A study of the known and hypothetical crystal structures of pyridine: why are there four molecules in the asymmetric unit cell?

The oldest crystal structure of pyridine is unusually complex, with four molecules in the asymmetric unit cell of Pna2(1) symmetry. In an attempt to understand why pyridine crystallises with 16 molecules in the unit cell, we have considered its thermodynamic stability relative to hypothetical pyridine structures. These were generated by search for minima in the lattice energy of pyridine amongst the more common space groups, using the crystal structure prediction procedure MOLPAK followed by lattice energy minimisation using a distributed multipole-based intermolecular potential. We find over two dozen distinct crystal structures in the energy gap of less than 6 kJ mol(-1) between the corresponding models for the observed and most stable (hypothetical) structure. Adding harmonic phonon estimates of the intermolecular zero point energy and entropy at the melting point of pyridine slightly improves the relative stability of the observed Z = 16 structure. Several of these hypothetical structures can be eliminated as only just mechanically stable, or because the growth rate of the crystal is estimated to be very slow by the attachment energy model. Nevertheless, there are still over a dozen structures that appear competitive with the know structure as polymorphs of pyridine. Following these predictions, an intense experimental search has found a new polymorph of perdeutero-pyridine (form II), which was not found in the search. This structure is also predicted to be metastable with a similar energy to form I. Although there is some evidence for kinetic factors favouring the observed structures, the metastable Z = 16 structure and the new form II remain a challenge for our understanding of crystallisation.