Empirical procedure that uses molecular structure to predict enantioselectivity of chiral stationary phases

Abstract

A total of 121 racemic compounds were separated in the normal-phase mode on a (S)-(1-naphthylethyl)carbamoylated beta-cyclodextrin (S-NEC-beta-CD) bonded phase and 74 on the R equivalent (R-NEC) chiral stationary phase (CSP). All compounds are of the type that have four substituents on a stereogenic center, rather than an "axis of chirality". It is shown that the binary solvent pair used as the mobile phase has a significant influence on chiral recognition. However, the proportions of the components of a specific pair have little effect. From the results, the individual contributions to chiral recognition by these CSPs were estimated for 81 different substituents of the stereogenic center. Varying the arrangement of these 81 substituents could produce over 1.6 million compounds. Hydrogen was chosen as the reference substituent and was assigned a 0 cal/mol free energy. The chiral recognition increased when sp2-hybridized carbons were connected to the stereogenic center. Conversely, sp3-hybridized carbons decreased the enantioselectivity. Amido groups increased the chiral recognition, especially when associated with pi-acid (3,5-dinitrobenzoyl) or pi-basic (naphthyl) groups. This approach does not allow one to know which enantiomer elutes first. However, the "substituent energy" list for chiral compounds can be used to obtain an estimated value for the enantioselectivity of a compound by adding the energy contributions of the four substituents connected to the stereogenic center. In this way one can predict a priori whether or not a compound will separate on a CSP and estimate its separation factor (alpha). Theoretically, this approach can be used for most CSPs, provided a sufficient data base is generated on them.

Enantiomeric separation of drugs and herbicides on a β‐cyclodextrin‐bonded stationary phase

“…24,28,44 We notice that, in spite of the lower coverage observed for the CSP synthesized in this work, the enantioselectivity power is comparable for most racemates. Moreover, some couples are better separated on the prepared chiral stationary phase (21,24,25,30).…”

Preparation and enantioseparation characteristics of two chiral stationary phases based on mono(6A‐azido‐6A‐deoxy)‐perphenylcarbamoylated α‐ and γ‐cyclodextrin

“…27,30 The insertion of a methylene group or an oxygen atom between an sp 2 -hybridized carbon and the stereogenic center seems to decrease the chiral recognition. 31 There is a methylene group and an oxygen atom between the sp 2 carbon and the chiral center in pindolol, but for chloroquine, only an amino group is inserted between the sp 2 -hybridized carbon and the stereogenic center. Consequently, chloroquine was separated much better than pindolol.…”

Comparison of cyclodextrin-barbiturate noncovalent complexes using electrospray ionization mass spectrometry and capillary electrophoresis

“…Direct evidence for chiral recognition was derived from the crystal structure of an inclusion complex between fenoprofen and b-cyclodextrin by Hamilton et al 3 Statistical thermodynamic theory for chiral recognition in liquid chromatography (LC) was developed by Boehm et al 4 Retention mechanisms have been studied and thermodynamic constants involved in the transfer of solute from mobile to b-CD bonded stationary phase were also determined by Guillaume et al 5 Armstrong et al 6 have also devised an empirical procedure that uses molecular structure to predict enantioselectivity for selected CSPs based on a library of substitution free energy contributions from various side chains attached to a chiral carbon. Armstrong et al 7 have studied enantioresolution mechanisms in GC with cyclodextrin CSPs.…”