Evaluation of solvent effects on protonation using NMR spectroscopy: Implication in salt formation

Investigation of the use of solution NMR spectroscopy to determine the effect of organic solvents on chemical shift changes in bases on addition of acids is reported. This information can be useful in the evaluation of solvents and counterion selection for salt formation. H-1 and N-15 chemical shift changes in three bases (pyrazine, phthalazine, and pyridine) on the addition of acids (1:1 ratio) were determined in various solvents. The effect of acid strength on chemical shift changes was examined. H-1 and N-15 chemical shift changes indicated protonation (salt formation). The media used affected the observed chemical shift changes. In D2O the data followed the Delta pK(a) (base-acid) general rule, that the pK(a) value of the acids should be 2 units lower than the pKa of the base to ensure proton transfer. Protonation, as measured by chemical shift changes using solution NMR spectroscopy, provided novel insight on potential salt formation in different media. Solution NMR spectroscopy appears to be a useful tool to evaluate counter ion and solvent selection for salt formation reaction. (C) 2009 Elsevier B.V. All rights reserved.