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Synthesis of Vanillin from 4-Hydroxy Benzaldehyde Laura M. Cotter, Jon D. Rainier* Department of Chemistry, University of Utah, 315 S. 1400 E., Salt Lake City, UT, 84112, USA Email:,, September 22, 2008

Vanillin was synthesized from 4-hydroxy benzaldehyde via an electrophilic aromatic substitution, which produced the 3-bromo-4-hydroxy benzaldehyde intermediate. This was followed by reductive elimination with copper (I) bromide and sodium methoxide to give the final product. The experiment was repeated twice, once with ethyl acetate in the first step from 4-hydroxy benzaldehyde to the brominated intermediate, and once without ethyl acetate. The yield of the first experiment was 3.2%; the yield of the second was 1.0%. Vanillin was isolated by extraction followed by flash column chromatography. The final product was recrystallized from boiling water. Purity of the final solid was determined by running 1H NMR, GC/MS, IR, and measuring the melting point. All of these indicated the presence of a large amount of impurities.

Introduction The purpose of this experiment was to synthesize vanillin from 4-hydroxy benzaldehyde using a two-step process. Vanillin has many practical uses such as a stain for thin layer chromatography. Vanillin is a particularly useful stain due to the variety of colors it produces. It is also used for flavoring in many foods. More recently, however, vanillin has taken on a new role: it has potential as an anti-metastic drug in treating cancer1 as well as an anti-tumor-promoting drug2. It is also an intermediate to many pharmaceuticals, such as ailanthoidol (an anti-tumor drug)3, dopamine (used in the treatment of Parkinson’s disease)4, and trimethoprim (an antibacterial, especially used for urinary tract infections)5, as well as many others.

The procedure was taken from Nobel, et al6. The experiment was repeated twice, once with ethyl acetate in the first step from 4-hydroxy benzaldehyde to 3-bromo-4-hydroxy benzaldehyde, and once without ethyl acetate. This was done to determine if ethyl acetate has any effect on the yield of the reaction. It was observed that when ethyl acetate was not used, the yield was about half of the yield from when ethyl acetate was used.

The overall purpose of these experiments was to review and refine organic chemistry laboratory techniques for future experiments. By first practicing a well established technique, it was obvious which techniques and procedures needed to be improved before continuing on.




In this mechanisum, the 4-hydroxy benzaldehyde undergoes an electrophilic aromatic substitution by bromine. This forms the 3-bromo-4-hydroxy benzaldehyde intermediate. After addition of copper (I) bromide and sodium methoxide, the intermediate undergoes reductive elimination where the bromine is replaced by the methoxy group. This gives the final product of vanillin.

Data The first experiment that was performed was the synthesis of vanillin with the use of ethyl acetate. There were many color changes noted throughout the reaction. When sodium methoxide, ethyl acetate and copper (I) bromide were combined, the mixture


turned blue. After the addition of this mixture to the 4-hydroxy benzaldehyde mixture, the solution became grayish-brown. The percent yield from this experiment was 3.2%, however, after examining the spectroscopy data, it was determined that most of this was 3,5-dibromo-4-hydroxy benzaldehyde. This is most noticeable in the gas chromatography/mass spectrometry. There are two peaks show on the chromatograph, one at 9.53 minutes and another at 11.49 minutes which indicates the presence of at least two products in the sample. The mass spectrometry of the 9.53 peak shows small amounts of vanillin (FW = 152.15). However, there are much larger peaks at FW = 198.9 to 201.9. It is believed that these represent the 3-bromo-4-hydroxy benzaldehyde with Br79 (FW = 199.9) and Br81 (FW = 201.9) isotopes both present. The molecular ion for the Br81 isotope is observed at FW = 200.9 and for Br79 at FW = 198.9. The peak at 11.49 minutes shows that there is an even greater abundance of 3,5-dibromo-4-hydroxy benzaldehyde, with both bromine isotopes present. The formula weight of the Br79 isotope is 279 with its molecular ion at FW = 278. The Br81 isotope appears at FW = 281 and its molecular ion is at FW = 280. Over 94% of the material examined falls within these peaks. The remaining 5% is a mixture of vanillin and 3-bromo-4-hydroxy benzaldehyde.

Examination of 1H NMR reveals a similar trend, although it is more difficult to interpret as there were many impurities present in the sample. The largest impurity was that of acetone left in the NMR sample tube. This results in a large peak at 2.15 ppm. There is also some chloroform observed at 7.27 ppm. Besides these impurities, the rest of the data suggests a large amount of the dibrominated product. A large peak at 7.983 ppm


represents the two aromatic hydrogens. The dibrominated product only has two hydrogens attached to the benzene ring, and since the molecule is symmetrical, they are equivalent. The monobrominated product and vanillin would both have three distinct aromatic hydrogen peaks. Since only one peak is observed instead of three, this indicates a high concentration of 3,5-bromo-4-hydroxy benzaldehyde. The fact that it represents two equivalent hydrogens is further confirmed by the fact that it is twice as large (area under the curve is 0.23) as the peak at 9.776 ppm which represents the single aldehydic hydrogen (area is 0.11). The peak at 3.97 ppm is the hydrogen on the alcohol group.

Infrared spectroscopy was hard to interpret since there were many contaminants in the sample. There appeared to be aromatic peaks around 682 cm-1, 1710 cm-1 and 3166 cm-1. Aldehydic peaks were also observed around 2700 – 2830 cm-1 and 1700 – 1710 cm-1. The alcohol peak was observed between 3100 cm-1 and 3200 cm-1. The melting point range of the final product was 156.0 – 156.2°C.

The second experiment, which was performed without ethyl acetate, produced a yield of 1.0%. One observation that differed from that of the first experiment was that large amounts of material remained on the silica gel column after flash column chromatography was performed. This was determined to be excess bromine from its redbrown color and its insolubility in organic solvents, except for methanol. It was also soluble in water.

The product of this reaction was also mainly 3,5-dibromo-4-hydroxy benzaldehyde. The


results from GC/MS are nearly identical to that of the first experiment. However, 92.8% of the sample was observed within the dibrominated peaks (11.49-11.55 minutes), with the remaining 7.2% being a mixture of vanillin and 3-bromo-4-hydroxy benzaldehyde.

This sample also had a 1H NMR that was similar to the first sample. Again, there was a large peak at 2.16 ppm from residual acetone in the NMR tube and a chloroform peak was observed at 7.270 ppm. The aromatic hydrogen peak was at 7.987 ppm and the aldehyde was at 9.781 ppm. The alcohol peak of this sample was identical to that of the first experiment, at 3.973 ppm. The infrared spectroscopy results were also nearly identical to that of the first experiment. The melting point range for this sample was 158.0 – 158.2°C.

Calculations Theoretical yield: 1 equivalent Br2 = 0.80 mmoles Æ 1 equivalent vanillin = 0.80 mmoles 0.80 mmoles x 152.15 g/mol = 121.72 mg Actual yield: 3.9 mg (Experiment 1), 1.2 mg (Experiment 2) Percent yield: Exp. 1: 3.9 mg / 121.72 mg = 3.2% Exp. 2: 1.2 mg / 121.72 mg = 1% Percent 3,5-dibromo-4-hydroxy benzaldehyde: Exp. 1: 3.9 mg x 94% = 3.7 mg Exp. 2: 1.2 mg x 93% = 1.1 mg


Conclusions Although some vanillin was successfully synthesized in these two experiments, the majority of the recovered product was 3,5-dibromo-4-hydroxy benzaldehyde, with some traces of 3-bromo-4-hydroxy benzaldehyde. There are a few reasons for why this occurred. During reflux the oil baths needed to be kept between 130 and 140°C, however the temperature reached almost 150°C several times. The first experiment was only allowed to reflux for one hour, but the second experiment was refluxing for about an hour and fifteen minutes. Both of these errors allowed bromine to be inserted into both ortho positions on 4-hydroxy benzaldehyde. The high melting point observed for the product can be accounted for by the large concentration of the dibrominated product. Literature data reports the melting point range of pure vanillin to be from 81 – 83°C while the observed values were nearly twice that.

The percent yields from both experiments were extremely low. In the second experiment, this may be due to some material remaining on the column with the bromine residue. In both cases recyrstallization was imperfect and a large amount of the product may have remained in the mother liquor.

Experimental Section One equivalent (1.6 mL) of Br2/MeOH was added to a reaction vial and placed in an ice bath to reduce the temperature to 0°C. In a second reaction vial, 1.4 mL of NaOMe/MeOH, 0.1 mL of EtOAc, and 0.080 g CuBr were combined. This solution turned blue in color. The second reaction vial was capped with a 10 mL syringe inserted


into the septum. It was heated in an oil bath at 130째C for 5 to 7 minutes.

After the first vial had cooled, 100 mg of 4-hydroxy benzaldehyde was added, causing a color change from red to brown. The vial was capped and shaken in the ice bath for 30 seconds. The contents of the two vials were then combined and heated in the oil bath at 130째C for one hour. At the end of the hour, the solution was gray-brown in color.

The reaction mixture was allowed to cool to room temperature and then transferred to a separatory funnel where it was extracted with 5 mL of EtOAc three times. The extracts were combined and dried with Na2SO4. The dried extracts were transferred to a round bottom flask and 0.5 g of silica gel was added. The product was concentrated via rotovaporation. The final solid was a brown powder.

The concentrated product was transferred to a silica gel column. Flash column chromatography was performed with 3:1 hexanes:EtOAc then increased to 2:1 solvent mixture. Separation was monitored via thin layer chromatography. The fractions that showed UV active by TLC were combined and concentrated by rotovaporation. The remaining product was a white solid. This was dissolved in a small amount of boiling water and then cooled to 0째C for recrystallization. This produced a white solid with a strong vanilla smell. The crystals were air dried for 48 hours before performing spectrometry.


References 1. Lierdprapamongkol, K.; Sakurai, H.; Kawasaki, N.; Choo, M., Saitoh, Y.; Aozuka, Y.; Singhirunnusorn, P.; Ruchirawat, S.; Svasti, J.; Saiki, I. Eur. J. Pharm. Sci. 2005, 25, 57-65. 2. Sawa, T.; Nakao, M.; Akaike, T.; Ono, K.; Maeda, H. J. Agric. Food Chem. 1999, 47, 397-402. 3. Kao, C.; Chern, J. J. Org. Chem. 2002, 67, 6772-6787. 4. Ashnagar, A.; Naseri, N. G.; Nematollahi, M. Orient. J. Chem. 2007, 23, 455460. 5. Afanas’eva, V. L.; Lyubeshkin, A. V.; Kovaleva, S. S.; Bagreeva, M. R.; Anisimova, O. S.; Glushkov, R. G. Pharm. Chem. J. 1987, 21, 805-809. 6. Nobel, D. J. Chem. Soc., Chem. Commun. 1993, 419-420.

Characterization Data Experiment 1 156.0-156.2°C; 1H NMR (400 MHz, CDCl3) δH 9.78 (1 H, s, CHO), 7.983 (2 H, s, Ph) , 3.97 (1 H, s, OH); IR (CDCl3) 3100-3200 (OH), 2800-3000 (CH), 2700-2830 (CHO), 1700-1710 (CHO); ESI/MS (m/z) 281 (M – C7H4O2Br812), 280 (M+ - C7H3O2Br812+), 279 (M – C7H4O2Br792), 278 (M+ - C7H3O2Br792+), 201.9 (M – C7H5O2Br81), 200.9 (M+ C7H4O2Br81+), 199.9 (M – C7H5O2Br79), 198.9 (M+ - C7H4O2Br79+)


Experiment 2 158.0-158.2°C; 1H NMR (400 MHz, CDCl3) δH 9.781 (1 H, s, CHO), 7.987 (2 H, s, Ph) , 3.973 (1 H, s, OH); IR (CDCl3) 3100-3200 (OH), 2800-3000 (CH), 2700-2830 (CHO), 1700-1710 (CHO); ESI/MS (m/z) 281 (M – C7H4O2Br812), 280 (M+ - C7H3O2Br812), 279 (M – C7H4O2Br792), 278 (M+ - C7H3O2Br792), 201.9 (M – C7H5O2Br81), 200.9 (M+ C7H4O2Br81), 199.9 (M – C7H5O2Br79), 198.9 (M+ - C7H4O2Br79)


vanillin lab report  
vanillin lab report  

final report for the vanillin experiment