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41 References


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Figure 11. Example chromatograms of metoprolol enantiomers on each of the commercial fluoro-methyl and chloro-methyl phases (CC4, CCO-F4-CF3, CCO-F4, and CCO-F2). Each column is 4.6mm I.D. x 250mm length containing 5-µm particles maintained at 25°C. The mobile phase consists of CO2


and 25% 20mM ammonia in isopropanol delivered at a flow rate of 3.0mL/min with 160 bar outlet pressure.


Determining if this trend was a general occurrence, we utilised several more compounds, both halogenated and non- halogenated, under similar conditions for each of the 3 phases. With a few exceptions, the trend in both selectivity and retention remains the same at CCO-F4 < CCO-F4-CF3 < CC4 (Figure 10).


To further emphasise the effect of the positional substitution differences, selectivity for the metoprolol enantiomers (Figure 11) can be affected by substituting the halogen (4-fluoro to 4-chloro), the methyl group (4-fluoro-3-methyl to 4-fluoro-3-trifluoromethyl), or the relative positions of both the halogen and methyl groups (4-fluoro to 2-fluoro). Although outside the scope of this paper, it would also be interesting to re-evaluate by SFC other halogenated CSPs previously reported using HPLC conditions. [31]


Conclusion


The use of fluorine as a halogen substituent for chiral polysaccharide stationary phases has demonstrated utility in our preliminary studies and appears comparable to commercial chlorinated phases. Since the CCO-F4, CCO-F4-CF3 (now CCO-F4-T3) and CCO-F2 are now readily available from ES Industries, they have been incorporated into our routine screening protocol. The magnitude of the selectivity differences from these fluorinated prototype phases appears to derive from potential changes in


the dipole of the benzylic functional groups. Nonetheless, the fluorinated versions offer several advantages in potential savings in organic modifier consumption and shorter retention times for SFC applications. Based on the enhanced selectivity from the CCO-F4 to CCO-F4-CF3, the introduction of the trifluoromethyl functionality as a replacement for the methyl group could potentially improve the selectivity of other commercial phases.


The enantioseparation of our fluorinated target compound was achieved using two different CSP chemistries and two different techniques, HPLC and SFC. The results using the fluorinated phases by SFC suggest that the properties of CO2


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, even as


a liquid without the presence of an organic modifier, have clear benefits as a strategy to enhance selectivity. Therefore, SFC is the technique of choice for enantioseparations and has the potential to significantly impact areas where fluorinated and other halogenated chemistry are heavily used.


Acknowledgments


Special thanks to Professor Bezhan Chankvetadze of Tbilisi State University, Tbilisi, Georgia, for the mechanistic discussion on halogenated chiral stationary phases and to Paul Richardson for his extensive review of this paper.


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