From NH + Chemical Shifts to Chemical Insights: A 1 H NMR Spectroscopic Window into Amine p K a , Anion p K BHX, and Charge-Assisted Intramolecular H-Bond Assessment from a Medicinal Chemistry Perspective

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 K BHX ) and by the p K a value of the amine, depending on the conditions used for the 1 H NMR spectroscopy. In the present study, we found an excellent p K BHX –δ (NH + ) correlation in various tertiary ammonium salts (RR 1 R 2 NH + X –, CDCl 3 ). Moreover, from a complementary standpoint, we also found an excellent amine p K 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 1 H NMR measurement of a given tertiary ammonium salt in CDCl 3, focusing on the δ (NH + ) value, one obtains reliable prediction of the amine aqueous p K a value, the counteranion p K BHX, or even an assessment of possible CA-IMHBs between the protonated amine and a nearby hydrogen bond acceptor group.