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 (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.