DFT study of species derived from the narcotic antagonist naloxone

Abstract

The functional hybrid B3LYP and the 6-31G* basis set have been employed to study the theoretical structures of free base, cationic and hydrochloride species of naloxone in gas phase and in aqueous solution. The SCRF methodology and the PCM method were used to optimize the species in solution while the solvation energies were computed with the universal solvation model. The harmonic force fields of three species in the two media were computed with the SQMFF methodology and the Molvib program while the complete vibrational assignments of bands observed in the experimental available ATR and Raman spectra were performed by using the harmonic force fields and the normal internal coordinates. Therefore, the expected 129, 132 and 135 vibration normal modes for the free base, cationic and hydrochloride species of naloxone, respectively are here reported. The free base of naloxone evidence the higher solvation energy value, as compared with those reported for S(-)-promethazine, R(+)-promethazine, cyclizine, morphine, cocaine, scopolamine, heroin, and tropane alkaloids. The cationic species shows a solvation energy value (-302.45 kJ/mol) closer to observed for morphine (-309.19 kJ/mol) while the value for the hydrochloride species (-122.28 kJ/mol) is near to scopolamine value (-122.74 kJ/mol). AIM analyses show ionic characteristic of N-HCl bonds in the hydrochloride species and suggest that this species in both media is as cationic one, as supported by the positive MK charges on the N5 atoms in the hydrochloride species in both media and by the absence in the ATR spectrum of band at 2405 cm-1, associated to N5-H46 stretching mode. Moreover, frontier orbitals studies evidence that the allyl chains present in the three species of naloxone diminishing the gap values increasing their reactivities, as compared with the other species containing the N-CH3 group. The f(N-H) force constants for the hydrochloride species is lower than the corresponding in solution, a result also observed for morphine (2.73 and 4.61 mdyn Å-1), cocaine (3.23 and 4.79 mdyn Å-1) and tropane (2.70 and 4.69 mdyn Å-1) alkaloids. Comparisons between experimental infrared, Raman and ultraviolet-visible spectra with the corresponding predicted show good correlations.