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 K_a 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.