Recent years have witnessed unprecedented advances in the development of fast multidimensional NMR acquisition techniques. This progress could open valuable new opportunities for the elucidation of chemical and biochemical processes. This study demonstrates one such capability, with the first real-time Two-dimensional (2D) dynamic analysis of a complex organic reaction relying on unlabeled substrates. Implementing such measurements required the development of new ultrafast 2D methods, capable of monitoring multiple spectral regions of interest as the reaction progressed. The alternate application of these acquisitions in an interleaved, excitation-optimized fashion, allowed us to extract new structural and dynamic insight concerning the reaction between aliphatic ketones and triflic anhydride in the presence of nitriles to yield alkylpyrimidines. Up to 2500 2D NMR data sets were thus collected over the course of this nearly 100 min long reaction, in an approach resembling that used in functional magnetic resonance imaging. With the aid of these new frequency-selective low-gradient strength experiments, supplemented by chemical shift calculations of the spectral coordinates observed in the 2D heteronuclear correlations, previously postulated intermediates involved in the alkylpyrimidine formation process could be confirmed, and hitherto undetected ones were revealed. The potential and limitations of the resulting methods are discussed.

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...

Ultrafast 2D HMBC spectroscopy permits real-time monitoring of a reaction based on the structural changes produced in a carbonyl carbon atom. This new technique was used to study the reaction of ketones, nitriles, and Tf(2)O, affording relevant information about new intermediates and kinetic data.

Ultrafast NMR spectroscopy (UF-NMR) can be used to monitor chemical reactions in real time and to provide insights into their mechanisms and the nature of the intermediates formed. Here, we have developed a 2D 1H,31P UF-HMBC method and the corresponding NMR experimental setup to enable the study of a Michaelis–Arbuzov reaction at two different temperatures, 25 and 70 °C. The specific reaction studied was between triethyl phosphite and benzyl bromide to produce diethylbenzyl phosphonate. Our results show that at 70 °C the reaction takes place directly, without the detection of an intermediate by 1H,31P UF-HMBC. In contrast, at 25 °C, using zinc bromide as a catalyst, our results show the formation of benzyltriethoxy phosphonium bromide as an intermediate. The experiments again show the power of UF-NMR in mechanistic studies of reactions involving various phosphorus chemical species.

The reaction of equimolecular amounts of a nitrile and triflic anhydride or triflic acid at low temperature produces an intermediate nitrilium salt that subsequently reacts with 2 equiv of a different nitrile at higher temperature to form 2,4-disusbstituted-6-substituted 1,3,5-triazines in moderate to good yields. This synthetic procedure has also been applied to the preparation of a 1,3,5-triazine having three different substituents. The results are explained in terms of a mechanism based on the relative stability of the intermediate nitrilium salts that are formed through a reversible pathway. The formation of a substituted isoquinoline using benzyl cyanide as the second nitrile supports the postulated mechanism as well as the structure of derivatives of the proposed intermediate when the reaction is carried out in the presence of different nucleophiles other than nitriles. Theoretical calculations and the monitoring of the reaction using (1)H and (13)C NMR spectroscopy are in agreement with the proposed mechanism pathway.