Effects of Positive and Negative Ionization on Prototropy in Pyrimidine Bases: An Unusual Case of Isocytosine

Abstract

Intramolecular proton-transfers (prototropic conversions) have been studied for the guanine building block isocytosine (iC), and effects of positive ionization, called one-electron oxidation (iC - e → iC), and negative ionization, called one-electron reduction (iC + e → iC), on tautomeric conversions when proceeding from neutral to ionized isocytosine have been discussed. Although radical cations and radical anions are very short-lived species, the ionization effects could be investigated by quantum-chemical methods. Such kind of studies gives some information about the labile protons and the most basic positions in the neutral and radical forms of the tautomeric system. For investigations, the complete isomeric mixture of isocytosine has been considered and calculations performed in two extreme environments, apolar {DFT(B3LYP)/6-311+G(d,p)} and polar {PCM(water)//DFT(B3LYP)/6-311+G(d,p)}. For selected isomers, the G4 theory has also been applied. There are no good relations for energetic parameters of neutral and ionized forms. Ionization energies depend on localization of labile protons. Tautomeric equilibria for neutral and ionized isocytosine, favored sites of protonation and deprotonation, and favored structures of protonated and deprotonated forms strongly depend on environment. Acidity of iC is close to that of the iC conjugate acid, and basicity of iC is close to that of the iC conjugate base. This increase of acid-base properties of charged radicals explains the proton-transfer in ionized pairs of nucleobases. When compared to other pyrimidine bases such as uracil (U) and cytosine (C), which exhibit analogous tautomeric equilibria between nine prototropic tautomers as isocytosine, the tautomeric preferences for iC, iC, iC, U, U, U, C, C, and C are completely different. The differences suggest that acid-base properties of functional groups, their stabilities, and ionization energies play a principal role in proton-transfers for pyrimidine bases and influence compositions of tautomeric mixtures.

On Analogies in Proton-Transfers for Pyrimidine Bases in the Gas Phase (Apolar Environment)—Cytosine Versus Isocytosine

“…In the case of isocytosine, the relative stabilities of the three potential mono-cationic isomers mc-iC-137, mc-iC-178a, and mc-iC-378b considered as protonated forms of selected three neutral isomers iC-17, iC-37, and iC-78a have been previously studied in our laboratory at the DFT level [7] and analogous stability-order has been reported as that found here. G4-calculations [63], performed for the two isomers mc-iC-137 and mc-iC-178a, confirmed the DFT-calculated stability-order and showed without any doubt that mc-iC-178a has the lowest Gibbs energy for protonated isocytosine in the gas phase. However, the mono-cationic isomer mc-iC-137 predominates in aqueous solution as confirmed by 1 H, 13 C, and 15 N NMR experiments and by PCM calculations [27,63].…”

“…G4-calculations [63], performed for the two isomers mc-iC-137 and mc-iC-178a, confirmed the DFT-calculated stability-order and showed without any doubt that mc-iC-178a has the lowest Gibbs energy for protonated isocytosine in the gas phase. However, the mono-cationic isomer mc-iC-137 predominates in aqueous solution as confirmed by 1 H, 13 C, and 15 N NMR experiments and by PCM calculations [27,63].…”

“…In our previous work on isocytosine-charged radicals [63], we tested deprotonation reaction of three neutral isocytosine isomers (iC-17, iC-37, and iC-78a). Considering seven among nine mono-anionic tautomers-rotamers studied here, we found analogous stabilityorder for them at the DFT level.…”

“…In an aqueous solution, only ma-iC-7 seems to be favored, and ma-iC-3a can be treated as a rare isomer. The solvation effect has been investigated by 1 H, 13 C, and 15 N NMR experiments, and also by PCM calculations [27,63].…”

“…The more basic and more acidic sites participate preferentially in protonation and deprotonation reactions, respectively, for isolated isomers. In the literature, one can find theoretical microscopic basicity parameters for the canonical forms and for some other isomers of pyrimidine bases [7,[28][29][30][31][32][33]63]. For example, Tureček and co-workers [33] performing calculations at different levels of theory (B3LYP, MP2, B3-MP2, CCSD(T) with various basis sets) for mono-protonated cytosine showed that the microscopic PA values of the two potential protonation sites (N3 and O7b) in the canonical isomer C-18 strongly depend on the level of calculations.…”