The Reactivity of Ambident Nucleophiles: Marcus Theory or Hard and Soft Acids and Bases Principle?

The model reactions CH 3 X + (NH—CH=O)M ➔ CH 3 —NH—NH═O or NH═CH—O—CH 3 + MX (M = none, Li, Na, K, Ag, Cu; X = F, Cl, Br) are investigated to demonstrate the feasibility of Marcus theory and the hard and soft acids and bases (HSAB) principle in predicting the reactivity of ambident nucleophiles. The delocalization indices (DI) are defined in the framework of the quantum theory of atoms in molecules (QT‐AIM), and are used as the scale of softness in the HSAB principle. To react with the ambident nucleophile NH═CH—O − , the carbocation H 3 C + from CH 3 X (F, Cl, Br) is actually a borderline acid according to the DI values of the forming C…N and C…O bonds in the transition states (between 0.25 and 0.49), while the counter ions are divided into three groups according to the DI values of weak interactions involving M (M…X, M…N, and M…O): group I (M = none, and Me 4 N) basically show zero DI values; group II species (M = Li, Na, and K) have noticeable DI values but the magnitudes are usually less than 0.15; and group III species (M = Ag and Cu(I)) have significant DI values (0.30–0.61). On a relative basis, H 3 C + is a soft acid with respect to group I and group II counter ions, and a hard acid with respect to group III counter ions. Therefore, N‐regioselectivity is found in the presence of group I and group II counter ions (M = Me 4 N, Li, Na, K), while O‐regioselectivity is observed in the presence of the group III counter ions (M = Ag, and Cu(I)). The hardness of atoms, groups, and molecules is also calculated with new functions that depend on ionization potential ( I ) and electron affinity ( A ) and use the atomic charges obtained from localization indices (LI), so that the regioselectivity is explained by the atomic hardness of reactive nitrogen atoms in the transition states according to the maximum hardness principle (MHP). The exact Marcus equation is derived from the simple harmonic potential energy parabola, so that the concepts of activation free energy, intrinsic activation barrier, and reaction energy are completely connected. The required intrinsic activation barriers can be either estimated from ab initio calculations on reactant, transition state, and product of the model reactions, or calculated from identity reactions. The counter ions stabilize the reactant through bridging N‐ and O‐site of reactant of identity reactions, so that the intrinsic barriers for the salts are higher than those for free ambident anions, which is explained by the increased reorganization parameter Δ r . The proper application of Marcus theory should quantitatively consider all three terms of Marcus equation, and reliably represent the results with potential energy parabolas for reactants and all products. For the model reactions, both Marcus theory and HSAB principle/MHP principle predict the N‐regioselectivity when M = none, Me 4 N, Li, Na, K, and the O‐regioselectivity when M = Ag and Cu(I). © 2019 Wiley Periodicals, Inc.