Determination of the Dimerization Equilibrium Constants of Omeprazole and Pirkle's Alcohol through Optical‐Rotation Measurements

Abstract

A new procedure to measure the equilibrium constants for the dimerization (homochiral and heterochiral) reactions of enantiomers in solution was applied to two different compounds, namely omeprazole and Pirkle×s alcohol, both in CHCl 3 . This procedure is based on the measurement of the optical rotation of the solution as a function of its composition, which exhibits a nonlinear dependence on the enantiomer enrichment. Such nonlinearity depends on the extent of dimerization, and it is a strong effect in the case of omeprazole, whose equilibrium constants are 14.0 AE 3.5 l/mol and 25.2 AE 4.0 l/mol for the formation of homochiral and of heterochiral dimers, respectively. Pirkle×s alcohol exhibits a weaker effect that allows only to estimate the order of magnitude of these constants, i.e., ca. 0.10 and 0.34 l/mol, respectively. Although, in solution, enantiomers and racemates of chiral compounds usually exhibit identical NMR spectra, small differences in the chemical shifts are sometimes observed (see [18] for an overview, as well as the ref. cit. therein). It is also known that nonracemic mixtures of enantiomers of compounds that strongly self-associate, e.g., amino alcohols, amides, and carboxylic acids, can exhibit anisochrony, thus reflecting the enantiomer composition even in the absence of shift reagents [19]. Association is often limited to the formation of dimers that may take place through the formation of H-bonds between enantiomers. This is the case for the enantiomers of the chiral [1,1'-binaphthalene]-2,2'-diol ( binaphthol) and 1-(anthracen-9-yl)-2,2,2-trifluoroethanol ( Pirkle×s alcohol). In the case of the enantiomers of binaphthol in CHCl 3 , we have recently been able, using an achiral chromatography column, to collect two fractions constituted of the pure enantiomer present in excess (reaching 100% e.e.) and of the racemic mixture, respectively [20]. In the case of Pirkle×s alcohol, the enantiomer enrichment of a nonracemic solution in hexane/CH 2 Cl 2 was also achieved through achiral chromatography on a silica stationary phase [12].

Single Enantiomer Versus Racemate: Chiral Distinction in the Proton Pump Inhibitors Omeprazole and Esomeprazole

“…The chiral distinction of the homochiral and heterochiral dimers of omeprazole revealed in the present study, which is indicative of different types of enantiomer–enantiomer interactions in omeprazole versus esomeprazole, is in line with the experimental dimerization equilibrium constants for the formation of these dimers in solution . It also corresponds well with the findings of different therapeutic effects of omeprazole, esomeprazole, and the (+)‐( R )‐enantiomer (vide supra), with the fact that the (+)‐( R )‐enantiomer is not an inactive impurity, and with the metabolic enantiomer–enantiomer interactions between ( S )‐omeprazole and ( R )‐omeprazole revealed in a pharmacological study .…”

“…The crystal structure of a toluene hemisolvate of the piperazinium salt of esomeprazole which exhibits intermolecular hydrogens bonds within the layers and van der Waals contacts between the layers have recently been determined . Omeprazole forms dimers not only in the crystal state, but also in solution (CHCl 3 ) . Mazzotti et al .…”

Self-disproportionation of enantiomers (SDE) of chiral sulfur-containing compounds via achiral chromatography

“…89 This proposal stems from both the X-ray crystallographic structure analysis of omeprazole 5, which showed the existence of a cyclic dimer of two enantiomers, [96][97] and a great extent of dimerization observed for a chloroform solution. 98 …”

Enantioseparations in Achiral Environments and Chromatographic Systems

“…Baciocchi et al . estimated the chemical equilibrium constants for 1,1′‐bi‐2‐naphthol (2,2′‐dihydroxy‐1,1′‐binaphthyl) 11 and for omeprazole and Pirkle's alcohol, i.e.,1‐(anthracen‐9‐yl)‐2,2,2‐trifluoroethanol in chloroform, by using a combination of optical rotation and UV absorbance measurements. Optical rotation of the solution was measured as a function of its composition when a nonlinear dependence on the enantiomer enrichment was exhibited.…”