Coordination sites for sodium and potassium ions in nucleophilic adeninate contact ion-pairs : a molecular-wide and electron density-based (MOWED) perspective

Buyens, Dominique M.S.; Pilcher, Lynne A.; Cukrowski, Ignacy

Coordination sites for sodium and potassium ions in nucleophilic adeninate contact ion-pairs : a molecular-wide and electron density-based (MOWED) perspective

Buyens, Dominique M.S.; Pilcher, Lynne A.; Cukrowski, Ignacy

Date: 2022-09-19

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 mol1, 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.

Description:

DATA AVAILABILITY STATEMENT : The data presented in this study are openly available in FigShare at https://figshare.com/s/59476a600bad4ba82fc4.

SUPPLEMENTARY MATERIAL : TABLE Table S1: CCSD-computed intermolecular diatomic interaction energies between Na+ with the atoms of the adeninate anion for the specified Na-Ade complexes (CIPs). All values in kcal mol1; TABLE S2: CCSD-computed intermolecular diatomic interaction energies between K+ with the atoms of the adeninate anion for the specified K-Ade complexes (CIPs). All values in kcal mol1; TABLE S3: DFT-computed intermolecular diatomic interaction energies between Na+ with the atoms of the adeninate anion for the specified Na-Ade complexes (CIPs). All values in kcal mol1; TABLE S4: DFT-computed intermolecular diatomic interaction energies between K+ with the atoms of the adeninate anion for the specified K-Ade complexes (CIPs). All values in kcal mol1; TABLE S5: DFT-computed changes in the total intramolecular interaction energy of the adeninate anion (DEAde int ), the total CB-interactions (DCBEAde int ) and total LD-interactions (DLDEAde int ) calculated for the indicated Na-Ade and K-Ade complexes. All values are in kcal mol1; TABLE S6: The total change in the exchange-correlation (DCBVAde XC ) and classical (DCBVAde cl ) terms of the interactions between covalently bonded atoms of the adeninate anion, calculated for Na-Ade and K-Ade complexes at the DFT level. All values in kcal mol1; TABLE S7: Net atomic charges of the atoms Q(A) of free Ade, the net molecular charge of Ade Q(Ade), and counter ions Q(Na+) and Q(K+). Relative to free ions, changes in these charges, obtained for each of the CIPs, are also included. All values are in e and are reported at the DFT level of theory (all values in e); FIGURE S1: DFT-optimized structures of the indicated out-of-plane Na- and K-Ade-(DMSO)4 systems and, relative to the lowest energy N-CIP in the main text (Figure 2), the energy difference DENa-Ade between Na-Ade complexes solvated by four DMSO molecules. The energy of formation (Ef) of the Na- and K-Ade-(DMSO)4 molecular systems and, relative to the lowest energy system in the main text (Figure 2), the electronic energy difference between entire molecular systems (DEsystem) are also provided. All values are in kcal mol1; TABLE S8: The total interaction energy EM+,DMSO int and its covalent VM+,DMSO XC and electrostatic VM+,DMSO cl components computed for the for DMSO-1 and DMSO-2 solvent molecules and counter ions Na+ and K+ in the in-plane M-Ade-(DMSO)4 molecular systems. All values in kcal mol1 at the DFT level of theory.; TABLE S9: Intermolecular diatomic interaction energies between the M+ counter ion (Na+ and K+) with the atoms A of the DMSO-3 solvent molecule of the in-plane M-Ade-(DMSO)4 molecular systems at the DFT level of theory. All values in kcal mol1; TABLE S10: Intermolecular diatomic interaction energies between the M+ counter ion (Na+ and K+) with the atoms A of the DMSO-4 solvent molecule of the in-plane M-Ade-(DMSO)4 molecular systems at the DFT level of theory. All values in kcal mol1; TABLE S11: The total interaction energy EAde,DMSO int and its covalent VAde,DMSO XC and electrostatic VAde,DMSO cl components computed for the for DMSO-3 and DMSO-4 solvent molecules and Ade in the in-plane M-Ade-(DMSO)4 molecular systems. All values in kcal mol1 at the DFT level of theory.

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