engleski

Role of substituents in Hofmann-Löffler-Freytag synthesis of nicotine. A quantum chemical study

Recently, synthesis of S-nicotine has been achieved by using Hofmann-Löffler-Freytag (HLF) methodology [1]. Original procedure using the same methodology has been done at the beginning of the 20th century, but the products were a racemic mixture [2]. Crucial step in the HLF reaction pathway is hydrogen atom transfer (HAT) from the N-radical to C-radical. Del Castillo and Muniz have achieved retention of stereoconfiguration by using a protective group on nitrogen and an additional activation of primary C atom via O-methylation. In this work we quantified substitution effects in the HAT step of the reaction on both nitrogen and carbon atom in order to find better synthetic routes both for the original (racemic mixture) product and the stereoselective one. In this study we will focus on the details of the rate determining HAT step. Earlier work [3] was focused exclusively on defining relative N- centered and C- centered radical stabilization energies (RSE) between commonly used fragments in this field, which can be used to estimate of the thermodynamics of the reaction. Our focus is now on defining energy barriers of the intermolecular HAT reactions of model substituted amines with ethane and reactions of model substituted alkanes with methylamine. Obtained results are then used to narrow down potentially successful substituents for different precursors to nicotine synthesis. Intramolecular HAT reaction of Löffler and Muniz are compared, and more efficient synthesis routes are presented.

DFT, N-centered radicals, rearrangement

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