Effect of Substituent Position on the Polymorphism of Salicylaniline Derivatives

To elucidate how substituent position regulates polymorphic crystallization, two chlorinated salicylideneaniline positional isomers4CC (4-chloro) and 5CC (5-chloro)were investigated. How the substituent position modulates the pathway from electronic structure to crystallization kinetics has not been systematically addressed. Electrostatic potential analysis and a Cambridge Structural Database survey reveal conformational dimorphisma twisted yellow form and a nearly planar orange formas a general feature of this compound class, with the substituent position fine-tuning the molecular electronic structure without fundamentally altering it. Both isomers share a twisted global-minimum conformation (≈40°) with low interconversion barriers. Although the yellow polymorph is metastable for both isomers, the lattice energy difference between the orange and yellow forms is substantially greater for 5CC (ΔUlat ≈ 4.8 kJ·mol−1) than for 4CC (≈0.1 kJ·mol−1), and the 5-chloro isomer exhibits systematically lower solubility, indicating selective stabilization of the thermodynamically favored polymorph. Lattice energy decomposition identifies dispersion forces as the dominant cohesive contribution, with electrostatic interactions playing a secondary but discriminating role. Kinetically, the 4-chloro isomer exhibits a lower crystal−liquid interfacial tension than the 5-chloro counterpart for the yellow polymorphs (1.05 vs. 1.43 mJ·m−2), correlating with shorter nucleation induction times, yet slower crystal growth ratesrevealing a complementarity between nucleation and growth. These findings establish substituent position as a versatile structural variable that, through modulation of conformation, intermolecular interactions, and interfacial energetics, differentially governs the thermodynamic stability and crystallization kinetics of 4CC and 5CC.