How Is the Oxidation Related to the Tautomerization in Vitamin B9?

The relationship between the lactim-lactam tautomerization and the free-radical scavenging reaction in vitamin B9 [folic acid (FA)] was investigated by density functional theory calculations. 6-Methylpterin was also adopted for the detailed analyses of various reaction paths. For pterin, the transition state of the tautomerization with two water molecules (n = 2) was calculated to be of the lowest activation energy. The proton-transfer circuit of n = 2 is retained (not broken) even with the addition of outer water molecules, n = 2 + 2, 2 + 4, 2 + 8, and 2 + 14. At the oxidation of the system composed of 6-methylpterin + (H₂O)₂ + HO^•, the radical character of HO^• is directly transmitted to the pterin ring along with the C-O → H → O → H → O → H → OH proton transfer. The patterns of the electron transfer (pterin ring → OX^•) and the concomitant proton transfer via the water dimer were commonly obtained for the oxidant (OX^•) = HO^•, Cl₃C-O₂^•, N₃^•, or SO₄^-•. The hydrogen atom transfer mechanism was ruled out. Two conformations of the puckered form with the -C(═O)-OH···N intramolecular hydrogen bonds of FA were found to have the stability similar to that of the linear conformer. Both the tautomerization and the oxidation were calculated to occur competitively in the three conformers.