Monitoring Mechanistic Details in the Synthesis of Pyrimidines via Real-Time, Ultrafast Multidimensional NMR Spectroscopy

Abstract

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.

On‐Line Monitoring of Chemical Reactions by using Bench‐Top Nuclear Magnetic Resonance Spectroscopy

“…The AP signals can only be seen after zooming into the spectrum (Figure 4 b). The spectral position of the signal corresponding to the aliphatic protons of AP is exactly in the middle of the 13 C NMR satellites of the methyl peak of isopropanol. As the natural abundance of the 13 C isotope is 1 %, their intensity is 0.56 % of the main signal, which can be used as a reference to appreciate the low concentration of AP and highlights the sensitivity of the instrument.…”

“…Some of the advantages that make NMR spectroscopy very attractive for real-time studies are that it is highly chemically specific, sensitive to all chemical groups, and that the signal is directly proportional to molecular concentration, requiring only a simple calibration that is valid for every reaction and all solvents. [6][7][8][9][10][11][12][13] In view of this it is striking to see that NMR spectroscopy is the only method that has not reached the degree of compactness required for use in the chemistry laboratory where the reactions are safely run. This is so because conventional high-field NMR spectrometers use large and expensive superconducting magnets to generate the very strong and highly homogeneous magnetic fields required to maximize sensitivity and spectral resolution.…”

Applications of high dimensionality experiments to biomolecular NMR

“…The majority of early attempts at real-time NMR [71][72][73][74][75][76][77] did not employ NUS. However, later it was demonstrated that fast NMR methods can also benefit from NUS, e.g., for…”

Optimization and practical implementation of ultrafast 2D NMR experiments

“…36 These values seem quite high, but lower concentrations are easily reached by signal averaging, a "multi-scan single shot" approach whose potentialities have been recently demonstrated. 37 Following these developments, ultrafast NMR has been recently applied to a variety of situations, such as monitoring of fast organic reactions, 28,38 the study of biologically relevant samples, 30,38 coupling with hyphenated techniques 39 and measurement of residual dipolar couplings in oriented media. 40 We are currently applying these experiments to the study of dynamic processes occurring on a very short timescale that could not hitherto be followed by any other kind of 2D NMR experiment.…”