Single-crystal neutron diffraction is the best technique available for the study of hydrogen bonding due to its ability to accurately locate the hydrogen atom. Different types of intermolecular hydrogen bonds – N-H…O, O-H…O, and N-H…O – have been studied, with important implications in pharmaceutical formulation and ferroelectric materials.

Chapter 1 gives the background to both the technique of single-crystal neutron diffraction and hydrogen bonding, as well introduces the concept of solid-state pK_a and the pK_a rule: it has been taken as a rule of thumb in the pharmaceutical industry that when the pKa difference between a pair of co-crystallising acid and base is greater than 2 or 3, a salt is expected to form rather than a neutral co-crystal.

However, in Chapter 2, the hydrogen bond...[ Read more ]

Single-crystal neutron diffraction is the best technique available for the study of hydrogen bonding due to its ability to accurately locate the hydrogen atom. Different types of intermolecular hydrogen bonds – N-H…O, O-H…O, and N-H…O – have been studied, with important implications in pharmaceutical formulation and ferroelectric materials.

Chapter 1 gives the background to both the technique of single-crystal neutron diffraction and hydrogen bonding, as well introduces the concept of solid-state pK_a and the pK_a rule: it has been taken as a rule of thumb in the pharmaceutical industry that when the pKa difference between a pair of co-crystallising acid and base is greater than 2 or 3, a salt is expected to form rather than a neutral co-crystal.

However, in Chapter 2, the hydrogen bonding in a series of tetrahydropalmatine (THP)-benzoic acids adducts we synthesised called its validity into question. THP, a component in traditional Chinese medicine, has a range of pharmaceutical uses. In attempts to enhance its solubility and stability through salt-formation by way of hydrothermal crystallisation, we discovered that neutral molecular co-crystals would form even with a pK_a difference of about 5. The proton positions were determined by examining the electron density peak in the N--H--O hydrogen bond and the difference in C-O bond lengths in the carboxylate group in X-ray diffraction studies, and, in some cases, corroborated by neutron diffraction results.

This finding was confirmed by other aromatic acid-base systems in Chapter 3, where the pK_a values of the bases have been well-established (due to its low aqueous solubility, the aqueous pK_a THP cannot be definitively determined). The ‘crossover’ pK_a difference is as high as 3.5 in these systems. Most of the H-bonds in Chapters 2 and 3 are short and strong N···O hydrogen bonds, and their potential energies range from low-barrier to somewhere between low-barrier and double-well. The D-H bonds show significant elongation, suggesting their stretchable nature and the energetic contributions of covalency as opposed to electrostatic/Coulombic interaction.

In Chapter 4, the same study methods were applied to the serendipitously discovered oxidation product of THP, THP-oxide (THP-O), co-crystallised with various benzoic acids as well and shed light on very short intermolecular O-H…O hydrogen bonds. The THP-hydroxide (THP-OH⁺) and benzoic acids (BA-H) both represent highly acidic entities with pKa’s typically below 4.0. The O-H…O hydrogen bonds have potential energies that lie between the low barrier H-bond and a true single well. Again, the O-H distances are mostly severely elongated from the more ‘normal’ covalent value.

The N-H…N chains in imidazoles, a class of molecules of biological relevance, have seldom been studied. They have the potential for induced chain reversal and thus ferroelectricity. In Chapter 5 we outline the geometric features of N-H…N hydrogen bonds, look at neutron-diffraction results of several imidazole compounds, and explore the possibility of engineering oriented imidazole H-bond chains.