C4,Ha204N&3: N, 11.6%; 8, 3.51%. 5'-CHLOROHYDROQUININE (3-ETHYL-g-HYDROXY-5'-CHLORO-6'METHOXYRUBIACINE). A solution of 17 grams (0.05 mole) Of 5'-aminohydroquinine in 100 ml. of hydrochloric acid (1:2) 1s diazotized a t 0" C. with 50 ml. of a 1 N sodium nitrate solution. The diazonium chloride is slowly poured into a solution of 20 grams of freshly brepared cuprous chloride in 150 ml of concentrated hydrochloric acid t o which some copper shavings have been added. The temperature is held at 80" C., nitrogen being evolved vigorously. The resulting dark brownish-green liquid is poured into 500 ml. of 2% hydrochloric acid. (When water instead of 201, hydrochloric is used, 5'-chlorohydroquinine separates in the form of a copper-containing brown oil.) The clear light brown solution is treated with hydrogen sulfide to
900
Vol. 40, No. 5
INDUSTRIAL AND ENGINEERING CHEMISTRY TABLE 11.
hCCELERATIXG h C T I V I T Y O F
Accelerator Captax
DPG
Quinidine
H ydroquinidine
t 20 30 40 60 80 100 120 40 60 80 100 120 150 40 60 80 100 120 150 40 60 80
Quinatoxine
in0 120 150 40 60 80
ion Cinohotoxine
Cinchotoxine-phenylhydrazone
120 40 60 80 100 120 40 60 80
ion
ARia (zinc salt of quitenine)
ARis
AR3L
.4 R PI
XRRl (quinine-Captax)
40 60 80 100 120 40 60 80 100 120 150 40 60 80 100 120 150 40 60 80 100 120 150 40 60 80 100 120 150 20 30 40 60 80
T 86 120 133 161 1806 173 169 49 78 89 140 157 170 14 30 31 63 83 89 28 42 41 78 97 111 12
28 38 58 77 8 23 38 52 77 12 24 40 56 0
03 1.3 1.6 11 6 21 17 45 57 71 15 30 33 80 104 118 32 47 42 98 141 b 139 32 52 45 104 112 144 117 164 170 197 204b
CINCHONA E 974 930 919 880 865 862 844 1005 989 924 9s3 929 881 1138 1128 1032 1039 1033 955 1122 1026 1103 999 990 930 1145 1138 1125 1116 1096 1100 1140 1126 1117 1090 1148 1140 1119 1079 800 7011 700 900 1000 970 1089 1030 983 961 934 1092 1017 949
ALKALOID3 AND
T-600
30
19
6
10
4
4
3
8
985
994 932 1090 1023 1091 1020 999 950 io70 1009 1110 1010 970 963 928 887 859 819 799
10
8
13
56
H 30 34 35 38 40 41 40 32 34 35 36 40 41 28 28 27 30 32 35 30 30 26 32 35 36 26 25 30 26 30 26 25 30 26 30 28 25 30 25 20 21 21 21 22 28 28 26 30 32 33 29 30 30 33 35 37 30 30 26 35 37 39 30 31 27 36 36 39 35 37 40 41 42
remove copper. 5'-Chlorohydroquinine is then precipitated with ammonia and extracted with ether. The ethereal solution yields crystals of the desired product after drying over sodium sulfate, shaking with charcoal, and concentrating t o a small volume. Recrvstalliaation from et,hyl acetate gives white silky prisms or needles melting sharply a t 206" C. Yield, 14 grams (80%). 5'-Chlorohvdroquinine is very soluble in chloroform, methanol, and ethanol;" fairly soluble in acetone and benzene; and only slightly soluble in ethyl acetate, ether, and ligcoin. Found: N, 7.42%; C1, 9.72%; calculated for C20H2j02K2C1:N,7.77%; Cl, 9.85y0. A& [ 8'-NITROHYDROCIXCHOKIXE (3-ETHYL-9-HYDROXY -8'NITRORUBIACINE)]. This compound was obtained as follows in a Rood vield and in a much simpler way than by the method given hy Giemsa and Oesterlin ( 5 ) . Seventy-five grams of hydrocinchonine sulfate are added in small portions t o a mixture of 200 grams of nitric acid (d = 1.40) and 300 grams of sulfuric
DERIVATIVES FOR
STOCK"
Accelerator
-4RBz (cinchonine-Captax)
+RHa (cinchonidine-Captax:
Cinchotoxine-Captax
Qainatoxine-Caytar
ARio
ARll
AR3
ARa PbX (lead salt of cinchotoxine dithiocarbamio acid)
ZnX (zinc salt of cinchotoxine dithiocarbamic acid)
b
CERED A T 127 ' c. (FIGURE 2) t 100 120 20 30 40 60 80 100 120 20 30 40 60 80 100 120 20 30 40 60 ion 120 20 30 40 60 80 100 20 30 40 60 80 100 20 30 40 60 80 100 120 40 60 80 100 120 150 40 60 80 100 120 40 60 80 ion 120 40 80 120 40 60
80 100 120 40 60 80 100 120
T 197 197 110 152 166 200 207b 200 207 148 187 203 207 b 210 206 200 142 171 162 1816 185 178 150 172 177 194b 192 180 87 125 139
138
1486 139 123 151 197b 174 180
161 176 62 56 88
101 121 125 31 55 77 81 95 121 149 l58b 146 162 124 138b 137 134 14 165 169b 159 92 104 111 104 111
E 773 771 949 902 876 843 821 810 804 902 870 851 815 796 788 774 984 922 886 874 856 833 964 910 884 875 846 834 1027 980
T-600
49
53
31
32
955
943 958 938 1045 982 928 890 885 866 878 1006 920 957 1000 1003 970 1140 1123 1107 1088 10G4 102.9 973 947 914 902 910 948 926 1039 958 936 926 888 1057 1022 1006 986 973
H 45 45 33 36 39 40 41 44 44 36 39 40 43 42 45 43 33 40 40 40 40 45 35 40 40 40 43 40 34 38 38
15
15
3d 40 35 31 34 37 39 38
9
J
17
15
21
9
40 40 33 31 33 34 36 37 25 27 28 30 32 31 35 35 37 38 32 35 36 32 35 33 40 40 30 31 32 35 33
Same stock a8 in Table I. Optimum cure.
acid (d = 1.98) a t 80-85" C. The pale yellow reaction mixture is left for 1 hour and then poured on crushed ice. After diluting with water, the solution is neutralized with sodium hydroxidt: and made alkaline with ammonia. The amorphous precipitat,e is filtered off, mashed thoroughly with water, and recryst,allized from dilute alcohol (yield, 8073. The prisms, which have a pale yellow color, turn brown a t 180" C. and decompose with cvolution of gas a t 253-255' C. AR,, is soluble in all organic solvents, especially in chloroform and methanol. The solut,ion in dilute hydrochloric acid has a dark yellow t o brown color. ?;: found, 12.26y0; calculated for C1BH2303K3, 12.327,. AR32 [8'-AXINOHYDRoCISCHOXIKE (3-ETHYL-9-IIYDROXY-8'AZIINORUBIACINE)] . This compound is prepared in quantit,ative yield from ARsl in the same manner as 5'-aminohydroquininc was obtained from 5'-nitrohydroquinine. The reaction temperature, however, can better be held at, 60" C. The raw product, when recrystallized from dilute alcohol, yields colorless microscopic
May 1948
INDUSTRIAL AND ENGINEERING CHEMISTRY
90 1
TABLE 111. ACCELERATING ACTIVITYO F CINCHONA ALKALOIDS AND DERIVATIVES (FIGURE 3) Accelerator Captax
(Stock: t 20 30 40 50 BO
DPG
H ydroquinidine
20 30 40 50 60 20 30 40 50 60
40 50 40 50 20 30 40 50 60 40 50 10 20 30
260;
ARio ( 1 part)
ARio (1.5 parts)
ARio (2 parts)
10 20 30 40 50 60 10 20 30 40 50 60 10 20 30 40 50 60
rubber 100, sulfur 3.5, stearic acid T H E T-600 111 963 36 945 37 117 40 1535 13 917 876 41 147 42 871 155 1140 27 18 1141 28 17 1130 30 38 31 1118 63 4 1075 32 66 2 27 838 2 28 896 30 1106 17 23 31 1077 45 32 1107 3 4 27 1033 27 1136 14 27 1046 8 26 1127 30 27 820 871 28 29 1119 ' 1i 1109 30 26 30 2 1089 37 1017 27 9 27 24 1129 25 2 878 26 ,1123 30 1100 55 30 32 1094 75 32 1054 93 6 1071 34 108 26 4 800 29 1082 88 32 1029 119 37 076 136 39 941 143. 40 938 156 17 952 30 13 33 in35 131 36 167 978 39 163 9 57 41 21 176a 933 43 912 171 29 18 975 3 3 120 1018 37 167 959 40 167 945 41 174a 907 26 42 170 889
...
TABLE IV. Accelerator Captax
DPG
Cinchonidine
0.5, accelerator 0.5; cured a t 127' C.) t Accelerator 10 ARza 20 30 40 50 60 20 P b X (lead salt of quinntovine dithiocarbamic acid) 30 40 50 60 20 ARBi (quinine-Ceptax) 30 40 50 60 20 ARBS lcinchonidin~-(;"aptax) ' 30 40 50 60 10 ARZJ(hydroquinine-Captax) 20 30 40 50 60 10 AR2r (hydroquinidine-Captax) 20 30 40 50 60 ARz6(hydrocinchonine-Captax) 10 20 30 40 50 60 ARw (hydrocinchonidine-Captax) 10 20 30 40 50 60 Optimum cure.
RESULTSWITH EATON AND BISHOP'SCOMPOUND (FIGURE 4)
47
E 1073 1112 1073 1040 1032 1018 1085
49 110 120a 104 125 142 166 ,18Za 178 55 73 110 139a 129 4 96 129 140 157a 152 2 76 111 114 129s 124 7 114 152 159 187 198 5 88 144 157 174" 177
1063 1044 994 923 917 900 850 826 812 945 917 868 859 822 749 952 852 848 803 779 711 946 870 848 806 773 850 959 868 870 827 816 809 985 883 887 840 81 8
T 6 53 84 101 1294 114
?'-600
8
8
26
15
37
29
44
AR32
31 35 36 38 37 38 41 42 45 34 36 40 41 42 26 35 39 42 45 46 26 35 39 41 43 43 27 36 40 41 45 46 27 34
34
40 42 44 46
'
(Stock: rubber 100, sulfur 10, accelerator 1; temperature of vulcanization 140' C.) t T E 2'-BOO H Accelerator t T E 785 24 ARzi 10 13 10. 0 1136 928 32 20 50 1052 20 26 977 36 30 64 969 30 74 946 39 40 95 942 40 94 912 15 41 964 60 147a 60 150a 100 13 276 46 100 158 858 10 59 984 30 ARM 10 10 1131 40 20 134 905 20 46 998 sn 713 940 835 23 41 30 164Q .. .. 774 43 40 163 40 iii 937 47 936 60 27 365 60 158a 100 17 232 51 100 146 809 10 0 474 23 ARw (hydroquinidine-Captax) 10 24 1096 20 37 1047 30 20 76 954 30 85 . 961 36 30 90" 826 40 111 928 41 40 15 410 60 143a 883 10 43 60 9 223 100 33 488 100 12 220 10 10 1084 Samples Tested b y Eaton a n d Bishop b 20 990 30 936 Cinchonine 25 145 1014 40 953 18 Cinchonidine 25 128 994 496 60 Quinine 35 142 985 267 100 i5 Quinidine 50 120 1020 Accelerator X 10 11 50 140 1025 Control test 20 60 165 142 1035 30 103 40 149 22 a Optimum cure. 161a 60 b Times recorded are optimum vulcanization times. 100 26
T-600
H
11
27 33 35 36 40 45 27 33
.
38 ..
13
14
..
Hydroquinidine
H 25 26 30 32 31 34 30
.. .. .. .... ..
36 41 42 27 35 41 40 43 48
.. .. .. .. ,. ..
E 02
INDUSTRIAL AND ENGINEERING CHEMISTRY
Vol. 40, No. 5 oil; could not be obtained in a crystalline form, even after repeated purifications. The purified product, was free from chlorine. S: found, 4.6%; calculated for CaoHls02NdS, 4.95YG7,. ARla [5'-NITROHYDROQUINIDIN E (d-3-ETHYL-9 - H Y DROXY-5' XITRO6'- METHOXYRUBIA C I N E ) ] was ob-
-
tained according to the method described by Jacobs and Heidelbcrger (6).
Anis. (~'-AMIso-
H Y D R 0 Q CI N IDINE). This com-
pound is prepared according to the method followed for the preparat,ion of 5'-aminohydroquinine ( 6 ) . I t appears as short yellow prisms (from e t h e r ) which prompt,ly MINUTES AT 127'C. darken in the air. Figure 3. Accelerating Activity of Cinchona Alkaloids and Derivatives in Stock of Rubber 100. M.p., 236" C . Sulfur 3.5, Zinc Oxide 6, Stearic Acid 0.5, Accelerator 0.5 N: fouud, 12.17'0; calculatd for G o H2,02N3, 12.32%:" DOUBLECOMPOUNDS O F CAPTAX TTITH CINCHONA ALKALOIDS. needles or prisms melting at 245" C. Thp compound is very These salts can easily be prepared as follows: Alcoholic solusoluble in chloroform: soluble in alcohol, acetone, and ethyl acet8ions,saturated a t boiling temperature and filtered if necessary, tate; and slightly soluble in henzene, ether, and water. A soluof equimolar weights of 2-mercaptobenzothiazole and the alkaloid tion in dilute hydrochloric acid has, in contradistinction to 5'are mixed and refluxed for half an hour. I n some cases the aminohydroquinine, an orange color. N : found, 13.72YQ; caldouble compound separates during refluxing; in most other cases culated for C19F12jON3,13.95%. ARS3(DOUBLE COMPOUND OF 1 h l o r x AR32 ASD 1 hlordi: 3on cooling. All the double compounds (Table V) crystal!ize ETHYL-~-HYDROXY-~'-DITHIOCARBAMIC ACID-RUBIACINE). The as pale yellow needles, often combined in stars. preparation was the same as for AR,,. Instead of benzene, alcohol is a more suit,able solvent,. AR,, crystallizes in colorless needles, which were not, analyzed because of their rapid decomposition at, ordinary t e m p e r a ture. AR21(DIQCINYL-SSCLFIDE) . 9-Chloroquinine (2) is heated with a saturated alcoholic solut,ion of potassium suifide in a bomb at, 120-130" C. foi, 6 to 8 hours. The dark-colored solution obtained is concentrated t o a small volume, treated with diluted acid, filtered, and made alkaline ivith ammonia. The desired product separates as an oil which is taken up with ethyl acet,ate. The solution is dried over sodium sulfate, shaken with charcoal, filtered, and evaporated to dryness. Theresid u e , a broTvnish HYDROpUlNlDlNE
INDUSTRIAL AND ENGINEERING CHEMISTRY
May 1948
CARBAMIC ACID (1-DITHIOCARBAMIC ACID-3-VINYLg-HYDRoXY6'-METHOXYRUBATOXINE) 1. This compound is obtained easily
TABLE V. DOUBLE COMPOUNDS OF CAPTAX N, %
I$;'.;:,
No.
Double Compd. with
ARB1 ARzz ARB2 ARB3 ARza AR24 ARzs AR2e
inchonine Cinchonidine Hydroquinine Hydroquinidine Hydrocinchonine Hydrocinchonidine
178 125 207 156 183 139 204 152
Formula Found C I T H Z ~ O Z N ~ S8Z. 3 2 Same 8.17 8.92 CzeHz~0NsSn Same 8 88 CzrHsiOzNaSz 8.08 Same 8.22 8.82 CzsHzsONaSi Same 8.67
'
Calcd. 8.55 8.55 9.11 9.11 8.52 8.52 9.06 9.06
RUBATOXINE DERIVATIVES
*
903
The toxines themselves were prepared by the method of Von Miller and Rohde (1I), either by boiling t h e alkaloid solutions in dilute acetic acid for several hours or by heating the alkaloid bisulfates for a short time at 140" C.
-4Rio [DOUBLE COMPOUND O F QUINATOXINE(3-VINYLgHYDROXY-6 -METHOXYRUBATOXINE) AND QUINATOXINE DITHIO-
and in a quantitative yield by treating a concentrated benzene solution of quinatoxine with carbon disulfide. The reaction is exothermic. After the mixture is left for some time, a crystalline mass separates. The latter is filtered off, washed with cold benzene, and recrystallized from benzene (m.p., 71 C.). ARio is very soluble in chloroform, methanol, and acetone; dightly soluble in alcohol, benzene, and ethyl acetate; and insoluble in ether ligroin, and water. I n dilute acid the double cpmpound is completely soluble with a pale yellow color; in dilute alkali, however, it dissolves only partly and leaves an oil, which could be extracted with ether and was identified as quinatoxine. S: found, 8.1%; calculated for C41H6204N4S2,8.79%. AR1 (SODIUMSALTOF QUINATOXINE DITHIOCARBAMIC ACID). This salt is prepared from ARlo by adding the calculated quantity of 0.5 N sodium hydroxide to the dry acid. Some quinatoxine separates as a n oil and is removed by extraction with ether. Freshly prepared, the aqueous solution of ARl has a pale yellow color, but on stlandingthe color turns to brown and the solution becomes turbid.
ARa (LEADSALTOF QUINATOXINEDITHIOCARBAMIC ACID).
This compound is formed as a pale yellow precipitate by treating
TABLE VI. DETERMINATION OF OPTIMUMVULCANIZATION TIMES Stock: rubber 100, sulfur 3, zinc oxide 5, D.P.G. T-600 Antioxidant t T E None (control) 20 166 848 48 300 796 180 40 753 179 50 181 758 Agerite powder (1/z part) 20 148 838 30 169 788 55 40a 758 180 50 758 178 Agerite resin part) 20 169 877 30 168 797 40a 57 754 179 50 172 753 Agerite powder (1 part) 157 20 873 30 168 802 40a 183 757 57 50 178 759 20 149 Agerite resin ( 1 part) 878 787 30 157 40a 170 54 743 50 168 750 ARLOwithout D.P.G. 20 ... i33 30a 961 13 40 113 931 50 910 115 111 931 60 20 178 828 30a 180 51 792 40 179 744 50 182 756 60 165 764
1 (or less), antioxidant under test, 1; stocks cured at 147O C.) H E Antioxidant t T 40 ARia 20 841 185 44 779 30 a 182 46 40 73 1 183 45 50 725 180 60 160 731 42 44 AR2o 20 853 185 799 46 30Q 181 45 40 774 181 50 770 171 40 60 795 162 44 44 Quitenine 20 877 147 46 30 833 162 772 40 a 172 40 763 50 178 43 771 60 164 45 44 5'-Nitrohydroquinin~ 20 812 187 30 878 174 39 749 40a . ~. 181 41 50 742 175 45 60 7 50 162 46 5'-Aminohydroquinine 20 843 168 ... 782 30a 194 37 40 735 184 36 729 50 175 37 163 748 BO 37 a Optimum cure. 40 45 45 45 46
2'-600
H 40 45 45 46 47 41 44 44 44 43 39 41 45 46 45 41 40 45 46 46 42 44 46 46 46
55
49
53
67
57
TABLE VII. RESULTS OF AGINGTESTS Antioxidant None (control)
Agerite powder (l/z part) Agerite resin part)
(1/2
Agerite powder ( 1 part)
ARm (11/% part)
Change in T,
t
Aging test
T
30
Unaged Oxygenbomb Air bomb Gcerovcn
182 147. 90 93
Unaged Oxygenbomb Airbomb Geeroven
177 158 116 101
Unaged Oxygen bomb Airbomb Geer oven Unaged Oxygenbomb Airbomb Geeroven
179 158 131 98 154 162 129
111
/'12 -16 -28
Unaged Oxygenbomb Air bomb Geer oven
127 82 50 50
-43 -61 -61
40
. 40
40
50
. ..
-19
'
-51 -49
. .. -11 -34
-43
.. .
-12 -27 -45
.. .
E
T-600
815 783 670 663
32 34 54 48
766 734 700 573
52 60 58
45 44 42 44
ARis
780 . 45 753 50 719 58 553 760 58 729 69 697 51 593 98
45 42 41 45 46
ARto
30
Quitenine
40
897 832 770 593
41 36 30 37
..
,.
16 14 14
..
H 42 41 39 38
45
Antioxidant
ARja
%
E
T-600
H
. ..
812 805 711 697
31 32 52
44 44 40 41
765 739 652 620
64 66 53 84
44 46 41 42
768 730 678 609
49 50 53 82
45 42 39 43
763 728 664 359
49 45 45 ,,
46 42 39 41
778 739 665 632
78 65 50 88
45 45 42 45
Aging test
T
30
TJnaged Oxygenbomb Airbomb Geeroven
177 156 117 116
Unaged Oxygenbomb Airbomb Geeroven
175 162 100 111
Unaged Oxygen bomb Air bomb Unaged Oxygenbomb Air bomb Geer oven
182 143 90 103 163 125 83 22
-23 -49 -86
Unaged Oxygen bomb Airbomb Geeroven
183 161 122 114
-12 -32 -38
30
Geeroven
42 44
5'-Aminohydroquinine
Change in T,
t
30
-12 -34 -34
.-7, .
-43 -37
...
-24 -51 -43
..
,
._.
58
9 04
INDUSTRIAL AND ENGINEERING CHEMISTRY
Vol. 40, No. 5
ACKh-OWLEDGM ENT ARI witJh a small excess of a 0.5% solution of lead acetate. The precipitate is purified bv washing with water, drying a t 70" C., The authors are indebted to P. Honig, director of the Rubber dissolving in benzene, filtering from lead oxide or other impuriResearch Institute a t Buit,enzorg, Java, for permission to publish ties, and precipitating with ether. 9I.p. (decomposed), 116 O C. Pb: found, 18.7%; calculated for (CZ,HZ,OZN&),Pb, 20.57,. the r e s u h , and to G. 6. Whitby for his invaluable help in revising (ZINC SALTOF QVINATOXISEDITHIOCARBAMIC k I U ) . the manuscript. The preparation is analogous to that of the lead salt. R1.p. (decomposed), 99' C. Zn: found, 6.7%; calculat'ed for (C21LITERATURE CITED H2a02NrS2)&h, 7.5473. ARii [DOURLE C O h l P o U S D O F CINCHOTOXINE (3-L'INYL-9(1) iiltman, R. F. A , , "Contribution h. 1'Qtudedes m6ciicanients de HYDROXYRUBATOXINE) ASD CIXCHOTOXISEDITHIOCARBAJIIC svnthkse contre la malaria," p. 117, dissertation, Leiden, ACID (~-DITHIOCARBALIIC l~CID-3-VIXYI>-F)-HYDROXYRUBATOXHolland; Rec. trai;. chim., 57, 954 (1938). INE) 1. The preparation is analogous to that of hR10. The com(2) Altman, R. F . A., dissertation ( I ) , pp. 128 et seq.; Rec. f m v . pound was obtained as a yellow-ish amorphous powder. At'chim., 57, 957 (1935). tempt,s to obtain the product in the crystalline form failed. S: (3) Deys, W. B., private communication of Exptl. Sta., Buitenaorg, found, 7.6%; calculated for C39H4802Xj4S2, 9.
