Interaction of Propargyl Cation with Tetrahydrofuran: Thermodynamics, Kinetics, and Biological Relevance

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Ab initio calculations have been carried out for the reaction of propargyl cation and tetrahydrofuran, a model for the novel stereoselective reductive dimerization of cobalt-complexed propargyl cations, mimicking, on a molecular level, DNA damage inflicted by electrophilic carcinogenic agents. The optimized geometries derived from semiempirical calculations (AM1) have been employed in ab initio calculations using Hartree−Fock (3-21G* and 6-31G* basis sets) and density functional theory (DFT) methods. The highly exothermic character of the major mechanistic pathways, a hydride-ion transfer toward the carbocationic center and a direct coordination of the latter with an oxygen atom in tetrahydrofuran, has been revealed (−49.74 to −72.85 kcal/mol). A two-electron, three-membered “late” transition state was found for the hydride-ion transfer pathway with an activation energy of +24.69 kcal/mol. A direct one-electron oxidation of tetrahydrofuran by propargyl cation is the mechanistic pathway most sensitive toward the calculation technique used: ab initio method employing 3-21G* and 6-31G* basis sets suggests exothermicity for the process in question, whereas DFT calculation using the numerical polarization basis sets indicates moderate endothermicity (+7.74 kcal/mol). The mechanistically distinct pathways thus identified“ionic”, “binding”, and “radical”imply that structural alteration of DNA caused by electrophilic carcinogenic agents may occur by (a) a delivery of hydride-ion originating from 1‘ and 4‘ positions of the sugar moiety toward the electrophilic center, (b) binding of the electron-deficient species to an oxygen atom in a ribose ring, and (c) a single-electron transfer toward the electrophile with a ribose ring acting as a reducing moiety.