How the nNu → σ*C-X hyperconjugation interaction affects intrinsic reactivity in an SN2 reaction

Abstract

Hyperconjugative interactions are widely recognized as stabilizing electronic effects in molecular systems. While their involvement in chemical transformations has been suggested, it remains as an open question whether their influence pertains to thermodynamic stabilization or if they directly affect intrinsic kinetic parameters (also referred to as intrinsic activation barrier). In this work, we address a fundamental question: can n_Nu →σ^∗_C–Cl hyperconjugation directly shape the intrinsic barrier in an asymmetric S_N2 reaction? To explore this, we present a systematic computational study using the MP2-SMD(THF)/cc-pVTZ level of theory, evaluating how n_Nu →σ^∗_C–Cl interactions influence the intrinsic activation barrier in reactions of the type Y⁻ + CH₃–Cl. It is worth noting that energy differences were also evaluated using the CCSD(T)-SMD(THF) method. Intrinsic barriers were extracted from the theoretical activation barrier using Marcus’ theory to isolate the required energy for the nuclear reorganization free from thermodynamic bias. The donor–acceptor interactions were quantified through Natural Bond Orbital (NBO) analysis; moreover, Quantum Theory of Atoms in Molecules (QTAIM) descriptors provided a complementary, orbital-independent perspective. In the studied systems, a strong correlation between the E⁽²⁾_n→σ^∗ stabilization energies and the intrinsic activation barriers was observed, one that is no evident when considering apparent barriers. This distinction underscores, within the present framework, the importance of isolating intrinsic contributions when evaluating fundamental reactivity trends. QTAIM descriptors, such as the electron density at the bond critical point (ρ_BCP) and the |V_BCP|/G_BCP ratio, captured aspects of the local electronic environment, particularly electronegativity and polarizability, that were consistent with the intrinsic reactivity observed across the specific nucleophile families examined. In systems bearing α-substituents, the presence of secondary stabilizing interactions, likely involving non-covalent contacts between the nucleophile and C–H bonds of the electrophile, may contribute to lowering the intrinsic barrier. Together, these findings demonstrate that both NBO and QTAIM analyses are robust tools to determine the electronic contributions that govern reactivity and selectivity in the analyzed S_N2 reactions. Furthermore, they position hyperconjugation not merely as a passive stabilizing effect but also as an active modulator capable of tuning intrinsic reactivity in organic reactions.