Chiral Discrimination of a Proline-Based Stationary Phase: Adhesion Forces and Calculated Selectivity Factors

Abstract

As early as 1992, proline was examined as a potential chiral selector for high-performance liquid chromatography. In recent years, brush-type selectors with up to 10 proline units have been examined, and the longer peptides were found to be competitive with commercial chiral stationary phases (CSPs). In this article, we report on a comprehensive examination of a t-butoxycarbonyl- (t-Boc-) terminated monoproline selector. This selector was grafted through an amide linkage to an aminopropyl siloxane-terminated Si(111) wafer and to a silicon atomic force microscopy tip. Chemical force spectrometry measurements were performed for interaction forces between two d- or l-monoproline monolayers in water and in the presence of various amino acid solutions. When exposed to amino acids, the adhesion forces measured between the proline layers were reduced. Amino acids containing hydrophilic side chains were found to exhibit a selectivity opposite to that seen for those containing hydrophobic side chains. Molecular dynamics simulations of the monoproline interfaces in the presence of racemic alanine and serine identified the importance of hydrogen-bonding interactions between the amino acids and the monoproline selectors. We found that, when amino acids are bound to the proline selector, their side chains protrude into the bulk solution, explaining the strong impact of side-chain hydrophobicity on the selectivity. Taken together, the experiments and simulations show that hydrogen-bonding interactions are key to effective chiral discrimination for proline-based CSPs.

Molecular dynamics simulations of enantiomeric separations as an interfacial process in HPLC

“…For example, an interface could consist of trimethylsilyl end caps corresponding directly to a truncated selector tether, silanol groups, and selectors covalently attached to a single underlying layer of Si that is stationary throughout the simulation. Alternately, the selector is grafted through an amide linkage to an aminopropyl siloxane-terminated Si(111) wafer, 39 or one could choose (c) not to include the solid support at all, instead compensate for the limited mobility of the polymer coated on solid support with restraining forces, 33,34 or (d) ignore the solid support and use a freely floating selector molecule or polymer fragment. 33,34 Second, there is the option of choosing the size of the selector fragment to use in the simulation; (a) for the polysaccharides some have used four 18-mer polymer strands, 32 (b) or a 12-mer single polymer strand, 33 (c) or even shorter strands, such as a 6-mer, 23 tetramer, dimer; use of a monomer (as in References 21,22) would not permit the analyte to feel the groove in the helical polymer structure.…”

“…For covalently-bonded selectors, the length of the tether is a variable. [36][37][38][39] Third, there is the option of the representation of the solvent system: (a) explicitly atomistic solvent molecules of the appropriate solvent composition can be used, 33,34 (b) or a continuum model for the solvent with variable dielectric constant adjusted for the composition, [40][41][42][43][44][45] or (c) vacuum. [46][47][48] Fourth, there is the option of keeping some parts of the system rigid to increase the efficiency of the MD runs.…”

“…Cann et al, 36 in seeking to understand how it may be possible to change length and chemical composition of the tether, or composition of the solvent system in order to improve the selectivity of a CSP. 36,39,57 The one-body distribution maps for the S and R analytes in β-cyclodextrin provide similarly useful insights. 44 Indeed, many such examples are provided by Cann et al, 36,37,40 and such radial distribution functions aid in understanding the separation process in the case of Whelk-O1 and proline-based CSPs.…”

Direct Organocatalytic Enantioselective Functionalization of SiOx Surfaces

“…The generation of chiral surfaces is an area of widespread fundamental interest, finding varied applications as chiral selectors (for example in HPLC to separate enantiomers), in selective crystallization, and in enantioselective heterogeneous catalysis . Chiral surfaces also play a central role in the life sciences and the study of biomaterials, as certain cell types are known to attach differentially to surfaces based on surface chirality, thus demonstrating sensitivity at the angstrom scale .…”

“…It can be applied to insulating films and substrates, in contrast to scanning tunneling microscopy. While χ‐AFM has previously been employed as a method for the enantiomeric discrimination of chiral surfaces prepared by adsorption of enantiopure substrates, in this manuscript the use of χ‐AFM to interrogate the enantioselective functionalization of a surface is described.…”