Amide Pyramidalization in Carbamazepine: A Flexibility Problem in Crystal Structure Prediction?

Carbamazepine is known to exist in various polymorphic forms. Here we report on crystal structure prediction
calculations for carbamazepine in an attempt to examine the predictability and relative stability of the various polymorphs. Hypothetical
crystal structures generated in 10 of the most common space groups were compared to the observed polymorphs. Particular attention
has been given to the influence of amide pyramidalization on the relative energies of the predicted structures. While the actual
generation of possible crystal structures was found to be independent of the degree of deformation of the amide group, their final
ranking in energy was greatly affected by pyramidalization of the amide nitrogen. This effect was examined in detail through
systematic variation of the NH2 geometry for each of the low-energy crystal structures; different amide geometries were favored in
the various low-energy crystal structures. The results demonstrate that energetically feasible deformation of the amide group may
occur in order to optimize hydrogen-bond interactions, and we conclude that neglect of amide pyramidalization introduces significant
errors in crystal structure prediction for carbamazepine and similar molecules.