Enhancing ¹⁹F Benchtop NMR Spectroscopy by Combining para-Hydrogen Hyperpolarization and Multiplet Refocusing

Abstract

Benchtop NMR spectrometers provide a promising alternative to high-field NMR for applications that are limited by instrument size and/or cost. 19 F benchtop NMR is attractive due to the larger chemical shift range of 19 F relative to 1 H and the lack of background signal in most applications. However, practical applications of benchtop 19 F NMR are limited by its low sensitivity due to the relatively weak field strengths of benchtop NMR spectrometers. Here we present a sensitivity-enhancement strategy that combines SABRE (Signal Amplification By Reversible Exchange) hyperpolarization with the multiplet refocusing method SHARPER (Sensitive, Homogeneous, And Resolved PEaks in Real time). When applied to a range of fluoropyridines, SABRE-SHARPER achieves overall signal enhancements of up to 5700-fold through the combined effects of hyperpolarization and linenarrowing. This approach can be generalized to the analysis of mixtures through the use of a selective variant of the SHARPER sequence, selSHARPER. The ability of SABRE-selSHARPER to simultaneously boost sensitivity and discriminate between two components of a mixture is demonstrated, where selectivity is achieved through a combination of selective excitation and the choice of polarization transfer field during the SABRE step.

SHARPER-DOSY: Sensitivity enhanced diffusion-ordered NMR spectroscopy

“…Collapsing NMR spectra into sharp singlets Using a benchtop NMR instrument, we have recently presented a SABRE-SHARPER experiment 10 , in which the SHARPER acquisition module provided a further boost (up to 17-fold) to a hyperpolarised signal by removing inhomogeneous broadening, refocusing homo-and heteronuclear J couplings and chemical shift differences on the order of 75 Hz. Using the pulse sequence of Fig.…”

Fluorinated Tags to Study Protein Conformation and Interactions Using 19F NMR

“…[84,85] However, structural perturbation may be especially notable for tags that contain higher numbers of fluorine atoms for sensitivity purposes, which will therefore, be larger, more lipophilic and more polarizing. Low signal-to-noise ratio can also be compensated by using advanced hardware such as cryoprobes or by developing new pulse sequences such as SHARPER, which collapses multiple fluorine signals into a singlet with greater signal-to-noise ratio, [86] albeit, this will be less useful for studying multiple species simultaneously.…”

Cryogen‐free 400‐MHz nuclear magnetic resonance spectrometer as a versatile tool for pharmaceutical process analytical technology

“…In addition, research has been ongoing in low-field benchtop NMRs to improve their sensitivity for low-sensitive nuclides through hyperpolarization. [70][71][72][73][74] Poor resolution issues in low-field NMR can sometimes be ameliorated with chemometrics for structural analysis of molecules with low-to-medium complexity. Low-field benchtop NMR spectrometers have a great range of applications as online detectors of molecules with low-to-medium structural complexity, in sample or reaction mixtures.…”

“…The study concluded that low‐field benchtop NMRs are not that useful for structure elucidation of complex unknown materials because of their low resolution compared with high‐field NMR spectrometers. In addition, research has been ongoing in low‐field benchtop NMRs to improve their sensitivity for low‐sensitive nuclides through hyperpolarization 70–74 . Poor resolution issues in low‐field NMR can sometimes be ameliorated with chemometrics for structural analysis of molecules with low‐to‐medium complexity.…”