Chem 334
Department of Chemistry and Biochemistry
University of Delaware
Synthesis of Vanillin

Synthesis of Vanillin

Introduction

Vanillin (4-hydroxy-3-methoxybenzaldehyde), a pleasant smelling aromatic compound, occurs naturally in vanilla beans. It is used widely as a flavoring additive for beverages, cooking, and as an aromatic additive for candles, incense, potpourri, fragrances, perfumes, and air fresheners. It may be isolated from the vanilla bean, and is often obtained as a byproduct of the pulp and paper industry by the oxidative breakdown of lignin. It may also be prepared by synthesis. We have developed (equation 1) a convenient two step synthesis of vanillin using electrophilic aromatic substitution, followed by an organometallic methoxylation procedure using copper bromide and sodium methoxide.

A. 3-Bromo-4-Hydroxybenzaldehyde (Miniscale preparation)

Bromination of 4-hydroxybenzaldehyde

(Caution: Bromine is very reactive and corrosive! Do this in the hood!)

To a 50 mL Erlenmeyer flask, add 8.3 mL (use a pipet with a bulb to measure it) of prepared Br2/MeOH solution (1.96 g of Br2 in 25 mL of methanol). Cool the flask for at least five minutes by swirling in an ice/water bath. Have 10 mL of 5% aqueous sodium bisulfite ready. Add 0.50 g of 4-hydroxybenzaldehyde to the cold Br2 solution with swirling. After 30 seconds, quench the reaction by adding the aqueous sodium bisulfite solution, swirling to mix. Extract the aqueous mixture with 3 x 25 mL of diethyl ether. Dry the solution over sodium sulfate and rotary evaporate to give a pink solid that is crude 3-bromo-4-hydroxybenzaldehyde.

B. 4-Hydroxy-3-Methoxybenzaldehyde (Vanillin)

(Microscale preparation)

Preparation of Vanillin

Weigh 200 mg of the crude 3-bromo-4-hydroxybenzaldehyde, and transfer it to a 5 mL reaction vial. Add 2.3 mL of the prepared sodium methoxide solution (Combine 113 mL of a 4.0 M sodium methoxide in methanol solution, 4.4 mL of ethyl acetate, and 2.2 g of CuBr). Seal the reaction vial, and heat in the oil bath at 100oC for 1 hour. Cool to room temperature, transfer the contents to a separatory funnel, then acidify with 3 M aqueous HCl until all solids dissolve (approximately 10 mL). Extract this aqueous mixture with 3 x 20 mL of diethyl ether. Combine the organic extracts, dry (Na2SO4), then filter. Add 1.0 g of flash silica gel, and concentrate to a dry powder on the rotary evaporator (use a vacuum adapter with a glass frit!). In the meantime, prepare a 10 g flash silica gel column. Using 10% ethyl acetate in petroleum ether as the solvent, elute the column, collecting 10 x 10 mL fractions, then 25% ethyl acetate in petroleum ether as the solvent, another 10 x 10 mL fractions. Check the fractions by TLC, comparing to an authentic sample of vanillin. It may be necessary to collect more than 15 fractions. Combine the fractions containing only in a tared round bottom flask, and rotary evaporate. Record the mass and percent yield (from 4-hydroxybenzaldehyde), and the melting range of the product. Pure vanillin melts at 81-83 oC.

Further elution of the column with 25% ethyl acetate in petroleum ether as the solvent will bring unreacted 3-bromo-4-hydroxybenzaldehyde.

Note: During the hour while the reaction vial is heating, prepare your chromatography column, and practice TLC of vanillin.

Extra if you have time, you may want to try:

Purify the crude 3-bromo-4-hydroxybenzaldehyde by crystallization or column chromatography.

- or,

Set up an additional reaction vial run, but for two hours. Does this improve the yield of vanillin?

Safety Notes: 2.5M bromine solutions are extremely caustic and the vapors are dangerous as well. Handle this solution in the hood as much as possible. 4.0M sodium methoxide solutions are extremely caustic and very water sensitive--be sure to replace the lid immediately after using.

References

1. Bromination

2. mp 3-bromo-4-hydroxybenzaldehyde

3. mp vanillin

4. other vanillin syntheses JCE?