Covalent assistance in supramolecular synthesis: in situ modification and masking of the hydrogen bonding functionality of the supramolecular reagent isoniazid in co-crystals

Abstract

The supramolecular reagent isonicotinic acid hydrazide (isoniazid) is a promising molecule in the supramolecular synthesis of multi-component molecular complexes. Due to the covalent reaction of the carbohydrazide functional group with simple ketones and aldehydes, the hydrogen bonding functionality of isoniazid can be modified, where two of the hydrogen bond donors are replaced with hydrogen bonding “inert” hydrocarbons. The ketones used are propanone, 2-butanone, cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone, 4′-methylacetophenone and benzophenone and the aldehyde 4′-methylbenzaldehyde. The “modifiers” bonded to the isoniazid then give a measure of control of the outcome of the supramolecular synthesis with 3-hydroxybenzoic acid depending on the identity and steric size of the modifier used. The steric size itself can be used to shield or to “mask” the remaining hydrogen bonding functionality of isoniazid such that common homomeric and heteromeric interactions are prevented from taking place. This process of covalent assistance to supramolecular synthesis has been carried out in a one-pot covalent and supramolecular reaction to make six unhydrated co-crystals 2–7 and five hydrated co-crystals 8–12.