The Synthesis Of 5-Hydroxyvanillin And 5-Hydroxyacetovanillone
Canadian Journal of Chemistry 40, 2175 (1962)
In connection with studies on the oxidation of lignin it became necessary to prepare various lignin model substances, one of which was 5-hydroxyvanillin (II).
An examination of the reported syntheses 1,2,3,4 indicated that no simple method was available other than those requiring heated autoclaves.
A study was made, therefore, of the most promising procedure, which involved the copper-catalyzed hydrolysis of 5-halovanillin. It was early shown that 5-iodovanillin (III) underwent reaction much more readily than either the 5-bromo- or 5-chloro-derivatives. A satisfactory synthesis of II could indeed be obtained under reflux conditions, thus avoiding the need for reactions under pressure as had been recommended by previous workers. Of importance was the recognition that both the effectiveness of the catalyst as well as the nature of the products obtained were markedly dependent on the particular copper that was used. The authors maintained that only if a reproducible catalyst could be described would a synthetic procedure be of real value. This desire was achieved by the discovery that the addition of cupric ions provided the necessary catalytic activity for this alkaline hydrolysis reaction.
A study of the ratio of reactants, and the time and temperature of the reaction, resulted in a procedure whereby complete conversion of 5-iodovanillin (III) was achieved. The major product was 5-hydroxyvanillin (II) but in all cases a minor amount of the reductive dehalogenation product, vanillin (I), was also formed. The separation and identification of these products was made using both paper and gas-liquid chromatography. Separation and purification of the required II was readily achieved by recrystallization from benzene. The yield of purified product was 65-70% based on III.
This ready conversion of vanillin to 5-hydroxyvanillin prompted the attempt to similarly convert another lignin oxidation product, acetovanillone (IV, 3-Methoxy-4-Hydroxy-acetophenone), to the previously unreported 5-hydroxyacetovanillone (V). No difficulty was experienced in this synthesis. The only modification involved an increase in the time of reflux from 4.5 to 6.5 hours in order to convert all the 5-iodoacetovanillone (VI). As expected, the only other product to accompany the major product (V), but in much less amount, was the reductive dehalogenation compound, acetovanillone (IV). The structure of V was confirmed by analyses, absorption spectra, and conversion, by methylation, to the previously known 3,4,5-trimethoxyphenyl methyl ketone. The yield of recrystallized product was 45-50%.
A more complete discussion of the significance of the role of the copper catalyst and of the mechanism of formation of the products in such copper-catalyzed alkaline dehalogenation reactions is being prepared.
Experimental
Paper Chromatography
5-Hydroxyvanillin, vanillin, and 5-iodovanillin were separated by descending chromatography using Whatman No. 1 paper and the solvent system of n-butanol saturated with 2% ammonia. A saturated solution of 2,4-dinitrophenylhydrazine in 1 N hydrochloric acid was the spray reagent. For these compounds the Rf values were 0.38, 0.50, and 0.48 respectively.
Gas-Liquid Chromatography
A Beckman GC-2 chromatograph, with a thermal conductivity detector unit, was used after some modification to place the injection system as close as possible to one end of the column, and to make it more comparable electronically to the GC-2A. The column was made from 3 ft x 1/4 in. I.D. copper tubing and packed with Apiezon N grease on Fluoropak 80 (Wilkens Instrument and Research Inc.) in the ratio of 3 to 17. The chromatographic separations were effected at 220° using 30 p.s.i. helium carrier gas at a flow rate of 0.9 cc/second. Under these conditions the retention times for vanillin, 5-hydroxyvanillin, and 5-iodovanillin were 2.25, 4.7, and 12.0 minutes respectively, and for acetovanillone, 5-hydroxyacetovanillone, and 5-iodoacetovanillone they were 3.0, 6.7, and 19.5 minutes respectively.
5-Hydroxyvanillin
5-lodovanillin (2.8 g), hydrated cupric sulphate (1.6 g), and 4 N sodium hydroxide (76 ml) were refluxed (105°C) for 4.5 hours with continuous stirring under nitrogen. After cooling to 60-70°C, the mixture was filtered under suction and. the residue washed with hot water (3x10 ml). The alkaline solution was cooled to 10°C and acidified to pH 3-4, by the dropwise addition of concentrated hydrochloric acid. During this addition the mixture was stirred continuously and the temperature maintained below 25°C.
The resulting mixture, which contained a small amount of precipitate, was extracted continuously with ether for 16 hours. After being dried over anhydrous magnesium sulphate, the ether was removed (60-65°) to leave a dark gray product, 1.5 g. All but 0.10 g was dissolved in hot benzene, from which, after concentration to 75 ml, 5-hydroxyvanillin crystallized (1.15 g, 68%), m.p. 128-129°. Recrystallization from benzene, with charcoaling, gave a chromatographically pure product, mp 133-134°C; reported 132-134°C (2). With the exception of traces of 5-hydroxyvanillin the mother liquors contained only vanillin as indicated by gas-liquid chromatography.
5-Hydroxyacetovanillone
5-Iodoacetovanillone (2.9 g) (5), hydrated copper sulphate (1.6 g), and 4 N sodium hydroxide (76 ml) were refluxed (105°) for 6.5 hours with continuous stirring under nitrogen. As a result of a procedure similar to that used for the isolation of II, an ether extract (1.3 g) was obtained. Of this, 0.3 g was sparingly soluble in boiling benzene but the remainder crystallized on cooling of the benzene solution to yield crude 5-hydroxyacetovanillone (0.8 g, 44%), m.p. 162-166°C. A sample recrystallized from n-hexane-ethanol (5:1) melted at 166-167°C. Methylation with alkaline dimethylsulphate gave 3,4,5-trimethoxyphenyl methyl ketone, mp 77-78°C; mixed mp with an authentic sample, 77-78°C. The infrared spectrum was identical with that of the authentic sample.
References:
[1] Monatsh. 43, 93 (1922).
[2] J. Chem. Soc. 793 (1930).
[3] J. Am. Chem. Soc. 74, 4262 (1952).
[4] Can. J. Chem. 34, 1562 (1956).