Crystal structure–solubility relationships in optical resolution by diastereomeric salt formation of DL-phenylglycine with (1S)-(+)-camphor-10-sulfonic acid

Abstract

The experimentally-optimized optical resolution of DL-phenylglycine (PG) with (1S)-(+)-camphor-10-sulfonic acid ((+)-CS) afforded the crystalline D-PG·(+)-CS salt in 45.7% isolated yield and 98.8% optical purity. This excellent resolution has been studied by comparison of the crystal properties of the diastereomeric salt pair, D- and L-PG·(+)-CS. Thermoanalysis (DSC) of the less-soluble D-PG·(+)-CS showed a higher melting point and a larger enthalpy of fusion than those of the more-soluble L-PG·(+)-CS. The difference in the solubilities of the two salts in water is very large because the more-soluble L-PG·(+)-CS is freely soluble. The X-ray crystal structure of D-PG·(+)-CS shows a dense and stable molecular conformation of alternating PG cation layers and (+)-CS anion layers, whereas that of L-PG·(+)-CS shows a coarser molecular conformation consisting of characteristic “holey” vacancy layers, an important factor in its free solubility. The difference in the two characteristic structures could be closely related to the high efficiency of the resolution. A geometrical discussion of the (+)-CS molecule predicted that its excellent resolving ability may be due to its combining two structural functions; a hydrophilic flexible methanesulfonic acid site and a hydrophobic rigid camphor site.