Cryogen-Free Zeeman-Perturbed NQR and Green Mechanochemistry for Halogen and Chalcogen Bonding in Molecular Solids

Abstract

Understanding the relationships between crystal structure, local electronic environment, and intermolecular interactions is fundamental to the rational design of molecular solids for applications in pharmaceuticals, supramolecular chemistry, and functional materials. This dissertation presents complementary advances in the sustainable characterization and synthesis of molecular solids through the development of cryogen-free Zeeman-perturbed nuclear quadrupole resonance (Zp-NQR) spectroscopy, integrated multimodal structural analysis, and mechanochemical synthesis.

The primary contribution of this work is the development of a practical and versatile cryogen-free Zp-NQR methodology for investigating quadrupolar nuclei in molecular solids. By introducing a weak magnetic field, generated by an adjustable electromagnet, to perturb the pure quadrupolar energy levels and analyzing the resulting spectral line shapes using exact Hamiltonian simulations, a robust experimental workflow was established for accurately determining the complete electric field gradient (EFG) tensor directly from powder samples. This approach eliminates the need for superconducting magnets and liquid-helium cryogens, significantly lowering the experimental barriers associated with quadrupolar spectroscopy while providing a more sustainable and accessible alternative to conventional high-field magnetic resonance techniques.

Building upon this methodological foundation, the analytical capabilities of Zp-NQR were further expanded. Zeeman perturbation was shown to enable direct experimental identification of quadrupolar isotopes by measuring their characteristic Zeeman response to an applied magnetic field. Analysis of the resulting spectral splitting allows the corresponding Larmor frequency and gyromagnetic ratio (γ), which is unique to each isotope, to be determined experimentally, thereby enabling unambiguous isotopic assignment and the identification of overlapping resonance lines in complex, and multicomponent, molecular solids without isotopic enrichment or prior structural information. The methodology was subsequently extended to demonstrate that experimentally determined quadrupolar interaction parameters serve as sensitive reporters of halogen bond strength. By combining Zp-NQR with relativistic density functional theory (DFT) calculations, strong correlations were established between quadrupolar coupling constants, electric field gradient tensors, electronic structure descriptors, and halogen-bond interaction energies, providing a direct experimental approach for quantifying halogen-bond strength in molecular solids.

The versatility of the methodology was further demonstrated through the site-resolved characterization of chlorine-bearing pharmaceutical materials. An integrated approach combining ³⁵Cl Zp-NQR, zero-field NQR, high-field solid-state NMR (SSNMR), three-dimensional electron diffraction 3D ED, and first-principles calculations enabled the structural characterization of pharmaceutical cocrystals, hydration-dependent materials, degradation products, and conformationally disordered systems directly from powder samples. The combined methodology resolved chemically inequivalent chlorine environments and provided detailed insight into crystal packing, hydration, disorder, and local electronic structure, establishing a multimodal framework for pharmaceutical solid-state characterization.

Complementary studies expanded the scope of this dissertation beyond quadrupolar resonance spectroscopy. Combined ⁷⁷Se magic-angle spinning (MAS) SSNMR spectroscopy and first-principles quantum chemical calculations were employed to investigate selenium-centred non-covalent interactions, providing detailed insight into the amphiphilic behaviour of selenium and its participation in halogen and chalcogen bonding. In parallel, resonant acoustic mixing (RAM) was demonstrated as a gentle, scalable, and solvent-efficient mechanochemical route for the synthesis of halogen-bonded cocrystals. RAM successfully produced phase-pure materials, enabled the discovery of previously unknown crystal forms, and expanded accessible polymorphic and stoichiometric landscapes beyond those attainable by conventional ball milling.

Overall, this dissertation demonstrates how advances in cryogen-free magnetic resonance spectroscopy, complementary crystallographic and computational techniques, and sustainable mechanochemical synthesis can be integrated into a unified framework for molecular solid research. Beyond expanding the analytical capabilities and accessibility of quadrupolar resonance spectroscopy, this work establishes experimentally grounded approaches for probing local electronic structure, intermolecular interactions, and structural complexity while promoting more sustainable practices in the characterization and synthesis of molecular materials.