On‐column deracemization of an atropisomeric biphenyl by quinine‐based stationary phase and determination of rotational energy barrier by enantioselective stopped‐flow HPLC and CEC

Abstract

The reversible enantiomerization of axially chiral 2'-dodecyloxy-6-nitrobiphenyl-2-carboxylic acid was studied in the presence of a brush type chiral stationary phase based on O-(tert-butylcarbamoyl) quinine as chiral selector unit by stopped-flow high-performance liquid chromatography (sfHPLC) and capillary electrochromatography (sfCEC). After initial separation of the enantiomers in the first section of the column, the flow was stopped and the resolved species allowed to enantiomerize on-column. From this conversion, which could be determined from the enantiomeric ratios at different enantiomerization times, kinetic rate constants were calculated. By sfHPLC at a constant temperature of 15 degrees C, kinetic rate constants in the presence of the CSP were found to be 4.1 x 10(-5) s(-1) and 2.2 x 10(-5) s(-1) for the (-) and (+)-enantiomers, respectively, corresponding to half-lives of 279 and 530 min. Thus, apparent activation energies of enantiomerization were calculated to be 93.0 and 94.6 kJ mol(-1) for the (-) and (+)-enantiomers. On the macroscopic level, the apparent difference of rotational energy barriers and kinetic rate constants for both enantiomers is reflected as deracemization. For example, starting from a racemic mixture, an enantiomeric excess (ee) of 14% was seen in the stopped-flow HPLC experiment described after an enantiomerization time of 220 min at 15 degrees C, and a maximal ee of 17% can be approximated after infinite enantiomerization time. There is good agreement between HPLC and CEC results as well as their experimental errors, confirming that the new sfCEC technique may be a valuable and convenient tool to study interconversion processes.

Investigation of the stereodynamics of molecules and catalyzed reactions by CE

“…Lindner and coworkers [151] investigated the enantiomerization of axially chiral 2 0 -dodecyloxy-6-nitrobiphenyl-2-carboxylic acid in the presence of a brush type CSP based on O-(tert-butylcarbamoyl) quinine as chiral selector by stopped-flow CEC. The activation barrier determined by sfCEC was 92.970.1 kJ/mol (at 151C) and was in very good agreement with sfHPLC measurements.…”

Resolution of Racemates and Enantioselective Analytics by Cinchona Alkaloids and Their Derivatives

“…t-BuCQN CSP has also been employed for the resolution and racemization studies of an atropisomeric biphenyl carboxylic acid 52 [93]. Researchers from Eli Lilly developed an HPLC-tandem mass spectrometric method using two parallel t-BuCQN columns for the quantification of chiral metabolites of antiplatelet prasugrel 53 in humans [92].…”

Fast and precise access to enantiomerization rate constants in dynamic chromatography

“…[13][14][15][16] In particular, dynamic chromatography has been used for the determination of kinetic parameters of stereolabile compounds, for example, atropisomers, [17][18][19][20][21][22][23] drugs and drug-related compounds, [24][25][26] compounds with chirotopic nitrogen and sulphur, [27][28][29][30][31][32][33] pheromones, 34 and even organic radicals. 35 In dynamic chromatography, peak profiles are characterized by peak broadening, plateau formation, and eventually peak coalescence.…”