Asymmetric Synthesis of DEHP

By Hannah Harris

Faculty Mentor: Professor Davis Oldham

Di(2-ethylhexyl) phthalate (DEHP) is a chiral molecule used as a plasticizer in many commercial products, and its metabolites have been linked to endocrine disruption and other adverse health effects in mice. Differences in the toxicity of the enantiomeric forms are not well studied. In order to synthesize (R,R)-DEHP, 2-ethyl-1-hexanol was reacted with vinyl acetate and Amano Lipase PS in dichloromethane at 0˚C for 48 hours to yield (R)-2-ethyl-1-hexanol (1) (60% yield, 75:25 e.r.) and 2-ethyl-1-hexyl acetate (2) (83% yield). (1) was refluxed with phthalic anhydride and pyridine at 120˚C for 3 hours yielding crude (R)-MEHP (3). After purification via column chromatography, the percent yield of pure (R)-MEHP, confirmed by 1H NMR, was 54% (75:25 e.r.). (3) was reacted with (R)-2-ethyl-1-hexanol (73:27 e.r.), N,N-dicyclohexylcarbodiimide, and 4-dimethylaminopyridine in dichloromethane at room temperature for 20 hours. The resulting (R,R)-DEHP (4) was purified via column chromatography (39% yield, approx. 75:25 e.r.) and confirmed by 1H NMR. (2) was hydrolyzed by potassium hydroxide in ethanol for 30 minutes at room temperature. (S)-2-ethyl-1-hexanol (5) was recovered (105% yield, 83:17 e.r.) and refluxed following the procedure previously described to produce (S)-MEHP (6), confirmed by 1H NMR in 15% yield after purification. Future work will optimize the enzymatic resolution of (1) and explore the reduction of 2-ethyl-2-hexenal by baker’s yeast as a more efficient method for synthesizing (2). Subsequently, the two other enantiomers of DEHP will be synthesized.