Deutsch
The full-text version of my PhD-Thesis is available for downloading as a
PDF file.
The thesis is written in German, but includes an English abstract.
Summary
Thickness Recognition with Cyclodextrins and
Synthesis of Cyclodextrin-Rotaxanes
Through Side-Chain Polyrotaxanes
The cavity of cyclodextrins is still considered to be conically shaped in the literature, even though and already drew a different shape of the cavity through computational methods in 1994.[1,2] They corrected the cavity dimensions measured by on CPK models in 1980.[3] Fig. 1 displays the molecular contact surface of α-cyclodextrin determined by et al., showing a clear constriction of the cavity.[2] Unfortunately, its dimension has never been determined, although a great influence on the complexation behavior has been predicted for the constriction.[1] In the course of this thesis, the existance of a constriction of the α-cyclodextrin cavity has been proven theoretically and experimentally. For the first time it could be shown that the cavity is not conically shaped, but constricted at the level of the H-5 atoms.
Fig. 1: Cross-section of the molecular contact surface of α-cyclodextrin[1,2] and the resulting cavity dimensions
For the theoretical approach the MolShape algorithm has been developed.[4] It computes the cross-sectional area of a cavity or a molecule at discrete points along a given spatial axis from the electron density. The so-called equivalent diameter deq is gained through a circular approximation of the cross-sectional area. If the algorithm is applied to the cavities of native cyclodextrins, the resulting equivalent diameter always assumes a minimum. Hence it follows that the cavities are constricted and not conically shaped. Fig. 2 shows the cavity profile of α-cyclodextrin.
Fig. 2: Cavity profile deq(z) of α-cyclodextrin on a PM3//PM3-strukture with a constrained C6-symmetry with the MolShape-algorithm. Origin of the z-axis is on the altitude of the O-3-atoms and the z-axis runs parallel to the C6-axis.
Quantities obtained by the algorithm depend primarily on the applied input structure. In the case of α-cyclodextrin the diameter of the cavity constriction is about 4.6 Å for a neutron structure. Equivalent diameters from molecular dynamics calculations with explicit water molecules scatter around the same value. MD simulations have shown that the constriction is not only present in the solid state, but also in solution. In addition, the minimal cross-sectional areas of the cavities have proven as an important criterion for the evaluation of inclusion compounds. In this way, a better understanding of the stoichiometry of polymeric cyclodextrin inclusion compounds[5] and the threading kinetics of cyclodextrins onto poly(bola-amphiphiles)[6] could be achieved.
Fig. 3: Homologous series of increasingly thicker guest molecules. Hydrophilic molecular entities are depicted blue, hydrophobic are colored yellow. Binding constants Kass are determined through microcalorimetry.
A homologous series of increasingly thicker guest molecules (siehe fig. 3), whose structural relationship could be verified through the MolShape algorithm, has been synthesized for the experimental proof of the cavity constriction. The focus was mainly on the preparation of water-soluble stilbene derivatives. Stilbenoid structures were synthesized through the McMurry reaction in excellent yields. Sufficiently water-soluble stilbene derivates with cationic benzyl ammonium groups were prepared through a combination of Wohl-Ziegler bromination followed by a Delépine reaction.
In addition to prove the existence of the constriction, microcalorimetric data have also shown that this constriction decisively influences the complexation behavior of α-cyclodextrin. The binding constant Kass for α-cyclodextrin increases dramatically with decreasing diameter of the guest molecule. Likewise, it has turned out, that the closest fit into the cavity does not yield to more stable complexes. Instead, rather loose fitting guests with remnant mobility in the cavity cause higher binding constants due to a decreased loss of entropy.[7] The same observation could be made with apolar guest molecules and different α-cyclodextrin derivatives by means of solubility isotherms.
The second part of the thesis is concerned with the synthesis of cyclodextrin side-chain polyrotaxanes. This structure type has mainly been investigated by et al.[8,9] In their cases, the cyclodextrin ring is always mechanically locked on a side-chain. Herein the synthesis of the first cyclodextrin side-chain polyrotaxane with a different topography has been described where the ring entities are covalently bound to the polymeric backbone (see fig. 4). First of all, the α-cyclodextrin rings have been grafted onto poly(maleinic anhydride-alt-methyl vinyl ether) via an ester bond. The degree of substitution has been determined to 72% by NMR spectroscopy. In the next step, the axis molecule (E)-4,4'-bis(amino methyl)-stilbene 3 has been mechanically bound to the polymeric matrix through reductive amination with D-maltose as the stopper entity. The degree of rotaxanation has been photometrically and microcalorimetrically determined to 71%.
Fig. 4: Approach for the synthesis of a new type of cycldextrin side-chain polyrotaxane and the cleavage of the rotaxane structure from the polymer yielding a cyclodextrin rotaxane with functionalized stoppers.
Finally, the polymeric-bound rotaxane could be cleaved off from the side-chain polyrotaxane by ammonia. In this way, the synthetically rather challenging isolation of a water-soluble α-cyclodextrin-rotaxane (5) with carbohydrate stoppers could be achieved (see fig. 5 for a structural formula). Even rotaxanation reactions with only poor yields can be applied in this procedure, since a surplus of reagents can be used. Excessive reagents and impurities are easily eliminated by ultrafiltration. In the course of this thesis, an experimental method has been developed that gives raise to the preparation of rotaxanes with functionalized stoppers. This method can even be utilized with only moderately soluble axis molecules, since they are solubilized during the rotaxanation.
Fig. 5: Structural formula of the synthesized rotaxane: [2]-{(E)-N,N'-bis[4-O-(α-D-glucopyranosyl)-1-desoxy-D-glucos-1-yl]-4,4'-bis(amino methyl)stilbene}-rotaxa-{α-cyclodextrin} (5).
| [1] | |
| [2] |
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"Computer Simulation of Chemical and Biological Properties of Saccharides: Sucrose, Fructose, Cyclodextrins, and Starch",
PhD Thesis, Darmstadt University of Technology,
1995.
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| [3] | |
| [4] |
,
"MolShape - Script for Determining Cavity and Molecular Profiles from the Electron Density",
2005,
URL: http://www.uni-saarland.de/fak8/wenz/molshape
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| [5] | |
[6]|
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[7]|
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[8]|
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| [9] |