Nucleophilic properties of purine bases: inherent reactivity versus reaction conditions

Anna Stachowicz-Kuśnierz,Jacek Korchowiec

doi:10.1007/s11224-015-0583-y

Anna Stachowicz-Kuśnierz, Jacek Korchowiec

Open Access

https://doi.org/10.1007/s11224-015-0583-y

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Journal: Structural Chemistry	Publication Date: Mar 15, 2015
Citations: 22	License type: CC BY 4.0

Affiliation: Jagiellonian University

Abstract

In the present study, nucleophilic properties of adenine and guanine are examined by means of density functional theory. H+ is used as a model electrophile. Two modes of H+ attack on the bases are considered: on the neutral molecule and on the anion. Solvent effects are modeled by means of polarizable continuum model. Regioselectivity of attack is studied by analyzing two contributions. The first one is the energetic ordering of the tautomers. The second is the relative inherent reactivity of nucleophilic sites in the bases. Atomic softnesses calculated by means of charge sensitivity analysis are employed for this purpose. The most reactive sites in various tautomers are identified on the ground of Li–Evans model. For adenine, it is demonstrated that both in basic and in neutral pH N7 atom possesses the most nucleophilic character. In polar solvents, N7 substitution is also most favored energetically. In basic pH and nonpolar solvents as well as in the gas phase, N9 substitution is slightly more probable. For guanine, a mixture of N7- and N9-substituted products can be expected in basic pH. In neutral pH, inherent reactivity and energy trends are opposite to each other; therefore, the substitution does not occur. Experimentally observed products of reactions with various electrophiles and in various conditions confirm the results obtained in this study.

Highlights

Electrophilic attack on nucleobases is a common molecular mechanism of mutagenicity or carcinogenicity [1, 2]
In the present study, nucleophilic properties of adenine and guanine are examined by means of density functional theory
The analyses examined include the following: Mulliken population analysis (MPA) [67,68,69], natural population analysis (NPA) [70], Bader’s atoms in molecules (AIM) [71, 72], Hirshfeld’s stockholder analysis (HSA) [73], CHELPG electrostatic potential fitted charges [74, 75] and Voronoi deformation density (VDD)-based charges [76]

Summary

Introduction

Electrophilic attack on nucleobases is a common molecular mechanism of mutagenicity or carcinogenicity [1, 2]. Atomic softnesses calculated by means of charge sensitivity analysis are employed for this purpose. Keywords Purine bases Á Electrophilic attack Á Solvent effects Á Reactivity indices Á Fukui function Diagonal atomic Fukui indices, fiX,X, or alternatively atomic softnesses, siX,X, can be used to probe inherent reactivities of different sites in the reagents.

Results

Conclusion