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All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexane

Nature Chemistry volume 7, pages 483–488 (2015)Cite this article

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Abstract

The highest-energy stereoisomer of 1,2,3,4,5,6-hexafluorocyclohexane, in which all of the fluorines are ‘up’, is prepared in a 12-step protocol. The molecule adopts a classic chair conformation with alternate C–F bonds aligned triaxially, clustering three highly electronegative fluorine atoms in close proximity. This generates a cyclohexane with a high molecular dipole (μ = 6.2 D), unusual in an otherwise aliphatic compound. X-ray analysis indicates that the intramolecular Fax···Fax distances (∼2.77 Å) are longer than the vicinal Fax···Feq­ distances (∼2.73 Å) suggesting a tension stabilizing the chair conformation. In the solid state the molecules pack in an orientation consistent with electrostatic ordering. Our synthesis of this highest-energy isomer demonstrates the properties that accompany the placement of axial fluorines on a cyclohexane and the unusual property of a facially polarized ring in organic chemistry. Derivatives have potential as new motifs for the design of functional organic molecules or for applications in supramolecular chemistry design.

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Figure 1: Structures and relative energies of all isomers of 1,2,3,4,5,6-hexafluorocyclohexane.
Figure 2: Synthetic route to all-cis 1,2,3,4,5,6-hexafluorocyclohexane 1.
Figure 3: 19F{1H} NMR spectra of all-cis 1,2,3,4,5,6-hexafluorocyclohexane 1.
Figure 4: Different representations of all-cis 1,2,3,4,5,6-hexafluorocyclohexane 1.
Figure 5: Representation of the crystal packing structure of 1, derived from single-crystal X-ray data.
Figure 6: Representation of the two-dimensional structure of C2F chair graphene21.

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References

  1. Fier, P. S. & Hartwig, J. F. Selective C–H fluorination of pyridines and diazines inspired by a classic amination reaction. Science 342, 956–960 (2013).

    Article  CAS  Google Scholar 

  2. Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317, 1881–1886 (2007).

    Article  Google Scholar 

  3. Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications 2nd edn (Wiley-VCH, 2013).

    Book  Google Scholar 

  4. O'Hagan, D. Understanding organofluorine chemistry. An introduction to the C–F bond. Chem. Soc. Rev. 37, 308–319 (2008).

    Article  CAS  Google Scholar 

  5. Biffinger, J. C., Kim, H. W. & DiMagno, S. G. The polar hydrophobicity of fluorinated compounds. ChemBioChem 5, 622–627 (2004).

    Article  CAS  Google Scholar 

  6. Burns, M. et al. Assembly-line synthesis of organic molecules with tailored shape. Nature 513, 183–188 (2014).

    Article  CAS  Google Scholar 

  7. Hunter, L., Kirsch, P., Slawin, A. M. Z. & O'Hagan, D. Synthesis and structure of stereoisomeric multivicinal hexafluoroalkanes. Angew. Chem. Int. Ed. 48, 5457–5460 (2009).

    Article  CAS  Google Scholar 

  8. Barton, D. H. R. The conformation of the steroid nucleus. Experientia 6, 316–320 (1950).

    Article  CAS  Google Scholar 

  9. Durie, A. J., Slawin, A. M. Z., Lebl, T., Kirsch, P. & O'Hagan, D. Synthesis and structure of all-syn-1,2,3,4-tetrafluorocyclohexane. Chem Commun. 47, 8265–8267 (2011).

    Article  CAS  Google Scholar 

  10. Durie, A. J., Slawin, A. M. Z., Lebl, T., Kirsch, P. & O'Hagan, D. Fluorocyclohexanes: synthesis and structure of all-syn-1,2,4,5-tetrafluorocyclohexane. Chem Commun. 48, 9643–9645 (2012).

    Article  CAS  Google Scholar 

  11. Durie, A. J., Slawin, A. M. Z., Lebl, T. & O'Hagan, D. The synthesis of η-1,2,3,4,5,6-hexafluorocyclohexane (benzene hexafluoride) from benzene. Angew. Chem. Int. Ed. 51, 10086–10088 (2012).

    Article  CAS  Google Scholar 

  12. Luo, Q., Randall, K. R. & Schaefer, H. F. Easy chairs: the conformational preference of polyfluorinated cyclohexanes. RSC Adv. 3, 6572–6585 (2013).

    Article  CAS  Google Scholar 

  13. Zdravkovski, Z. Theoretical study of the stability of hexachloro- and hexafluorocyclohexane isomers. Bull. Chem. Technol. Macedonia 23, 131–137 (2004).

    CAS  Google Scholar 

  14. Ogawa, S., Oki, S. & Suami, T. Inositol derivatives. 11. Synthesis of dianhydroinositols. Bull. Chem. Soc. Jpn 52, 1095–1111 (1979).

    Article  CAS  Google Scholar 

  15. Lal, G. S., Pez, G. P., Pesaresi, R. J. & Prozonic, F. M. Bis(2-methoxyethyl)aminosulfur trifluoride: a new broad-spectrum deoxofluorinating agent with enhanced thermal stability. Chem. Commun. 215–216 (1999).

  16. Middleton, W. J. New fluorinating reagents. Dialkylaminosulfur fluorides. J. Org. Chem. 40, 574–578 (1975).

    Article  CAS  Google Scholar 

  17. Beaulieu, F. et al. Aminodifluorosulfinium tetrafluoroborate salts as stable and crystalline deoxofluorinaing reagents. Org. Lett. 11, 5050–5053 (2009).

    Article  CAS  Google Scholar 

  18. Schmidt, M. W. et al. General atomic and molecular electronic structure system. J. Comput. Chem. 14, 1347–1363 (1993).

    Article  CAS  Google Scholar 

  19. Gordon, M. S. & Schmidt, M. W. in Theory and Applications of Computational Chemistry. The First Forty Years (eds Dykstra C. E., Frenking G., Kim K.S. & Scuseria, G. E.) Ch. 41 (Elsevier, 2005).

    Google Scholar 

  20. Dunitz, J. D. Organic fluorine: odd man out. ChemBioChem 5, 614–621 (2004).

    Article  CAS  Google Scholar 

  21. Kashtiban, R. J. et al. Atomically resolved imaging of highly ordered alternating fluorinated graphene. Nature Commun. 5, 4902 (2014).

    Article  CAS  Google Scholar 

  22. Sahin, H., Topsaka, M. & Ciraci, S. Structures of fluorinated graphene and their signatures. Phys. Chem. Rev. B 83, 115432 (2011).

    Article  Google Scholar 

  23. Goodman, L., Gu, H. & Pophristic, V. Gauche effect in 1,2-difluoroethane. Hyperconjugation, bent bonds, steric repulsion. J. Phys. Chem. A 109, 1223–1229 (2005).

    Article  CAS  Google Scholar 

  24. Perrin, C. L. & Dwyer, T. J. Application of two-dimensional NMR to kinetics of chemical exchange. Chem. Rev. 90, 935–967 (1990).

    Article  CAS  Google Scholar 

  25. Anet, F. A. L. & Bourn, A. J. R. Nuclear magnetic resonance line-shape and double-resonance studies of ring inversion on cyclohexane-d11 . J. Am. Chem. Soc. 89, 760–798 (1967).

    Article  CAS  Google Scholar 

  26. Badenhoop, J. K. & Weinhold, F. Natural bond order analysis of steric interactions. J. Chem. Phys. 107, 5406–5421 (1997).

    Article  CAS  Google Scholar 

  27. Glendening, E. D., Landis, C. R. & Weinhold, F. NBO 6.0: Natural bond orbital analysis program. J. Comput. Chem. 34, 1429–1437 (2013).

    Article  CAS  Google Scholar 

  28. Reed, A. E., Curtiss, L. A. & Weinhold, F. Intermolecular interactions from a natural bond orbital, donor–acceptor viewpoint. Chem. Rev. 88, 899–926 (1988).

    Article  CAS  Google Scholar 

  29. Weinhold, F. & Landis, C. R. Valency and Bonding: A Natural Bond Orbital Donor–Acceptor Perspective (Cambridge Univ. Press, 2005).

    Book  Google Scholar 

  30. Nelson, R. D., Lide, D. R. & Maryott, A. A. Selected Values of Electric Dipole Moments for Molecules in the Gas Phase (National Standards Reference Data Series 10, National Bureau of Standards, 1967).

  31. Haynes, W. M. CRC Handbook of Chemistry and Physics 95th Edn, Section 9-15 (CRC Press, 2014).

    Google Scholar 

  32. Kawai, H. The piezoelectricity of poly (vinylidine fluoride). Jpn J. Appl. Phys. 8, 975–976 (1969).

    Article  CAS  Google Scholar 

  33. Patrick, C. R. & Prosser, G. S. A molecular complex of benzene and hexafluorobenzene. Nature 187, 1021 (1960).

    Article  CAS  Google Scholar 

  34. Williams, J. H., Cockroft, J. K. & Fitch, A. N. Structure of the lowest temperature phase of the solid benzene–hexafluorobenzene adduct. Angew. Chem. Int. Ed. 31, 1655–1657 (1992).

    Article  Google Scholar 

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Acknowledgements

This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council (ERC). D.O'H. thanks the Royal Society for a Wolfson Research Merit Award. The authors acknowledge the EPSRC National Mass Spectrometry Facility (Swansea) for analytical assistance.

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Authors and Affiliations

  1. EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK

    Neil S. Keddie, Alexandra M. Z. Slawin, Tomas Lebl, Douglas Philp & David O'Hagan

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  1. Neil S. Keddie
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  2. Alexandra M. Z. Slawin
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  3. Tomas Lebl
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  4. Douglas Philp
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  5. David O'Hagan
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Contributions

N.K. and D.O'H conceived the synthesis of 1. N.K. designed the synthetic route and performed all of the synthesis and standard characterization. A.M.Z.S. obtained and solved the crystallographic data. T.L. conducted the low-temperature EXSY NMR studies and analysed the data. D.P. carried out the density functional theory and NBO theory studies. The manuscript was co-written by N.K. and D.O'H. All authors discussed the results and commented on the manuscript.

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Correspondence to David O'Hagan.

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The authors declare no competing financial interests.

Supplementary information

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Supplementary information (PDF 24174 kb)

Supplementary information

Crystallographic data for compound 1 (CIF 88 kb)

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Crystallographic data for compound 3 (CIF 268 kb)

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Crystallographic data for compound 5 (CIF 599 kb)

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Crystallographic data for compound 7 (CIF 128 kb)

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Crystallographic data for compound 8 (CIF 242 kb)

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GAMESS-US output for electronic structure calculation performed on Compound 1 at the M11/6-311G(2d,p) level of theory (TXT 2119 kb)

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NBO6 .47 archive file for Compound 1 (TXT 8640 kb)

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Output file from NBO analysis of Compound 1 (TXT 1854 kb)

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Keddie, N., Slawin, A., Lebl, T. et al. All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexane. Nature Chem 7, 483–488 (2015). https://doi.org/10.1038/nchem.2232

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