Nucleophilic Affinity of Conjugated Heterocycles in Protonation, Alkylation and Cation Binding

Abstract

The problem of the relative nucleophilicity of the various sites in large heterocyclic molecules has always represented a difficult challenge for quantum chemistry. Although in the early times, the classical indices of molecular structure were quite successful in accounting for the various kinds of reactivity of conjugated hydrocarbons, their utilization for heterocycles proved less straightforward. The activity of these molecules towards electrophilic reagents is an example where considerable energy has been spent on defining appropriate indices. It was soon recognized that, despite an apparent logical basis, correlations between the electronic charge of an atom and its basicity (or more generally its nucleophilic reactivity) were very limited. True already for the rating of molecules containing a single heteroatom (quinolein with respect to isoquinolein, for instance), the situation still worsens when a number of the same heteroatoms are present in the same compound, where the problem is then to discriminate between their relative affinities for electrophilic attacks as for instance (Figure 1) is the case for nitrogens N₁, N₃, N₇ of adenine, N₃, N₇ of guanine, O₂ and O₄ of thymine or uracil; still more difficult is the discrimination between two sites of different nature in the same molecule, for instance between a nitrogen in a ring, a nitrogen of an extracyclic amino group or a carbonyl oxygen.