AkNTIOXYGENICACTION OF ASCORBIC
May, 1941
TABLE I Yield,
%
Compound
4-Methoxyisophthalyl chloride
83
5.2, 78
1279
ACID
Formula
CvHdX!b
Analyses, % ’ Calcd. Found
C1, 30.47
30.18
-(isophthalate)-
Dimethyl-4-methoxy-(-) 98 94 59.01 74 57 61.80 Diethyl-4-methoxy-(-) 70 209-210 5.94 Diethylaminoethyl-4-methoxy-(-) b 69’ 3.58 Di-n-propylarninoethyl-4-methoxy-(-) borate d 6.12 Di-n-propylarninoethyl-4-methoxy(-) 61 4.79 60 120-122 Di-n-butylaminoethyl-4-methoxy-(-) 75 193-195 5.75 Diethylaminopropyl-4-rnethoxy-(-)hydrochloride 69 150-1 52 5.05 Di-n-propylarninopropyl-4-methoxy-(-) hydrochloride d 4.79 Di-n-butylaminopropyl-4-methoxy(-) 69 ‘Yield based on free base. Decomposes. By analogy with formula for procaine borate given in May, “Chemistry Darkens without boiling a t 210’ < 0.1 mm. of Synthetic Drugs,” Longmans, Green & Co., New York, 1939, p. 123. prepare the hydrobromide and the borate were unsuccessful, sticky products being obtained in each case. The constants and yields of the compounds prepared are given in Table I.
summary 1. Some normal and alkamine esters of
4-methoxyisophthalic acid have been prepared. 2. Preliminary pharmacological data indicate a n anesthetic efficiency approximately equal t o that of procaine. CHICAGO, ILLINOIS
RECEIVEDDECEMBER 30, 1940
[CONTRIBUTION FROM THE BIOCHEMICAL LABORATORY, STATE UNIVERSITY O F IOWA]
Antioxidants and the Autoxidation of Fats. XIII. The Antioxygenic Action of Ascorbic Acid in Association with Tocopherols, Hydroquinones and Related Compounds BY CALVINGOLUMBIC AND H. A. MATTILL The capacity of ascorbic acid to act as an inhibitor of fat oxidation has been suggested or implied in a number of recent papers.l Notwithstanding the slight solubility in lipids, both d- and 2-ascorbic acid alike have an appreciable antioxygenic action in various fat substrates (Table I). To lengthen the induction period of lard a fairly high concentration must be used, but in cottonseed oil or its esters much smaller quantities suffice. These substrates contain inhibitols, principally tocopherols, and ascorbic acid reinforces their stabilizing action. When tocopherol is removed from vegetable oils, as can be done by various means, the recovered oils are no longer stabilized by ascorbic acid. According to Isler2 the extent of oxidation of a-tocopherol adsorbed on an inert carrier in the presence of ascorbic acid was only 6% of that which occurred during the same period in the (1) Kieferle and Seuss, M i l c h . Forsch., 20, 23 (1939); Trout and Gjissing, J . D a i ~ rSci., 22, 271 (1939); Gray and Stone, Rood I n dusf., 2, 629 (1939). (2) Mer, Hclw. Chim. Acta, 21, 1756 (1938).
absence of ascorbic acid. The oxidation of a-tocopherol when dissolved in an animal fat substrate is also retarded by ascorbic acid; this appears from the figures given in Table 11. With like amounts of tocopherol initially present, inTABLE I THEANTIOXYGENIC PROPERTIES O F ASCORBICACID
Substrate
Lard
Inhibitors added
0.40% Ascorbic acid .20% Ascorbic acid .lo% Ascorbic acid .04% 8-Tocopherol .04% 8-Tocopherol 0.10% Ascorbic acid
Induction perioda at 75O With Coninhibitor, trol, hr. hr.
39 31 24 169
19 19 21 21
+
268 21 Hydrogenated cottonseed oil .Ol%Ascorbic acid 73, 80b 40, 45b Crude ethyl esters of hydrogenated 210 4 cottonseed oil .020/, Ascorbic acid 223 5 Oxygen absorption method. The induction period is given in days (oven test, 63’).
CALVINGOLUMBW AND H. A. MATTILL
1280
VOl. 63
TABLE I1 observations may be made. The oxidation THEOXIDATION OF CY-TOCOPHEROL IN THE ETHYL ESTERS potentials of the antioxygenic hydroquinones8 OF LARDFATTY ACIDS,IN THE PRESENCE AND ABSENCEOF and of tocopherol' (0.656-0.597 v.) are appreASCORBICACID
ciably higher than that of ascorbic acid* (0.390 v.). Fat peroxides oxidize tocopherols and hydroTime, hours Y Y Y quinones, hence their oxidation potentials are 0 1000 1000 1000 higher than those of the phenolic inhibitors. 3 540 482 Despite the large difference in potential which 5 66 must exist between the fat peroxides and ascorbic 10 trace acid, the latter is not appreciably oxidized during 20 0 313 336 the induction period and does not delay the 44 120 164 66 0 35 accumulation of fat peroxides unless hydro70 0 quinones or tocopherols are also presentg This Length of induction type of sluggish two-step oxidation between sysperiod,bhours 11 59 68 tems a t widely different potential levels and re' Determined by the method of Emmerie and EngeL3 quiring an intermediary agent is not unknown ' Determined by the oxygen absorption method, at 75'. even in inorganic chemistrylO and has been parcreasing amounts of ascorbic acid prolonged ticularly exemplified by certain biological oxidathe induction period and a t its termination, in tions." A study of these relations in fat systems each case, the tocopherol was completely oxidized. involves many complications which are being Determination of ascorbic acid by the method of further investigated. Bukatsch4 showed that it too was being oxidized The authors are indebted to Lever Brothers but a t a much slower rate. Company, Cambridge, Massachusetts, for a grant This reinforcing action of ascorbic acid is not in support of this work. confined to tocopherol but extends t o hydroxy chromans and related compounds which are also summary fat stabilizers5 and to hydroquinones and quiAscorbic acid is a n effective antioxidant for nones. When, with the successive introduction certain vegetable oils, their hydrogenated prodof alkyl groups, hydroquinones and quinones ucts and esters. It enhances the antioxygenic progressively lose their capacity as inhibitors, activity of tocopherols, hydroxy chromans, hyadded traces of ascorbic acid no longer have a droquinones and related compounds. stabilizing effect. CITY, IOWA RECEIVED JULY 29, 1940 Although the mechanism of the reaction be- IOWA tween ascorbic acid and tocopherols and hydro(6) Conaut and Fieser. ibid., 46, 1858 (1924). (7) Golumbic and Mattill, J. B i d . Chem., 134, 533 (1940). quinones is not yet understood, certain suggestive (8) Ball, i b i d . , 118, 219 (1937). Amount of a-Tocopherol in 1 g. of Ester0 (0.05% ascorbic (0.10% ascorbic acid) , acid) acid)
(No ascorbic
(3) Emmerie and Eugel. Rec. fr'au. chim., 67, 1351 (1938). (4) Bukatsch, 2. 9hysiol. Chcm., 161, 20 (1939). ( 5 ) Golumbic, THIS JOURNAL, 63, 1142 (1941).
(9) Golumbic, unpublished work. (10) Shaffer, 1.Phys. Chcm., 40, 1021 (1936). (11) Barron, Physiol. Reo., 19, 184 (1939).
