Saturday, April 08, 2017

HOMO calculations of phenothiazines

Molecular orbital calculations of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies reflect the electron-donating and electron-accepting properties of a molecule.

In a seminal paper in 1959, Karreman et al. suggest that the neuroleptic properties of chlorpromazine are related to the unique negative K value (K=-0.217) obtained for its HOMO. Their work extended that of the Pullmans, who had found a negative K value for FMNH2, the reduced form of flavin monocleotide (FMN).  Karreman also found a negative K value for phenothiazine (K=-0.210), indicating the the strong donor properties of chlorpromazine would be linked to its phenothiazine rings. There is a lot of structural similarity between phenothiazine, chlorpromazine, and FMNH2. 

Methods for calculating HOMO and LUMO energies of a molecule have become more advanced over the years.  There do not seem to be many researchers who focus on the so-called ``negative K values'' that were discussed with some excitement in 1959.  It is accepted however that phenothiazine is a good electron donor.

In more recent work by Cogordan et al., the HOMO energies of several tricyclic antidepressants and neuroleptics were calculated with 3 different methods, referred to as the RHF, LSD, and SE-AM1 methods. The drugs studied were promazine, chlorprothixene, chlorpromazine, dibenzepine, amitriptyline, imipramine, clomipramine and opipramol. These eight drugs have a phenothiazine-like structure in common.

When the HOMO energies of these drugs were calculated using the RHF method, all values were between 7.4-8.87 electron volts (eV). HOMO values for these drugs ranged from 7.36-8.34 eV using the SE-AM1 method. These HOMO energies, obtained theoretically, are similar to the ionization energies of phenothiazine drugs obtained experimentally with photoelectron spectroscopy.

Most of the drugs studied have Nitrogen or Sulfur on the main ring. Out of this series of eight, promazine consistently had the smallest absolute value for HOMO energy.
“The contribution to the HOMO and LUMO from the atomic orbitals of the Nitrogen in the central ring is remarkable.” (Cogordan,J.A. 1999)


KARREMAN G., I. ISENBERG and A. SZENT-GYORGYI (1959). On the mechanism of action of chlorpromazine. Science 130, 1191-1192. doi:10.1126/science.130.3383.1191

Cogordan J. A., M. Mayoral, E. Angeles, R. A. Toscano and R. Martinez (1999). Neuroleptic and antidepressant tricyclic compounds: Theoretical study for predicting their biological activity by semiempirical, density functional, and hartree-fock methods. International journal of quantum chemistry 71, 415-432.