Friday, April 07, 2017

Domelsmith 6, photoelectron spectra of 4,5-methylenedioxy-DMT

In 1982, Domelsmith and colleagues studied 5 dimethyl-tryptamine (DMT) analogs with photoelectron spectroscopy. The compounds studied were 4,5-methylenedioxy-DMT (first ionization potential, 7.25 eV), 5,6-methylenedioxy-DMT (7.46 eV), 4-methylthio-DMT (7.43 eV), 5-methylthio-DMT (7.68 eV), and 6-methylthio-DMT (7.52 eV). Figure 1 shows the photoelectron spectra of methylenedioxy- and methylthio-substituted DMT.


Methylthio substitution of DMT at the 4- or 6-position enhanced the electron donating properties of the drug. These experiments with photoelectron spectroscopy confirm the importance of attachment at the 4-position, for example psilocin is 4-hydroxy DMT. Compared to 5- or 6-methylthio-DMT, the drug 4-methylthio-DMT had the most favorable configuration, with a first ionization potential energy of 7.43 eV, compared with the parent molecule DMT (first ionization potential energy, 7.57 eV).

The readers of this blog may know that 5-methoxy-DMT is a very powerful hallucinogen. Methoxy groups often have the effect of lowering the ionization potential energy, but in these studies the first ionization potential energies of 5-methoxy-DMT (7.61 eV) and 5-methylthio-DMT (7.68 eV) were slightly higher in energy than the parent molecule DMT (first ionization potential energy=7.57 eV), suggesting that the 5-methoxy groups on DMT may confer bioavailability rather than electron-donating ability.

Methylenedioxy-substituted DMT analogs were even better electron donors than methylthio-substituted DMT molecules. The electronic configuration of 4,5-methylenedioxy-DMT is very interesting because it is the only tryptamine studied by Domelsmith with an ionization potential energy equal to 7.25 eV, which is equivalent to the first ionization potential energy of LSD. These two drugs are different structurally, see below, but they have the same electron-donating ability.


It is noteworthy that 4,5-methylenedioxy-DMT had the lowest ionization potential of the 5 DMT analogs, and it was the most rigid tryptamine studied. This is a clue to the potential importance of a rigid planar structure for electron donation. Another way to see the effects of planarity on the ionization potential is to compare between 4,5-dimethoxy-amphetamine and 4,5-methythlenedioxy-amphetamine.


4,5-dimethoxy-amphetamine (above left) has one planar and one perpendicular methoxy group, whereas oxygens from the methylenedioxy group (above right) are both in the plane of the ring. Conformational constraint in 4,5-methylenedioxy-amphetamine would force the p orbitals of oxygen into more overlap with the planar pi system; this configuration has a pi system that will eject a single electron or pair of electrons with slightly less external perturbation than the pi system of 4,5-dimethoxy-amphetamine. The first ionization potentials energies of 4,5-dimethoxy-amphetamine and 4,5-methylenedioxy-amphetamine are close, but the methylenedioxy compound is a slightly better electron donor by 0.02 eV.

Reference

Kline T. B., F. Benington, R. D. Morin, J. M. Beaton, R. A. Glennon, L. N. Domelsmith, K. N. Houk and M. D. Rozeboom (1982). Structure-activity relationships for hallucinogenic N,N-dialkyltryptamines: photoelectron spectra and serotonin receptor affinities of methylthio and methylenedioxy derivatives. Journal of Medicinal Chemistry 25, 1381-1383. 10.1021/jm00353a021