Friday, April 07, 2017

Domelsmith 4, photoelectron spectra of phenothiazines

Many antipsychotic drugs have a phenothiazine group, which is an excellent electron donor. In 1977, Domelsmith studied phenothiazine, N-methyl-phenothiazine, promazine, chlorpromazine, thioridazine, and trifluoperazine with photoelectron spectroscopy.  There was some question about whether neuroleptic properties are related to low ionization potentials and good electron donating ability, but the first ionization potential was insufficient to predict antipsychotic activity in this series, so the hypothesis was not validated.

Phenothiazine, N-methyl-phenothiazine and promazine have 4-5 ionization bands from pi orbitals, which come from pi orbitals and correspond to 4 very clear peaks in the photoelectron spectra (Figure 3), and range in energy from 7.26-10.43 eV. The first two ionization potentials at 7.26 eV and 8.35 eV were assigned to central Nitrogen and Sulfur pi orbitals, which are significantly delocalized over the whole ring.

The photoelectron spectra of chlorpromazine, thioridazine, and trifluoperazine are shown below. Thioridazine, with 2-position methylthio, has the lowest ionization energy (7.00 eV) studied in Domelsmith's research, meaning that its electrons are very much on the fringe. Like promazine, the first and second ionization potential bands are assigned to the ring Sulfur and Nitrogen. In chlorpromazine, the 2-position Chlorine atom gives rise to a band at 11.24 eV. The trifluoromethyl groups in position-2 of trifluoperazine were not as electron withdrawing as predited by calculations. Trifluoperazine's first ionization potential energy of 7.31 eV was slightly higher than that of phenothiazine, 7.26 eV.

Nitrogen methylation tended to enhance the overall electron-donating ability of the molecule, as revealed by comparison between phenothiazine (first ionization potential energy, 7.26 eV) and N-methyl-phenothiazine (7.15 eV). A similar trend was observed in the tryptamine series; a Nitrogen side chain ionization potential was lowered from 9.25 eV in tryptamine, to 8.9 eV in N-methyl-tryptamine, to 8 eV in N,N-dimethyl-tryptamine.

Thioridazine (first ionization potential, 7.00 eV) surpassed chlorpromazine (7.16 eV), and LSD (7.25 eV) as an electron donating molecule. The results for the phenothiazine series are summarized in Table I (above).


Domelsmith L. N., L. L. Munchausen and K. N. Houk (1977). Photoelectron spectra of psychotropic drugs. 2. Phenothiazine and related tranquilizers. Journal of the American Chemical Society 99, 6506-6514. doi:10.1021/ja00462a007