5-bromovanillin (Br2 + H2O2)
(Rated as: excellent)
Two alternative methods to produce the title compound use the oxidative bromination of vanillin by less than stechiometrical amount of molecular bromine and hydrogen peroxide in acetic acid or bi-phasic media. This process is economically convenient, because use only half of the bromine required in the standard procedure.
From Patent US4551558: Bromination of substituted benzaldehydes
Anhydrous acetic acid (20 ml) followed by vanillin (7.5 g; 0.05 mole) were charged into a 100-ml round glass flask equipped with a stirring system, thermometer, a dropping funnel and cooled with a water bath at 20 C. Stirring was begun and then, when the vanillin had dissolved, a solution of bromine (4.8 g; 0.03 mole) in acetic acid (10 ml) was added dropwise. The temperature gradually increased to 30 C. When the bromine addition was complete, acetic acid (20 ml) was added, followed, dropwise, by hydrogen peroxide at a concentration of 30% of H2O2 (2.26 g; 0.02 mole). Stirring was continued for 10 min upon completion of the addition and the heterogeneous reaction mixture was cooled to 20 C. It was next filtered and the cake was washed on the filter with fresh acetic acid (10 ml) followed by ice water (30 ml). After drying under vacuum, a product (10.8 g) melting at 162 C. was obtained, in which 5-bromovanillin (10.60 g) was determined by high pressure liquid chromatography. Unconverted vanillin (0.45 g) was determined in the filtrate and the acetic acid wash. The degree of conversion of vanillin was 94% and the yield of 5-bromovanillin relative to the vanillin converted was 98%.
Chloroform (110 ml) followed by vanillin (15.15 g) were charged into the reactor and stirring was begun. When the vanillin had dissolved a 2N aqueous solution of H2SO4 (20 ml) was added. Bromine (9.6 g; 0.06 mole) was then added dropwise to the heterogeneous mixture thus obtained. The temperature gradually increased to 30 C. When the addition of bromine was complete, an aqueous solution containing 30% by weight of H2O2 (4.42 g, i.e., 0.04 mole) was charged in the same manner. The 5-bromovanillin which had precipitated as it was formed was separated off by filtration. The liquid phases of the filtrate were separated by decantation and the aqueous phase was extracted with methylene chloride (3×150 ml each time). By employing the same procedure as in the previous examples, a total of 1.21 g of unconverted vanillin (corresponding to a degree of conversion of 92%) and 21.07 g of 5-bromovanillin, which represents a yield of 99.5% relative to the vanillin converted, were determined.
From Kchim. Farm. Zh. 21(11), 1367 (1987), in Russian:
Virtually the same procedure as in example 5, just the author used 120 ml of dichloromethane as a solvent, 25 ml 55% H2SO4 , 8.79 g (0.55 mol) Br2, temp < 45°C and 5.5 ml 30% H2O2 (i.e., 0.055 mole). Yield 90-92%, purity 99,5%.
An interesting procedure can be found in Patent US4588844. 4-trifluoromethylthiobenzaldehyde is produced from trifluoromethylbenzene by formylation with urotropine and HF in 28 % yield.