NMR Quantification of Hydrogen-Bond-Accepting Ability for Organic Molecules.

The hydrogen-bond-accepting abilities for more than 100 organic molecules are quantified using 19F and 31P NMR spectroscopy with pentafluorobenzoic acid (PFBA) and phenylphosphinic acid (PPA) as commercially available, inexpensive probes. Analysis of pyridines and anilines with a variety of electronic modifications demonstrates that changes in NMR shifts can predict the secondary effects that contribute to H-bond-accepting ability, establishing the ability of PFBA and PPA binding to predict electronic trends. The H-bond-accepting abilities of various metal-chelating ligands and organocatalysts are also quantified. The measured Δδ(31P) and Δδp(19F) values correlate strongly with Hammett parameters, pKa of the protonated HBA, and proton-transfer basicity (pKBH+).

NMR quantification of H-bond donating ability for bioactive functional groups and isosteres.

The H-bond donating ability for 127 compounds including drug fragments and isosteres have been quantified using a simple and rapid method with 31P NMR spectroscopy. Functional groups important to medicinal chemistry were evaluated including carboxylic acids, alcohols, phenols, thioic acids and nitrogen group H-bond donors. 31P NMR shifts for binding to a phosphine oxide probe have a higher correlation with equilibrium constants for H-bonding (log KHA) than acidity (pKa), indicating that these binding experiments are representative of H-bonding ability and not proton transfer. Additionally, 31P NMR binding data for carboxylic acid isosteres correlates with physicochemical properties such as lipophilicity, membrane permeability and plasma protein binding. This method has been used to evaluate the H-bond donating ability of small molecule drug compounds such as NSAIDs and antimicrobials.