High-performance liquid chromatography enantioseparation of atropisomeric 4,4′-bipyridines on polysaccharide-type chiral stationary phases: Impact of substituents and electronic properties

doi:10.1016/j.chroma.2012.06.035

Journal of Chromatography A

Volume 1251, 17 August 2012, Pages 91-100

https://doi.org/10.1016/j.chroma.2012.06.035 Get rights and content

Abstract

The high performance liquid chromatography (HPLC) enantioseparation of eleven atropisomeric 4,4′-bipyridines was performed in the normal and polar organic phase mode using three cellulose-based chiral stationary phases (CSPs), namely Lux^® Cellulose-1, Lux^® Cellulose-2, Lux^® Cellulose-4, and two amylose-based CSPs, Chiralpak^® AD-H and Lux^® Amylose-2. n-Hexane/2-propanol mixtures and pure ethanol were employed as mobile phases. The combined use of Chiralpak^® AD-H and Lux^® Cellulose-2 allowed to enantioseparate all the considered bipyridines. Ten bipyridines were enantioseparated at the multimilligram level allowing the elution sequence determination of the enantiomers as well as their future use for the preparation of homochiral metal organic frameworks (MOFs). Moreover, the performance of the CSPs regarding the same bipyridine was different and dependent on the backbone as well as on the side chain of the polymer. The impact of substitution pattern, shape and electronic properties of the molecules on the separation behavior was investigated through the evaluation of retention factors (k), separation factors (α), resolution (R_s) and molecular properties determined using density functional theory (DFT) calculations. In this regard, the substituents at the 3,3′,5,5′ positions of the 4,4′-bipyridyl rings exhibited a pivotal role on the enantioseparation.

Highlights

▸ Chiralpak AD-H and Lux Cellulose-2 allowed to enantioseparate 4,4′-bipyridines. ▸ Ten out of eleven bipyridines were enantioseparated at the multimilligram level. ▸ Impact of substituents and electronic properties on enantioseparation is discussed.

Introduction

Since the first synthesis of paraquat published by Weidel and Russo [1], the 4,4′-bipyridine framework has been widely used as synthetic intermediate [2], [3], [4], as building block for the synthesis of viologens [5] and liquid crystals [6], [7], as target for biological applications [8] and as metal ligand for supramolecular chemistry [9], [10], [11]. In particular, the 4,4′-bipyridyl system is one of the most used connectors between transition metal atoms for building metal organic frameworks (MOFs) due to its structural and topological characteristics [10]. Chiral MOFs are of great interest in asymmetric catalysis [12] and the easy access to enantiopure 4,4′-bipyridines is therefore highly required. Indeed, only few examples of chiral 4,4′-bipyridines are reported in the literature. In some cases, chirality has been engendered by introducing chiral substituents onto the heteroaromatic rings [13], [14]. Chirality can also emerge from restricted rotation induced by sterically hindered atoms or functional groups located around the 4,4′-biaryl bond (chiral axis). In 2008, the first atropisomeric 3,3′,5,5′-tetrasubstituted 4,4′-bipyridines were prepared and used as ligands for the self-assembly of metallo-supramolecular squares by Schalley and co-workers [15]. Successively, a diastereoisomeric 3,3′-bis[(S)-alanine]-substituted 4,4′-bipyridine was prepared by the same group [16]. In this case, the chiral axis showed to be not fixed and the two bipyridine diastereomers interconverted.

Due to the novelty of the field, currently no asymmetric synthesis to produce atropisomers of 4,4′-bipyridines is available in the literature. Pure enantiomers can be obtained by separating racemate mixtures of synthesized compounds. Thus, high-performance liquid chromatography (HPLC) methods for producing pure enantiomers can play a key role in research plan development. In the case of the well known atropisomeric biphenyls, polysaccharide-type chiral stationary phases (CSPs) were found to efficiently enantioseparate molecular systems featuring a chiral axis as exclusive source of molecular dissymmetry [17]. Similarly, the first analytical and semipreparative enantioseparations (≥92% e.e.) of three atropisomeric 4,4′-bipyridines were performed on a home-made immobilized Chiralcel OD stationary phase, under normal phase liquid chromatography (NPLC) elution mode [15].

Recently, the preparation of a new family of configurationally stable atropisomeric 3,3′-dibromo-5,5′-disubstituted-4,4′-bipyridines where bulky substituents hinder the pyridyl–pyridyl rotation was published by us (Fig. 1) [18]. The absolute configurations of all the HPLC enantioseparated enantiomers were assigned by X-ray diffraction and electronic circular dichroism (ECD).

Herein, the results of the full HPLC screening to directly enantioseparate chiral 4,4′-bipyridines 1–11 [18], [19] (Fig. 2) on the polysaccharide-type CSPs 1–5 (Fig. 3) by using n-hexane/2-propanol = 90:10 as well as pure ethanol as mobile phases are described.

The recognition mode of the selected polysaccharide-type CSPs has been extensively studied and a number of information has been collected in this regard. These CSPs contain polymeric chains of phenyl carbamate d-glucose residues with β-1,4 linkage in cellulose (CSPs 1–3) and with α-1,4 linkage in amylose (CSPs 4 and 5). The chromatographic behavior can depend on the polymer backbone as well as on the type of side chain [20], which contribute to determine size and shape of the chiral pathway covered by the enantiomers inside the column. As shown in Fig. 3, CSPs 1–3 have the same cellulose backbone but different side chains, CSPs 4 and 5 have the same amylose backbone but different side chains, CSPs 1 and 4 have a different backbone bearing the same 3,5-dimethylphenylcarbamate side chain. Attractive interactions (π–π, dipole–dipole and hydrogen-bonding) play an important role in the recognition as well as the steric fit of the analyte inside the chiral cavity [21], [22], where polar carbamate groups are considered as important chiral adsorbing sites. By changing the carbamate group polarity, methyl and chloro substituents onto the carbamate aromatic moiety modify the recognition ability of the CSP. Therefore, the chloro-substituted CSPs (as CSPs 2, 3 and 5) usually work in a different and complementary fashion compared to the completely alkylated ones (CSPs 1 and 4) [23], [24], [25].

Bipyridines 1–11 contain a number of aromatic rings compared to hydrogen bond (HB) centers. This structural characteristic represents a useful tool to investigate on the role of hydrophobic π–π interactions during chromatographic chiral recognition both in NPLC and polar organic solvent chromatography (POSC) elution modes. With this purpose, the impact of structural modifications inside the bipyridyl skeleton on the separation behavior was investigated through a parallel evaluation of experimental data, such as retention (k) and separation factors (α) and resolution (R_s), and density functional theory (DFT) computed molecular properties of the analytes. The elution sequence was determined for all compounds [18], [19].

Section snippets

Chemicals

Rac-4,4′-bipyridines 1–11 were prepared as previously reported [18], [19].

HPLC instrument

An Agilent Technologies (Waldbronn, Germany) 1100 Series HPLC system [high-pressure binary gradient system equipped with a diode-array detector operating at multiple wavelengths (220, 254, 280, 360 nm), a 20 μl sample loop and a thermostatted column compartment] was employed both for analytical enantioseparations and multimilligram recovery of the enantiomers. Data acquisition and analysis were carried out with Agilent

Chromatographic screening. POSC vs NPLC elution mode

Several preliminary tests were performed by varying chiral column, mobile phase composition and flow rate. All the bipyridines were unresolved on Whelk-O^®1 eluting with hexanic mobile phases, pure methanol or ethanol, as well as on Chiralcel^® OJ under NPLC elution mode. In the latter case, all bipyridines exhibited high retention and, in almost all cases, remarkable peak tailing, which made this column unsuitable for the purpose, even by increasing the strength of the mobile phase (hex/EtOH

Conclusions

With the aim to develop a methodological platform for the enantioseparation of atropisomeric 4,4′-bipyridines, a pilot screening was performed on eleven compounds of this family by using five polysaccharide-based CSPs under NPLC and POSC elution modes. Representative of different recognition mechanisms, two amylose-based and three cellulose-based CSPs were chosen, which are characterized by the classical 3,5-dimethylphenylcarbamate side chain as well as by the more recent chloro-substituted

Acknowledgements

This work has been supported by Università Ca’ Foscari di Venezia (ex 60% funds). The authors thank in particular Dr. Rosaria Villano (ICB – CNR) for providing us access to Chiralpak^® AD-H and Mr. Alessandro Dessì (ICB – CNR) for helpful discussion on computational methods.

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High-performance liquid chromatography enantioseparation of atropisomeric 4,4′-bipyridines on polysaccharide-type chiral stationary phases: Impact of substituents and electronic properties

Abstract

Highlights

Introduction

Section snippets

Chemicals

HPLC instrument

Chromatographic screening. POSC vs NPLC elution mode

Conclusions

Acknowledgements

Bioorg. Med. Chem. Lett.

J. Chromatogr. A

J. Chromatogr. A

J. Chromatogr. A

J. Chromatogr. A

J. Chromatogr.

J. Chromatogr. A

J. Chromatogr. A

J. Chromatogr. A

Monatsh. Chem.

J. Org. Chem.

Beilstein J. Org. Chem.

The Viologens: Physicochemical Properties, Synthesis and Applications of the Salts of 4,4′-Bipyridines

Angew. Chem. Int. Ed. Engl.

J. Mater. Chem.