pKa slide rule predictions against CSD structural results

Bond energies and intramolecular distances of normal chemical bonds are weakly affected by their environment, which has made it possible to produce extended compilations of these quantities. Hydrogen bonds (HBs) have a quite different behavior, their binding energies depending not only on the electronegativities of the HB donor (D) and acceptor (A) atoms, but displaying a large spread of values even for a same donor-acceptor couple. This surprising behavior (the H-bond puzzle) is presently interpreted by saying that the forces determining HB strength are a mixture of electrostatic and covalent contributions, that the covalent part is steeply increasing while the donor-acceptor difference of the proton affinities, DPA= PA(DG) – PA(A), or acidic constants, DpKa=pKAH(D-H) - pKBH+(A-H+), tends to zero, and that, when this limit is achieved, the strong and symmetrical D…H…A bond formed is better classified as a true three-center-four-electron covalent bond. This emphasizes the essential role played by PA/pKa equalization in strengthening the HB. We have undertaken a wide research program intended to verify the validity of such a PA/pKa equalization rule which consists of two steps. The first requires the compilation of pKa table for the most typical HB donor and acceptor molecules. The results so obtained have been organized in an unique graphical table called the pKa slide rule which is a practical tool for the prediction of HB strengths based on the fact that, according to the rule, only the donor-acceptor couples lying on a same horizontal line of the rule can give rise to strong HBs with DpKa=0. In the second part of the project the validity of the pKa equalization rule and the reliability of the pKa slide rule prediction has been carried out by a wide search on the Cambridge Structural Database (CSD) for specific classes of HBs. For each D-H…A bond the values of dD…A, dD-H, dH…A and D-H-A angle were registered and the relative HB strength were evaluated from the donor-acceptor distance corrected for the D-H-A angle. Such a verification is not an easy matter because there are tens of thousands of H-bonded crystal structures and thousands of combining molecules with often uncertain pKa values. We have pointed to two main projects that, though handling only a few thousand structures, still retain large diagnostic capabilities: (i) all strong (short) HBs have small or null DpKa value; (ii) in the selected N-H…O/O-H…N system, HB strengths (lengths) are modulated by DpKa in the full DpKa range.