DFT investigation of naproxen isomerization to pure (S)-naproxen: The pharmacologically active form

Density functional theory method was utilized in order to investigate the isomerization and conversion mechanism of the widely used and well-known nonsteroid anti-inflammatory drug naproxen. Based upon the results the rearrangement reaction of (R)-naproxen to (S) isomer can happen in a ۱,۳-hydrogen shifts. From the obtained results, we can understand that the rate-limiting stage of naproxen isomerization is the excitation of (R)-naproxen methyl ester to the primary excited state S۱ at λ=۲۸۱ nm. Moreover, we investigated this process via scanning and analyzing the distance of C۱۱-H۱۶ for the excited singlet to gain a comprehensive insight about the isomerization reaction occurring upon excitation. The obtained results indicated that passing through a barrier of around ۶۹ kcal/mol is necessary for this isomerization process. The (S)-naproxen methyl ester is more stable than (R) isomer. The outcomes confirm that the (S)-naproxen methyl ester possesses more thermodynamic stability (around -۱.۱۸ kcal/mol)