Homonuclear Dipolar Decoupling Research Articles

Slice selection in low-temperature, DNP-enhanced magnetic resonance imaging by Lee-Goldburg spin-locking and phase modulation

Large enhancements in nuclear magnetic resonance (NMR) signals provided by dynamic nuclear polarization (DNP) at low temperatures have the potential to enable inductively-detected 1H magnetic resonance imaging (MRI) with isotropic spatial resolution on the order of one micron, especially when low temperatures and DNP are combined with microcoils, three-dimensional (3D) phase encoding of image information, pulsed spin locking during NMR signal detection, and homonuclear dipolar decoupling by Lee-Goldburg (LG) irradiation or similar methods. However, the relatively slow build-up of nuclear magnetization under DNP leads to very long acquisition times for high-resolution 3D images unless the sample volume or field of view (FOV) is restricted. We have therefore developed a method for slice selection in low-temperature, DNP-enhanced MRI that limits the FOV to about 50 μm in one or more dimensions. This method uses small-amplitude phase modulation of LG irradiation in the presence of a strong magnetic field gradient to invert spin-locked 1H magnetization in the selected slice. Experimental results are reported, including effects of radio-frequency field inhomogeneity, variations in the amplitude of phase modulation, and shaped phase modulation.

Static Solid Relaxation Ordered Spectroscopy: SS-ROSY

A two-dimensional pulse sequence is introduced for correlating nuclear magnetic resonance anisotropic chemical shifts to a relaxation time (e.g., T1) in solids under static conditions. The sequence begins with a preparatory stage for measuring relaxation times, and is followed by a multiple pulse sequence for homonuclear dipolar decoupling. Data analysis involves the use of Fourier transform, followed by a one-dimensional inverse Laplace transform for each frequency index. Experimental results acquired on solid samples demonstrate the general approach, and additional variations involving heteronuclear decoupling and magic angle spinning are discussed.

High-resolution 1H NMR of powdered solids by homonuclear dipolar decoupling.

The development of homonuclear dipolar decoupling sequences to obtain high-resolution 1H NMR spectra from solids has recently celebrated its 50th birthday. Over the years, a series of different decoupling schemes have been developed, starting with the pioneering Lee-Goldburg and WAHUHA sequences up to the most recent generation of experimentally optimized phase-modulated schemes such as eDUMBO-122 and LG4. These schemes can all yield over an order of magnitude reduction in 1H NMR linewidths in solids. Here we provide an overview and a broad experimental comparison of the performance of the main sequences, which has so far been absent in the literature, especially between the newest and the oldest decoupling schemes. We compare experimental results obtained using eight different decoupling schemes (LG, WHH-4, MREV-8, BR-24, FSLG/PMLG, DUMBO-1, eDUMBO-122 and LG4) on three different microcrystalline powdered samples (alanine, glycine and β-AspAla) and at three different MAS rates (3.0, 12.5 and 22.0 kHz). Finally, since these sequences can be technically demanding, we describe the experimental protocol we have used to optimize these schemes with the aim to provide simple guidelines for the optimization of CRAMPS experiments for all NMR users.

Simultaneous homonuclear and heteronuclear spin decoupling in magic-angle spinning solid-state NMR

We show here an effective way of implementing simultaneously homonuclear and heteronuclear dipolar decoupling in magic-angle spinning (MAS) solid-state NMR. Whilst the homonuclear spin decoupling is applied on the 1H channel, heteronuclear spin decoupling is applied on the 13C channel. The 1H spins are observed in a windowed fashion in this case. The resultant 1H spectrum has higher resolution due to the attenuation of broadening arising from both homonuclear 1H-1H and heteronuclear 1H-13C interactions, with the latter normally leading to additional line broadening in 13C labelled samples. The experiments are performed at MAS frequencies of ca. 60 kHz.

Revealing the Local Proton Network through Three-Dimensional 13C/1H Double-Quantum/1H Single-Quantum and 1H Double-Quantum/13C/1H Single-Quantum Correlation Fast Magic-Angle Spinning Solid-State NMR Spectroscopy at Natural Abundance.

1H double quantum (DQ)/1H single quantum (SQ) correlation solid-state NMR spectroscopy is widely used to obtain internuclear 1H-1H proximities, especially at fast magic-angle spinning (MAS) rate (>60 kHz). However, to date, 1H signals are not well-resolved because of intense 1H-1H homonuclear dipolar interactions even at the attainable maximum MAS frequencies of ∼100 kHz and/or under 1H-1H homonuclear dipolar decoupling irradiations. Here we introduce novel three-dimensional (3D) experiments to resolve the 1H DQ/1H SQ correlation peaks using the additional 13C dimension. Although the low natural abundance of 13C (1.1%) significantly reduces the sensitivities, the 1H indirect measurements alleviate this issue and make this experiment possible even in naturally abundant samples. The two different implementations of 13C/1H DQ/1H SQ correlations and 1H DQ/13C/1H SQ correlations are discussed and demonstrated using l-histidine·HCl·H2O at natural abundance to reveal the local 1H-1H networks near each 13C. In addition, the complete 1H resonance assignments are achieved from a single 3D 13C/1H DQ/1H SQ experiment. We have also demonstrated the applicability of our proposed method on a biologically relevant molecule, capsaicin.

Solid-state NMR analysis of a complex crystalline phase of ronacaleret hydrochloride.

A crystalline phase of the pharmaceutical compound ronacaleret hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) spectroscopy and single-crystal X-ray diffraction. The crystal structure is determined to contain two independent cationic molecules and chloride anions in the asymmetric unit, which combine with the covalent structure of the molecule to yield complex SSNMR spectra. Experimental approaches based on dipolar correlation, chemical shift tensor analysis, and quadrupolar interaction analysis are employed to obtain detailed information about this phase. Density functional theory (DFT) calculations are used to predict chemical shielding and electric field gradient (EFG) parameters for comparison with experiment. (1)H SSNMR experiments performed at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling provide information about hydrogen bonding and molecular connectivity that can be related to the crystal structure. (19)F and (13)C assignments for the Z' = 2 structure are obtained using DFT calculations, (19)F homonuclear dipolar correlation, and (13)C-(19)F heteronuclear dipolar correlation experiments. (35)Cl MAS experiments at 16.4 T observe two chlorine sites that are assigned using calculated chemical shielding and EFG parameters. SSNMR dipolar correlation experiments are used to extract (1)H-(13)C, (1)H-(15)N, (1)H-(19)F, (13)C-(19)F, and (1)H-(35)Cl through-space connectivity information for many positions of interest. The results allow for the evaluation of the performance of a suite of SSNMR experiments and computational approaches as applied to a complex but typical pharmaceutical solid phase.

Homonuclear Decoupling of 1H Dipolar Interactions in Solids by means of Heteronuclear Recoupling

AbstractLine narrowing has been traditionally achieved in solid‐state 1H NMR spectroscopy by applying pulse sequences that combine multiple‐pulse operations with magic‐angle spinning (MAS), to effectively average out the dipoledipole homonuclear Hamiltonian. The present study explores a new alternative that departs from the usual concept of directly acting on the strongly coupled spins with radiofrequency pulses; instead, we seek to achieve a net homonuclear dipolar decoupling in solids by exploring the reintroduction of MAS‐averaged heteronuclear dipolar couplings between the 1H nuclei and directly bonded 13C or 15N nuclei. This recouplinganti‐recoupling (RaR) scheme thus relies on the recoupling of the dipolar interaction with heteronuclear spins, which, under fast MAS, will exceed the strength and will not commute with the homonuclear 1H1H coupling one is intending to average out. Subsequent removal (“antiRecoupling”) of these heteronuclear interactions can lead to narrowed 1H resonances, without ever pulsing on the aforementioned channel. The line‐narrowing properties of RaR are illustrated with numerical simulations and with experiments on model organic solids.

High‐Resolution 1H Solid‐State NMR Spectroscopy Using Windowed LG4 Homonuclear Dipolar Decoupling

AbstractWe investigate the optimal implementation of windowed LG4 decoupling for the direct acquisition of high‐resolution 1H solid‐state NMR spectra in the moderate magic‐angle spinning regime (ωr<2π × 35 kHz). We determine how the optimal value of the azimuth of the LG rotation axis, α, is affected by the choice of windowing parameters. We find that for both the windowless and windowed implementation of LG4, the optimal value of α is that for which the chemical‐shift scaling factor is approximately 0.43. We then provide an analytical expression for estimating the chemical‐shift scaling factor as a function of both α and the windowed decoupling parameters, which allows the optimal value of α to be easily determined for any implementation of LG4. We also introduce a simple and general method for improving the performance of any phase‐modulated homonuclear dipolar decoupling sequence by compensating for pulse imperfection errors that accumulate in windowed spectra due to the repeated switching of the RF irradiation. This method involves the introduction of short (<0.5 µs) compensation pulses at the start and end of each decoupling pulse, the duration and phase of which are chosen to cancel the effects of the amplitude and phase transients that arise as a result of the RF switching. We demonstrate how this method can be implemented for homonuclear dipolar decoupling sequences such as wPMLG and wLG4 to reduce the chemical‐shift scaling factor distortions generated by phase transients such that high‐quality, high‐resolution 1H NMR spectra can be acquired at arbitrary RF offsets.

Solid-State NMR Analysis of a Boron-Containing Pharmaceutical Hydrochloride Salt

A novel crystalline form of the boron-containing antibacterial drug (S)-3-(aminomethyl)-7-(3-hydroxypropoxy)benzo[c] [1,2]oxaborol-1(3H)-ol hydrochloride is studied by solid-state nuclear magnetic resonance (SSNMR) and single-crystal X-ray diffraction techniques. After determination of the crystal structure by X-ray diffraction, SSNMR spectroscopy of this form is performed to obtain structural information using experimental approaches based on dipolar correlation, chemical shift analysis, and quadrupolar interaction analysis. 1H SSNMR experiments at 16.4 T using magic-angle spinning (MAS) and homonuclear dipolar decoupling, 2D SSNMR experiments based on (1)H–(13)C and (1)H–(11)B dipolar heteronuclear correlation, and density functional theory (DFT) calculations are combined in a novel approach to obtain a nearly complete assignment of the (1)H spectrum of this crystalline phase. (11)B and (35)Cl chemical shift and quadrupolar parameters are obtained using the analysis of MAS spectra and are found to be accurately reproduced using DFT calculations. NMR chemical shielding and electric field gradient parameters obtained using these methods are related to hydrogen-bonding trends in the crystal structure. The results illustrate the increasing capability of SSNMR techniques involving (1)H, (11)B, and (35)Cl SSNMR in the analysis of the crystal structure of a pharmaceutical compound containing covalently bonded boron.

Selective inversion of 1H resonances in solid-state nuclear magnetic resonance: Use of double-DANTE pulse sequence

We here present a method based on DANTE pulses and homonuclear dipolar decoupling scheme to invert selectively any desired resonance in a proton spin system under magic-angle spinning. Experimental results are reported on a sample of L-histidine·HCl·H2O at magic-angle spinning frequencies of 15 and 60kHz. The results are also substantiated numerically.

Improved Phase-Modulated Homonuclear Dipolar Decoupling for Solid-State NMR Spectroscopy from Symmetry Considerations

We explore the effects of symmetry on the performance of phase-modulated homonuclear dipolar decoupling in (1)H solid-state NMR. We demonstrate that the symmetry of the DUMBO family of decoupling sequences is the result of two well-defined symmetry expansions. The first is an antipalindromic expansion that arises from the symmetrization step that was built into the original architecture of the DUMBO sequence. The second is a mirror-pair expansion that inverts the sign of the phase modulation in the second half of the pulse sequence relative to the first. The combination of these two symmetry expansions generates a sequence of four Lee-Goldburg-type rotations in the rotating frame. The axes of rotation, oriented at the magic angle, are separated in the transverse plane by 2α, where α is chosen to minimize the sensitivity of the sequence to instrument imperfections such as rf inhomogeneity. The efficiency of the DUMBO symmetry for decoupling is demonstrated experimentally, and the effect of the α-phase-shift parameter is investigated. A new decoupling sequence (LG4) that combines the DUMBO symmetry with α = 55° is introduced and is shown to produce very efficient decoupling as well as a nearly 2-fold increase in coherence lifetimes when compared to standard PMLG/FSLG decoupling.

A common theory for phase-modulated homonuclear decoupling in solid-state NMR

We propose a new framework for homonuclear dipolar decoupling in solid-state NMR that provides a theoretical link between the FSLG, PMLG and DUMBO families. We show that through the use of a Legendre polynomial basis, the phase modulation of these decoupling schemes can be described by the same set of parameters, permitting for the first time a direct theoretical comparison between these methods. Use of this common basis reveals that the central decoupling mechanism is the same for DUMBO and FSLG/PMLG and that a similar vector picture can be used to describe both methods. In addition to the common root of decoupling efficiency, this new analysis highlights two major points of difference between the methods. First, the DUMBO phase modulation consists not only of a linear change in phase with time à la PMLG but also smaller high-order oscillations, which act to improve line-narrowing performance. Second, we show how the DUMBO phase waveforms are generated from a four-step permutation of a single asymmetric unit, in contrast to the two-step permutation of PMLG. Numerical simulations and experimental results suggest that this latter point of difference is responsible for the superior performance of DUMBO in the presence of significant RF inhomogeneity.

Practical choice of 1H– 1H decoupling schemes in through-bond 1H–{X} HMQC experiments at ultra-fast MAS

Three 1H– 1H homonuclear dipolar decoupling schemes for 1H indirect detection measurements at very fast MAS are compared. The sequences require the following conditions: (i) being operable at very fast MAS, (ii) a long T 2 ′ value, (iii) a large scaling factor, (iv) a small number of adjustable parameters, (v) an acquisition window, (vi) a low rf-power requirement, and (vii) a z-rotation feature. To satisfy these conditions a modified sequence named TIlted Magic-Echo Sandwich with zero degree sandwich pulse (TIMES 0) is introduced. The basic elements of TIMES 0 consist of one sampling window and two phase-ramped irradiations, which realize alternating positive and negative 360° rotations of 1H magnetization around an effective field tilted with an angle θ from the B 0 axis. The TIMES 0 sequence benefits from very large chemical shift scaling factors at ultra-fast MAS that reach κ cs = 0.90 for θ = 25° at ν r = 80 kHz MAS and only four adjustable parameters, resulting in easy setup. Long κ cs T 2 ′ values, where T 2 ′ is a irreversible proton transverse relaxation time, greatly enhance the sensitivity in 1H–{ 13C} through-bond J-HMQC (Heteronuclear Multiple-Quantum Coherence) measurements with 1H– 1H decoupling during magnetization transfer periods. Although similar sensitivity can be obtained with through-space D-HMQC sequences, in which 13C– 1H dipolar interactions are recoupled, J-HMQC experiments incorporating 1H– 1H decoupling benefit from lower t 1-noise, more uniform excitation of both CH, CH 2 and CH 3 moieties, and easier identification of through-bond connectivities.

A scaling factor theorem for homonuclear dipolar decoupling in solid-state NMR spectroscopy

A relationship between the dipolar and the chemical-shift scaling factors of cyclic radio-frequency irradiation schemes is introduced. This scaling factor theorem is derived analytically using Average Hamiltonian Theory, and its validity is illustrated numerically with homonuclear dipolar decoupling sequences generated randomly, and with the analysis of existing sequences. While derived for a static sample, the theorem provides insight into homonuclear dipolar decoupling schemes that combine radio-frequency irradiation with fast rotation of the sample at the magic-angle with respect to the static magnetic field.

A tunable homonuclear dipolar decoupling scheme for high-resolution proton NMR of solids from slow to fast magic-angle spinning

A homonuclear dipolar decoupling scheme is introduced for obtaining proton high-resolution NMR spectra of solids under slow to fast magic-angle spinning (MAS). The basic unit is an extension of magic-echo sequence with its effective field tilted in the rotating frame, bracketed by two sandwich pulses. The angle of the tilt can be tuned for obtaining optimal spectral resolution according to the spinning frequency. Improved resolution has been obtained using this tunable sequence on a sample of glycine at 10 and 60kHz of MAS compared with windowed phase-modulated Lee-Goldburg and magic-echo sandwich schemes.

Homonuclear dipolar decoupling with very large scaling factors for high-resolution ultrafast magic angle spinning 1H solid-state NMR spectroscopy

We present a new phase modulated radio-frequency pulse sequence for homonuclear dipolar decoupling in proton solid-state NMR spectroscopy, eDUMBO-PLUS-1, with a chemical shift scaling factor of 0.73. This sequence was determined by screening random sequences, and experimentally optimizing the best candidates directly on 1H NMR spectra with 60 kHz magic angle spinning. It yields efficient decoupling with linewidths as little as 150 Hz for 1.3 mm MAS probes on different spectrometers. Experiments and calculations support the hypothesis of a radio-frequency and MAS joint averaging regime, in which the large scaling factor contributes significantly to the overall performance of the decoupling sequence.

1H Homonuclear dipolar decoupling using symmetry-based pulse sequences at ultra fast magic-angle spinning frequencies

We demonstrate here the application of symmetry-based pulse sequences for homonuclear dipolar decoupling in solid-state NMR at magic-angle spinning (MAS) frequencies up to 65 kHz using moderate radiofrequency (RF) amplitudes. Theoretical arguments favouring the requirement of low RF amplitudes at high MAS frequencies are given for these sequences. A comparison with w PMLG mm x x ¯ is given at 65 kHz of MAS frequency to emphasise that the symmetry-based pulse sequences have a lower RF amplitude requirement at high MAS frequencies.

1H homonuclear dipolar decoupling using rotor-synchronised pulse sequences: Towards pure absorption phase spectra

We demonstrate a pulse sequence using symmetry-based rotor-synchronised RN n ν sequences for homonuclear dipolar decoupling that achieves pure absorption phase high-resolution 1H spectra in solid-state NMR. This sequence is compared with the phase-modulated Lee-Goldburg scheme. Experimental results are shown for samples of glycine and l-histidine·HCl·H 2O for magic-angle-spinning frequencies in the range of 14–30 kHz and at two different magnetic fields.

Homonuclear dipolar decoupling under fast MAS: Resolution patterns and simple optimization strategy

A simple method is shown for optimization of 1H homonuclear dipolar decoupling at MAS rates exceeding 10 kHz. By monitoring the intensity of a spin-echo under the decoupling conditions, it is possible to optimize the amplitude of the RF magnetic field, the cycle time of the decoupling sequence and the resonance offset within minutes. As a result, the decoupling efficiency can be quickly and reliably fine-tuned without using a reference sample. The utility of this method has been confirmed by studying the resolution patterns for the supercycled PMLG scheme, which were found to be in excellent agreement with earlier theoretical predictions and verified in high-resolution 2D 1H– 1H experiments.

Indirect Detection via Spin-1/2 Nuclei in Solid State NMR Spectroscopy: Application to the Observation of Proximities between Protons and Quadrupolar Nuclei

We present a comprehensive comparison of through-space heteronuclear correlation techniques for solid state NMR, combining indirect detection and single-channel recoupling method. These techniques, named D-HMQC and D-HSQC, do not suffer from dipolar truncation and can be employed to correlate quadrupolar nuclei with spin-1/2 nuclei. The heteronuclear dipolar couplings are restored under magic-angle spinning by applying supercycled symmetry-based pulse sequences (SR412) or simultaneous frequency and amplitude modulation (SFAM). The average Hamiltonian theory (AHT) of these recoupling methods is developed. These results are applied to analyze the performances of D-HMQC and D-HSQC sequences. It is shown that, whatever the magnitude of spin interations, D-HMQC experiment offers larger efficiency and higher robustness than D-HSQC. Furthermore, the spectral resolution in both dimensions of proton detected two-dimensional D-HMQC and D-HSQC spectra can be enhanced by applying recently introduced symmetry-based homonuclear dipolar decoupling schemes that cause a z-rotation of the spins. This is demonstrated by 1H-13C and 1H-23Na correlation experiments on l-histidine and NaH2PO4, respectively. The two-dimensional heteronuclear 1H-23Na correlation spectrum yields the assignment of 23Na resonances of NaH2PO4. This assignment is corroborated by first-principles calculations.