Effect of the Solvent and Substituent on Tautomeric Preferences of Amine-Adenine Tautomers

Abstract

Adenine is one of the basic molecules of life; it is also an important building block in the synthesis of new pharmaceuticals, electrochemical (bio)sensors, or self-assembling molecular materials. Therefore, it is important to know the effects of the solvent and substituent on the electronic structure of adenine tautomers and their stability. The four most stable adenine amino tautomers (9H, 7H, 3H, and 1H), modified by substitution (C2- or C8-) of electron-withdrawing NO₂ and electron-donating NH₂ groups, are studied theoretically in the gas phase and in solvents of different polarities (1 ≤ ε < 109). Solvents have been modeled using the polarizable continuum model. Comparison of the stability of substituted adenine tautomers in various solvents shows that substitution can change tautomeric preferences with respect to the unsubstituted adenine. Moreover, C8 substitution results in slight energy differences between tautomers in polar solvents (<1 kcal/mol), which suggests that in aqueous solution, C8-X-substituted adenine systems may consist of a considerable amount of two tautomers-9H and 7H for X = NH₂ and 3H and 9H for X = NO₂. Furthermore, solvation enhances the effect of the nitro group; however, the enhancement strongly depends on the proximity effects. This enhancement for the NO₂ group with two repulsive N···ON contacts can be threefold higher than that for the NO₂ with one attractive NH···ON contact. The proximity effects are even more significant for the NH₂ group, as the solvation may increase or decrease its electron-donating ability, depending on the type of proximity.

Scheme 1. Structures and Numbering of Atoms of the Four Most Stable Amino Tautomers of Adenine

Figure 1

Dependences of cSAR(X) (a) and cSAR(NH₂) (b) on ε for the C8–X-substituted 9H adenine tautomer (X = NO₂, H, and NH₂). The left and right linear regression equations correspond to two ε intervals, <10 and >10, with their determination coefficients (R²).

Scheme 2. Possible Proximities of Substituents, with Two Neighboring Nitrogen Atoms with a Lone Pair in a Plane of the Ring (I-type) and with One Nitrogen Atom of This Kind and Another of the NH Type (II-type)

Dashed lines denote through-space interactions with neighboring atoms, attractive black, repulsive red.

Figure 2

Dependences of cSAR(X) (a,b) and cSAR(NH₂) (c,d) on the reciprocal of solvent permittivity 1/ε for C8–X and C2–X substitution of the 9H adenine tautomer.

Figure 3

Dependences of the CFI on the reciprocal of solvent permittivity 1/ε for C8–X, X = H (a), X = NO₂ (b), and X = NH₂ (c) and C2–X, X = H (d), X = NO₂ (e), and X = NH₂ (f) substituted adenine tautomers.

Figure 4

Dependences of total electronic energy, E (in hartrees), on 1/ε in unsubstituted (a) and C8–NO₂- (b), C8–NH₂- (c), C2–NO₂- (d), and C2–NH₂ (e)-substituted adenine tautomers.