Oscillatory transenantiomerization

The same technique was used by Kowalska and coworkers [29] to investigate the oscillatory transenantiomerization of some profens [i.e., S-(-l-)-ibuprofen, 5-(-l-)-naproxen, and S,/ -( )-2-phenylpropionic acid] when stored in 70% ethanol at two different temperatures (6 C and 22°C). In this work, the instability of various optical antipodes was pointed out and attributed to change their steric configurations from the S-form to the i -form, and vice versa. Such phenomenon, which took place by a keto-enol tautomerism, was much more remarkable at low temperatures. 

According to the same authors [30], tautomeric isomerization proceeded through the migration of a proton from the moiety of a profen molecule to another in aqueous alcoholic medium. A suppression of the oscillatory transenantiomerization of profens was observed storing them in dichloromethane, owing to their much less pronounced electrolytic dissociation. 

ARYLPROPIONIC ACIDS AND THEIR SPONTANEOUS OSCILLATORY TRANSENANTIOMERIZATION... 

Tracing of Oscillatory Transenantiomerization with THE Selected APAs by Means of TLC... 

The analogous, although considerably less pronounced changes in the respective values, the chromatographic peaks concentration profiles, and the specific rotation ([ckId) values were established by means of polarimetry and TLC with densitometric detection in the case of ibuprofen, naproxen, and 2-phenylpropionic acid, when stored as solutions in dichloromethane and physiological salt [2,3], Finally, we arrived at a conclusion that the true reason for all these oscillatory changes was a spontaneous and oscillatory transenantiomerization of the investigated APA solutions in the spirit of the classical Zhabotinskii-Belousov type oscillatory reactions. 

We then decided to perform an independent experiment to additionally confirm the importance of the environment (and more precisely, of either its acidity or basicity) for the oscillatory transenantiomerization of ibuprofen, naproxen, and 2-phenylpropionic acid, perceived in our earlier studies. For this purpose, we selected 5-(- -)-naproxen as the best performing out of the three test species. The results of our experiment are extensively described in the paper cited under Reference [7]. 

Bottleneck 1. The investigated pairs of enantiomers — as it is the case, for example, with the chiral APAs—can occasionally demonstrate a striking chromatographic behavior, which makes their enantioseparation unrepeatable in terms of the measured retention parameters, incomplete, or even impossible. Such effects are certainly not due to an insufficient separation performance of the TLC systems involved, but because of the chemical processes themselves (e.g., the oscillatory transenantiomerization, uninterruptedly running within the investigated samples). Sometimes, the lack of a good separation result can be counterbalanced by an evident applicability of TLC to the advanced physicochemical studies (even as a replacement for polarimetry, as was shown in this section). 

As mentioned in Sections 9.2.1 and 9.2.2, in the case of the selected APAs (i.e., of ibuprofen, naproxen, and 2-phenylpropionic acid) dissolved both in the aqueous and the nonaqueous solvents, the oscillatory transenantiomerization occurs, which can schematically be illustrated by equation (9.3) (see Section 9.2.1). The process is spontaneously carried out and it consists of a repeated and alternate transformation of the respective -(-F) enantiomers into their / -(-) antipodes and vice versa, via the keto-enol tautomerism. This process can be easily traced by means of TLC (Sections 9.2.1 and 9.2.2) and even easier by means of HPLC (which is beyond the scope of this book), and in the first instance with the aid of polarimetry, an optical technique of a paramount importance for any research in the field of the crystalline and molecular chirality. 

Formation of keto-enols as intermediates in many organic reactions is known to be vigorously catalyzed in the basic environment and effectively hindered in the acidic one. The ethanol-aqueous environment, most often utilized in our experiments with the APAs, can rightfully be described as ampholytic. It seems that ampholytic environment combined with certain growth of viscosity of the APA solutions (in comparison with that of the pure solvents) [8] sufficiently M-fils the requirements for oscillatory transenantiomerization of the chiral analytes discussed. 

The analogical densitometric quantification of the nonchiral analytes (i.e., those that do not undergo an oscillatory transenantiomerization and, hence, show no resulting fluctuation of their respective UV absorption spectra) is relatively more accurate and the respective SD values per chromatographic plate are usually... 

The usefulness of TLC has been demonstrated in physiological studies of the oscillatory instability of profens when stored for long periods of time in aqueous media. The oscillatory transenantiomerization of the profens from the (5)- to the (/ )-form, and the vice versa, during storage has been shown using TLC. The TLC assessment of the stmctural oscillation of enantiomeric profens was also confirmed by polarimetry [24]. 

It has been concluded by these studies that there occurs an oscillatory change of configuration with the three selected profens, namely, (5)-(- -)-naproxen, (5)-(- -)-ibuprofen, and (5,/ )-( )-2-phenylpropionic acid, when stored for a long enough period of time in certain solvents and it occurred via keto-enol tautomerism. Thus, it was deduced that profens stored both in the aqueous and the nonaqueous media oscillate the only difference is the frequency and the amplitude of these oscillations, which depends on the solvent and the storage temperature applied. However, TLC performed excellently and allowed tracing oscillatory transenantiomerization of profens in its own independent way. 

These oscillatory changes were observed not only for the optically pure enantiomers but also with the racemic 2-phenyl propionic acid sample. The molecular mechanism was attributed to keto-enol tautomerism that is acid catalyzed as well. All the profens are carboxylic acids with relatively well-pronounced electrolytic dissociation. Thus, the keto-enol transenantiomerization of profens in aqueous media was considered justified because of the self-catalytic effect of the protons originating from the dissociated carboxyl groups. Since reducing the temperature stabilizes the short-lived tautomers there was greater amplitude of oscillation at 6°C than at 22- C. 

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