Solubility measurement and molecular simulation of 1,1′-binaphthyl-2,2′-diyl hydrogenphosphate racemate and enantiomers in organic solvents with and without reverse micelles

Abstract In this work, the solubility of the racemate and the enantiomers of 1,1′-binaphthyl-2,2′-diyl hydrogenphosphate (BNP) in methanol, ethanol, n-propyl alcohol, isopropanol, n-butyl alcohol, isobutanol and ethyl acetate was firstly experimentally determined in the temperature range from (288.15 to 333.15) K at atmospheric pressure. The results indicated that the solubility of (R,S)-BNP and (S)-BNP in seven solvents generally increased with the temperature in the temperature range investigated and at room temperature was in sequence of n-butyl alcohol > n-propyl alcohol > ethanol > isobutanol > isopropanol > methanol > ethyl acetate. Meanwhile, the solubility of (R,S)-BNP was close twice that of (S)-BNP, which revealed the crystalline (R,S)-BNP was a racemic conglomerate. In particular, the effect of sodium deoxycholate (NaDC) reverse micelles on the solubility of BNP enantiomers in methanol, ethanol, n-propyl alcohol and n-butyl alcohol was experimentally studied as well. The results showed that, the NaDC reverse micelles had a solubilization effect on both enantiomers which increased with the concentration of NaDC. However, the solubilization on (S)-BNP was larger than that on (R)-BNP, and the difference in the solubility between two enantiomers increased with the concentration of NaDC. To further clarify the effect mechanism of solvent and reverse micelles on the solubility of enantiomers and racemate, the binding processes of solute to solvent cells and different sizes of micelles were firstly simulated by molecular dynamics and docking. The docking simulation clearly showed that bile salt micelles could form more stereoselective hydrogen bonds with the S enantiomer than those with the R enantiomer, which leaded to the S enantiomer penetrating more deeply into the pockets of micelles with a more negative binding free energy, resulting in a higher solubility of S enantiomer than R enantiomer in organic solvents with bile salt micelles.