Quantum-chemical study of nucleophilic substitution in protonated trisindolylmethane*

Abstract

The total energies of reactants, products, and transition states of nucleophilic substitution reactions in protonated tris(indol-3-yl)methane have been assessed with the semiempirical AM1 method and the theory of functional density B3LYP/6-31(d) method. The results of calculations indicated that the reactions proceed by an SN1-like mechanism, since the activation barrier for it is significantly lower than in the case of the SN2-like mechanism. Tris(1-alkylindol-3-yl)methanes are the starting materials for obtaining tris(indol-3-yl)methylium salts possessing high cytotoxic activity. Tris(1-alkylindol-3-yl)methylium salts possess high cytotoxic activity and are inducers of apoptosis. The cytotoxic activity grows with increasing length of the alkyl substituent up to C(5) and then falls (1). The properties of unsymmetrically N-substituted tris(1-alkylindol-3-yl)methylium salts have not been studied, since on synthesis of the initial unsymmetrical tris(1-alkylindol-3-yl)methanes by known methods mixtures of compounds are formed. Thus, on interacting 3-formyl-1-methylindole with 1-ethylindole in the presence of acid catalysts a mixture of tris(1-methylindol-3-yl)methane, tris(1-ethylindol-3-yl)methane, bis-(1-ethylindol-3-yl)(1- methyl-indol-3-yl)methane, and (1-ethylindol-3-yl)bis(1-methylindol-3-yl) methane is formed. The ratio of these products is determined by the reaction conditions and the means of separating the mixtures. Analogous mixtures are formed on interacting tris(1-alkylindol-3-yl)methane with 1-alkylindoles in the presence of acid catalysts (Lewis acids) (Scheme 1). It may be proposed that under the action of Lewis acids an electrophilic center is induced in the trisindolylmethane molecule. This center is subject to attack by a nucleophile present in the reaction system (indole and its substituted derivatives). As quantum-chemical calculations of the partial Mulliken charges and Fukui indexes showed, the electron density on the C(3) atom of N-substituted derivatives of indole (possible