To what extent do bond length and angle govern the 13C and 1H 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 CHMIDLINE HORIZONTAL ELLIPSISO hydrogen bonds in a series of cocrystals of theophylline and caffeine and assess to what extent the CHMIDLINE HORIZONTAL ELLIPSISO distance and angle govern the observed C-13 and H-1 isotropic chemical shifts. Gauge-including projector-augmented wave density functional theory (GIPAW DFT) calculations consistently predict a decrease in the C-13 and H-1 magnetic shielding constants upon hydrogen bond formation on the order of 2-5 ppm (C-13 ) and 1-2 ppm (H-1). These trends are reproduced using the machine-learning approach implemented in Shift ML. Experimental C-13 and 1H 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 13C NMR response only correlates moderately well with the hydrogen bond length and angle, while the experimental H-1 chemical shifts only show very weak correlations to these local structural elements. DFT computations on isolated imidazole-formaldehyde models show that the C-13 and 1H chemical shifts generally decrease with the C center dot center dot center dot O distance but show no clear dependence on the CH center dot center dot center dot O angle. These results demonstrate that the C-13 and H-1 response to weak CH center dot center dot center dot O hydrogen bonding is influenced significantly by additional weak contacts within cocrystal heterodimeric units.

Automated summary

Weak hydrogen bonds play an important role in directing structure in supramolecular chemistry and biochemistry. In this study, the effects of CH distance and angle on the observed C-13 and H-1 isotropic chemical shifts in a series of theophylline-caffeine cocrystals were assessed. The results from density functional theory calculations and machine-learning approach showed a consistent decrease in C-13 and H-1 magnetic shielding constants upon hydrogen bond formation. Experimental NMR spectroscopy results correlated well with the computational results. However, the correlations between experimental NMR responses and hydrogen bond length and angle were only moderate.