A simple phase‐transfer‐catalyzed mild N1‐methylation of isatin for 1‐methylindoline‐2,3‐dione: X‐ray crystallography, topological analysis, molecular electronic property investigation, and COSMO‐RS modeling

Abstract

Phase-transfer catalysis (PTC) enables a mild and efficient alternative to harsh or electrochemical N1-methylation routes. In this work, a simple yet effective N1‑methylation protocol for 1‑methylindoline‑2,3‑dione was demonstrated, providing a high-yield route that leverages phase-transfer catalysis under mild conditions. The resulting compound's crystal structure, solved by single-crystal X-ray diffraction, confirmed a near-planar indoline‑2,3‑dione ring system with short C–H···O contacts indicative of potential hydrogen-bond acceptor behavior. Parallel DFT/B3LYP/6‑311+G(d,p) calculations validate the experimentally observed geometry, permitting in-depth probing of frontier molecular orbitals, global reactivity indices, and nonlinear optical (NLO) parameters. Subsequent electronic evaluations revealed a HOMO–LUMO gap of approximately 3.72 eV. Calculated reactivity indices, including ionization potential (IP), electron affinity (EA), hardness (η), and electrophilicity index (ω), implied a moderately stable framework with enhanced donor–acceptor characteristics, where the carbonyl oxygens and the ring nitrogen emerge as the most reactive sites. Moreover, the molecule's modest nonlinear optical (NLO) properties (β<inf>tot</inf>=2.26 × 10−30 esu) suggested potential for second-order optical processes under further optimization. Natural Bond Orbital (NBO) investigations pointed to extended hyperconjugation between ring-based σ (BD) donors and antibonding (BD*) orbitals, as well as lone-pair → antibonding interactions from carbonyl oxygens and the ring nitrogen. Wavefunction-based topological tools, including Reduced Density Gradient (RDG), Electron Localization Function (ELF), and Localized Orbital Locator (LOL), revealed a notable electron delocalization within the ring and localized donor capabilities at carbonyl centers and the N1-substituted nitrogen. In addition, COSMO-RS analysis across water, ethanol, and DMSO highlighted stable, moderately varying solvation energies driven by hydrogen-bond acceptance at carbonyl groups. These findings highlight that phase-transfer catalysis provides a cost-effective and milder alternative to classical or electrochemical N1-methylation routes, enabling streamlined access to N1-substituted isatin scaffolds for further functionalization in drug discovery and materials science. © 2025 Elsevier B.V., All rights reserved.