Thermodynamic and Kinetic Aspects of Leflunomide to Teriflunomide Interconversion and the Tautomeric Equilibrium of Teriflunomide: A Quantum-Chemical DFT Study

The isoxazole ring opening in a leflunomide molecule was modeled at the B3LYP-D3/6-311++G(d,p) level of theory, giving an activation Gibbs free energy of 11.9 kcal/mol for water environment conditions, confirming easy leflunomide-to-teriflunomide interconversion. The HOMO of the teriflunomide anion and the NPA total charges indicate four possible sites of protonation, giving two enol, one keto, and one imino tautomer, further undergoing proton transfer processes, yielding mainly <i>E</i>-enol1, <i>Z</i>-enol1, and keto forms. Three additional tautomers, previously not known in the literature, are introduced in this paper: <i>E</i>-enol2, <i>Z</i>-enol2, and imino. Thermodynamic stability and kinetics of interconversions of all six tautomers were analyzed within DFT theory. At the B3LYP-D3/aug-cc-pVTZ level, the <i>Z</i>-enol1 form is dominant, and <i>E</i>-enol1 is 8.49 kcal/mol less stable in water environment conditions. The kinetics of <i>E</i>-enol1-to-<i>Z</i>-enol1 interconversion is, however, slow, with a Gibbs free energy of activation as high as 28.5 kcal/mol at the B3LYP-D3/6-311++G(d,p) in water environment conditions. Thus, the <i>E</i>-enol1 form interconverts slowly, which is in agreement with the experimental findings. In basic environments where the amounts of enol anions become larger, the reverse interconversion may occur: from <i>Z</i>-enol1 to <i>E</i>-enol1, due to the lower Gibbs free energy of the <i>E</i>-enol1 anion.