# Combining heteronuclear correlation NMR with spin-diffusion to detect relayed Cl-H-H and N-H-H proximities in molecular solids

Parth Raval, Julien Trebosc, Tomasz Pawlak, Yusuke Nishiyama, Steven P.

Brown, Manjunatha Reddy

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Parth Raval, Julien Trebosc, Tomasz Pawlak, Yusuke Nishiyama, Steven P. Brown, et al.. Combining heteronuclear correlation NMR with spin-diffusion to detect relayed Cl-H-H and N-H-H proximities in molecular solids. Solid State Nuclear Magnetic Resonance, 2022, 120, pp.101808. 10.1016/j.ssnmr.2022.101808. hal-04094784

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# Combining heteronuclear correlation NMR with spin-diffusion to detect
relayed Cl–H–H and N–H–H proximities in molecular solids

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Parth Raval<sup>a</sup>, Julien Trébosc<sup>b</sup>, Tomasz Pawlak<sup>c</sup>, Yusuke Nishiyama<sup>d,e</sup>, Steven P. Brown<sup>f,**</sup>, G.N. Manjunatha Reddy<sup>a,*</sup>

## ARTICLE INFO

### Keywords:

Structure elucidation

Fast MAS

HMQC

NMR crystallography

GIPAW

DFT

Pharmaceutical

Solid-state NMR

## ABSTRACT

Analysis of short-to-intermediate range intermolecular interactions offers a great way of characterizing the solid-state organization of small molecules and materials. This can be achieved by two-dimensional (2D) homo- and heteronuclear correlation NMR spectroscopy, for example, by carrying out experiments at high magnetic fields in conjunction with fast magic-angle spinning (MAS) techniques. But, detecting 2D peaks for heteronuclear dipolar coupled spin pairs separated by greater than 3 Å is not always straightforward, particularly when low-gamma quadrupolar nuclei are involved. Here, we present a 2D correlation NMR experiment that combines the advantages of heteronuclear-multiple quantum coherence (HMQC) and proton-based spin-diffusion (SD) pulse sequences using radio-frequency-driven-recoupling (RFDR) to probe inter and intramolecular ¹H-X (X = ¹⁴N, ³⁵Cl) interactions. This experiment can be used to acquire 2D ¹H{X}-HMQC filtered ¹H–¹H correlation as well as 2D ¹H-X HMQC spectra. Powder forms of dopamine-HCl and l-histidine-HCl·H₂O are characterized at high fields (21.1 T and 18.8 T) with fast MAS (60 kHz) using the 2D HMQC-SD-RFDR approach. Solid-state NMR results are complemented with NMR crystallography analyses using the gauge-including projector augmented wave (GIPAW) approach. For histidine·HCl·H₂O, 2D peaks associated with ¹⁴N–¹H–¹H and ³⁵Cl–¹H–¹H distances of up to 4.4 and 3.9 Å have been detected. This is further corroborated by the observation of 2D peaks corresponding to ¹⁴N–¹H–¹H and ³⁵Cl–¹H–¹H distances of up to 4.2 and 3.7 Å in dopamine-HCl, indicating the suitability of the HMQC-SD-RFDR experiments for detecting medium-range proximities in molecular solids.

## 1. Introduction

Solid-state (ss)NMR spectroscopy is widely used to characterize the local structures and dynamics of molecular solids today. Site selectivity, natural isotopic abundance of several NMR active nuclei, and availability of a large pool of one- (1D) and two-dimensional (2D) pulse sequences to carry out homo and heteronuclear correlation experiments are among the unique capabilities of ssNMR spectroscopy for characterizing the solid form. Applications have been presented in the areas of optoelectronics, catalysis, biomacromolecules, pharmaceutical formulations, energy harvesting and storage materials [1–7]. In addition,

ssNMR, in conjunction with diffraction-based techniques and modelling approaches (also referred to as NMR crystallography), is increasingly applied to characterize the intermolecular interactions and to determine the three-dimensional structures of (semi)crystalline and amorphous solids [8–18].

The vast majority of ssNMR-based structure elucidation studies involve the analysis of chemical shifts and dipolar couplings and often quadrupolar interactions [3]. The chemical shifts are sensitive to local bonding environments, and the dipolar couplings are sensitive to interatomic distances and site-specific dynamics. Information on the isotropic chemical shifts of spin-half nuclei such as ¹H, ¹⁹F, ¹³C, and ¹⁵N

<footnote><sup>a</sup> University of Lille, CNRS, Centrale Lille Institut, Univ. Artois, UMR 8181–UCCS– Unité de Catalyse et Chimie du Solide, F, 59000, Lille, France</footnote>

<footnote><sup>b</sup> Univ. Lille, CNRS, INRAE, Centrale Lille, Univ. Artois, FR 2638 - IMEC – Institut Michel-Eugène Chevreul, F, 59000, Lille, France</footnote>

<footnote><sup>c</sup> Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363, Lodz, Poland</footnote>

<footnote><sup>d</sup> RIKEN-JEOL Collaboration Centre, RIKEN, Yokohama Campus, Yokohama, Kanagawa, 230-0045, Japan</footnote>

<footnote><sup>e</sup> JEOL RESONANCE Inc., Akishima, Tokyo, 196-8558, Japan</footnote>

<footnote><sup>f</sup> Department of Physics, University of Warwick, Coventry, CV4 7AL, UK</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail addresses: S.P.Brown@warwick.ac.uk (S.P. Brown), gnm.reddy@univ-lille.fr (G.N. Manjunatha Reddy).</footnote>
can be obtained by acquiring and analyzing 1D magic-angle spinning (MAS) spectra. In addition, 2D homo- and hetero-nuclear correlation (HETCOR) experiments provide information on through-space proximities and dipolar interactions that can be used to estimate interatomic distances and molecular conformations, which help to determine the 3D structures of molecular solids. For example, double-quantum (DQ) peaks can be excited and detected for ¹H–¹H spin pairs at sub-nanometer (within 5 Å) distances, and ¹H–¹H spin-diffusion (SD) and cross-polarization (CP)-based ¹H-X (e.g., X = ¹³C, ¹⁵N, ¹⁹F) HETCOR experiments enable the interatomic proximities to be probed within, or even beyond a nanometer. For 2D experiments involving both spin-half and quadrupolar nuclei, heteronuclear multiple-quantum coherence (HMQC)-type or insensitive nuclei enhancement by polarization transfer (INEPT)-type experiments have been used to efficiently transfer the polarization from spin-half nuclei to quadrupolar nuclei [19–25]. For example, N–H proximities can be probed at natural abundance (¹⁴N spin 1, 99.6% natural isotopic abundance) using *J*-couplings (*J*-HMQC, dipolar couplings (*D*-HMQC), and using overtone (OT) ¹⁴N transitions [23,25–33]. Specifically, 2D HMQC experiments have been applied to characterize ¹⁴N–¹H proximities [28,34–38] as well as ³⁵Cl–¹H proximities [38–42] in small molecules and pharmaceutical solids.

To take full advantage of NMR analysis of molecular solids, it is important to probe packing interactions in the sub-nanometer to nanometer range, or even greater than a nanometer distance. Gaining access to the intermediate-range (1–10 nm) length scale is particularly important to fill the gap between the structural analysis enabled by the short-range probes (e.g., conventional magnetic resonance spectroscopy probes local structures at sub-nanometer distances) and the long-range techniques such as X-ray scattering and electron microscopy that offer morphological and structural information at tens to hundreds of nanometers regimes. For example, it has been feasible to probe intermediate-to-long range distances via spin-diffusion experiments by making use of spin magnetization exchange between nuclei at high natural abundance such as ¹H and ¹⁹F due to the strong dipolar interactions between them, or between isotopically enriched nuclei [43–51]. Several structural elucidation studies benefit from the analysis of such intermediate-range to long-range structures, including catalytic surfaces, reactive interfaces in stacked thin films in optoelectronic devices, bio-macromolecules, polymers, functional supramolecular assemblies, and pharmaceutical formulations [44,52–64]. Notably, analysis of spin-diffusion build-up curves in conjunction with computational modelling has been used to determine three-dimensional structures of small to moderately sized molecules [47,48,65–68]. Since these molecular systems contain both spin-half and quadrupolar nuclei, detecting 2D NMR peaks for heteronuclear ¹H-X spin-pairs involving low-gamma quadrupolar nuclei (X = ¹⁴N, ³⁵Cl), probing long-range proximities of up to 5 Å or beyond is difficult due to the weak heteronuclear dipolar interactions. Thus, a combination of features involving a 2D HMQC-type experiment and ¹H–¹H spin diffusion to probe the short-to-medium range interactions is expected to facilitate structure elucidation in organic solids and materials.

Here we combine HMQC and SD using RFDR pulse sequence elements so as to probe ³⁵Cl–¹H–¹H and ¹⁴N–¹H–¹H interatomic proximities in small organic molecules. Results are demonstrated for powdered compositions of *l*-histidine·HCl·H₂O and dopamine·HCl (Fig. 1). Pulse sequences used to acquire the conventional 2D HMQC and 2D HMQC-SD-RFDR experiments are shown in Fig. 2. For each sample, the ¹H {¹⁴N} and ¹H{³⁵Cl}-HMQC filtering efficiency is demonstrated on 1D versions of the HMQC and HMQC-RFDR pulse sequences. Then, the ability of a ¹H{¹⁴N/³⁵Cl}-HMQC filtered 2D ¹H–¹H spin-diffusion experiment to detect the peaks corresponding to proton pairs that are in close proximities to ¹⁴N sites is illustrated. Next, proton-detected 2D ¹H–¹⁴N and ¹H–³⁵Cl HMQC spectra were acquired and analyzed to demonstrate how medium-range N–H–H and Cl–H–H correlations are observed for the interatomic N–H and Cl–H distances reaching and exceeding 4 Å. The solid-state NMR results are correlated and

<figure><img src="image_4.png" /><figcaption>Fig. 1. Chemical structures of *l*-histidine·HCl·H₂O and dopamine·HCl.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>Fig. 2. Pulse sequences used to acquire two-dimensional (a) HMQC and (b) HMQC-SD-RFDR spectra. The sequence shown in (b) can be used to acquire ¹H {X}-filtered ¹H–¹H SD correlations spectra as well as ¹H-X HMQC-SD-RFDR correlation spectra, depending on the placing of the *t*₁ evolution period. In both cases, SR4ᵢ² pulses are applied for the recoupling of ¹H-X (X = ³⁵Cl, ¹⁴N) dipolar interactions, and in (b), an RFDR block is added to enhance the spin diffusion process leading to a ¹H-detected 2D experiment. The evolution during *t*₁ and the ¹H RFDR pulses during spin diffusion are rotor-synchronized with respect to the sample spinning.</figcaption></figure>

complemented by periodic density functional theory calculations using the gauge-including projector augmented wave (GIPAW-DFT) approach. These results suggest that the proposed method has wider relevance in investigating the medium-range interatomic proximities between spin-half and low-gamma quadrupolar nuclei in molecular solids.

## 2. Experimental details

**Solid-state NMR spectroscopy** Powders of *l*-histidine·HCl·H₂O [C₆H₉N₃O₂·HCl·H₂O] and dopamine·HCl [(HO)₂C₆H₃(CH₂)₂NH₂·HCl)] were purchased from Sigma Aldrich and used as received. Approximately 2.3 mg of *l*-histidine·HCl·H₂O and dopamine·HCl were separately packed into 1.3 mm (outer diameter) rotors. All 1D ¹H MAS and 2D ¹H–¹H correlation experiments were performed on a Bruker Avance Neo solid-state NMR spectrometer operating at a ¹H Larmor frequency of 900 MHz, equipped with a 1.3 mm double-resonance MAS probe head. The ¹H and ¹⁴N pulse lengths, dipolar recoupling periods (τ<sub>rcpl</sub>), and spin diffusion times using RFDR (τ<sub>RFDR</sub>) were empirically optimized using 1D versions of the HMQC and HMQC-SD-RFDR pulse sequence shown in Fig. 2. 1D ¹H MAS NMR spectra of *l*-histidine·HCl·H₂O and dopamine·HCl were acquired with 128 co-added transients. 1D ³⁵Cl spectra of *l*-histidine·HCl·H₂O and dopamine·HCl·H₂O were acquired with 512 and 4096 co-added transients using a Quadrupolar Carr-Purcell-Meiboom-Gill (QCPMG) sequence [69]. All ¹H chemical shifts are calibrated with respect to neat TMS using adamantane as an external reference (¹H resonance, 1.85 ppm) [70]. ¹⁴N shifts were referenced to a saturated NH₄Cl aqueous solution at –352.9 ppm, corresponding to the primary reference, liquid CH₃NO₂ (0 ppm) [71]. To compare with the
alternative IUPAC reference of liquid NH₃ at -50 °C as used in protein NMR, it is necessary to add 379.5 ppm [71]. ³⁵Cl experimental shifts are referenced to 0.1 M NaCl solution in D₂O based on the IUPAC recommendation (see Table A1 in Ref. [72]).

**HMQC.** All 2D HMQC NMR experiments were performed on a Bruker Avance Neo (21.1 T Larmor frequency of ¹H = 900.2 MHz, ¹⁴N = 65.0 MHz or 18.8 T Larmor frequency of ¹H = 800.1 MHz, ¹⁴N = 57.8 MHz, and ³⁵Cl = 78.4 MHz) spectrometer, using a 1.3 mm Bruker probe operating in double-resonance mode at a 60.241 kHz MAS frequency. The pulse sequence used to acquire the ¹⁴N-¹H HMQC spectra is reported in Fig. 2a. SR4₂<sup>1</sup> recoupling elements were used to reintroduce the heteronuclear ¹⁴N-¹H dipolar couplings, using a duration τrcpl = 166 µs. [73]. The ¹H π/2 pulse duration and the ¹⁴N pulse durations were 2.2 µs and 16.6 µs, respectively. For each of 80 t₁ FIDs acquired using the States method to achieve sign discrimination in the indirect F₁ dimension with a rotor synchronized increment of 16.6 µs, 32 transients were coadded with a recycle delay of 2 s. A ¹H nutation frequency of 208.3 kHz was used for the 90° pulse in the single-pulse experiments. For L-histidine·HCl·H₂O, all the 2D ¹H-¹⁴N and ¹H-³⁵Cl (HMQC and HMQC-SD-RFDR) spectra were acquired with 48 t₁ FIDs, each with 32 and 128 co-added transients, respectively. For 2D ¹H-¹⁴N and ¹H-³⁵Cl correlation experiments, the total experimental times were respectively ~1 h and ~3.5 h each. For both HMQC and HMQC-RFDR sequences, a ¹H nutation frequency of 113.6 kHz was applied for the 90° pulse (2.2 µs) and 180° pulse (4.4 µs). A rotor-synchronized SR4₂<sup>1</sup> pulse was employed to recouple ¹H-¹⁴N or ¹H-³⁵Cl dipolar interactions. For dopamine·HCl, all 1D ¹H MAS and ¹H{¹⁴N} filtered 1D MAS, and 2D ¹H-¹⁴N HMQC spectra were acquired on a Bruker Avance Neo (21.1 T, Larmor frequency of ¹H = 900.2 MHz, ¹⁴N = 65.0 MHz) spectrometer. The ¹H nutation frequency was 175.4 kHz for a 90° pulse. 2D ¹H-¹⁴N HMQC spectra were acquired with 48 t₁ FIDs, each with 32 co-added transients, corresponding to an experimental time of ~1.3 h each. 2D ¹H-³⁵Cl spectra were acquired with 80 t₁ FIDs, each with 128 co-added transients, corresponding to an experimental time of ~8.5 h each.

**HMQC-SD-RFDR pulse sequence:** To begin with, an HMQC pulse sequence (Fig. 2a) is used for the excitation and reconversion of HMQC coherences, whereby the interval between the two ¹⁴N pulses are rotor synchronized with sample spinning, i.e., t₁ = nτr, where n is an integer. During this sequence, the SR4 pulse sequence was applied during the excitation and reconversion periods to decouple the ¹H-¹H homonuclear dipolar interactions and recouple the ¹H-¹⁴N heteronuclear dipolar interactions. To this sequence, a spin-diffusion filter is added with two 90° pulses separated by a mixing delay, also referred to as a spin diffusion delay. Since ¹H-¹H spin diffusion is suppressed when experiments are carried out at fast sample spinning (here 60 kHz MAS), radio-frequency-driven recoupling (RFDR) [74] pulses (Fig. 2b) are added within the spin diffusion filter to enhance the spin diffusion process. This leads to a ¹H detected 2D pulse sequence that can be applied to acquire 2D ¹H{¹⁴N}-HMQC filtered ¹H-¹H NOESY-like spectra (by placing the t₁ evolution between the HMQC block and the spin diffusion block, as depicted in gray color) as well as 2D ¹H-¹⁴N relay HMQC spectra. To compare the spectral filtering efficiency, spectra acquired using the 1D versions of the HMQC and HMQC-SD-RFDR experiments are compared with a single-pulse experiment in Fig. 3 and in a later section (all spectra are acquired at identical experimental conditions). The sensitivity of the conventional 1D ¹H{¹⁴N/³⁵Cl} HMQC experiment is about 5%, and the ¹H{¹⁴N/³⁵Cl}-HMQC-SD-RFDR experiment is about 1%, as compared to the single-pulse ¹H MAS experiment. Of particular note, the sensitivity of the proposed experiment depends on the relative strengths of both homo and heteronuclear dipolar couplings. For example, in both samples, the efficiency for NH₃ protons is less due to the rotational dynamics of the NH₃ group as compared to the aromatic protons. 2D HMQC-SD-RFDR experiments were acquired under identical conditions to those of conventional HMQC experiments, except the RFDR-based spin-diffusion mixing times are added as indicated in the appropriate

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Experimental ¹H NMR spectra are presented for L-histidine·HCl·H₂O; (top-to-bottom) a ¹H (800 MHz, 50 kHz MAS) single-pulse spectrum, a ¹H{¹⁴N} HMQC-filtered ¹H spectrum recorded using τrcpl of 320 µs and also with τRFDR = 1000 µs, and a ¹H{³⁵Cl} HMQC-filtered ¹H spectrum (800 MHz, 60.24 kHz MAS) recorded using τrcpl = 265.6 µs and also with τRFDR = 265.6 µs.</figcaption></figure>

figure captions.

**Quantum mechanical calculations using a periodic-DFT approach.**

The molecular coordinates obtained from previously published crystal structures of L-histidine·HCl·H₂O (CCDC code: HISTCMO1) [75] and dopamine·HCl (CCDC codes for the HCl salt and zwitterionic forms are DOPAMN and TIRZAX) [76] were taken to prepare input files for the quantum mechanical calculations. The geometry optimizations of crystal structures were carried out with periodic density functional theory (DFT) calculations. For all the geometry optimized structures, the NMR chemical shifts were computed using the gauge including projected augmented wave (GIPAW) method as described by Pickard and Mauri [77,78]. All periodic DFT calculations were performed using the CASTEP 19.11 code [79]. Each self-consistent field (SCF) loop was performed until the energy was converged to within 3.67 × 10⁻⁸ Hartrees. For all calculations, the generalized density approximation DFT functional PBE with the Tkatchenko-Scheffler (TS) dispersion correction scheme (DFT-D method) was applied with ultrasoft pseudopotentials [80,81]. The maximum plane wave cut-off energy was 23.15 Hartrees. The Broyden–Fletcher–Goldfarb–Shanno (BFGS) optimization algorithm was used, and a Monkhorst–Pack grid of minimum sample spacing 0.07
$2\pi \AA^{-1}$ was applied to sample the Brillouin zone. The positions of the atoms were allowed to vary within the unit cell until the average forces, energies, and displacements remaining were below $3.6749 \times 10^{-7}$ Hartree/Å, 0.0011025 Hartrees, and 0.001 Å, respectively. The interatomic distances for histidine.HCl.H₂O and dopamine.HCl molecules stated in this study correspond to the DFT optimized structures.

### 3. Results and discussion

**L.histidine.HCl·H₂O:** The solid-state form of L-histidine.HCl·H₂O, and protonated and tautomeric structures of histidine have been well characterized by ¹H, ¹³C, ¹⁴N/¹⁵N, and ³⁵Cl MAS NMR spectroscopy in previous studies [36,38,40,82,83]. Here, we used L-histidine.HCl·H₂O as a control sample to test the proposed HMQC-SD-RFDR experiment. Fig. 3 compares ¹H MAS spectra of L-histidine.HCl·H₂O acquired by a single-pulse as well as 1D versions of ¹H{¹⁴N} and ¹H{³⁵Cl} HMQC and HMQC-SD-RFDR pulse sequences. A single-pulse ¹H MAS NMR spectrum exhibits peaks at 2.8 ppm corresponding to the CH₂/CH sites and at 5.2 ppm originating from water molecules, and the partially resolved signals at 8.9 and 7.7 ppm are due to H6, H1, H8 sites as depicted in the schematic structure. The ¹H chemical shifts of hydrogen bonded protons are observed at higher frequencies (i.e., 8.4, 12.5, and 17.1 ppm): N–H (1)···O(w) hydrogen bonding interactions with oxygen atoms of water molecules, intermolecular N–H(5)···O and N–H(7)···O hydrogen-bonding interactions with the carboxylic acid groups of the neighboring histidine molecules, for which the intermolecular donor (N)-acceptor(O) distances are 2.61 and 2.78 Å, respectively. A ¹H–¹H double-quantum-single-quantum (DQ-SQ) correlation NMR spectrum together with the DQ peak assignments corresponding to ¹H–¹H distances between 3 Å and 4.5 Å is presented in Fig. S1 (Supporting Information). For the spectra acquired under identical experimental

conditions, spectral simplification and sensitivity of the ¹H signals achieved by ¹H{¹⁴N} and ¹H{³⁵Cl} HMQC filters with respect to the single-pulse experiment are examined and compared (Fig. 3, colored shaded regions). The 1D ¹H{¹⁴N}-HMQC filtered spectra acquired with 320 µs of SR4 recoupling time exhibited signals corresponding to the directly bonded ¹H–¹⁴N sites, i.e., H1, H5, and H7 peaks are detected, while the signals originating from all other protons are poorly detected (or undetected). Although the addition of a spin diffusion delay leads to the exchange of magnetization from ¹H{¹⁴N} sites to the neighboring ¹H sites, the proton spin-diffusion (SD) is less efficient when experiments are carried out under fast MAS [84–86]. Therefore, the RFDR pulses have been used within the spin-diffusion filter to enhance the ¹H–¹H spin-diffusion process. The addition of a SD-RFDR block (1000 µs) to the 1D HMQC experiment with the same 320 µs of SR4 recoupling time enables the weak intensity signals (H2, H3, H4, and Hw) to be detected with much higher intensities, although the intensities of H5 and H7 peaks are reduced, yielding signal uniformity like that of single-pulse experiment. A similar trend is observed for the ¹H{³⁵Cl} HMQC filtered spectra of L-histidine·H₂O·HCl, whereby the spectra acquired with 265.6 µs of SR4 recoupling time before and after the addition of RFDR (265.6 µs) showed different ¹H peak intensities. In the latter, the H5 and H2–H4 sites exhibited signal enhancements, as indicated in Fig. 3. A striking advantage of the SD-RFDR block is that it enables the ¹H signals corresponding to the dipolar coupled ¹H–¹H pairs in the vicinity of ¹⁴N and ³⁵Cl sites to be detected, demonstrating the sensitivity enhancements for specific ¹⁴N–¹H–¹H and ³⁵Cl–¹H–¹H sites via relay transfer.

To test the role of RFDR blocks in enhancing the ¹H–¹H spin-diffusion process to the neighboring ¹H sites, NOESY-like 2D ¹H–¹H NMR spectra of L-histidine.HCl·H₂O were acquired (21.1 T, 60 kHz MAS) with and without SD-RFDR blocks. The conventional NOESY-like 2D ¹H–¹H

<figure><img src="image_7.png" /><figcaption>**Fig. 4.** Two-dimensional ¹H–¹⁴N correlation spectra with skyline projections of L-histidine.HCl·H₂O acquired at 18.8 T and 60.24 kHz MAS with (a, b) conventional HMQC and (d,e) HMQC-SD-RFDR pulse sequences as shown in Fig. 2. In all cases, SR4 recoupling for a τRCPL duration of 166 µs was used except for (b) where the SR4 recoupling time was 498 µs. RFDR durations were 166 µs (d) and 498 µs (e). The base contour levels are at 6% of the maximum peak height. Representations of the periodic DFT geometry optimized structure of L-histidine.HCl·H₂O illustrating the short- and long-range interactions probed by the HMQC and HMQC-SD-RFDR approaches are shown in (c) and (f) with spheres representing the distances between ¹⁴N and ¹H sites.</figcaption></figure>
correlation spectra of L-histidine.HCl.H₂O acquired with different mixing times in the 1–100 ms range are presented in Supporting Information (Fig. S2), whereby the short mixing time of 10 ms was insufficient to exchange the magnetization between the neighboring sites, and 100 ms enabled magnetization exchange between different sites. The advantage of using RFDR blocks to enhance spin-diffusion process in 2D experiments acquired under fast MAS is demonstrated in Fig. S3. By adding an HMQC filter prior to the ¹H–¹H SD-RFDR pulse sequence, a 2D ¹H{¹⁴N} HMQC-filtered ¹H–¹H SD spectrum can be acquired. In a HMQC-filtered 2D ¹H–¹H SD-RFDR spectrum acquired with a mixing time of 16.6 µs, i. e., one rotor period (Fig. S3c), the diagonal peaks associated with NH₃, H5, and H7 protons are observed. By comparison, the RFDR mixing time of 531.2 µs enabled the 2D correlation peaks between all the sites to be observed (Fig. S3d), confirming that the RFDR enhances the spin-diffusion process. It is to be noted that similar experiments can be carried out using a³⁵Cl{¹H} HMQC filter to achieve spectral simplification in HCl salts of small organic molecules.

Next, 2D ¹H–¹⁴N HMQC spectra were acquired without and with SD-RFDR pulses (Fig. 4) in order to probe N–H and N–H–H proximities. We start by analyzing the conventional 2D ¹H–¹⁴N HMQC spectra of L-histidine.HCl.H₂O acquired with different ¹H–¹⁴N recoupling times considering the molecular packing interactions in the vicinity of ¹⁴N sites as obtained from the periodic DFT optimized L-histidine.HCl.H₂O crystal structure. In an HMQC spectrum acquired with a short recoupling time of 166 µs (Figure 4a), 2D peaks corresponding to directly bonded NH moieties are observed, including N7–H7, N5–H5 within the imidazole ring, and N1–H1 within the NH₃⁺ group. In the 2D HMQC experiment acquired with a recoupling time of 498 µs (Fig. 4b), peaks associated with stronger (one-bond) and weaker dipolar coupled N–H sites are observed including N5–H6, N7–H6, N7–H8, and N1–H2 corresponding to the shortest N–H distances of 2.17, 2.15, 2.15 and 2.08 Å,

respectively. These distances are depicted in the periodic DFT optimized crystal structure of L-histidine·HCl·H₂O shown in Fig. 4c. Further increase in the recoupling time up to 800 µs (spectra not shown) yields a poor signal to noise ratio and no additional long-range N–H correlations were detected, suggesting that the conventional HMQC experiment is unable to probe through-space proximities with N–H exceeding 3 Å (dashed boxes in Fig. 4b) [87]. This is because of the dipolar-based HMQC experiment utilizing heteronuclear dipolar interactions ($D_{NH}$), which are an order magnitude weaker than the homonuclear proton-proton dipolar couplings ($D_{HH}$). For example, a through-space dipolar coupled ¹⁴N–¹H pair separated by ~4.43 Å distance exhibits a dipolar coupling of ~100 Hz, which is too weak to produce a detectable 2D peak in the conventional HMQC spectrum. For the same ¹⁴N–¹H heteronuclear recoupling of 166 µs, the addition of RFDR pulse of 166 µs leads to the detection of poorly dipolar coupled ¹⁴N–¹H sites ($>3$ Å): for example, 2D peaks correlating N1 and Hw, H2, H3 and H4 chemical shifts with a nearest ¹⁴N to Hw distance of 3.4 Å and ¹⁴N to H2, H3, H4 distances of 3.4 Å are observed. In addition, these 2D peaks are detected with much higher intensities when RFDR with a duration of 512 µs is used. This is evidenced in the HMQC-SD-RFDR spectra of L-histidine. HCl.H₂O (Fig. 4d and e), whereby RFDR-assisted recoupling of ¹H–¹H dipolar interactions enables medium-range ¹⁴N–¹H–¹H interactions to be probed via relay transfer (solid boxes). Such relayed correlations are observed due to the magnetization transfer between strongly dipolar coupled ¹H–¹H pairs in the vicinity of ¹⁴N sites and can be strengthened by utilizing the larger $D_{HH}$ values, particularly by using ¹H-RFDR transfer. 2D peaks are observed for the proton pairs that are up to 4 Å away from the ¹⁴N sites (Fig. 4f), suggesting that the correlations between nitrogen atoms and remote protons can be observed using this approach. It is noteworthy that 3D ¹H–¹H–¹⁴N or ¹H–¹H–¹⁹F correlation experiments provide identical information [36,88,89], however, the 2D

<figure><img src="image_8.png" /><figcaption>**Fig. 5.** Two-dimensional ¹H–³⁵Cl HMQC spectra with skyline projections of L-histidine·HCl·H₂O acquired at 18.8 T and 60.24 kHz MAS without (a, b) and with (d, e) SD-RFDR blocks. SR4 recoupling with a $τ_{RCPL}$ duration of (a,d, and e) 265.6 µs and (b) 531.2 µs was used to reintroduce the heteronuclear ³⁵Cl–¹H dipolar interactions. RFDR durations were 265.6 µs (d) and 531.2 µs (e). The base contour levels are at 6% of the maximum peak height. The peak at ~59 ppm in the vertical ³⁵Cl dimension is a satellite transition. Representations of the periodic DFT geometry optimized structure of L-histidine·HCl·H₂O illustrating the ³⁵Cl–H and ³⁵Cl–H–H proximities probed by the (c) HMQC and (f) HMQC-SD-RFDR approaches, with small and large spheres representing the proximities of up to 3 Å and 4 Å, respectively.</figcaption></figure>
HMQC-SD-RFDR experiment presented in this study requires shorter acquisition times than the 3D experiments to provide identical information, which is an added advantage.

The proposed HMQC-SD-RFDR approach has been applied to examine relayed ³⁵Cl···¹H⁻¹H proximities in L-histidine.HCl.H₂O. A 1D ³⁵Cl NMR spectrum acquired with a QCPMG sequence is presented in Fig. S4 (Supporting Information) together with a lineshape fitting analysis to obtain the isotropic chemical shifts and quadrupolar coupling constants, as listed in Table S1. The narrow quadrupolar lineshape is due to the weak quadrupolar interaction associated with the chloride anions. Fig. 5 compares 2D ¹H⁻³⁵Cl D-HMQC spectra recorded without and with SD-RFDR pulses. In the conventional ¹H⁻³⁵Cl HMQC spectra of L-histidine.HCl.H₂O acquired with a short recoupling time of 265.6 µs (Fig. 5a), the 2D correlation peaks associated with closely proximate and dipolar coupled ¹H⁻³⁵Cl are observed for the Cl atoms and H1, H6 and H8, and Hw protons. The inter and intramolecular Cl···H distances associated with Cl···H1, Cl···H6, Cl···H7, Cl···H8, and Cl···Hw are 2.20, 2.44, 2.94, 2.75 and 2.16 Å, respectively (Fig. 5c). Similar 2D peaks are observed for a 2D HMQC spectrum acquired with a recoupling time of 531.2 µs, shown in Fig. 5b; however, a weak intensity peak corresponding to Cl···H5 (3.86 Å) appears. This indeed corroborates that the detection of the 2D ³⁵Cl⁻¹H peak for a Cl···H distance closer to 4 Å is difficult to achieve in a conventional 2D HMQC experiment due to the weaker D<sub>Cl-H</sub>. By combining heteronuclear ³⁵Cl···¹H and homonuclear ¹H⁻¹H spin diffusion process, these weak intensity peaks are detected with much higher intensities, as shown in the HMQC-SD spectra presented in Fig. 5d and e. In addition, the enhanced uniformity of 2D peak intensities is apparent from these spectra, which indicates the addition of RFDR enables the detection of relayed ³⁵Cl⁻¹H⁻¹H peaks with an interatomic ³⁵Cl⁻¹H distance exceeding 3.8 Å (Fig. 5f).

**Dopamine-HCl.** Dopamine is a catecholamine derived from L-tyrosine, which has key biological significance as a neurotransmitter in the central nervous system and as a hormone in vesicles of the adrenal medulla that influences and controls the heartbeat rate, oxidative stress, and blood pressure [90,91]. The impaired dopamine metabolism and the absence of dopamine-containing neurons are associated with brain disorders such as Parkinson's disease [92]. In addition, dopamine is a food supplement (L-Dopa) that can be used as a direct precursor to increase the dopamine level in the body. In the presence of oxygen and alkaline/acidic environments, dopamine self-assembles into polydopamine (pDA) [93]. Care was taken to prevent the self-polymerization of dopamine by storing the powder form in a glass desiccator. To ensure that the dopamine characterized in this study is in monomeric form, liquid-state 1D ¹H and 2D ¹H⁻¹H and ¹H⁻¹³C correlation NMR spectra were acquired and analyzed (Supporting Information, Figs. S5-S7): the narrow ¹H signals indicate the monomeric form of dopamine rather than the polymeric form. In the solid state, dopamine exists in different crystalline polymorphs such as neutral and zwitterionic forms, for which crystal structures have been previously solved [76,94]. Here, the solid-state form of dopamine-HCl is characterized by an NMR crystallography approach that combines solid-state NMR and periodic DFT calculations of previously published crystal structures. To further ensure that the dopamine preserved its molecular form, the GIPAW-DFT calculated chemical shifts for ¹H SQ, and DQ correlation peaks for all ¹H⁻¹H pairs (within 3 Å) in molecular and zwitterionic forms are overlaid on the experimental DQ-SQ peaks (Supporting Information, Fig. S8). A good agreement between the experimental ¹H SQ and DQ chemical shifts and the GIPAW-DFT calculated ¹H NMR chemical shifts is observed for the molecular form, but not for the zwitterionic form.

In Fig. 6 and 1D ¹H{¹⁴N} and ¹H{³⁵Cl} HMQC spectra acquired with and without SD-RFDR blocks are compared with a single-pulse ¹H spectrum. The broad peak centered at ~7.6 ppm is due to an overlapped contribution from the NH₂ and aromatic protons. In the aliphatic region, the chemical shifts at 3.4 ppm and 5.9 ppm correspond to a CH₂ group next to the aromatic ring, and one of these protons is hydrogen-bonded to the oxygen atoms of the adjacent dopamine molecules. The peak at

<figure><img src="image_9.png" /><figcaption>**Fig. 6.** Experimental ¹H NMR spectra are presented for dopamine-HCl: (top-bottom) single-pulse ¹H (900 MHz, 60.24 kHz MAS) spectrum, ¹H{¹⁴N} HMQC-filtered ¹H spectrum acquired with τ<sub>RCPL</sub> = 132.8 µs and with τ<sub>RFDR</sub> = 531.2 µs (cyan shaded region), and ¹H{³⁵Cl} HMQC-filtered ¹H spectrum acquired with τ<sub>RCPL</sub> = 265.6 µs and with τ<sub>RFDR</sub> = 531.2 µs recoupling times (purple shaded region).</figcaption></figure>

4.9 ppm corresponds to the CH₂ group next to the NH₃ group. The peak integral ratio of 7:4 associated with the signals at 6.5–9.5 ppm and 2.5–6.5 ppm further confirms the peak assignments. While all ¹H peaks are observed in the conventional ¹H spectrum, the ¹H{¹⁴N}-HMQC filtered 1D spectrum acquired with 132.8 µs of ¹H⁻¹⁴N dipolar recoupling time using the SR4 sequence yields the ¹H signals of NH₃ peaks, and the ¹H signals of CH₂ protons are suppressed. For the same SR4 recoupling time, the addition of RFDR pulses (531.2 µs) leads to a ¹H NMR lineshape similar to that of the single-pulse experiment, i.e., the ¹H signal intensities in the 2.5–6.5 ppm range are enhanced. This trend is also evidenced in the ¹H{³⁵Cl} HMQC filtered experiments (τ<sub>rcpl</sub> = 265.6 µs) with and without RFDR blocks, whereby the signals in the range of 2–7 ppm were only detected when an RDFR duration of 531.2 µs was added. Furthermore, 2D ¹H⁻¹H spin diffusion NMR spectra
<figure><img src="image_10.png" /><figcaption>**Fig. 7.** Two-dimensional ¹H–¹⁴N correlation spectra with skyline projections of dopamine·HCl acquired at 21.1 T and 60.24 kHz MAS with conventional HMQC (top) and HMQC-SD-RFDR pulse sequences (bottom), using SR4 recoupling for a τRCPL duration of (a, d, e) 132.8 µs and (b) 332 µs? RFDR durations were (d) 132.8 µs and (e) 1162 µs? The base contour levels are at 4% of the maximum peak height. Periodic DFT geometry optimized structures presented in (c) and (f) dopamine·HCl illustrate the short- and medium-range interactions probed by the HMQC and HMQC-SD-RFDR approaches. Spheres represent the long-range correlations of up to 4.2 Å between NH₃ groups and proton sites.</figcaption></figure>

without and with RFDR pulses (Supporting Information, Fig. S9) are acquired and compared in order to highlight the role of RFDR pulses in enhancing the magnetization exchange between the neighboring ¹H sites in dopamine·HCl.

Conventional 2D ¹H–¹⁴N HMQC spectra of dopamine·HCl acquired with different recoupling times of 132.8 µs and 332 µs are presented in Fig. 7a and b (top) together with the molecular packing interactions in the periodic DFT optimized crystal structure of dopamine·HCl. For both recoupling times, 2D peaks at ~7.6 ppm (¹H) and approximately –325 ppm (¹⁴N) indicate that the short-range interactions between N1–H1 within the NH₃ groups are detected. However, 2D peaks corresponding to the long-range N–H correlations were not detected in the conventional HMQC experiment. In the HMQC-RFDR spectra shown in Fig. 7d and e (bottom), 2D peaks between ~–325 ppm (¹⁴N) and 2–6 ppm (¹H) indicate the relayed correlation signals enabled by the spin diffusion process.

We extend this analysis to probe the ¹H–³⁵Cl proximities in dop-
amine·HCl. A 1D ³⁵Cl NMR spectrum acquired with a QCPMG sequence
is presented in Fig. S10 (Supporting Information) together with a line-
shape fitting analysis. The isotropic chemical shift, quadrupolar
coupling constant, and asymmetry parameter are listed in Table S2. In
¹H–³⁵Cl HMQC spectra of dopamine·HCl acquired with and without SD-
RFDR blocks (Fig. 8), short and long-range correlations are observed.
For a SR4 recoupling duration of 1024 µs (Fig. 8a), 2D peak at 7.6 ppm
(¹H) and –150 to 10 ppm (³⁵Cl) is observed, which corresponds to the
Cl–NH₃ and Cl–OHproximities with interatomic distances of ~2.2 Å.
When RFDR pulses of duration 1024 µs are applied, 2D peaks between
³⁵Cl and CH₂ groups are also observed, as evident in Fig. 8b. The nearest
internuclear ³⁵Cl–CH₂ (adjacent to NH₂) and ³⁵Cl–CH₂ (adjacent to the
aromatic ring) distances are 3.5 and 3.7 Å, respectively. Although the 2D

HMQC-SD-RFDR approach enables the relayed correlation peaks to be detected, the measurement of interatomic distances from 2D volume integrals is less straightforward. In order to gain a quantitative insight into the distance constraints, a series of 2D experiments varying the heteronuclear recoupling time and spin diffusion mixing time would need to be acquired and the signal intensity buildup would need to be analyzed.

Further improvements to the proposed HMQC-SD-RFDR approach can
be sought, for example, using the TRAPDOR-HMQC (TRAPDOR - transfer
of population in double resonance) approach [42,95], by detecting the
double-quantum (DQ) satellite transitions of quadrupolar nuclei. It has
been shown that the DQ version is less sensitive to MAS instabilities and
also benefits from a slightly higher resolution since the DQ chemical shift
evolves at a frequency twice as large as the SQ chemical shifts. It has also
been demonstrated that frequency-swept ¹⁴N overtone CW-RESPDOR
(continuous wave rotational-echo saturation-pulse double-resonance)
experiments efficiently probe ¹H–¹⁴N proximities with much longer
internuclear distances than for the HMQC experiment [30]. The use of
SD-RFDR block with CW-RESPDOR is expected to further extend the limit
of detection of 2D peaks. Acceleration in the acquisition times can also be
achieved at fast MAS by frequency selective (FS)-HMQC experiments,
whereby selective excitation and detection of ¹H leads to a reduction in
the inter-scan delays [41]. Notably, the proposed pulse sequence and its
variants can be applied to detect ¹H–¹H and ¹H–¹⁴N/³⁵Cl proximities in
order to facilitate the structure elucidation of weak intermolecular in-
teractions in organic molecules, reactive surfaces and interfaces of func-
tional materials. It is to be noted that the SD transfer at fast spinning (>60
kHz MAS) may also be influenced by the chemical shift offset difference
particularly when there is a small range of chemical-shift differences in
the ¹H MAS spectra. It can be compensated by the addition of a spin lock,
<figure><img src="image_11.png" /><figcaption>**Fig. 8.** Two-dimensional ¹H–³⁵Cl correlation spectra with skyline projection of dopamine·HCl acquired at 18.8 T and 62.5 kHz MAS with (a) conventional HMQC and (b) HMQC-SD-RFDR pulse sequences with SR4 recoupling of 1024 µs and τ<sub>RFDR</sub> of 304 µs? In both cases, data were acquired with 128 coadded transients and 80 t₁ FIDs, corresponding to a total experimental time of 8.5 h each. The base contour levels are at 3% of the maximum peak height. A schematic representation of crystal packing in periodic DFT geometry optimized structures illustrating the short- and long-range interactions probed by the HMQC and HMQC-SD-RFDR approaches. Specifically, spheres represent the ¹H–³⁵Cl proximities within a distance of (a) 2.2 Å and (b) 3.7 Å.</figcaption></figure>

although the short T₁ρ of protons allows only short mixing times to be
applied and long mixing times often reduce sensitivity. Reverse
amplitude-modulated mixed rotational and rotary-resonance (AM-MIR-
OR) sequences can be tailored to compensate for offsets in the relevant
range of chemical-shift differences, and these sequences also offer rela-
tively high sensitivity compared to other sequences [84]. In addition, the
reverse AM-MIRROR sequence requires lower rf fields than RFDR, and the
optimum rf frequencies do not depend on the MAS frequency but only on
the recoupled chemical-shift range.

4. Conclusions

This study presents a 2D HMQC-SD-RFDR experiment for probing the ¹H–¹H and ¹H–X (here, X = ¹⁴N and ³⁵Cl) proximities in small organic molecules. A detailed analysis of 1D and 2D HMQC-SD-RFDR spectra is presented for L-histidine·HCl·H₂O and dopamine·HCl. The 1D version of the SD-HMQC sequence leads to spectral simplification by detecting ¹H {¹⁴N} and ¹H{³⁵Cl} peaks for protons that are either J-coupled or dipolar coupled with ¹⁴N or ³⁵Cl sites. By introducing an SD-RFDR block, ¹H peaks associated with ¹⁴N–¹H–¹H and ³⁵Cl–¹H–¹H sites can be selectively excited and detected through relay transfer. Therefore, the spectral simplification in 1D spectra can be achieved by tuning the heteronuclear recoupling durations within the HMQC block as well as the spin diffusion time in the RFDR blocks. This can be simply achieved through the one-dimensional version of the proposed experiment. More elaboratively, the proposed experiments can be used to acquire 2D ¹⁴N- filtered ¹H–¹H spin-diffusion spectra and ¹H–¹⁴N or ³⁵Cl–¹H correlation NMR spectra. Specifically, the 2D ¹H–¹⁴N D-HMQC-SD-RFDR correla- tion experiment demonstrates a strong ability for observing remote ¹⁴N–¹H correlations for which the N–H distances exceed 4 Å, which is difficult to achieve with the conventional ¹H–¹⁴N HMQC experiment. The proposed approach particularly benefits from using higher magnetic field strengths under fast MAS conditions.

Declaration of competing interest

The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.

Data availability

Data will be made available on request.

Acknowledgements

This work is supported by EU-H2020 research and innovation pro-
gramme under the Marie Skłodowska-Curie Grant 795091. G.N.M.R.
and S.P.B. acknowledge funding from the UK Engineering and Physical
Sciences Research Council (EPSRC, EP/K003674/1). The authors thank
the Chevreul Institute (FR 2638), supported by the Ministère de l'En-
seignement Supérieur et de la Recherche et de l'Innovation, CNRS,
Région Hauts-de-France, Métropole Européenne de Lille, and the EU
regional development funds. Financial support from the IR INFRANA-
LYTICS FR2054 for conducting the research is gratefully acknowledged.
For DFT calculations, computational resources were partially provided
by the Polish Infrastructure for Supporting Computational Science in the
European Research Space (PL-Grid). Y.N. acknowledges the support of
JSPS KAKENHI Grant Number 20K05483 and by the JST-Mirai Program
(Grant No. JPMJMI17A2, Japan). The experimental and calculated data
can be downloaded from Warwick research active portal at http://wrap.
warwick.ac.uk/166510/.

**Appendix A. Supplementary data**

Supplementary data to this article can be found online at https://doi.
org/10.1016/j.ssnmr.2022.101808.

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