From NH+ Chemical Shifts to Chemical Insights: A 1H NMR Spectroscopic Window into Amine pKa, Anion pKBHX, 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 (pKBHX) and by the pKa value of the amine, depending on the conditions used for the 1H NMR spectroscopy. In the present study, we found an excellent pKBHX–δ(NH+) correlation in various tertiary ammonium salts (RR1R2NH+ X–, CDCl3). Moreover, from a complementary standpoint, we also found an excellent amine pKa–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 pKa value, the counteranion pKBHX, or even an assessment of possible CA-IMHBs between the protonated amine and a nearby hydrogen bond acceptor group.