Unique nuclear magnetic resonance behaviour of γ-cyclodextrin in organic solvents

  • Keiko TakahashiEmail author
  • Kentaro Hamamura
  • Yoshihisa Sei
Original Article


The nuclear magnetic resonance (NMR) behaviour of dry α-, β-, and γ-cyclodextrin (CyD) in non-aqueous solutions with the solvents pyridine-d5, N,N-dimethyl formamide-d7 (DMF-d7), and dimethyl sulfoxide-d6 (DMSO-d6) were examined in order to study the interactions among hydroxyl groups on the rims of CyD. All signals were assigned using H-H correlation spectroscopy (COSY) and 1H-detected multiple quantum coherence spectroscopy (HMQC) spectra. In pyridine-d5, the hydroxyl groups of γ-CyD and water were observed as appreciably broad signals. Over 95 °C, a white precipitate appeared immediately, and after 4 days, it disappeared completely. All signals of α- and β-CyDs were sharp and exhibited a high field shift as the temperature increased. These spectral changes were reversible, but in the case of γ-CyD in dry pyridine-d5, the time temperature-fall for reaching the equilibrium state took longer than that of temperature rise. The dependency of NMR spectroscopy of γ-CyD on the solvent, the concentration of water, and temperature suggested that hydroxyl groups on γ-CyD are sufficiently flexible to interact via intermolecular hydrogen bond formation and to form insoluble aggregates.


NMR γ-Cyclodextrin Pyridine Hydrogen bonding Non-aqueous solvent 



We are grateful to Dr. Toshiaki Narusawa for his calculation and useful comments regarding drawing molecular structures with MOPAC.

Supplementary material

10847_2018_847_MOESM1_ESM.docx (1.9 mb)
Supplementary material 1 (DOCX 1928 KB)


  1. 1.
    Szejtli, J.: Comprehensive Supramolecular Chemistry, vol. 3. Oxford, Pergamon (1996)Google Scholar
  2. 2.
    Inomata, A., Sakai, Y., Zhao, C., Ruslim, C., Shinohara, Y., Yokoyama, H., Amemiya, Y., Ito, K.: Crystallinity and cooperative motions of cyclic molecules in partially threaded solid-state polyrotaxanes. Macromolecules 43(10), 4660–4666 (2010)CrossRefGoogle Scholar
  3. 3.
    Ito, K.: Novel entropic elasticity of polymeric materials: why is slide-ring gel so soft? Polym. J. 44(1), 38–41 (2012)CrossRefGoogle Scholar
  4. 4.
    Yasumoto, A., Gotoh, H., Imran, A.B., Hara, M., Seki, T., Sakai, Y., Ito, K., Takeoka, Y.: Highly responsive hydrogel prepared using poly(N-isopropylacrylamide)-grafted polyrotaxane as a building block designed by reversible deactivation radical polymerization and click chemistry. Macromolecules 50(1), 364–374 (2017)CrossRefGoogle Scholar
  5. 5.
    Pontikis, C.C., Davidson, C.D., Walkley, S.U., Platt, F.M., Beqley, D.J.: Cyclodextrin alleviates neuronal storage of cholesterol in Niemann-Pick C disease without evidence of detectable blood-brain barrier permeability. J. Inherit. Metab. Dis. 36(3), 491–498 (2013)CrossRefGoogle Scholar
  6. 6.
    Davidson, C.D., Fishman, Y.I., Puskás, I., Szemán, J., Sohajda, T., McCauliff, L.A., Sikora, J., Storch, J., Vanier, M.T., Szente, L., Walkley, S.U., Dobrenis, K.: Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease. Ann. Clin. Transl. Neurol. 3(5), 366–380 (2016)CrossRefGoogle Scholar
  7. 7.
    Ory, D.S., Ottinger, E.A., Farhat, N., King, N.Y., Jiang, K.A., Weissfeld, X., Berry-Kravis, L., Davidson, E., Bianconi, C.D., Keener, S., Rao, L.A., Soldatos, R., Sidhu, A., Walters, R., Xu, K.A., Thurm, X., Solomon, A., Pavan, B., Machielse, W.J., Kao, B.N., Silber, M., McKew, S.A., Brewer, J.C., Vite, C.C., Walkley, C.H., Austin, S.U., Porter, C.P.: F. D.: Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial. Lancet 390(10104), 1758–1768 (2017)CrossRefGoogle Scholar
  8. 8.
    Fourmentin, S., Crini, G., Lichtfouse, E.: Cyclodextrin Fundamentals, Reactivity and Analysis. Springer, Cham (2018)CrossRefGoogle Scholar
  9. 9.
    Schneider, H.-J., Hacket, F., Rüdiger, V., Ikeda, H.: NMR studies of cyclodextrins and cyclodextrin complexes. Chem. Rev. 98, 1755–1785 (1998)CrossRefGoogle Scholar
  10. 10.
    Bekiroglu, S., Kenne, L., SandstrÓ§m, C.: 1 H NMR studies of maltose, maltoheptaose, α-, β-, and γ-cyclodextrins, and complexes in aqueous solutions with hydroxy protons as structural probes. J. Org. Chem. 68, 1671–1678 (2003)CrossRefGoogle Scholar
  11. 11.
    Onda, M., Yamamoto, Y., Inoue, Y., Chûjô, R.: 1H NMR study of intramolecular hydrogen-bonding interaction in cyclodextrins and their di-O-methylated derivatives. Bull. Chem. Soc. Jpn 61, 4015–4021 (1988)CrossRefGoogle Scholar
  12. 12.
    Christofides, J.C., Davies, D.B.: 1 H and 13C n. m. r. observation of 2H isotope effects transmitted through hydrogen bonds. J. Chem. Soc., Chem. Commun. 10, 560–562 (1982)CrossRefGoogle Scholar
  13. 13.
    Kida, T., Sato, S., Yoshida, H., Teragaki, A., Akashi, M.: 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) as a novel and effective solvent to facilely prepare cyclodextrin-assembled materials. Chem. Commun. 50, 14245–14248 (2014)CrossRefGoogle Scholar
  14. 14.
    WinMOPAC v3.9, Fujitsu Ltd, Tokyo, Japan, (2004)Google Scholar
  15. 15.
    Stewart, J.J.P.: MOPAC2002 v1.5. Fujitsu Ltd, Tokyo (2003)Google Scholar
  16. 16.
    Dewar, M.J.S., Zoebisch, E.G., Healy, E.F., Stewart, J.J.P.: Development and use of quantum mechanical molecular models. 76. AM1: a new general purpose quantum mechanical molecular model. J. Am. Chem. Soc. 107, 3902–3909 (1985)CrossRefGoogle Scholar
  17. 17.
    Ueno, A., Takahashi, K., Osa, T.: One host-two guests complexation between γ-cyclodextrin and sodium α-naphthylacetate as shown by excimer fluorescence. J. Chem. Soc. Chem. Commun. 19, 921–922 (1980)CrossRefGoogle Scholar
  18. 18.
    Ueno, A., Takahashi, K., Hino, Y., Osa, T.: Fluorescence enhancement of α-naphthyloxyacetic acid in the cavity of γ-cyclodextrin, assisted by a space-regulating molecule. J. Chem. Soc. Chem. Commun. 4, 194–195 (1981)CrossRefGoogle Scholar
  19. 19.
    Rango, C., Charpin, P., Navaza, J., Keller, N., Nocolis, I., Villain, F., Colemanm, A.W.: β-Cyclodextrin/pyridine gel systems. The crystal structure of a first β-cyclodextrin-pyridine-water compounds. J. Am. Chem. Soc. 114, 5475–5476 (1992)CrossRefGoogle Scholar
  20. 20.
    Szejtli, J.: Introduction and general overview of cyclodextrin chemistry. Chem. Rev. 98(5), 1743–1754 (1998)CrossRefGoogle Scholar
  21. 21.
    Ryzhakov, A., D-Thi, T., Stappaerts, J., Bertoletti, L., Kimpe, K., Couto, A.R.S., Saokham, P., Mooter, G.V., Augustijns, P., Somsen, G.W., Kurkov, S., Inghelbrecht, S., Arien, A., Jimidar, M.I., Schrijnemakers, K., Loftsson, T.: Self-assembly of cyclodextrins and their complexes in aqueous solutions. J. Pharm. Sci. 105, 2556–2569 (2016)CrossRefGoogle Scholar
  22. 22.
    Szente, L., Szejtli, J., Kis, G.L.: Spontaneous opalescence of aqueous γ-cyclodextrin solutions: complex formation or self-aggregation? J. Pharm. Sci. 87(6), 778–781 (1998)CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Keiko Takahashi
    • 1
    Email author
  • Kentaro Hamamura
    • 1
  • Yoshihisa Sei
    • 2
  1. 1.Department of Life Science and Sustainable Chemistry, Faculty of Engineering, The Centre for Nanoscience and TechnologyTokyo Polytechnic UniversityAtsugiJapan
  2. 2.Division of Materials Analysis Suzukaked-daiTokyo Institute of TechnologyYokohamaJapan

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