A fast, new method to enhance the enantiomeric purity of non-racemic mixtures: self-disproportionation of enantiomers in the gas antisolvent fractionation of chlorine-substituted mandelic acid derivatives

Abstract

Gas antisolvent precipitation is a particle formation technique, when typically pressurized carbon dioxide is added to an organic solution resulting in immediate and high oversaturation and precipitation of fine particles. Provided that a reasonable share of the originally dissolved material remains dissolved in the carbon dioxide – organic mixed solvent, these components can be extracted during the washing phase. This method is called gas antisolvent fractionation. Gas antisolvent fractionation has been applied for the first time to enantiomeric enrichment of non-racemic mixtures, and demonstrated on the example of chlorinated mandelic acid derivatives. Due to self-disproportionation of enantiomers, the precipitated solid and the extracted fractions have different enantiomeric excesses if gas antisolvent fractionation is carried out on a non-racemic mixture. However, there is a limit in the enantiomeric excess (ee) that can be achieved correlating strongly with the atmospheric melting eutectic behavior of the compounds. Thus, if initial enantiomeric mixtures have a higher than eutectic ee, a >99% ee can be reached in the crystalline product. The strong correlation between the high-pressure experiments and the atmospheric melting eutectic behavior suggest that despite the very large oversaturation during the antisolvent precipitation, the composition of the products (i.e., the crystalline and the extracted phases) is thermodynamically determined. Technological advantages such as short operational time, or the possibility of controlling the crystal morphology suggest that the development of an efficient technique of enantiomeric purification is possible based on gas antisolvent fractionation.