NMR Quantification of Hydrogen-Bond-Activating Effects for Organocatalysts including Boronic Acids

The hydrogen-bonding activation for 66 organocatalysts has been quantified using a 31P NMR binding experiment with triethylphosphine oxide (TEPO). Diverse structural classes, including phenols, diols, silanols, carboxylic acids, boronic acids, and phosphoric acids, were examined with a variety of steric and electronic modifications to understand how the structure and secondary effects contribute to hydrogen-bonding ability and catalysis. Hammett plots demonstrate high correlation for the Δδ 31P NMR shift to Hammett parameters, establishing the ability of TEPO binding to predict electronic trends. Upon correlation to catalytic activity in a Friedel-Crafts addition reaction, data demonstrate that 31P NMR shifts correlate to catalytic activity better than p Ka values. Boronic acids were investigated, and 31P NMR binding experiments predicted strong hydrogen-bonding ability, for which catalytic activity was confirmed, resulting in the greatest rate enhancement observed in the Friedel-Crafts addition of all organocatalysts studied. A detailed investigation supports that boronic acid activation proceeds through hydrogen-bonding interactions and not coordination with the Lewis acidic boron center. Using 31P NMR spectroscopy offers a simple and rapid tool to quantify and predict hydrogen-bonding abilities for the design and applications of new organocatalysts and supramolecular synthons.