Sunday, October 28, 2012

Karreman 1959

In a classic paper by Karreman and Szent-Gyorgyi in 1959, the authors propose that a charge-transfer reaction may be a prominent factor in the mental changes caused by certain drug molecules. Karreman and Szent-Gyorgyi reported, for the first time, a negative K value for the highest occupied molecular orbital (HOMO) of chlorpromazine, implying particularly good electron-donor properties for this mind-affecting drug.
"Chlorpromazine is the first substance ever found in which, in its ordinary stable state, the highest filled level corresponds to an antibonding orbital, as indicated by the minus sign of K. This makes chlorpromazine a quite extraordinary strong electron donor." (Karreman,G. 1959)
The reported K value=-0.217 for the highest filled orbital of chlorpromazine, was somewhat unexpected since it meant that the HOMO of chlorpromazine would be classified as an anti-bonding orbital. As its name states, the HOMO is usually "occupied"; typically one or two electrons occupy the HOMO. In comparison, anti-bonding orbitals are usually unoccupied; anti-bonding orbitals typically contain zero electrons in the ground state. How would the HOMO of chlorpromazine have properties of an anti-bonding orbital?

Anti-bonding orbitals do form bonds with other orbitals, that are as stable as typical bonds formed by bonding molecular orbitals, and in this regard the term "anti-bonding" orbital is unfortunate. But obviously anti-bonding orbitals wouldn't be named as such if they were usually occupied by electrons.

In addition to their work on chlorpromazine, Karreman and Szent-Gyorgyi performed Huckel calculations on LSD, serotonin, and phenothiazine. They obtained a small positive value of K=0.218 for the HOMO of LSD, and concluded that LSD should be a very good electron donor based on this value. They further suggested that the psychoactive action of drugs like LSD and chlorpromazine may be due to the electron-donating function of the drug.

What is the significance of a HOMO orbital with a negative K value?

The Pullmans had recently shown a negative K value of the HOMO in reduced FMNH2, a riboflavin coenzyme (Table 1, below). According to these authors, the reduced form of FMNH2 possessed a very unusual characteristic, which had not been observed previously in any other existing compound, namely that its HOMO was not only a very high-lying one but an anti-bonding one, of the type of orbital which is generally occupied by electrons only in the excited states of molecules. This represents a fundamentally unstable arrangement and suggests that reduced FMNH2 has an exceptionally strong natural tendency to expel the electrons located at its HOMO. Experimental observation confirms that FMNH2 in the reduced form tends to give up electrons, and this property accounts for its electron donor properties and autooxidizability.

Table 1 (below) shows HOMO and LEMO values for protonated and unprotonated forms of methylene blue (MeB), DPN, and FMN. MeBH (K=-0.232) and FMNH2 (K=-0.105) are the only two compounds in this table with a negative K HOMO value, and these two compounds are distinguished from the other compounds by their unusual electron-donating ability.

Negative values for highest orbitals are usual only for orbitals occupied in the excited states of molecules. The calculations suggest that the ground state of certain chemical substances, such as FMNH2, methylene blue, and chlorpromazine, can mimic the configuration of an excited state molecule. This property should be associated with an unusually low ionization potential energy and extremely pronounced electron donor capacities. 

While a negative K value of the HOMO was not found for the LSD molecule, its K value was small, implying good electron donating ability.

What is the normal relationship of an anti-bonding orbital to the ground state, and what is the "ground state"?
In the ground state molecule, all electrons have coalesced into a single piece of matter. The ground state is comprised of certain energy levels, that are occupied by the completed set of electrons. Pairs of electrons fill the bonding orbitals, and the anti-bonding orbitals are usually empty. High-lying orbitals such as the HOMO have the ability to accommodate 1-2 electrons, and these electrons are susceptible to being ejected from the molecule, aka ionized, if and when stimulus energy hits a molecule. An ionized electron is less attached to the molecule; sometimes it is said to be free. This can be achieved with an input of a definite amount of energy hv. It is said that the energy hv promotes the electron from a bonding to an anti-bonding orbital. The anti-bonding orbital is a construction of the mind; it represents a space that is somehow attached to the molecule, but for all purposes, it is never actually occupied by electrons in the molecule's ground state configuration. The process is reversible. Movement of the electron from the anti-bonding to bonding orbital results in an emission of the energy hv, with a certain color or certain definite frequency. 

The ground state of most molecules is described as having electrons in bonding orbitals only. Yet with chlorpromazine, FMNH2, and methylene blue, we encounter the unique situation where the HOMO is anti-bonding, so a spontaneous expulsion of the high-lying electron at this orbital is expected in the same way that it is expected that electrons generally move from anti-bonding to bonding orbitals.

It is not ordinary to discuss the excited state and the ground state at the same time, and typically, for electrons to occupy the anti-bonding orbitals, energy must be put into the molecule in the form of light, but presumably in the case of some biologically active molecules like chlorpromazine or FMNH2, an electron already populates the anti-bonding HOMO, readying the compound to be able to exchange electrons while in the ground state.

Most descriptions of matter are descriptions of matter in the ground state, containing electron pairs. These descriptions are sufficient as long as the molecule is kept away from light or heat energy, which perturb its ground state. But in reality, electron pairs in matter are constantly interacting with single electrons or photons. Energy is transferred from matter to field and back again. Though we have the concept of a "united molecule" and ground state energy level diagrams to describe matter, the field in which these electrons are radiated or absorbed is an active participant at all times. Presumably the field is just there to absorb or radiate photons when the matter is ready to take them or give them up, but when Huckel calculations showed that an anti-bonding orbital may be considered as part of the ground state of chlorpromazine, I began to imagine the embeddedness of the field within matter. With this discovery, the distinction between ground and excited states becomes less clear. Certain organic molecules are prepared to "do work" and exchange electrons in the ground state.

There is no reason to doubt the calculations. Huckel analysis gave evidence of negative KHOMO value for chlorpromazine and so this molecule is described in further terms as an excellent electron donor. Naturally the researchers who discovered this presumed that this physical property could be related with the mind-altering ability of the drug.

Concept of free radicals, after 1959
The existence of stable free radicals, such as FMNH2 and chlorpromazine, has since been confirmed. Whereas most molecules pass through an odd-electron configuration on the transition state to another molecule and then settle back down to an even-electron configuration, there are certain molecules whose ground state is more favorable to the existence of odd-electrons, and these are called "stable" radical molecules. 

The reduced form of FMNH2 is a good example, but there are many small molecules that form stable radicals. The oxidation of phenol can lead to the final formation of quinoid structures, a system where the delocalization of the unpaired electron is developed very strongly. Quinoid radicals have considerably greater stability than the phenol radicals that formed them. Another example is Wurster's blue cation radical, which is stable even at room temperature. Its stability is ascribed to electron delocalization in its semiquinone structure. Indole and tryptophan are considered to be stable radical molecules. Another stable radical is melanin, which has an ESR spectra that resists 24 h of refluxing in hydrochloric acid. The planar molecule anthracene has a radical state at room temperature. Diphenylpicrylhydrazyl (DPPH) is a free radical that is often used as an ESR standard. Nitric oxide, chlorine dioxide, and alkali superoxides are examples of stable inorganic free radicals.

The existence of radicals in the ground state has been more or less proven since Karreman,Isenberg, and Szent-Gyorgyi's paper on chlorpromazine and LSD. These molecules seem to serve as miniature case studies of what life is itself, in terms of the number of atoms, types of atoms, and the connectivity that is needed to harbor a little electron well in a little piece of matter, which will be able to exchange electrons in the ground state. This ushers in a new era where energy is not bounding and rebounding off of everything. In the world of stable free radicals, no action is required to reach the action state.


Ingram D. J. E. Free radicals as studied by electron spin resonance. Butterworths Scientific Publications: London, 1958.

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

PULLMAN B. and A. PULLMAN (1959). The oxido-reductive properties of organic dyes of biological importance. Biochimica et Biophysica Acta 35, 535-537.

ORLOFF M. K. and D. D. FITTS (1961). Molecular-orbital treatment of phenothiazine and some related molecules. Biochimica et Biophysica Acta 47, 596-599.

Kier L. B. Molecular orbital theory in drug research. De Stevens G. (Ed.); Academic press: New York, 1971.

Bock H., K. Gharagozloo-Hubmann, M. Sievert, T. Prisner and Z. Havlas (2000). Single crystals of an ionic anthracene aggregate with a triplet ground state. Nature 404, 267-269.