DFT guided substitution effect on azomethine reactive center in newly synthesized Schiff base aromatic scaffolds; syntheses, characterization, single crystal XRD, Hirshfeld surface and crystal void analyses

Abstract

This paper aims to unfold the effect of substitution (ring A & B) on reactivity of newly synthesized crystalline azomethine linked aromatic compounds/Schiff bases (3a-c). Condensation reaction between 2-iodo-4-chloro substituted aniline with various suitably substituted aromatic aldehydes under acidic catalyzed reaction conditions gave crystalline compounds (3a-c) in good yields. The synthesized compounds were initially investigated in the solid state by single crystal X-ray crystallography besides other structural characterizations. Possible reactivity of azomethine pharmacophore is explained based on the electronic features of attached substituents on the aromatic rings A and B. DFT calculations further backed up the reactivity profile translated for compounds (3a-c) based on electronic grounds, while mechanistic investigation for further chemical reactivity is unfolded via frontier molecular orbital calculations and transition state predictions. Prominent nucleophilic character based on DFT study has been attributed to the halo i,e., -Cl and -I substituents on aromatic ring (ring A) in all the synthesized derivatives (3a-c) with pronounced effect in 3c due to added nucleophilic behavior depicted by cyano substitution in ring B. However, HOMO orbital energy values for (3a-c) predict electron donor behavior of substituents (-CH3, -N(CH3)2, -C=N) on ring B with higher donation capacity predicted for 3b, thus indicating its oxidation in possible chemical transformations. Hirshfeld surface analysis revealed the prevalence of potential van der Waals interactions and hydrogen bonding as major intermolecular interactions in their (3a-c) crystal packings. In addition, crystal void analyses depicted high mechanical stabilities for (3a-c) due to absence of large cavities in their crystal packings. Moreover, reaction scope guided by the joint DFT and electronic explanations for the effect of substituents used on azomethine linkage has also been proposed/predicted as part of the study.