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| From Domelsmith ionization potential |
In this section, we will examine the effects of methoxy and methylthio substitution on the photoelectron spectra of amphetamine. Photoelectron spectroscopy permits the assessment of substituent effects on individual molecular orbitals.
The figure below is 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.
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| From Domelsmith ionization potential |
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), 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.
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| From Domelsmith ionization potential |
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.
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| From Domelsmith ionization potential |
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. Benzene is electronically similar to amphetamine and phenethylamine, except that its aromatic ionization potentials have slightly less electron-donating ability. In the bottom row of the next figure, 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 and higher electron-donating ability than methoxy-benzene. There is a general trend for methoxy groups to lower the ionization potential energy.
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| From Domelsmith ionization potential |
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. 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 3 drugs 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.
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| From Domelsmith ionization potential |
References
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. Int. J. Quant. Chem. Quant. Biol. Symp. 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. J. Med. Chem. 24, 1414-1421. 10.1021/jm00144a009
