Structural, solvatochromic, NLO, and molecular docking studies of positional isomers of chlorobenzaldehyde phenylhydrazone: An experimental and computational investigation A. Hemamalini a , C. Rajarathinam a , M. Wilson Bosco Paul b , A. Irudaya Jothi a,* a Department of Chemistry, St. Joseph’s College (Autonomous), Tiruchirappalli 620002 (Affiliated to Bharathidasan University, Tiruchirappalli 620024), Tamil Nadu, India b Department of Chemistry, Sacred Heart College (Autonomous), Tirupattur 635601, Tamil Nadu, India A R T I C L E INFO Keywords: Chlorobenzaldehyde phenylhydrazone DFT NLO Solvatochromism SHG Molecular docking ABSTRACT Aryl phenylhydrazones find wider applications in organic synthesis and drug discovery. They also exhibit sig- nificant solvatochromic shifts in absorption and emission spectra which are manifested in optical sensing and environmental monitoring. Three positional isomers of chlorobenzaldehyde phenylhydrazones (PHs) were syn- thesized and their crystal structures were analyzed by single crystal XRD. Meta isomer is closer to planarity and para isomer deviates more from planarity than ortho isomer. Theoretical investigations using DFT/B3LYP/6- 311g(d) offered a qualitative quantum chemical account on the trends in structural, electronic, linear, and nonlinear optical, and chemical reactivity parameters of the isomers. The experimental and TD-DFT simulated UV–Vis spectra of PHs were investigated in solvents of different polarity from n-hexane to water to corroborate the influence of positional isomerism on benzylidene ring and solvent polarity on excitation processes, which together imposed significant shifts in λ max and ε max of charge transfer (CT) bands. The shifts were validated by linear plots of Reichardt’s E T (30) values of solvents against λ max of absorption bands. The second harmonic generation (SHG) coefficients evaluated from Kurtz-Perry powder method are 3.34 and 1.12 times greater for meta and para isomers, respectively, than the reference compound, urea. Ortho and meta isomers exhibit stronger binding affinities with HMGCS protein residues than its para isomer in molecular docking studies. 1. Introduction Arylhydrazone chemistry owes its foundation to Emil Fischer and the importance of arylhydrazones stems out from three important factors. Firstly, derivatization of a carbonyl compound using hydrazine and arylhydrazines was a routine analytical tool for the characterization of aldehydes and ketones. Phenylhydrazine (PH), 4-nitrophenylhydrazine (4-NPH) and 2,4-dinitrophenylhydrazine (2,4-DNPH) derivatives of carbonyl compounds usually form colorful, stable, highly crystalline and insoluble derivatives with sharp melting points than alkylhydrazones formed from hydrazine which usually have unfavorable equilibrium constants and low melting points [1]. Secondly, the importance of phenylhydrazones lies in the synthesis of versatile heterocyclic com- pounds (Chart 1), such as indoles (1) [2,3], indazoles (2) [4], pyrazo- lines (3–5) [5–7], pyrazolidines (6) [5], pyridazinones (7) [5], thiadiazoles (8–10) [8–10], and quinoxalinones (11,12) [11,12] and benzofurans (13) [13]. Hydrazone-based metal complexes are also of recent interest for their catalytic, analytical, and biomedical applica- tions and serve as substrates for homogeneous catalysis for hydrogena- tion and hydroalkylations [14]. Thirdly, phenylhydrazones exhibit a variety of biological activities, such as antibacterial, antifungal, cytotoxic, anti-inflammatory, and antioxidant activity [15–17]. Phenylhydrazones derived from natural products are very rare such as cytotoxic phenylhydrazone alkaloids, talarohydrazones A-D (23–26) that were isolated from the deep-sea fungus Talaromyces amestolkiae [18] (Chart 2). Muti-stimuli responsive materials exhibiting a combination of more than one of the responsive traits such as solvatochromic, phtotochromic, thermochromic, mechanochromic, electrochromic, halochromic, ion- ochromic, acidichromic, vapochromic, and hydrochromic, have attrac- ted much attention in recent years [19,20]. Solvatochromism has been of constant interest for it allows the analysis of the solvent-solute * Corresponding author. E-mail addresses: irudayajothi_ch1@mail.sjctni.edu, irudayajyothi@gmail.com (A.I. Jothi). Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstr https://doi.org/10.1016/j.molstruc.2025.141425 Received 27 November 2024; Received in revised form 4 January 2025; Accepted 11 January 2025 Journal of Molecular Structure 1329 (2025) 141425 Available online 12 January 2025 0022-2860/© 2025 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.