[CONTRIBUTION FROM
THE
LABORATORY OF ORGANIC CHEMISTRY OF
THE
STATE UNIVERSITY OF IOWA]
CHLORINE SUBSTITUTION PRODUCTS OF VERATRALDEHYDE, VERATRIC ACID, AND RELATED COMPOUNDS L. CHAS. RAIFORD
AND
DON E. FLOYD
Received May &,19.@
The monochloro substitution products of veratraldehyde were obtained by Raiford and Perry (1) by methylation of the corresponding halogen derivatives of vanillin, the structures of which had previously been established in this Laboratory (2). These aldehydes have now been oxidized by potassium permanganate into the corresponding veratric acids. Examination of the literature shows that Feist, Awe, and Volksen (3) obtained in 1936 a compound they regarded as 2-chloroveratric acid and which was recorded as melting a t 169". However, this melting point is out of line when compared with the values obtained for the ortho halogenated substitution products of veratric acid studied by others. In this connection it should be noted that Zincke and Francke (4) prepared the three possible monobromoveratric acids, and called special attention to the fact that the relations between the numerical values of the melting points and the relative positions of the halogen atoms are significant. They found the lowest value for position 6 (COOH = l ) , the next higher one for 5 and the highest, 201-202", for 2. In repetition of Zincke's work in this Laboratory the same order was found ( l ) ,and reference to Table I1 will show that the values determined for the monochloro acids now reported places them in the order found for the bromine derivatives. The 2chloro compound melts at 200-202'. In addition, only one of these values, that for the &isomeride, falls below 179-180', the recorded melting point of the mother substance, veratric acid ( 5 ) . Other facts, also, seem to suggest some uncertainty concerning the identity of the acid reported by Feist and co-workers. They did not prepare the remaining isomers of the series so that one could make the comparison emphasized by Zincke. In some preparations they used quite small quantities of starting materials, and they noted that certain reactions tested gave mixtures which might involve difficulty in separation and purification. In extension of our work in this field it seemed of interest to examine further the chlorine substitution products of veratraldehyde and veratric acid. The method of preparation found satisfactory for the monochloro aldehydes, as indicated above, is that previously employed in the study of the monobromo compounds. Some of the dihalogenated derivatives were methylated with difficulty, or not a t all, under the conditions of our experiments; consequently, in these cases, the desired products were obtained indirectly as shown below. The structure of 2,5-dichloroveratric acid was fixed as follows. A monochlorovanillin previously obtained by Peratoner (6) and by Menke and Bentley (7), who did not orient the halogen atom, was later prepared and studied in more detail by Hann (8) who assumed, without proof, that it was the 5-chloro derivative (CHO = 1). Proof for this position was brought later by Raiford and 358
359
CHLORINATED VERATRYL DERIVATIVES
t
I n
Y
CLi
6 o z
V
O G
0
w
0
u
U
k
7 ,
v
T h n
I
M"
8
-
2 x
u
t I
6
0
Y 0
8 d 8 =1 U
0 t
u
H
2
x" z
T h
0
8 0 %E
i
T
x" u
n
Y
h
-+
H
2
0" z
T x"
5
2
360
L. CHAS. RAIFORD AND DOK E. FLOYD
Lichty (9) and confirmed by Raiford and Wells (2). In one part of our work, the nitrovanillin which Vogl (10) proved to have the nitro radical in position 5 was reduced to the corresponding amine, VIII, Figure 1. This mas diazotized and the resulting salt was converted by means of cuprous chloride into 5-chlorovanillin, 111,which was found to be identical with the product prepared by Hann and others specified above. Heating a mixture of this compound, excess of acetic anhydride, and a few drops of sulfuric acid gave 3-methoxy-4-acetosy-5chlorobenzal diacetate, IV. Treatment of this product with fuming nitric acid at about 10" gave compound T, in which the nitro group must have entered position 2 or 6 . The acetyl group a t position 4 mas removed by alkaline hydrolysis and the resulting nitrochlorovanillin, X, was reduced to the corresponding amine IX. Replacement of the amino radical by the method specified above gare the dichloroxTanillin XIV. To determine the position occupied by the second chlorine atom, which is also that taken by the nitro radical in the nitration of IV, compound XIV was prepared from a different starting material. Acetylvanillin was converted by nitration into Pschorr and Sumuleanu's (11) nitrovanillin XI. To fix the position of the nitro radical in that product they methylated the exposed hydroxyl and oxidized the resulting nitroveratraldehyde by potassium permanganate into the related nitroveratric acid. The nitro group was reduced, the resulting amine was diazotized, and the salt was converted by means of cuprous cyanide into the corresponding nitrile. By hydrolysis of the latter they obtained hemipinic acid, 3,4-dimethoxy-o-phthalicacid. From this it follows that the amino compound XII, m.p. 127" (12) used in the present work, previously prepared by Sumuleanu (13) who reported 128-129", and further characterized by Pschorr (14), is 2-aminovanillin. This product was converted by the method indicated above into 2-chlorovanillin7 XIII, and direct chlorination of the latter (9) gave compound XIV, which must be the 2,5-dichloro derivative. Methylation of this substance gave the related veratraldehyde XV, which was oxidized by potassium permanganate to 2 5-dichloroveratric acid XVI, m.p. 164-165'. The methyl ester of this compound was found to be a liquid that boiled a t 185187'/5 mm. while that obtained from Mazzara's supposed 2,5-acjd (see below) is a solid. The only dichloroveratric acid found in the literature is recorded by Beilstein (15a) as having a t least one of the chlorine atoms in an unknown position. This compound mas obtained by Mazzara (16), who treated an ether solution of the methyl ester of protocatechuic acid, previously obtained by Matsmoto (17), with two molecular proportions of sulfuryl chloride, and isolated two dichloro esters, recorded as the 2( ?),5- and 5 , G ( ?)-dichloro compounds with melting points of 105" and 223-225", respectively (15a). I-Iydrolysis of these esters with caustic potash gave the corresponding protocatechuic acids, m.p. 220" and 239", with decomposition. By heating a mixture of the higher-melting acid, methanol, methyl iodide, and caustic potash in a sealed tube for 20 hourc a t 120", Xazzara obtained a product that gave a satisfactory C and H analysis for the methyl ester of a dichloroveratric acid. This product melted at 95-96', and hydrolysis of it with aqueous potash gave an acid, m.p. 182-183', that was not analyzed
361
CHLORINATED VERATRYL DERIVATIVES
m"
k"
ij 0
x x
c
3c
T y"
44
u o g
Y
8
3x
3 5 a
d
t
*
i;l
t
t
I
I
0
I
D
u"
0 2 H
Y U
k-
n
5
9
U
U
rj
a
2a 4
a
?
Ea
Ei
u1
I
t
ui
T
I
sa G
u
6 0 a
t
T
T I
I
I
r"
Y 0
w
3
0 H
c
W
0
362
L. CHAS. RAIFORD AND DON E. FLOYD
and which was not further characterized by the author except to convert it back into the ester from which it was originally obtained. As support for the suggested position for the second halogen atom in this acid, Mazzara called attention to the fact that the melting point of his product coincided closely with that of the related dibromoveratric acid, m.p. 182", previously prepared by Boyen (18) (Mazzara records "Royen"), and for which Boyen suggested no structure. Richter (19) listed Boyen's acid as having the halogen atoms in unknown positions. It is true that the current edition of Beilstein (15b) records this product as a 2 ,5-dibromo compound, but Raiford and Perry (1)have recently shown that these positions were assigned on the basis of insufficient evidence, that this acid melts at 186-187', and is a 5 6-dibromo derivative. To establish the structure of Mazzara's acid, 5-chloroveratraldehyde I, Figure 2, was converted by treatment with fuming nitric acid into a mononitro compound, 11, m.p. 122-123", in which the nitro group must have entered position 2 or 6, and which was characterized by conversion into a number of derivatives. It was oxidized by potassium permanganate into the related nitrocarboxylic acid 111. This was reduced to the amine, which was then converted, as indicated above, into the dichloroveratric acid, m.p. 186-187". A mixture of this acid and that of m.p. 164-165', described above and proved to be the 2,5-dichloro derivative, melted over a range of 145-150". The one here under consideration must therefore be the 5,6- compound. It was identified with Mazzara's acid by converting it into the methyl ester which was obtained in the form of long colorless needles that melted at 95-96', as he reported. The third dichloroveratric acid required by theory, the 2,6-derivative, is related to a new nitrochloroveratraldehyde, VIII, m.p. 101-102". This compound is different from I1 and was obtained by two routes. First, in agreement with the observations of Raiford and Ravely (20) to the effect that the alkoxy1 radical directs more strongly to the para than to the ortho position, it was found that chlorination of veratraldehyde, XII, gave product VII, which was isomeric with, but different from I, that had been obtained by methylation of 5-chlorovanillin. Nitration of this new chloroveratraldehyde gave compound VIII, which was carried through the changes indicated in Figure 2 to give a dichloroveratic acid, XV, that should be the 2,6-derivative. By the second route, the monochloro compound XVII, obtained by chlorination (9) of 3-methoxy-4-acetoxybenzaldiacetate (21), was converted by fuming nitric acid, and subsequent removal of acetyl, into a chloronitro compound XIII, in which the nitro group must have entered position 2 or 5 . But 5 is excluded here, because product XI11 was converted by two routes, as shown, into acid XV which is quite different from Mazzara's acid that was proved above to be the 5 6-dichloro compound. 2,5,6-Trichloroveratric acid was obtained by oxidation of the related veratraldehyde which was prepared by methylation of the known trichlorovanillin (9). EXPERIMENTAL
In general, the compounds listed in the tables were prepared by standard methods. To avoid repetition details have been given for the preparation of four derivatives, repre-
363
CHLORINATED VERATRYL DERIVATIVES
.
.
.
.
.
.
.
.
.
.
.. . . .. . .
... . ... .
.
... ... ...
.
.
.
.
.
.
.
. . . ,
.
.
, . .
364
L. CHAS. RAIFORD AND DOK E. FLOYD
. .
.. .. .. . . .. .., ... ... ... ... .,, .. ,
. .
.. .
.
.
. .. .
. .
.. .. . . .
.
. .
.. .. .. . . . .
.
.
CHLORINATED VERATRTL DERIVATIVES
365
senting a methylation, a halogenation, a nitration, and an oxidation. Related compounds were obtained by following these methods w-ith slight variations required in individual cases. d,5,6-Trtbromoueratraldehyde. Five grams of the related tribromovanillin, prepared as directed by Raiford and Stoesser (22), was mixed with 100 cc. of water containing 20 g. of sodium bicarbonate, the mixture was warmed t o about 70°, 5 cc. of dimethyl sulfate was added, the whole was stirred for a n hour, and filtered. The filtrate was treated with dimethyl sulfate as before, the resulting solid was collected, and the total product was purified by crystallization from a suitable solvent. Analytical d a t a and other properties for this and related aldehydes prepared in a similar way are given i n Table I. This method of alkylation was used i n several instances, though caustic alkali in place of bicarbonate was more suitable in some cases. 6-Chloro~,eratraEdehyde. Fifty grams of veratraldehyde, prepared according to directions of Rarger and Silberschmidt (23), was dissolved in about 75 cc. of chloroform, the liquid was placed in a three-necked flask fitted with a mechanical stirrer and a return condenser, and while the temperature was held at 40-50" chlorine was passed in as long as solid separated. X t r o g e n was then bubbled through the mixture to sweep out chlorine and hydrogen chloride, and the solid was collected. Concentration of the filtrate gave more of the product. The total yield was 86%. Crystallization from absolute ethanol gave colorless needles t h a t melted a t 144". This compound, previously prepared by Raiford and Perry (1) in a different way, was found t o melt a t 141". ii mixed melting point determination of these products showed no depression. ~-Sztro-6-chloroveratraldehyde. Thirty grams of the required chloroaldehyde was added slowly, in small portions and with vigorous shaking, to 120 g. of fuming nitric acid which was held between 0 and 10". The resulting deep red solution was kept below 10" for fifteen minutes longer, and then poured into about three volumes of cracked ice, and the mixture allowed to stand for a n hour to precipitate the product. Crystallization from ethanol gave a 70y0 yield of pale yellow needles t h a t melted a t 101-102". This product was also obtained by methylation of 2-nitro-6-chlorovanillin (9) by the method described above. Analytical data are given in Table I. 2-A'ztro-6-chEoroveratrzc acid. -4hot 5% solution of potassium permanganate was added very slowly and with vigorous shaking to a warm (50-60") solution of 10 g. of the required aldehyde in 60 cc. of pyridine until a faint purple tinge remained, the color was discharged by sodium bisulfite, the mixture was filtered, the filtrate was evaporated t o half its volume, and concentrated hydrochloric acid was added. The solid obtained crystallized from dilute ethanol in nearly colorless prisms that melted a t 192-193". The yield of purified product was 68%. Analytical data for this and related compounds are given in Table 11. SUMMARY
1. The monochloroveratraldehydes demanded by theory were previously prepared in this Laboratory by alkylation of the corresponding substitution products of vanillin. These aldehydes have now been converted by oxidation with potassium permanganate into the related veratric acids. It is significant that the relations between the numerical values of the melting points and the positions of halogen in these compounds are of the same order as that previously found for the bromine derivatives. 2. The structures of the dichloro acids have been established by relating them to the required vanillin substitution products in which the halogen atoms have previously been oriented. The only known dichloroveratric acid, that recorded by Mazzara, has been shown to be the 5,6-dichloro compound. IOWA CITY,IOWA
366
L. CHAS. RAIFORD AND DON E. FLOYD
REFERENCES (1) RAIFORD AND PERRY, J . Org.Chem., 7,354 (1942). AND WELLS,J . Am. Chem. SOC., 67, 2501 (1935). (2) RAIFORD AWE,AND V ~ L K S EBer., N , 69, 2748 (1936). (3) FEIST, (4) ZINCKE AND FRANCKE, Ann. 293, 188 (1896). (5) GOLDSCHMIEDT, Monatsh., 6, 379 (1885). (6) PERATONER, Gazz. chim. ital., 28, I, 235 (1898). J . Am. Chem. SOC.,20, 316 (1898). (7) MENKEAND BENTLEY, 47, 2000 (1925). (8) HANN,J . Am. Chem. SOC., AND LICHTY, J . Am. Chem. SOC.,62, 4577 (1930). (9) RAIFORD (10) VOGL,Monatsh., 20, 385 (1899). (11) PSCHORR A N D SUMULEANU, Ber., 32, 3408 (1899). AND STOESSER, J . A m . Chem. SOC.,49, 1077 (1927). (12) RAIFORD Ann. sci. univ. Jassy, 2, 131 (1902-1903). (13) SUMULEANU, Ber., 39, 3122 (1906). (14) PSCHORR, (15) BEILSTEIN,“Handbuch der organischen Chemie,” vierte Auflage, Bd. X, Springer, Berlin, 1927, (a) p. 399 (b) p. 401. (16) MAZZARA, Gazz. chim. ital., 31, 11, 103 (1901). Ber., 11, 129 (1878). (17) MATSMOTO, (18) BOYEN,Ber., 21, 1396 (1888). (19) RICHTER,“Lexikon der Kohlenstoff Verbindungen,” dritte Auflage, Vom, Hamburg, 1910, Teil I, p. 1217. (20) RAIFORD AND RAVELY, J . Org. Chem., 6, 204 (1940). AND NAGAI,Ber., 8, 1143 (1875). (21) TIEMANN AND STOESSER, J . Am. Chem. SOC., 60, 2563 (1928). (22) RAIFORD AND SILBERSCHMIDT, J . Chem. Soc., 2924 (1928). (23) BARGER
