[CONTRIBUTION FROM TEB LABORATORY OF ORQANIC CHEMISTRY OP THE STATEUNIVERSITY OF IOWA]
CONDENSATION OF VANILLIN SUBSTITUTION PRODUCTS WITH NITROMETHANE L. CHAS. RAIFORD
AND
DONALD E. FOX
Received November 12, 1943
Priebs (1) obtained a 56% yield of P-nitrostyrene by condensing benzaldehyde with nitromethane in the presence of zinc chloride in a sealed tube a t 160". Posner (2) carried out this reaction with o- and m-nitrobenzaldehyde, but he reported that neither with zinc chloride nor with any other reagent could he condense other substitution products of benzaldehyde. Henry (3) found that nitromethane condenses with aliphatic aldehydes in the presence of potassium hydroxide or carbonate, while Thiele (4)showed that with aromatic aldehydes the carbonate was unsatisfactory but that alcoholic potash gave good results. Under these conditions he reported that o-, m-and p-nitrobenzaldehyde, respectively, condensed with equal ease, though he recorded no yields. Knoevenagel and Walter ( 5 ) found that vanillin, 3-methoxy-4-hydroxybenzaldehyde,condensed with nitromethane to give a 90% yield of product when an alcoholic solution of the reactants was allowed to stand a t room temperature in the presence of methylamine. They tested none of the substitution products of vanillin. Remfry (6) studied the behavior of many monosubstituted benzaldehydes and found "that the hydroxyl group in the ortho- and meta-positions exercised no influence on the course of the reaction, but that a para-hydroxyl group, either alone or in conjunction with other groups (except in one instance), rendered condensation impossible". Rosenmund's (7) work with anisaldehyde showed in that one case, at least, that condensation occurs readily if the hydroxyl group has been methylated, and the reaction is carried out a t 5" or below in the presence of alcoholic potash. Later he reported (8) that when the reaction was carried out with benzaldehyde below 8", with sodium methoxide as condensing agent, he was able to isolate the addition product a-phenyl-P-nitroethanol which, when distilled under reduced pressure was, in part, decomposed by loss of water to give the related styrene. In the present work several vanillin substitution products were used and a number of condensing agents were tested. Best results were obtained in most cases by gently refluxing a glacial acetic acid solution of the reactants with ammonium acetate as directed by Rao, Srikantia, and Iyengar (9). In a few instances condensation occurred when an absolute ethanol solution of the reactants was allowed to stand for several days a t room temperature in the presence of the acetate. Certain properties of these condensation products are of interest. When the compound XII, obtained from vanillin and nitromethane, was treated with slightly more than two molecular proportions of bromine, hydrogen bromide was evolved and a tribromo derivative, IX, m.p. 127", was formed. The same substance was obtained by bromination of the condensation product, VI, ob170
171
VANILLIN DERIVATIVES AND NITROMETHANE
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6 z ;r: u II
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u xI1
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1'72
L. CHAS. RAIFORD AND DONALD E. FOX
tained from 5-bromovanillin, which shows that one of the halogen atoms in the tribromo derivative was attached to the phenyl nucleus. Proof that the other two were in the side chain was brought by oxidation with potassium permanganate, which caused loss of two bromine atoms and gave 5-bromovanillin, V. Formation of an aldehyde in this case agrees with the observations of Webster (lo), made in this laboratory, to the effect that oxidation of the unsaturated side chain of a benzene derivative that contains a hydroxyl group in position 4 usually gives the aldehyde instead of the related acid. The above results stand in marked contrast to those observed in oxidation of the halogen derivative XVII obtained from the condensation product XVI, prepared in turn from veratraldehyde, n-hich contained no exposed hydroxyl group. In this case, as reported in studies by Raiford and Perry (ll), the side chain was converted into carboxyl, to give veratric acid V. They found that vanillin and its substitution products were not changed by treatment for a few minutes with boiling potassium permanganate solution while the corresponding methylated compounds, veratraldehydes, were converted into the related acids in yields of 75% or more. In a similar way, bromination of the condensation product IV, obtained from 6-bromovanillin, gave a tetrabromo derivative 111 that was identical with the compound produced by bromination of substance, 11, formed when the condensation m ~ carried s out with 5,6-dibromovanillin. This fixes the position of the second nuclear halogen atom in the tetrabromo derivative as 5. The compounds containing halogen in the side chain were active toward other reagents. Repeated crystallization from ethanol of the tribromo compound IX, m.p. 127",mentioned above, gave a dibromo product X that melted a t 166-167'. This substance was also obtained when a thin ethanol paste of the tribromo compound was mixed with anhydrous sodium acetate and heated under reflux for an hour. Analysis of the product showed the presence of two bromine atoms, which indicates that in its formation the tribromo derivative had lost the elements of hydrogen bromide. The position of the remaining bromine atom in the side chain is suggested by the results of Thiele and Haeckel (12) who found that removal of hydrogen bromide from [a, /3-dibromo-~-nitroethyl]benzenegave a-phenyl-P-bromo-P-nitroethene, as shoun. C6H5CHBrCHBrN02+ C6H5CH=CBrN02 HBr Relations established in the present study are shown in Figure 1.
+
EXPERIMENTAL
a-[$,~-DimethoxyphenyZ]-p-nitroethene. A mixture of 5 g. of vertraldehyde, 2 g. of ammonium acetate, 2.5 cc. of nitromethane, and 20 cc. of glacial acetic acid was gently refluxed for two hours. On cooling, a crystalline mass separated. The yield was 85%. Recrystallization from 50% acetic acid gave yellow prisms that melted a t 140-141". A weighed portion was reduced by a mixture of zinc and concentrated hydrochloric acid, and the resulting material was subjected to a Kjeldahl analysis. Anal. Calc'd for CloHllh'Ol: N, 6.69. Found: pu', 6.59. Data for other products obtained by the same general procedure, modified to meet the requirements of individual cases, are given in Table I. a-[$-Methoxy-~-hydroxy-6-bromophenyZ]-or,~-dibromo-~-nitroethane. Slightly more than two molecular proportions of bromine dissolved in an equal volume of chloroform was gradually added with rapid stirring to a suspension of 10 g. of vanilla1 nitromethane in 250 cc. of chloroform, stirring was continued until nearly all solid was dissolved, and the mixture was
173
VANILLIN DERIVATIVES AND NITROMEYTHANE
allowed t o stand overnight. Some hydrogen bromide was evolved. A small portion of insoluble material was removed by filtration, the filtrate was evaporated t o dryness at 5060' in a current of air. Excessive heat decomposed the product. The yield was nearly quantitative. Crystallization from carbon disulfide gave fine, pale yellow needles that melted a t 127". The same product was obtained in 87% yield by treatment of a carbon disulfide solution of the condensation product obtained from nitromethane and 5-bromovanillin with somewhat more than one molecular proportion of bromine. Anal. Calc'd for CeHaBrlNQl: Br, 55.29. Found: Br, 55.15. a- [S-Methozy-4-hydrozy-6,6-dibromophenyll-a,p-dib~omo-p-nitroethane. A suspension of 10 g. of 6-bromovanillalnitromethane in 100 cc. of chloroform was treated with two molecular proportions of bromine as indicated above; hydrogen bromide was evolved and the product was isolated as described. The yield was nearly theoretical. Crystallization TABLE I SUBSTITUTION PRODUCTS OF a-[3-METHOXY-4-HYDROXYPHENYL]-@-NITROETHENE ADDITIONAL SUBSTITUENT IN PHENYL
SOLVENT
~
2-Bromo-
67
5-Bromo-
50
6-Bromo-
61
Ethanol 25%" Ethanol (abs.) Ethanol
5,6-Dibromo-
52
Ethanol
2-Ni tro-
65
5-Ni tro-
73
2-Ni tro-5-bromc
82
Ethanol 30% Ethanol 50% Ethanol 30%
CRYSTAL FORM
1 1
AN.4LYSES FORMULA
~Yellow 134-135 C9HaBrNO4 needles Red 190-191 C&BrN04 needles Yellow 168-169 CsHaRrN04 needlesb Yellow 166-167 C ~ H ~ R ~ ~ needles Yellow 188-189 CsHslC2Oc plates Yellow 183-184 CgHsNpOs needles Yellow 169-170 CgHiBrSzOa needles
alc'd bund, Calc'd Found, Br Br N N - ____
3.20 39.24 3.20 39.28
3.x
z9.17
N5.32 O I L5.29 -
- 11.6( 11.59
__
-
11.6( 11.58
6.0;15.13
Proper volume of water to give this concentration was added to a hot alcoholic solution of the compound. * The same product was obtained when an absolute ethanol solution of the reactants was allowrd to stand a t room temperature for two days.
from ligroin (65-70") gave pale yellow granules that melted a t 126-128" with softening a few degrees lower. This product was also obtained in 80% yield by bromination of a chloroform solution of 5,6-dibromovanillalnitromethane. Anal. Calc'd for CoHrBr4N04: Br, 62.37. Found: Br, 62.54. To a suspension of 5 g. of veratrala-[S,~-Dimethoxyphenyl]-a,~-dibromo-~-nitroe~hane. nitromethane in about 350 cc. of carbon disulfide was added slowly with stirring slightly more than two molecular proportions of bromine in about ten volumes of carbon disulfide, the mixture was allowed t o stand overnight, and the solvent distilled off. A yield of 90% was obtained. Crystallization from carbon disulfide gave nearly colorless granules that separated with one-half molecular proportion of solvent and melted at 113-114". A,nal. Calc'd for CloHl1BraNO4.0.5CSI: Br, 39.31. Found: Br, 39.90; 40.03. A portion of the above product was heated for an hour a t about 65" to remove solvent of crystallization, The residue gave the following analysis. Anal. Calc'd for ClaH11BraN04: Br, 43.36. Found: Br, 43.25. a-[3-Methoxy-~-hydroxy-6-b~omophenyl]-p-bromo-~-nit~oethene. The tribromo compound, m.p. 127", specified above and obtained by action of bromine on vanillalnitrometh-
1'14
L . CHAS. RAIFORD A N D DONALD E. FOX
ane, was repeatedly crystallized from ethanol from which i t finally separated in yellow needles that melted a t 166-167". In a second experiment a thin ethanolic paste of the tribromide wns gently refluxed with fused sodium acetate for an hour. The solid left after cooling was collected and crystallized from ethanol which gave yellow needles that melted as indicated above. Anal. Calc'd for C~I-17Br2KOa: Br, 45.32. Found: Br, 45.29. u-[S-~Iethoxy-~-hydrox~-5,6-dibromophenyl]-~-bromo-~-nitroethene. A portion of the tetrabromo compound, m.p. 126-128", obtained from 6-bromovanillahitromethane as indicated above, was boiled under reflux with a small amount of alcohol for an hour. An almost quantitative yield of a tribromo derivative, m.p. 175-176", was obtained. Anal. Calc'd for CgHaBrrNO,: Br, 55.55. Found: Br, 55.58. u-[3,4-DimethoxyphenylI-p-bromo-8-nitroethene. One and one-half grams of finely powdered anhydrous sodium acetate was gradually added, with shaking, to a cool saturated ethanol solution of 1 g. of the required dibromoethane derivative, m.p. 113-114". When nearly all the salt was in, a sudden and almost complete precipitation of the monobromide occurred. The yield was 80%. Sublimation of the product in a partial vacuum gave bright yellow needles that melted a t 119-120". Anal. Calc'd for CloHIoBrN04:Br, 27.77. Found: Br, 27.93. A portion of the compound mentioned immediately above was oxidized by a calcium permanganate solution in acetone that had previously been distilled from permanganate, as directed by Reichert and Koch (13). Some degradation occurred, but there was isolated a product that melted a t 177-178", and which did not depress the melting point, 179", of an authentic sample of veratric acid. SUMMARY
1. Vanillin and a number of its substitution products have been condensed with nitroniethane to give the related ,G'-nitrostyrenes, 2. Treatment of these compounds with bromine saturates the side chain and introduces bromine into position 5 by substitution if position 4 is occupied by hydroxyl. 3. Oxidation of these condensation products, as well as their bromine addition compounds, with permanganate causes loss of bromine from the side chain and gives the related aldehyde. 4. When veratraldehyde is used as starting material, oxidation of the condensation product gives the related acid. This emphasizes the retarding effect of the parahydroxyl group. IOWACITY, Iowa. REFERENCES (1) (2) (3) (4) (5) (6) (7) (S) (9) (10) (11) (12) (13)
PRIEBS, Ber., 16, 2591 (1883); Ann., 226, 321 (1884). POSNER,Ber., 31, 656 (1898). HENRY,Compt. rend., 121, 211 (1895). THIELE,Ber., 32, 1293 (1899). KNOEVENAGEL AND WALTER,Ber., 37, 4506 (1904). REMFRY, J. Chem. SOC.,99, 283 (1911). Ber., 42, 4780 (1909). ROSENMUND, ROSENMUND, Ber., 46, 1037 (1913). RAO,STRIKANTIA, AND IYENGAR, Helv. Chim. Acta, 12, 581 (1929). WEBSTER, Am. J . Pharni., 112, 291 (1940). RAIFORD A N D PERRY, J. O r g . Chem., 7, 354 (1942). THIELEAND HAECKEL, Ann. 325, 8 (1902). REICHERT AND KOCH,Rer., 68, 482 (1935).
