Enantioseparation and Oscillatory Transenantiomerization of S,R‐(±)‐Ketoprofen, as Investigated by Means of Thin Layer Chromatography with Densitometric Detection

Abstract

In the course of our earlier and rather extensive investigations, we discovered a striking ability of the two non‐steroidal anti‐inflammatory drugs (NSAIDs) from the group of 2‐arylpropionic acids (2‐APAs), i.e., ibuprofen and naproxen, and also of 2‐phenylpropionic acid (which is not a drug) to, in vitro, undergo a repeated structural conversion from one chiral configuration to the opposite one. We labelled the discovered phenomenon ‘oscillatory transenantiomerization’ and formulated a hypothesis that all the 2‐APAs can behave in a similar manner when dissolved in certain low‐molecular‐weight (aqueous or non‐aqueous) solvents. Furthermore, we assumed that structural differences among the various 2‐APAs can result in differentiated dynamics of oscillatory transenantiomerization, which is omnipresent with this class of compounds. In this paper,we present the results of an analogous study, this time devoted to still another 2‐APA, S,R‐(±)‐ketoprofen. The chemical structure of ketoprofen is, in a sense, unique as a keto‐enol tautomer (a transition form between S‐(+)‐ketoprofen and its R‐(‐) antimer) that contains a long assembly of eight conjugated π‐electron pairs. Such a peculiar electron structure seems to particularly well stabilize the keto‐enol tautomer derived from ketoprofen and, consequently, to efficiently promote oscillatory transenantiomerization of this compound. The results of our investigations fully confirmed this intuition, and in our thin‐layer chromatographic experiment, we managed to demonstrate the ability of S,R‐(±)‐ketoprofen to undergo oscillatory transenantiomerization, in a manner similar to that of the other already examined 2‐APAs. Moreover, we performed a successful densitometric scrutiny of the chromatograms of S,R‐(±)‐ketoprofen, proved to have separated three different species, to run, in situ, their respective UV spectra (all three of them practically identical), and to speculate about their chemical nature. In the HPLC experiment we produced evidence of a considerable viscosity of S,R‐(±)‐ketoprofen when chromatographed with pure acetonitrile and with the acetonitrile+water mixtures (containing very low amounts of water). This viscosity seems to be the main factor that contributes to the oscillatory (i.e., repeated) nature of the observed transenantiomerization.

Keywords:

• S,R‐(±)‐Ketoprofen
• TLC
• Chirality
• Oscillatory transenantiomerization
• UV absorption spectra
• Viscosity

Acknowledgment

The authors wish to thank Merck KGaA (Darmstadt, Germany) for supplying the TLC plates used in our experiments.