From NH⁺Chemical Shifts to Chemical Insights: A¹H NMR Spectroscopic Window into Amine pK_a, Anion pK_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 (pK_BHX) and by the pK_a value of the amine, depending on the conditions used for the ¹H NMR spectroscopy. In the present study, we found an excellent pK_BHX–δ_(NH⁺) correlation in various tertiary ammonium salts (RR¹R²NH⁺ X^–, CDCl₃). Moreover, from a complementary standpoint, we also found an excellent amine pK_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 pK_a value, the counteranion pK_BHX, or even an assessment of possible CA-IMHBs between the protonated amine and a nearby hydrogen bond acceptor group.