To what extent do bond length and angle govern the C and H NMR response to weak CH⋯O hydrogen bonds? A case study of caffeine and theophylline cocrystals.

Weak hydrogen bonds are important structure-directing elements in supramolecular chemistry and biochemistry. We consider here weak CH⋯O hydrogen bonds in a series of cocrystals of theophylline and caffeine and assess to what extent the CH⋯O distance and angle govern the observed C and H isotropic chemical shifts. Gauge-including projector-augmented wave density functional theory (GIPAW DFT) calculations consistently predict a decrease in the C and H magnetic shielding constants upon hydrogen bond formation on the order of 2-5 ppm (C) and 1-2 ppm (H). These trends are reproduced using the machine-learning approach implemented in ShiftML. Experimental C and H chemical shifts obtained for powdered samples using one-dimensional NMR spectroscopy as well as heteronuclear correlation (HETCOR) spectroscopy correlate well with the GIPAW DFT results. However, the experimental C NMR response only correlates moderately well with the hydrogen bond length and angle, while the experimental H chemical shifts only show very weak correlations to these local structural elements. DFT computations on isolated imidazole-formaldehyde models show that the C and H chemical shifts generally decrease with the C⋯O distance but show no clear dependence on the CH⋯O angle. These results demonstrate that the C and H response to weak CH⋯O hydrogen bonding is influenced significantly by additional weak contacts within cocrystal heterodimeric units.