On the Mechanism of Oscillatory Changes of the Retardation Factor (R_F) and the Specific Rotation [α]_D with Selected Solutions of S‐(+)‐Naproxen

Abstract

In our earlier investigations, we demonstrated oscillatory instability of selected profens (S‐(+)‐ibuprofen, S‐(+)‐naproxen, and S,R‐(±)‐2‐phenylpropionic acid), and their marked tendency to change chiral configuration, most probably via the keto‐enol tautomerism. In our earlier papers oscillatory transenantiomerization of the profens had been demonstrated in a standard manner, i.e., by means of polarimetry, and also by means of thin‐layer chromatography (TLC). The ability of profens to change chiral configuration is due to their gelating property (as the low‐molecular‐weight gelators) and a subsequent increase of solutions' viscosity. In this study, we attempt to provide sufficient experimental evidence in favor of keto‐enol tautomerism as a cause of the oscillations observed. Keto‐enol tautomerism is catalyzed in a basic environment and is hampered in acid. In our study focused on the molecular‐level mechanism of the observed oscillations, we purposely stored samples of S‐(+)‐naproxen in an acidic and a basic solution. It was clearly shown that the acidic environment both hampers transenantiomeric oscillations of S‐(+)‐naproxen and stabilizes naproxen in its S‐(+)‐form. Conversely, a basic environment facilitates partial transformation of S‐(+)‐naproxen to the R‐(−)‐form, which is the best proof of keto‐enol tautomerism as a mechanism of the oscillatory instability of profens. Culminating our experiments were the attempts to obtain two‐dimensional chiral separations of S‐(+)‐naproxen from its R‐(−)‐antipode, generated in the course of storage of the S‐(+)‐sample in basic and acidic solutions. The results obtained provided direct confirmation as to the key role played by the basic environment in generating R‐(−)‐naproxen via keto‐enol tautomerism. To our best knowledge, this is the first thin‐layer chromatographic separation of the two chiral antipodes of naproxen.

Keywords:

• Naproxen
• TLC separation of naproxen enantiomers
• Oscillatory transenantiomerization
• Keto‐enol tauromerism

Acknowledgment

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