Strong Intermolecular Ring Current Influence on ¹H Chemical Shifts in Two Crystalline Forms of Naproxen: a Combined Solid-State NMR and DFT Study

Abstract

The anhydrous crystalline forms of Naproxen [( S )-(+)-2-(6-methoxy-2-naphthyl)propionic acid], (NAPRO-A) and its sodium salt (NAPRO-S), widely used anti-inflammatory drugs, have been investigated by means of 1D and 2D MAS NMR and density functional theory (DFT) based calculations. From calculations, 1D 13 C CP MAS and 1 H CRAMPS and 2D 1 H– 13 C MAS-J-HMQC, refocused INEPT, FSLG-HETCOR, and 1 H– 1 H DQ-CRAMPS solid-state NMR experiments, 1 H and 13 C resonances have been fully assigned for NAPRO-A and -S. In the case of NAPRO-S, all of the nuclei belonging to the two inequivalent molecules of the asymmetric cell gave rise to distinct signals, which could be completely assigned. Interesting intermolecular ring current effects on 1 H chemical shifts have been experimentally observed for the two samples, even if with significant differences between the two cases. The measured and calculated proton chemical shift values showed a very good agreement for both NAPRO-A and -S, allowing us to correlate the different ring current effects with the crystal structures. The comparison between the proton chemical shifts calculated in the crystal structures and in vacuo allowed us to confirm the mainly intermolecular character of the ring current effects and to quantify them.