Measurement of Accurate Interfluorine Distances in Crystalline Organic Solids: A High-Frequency Magic Angle Spinning NMR Approach

Abstract

Long-range interatomic distance restraints are critical for the determination of molecular structures by NMR spectroscopy, both in solution and in the solid state. Fluorine is a powerful NMR probe in a wide variety of contexts, owing to its favorable magnetic properties, ease of incorporation into biological molecules, and ubiquitous use in synthetic organic molecules designed for diverse applications. Due to the large gyromagnetic ratio of the 100% naturally abundant 19 F isotope, interfluorine distances as long as 20 Å are accessible in magic angle spinning (MAS) dipolar recoupling experiments. Herein, we present an approach for the determination of accurate interfluorine distances in multi-spin systems, using the finite pulse RFDR (fpRFDR) at high MAS frequencies of 40-60 kHz. We use a series of crystalline "molecular ruler" solids, difluorobenzoic acids and 7F-L-tryptophan, for which the intra-and intermolecular interfluorine distances are known. We describe the optimal experimental conditions for accurate distance determinations, including the choice of a phase cycle, the relative advantages of selective inversion 1D vs. 2D correlation experiments, and the appropriate numerical simulation protocols. A best strategy for the analysis of RFDR exchange curves in organic solids with extended spin interaction networks is presented, which, even in the absence of crystal structures, can be potentially incorporated into NMR structure determination.

Fast 19F Magic Angle Spinning NMR Crystallography for Structural Characterization of Fluorine-Containing Pharmaceutical Compounds

“…19,20,25 Furthermore, homonuclear 19 recoupling experiments, such as two-dimensional (2D) radio frequency driven recoupling (RFDR) and delays alternating with nutation for tailored excitation (DANTE)-RFDR, are effective and can be used for interfluorine distance measurements, including in multispin systems. 15,18,19,24 In particular, long-range 1 H− 19 F and 19 F− 19 F interatomic distances 27 together with 19 F− 13 C contacts 13,21,28,29 are indispensable parameters 30 in structure elucidations.…”

Meet the IUPAB councilor — Angela M. Gronenborn

“…Currently, my emphasis is on advancing fluorine as an NMR probe, particularly for in situ NMR. We have established benchmark data using model proteins as well as strategies and methods to exploit fluorine labeling for structural work (Campos-Olivas et al 2002;Fritz et al 2019;Lu et al 2019a, b;Matei and Gronenborn 2016;Sharaf and Gronenborn 2015;Sharaf et al 2016). I am particularly excited to develop fluorine in-cell NMR .…”

Heteronuclear and homonuclear radio-frequency-driven recoupling

“…The recoupling of the homonuclear dipolar interactions with a train of π pulses every rotor period was originally introduced by Gullion and Vega (1992) and Bennett et al (1992). Since then, the homonuclear radio-frequencydriven recoupling (RFDR) sequence (Bennett et al, 1992) has been successfully applied for the qualitative and quantitative determinations of the dipolar spin correlations in materials (Saalwächter, 2013;Messinger et al, 2015;Fritz et al, 2019;Roos et al, 2018;Nishiyama et al, 2014a;Wong et al, 2020;Hellwagner et al, 2018;Pandey and Nishiyama, 2018) and biomolecular samples (Zheng et al, 2007;Tang et al, 2011;Shen et al, 2012;Pandey et al, 2014;Grohe et al, 2019;Andreas et al, 2015;Petkova et al, 2002;Aucoin et al, 2009;Zinke et al, 2018;Zhang et al, 2017;Zhou et al, 2012;Jain et al, 2017;Colvin et al, 2015;Shi et al, 2015;Daskalov et al, 2021). Sun et al (1995) showed that the RFDR pulse sequence element could also be used as a part of the SPICP experiment (Wu and Zilm, 1993) for removing the undesired effect of the chemical shift terms to zero order.…”