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

Resolution of 2‐chloromandelic acid with (R)‐(+)‐N‐benzyl‐1‐phenylethylamine: chiral discrimination mechanism

“…The crystal structure of the less soluble diastereomeric salt ( R )‐2‐ClMA·( R )‐BPA was obtained by single crystal X‐ray diffraction. The chiral discrimination mechanism was investigated by examining the weak intermolecular interactions in crystals, such as hydrogen bond, CH/π, and van der Waals interactions, and supramolecular packing mode, which is a promising approach employed by many researchers to explore the chiral recognition in diastereomeric salt resolution …”

How to Use Pasteur’s Tweezers

“…Two industrial scale examples may be given. The first (Scheme 21.1) is the process used for resolution of the unnatural amino acid, phenylglycine, which is used often as a side chain of antibiotics [17]. In this highly optimised process, racemic phenylglycine is converted into the salt form using commercially available camphor 4 For a brief and clear discussion of Ostwald ripening and the Gibbs-Thompson effect, see Mullin [13] and Ostwald Ripening [14].…”

Enantioseparations in Achiral Environments and Chromatographic Systems

“…One interesting example at the commercial level includes the enantioseparation of ( RS )‐phenylglycine on a scale of 1000 t per year by preparing its ionic diastereomers (Figure , 1a and 1b ) with enantiomerically pure (1 S )‐(+)‐10‐camphorsulfonic acid. The molecular structures show a different extent of hydrogen bonds in the lattices of the two salts 1a , 1b arising from the conformational differences in the cations and in the methylenesulfonate segments of the anions of the salts corresponding to the ( R )‐ and ( S )‐enantiomers, resulting in lower solubility of the salt corresponding to the ( R )‐enantiomer in water. Therefore, one of the diastereomeric salts preferentially remains in solution and the other one preferentially crystallizes.…”

“…Various studies, mentioned above, on the separation of nonracemic mixtures (i.e., enantiomeric enrichment) by sublimation or by crystallization, have proposed an explanation on different aspects of crystal lattices with respect to differences in intramolecular hydrogen bonding in the crystals of a racemate and the crystals of the constituent enantiomers. For example: (i) in the separation of ( RS )‐phenylglycine by preparing its ionic diastereomers (Figure , 1a , 1b ) with enantiomerically pure (1 S )‐(+)‐10‐camphorsulfonic acid, the unequal extent of the hydrogen bonds in the lattices of the two salts arising from the (conformational) differences in the cations and in the methylenesulfonate segments of the anions of the salts corresponding to the ( R )‐ and ( S )‐enantiomers have been held responsible for the lower solubility of the salt corresponding to the ( R )‐enantiomer in water; (ii) Kwart and Hoster, who based on their sublimation studies on (−)‐α‐ethylbenzylphenyl sulfide (Figure , 5 ), contended that there were forces involved that controlled crystal structure and crystal growth, rather than the disparities of bonding forces within the racemate and the pure enantiomer; (iii) Garin et al ., [ 66 ] in 1977, in the study of fractional sublimation of enantiomerically enriched mandelic and camphoric acids, matched their experimental data in terms of the fact that both fusion temperature and volatility were related to the intercrystalline forces; (iv) Katagiri et al ., [ 58 ] in 1996, attributed enantiomeric enrichment to stereoselective hydrogen bonding in the liquid state of the sample of isopropyl trifluorolactate 4 subjected to distillation; (v) while establishing nonlinear dependence on the enantiomer enrichment via measuring the equilibrium constants for the dimerization of enantiomers (i.e., the formation of homo‐ and heteroenantiomeric associates) of omeprazole, Baciocchi et al . [ 92 ] postulated that formation of hydrogen bonds between the sulfoxide (proton acceptor) and the benzimidazole (proton donor) moieties were responsible for the existence of diastereomeric dimers and the aprotic solvent CHCl 3 did not prevent the formation of hydrogen bonds; and (vi) Takahashi et al .…”