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

Abstract

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, C6H7N3O·C11H14O2, 4‐tert‐butylbenzoic acid–N′‐(propan‐2‐ylidene)isonicotinohydrazide, C9H11N3O·C11H14O2, 4‐tert‐butylbenzoic acid–N′‐(butan‐2‐ylidene)isonicotinohydrazide, C10H13N3O·C11H14O2, 4‐tert‐butylbenzoic acid–N′‐(diphenylmethylidene)isonicotinohydrazide, C19H15N3O·C11H14O2, and 4‐tert‐butylbenzoic acid–N′‐(4‐hydroxy‐4‐methylpentan‐2‐ylidene)isonicotinohydrazide, C12H17N3O2·C11H14O2. 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.

Weak Interactions in Cocrystals of Isoniazid with Glycolic and Mandelic Acids

“…The crystal structure consists of a 1D network of C(4) chains formed by homomeric hydrogen bonding of the amide group, i.e., N12−H12A•••O20, linking symmetrically related pinh molecules to form chains along the c-axis (Figure 8a). Such chains have been observed in N'-(propan-2-ylidene)isonicotino-hydrazide cocrystals with carboxylic acids [52,53]. Furthermore, the characteristic carboxylic acid-pyridine hetero-synton of R 2 2 (7) graph-set motif [52,53], that is formed between the COOH group and the N -(propan-2-ylidene)isonicotin-hydrazide molecule in carboxylic acid cocrystals with the modified isoniazid, in (3) is replaced by a water-pyridine hydrogen bond (Figure 8b).…”

“…The process consists of a one-pot synthesis, with covalent modification occurring in situ, where inh is reacted with acetone, or in general with molecules containing ketone or aldehyde functional groups (RC=O), so that the NH2 group of the carbohydrazide moiety undergoes a condensation reaction and replaces the two H atoms with alkyl groups to form isonicotin-hydrazides (Scheme 2). This technique is similar to what has been called "covalence-assisted supramolecular synthesis", with the difference that in this case a hemihydrate has been obtained instead of a cocrystal with a glycolic acid molecule as co-former, as expected [53]. The asymmetric unit of 3 contains one N'-(propan-2-ylidene)isonicotin-hydrazide molecule and half a molecule of water.…”

Interactions between Isoniazid and α-Hydroxycarboxylic Acids

“…The crystal structure consists of a 1D network of C(4) chains formed by homomeric hydrogen bonding of the amide group, i.e., N12-H12A•••O20, linking symmetrically related pinh molecules to form chains along the "c"-axis (Figure 3b). Such chains have been observed in N'-(propan-2ylidene)isonicotinohydrazide cocrystals with carboxylic acids [18,19]. Furthermore, the characteristic carboxylic acid-pyridine heterosynton of 2 2 (7) graph-set motif [18,19], that is formed between the COOH group and the N'-(propan-2-ylidene)isonicotinohydrazide molecule in carboxylic acid cocrystals with the modified isoniazid, in (3) is replaced by a water-pyridine hydrogen bond.…”

“…Such chains have been observed in N'-(propan-2ylidene)isonicotinohydrazide cocrystals with carboxylic acids [18,19]. Furthermore, the characteristic carboxylic acid-pyridine heterosynton of 2 2 (7) graph-set motif [18,19], that is formed between the COOH group and the N'-(propan-2-ylidene)isonicotinohydrazide molecule in carboxylic acid cocrystals with the modified isoniazid, in (3) is replaced by a water-pyridine hydrogen bond. Thus, each water molecule acts as a bridge joining two chains of pinh molecules to form a 2D structure parallel to the "ac" plane, where a graphic set 2 2 (4) is present (Figure 3b).…”

“…The process consists of a one-pot synthesis, with covalent modification occurring in situ, where inh is reacted with acetone, or in general with molecules containing ketone or aldehyde functional groups (RC=O), so that the NH2 group of the carbohydrazide moiety undergoes a condensation reaction and replaces the two H atoms with alkyl groups to form isonicotinohydrazides (Scheme 2). This technique is similar to what has been called "covalence-assisted supramolecular synthesis", with the difference that in this case a hemihydrate has been obtained instead of a cocrystal with a glycolic acid molecule as coformer, as expected [19]. The replacement of the two hydrazine hydrogen atoms by the propylidene group removes most of the functionality of the hydrogen bonds of isoniazid.…”