Creating carboxylic acid co-crystals: The application of Hammett substitution constants

Abstract

The creation of multi-component crystalline phases is currently experiencing a growth in interest in academia and industry. The designed creation of novel phases through control and manipulation of the potential intermolecular interactions is a key aim of crystal engineering. This work highlights recent attempts to develop a design methodology for the creation of co-crystals between carboxylic acids using the values of Hammett substitution constants of the acid pairs. From a combined experimental and computational study, it was observed that systems with Hammett constant differences greater than a half frequently co-crystallise. From DFT energy calculations of a selected subset of acid pairs, this was seen to be due to the increased interaction energy between the heteromolecular pairs over the homomolecular pairs. However, the formation of a multi-component crystal does not mean that the desired supramolecular synthon forms. In cases with large Hammett differences, salt formation can occur in competition due to the presence of amine groups (large negative Hammett constants) and strong acids (large positive Hammett constants) but consideration of the pK_a differences in this case allows for prediction of salt or co-crystal formation.