Real‐Time Monitoring of Organic Reactions with Two‐Dimensional Ultrafast TOCSY NMR Spectroscopy

Abstract

Multidimensional nuclear magnetic resonance plays a number of essential roles in present day spectroscopy. It is also an integral part of the image formation protocol in magnetic resonance imaging (MRI).[1] Traditional two-dimensional experiments are intrinsically time consuming, because many t 1 increments have to be acquired to obtain twodimensional spectra with adequate digital resolution in the indirect dimension.[2] Proposals for accelerating multidimensional NMR spectroscopy include non-Fourier transform schemes, [3] the acquisition of multiple NMR spectra in a single experiment, [4] and "single scan" multidimensional NMR spectroscopy, also called ultrafast NMR spectroscopy (UF NMR), have been introduced. The latter methodology was inspired by echo planar imaging (EPI) [5] and was developed by Frydman et al. [6] It permits the collection of complete multidimensional NMR data sets within a single continuous acquisition. This new methodology is compatible with existing standard (TOCSY, HSQC, MRI) and recently described combined multidimensional pulse sequences, [7] and it can be implemented with conventional hardware. This attractive feature enables ultrafast NMR to examine dynamic processes, that is, organic reactions and their mechanisms as they happen in real time.[8] Figure 1 shows the schematic of the two-dimensional UF-TOCSY sequence used.[9] The sequence uses a continuous spatial encoding [10] which was implemented by pairs of RF pulses which excite/store spins over the full length, L, of the sample. The sample was swept over intervals t 1 max /2 whereas AE G e external gradients were applied. The offsets of such pulses were thus chirped over a AE gG e L/2 span, and their amplitudes calibrated as effective p/2 nutations by setting gB 1 as a function of 0.25 [(2 gG e L/t 1 max )] 1/2 .We focused our attention on one-pot syntheses of pyrimidines and similar heterocyclic compounds, which we had previously developed. [11] Pyrimidines are an important class of compounds which includes numerous natural, pharmaceutical, and functional materials.[12] Elegant new procedures have been described [13] and revealed decisive information on the mechanistic details of the reaction between carbonyl compounds and strong electrophiles such as trifluoromethanesulfonic acid anhydride (Tf 2 O). [11,14] In spite of the importance of these reactions, no spectroscopic confirmation of the postulated intermediates or kinetic data on the reaction have been reported.Using a medium field 500 MHz spectrometer, we have now applied UF NMR methodology to monitor the reaction between aliphatic ketones and Tf 2 O in the presence of nitriles. We have determined how the signals of the starting and final products evolve as they happen, in real time and attempted to detect the presence of intermediates. We chose a symmetric aliphatic ketone, 3-pentanone (1), as the model compound to react with a two-fold amount of Tf 2 O in [D 3 ]acetonitrile, which served as both a co-reactant and solvent.Scheme 1 shows the previously proposed reaction mec...

Fast access to residual dipolar couplings by single‐scan 2D NMR in oriented media

“…Also noticeable is the spatial apodization procedure that we recently developed to improve lineshape and sensitivity at no cost in terms of resolution . Thanks to these improvements, the performances of UF NMR have been notably increased, and in recent years, we have witnessed numerous practical applications of this methodology, from reaction monitoring to quantitative measurements in complex biological mixtures, while recent results have even paved the way towards in vivo UF spectroscopy …”

“…Although UF methods were investigated here with a focus on small organic molecules in organic solvents, they should be applicable to other classes of compounds and particularly in the biomolecular context, a field where the efficiency of UF 2D NMR has already been highlighted . UF 2D NMR also offers the possibility to perform real‐time measurement of RDCs on unstable compounds or on those undergoing chemical or biological reactions . Research along these avenues is currently under investigation.…”

Reverse detection for spectral width improvements in spatially encoded dimensions of ultrafast two-dimensional NMR spectra

“…Many improvements, including developments of the spatially encoded technique [5][6][7] and combinations with other techniques, [8][9][10] render the spatially encoded technique more effective and more widely applicable. The spatially encoded technique has demonstrated its feasibility and effectiveness in various systems and aspects including real-time detections of chemical reactions, [11][12][13] fast analyses of metabolites, [14] acquiring high-resolution spectra under inhomogeneous magnetic fields along with the intermolecular multiple-quantum coherence technique [15] or spin echo, [16,17] and fast localized study of biological tissues. [18] Significant applications to hyphenated techniques can also be found, including dynamic nuclear polarization, [19] chromatography [20] , etc.…”

Fast high-resolution J-resolved correlation spectroscopy in inhomogeneous fields

“…Nevertheless, conventional three-dimensional acquisition protocols introduce additional evolution delay and thus consume hours to record the data. As a means of spurring the 2D NMR detection, the spatial encoding technique, achieving a 2D NMR spectrum within a single scan, has been applied in real-time monitoring and dynamic detections [21][22][23][24]. In this study, associating with spatial encoding technique, we develop new pulse sequences capable of gaining high-resolution homonuclear correlation and JRES spectra simultaneously in inhomogeneous fields, within the time scale required for a conventional 2D spectrum.…”