Bromohexanoyl chloride

Organic Chemistry of Hormones Laboratory, College of France, 75231, Paris, Cedex05. 

Chrtstophfr Coyle, John G. Gleason, and Sharon Horovitoh1 Checked by James E. Kleckner and Robert E. Ireland 

Caution This reaction should be conducted in a good hood since hydrogen chloride and bromine vapors are evolved. 

A 200-ml., round-bottomed flask equipped with a magnetic stirring bar is charged with 11.6 g. (0.1 mole) of hexanoic acid (Note 1) and 10 ml. of carbon tetrachloride. After 28.8 ml. (0.4 mole) of thionyl chloride (Note 2) is added to the solution, an efficient reflux condenser with an attached drying tube is fitted to the flask. The solution is then stirred and heated with an oil bath at 65° for 30 minutes (Note 3). 

The flask is removed from the oil bath and cooled to room temperature. To the reaction mixture are added successively 21.4 g. (0.12 mole) of finely powdered Nduomosuccininiide (l-bromo-2,5-pyrrolidinedione) (Note 4), 50 ml. of carbon tetrachloride, and 7 drops of aqueous 48% hydrogen bromide (Note 5). The flask is heated at 70 for 10 minutes (Note 6), and the temperature of the bath is then increased to 85° until the color of the reaction becomes light yellow (ca. 1.5 hours Note 7). The reaction mixture is cooled to room temperature, and the carbon tetrachloride and excess thionyl chloride are removed under reduced pressure (Note 8). The residue is suction filtered, and the solid (Note 9) is washed several times with carbon tetrachloride (total 20 ml.) and the combined filtrate collected in a 50-rnl. flask. The solvent is removed from the solution as before, and the residue is distilled into a dry ice-cooled receiver (short-path column) to give, after a small forerun, 16.1-17.1 g. (76-80%) of 2-bromohexanoyl chloride, b.p. 44-47 (1.5 mm.) as a clear, slightly yellow oil, n12 d 1.4707. This material is of sufficient purity for most synthetic purposes (Note 10). 

---

The decolonization of the yellow product (Note 11) is achieved by dissolving the product in an equal volume of carbon tetrachloride (ca. 12 ml.) and vigorously shaking the solution thus obtained with 1.5 ml. of a freshly prepared aqueous 35% sodium thiosulfate. The two layers are completely separated after 5 minutes. The colorless bottom layer is drawn off into a 50-ml. Erlenmeyer flask. The top layer is extracted three times with 1.5 ml. of carbon tetrachloride. The combined carbon tetrachloride solution is dried over 0.5 g. (Note 12) of anhydrous magnesium sulfate for 30 minutes. The solution is then filtered into a 50-ml. distilling flask, and the magnesium sulfate is washed several times with carbon tetrachloride (total 5 ml.). The solvent is removed, and the colorless product is distilled as described above, affording 14.7-15.8 g. (69-74% overall, based on hexanoic acid 88-92% for the decolonization step) of colorless 2-bromohexanoyl chloride, b.p. 45-47° (1.5 mm.), n22 d 1.4706 (Note 13), i 4 1.4017 (Notes 14 and 15). 

Cognate preparations. 2-Bromohexanoyl chloride and 2-bromohexanoic acid. 

Unfortunately, the yield depends highly on the concentration of the reaction mixture (Scheme 12). As shown below, in the case of the reaction of 6-bromohexanoyl chloride with propylmagnesium chloride, the yield jumps from 38% to 91% when the concentration decreases from 1.2 M to 0.4 M. It is a drawback for large-scale applications since the concentration cannot be higher than 0.5 M. 

Bromohexanoyl chloride (15 g, 70.3 mmol) in dichloromethane (150 mL) is placed in the dropping funnel. This is then added drop-wise to the flask at 20°C and the mixture allowed to stir for 20 min. 

---