From NH ⁺ Chemical Shifts to Chemical Insights: A ¹ H NMR Spectroscopic Window into Amine p <i>K</i> _a , Anion p <i>K</i> _BHX, and Charge-Assisted Intramolecular H-Bond Assessment from a Medicinal Chemistry

The chemical shift of the NH⁺ proton of protonated amines (δ_(NH⁺)) may be influenced by both the H-bond basicity of the counteranion (p<i>K</i>_BHX) and by the p<i>K</i>_a value of the amine, depending on the conditions used for the ¹H NMR spectroscopy. In the present study, we found an excellent p<i>K</i>_BHX-δ_(NH⁺) correlation in various tertiary ammonium salts (RR¹R²NH⁺ X^-, CDCl₃). Moreover, from a complementary standpoint, we also found an excellent amine p<i>K</i>_a-δ_(NH⁺) correlation, for each counteranion separately, provided that no charge-assisted intramolecular H-bond (CA-IMHB) occurs. Thus, we show that in a simple single ¹H NMR measurement of a given tertiary ammonium salt in CDCl₃, focusing on the δ_(NH⁺) value, one obtains reliable prediction of the amine aqueous p<i>K</i>_a value, the counteranion p<i>K</i>_BHX, or even an assessment of possible CA-IMHBs between the protonated amine and a nearby hydrogen bond acceptor group.