Characterization of Small Combinatorial Chemistry Libraries by 1H NMR. Quantitation with a Convenient and Novel Internal Standard

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Abstract
A novel silane standard, 1,4-bis(trimethylsilyl)benzene (BTMSB), is introduced for the generic quantitation of small organic molecules in DMSO-d6 solution by 1H NMR. This standard is an easily weighable solid and is stable for at least 1 month in DMSO solution, and its 1H NMR spectrum contains a strong singlet in a region usually free of signals. With a set of certified standards, concentration determination with about 2% precision and accuracy is verified after solution preparation with fully automated procedures, thus making very effective the characterization of small combinatorial chemistry libraries for identity and purity when combined with other physicochemical or biochemical tests. As an example, for a set of about 400 compounds, results of 1H NMR characterization are compared to the more customary LC−UV−MS method. NMR and MS data agree for identity on the vast majority of cases (84% positive and 5% negative), whereas the remaining cases (11%) are marked as highly impure only after NMR spectra analysis. Most importantly, determination of concentration rather than that of relative purity appears the right choice for a correct evaluation of biochemical potency.