Spatially encoded 2D and 3D diffusion-ordered NMR spectroscopy

Abstract

We show that the acquisition of 3D diffusion-ordered NMR spectroscopy (DOSY) experiments can be accelerated significantly with the use of spatial encoding (SPEN). The SPEN DOSY approach is discussed, analysed with numerical simulation, and illustrated on a mixture of small molecules.The analysis of complex mixtures of small molecules is a major challenge in chemistry, with applications in metabolomics, natural-product research and chemical synthesis. Nuclear magnetic resonance (NMR) spectroscopy is a powerful tool to address this challenge; arrays of NMR spectra are commonly used for identification and structure elucidation. A variety of schemes have been reported to recover the "pure" spectra of components in mixtures. 1 Diffusion-ordered spectroscopy (DOSY) is the most widely used approach for such spectral separation. 2 In DOSY, signal amplitudes are attenuated by a pair of gradient pulses (each of area K) separated by a diffusion delay; a fit of the diffusion-induced decay returns the diffusion coefficient D for each resonance, so that sub-spectra can be separated according to the value of D.The DOSY approach is applicable to a range of Ndimensional (ND, with N typically 1 or 2) NMR experiments. 2a, 3 The use of an incremented gradient area, however, results in a pseudo-(N+1)D experiment and increases the total experimental time by a factor of about 10. Several strategies have been described for the acceleration of DOSY experiments. The original HR-DOSY pulse sequence requires multiple steps of phase cycling, which may be reduced to one with the Oneshot approach. 4 The number of gradient increments can be reduced, using a non-uniform sampling of the diffusion dimension. 5 For 3D DOSY, the diffusion information may also be encoded in the width of the NMR peaks, with the accordion approach. 6 Single-scan DOSY implementations include the Difftrain approach, 7 which has found applications for the analysis of heterogeneous media. Alternatively, the acquisition of the DOSY data may be parallelised, with a spatial encoding of the K dimension. 8 This concept, introduced by Keeler and co-workers, makes it possible to acquired 2D DOSY data in a single scan. It is particularly useful for the analysis of transient processes and hyperpolarised samples. 9 In this communication, we show that spatially encoded diffusion-ordered spectroscopy (SPEN DOSY) can be used for fast separation of 2D correlation spectra of components in mixtures. In order to gain insight into the SPEN DOSY mechanism, we first introduce a numerical simulation framework that can simultaneously account for the complex spin and spatial dynamics. We then describe a generalised implementation of SPEN DOSY. As an example of SPEN 3D DOSY, the acquisition of a 3D DOSY COSY spectrum is accelerated by over an order of magnitude. Figure 1a shows a schematic pulse sequence for spatially encoded multidimensional DOSY experiments. The gradient pulses of the classic STE-based DOSY pulse sequence are replaced with the concurrent application of linearly swept chirp ...

Acceleration of 3D DOSY NMR by Spatial Encoding of the Chemical Shift

“…[22] (in particular, a figure analogous to Figure 4, using SPEN DOSY COSY instead of ufCOSY-DOSY, may be found in Figure 2 of Ref. While the latter is described here, the former was recently reported in Ref.…”

“…For 2D NMR, the fastest methods rely on spatial encoding of the indirect dimension, as proposed by Frydman and co-workers for indirect spectral dimensions [12][13][14] and Keeler and co-workers for the diffusion dimension. It has already been studied for 2D experiments such as COSY, [17] J-resolved, [18] DQS [19,20] and also with pseudo 2D experiments such as DOSY [21,22] or diffusion-relaxation correlation experiments. It has already been studied for 2D experiments such as COSY, [17] J-resolved, [18] DQS [19,20] and also with pseudo 2D experiments such as DOSY [21,22] or diffusion-relaxation correlation experiments.…”

“…It has already been studied for 2D experiments such as COSY, [17] J-resolved, [18] DQS [19,20] and also with pseudo 2D experiments such as DOSY [21,22] or diffusion-relaxation correlation experiments. [22] In this paper, we show that the acquisition of 3D DOSY spectra can be accelerated by one order or magnitude or more, with spatial encoding of the indirect spectral dimension. [22] In this paper, we show that the acquisition of 3D DOSY spectra can be accelerated by one order or magnitude or more, with spatial encoding of the indirect spectral dimension.…”

DOSY Analysis of Micromolar Analytes: Resolving Dilute Mixtures by SABRE Hyperpolarization

“…Furthermore,the two pairs of isomeric alkyl pyridines 2-3 and pyrazines 4-5 are clearly resolved. We acknowledge that the approach is limited to analytes that can reversibly bind the iridium-based SABRE catalyst, however, key analytical applications within this realm have been demonstrated [9a-b] and are poised to grow.W ithout SABRE and its corresponding (100 +)-fold sensitivity gains,D OSY analysis of low-micromolar mixtures would not be feasible.F urthermore,a dditional gains will be straightforward to achieve in this framework by moving to > 90 % pH 2 .C ombining the present approach with recent advances in single-scan DOSY [16] could allow < 1min measurement times,b ut the spatial encoding employed in such experiments would reduce sensitivity with ac orresponding tradeoff on the detection limit of SABRE-DOSY.T he resolution and sensitivity of the method herein provide an important new piece in the toolbox for mixture analysis by NMR spectroscopy and take steps forward in the everexpanding fields of DOSY and nuclear hyperpolarization. [24] Finally,aremaining problem is that one of the peaks from 5 (asterisk in Figure 2) overlaps with ac atalyst-mtz signal ( Figure S4) and does not properly correlate with other resonances from 5.R esolving such overlap is aw ell-recognized issue in DOSY that could potentially be solved by more advanced data processing techniques.…”

“…[13] Figure 1d epicts the aromatic region of as ingle-scan SABRE spectrum of am ixture of six dilute analytes.T he molecules 1-6 and similar analogues occur as low-micromolar concentration flavor components in food extracts, [14] but spectral elucidation of their mixtures is complicated if based on 1D spectra alone.Herein, we overcome this challenge with anew method that combines SABRE with DOSY to resolve the signals of analytes 1-6 at low-micromolar concentrations. [13] Single-scan diffusion NMR techniques are not applicable for this purpose,s ince these either sacrifice resolution for measurement time, [15] have reduced sensitivity due to spatial encoding, [16] or are not compatible with the T 1 relaxation rate of 1 Hn uclei. SABRE hyperpolarization.…”