Coordination Sites for Sodium and Potassium Ions in Nucleophilic Adeninate Contact ion-Pairs: A Molecular-Wide and Electron Density-Based (MOWED) Perspective

Abstract

The adeninate anion (Ade^-) is a useful nucleophile used in the synthesis of many prodrugs (including those for HIV AIDS treatment). It exists as a contact ion-pair (CIP) with Na⁺ and K⁺ (M⁺) but the site of coordination is not obvious from spectroscopic data. Herein, a molecular-wide and electron density-based (MOWED) computational approach implemented in the implicit solvation model showed a strong preference for bidentate ion coordination at the N3 and N9 atoms. The N3N9-CIP has (i) the strongest inter-ionic interaction, by -30 kcal mol^-1, with a significant (10-15%) covalent contribution, (ii) the most stabilized bonding framework for Ade^-, and (iii) displays the largest ion-induced polarization of Ade^-, rendering the N3 and N9 the most negative and, hence, most nucleophilic atoms. Alkylation of the adeninate anion at these two positions can therefore be readily explained when the metal coordinated complex is considered as the nucleophile. The addition of explicit DMSO solvent molecules did not change the trend in most nucleophilic N-atoms of Ade^- for the in-plane M-Ade complexes in M-Ade-(DMSO)₄ molecular systems. MOWED-based studies of the strength and nature of interactions between DMSO solvent molecules and counter ions and Ade^- revealed an interesting and unexpected chemistry of intermolecular chemical bonding.

Keywords: DMSO; REP-FAMSEC; adeninate anion; alkali metals; computational chemistry; coordination modes; ion-pairs; molecular-wide and electron density-based (MOWED) approach; nucleobases.

Figure 1

CCSD-optimized structures and corresponding energies of formation ($E_{\mathrm{f}}$) and the electronic energy differences ($\Delta E$), both in kcal mol⁻¹. $\Delta E$ values were computed relative to the lowest energy conformers, i.e., N9-CIP for the Na-Ade complex and N3N9-CIP for the K-Ade complex. For comparison, the DFT values, marked with an asterisk, are also provided.

Scheme 1

The reference and final states used to study the formation of CIPs of the M-Ade complexes.

Figure 2

The DFT-optimized structures of the indicated in-plane Na- and K-Ade-(DMSO)₄ systems and, relative to the lowest energy N-CIP, the energy difference, ΔE_Na-Ade, between Na-Ade complexes solvated by four DMSO molecules. The energy of formation (E_f) of the Na- and K-Ade-(DMSO)₄ molecular systems and, relative to the lowest energy system, the electronic energy difference between entire molecular systems (ΔE_system) are also provided. All values are in kcal mol⁻¹. Somewhat larger energy differences were found for K-Ade complexes, whereby the N7- and N1-CIP were 8.3 and 9.4 kcal mol⁻¹ higher in energy than the N3N9-CIP.