A High-Level Quantum Chemical Study of the Thermodynamics Associated with Chlorine Transfer between N-Chlorinated Nucleobases

<p>Geometries of the isomers of the N-Chlorinated nucleobases (adenine, guanine and thymine) as well as the lowest energy structures of the DNA bases (adenine, cytosine, guanine and thymine) obtained at the B3LYP/6-31G(2df,p) level of theory (in Cartesian Coordinates).</p> <p>&nbsp;</p> <p><strong>ABSTRACT: </strong>The relative free energies of the isomers formed upon <em>N</em>-chlorination of each nitrogen atom within the DNA nucleobases (adenine, guanine, and thymine) have been obtained using the high-level G4(MP2) composite ab initio method (the free energies of the <em>N</em>-chlorinated isomers of cytosine have been reported at the same level of theory previously). Having identified the lowest energy <em>N</em>-chlorinated derivatives for each nucleobase, we have computed the free energies associated with chlorine transfer from <em>N</em>-chlorinated nucleobases to other unsubstituted bases. Our results provide quantitative support pertaining to the results of previous experimental studies, which demonstrated that rapid chlorine transfer occurs from an <em>N</em>-chlorothymidine to cytidine or adenosine. The results of our calculations in the gas-phase reveal that chlorine transfer from <em>N</em>-chlorothymine to either cytosine, adenine, or guanine proceed via exergonic processes with &nbsp;D<em>G</em>^o values of &shy;&ndash;50.3 (cytosine), &ndash;28.0 (guanine), and &ndash;6.7 (adenine) kJ mol^&ndash;1. Additionally, we consider the effect of aqueous solvation by augmenting our gas-phase G4(MP2) energies with solvation corrections obtained using the conductor-like polarizable continuum model. In an aqueous solution, we obtain the following G4(MP2) free energies associated with chlorine transfer from <em>N</em>-chlorothymine to the three other nucleobases: &ndash;58.4 (cytosine), &ndash;26.4 (adenine), and &ndash;18.7 (guanine) kJ mol^&ndash;1. Therefore, our calculations, whether in the gas phase or in an aqueous solution, clearly indicate that chlorine transfer from any of the <em>N</em>-chlorinated nucleobases to cytosine provides a thermodynamic sink for the active chlorine. This thermodynamic preference for chlorine transfer to cytidine may be particularly deleterious since previous experimental studies have shown that nitrogen-centered radical formation (via N&ndash;Cl bond homolysis) is more easily achieved in <em>N</em>-chlorinated cytidine than in other <em>N</em>-chlorinated nucleosides.</p>