A Compact and Lipophilic Enantiomer Showing a Bilayer Crystal Structure − Free Energy of Spontaneous Resolution of the Racemic Compound into the Crystalline Enantiomers

Abstract

AbstractThe melting points and the enthalpies and entropies of fusion of (R)‐1 and rac‐1, with the racemate both as the conglomerate and as the true racemic compound, were determined by differential scanning calorimetry: the melting points were 113.2 ± 0.3, 90.7 ± 0.4, and 80.5 ± 0.6 °C, respectively, the ΔHfus values 8.82 ± 0.03, 7.94 ± 0.27, and 5.98 ± 0.59 kcal·mol−1, respectively, and the ΔSfus values 22.8 ± 0.1, 21.8 ± 0.7, and 16.9 ± 1.7 cal·deg−1·mol−1, respectively. The specific heat of fusion (ΔCfus) of the pure enantiomer 1 calculated from these data is 39.1 cal·deg−1·mol−1. The ΔHfus, ΔSfus, and ΔCfus values of these enantiomers are consistently high relative to average values for organic compounds. The enthalpy, entropy, and free energy of formation of the racemic compound from the crystalline enantiomers are 1.56 kcal·mol−1, 3.8 cal·deg−1·mol−1, and 0.22 kcal·mol−1, as calculated from the above data. The positive sign of the free energy of formation bears out the observed spontaneous resolution of the racemic compound into the crystalline enantiomers. A statistical thermodynamic model of melting, weighing the different mechanical contributions to the crystalline and the liquid states, is described in conjunction with the interpretation of the data. It is concluded that both the interaction potential energy of the crystal of the pure enantiomer 1 and the vibrational mobility of the crystal structure are low, features pertinent to a low enthalpy and entropy of the crystal, respectively. X‐ray crystallography of (R)‐1 revealed a simple bilayer arrangement of the roughly ellipsoidal molecules: a characteristic bilayer consists of two monomolecular layers with interactions between the lipophilic groups in between, featuring a methyl−phenyl interaction, while the cyano groups project towards the outsides of the bilayer, which stacks by means of dipolar interactions to a constant distance. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)