London Dispersion versus Intramolecular Hydrogen Bond in Bis-Pyridines: How Accurate Is DFT for Competing Noncovalent Interactions in the Condensed Phase?

Abstract

We report a systematic investigation of noncovalent interactions-particularly an intramolecular hydrogen bond and London Dispersion forces-in singly protonated bis-pyridines, studied across solution and crystalline states. Building on our previous gas-phase study, we combine variable-temperature ¹H NMR spectroscopy, single-crystal X-ray diffraction, and density functional theory (DFT) calculations. The measured ¹H NMR chemical shifts of the acidic proton serve as a solution-phase structural readout, which we correlate with an independent crystallographic metric. By systematically varying the linker (-CH₂-, -O-, and -CH₂CH₂-) and the pendant substituents (H, methyl, tert-butyl), we examine how increasingly bulky "dispersion energy donors" affect both the intramolecular hydrogen bond and the accessible conformational states. In reference systems, where a single noncovalent interaction governs the geometry, even relatively simple computational models correctly reproduce the experimentally observed structures. However, for molecules featuring two competing noncovalent interactions, the tested, dispersion-corrected, DFT often fails to predict the relative energies of accessible conformers accurately, highlighting current limitations in predictive accuracy. We briefly discuss broader implications of currently achievable predictive accuracy for homogeneous catalysis.