Enantiodifferentiation of chiral baclofen by β-cyclodextrin using capillary electrophoresis: A molecular modeling approach

Using capillary electrophoresis baclofen (BF) enantiomers were separated only in the presence of beta-cyclodextrin (beta CD) as a chiral selector when added to the background electrolyte. Proton nuclear magnetic resonance and electrospray ionization mass spectrometry (ESI-MS) techniques were used to determine the structure of the BF-beta CD inclusion complexes. From the MS data BF was found to form a 1:1 complex with alpha- and beta CD, while the NMR data suggest location of the aromatic ring of BF into the cyclodextrin cavity. A molecular modeling study, using the semiempirical PM6 calculations was used to investigate the mechanism of enantiodifferentiation of BF with cyclodextrins. Optimization of the structures of the complexes by PM6 method indicated that separation is obtained in the presence of beta-CD due to a large binding energy difference (Delta Delta E) of 46.8 kJ mol(-1) between S-BF-beta CD and R-BF-beta CD complexes. In the case of alpha CD complexes Delta Delta E was 1.3 kJ mol(-1) indicating poor resolution between the two enantiomers. Furthermore, molecular dynamic simulations show that the formation of more stable S-BF-beta CD complex compared to R-BF-beta-CD complex is primarily due to differences in intermolecular hydrogen bonding. (C) 2012 Elsevier B.V All rights reserved.