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Org. Synth. 1945, 25, 33
DOI: 10.15227/orgsyn.025.0033
2,5-DIMETHYLMANDELIC ACID
[Mandelic acid, 2,5-dimethyl-]
Submitted by J. L. Riebsomer and James Irvine.
Checked by H. R. Snyder and R. L. Rowland.
1. Procedure
A. Ethyl 2,5-dimethylphenylhydroxymalonate. One hundred and seventy-four grams (1 mole) of ethyl oxomalonate (Note 1) and 265 g. (2.5 moles) of p-xylene are mixed in a 1-l. three-necked flask equipped with a good stirrer, a dropping funnel, and a calcium chloride drying tube. Suitable precautions are taken to exclude moisture from the reaction mixture. While the mixture is cooled in an ice-water bath and stirred vigorously, 325 g. (1.25 moles) of anhydrous stannic chloride is added dropwise from the funnel. After the addition is complete, the cooling bath is removed and stirring is continued for 3 hours. The reaction mixture is poured with stirring into about 300 g. of cracked ice containing 50 ml. of concentrated hydrochloric acid. On standing this mixture separates into two layers. Two hundred milliliters of ether is added, and the ether layer is washed with 100-ml. portions of water until the wash water is free from chlorides. The ether solution is dried with anhydrous sodium sulfate and distilled. After removal of the ether and the excess of reagents (Note 2), the fraction boiling at 154–156°/5 mm. is collected. The yield of 2,5-dimethylphenylhydroxymalonic ester is 144.5–160 g. (51.5–57%).
B. 2,5-Dimethylmandelic acid. A mixture prepared from 140 g. (0.5 mole) of 2,5-dimethylphenylhydroxymalonic ester and a cold solution of 140 g. of potassium hydroxide in 560 ml. of water in a 1-l. round-bottomed flask is warmed on a steam bath for 5 hours. The alkaline solution is cooled and extracted with one 100-ml. portion of ether to remove any material not soluble in alkali. The alkaline solution is acidified with 300 ml. of concentrated hydrochloric acid and then warmed on a steam bath and stirred for 2 hours (or until there is no further evidence that carbon dioxide is escaping). The mixture is cooled, the oily layer is extracted with ether, the ethereal solution is dried with anhydrous sodium sulfate, and the ether is distilled under partial vacuum (Note 3). The oily residue is crystallized from benzene. The yield of 2,5-dimethylmandelic acid melting at 116.5–117° is 55–63 g. (63–70%) (Note 4).
2. Notes
1. The ethyl oxomalonate must be of good quality. It has been found possible to use nitrogen peroxide (now available in cylinders from the du Pont Company) in the preparation of this reagent. The general conditions are the same as in the previous method in Organic Syntheses1 except that the generating flask containing arsenious oxide and nitric acid is replaced with a cylinder of nitrogen peroxide. This method is much more satisfactory.
2. The excess p-xylene can be recovered easily.
3. It is important to avoid long heating after removal of the ether. The mandelic acid tends to react with itself.
4. This general method has been applied to the synthesis of a variety of alkyl-substituted mandelic acids.2
3. Discussion
2,5-Dimethylmandelic acid has been prepared by the procedure described above;2 and by the reaction between 2,5-dimethyphenylmagnesium bromide and chloral, followed by alkaline hydrolysis.3

References and Notes
  1. Org. Syntheses Coll. Vol. 1, 266 (1941).
  2. Ando, J. Chem. Soc. Japan, 56, 745 (1935) [C. A., 29, 7960 (1935)]; Riebsomer, Irvine, and Andrews, J. Am. Chem. Soc., 60, 1015 (1938); Proc. Indiana Acad. Sci., 47, 139 (1938); Riebsomer, Baldwin, Buchanan, and Burkett, J. Am. Chem. Soc., 60, 2974 (1938); Riebsomer, Stauffer, Glick, and Lambert, J. Am. Chem. Soc., 64, 2080 (1942).
  3. Savarian, Compt. rend., 146, 297 (1908) [C. A., 2, 1443 (1908)].

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

arsenious oxide

2,5-dimethylphenylhydroxymalonic ester

2,5-dimethyphenylmagnesium bromide

hydrochloric acid (7647-01-0)

Benzene (71-43-2)

ether (60-29-7)

Mandelic acid (90-64-2)

nitric acid (7697-37-2)

sodium sulfate (7757-82-6)

carbon dioxide (124-38-9)

potassium hydroxide (1310-58-3)

p-xylene (106-42-3)

Ethyl oxomalonate

stannic chloride (7646-78-8)

chloral (75-87-6)

2,5-Dimethylmandelic acid,
Mandelic acid, 2,5-dimethyl-

nitrogen peroxide

Ethyl 2,5-dimethylphenylhydroxymalonate