Covalent-assisted supramolecular synthesis: The effect of hydrogen bonding in cocrystals of 4-tert-butylbenzoic acid with isoniazid and its derivatized forms

A series of cocrystals of isoniazid and four of its derivatives have been produced with the cocrystal former 4-tert-butylbenzoic acid via a one-pot covalent and supramolecular synthesis, namely 4-tert-butylbenzoic acid–isoniazid, C ₆ H ₇ N ₃ O·C ₁₁ H ₁₄ O ₂ , 4-tert-butylbenzoic acid–N′-(propan-2-ylidene)isonicotinohydrazide, C ₉ H ₁₁ N ₃ O·C ₁₁ H ₁₄ O ₂ , 4-tert-butylbenzoic acid–N′-(butan-2-ylidene)isonicotinohydrazide, C ₁₀ H ₁₃ N ₃ O·C ₁₁ H ₁₄ O ₂ , 4-tert-butylbenzoic acid–N′-(diphenylmethylidene)isonicotinohydrazide, C ₁₉ H ₁₅ N ₃ O·C ₁₁ H ₁₄ O ₂ , and 4-tert-butylbenzoic acid–N′-(4-hydroxy-4-methylpentan-2-ylidene)isonicotinohydrazide, C ₁₂ H ₁₇ N ₃ O ₂ ·C ₁₁ H ₁₄ O ₂ . The co-former falls under the classification of a `generally regarded as safe' compound. The four derivatizing ketones used are propan-2-one, butan-2-one, benzophenone and 3-hydroxy-3-methylbutan-2-one. Hydrogen bonds involving the carboxylic acid occur consistently with the pyridine ring N atom of the isoniazid and all of its derivatives. The remaining hydrogen-bonding sites on the isoniazid backbone vary based on the steric influences of the derivative group. These are contrasted in each of the molecular systems.