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Absolute configuration of chirally deuterated neopentane

Abstract

The relationship between macroscopic chirality and chirality on the molecular level was unequivocally established in 1951 through anomalous X-ray scattering1. Although this technique became the definitive method for determining the absolute configuration of a molecule, one important limitation of the approach is that the molecule must contain ‘heavy’ atoms (for example, bromine). The direct determination of absolute configurations for a wider range of molecules has recently become possible by measuring a molecule’s vibrational optical activity2,3. Here we show that instrumental advances in Raman optical activity4,5, combined with quantum chemical computations6,7,8, make it possible to determine the absolute configuration of (R)-[2H1, 2H2, 2H3]-neopentane9. This saturated hydrocarbon represents the archetype of all molecules that are chiral as a result of a dissymmetric mass distribution. It is chemically inert and cannot be derivatized to yield molecules that would reveal the absolute configuration of the parent compound. Diastereomeric interactions with other molecules, optical rotation, and electronic circular dichroism are, in contrast to the well-known case of bromochlorofluoromethane10,11,12, not expected to be measurable. Vibronic effects in the vacuum ultraviolet circular dichroism might reveal that the molecule is chiral, but the presence of nine rotamers would make it extremely difficult to interpret the spectra, because the spatial arrangement of the rotamers’ nuclei resembles that of enantiomers. The unequivocal spectroscopic determination of the absolute configuration of (R)-[2H1, 2H2, 2H3]-neopentane therefore presented a major challenge, one that was at the very limit of what is possible.

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Figure 1: Synthetic route to chirally deuterated neopentane 1.
Figure 2: 13 C-NMR characterization of the quaternary centre.
Figure 3: ROA spectra of ( R)-[2H1, 2H2, 2H3]-neopentane.
Figure 4: Raman spectra of ( R)-[2H1, 2H2, 2H3]-neopentane.

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Acknowledgements

We thank F. Nydegger and F. Fehr for their analytical work. This work was supported by the Swiss National Science Foundation.

Author Contributions W.H. developed the design of the instrument. J.H. constructed the spectrometer used in this work and performed the ROA measurements. J.H. and I.S. isolated the sample in the capillary. J.H. performed the ab initio calculations. I.S. and E.R. performed and optimized the synthesis. C.G.B. designed the synthetic route. W.H. proposed this work. W.H. and C.G.B. wrote the paper. All authors discussed the results and commented on the manuscript.

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Correspondence to J. Haesler or W. Hug.

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S8 with Legends. Supplementary Figure S1 is a summary of the main findings. Supplementary Figure S2 shows the ratio Δ of ROA to Raman backscattering of (R)-[2H1, 2H2, 2H3]-neopentane and the degree of circularity. Supplementary Figure S3 shows an overview of the ROA spectrometer used in this work. This file also contains Supplementary Scheme S1 and Supplementary S2. Scheme S1 shows the intuitive conventional retrosynthetic analysis and Scheme S2 shows the synthetic route to chirally deuterated Neopentane. Finally, this file contains the synthetic protocols for all the intermediates and the detailed spectral data (1H-NMR, 13C-NMR, DEPT 135, 2H-NMR and MS-EI) for the characterization of (R)-[2H1, 2H2, 2H3]-neopentane (Figures S4-S8). (PDF 2760 kb)

Supplementary Data 1

This file contains Supplementary Data 1 with the spectral data for (4S)-Tiglyloxazolidinone 4, Oxazolidinone 5 and Alcohol 6. (PDF 3903 kb)

Supplementary Data 2

This file contains Supplementary Data 2 with the spectral data for Diol 7, Dimesylate 8 and Neopentane 1. (PDF 3098 kb)

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Haesler, J., Schindelholz, I., Riguet, E. et al. Absolute configuration of chirally deuterated neopentane. Nature 446, 526–529 (2007). https://doi.org/10.1038/nature05653

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