Covalent-Assisted Supramolecular Synthesis: Masking of Amides in Co-Crystal Synthesis using Benzophenone Derivatives

Abstract

Control over hydrogen bonding patterns and the dimensionality of supramolecular structures is possible through covalent assisted supramolecular synthesis. Consistent and predictable 'masking' of the amide functionality has been achieved through the covalent modification of isoniazid with benzophenone and benzophenone derivatives while co-crystallizing with salicylic acid. A series of co-crystals using benzophenones as masking agents was prepared using one-pot synthetic methods. No short intermolecular contacts were present between the amide nitrogen atoms in isoniazid and neighbouring isoniazid or salicylic acid atoms.

The supramolecular effect of aromaticity on the crystal packing of furan/thiophene carboxamide compounds

“…Additionally, the orientation of the ring oxygen and sulfur atoms to the oxygen of the carbonyl group affects the area of the electropositive and electro-negative regions on the side of title molecules which have high potential for electrophilic and nucleophilic attack, respectively, in various hydrogen bond interactions in the crystal packing. 27 It is noteworthy that the privileged formation of the π Thio ⋯π Pyz interaction in I can be also explained based on the "aromatic donor-acceptor" description term suggested by Martinez and Iverson in which stacking between aromatics with differential polarization was described as the interaction of relatively electron-deficient and electron-rich aromatic molecules in an alternating fashion. 4b In this regard, the pyrazine ring as an electron acceptor and the thiophene ring as a donor group formed this significant interaction.…”

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

“…1b) to form isonicotinohydrazides. This process is referred to by us as 'modifying' the hydrogen-bonding functionality of isoniazid (Smith et al, 2015(Smith et al, , 2018. Subsequently, depending on the steric size of the now added R groups, the amide H-atom donor and/or the imine lone pair can be 'masked' by making access to them improbable for any hydrogen-bonding donors or acceptors via their steric size.…”

Covalent Assisted Supramolecular Synthesis: The Influence of Crystallization Conditions on Co-Crystals of “Masked” Isoniazid Derivatives

“…MacGillivray et al demonstrated that, depending on the stoichiometry, either moderate synthon success or complete masking could be achieved by the interjection of water molecules. 7 In Smith et al, 5 isoniazid was modified with a series of benzophenone derivatives and co-crystallized with 2-hydroxybenzoic acid. The predictable "masking" of the amide functionality was achieved, and it was shown that the bulky benzophenone modifiers rendered the amide nitrogen atom inaccessible for hydrogen bonding and that no short intermolecular contacts were present between the amide nitrogen atoms in "masked" isoniazid derivatives and any neighboring isoniazid or 2-hydroxybenzoic acid atoms.…”

“…A series of papers have been written on covalent-assisted supramolecular synthesis. − Covalent assisted supramolecular synthesis can be defined as the covalent modification of a molecule with the purpose of gaining control over some aspect of the supramolecular synthesis (e.g., the altering of the hydrogen-bonding characteristics of a functional group or control over dimensionality of the packing), together with the co-crystallization of the modified molecule with a co-former.…”