Quantum Mechanical Quantitative Nuclear Magnetic Resonance Enables Digital Reference Standards at All Magnetic Fields and Enhances qNMR Sustainability
Yuzo Nishizaki, Naoki Sugimoto, Toru Miura, Katsuo Asakura, Takako Suematsu, Samuli‐Petrus Korhonen, Juuso Lehtivarjo, Matthias Niemitz, Guido F. Pauli
Abstract
Quantum mechanics (QM)-driven 1 H i terative f unctionalized s pin a nalysis produces HifSA profiles, which encode the complete 1 H spin parameters (“nuclear genotype”) of analytes of interest. HifSA profiles enable the establishment of digital reference standards (dRS) that are portable, FAIR (findable - accessible - interoperable - reusable), and fit for the purpose of quantitative 1 H NMR (qHNMR) analysis at any magnetic field. This approach enhances the sustainability of analytical standards. Moreover, the analyte-specific complete chemical shift and J -coupling information in HifSA-based dRS enable computational quantitation of substances in mixtures via QM-total-line-shape fitting (QM-qHNMR). We present the proof of concept for HifSA-based dRS by resolving the highly overlapping NMR resonances in the experimental spectra (“nuclear phenotypes”) of the diastereomeric mixture of (2 RS, 4 RS )- and (2 RS, 4 SR )-difenoconazole (DFZ), a widely used antifouling food additive. The underlying 1 H spin parameters are highly conserved in various solvents, are robust against variation in measurement temperature, and work across a wide range of magnetic fields. QM-qHNMR analysis of DFZ samples at 80, 400, 600, and 800 MHz showed high congruence with metrological reference values. Furthermore, this study introduces QM-qHNMR combined with chiral shift reagents for the analysis of all four DFZ stereoisomers: (2 R, 4 R )-, (2 S, 4 S )-, (2 R, 4 S )-, and (2 S, 4 R )-DFZ to perform chiral qHNMR measurements.