[FROM THE RESEARCII LABOR.4TORIES
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ACYCLIC ENEDIOLS. A NEW METHOD OF PREPARATION H. HERBERT FOX Received February 81, 1947
During the course of an investigation of anti-oxidants in these laboratories, it was decided to prepare some acyclic enediols upon the supposition that such compounds would exhibit pronounced activity as anti-oxidants. A search through the literature revealed that information pertinent to the enediol structure was very meager, and that few enediols had ever been synthesized. In fact, of the acyclic enediols, only dihydroxymaleic acid and its dimethyl and diethyl esters were known (1). In addition, a sample of the dilauryl ester of dihydroxymaleic acid- was obtained through the courtesy of Dr. A. Weissberger of Eastman Kodak Company. Quite surprisingly, the dilauryl compound, though analyzing correctly, did not exhibit the anticipated reducing action upon iodine. Dihydroxymaleic acid was first prepared by Fenton (2) who described its reactions and elucidated its structure in a series of papers (3, 4, 5 , 6, 7). The method first used by Fenton (2) involved the oxidation of tartaric acid with hydrogen peroxide in the presence of a little iron as catalyst. This method, and a slight modification by Mef (8), constituted the standard procedure for making the enediol. I t is significant that Fenton and other workers in this field (9), with but one exception, failed to report the yields obtained in this reaction, which would seem to indicate that the yields were poor. Fischer and Feldman (lo), using a modification of Nef’s procedure, reported a notable yield of 24% of discolored product. I n these laboratories an attempt to reproduce the work of Fischer and Feldman resulted in a 3.574 yield of crude dihydroxymaleic acid. To obviate the need of preparing the enediol esters from the difficultly prepared and relatively unstable dihydroxymaleic acid, it was decided to esterify before incorporating the enediol structure into the molecule. Accordingly, disodium dihydroxytartrate was esterified with ethyl alcohol as described by Anschiitz and Parlato (11). The resulting ester was then subjected to reduction. H?S proved an immediate failure, so recourse was had to hydrogenation with Raney nickel and platinum as catalysts. The desired diethyl dihydroxymaleate could not be isolated despite repeated attempts under a variety of conditions. The reaction products however gave a strong enol test with ferric ion and pyridine and had some reducing action on iodine, which proved on analysis to be approximately 1.5% of theory. At this rather discouraging stage of the investigation, an attempt was made to use sodium hydrosulfite as the reducing agent. The r e d t obtained with this reagent was gratifying. The reduction went rapidly-within the space of a few minutes -and produced an almost pure product in good yield. The reaction was subsequently tried with the methyl, n-propyl, n-butyl, and n-amyl esters of diketosuccinic acid and in all cases, the corresponding enediol esters were readily obtained. The esters all gave the charmteristic enol test with ferric ion and 535
636
H. HERBERT FOX
pyridine and reduced the theoretical quantity of iodine in acid solution. It was interesting to note, however, that the higher esters were slower in reducing iodine than the lower esters. This phenomenon might account for the failure of Weissberger's dilauryl ester to react with iodine at all. In addition to the esters, the monosodium salt of dihydroxymaleic acid was also readily prepared by this process. To obtain this salt, disodium dihydroxytartrate was converted to the corresponding acid by means of HCI, and the acid was reduced to the enediol with sodium hydrosulfite. Instead of the free dihydroxymaleic acid however, the relatively insoluble monosodium salt precipitated out. The reaction may be represented schematically as follows:
OH
OH
I
1
NaOOCC---CCOONa
I
OH
OH
[
1"
HOOCC-CCOOH
--+
I
Hcl
OH
013
1
+ NaCi
P 2 0 4
HOOCC=CCOOY
I
OH
I
1
a G'L
[HOOCjbJ~OH]
OH
The monosodium dihydroxymaleate was in turn esterified with methyl alcohol and hydrogen chloride. The resulting dimethyl dihydroxymaleate was identical in all respects with the compound previously prepared by reduction of dimethyl diketosuccinate. The diketosuccinic esters prepared in this study were obtained as oils which ranged in color from yellow to orange, due to the presence of the chromophoric alpha diketo group. Upon solution of the oils in water or alcohol it was noted that the color was immediately discharged, a change ascribable to destruction of the chromophoric grouping by hydration or alcoholation. Thus, dimethyl diketosuccinate which was obtained as a yellow-orange oil, readily hydrated even on exposure to atmospheric moisture, to form a white crystalline dihydrate which melted at 110-1 12'. The isomeric picture presented by the enediols is rather complicated. Theoretically, several geometric and optical isomers are possible for each compound. For example, diethyl dihydroxymaleate may exist in both ketonic and enolic form. hloreover, in the ketonic form two optically active isomers and a racemate are possible whereas the enolic variety presents the possibilities of cis-trans isomerism. Fenton (I, 2) succeeded in isolating two isomeric forms of the dimethyl and diethyl dihydroxymaleates. The dimethyl ester (2) was obtained in two forms which had the same melting point, but differed in crystal structure and solubility. The diethyl ester (l), melting initially at 72-73' was resolved into two components, one of which (aform) melted a t 68", and the other (0 form) at 126-128". The two forms varied considerably in chemical properties. The a variety was
PREPARATION OF ACYCLIC ENEDIOLS
537
readily acetylated with acetyl chloride to give the diacetoxy derivative, whereas the ,8 form did not react even on prolonged boiling. Treatment with acetic anhydride, however, converted the ,8 ester to the a form. The a variety also decolorized permanganate instantly whereas the /3 compound reacted rather slowly. An interesting observation made by Fenton and confirmed by the present study was that diethyl dihydroxymaleate, though stable in air, was rapidly oxidized and dehydrated when kept in air over a desiccant. Fenton (1) later reported that this remarkable instability was a characteristic of the a form; the p form was completely stable. In general, Fenton found the cr form to be the more reactive isomer but was unable to determine conclusively whether the difference in properties was due to keto-enol tautomerism or cis-trans isomerism. He was however inclined to favor the former interpretation. In this study, no attempt was made to separate the isomeric forms of the esters. However, in the light of Fenton's findings, and in view of the fact that the butyl and amyl esters react much more slowly with iodine than the lower esters, it may be postulated that the esters of dihydroxymaleic acid, when synthesized as described above, are obtained as mixtures of a and p forms and that the proportion of the less reactive /3 form increases with increasing molecular weight.
Acknowledgment. The author wishes to acknowledge his gratitude towards Dr. H. M. Wuest for his many suggestions and encouragement during the course of this work. The author is also indebted to Dr. A. Steyermark for the microanalyses. EXPERIMENTAL
All melting points are corrected. Diketosuccinic esters. The esters listed in Table I were all prepared according to the method of Anschutz and Parlato (11). T o illustrate the general procedure, the preparation of diamyl diketosuccinate is described in detail. h suspension of 120 g. of disodium dihydroxytartrate in 480 cc. of normal amyl alcohol was saturated with hydrogen chloride at 0". The mixture was permitted to stand in the refrigerator for 3 days, and was filtered t o remove the precipitated sodium chloride. The clear filtrate n-as distilled under vacuum (water-pump) and the amyl alcohol was removed t o yield a yellow oily residue. Upon distillation of the yellow oil, 55 g. of an orange-yellow fraction was obtained boiling at 120-127" a t 0.4-0.5 mm. .4naZ. Calc'd for CvH220s:C, 58.7; H, 7.7. Found: C, 59.1; 11, 8.0. Damethyl dihydroxymaleate. This compound was prepared by two methods: (a) Ten grams of dimethyl diketosuccinatc? (dihydrate) dissolved in a few cc. of water was added to a cold solution of 10 g. of sodium hydrosulfite in about 65 cc. of water. A white crystalline precipitate appeared almost immediately and was filtered off to give 9 g. of nearly pure product melting a t 148-152'. Fenton and Wilks (1) reported the melting point 151". However, upon recrystallization irom benzene the enediol ester was obtained in the form of colorless needles and plates melting at 174-175" and soluble in hot and insol. in cold benzene, alcohol, and water. The product gave a deep blue color with dilute ferric chloride solution and 1 drop of pyridine. Anal. Calc'd for CeHaOs: C, 41.0; H, 4.6; Mol. wt., 176. Found: C , 40.7; H, 4.6; Mol. wt. (iodine titration), 176.5.
538
H. HERBERT FOX
(b) Twenty grams of disodium dihydroxytartrate waa dissolved in 5 N hydrochloric acid. T o the solution was added a large excess of acetone and the precipitated sodium chloride was filtered off. The acetone was then removed under vacuum, and a solution of 15 g. of sodium hydrosulfite in water was added to the residue. A heavy white crystalline precipitate of monosodium dihydroxymaleic acid appeared upon scratching the walls of the vessel; yield 11 g. The monosodium salt (9 9.) dissolved in methyl alcohol was saturated at 0" with hydrogen chloride and the mixture was permitted t o stand a t room temperature overnight. The methyl alcohol and water were removed under vacuum at low temperature, and the residue was dissolved in hot benzene, filtered to remove the sodium chloride, and cooled. Two grams of dimethyl dihydroxymaleate was obtained, which was identical with the product obtained in (a). Diethyl dihydroxymaleate. Diethyl diketosuccinate (2.5 9 . ) was treated with an excess of sodium hydrosulfite in cold aqueous solution. A precipitate of fine white needles appeared immediately. The needles gave the characteristic enediol test with ferric ion and TABLE I DIKETOSUCCIXIC ESTERS O=C-COOR
I
O=C-COOR
I R=
Methyla Ethylb n-Propylc n-Butyl n-Amyl
i I
APPEARANCE
I
i
Yellow-orange oil 1 Yellow oil j Orange oil 1 Orange oil Orange-yellow oil
1
I B.P."C/MM.
i 1
j nn
1
ANALYSIS
Calc'd
Found
c
__
102-110/12-13 I - l34.3 108-113/&10 1.4420 100-108/1-2 1.4307 50.1 125-130/0.8-1 1.4325 55.8 120-127/0.4-0.5 1.4368 58.7
'' I
1
11 1
€I
I
4.8
34.5
1 1
-
-
6.3 7.0 7.7
49.7 56.3 59.1
6.9 7.1 8.0
~
-
-___
4.8
--
pyridine. On reprecipitation from methyl alcohol with water, the needles melted a t 71-73' (5) ; yield 1 g. Di-n-propyl dihydroxymaleate. T o a suspension of 10 g. of the corresponding diketone in 20 cc. of cold water was added a cold solution of 10 g. of sodium hydrosulfite in 100 cc. of water. The suspended oil solidified after a short q-hile. The reaction mixture was then stronglycooled, and the product was filtered off and mashed with ice-water; m.p. 67-69'. On recrystallization from warm methyl alcohol (40"), the enediol ester was obtained in the form of colorless plates melting a t 68-70"; yield 4.5 g of pure material. A n d . Calc'd for ClOIIL6OB: C, 51.7; H , 6.9; Mol. wt., 232. Found: C, 51.4; €1, 7.0; hfol. wt. (iodine titration), 240. Ili-n-butyl dihydrosymaleate. Ten grama of the c-orresponding diketono in 20 c c . of cold water waa added t o H solution of 10 g. of sodium hydrosulfite in 20 cc. of cold water. The reaction mixture WRS stirred a t room temperature for about 15 minutes or until precipitation was complete and then was strongly cooled. The precipitate was filtered off and waehed with ice-water t o yield 9 g. of nearly pure product. The enediol ester was further purified by solution in methyl alcohol at room temperature and then adding water t o incipient cloudiness. Upon cooling t o -10" with occasional stirring, colorless plates wpre obtained which melted a t 34"; yield 7.8 g. of pure material.
PREPARATION OF ACYCLIC BNEDIOLB
539
+
Anal. Calc'd for C&loOs 0.5CHSOII: C, 54.4;H, 8.0. Found: C, 54.4; H, 8.0. Di-n-amyl dihydroxymaleate. The diketone (9.5 9.) was treated with sodium hydrosulfite BLJ described for the dibutyl compouiid. The product waa obtained in the form of glistening colorless plates melting at 29-30"; yield 5.2 g. -4naZ. Calc'd for C&40e CHIOH: C, 56.3; I-I, 8.8. Found: C , 56.3; 11, 8.0.
+
SUM:URY
A new method has been elaborated for the preparation of enediols of the dihydroxymaleic ester type. The process involves the reduction of diketosuccinic esters to the corresponding enediols with sodium hydrosulfite. The reductions are rapidly effected and result in good yields of almost pure products. The enediols thus formed all reduce iodine, but the rate of reduction decreases with increasing molecular weight. NUTLEY,N. J.
REFEFLENCES (1) FENTON AND WILKS, J. Chem. SOC.,101, 1571 (1912). (2) FENTON, J . Chen. Soc., 66, 899 (1894). (3) FENTON, J . Chem. SOC.,67, 774 (1895). (4) FENTON, J. Chem. SOC..69, 561 (1896). (5) FENTON, J . Chem. SOC.,73, 71 (1898). (6) FENTON AND JACKBOK, J.Chem. SOC.,76, ,575 (1899). (7) FENTON, J . Chem. Soc., 87, SO4 (1905). (8) NEF, Ann.,367, 291 (1907). (9) NEUBEROAND SCHWENK, Biochem. Z.,71, 112 (1915). (10) FISCHER AND FELDMAN, Be?., 62,865 (1929). (11) ANSCH~TZ AND PARLATO, BER.,26, 1975 (1892).
