Sunday, December 06, 2015

Domelsmith 3, photoelectron spectra of substituted amphetamines

The photoelectron spectra of phenethylamine and amphetamine are given in Figure 7 below. The ionizations between 8-10 eV are due to two high-lying pi orbitals in the ring system. The broad featureless band is due to the amino lone pair orbital of the side chain. Phenethylamine and amphetamine are mostly equivalent in terms of the energy levels of the outermost molecular orbitals.

In this section, the effects of methoxy and methylthio substitution on the photoelectron spectra of amphetamine will be examined. Photoelectron spectroscopy permits the assessment of substituent effects on individual molecular orbitals.

The figure below shows the photoelectron spectra of 2,4,5-trimethoxy-amphetamine, or TMA-2. Its first ionization potential (7.66 eV) is much lower than that of amphetamine (~8 eV), thus methoxy-substitution of amphetamine is said to lower the aromatic ionization potential energies. It requires less energy to ionize the high-lying orbitals of TMA-2 than amphetamine.

It is known that 2,5-dimethoxy (para) substitution is generally associated with high psychotomimetic activity, and objectively it has been found that, out of a series of ortho-, para-, and meta-substituted amphetamines, para-dimethoxy-amphetamine had the lowest first ionization potential energy (7.70 eV). The evidence of this trend is provided in Figure 2 below, which shows the photoelectron spectra of 2,3-dimethoxy-amphetamine (first ionization potential energy, 8.03 eV), 2,5-dimethoxy-amphetamine (7.70 eV), and 2,4-dimethoxy-amphetamine (7.91 eV). The 2,5-dimethoxy pattern is particularly effective at lowering the ionization potential energy, which may have some bearing on the enhanced hallucinogenic activity of 2,5-dimethoxy-substituted drugs.

In a series of substituted amphetamines, the best electron donors (e.g. drugs that donate an electron or pair of electrons with the least amount of energy input) are those with 2,5-dimethoxy- and 2,4,5-trimethoxy-substitution. This pattern, summarized in column 1 of Table IV below, is also present in the most potent amphetamine hallucinogens.

The effectiveness of methoxy-substitution in lowering the ionization potential is clearly seen in benzene, which is a much simpler molecule than 2,5-dimethoxy-amphetamine. In the figure below , starting from the left, benzene shows a first ionization potential energy = 9.25 eV. Methoxy-benzene is a slightly better electron donor than benzene, with first ionization potential energy = 8.39 eV. Para- and meta-dimethoxy-benzene have two methoxy groups, and both have a lower ionization potential (7.90 and 8.18 eV) than methoxy-benzene. There is a general trend for methoxy groups to lower the ionization potential energy.

There is a similar trend with amphetamine, which is electronically similar to benzene, except that its aromatic system has slightly more electron-donating ability. As shown in the energy level diagram (below), amphetamine has a first ionization potential energy of 8.99 eV. Addition of a methoxy group lowers the first ionization potential by 0.83 eV, to 8.16 eV. Dimethoxyamphetamines have first ionization potential energies that are even lower, in the range of 7.70-8.03 eV.

Last we consider the effect of methylthio-substitution of amphetamine. Two methoxy groups and one methylthio group were attached to amphetamine in a 2,4,5-pattern and the photoelectron spectra were assessed (Figure 7 below). The optimum configuration was 2,5-dimethoxy-4-methythio-amphetamine (first ionization potential energy 7.64 eV), which was nearly equivalent to 2,4-dimethoxy-5-methylthio-amphetamine (7.64 eV). Sulfur and Oxygen, being in the same column of the periodic table, share a similar outer shell electronic configuration, thus methoxy and methylthio groups have similar electron-donating properties, and the three compounds were found to be very similar electronically. According to the authors, methylthio Sulfur atoms have high-lying lone-pair orbitals which give rise to ionization potential energies in the same region as aromatic ionization potentials, near 8-9 eV, giving rise to extra peaks in the photoelectron spectra of methylthio-amphetamines as compared to methoxy-amphetamines.


Domelsmith L. N. and K. N. Houk (1978). Photoelectron spectra of psychotropic drugs. 3. Ionization potentials and partition coefficients as predictors of substituted amphetamine psychoactivities. International journal of quantum chemistry: quantum biology symposium 5, 257-268.

Domelsmith L. N., T. A. Eaton, K. N. Houk, G. M. Anderson 3rd, R. A. Glennon, A. T. Shulgin, N. Castagnoli Jr and P. A. Kollman (1981). Photoelectron spectra of psychotropic drugs. 6. Relationships between the physical properties and pharmacological actions of amphetamine analogues. Journal of Medicinal Chemistry 24, 1414-1421. 10.1021/jm00144a009