4-Benzoylamino-3-hydroxybutyric Acid, Historically First “Anomalous Racemate”: Reinvestigation

Abstract

The chiral 4-benzoylamino-3-hydroxybutyric acid (1) was recognized in 1930 as the first example of "anomalous racemates" (correct to say -anomalous conglomerates), i.e. specific addition compounds formed by different enantiomers in unequal ratio. Through the comparative (racemic against homochiral samples) investigation using IR spectrometry, single crystal X-ray diffraction, PXRD analysis, and solubility studies, we have found that this substance forms a normal racemic compound in the solid state, and thus must be excluded from the very short list of anomalous conglomerates. At the same time homo-1 is dissolved in 25 times better than rac-1, and this feature belongs to another interesting and rare type, namely "anticonglomerates". We discuss some of the reasons for this behavior. ABSTRACTChiral 4-benzoylamino-3-hydroxybutyric acid (1) was recognized in 1930 as the first example of "anomalous racemates" (correct to say -anomalous conglomerates), i.e. specific addition compounds formed by different enantiomers in unequal ratio. Through the comparative (racemic against homochiral samples) inspection of the IR spectra, single crystal X-ray diffraction, PXRD analysis, and solubility data we have found that this substance forms normal racemic compound in the solid state, and must be excluded from the very short list of anomalous conglomerates. At the same time homo-1 is dissolved in 25 times better than rac-1, and this feature belongs to another interesting and rare type, namely "anticonglomerates". Some of the reasons for this behavior are discussed.

An exceptional 5:4 enantiomeric structure

“…Flack (2003) recommended calling the examples M:N enantiomeric structures, where M:N is the enantiomeric ratio. The phenomenon has been discussed more recently by Tabora et al (2007) and Bredikhin et al (2015).…”

Stereoselective Crystallization as a Basis for Single‐Enantiomer Drug Production

“…Thirdly, because in the case of normal conglomerate formation the opposite enantiomers are immiscible in the solid state, a normal conglomerate is a single‐eutectic system; here, the enantiomeric composition of the eutectic ee eu = 0. It is easy to demonstrate that for any eutectic system the solution composition in equilibrium with the solid phase, regardless of the composition of the solid phase, matches the composition of the eutectic, provided that all the components of the eutectic are firstly soluble in the solvent and secondly are stored in the solid phase under equilibrium conditions , . Consequently, under these conditions, for samples of a conglomerate‐forming substance with a different enantiomeric excess, including arbitrarily close but not equal to ee = 1, the composition of the equilibrium solution is strictly racemic, ee = 0 , .…”

“…Thirdly, because in the case of normal conglomerate formation the opposite enantiomers are immiscible in the solid state, a normal conglomerate is a single-eutectic system; here, the enantiomeric composition of the eutectic ee eu = 0. It is easy to demonstrate that for any eutectic system the solution composition in equilibrium with the solid phase, regardless of the composition of the solid phase, matches the composition of the eutectic, provided that all the components of the eutectic are firstly soluble in the solvent and secondly are stored in the solid phase under equilibrium conditions [37,38]. Consequently, under these conditions, for samples of a conglomerate-forming substance with a different enantiomeric excess, including arbitrarily close but not equal to ee = 1, the composition of the intensities are identical, a small (1 cm -1 ) shift in frequency, the trajectory is a narrow loop around the diagonal; (c) significant (5 cm -1 ) shift in frequency, wide loop; (d) peaks vary in height (two times), straight line, deviating from the diagonal the stronger, the more differences; (e) peaks are completely separated or the corresponding peak is absent in one of the spectra, the trajectory degenerates into a horizontal and/or vertical lines; (f) peaks have an identical integral extinction but differ two times in extinction at the maximum, the trajectory is curved; (g) peaks are observed on the background of a baseline shift of one of the spectra, a trajectory that is parallel to the diagonal.…”