A Synergistic Approach to the Structural Characterization of 2-(Morpholin-4-yl)quinoline-3-carbaldehyde by Solution and Solid-State NMR Spectroscopy, Supported by Single-Crystal X-Ray Diffraction and DFT Calculations.

Abstract

Heterocyclic building blocks incorporating quinoline and morpholine units are central to the synthesis of a wide range of biologically active molecules, where conformational preferences and solid-state organization can directly influence the reactivity and functional performance. In this study, the molecular structure of 2-(morpholin-4-yl)quinoline-3-carbaldehyde (abbreviated as MQ3CA), a key intermediate for quinoline-, morpholine-, and piperazine-based drug scaffolds, is examined using a synergistic combination of solution and solid-state NMR spectroscopy, complemented by single-crystal X-ray diffraction (SC-XRD) and density functional theory (DFT) calculations. Complete resonance assignments, including chemical shifts, scalar coupling constants, and through-bond and through-space correlations, were achieved using 2D J-resolved, COSY, NOESY, HSQC, and HMBC experiments, enabling an unambiguous description of molecular connectivity and conformation in solution. Solid-state 13C CPMAS-TOSS and two-dimensional 1H-13C HETCOR NMR measurements provided atomic-level insight into the solid-state organization of MQ3CA. The observed differences between the solid- and solution-state 13C chemical shifts indicate the influence of crystal packing and weak intermolecular interactions, consistent with the crystallographic analysis. PXRD analysis further confirmed the absence of polymorphic phases in the investigated sample. The SC-XRD information supports that the morpholine ring adopts a chair conformation with the quinoline ring positioned in the equatorial plane, whereas C-H···O hydrogen bonds and π···π interactions dominate the crystal packing. DFT-derived electronic descriptors further support the experimentally observed structural stability. This work demonstrates the effectiveness of integrated magnetic resonance approaches for resolving structure-packing relationships in pharmaceutically relevant intermediates.