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37 Figure 2. Compounds used for evaluation of the chiral stationary phases.


recognition. Studies have shown that changes in chiral recognition are driven by modifi cations to the structure of the polysaccharide phase, and the addition of electron-donating/electron-withdrawing substituents to specifi c positions on the benzylic ligand has resulted in several new phases [16]. For instance, an electron- withdrawing chlorine substituent on the polysaccharide CSP has demonstrated better chiral recognition abilities than without chlorine in both HPLC and SFC. [17-21] Research on halogenated substituents of polysaccharide CSPs


dates back to the 1980’s, where chloro-, bromo- and fl uoro-substituted methylphenylcarbamates demonstrated enhanced chiral recognition for halogenated compounds [22,23]. As a result, several chloro-phenyl substituted CSPs have become commercially available over the last decade, such as the Lux Cellulose-2 (cellulose tris (3-chloro- 4-methylphenylcarbamate) and the Lux Amylose-2 (amylose tris (5-chloro- 2-methylphenylcarbamate) phases (Phenomenex, Torrance, CA, USA).


The driving force for this study,


Table 1. Representative structures of prototypes and widely used commercial CSPs. Column


Column Type Coated-Amylose Chiralpak AD Coated-Amylose Chiralpak AS Immobilized-Cellulose Chiralpak IC Coated-Cellulose Chiralcel OJ Coated-Cellulose Chiralcel OD Coated-Cellulose CCO-F4 Coated-Cellulose CCO-F2 CCO-F4-CF3 CCO-DiF Coated-Cellulose CC4 Coated-Cellulose Whelk-O1 Bonded Pirkle-type Lux Amylose-2 Lux Cellulose-4 Coated-Amylose Lux Cellulose-2 Coated-Cellulose Chiral Selector - R Column Column Type Coated-Cellulose


however, is the continued resurgence in fl uorinated compounds required to support drug discovery campaigns. Fluorine is widely used in medicinal chemistry to enhance metabolic stability, and greater than one-third of newly approved drugs contain fl uorine [24-26]. One compound of interest, (2,2-difl uorocyclopropyl) methyl benzoate, shown in Figure 2, is lipophilic, has low molecular weight, and possesses limited diversity at the chiral centre. The compound exhibited limited retention and negligible separation on nearly every CSP in Table 1, with only a partial separation achieved on the Chiralcel OJ column using normal phase HPLC. Speculating that a fl uorophilic mechanism could potentially enhance selectivity and retention of this compound, we sought to create several fl uorinated chiral phases since the few that were commercially available were unsuccessful. In this paper, we demonstrate the unique enantioselectivities of these prototype fl uorinated polysaccharide CSPs for SFC not only for compounds containing fl uorine but for other halogen-containing compounds. We also compare differences in chiral recognition abilities between these fl uorinated phases and other commercially available halogenated CSPs.


Experimental Chemicals and Materials Chiral Selector - R Coated-Cellulose


The following were purchased from Sigma-Aldrich (St. Louis, MO, USA): 4-fl uoro-3-methylphenyl isocyanate, 2-fl uoro-5-methylphenyl isocyanate, 4-fl uoro-3-(trifl uoromethyl) benzoyl chloride and 3,4-difl uorobenzoyl chloride. These monomers were bonded to cellulose by ES Industries, Inc (West Berlin, NJ, USA) to form tri-substituted carbamates or benzoates, and then coated over silica gel with 5-µm particle using a proprietary process. Each phase was packed into 4.6mm I.D. x 250mm columns. The fi rst generation prototypes created were the CCO-F4 (cellulose tris(4- fl uoro-3-methylphenylcarbamate) and the CCO-F2 (cellulose tris(2-fl uoro-5- methylphenylcarbamate). A second set of prototype columns were made after the initial evaluation of fi rst generation phases, and these were the CCO-F4-CF3 (cellulose tris(4-fl uoro- 3-trifl uoromethylphenylbenzoate) and the CCO-DiF (cellulose tris(3,4- difl uoromethylphenylbenzoate). The


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