Substituent Effects on NMR Chemical Shifts and Cyclic Hydrogen Bonding in 2-Pyridone Dimers: An Accurate Approach to Hammett Constant Determination Linking Structure, Energetics, and Electron Distribution

The Hammett substituent parameter (<b>σ</b>_p) is fundamental to physical organic chemistry but often suffers from inconsistencies in experimental determination across diverse substituents. This study presents a quantum chemical approach for estimating <b>σ</b>_p values using ¹H NMR chemical shift differences (Δ<b>δ</b>) in hydrogen-bonded 2-pyridone heterodimers. Using density functional theory (M06L/6-311++G(d,p)), we examined four dimer topologies─<b>d_a</b>, <b>d_b</b>, <b>d_c</b>, and <b>d_d</b>─and found that the Δ<b>δ</b> values in the <b>d_b</b> configuration, where the substituent is spatially remote from the hydrogen-bonding region, exhibit the strongest correlation with <b>σ</b>_p. This aligns with the sterically free nature of <b>σ</b>_p. Additional correlations are observed between <b>σ</b>_p and structural (Δ<b>r</b>), energetic (Δ<b>E</b>), and electronic descriptors (MESP, QTAIM) of CO···HN hydrogen bonds. Among the topologies, <b>d_b</b> and <b>d_c</b> systems provide the most reliable correlations, while deviations in <b>d_a</b> and <b>d_d</b> dimers arise due to proximity-induced secondary interactions. The NMR-derived substituent constant, <b>σ</b>_p_(NMR), was computed for a diverse set of 99 substituents, offering a unified, reliable, and computationally efficient framework for predicting and refining the Hammett constants. These findings underscore the potential of NMR chemical shifts as a powerful experimental and computational tool for quantifying substituent effects and enhance the theoretical foundation for structure-reactivity relationships in organic chemistry.