Kinetic and mechanistic insight into the formation of amphetamine using the Leuckart–Wallach reaction and interaction of the drug with GpC·CpG base-pair step of DNA: a DFT study

Abstract

The Leuckart–Wallach reductive amination reaction in clandestine amphetamine synthesis is the most popular, simple, rapid, and safe non-metal reduction route, in which its mechanism is not known with certainty. The Minnesota 2006 exchange correlation functional M06-2X in conjugation with aug-cc-pVTZ basis set and SMD universal solvation model have been used to elucidate the kinetics and mechanism of the Leuckart–Wallach reaction for the formation of amphetamine via a five-step pathway mechanism in 1-butanol and benzene solvents. The unimolecular and bimolecular rate constants were calculated at the experimentally employed temperature 403.15 K using canonical transition state theory corrected by the quantum tunneling factors. The overall reaction is thermodynamically spontaneous and kinetically second order (first order in ammonium formate and first order in phenyl-2-propane) which is in agreement with experimental results. In the following, drug–DNA interaction in four different models has been studied in the water solvent using the mPW1B95/6–31G* level of theory. The mPW1B95/6–31G* energies were corrected for the basis set superposition error and the underestimation of London dispersion interactions by adding the gCP and D3(BJ) correction terms, respectively. According to the interaction energies, topological analysis of electron localization function and localized orbital locator, interaction of amphetamine with GpC·CpG base-pair step of DNA is non-covalent in nature. Non-covalent interaction index plots indicated that there are weak van der Waals and strong stabilizing hydrogen bond attractions between the drug and DNA. The presence of strong stabilizing hydrogen bond attractions is the responsible for the higher negative interaction energies in the interaction models including hydrogen bonds between amphetamine and DNA.