Theoretical Prediction of Hydrogen-Bond Basicity pK(BHX) Using Quantum Chemical Topology Descriptors

[Image: see text] Hydrogen bonding plays an important role in the interaction of biological molecules and their local environment. Hydrogen-bond strengths have been described in terms of basicities by several different scales. The pK(BHX) scale has been developed with the interests of medicinal chemists in mind. The scale uses equilibrium constants of acid···base complexes to describe basicity and is therefore linked to Gibbs free energy. Site specific data for polyfunctional bases are also available. The pK(BHX) scale applies to all hydrogen-bond donors (HBDs) where the HBD functional group is either OH, NH, or NH(+). It has been found that pK(BHX) can be described in terms of a descriptor defined by quantum chemical topology, ΔE(H), which is the change in atomic energy of the hydrogen atom upon complexation. Essentially the computed energy of the HBD hydrogen atom correlates with a set of 41 HBAs for five common HBDs, water (r(2) = 0.96), methanol (r(2) = 0.95), 4-fluorophenol (r(2) = 0.91), serine (r(2) = 0.93), and methylamine (r(2) = 0.97). The connection between experiment and computation was strengthened with the finding that there is no relationship between ΔE(H) and pK(BHX) when hydrogen fluoride was used as the HBD. Using the methanol model, pK(BHX) predictions were made for an external set of bases yielding r(2) = 0.90. Furthermore, the basicities of polyfunctional bases correlate with ΔE(H), giving r(2) = 0.93. This model is promising for the future of computation in fragment-based drug design. Not only has a model been established that links computation to experiment, but the model may also be extrapolated to predict external experimental pK(BHX) values.