Covalent Assisted Supramolecular Synthesis: The Influence of Crystallization Conditions on Co-Crystals of "masked" Isoniazid Derivatives

Eight co-crystals of covalently modified isoniazid were synthesized, using either 3- or 4-hydroxybenzoic acid as the co-former. It was demonstrated that, for the co-crystallization of "masked" isoniazid by benzophenone derivatives, a small change in reaction or crystallization conditions played a large role in the outcome of the resulting supramolecular structure, whereas the addition of either one or two methyl substituents to the benzophenone rings did not affect the supramolecular structure of the resulting co-crystals. Changing the reflux time for the supramolecular synthesis resulted in stoichiometric variation. Adding larger quantities of one of the starting supramolecular reagents as "additives" resulted in polymorphism. Using a catalyst for the covalent modification of isoniazid during one-pot supramolecular synthesis prevented the formation of a solvate.