Cyclofructins with Six to Ten β(1→2)-linked Fructofuranose Units: Geometries, Electrostatic Profiles, Lipophilicity Patterns, and Potential for Inclusion Complexation
Stefan Immel, Guido E. Schmitt, and Frieder W. Lichtenthaler
Carbohydr. Res., 1998, 91-105.
Cyclofructins composed of six (1, "CF6") to ten (5, "CF10") β(1→2)-linked fructofuranose
units were subjected to conformational analysis using Monte-Carlo simulations based on the
PIMM91 force-field. Breaking the molecular symmetry partially by alternating inclination of
the spiro-type anellated fructofuranoses relative to the crown ether ring core, i.e. the 3-OH
groups pointing either towards or away from the molecular center, substantially lowers the
strain energy of the cyclofructins. The global energy-minimum geometries of CF6, CF8, and
CF10 exhibit Cn/2 rotational symmetry, whilst the odd-membered macrocycles in CF7 and CF9
adopt C1 symmetry. Identical conformations of the solid-state geometry of CF6 (1) and its
computer-generated form manifest the reliability of the computational analysis. The molecular
surfaces calculated for the energy-minimum structures establish a disk-type shape for CF6 (1),
CF7 (2), and CF8 (3), whereas further ring enlargement to CF9 (4) and CF10 (5) leads to torus-
shaped molecules with through-going cavities. Color-coded projection of the molecular
lipophilicity patterns (MLPs) and the electrostatic potential profiles (MEPs) onto these
surfaces cogently displays the crown ether-like properties, favoring the complexation of metal
cations via strong electrostatic interactions through the 3-OH groups located on the
hydrophilic molecular side. The central cavities of CF9 and CF10 are characterized not only by
significantly enhanced hydrophobicity, but also by highly negative electrostatic potentials
around the narrow aperture of the tori made up by the 3-OH / 4-OH groups, and positive
potentials on the opposite rim. Accordingly, CF9 and CF10 are capable to form inclusion
complexes, the cavity of the latter being approximately as large as the one of a-cyclodextrin.
Calculation of the inclusion complex geometries of CF9 with β-alanine and of CF10 with
p-aminobenzoic acid revealed the guest to be deeply incorporated into the respective cavities,
masking the guest's hydrophobic parts. Analysis of the electrostatic interactions at the
interface of the zwitter-ionic guests with the oppositely polarized hosts predicts a high degree
of regiospecificity for complex formation.
cyclo[D-Frufβ(1→2)]6
cyclo[D-Frufβ(1→2)]7
cyclo[D-Frufβ(1→2)]8
cyclo[D-Frufβ(1→2)]9
cyclo[D-Frufβ(1→2)]10
Cyclofructin formula
Cross-section contours through the surfaces of the most stable
structures computed for the inclusion complexes of 4 with
β-alanine (left) and 5 with p-amino benzoic acid (right).
S. Immel, G.E. Schmitt, and F.W. Lichtenthaler, in J.J. Torres Labandeira (Ed.), Proceedings 9th Internat. Cyclodextrin Symp., Kluwer Academic, Dordrecht, The Netherlands, in press.
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