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Assisted NMR Data Interpretation in Synthetic Chemistry

Authors: Johan Bartholoméüs1, Martine Monette2, Rajeev Kumar2, Sandra Groscurth3, Hélène Lebel1.

1 Universite de Montreal, 2 Bruker BioSpin Canada, 3 Bruker BioSpin Switzerland

One of Prof. Lebel’s current research topics aims to synthesize chiral amines via a C-H insertion reaction, using a novel chiral N-methanesulfony- loxycarbamate [1].

For instance, reaction of alkyne 1 with reagent 2 in the presence of a chiral rhodium dimer led to chiral amine 3 in good yields and high stereoselectivity (See Figure 1).

Figure 1: Stereoselective and regioselective rhodium-catalyzed propargylic C–H amination reaction
Figure 1: Stereoselective and regioselective rhodium-catalyzed propargylic C–H amination reaction

As these propargylic C-H amination reactions typical yield around 60-65% of the desired product, they looked at the by-products formed during this reaction. One of them was isolated in the 5-10% yield.

As 1H NMR spectra reveals the presence of the ethyl group, as well as the proton alpha to the CCl3 group, they hypothesized a reaction with the alkyne moiety to form 1H-azirine 4, which is known to rearrange and form the corresponding oxazole 5. The full interpretation of the NMR spectra would have been quite complex, and giving the small amount of material obtained (few mg) the suitable crystals for X-ray crystal structure analysis would have been particularly challenging.

In order to support the chemist in this complex but essential routine task, Bruker developed powerful software tools for interactive and assisted NMR data analysis.

In most cases, verification of reaction products is based on molecular mass determination and the interpretation of NMR spectra, typically 1D proton spectra. With the aid of Bruker’s CMC-assist software solution, these 1D proton spectra can be processed and analyzed at the push of a button. Instead of having to concentrate on the appropr- iate processing method and then having to analyze the spectrum manually step by step, the CMC-assist software performs these tasks and provides a consistency statement within a few seconds.

In the case of the stereospecific reaction (Figure 1), the automated spectra interpretation first confirms that structure 3 and experimental data are not in agreement.

Figure 2: 1D 1H spectrum analyzed by the automated structure verification software CMC-assist. Although the signals in the spectrum do not match the expected molecular structure, the spectrum gets analyzed with respect to peak integration, proton number determination and multiplet analysis.
Figure 2: 1D 1H spectrum analyzed by the automated structure verification software CMC-assist. Although the signals in the spectrum do not match the expected molecular structure, the spectrum gets analyzed with respect to peak integration, proton number determination and multiplet analysis.

In order to identify the actual synthesized compound a complete structure elucidation was performed. Based on the information from additional NMR data such as 1D 13C, HSQC, HMBC and COSY spectra, the software CMC-se assists with the process of structure elucidation by analyzing the spectra automatically, translating the NMR correlations into atomic connectivities and proposing possible structures that fit all experimental data.

Although structure elucidation still requires some manual interaction, the software CMC-se speeds up the process significantly and provides a convenient tool to both handle the data and to identify the unknown structure.

Figure 3: Complete structure elucidation assisted by the software CMC-se.
Figure 3: Complete structure elucidation assisted by the software CMC-se.

In the case of the by-product obtained from the amination reaction, initially assigned as 5, CMC-se readily identified the actual synthesized compound. By providing the CMC-assist software with the newly identified reaction product, the automated structure verification then confirms the consistency of spectrum and structure.

1D 1H spectrum anayzed by the automated structure tool
Figure 4: 1D 1H spectrum analyzed by the automated structure verification software CMC-assist. The assignment can be visualized by hovering the mouse over any peak and the corresponding atom of the molecule will be highlighted. In order to document the spectrum interpretation, different reports can be generated and attached to the records in the lab notebook. In addition, the spectrum description can be readily exported as publication string in various journal formats.

Isocyanate 6a was assigned as the by-product, instead of the expected oxazole 5. This information was relevant to Prof. Lebel’s group, as it showed that the 1H-azirine 4 rearrange in an unexpected fashion, and thus could help them in designing novel reaction pathways.

This stereospecific organic reaction, performed at Prof. Lebel’s lab as part of her research on the development of novel synthetic strategies, represents a typical example of the daily work of a chemist.

Nowadays the chemistry underlying syntheses such as this is quite complex. Ideally the chemist should not be additionally occupied by the interpretation of the NMR data.

With the chemist in mind Bruker has further developed the software packages CMC-assist – for automated structure verification, and CMC-se – for computer aided structure elucidation. As shown by Prof. Lebel’s example, these software packages reliably analyze NMR spectra, significantly speeding up the process of analytical data interpretation.

1 – Lebel, H.; Trudel, C.; Spitz, C., Chem. Commun. 2012, 48, 7799.