Cyclodextrin oriented

Cyclodextrins are macrocyclic compounds comprised of D-glucose bonded through 1,4-a-linkages and produced enzymatically from starch. The greek letter which proceeds the name indicates the number of glucose units incorporated in the CD (eg, a = 6, /5 = 7, 7 = 8, etc). Cyclodextrins are toroidal shaped molecules with a relatively hydrophobic internal cavity (Fig. 6). The exterior is relatively hydrophilic because of the presence of the primary and secondary hydroxyls. The primary C-6 hydroxyls are free to rotate and can partially block the CD cavity from one end. The mouth of the opposite end of the CD cavity is encircled by the C-2 and C-3 secondary hydroxyls. The restricted conformational freedom and orientation of these secondary hydroxyls is thought to be responsible for the chiral recognition inherent in these molecules (77). 

Nishioka and Fujita 78> have determined the Kd values for a- and P-cyclodextrin complexes with m- and p-substituted phenols at pH 7.0. Taking into account the directionality in inclusion of a guest molecule, they assumed three and two probable orientational isomers for the cyclodextrin complexes with m- and p-substituted phenols respectively (Fig. 6). Then the observed Kd values were divided into two or three terms corresponding to the dissociation of the orientational isomers involved (Eqs. 16, 17) ... 

Fig. 6. Probable orientational isomers for cyclodextrin complexes with m- and p-substituted phenols...

The problem of molecular recognition has attracted biologically oriented chemists since Emil Fischer s lock-and-key theory l0). Within the last two decades, many model compounds have been developed micelle-forming detergents11, modified cyclodextrins 12), many kinds of crown-type compounds13) including podands, coronands, cryptands, and spherands. Very extensive studies using these compounds have, however, not been made from a point of view of whether or not shape similarity affects the discrimination. 

Micellar medium has received great attention because it solubilizes, concentrates and orientates the reactants within the micelle core and in this way accelerates the reaction and favors the regio- and stereoselectivity of the process [68], In addition the micellar medium is cheap, can be reused, is more versatile than cyclodextrins and more robust than enzymes. With regard to Diels Alder reactions, we may distinguish between (i) those in which one or both reagents are surfactants which make up the micellar medium, and (ii) those that are carried out in a micellar medium prepared by a suitable surfactant. 

Lyotropic polymeric LC, formed by dissolving two aromatic polyamides in concentrated sulphuric acid, have been studied using variable-director 13C NMR experiments.324 The experimental line shapes at different angles w.r.t the external field were used to extract macromolecular order and dynamic in these ordered fluids. An interesting application of lyotropic LC is for the chiral discrimination of R- and S-enantiomers, and has recently been demonstrated by Courtieu and co-workers.325 The idea was to include a chiral compound 1-deutero-l-phenylethanol in a chiral cage (e.g., /1-cyclodextrin) which was dissolved and oriented by the nematic mean field in a cromolyn-water system. Proton-decoupled 2H NMR spectrum clearly showed the quad-rupolar splittings of the R- and S-enantiomers. The technique is applicable to water-soluble solutes. 

In recent years, supramolecular chemistry has produced a number of systems which have been shown to be able to effectively catalyze a Diels-Alder reaction. Most systems selectively afforded only one diastereomer because of a pre-organized orientation of the reactants. These systems include cyclodextrines, of which applications in Diels-Alder chemistry have recently been reviewed89. Some other kinds of non-Lewis acid catalyzed Diels-Alder reactions, including catalysis by proteins and ultrasound, have been discussed by Pindur and colleagues90. 

The synthesis of the bis-P-cyclodextrin 35 is outlined in Fig. 14. Interestingly, however, the X-ray structure of 36, the de-tosylated 35, revealed that P-carotene would not be incorporated into both CD units due to the unfavorable orientation of the diamide linker which blocks the entrance to the second P-CD. In agreement with this result are experiments with the target Ru complex 37 which displayed central cleavage on P-carotene 1 5delding retinal 2 as the major product (Fig. 15) (19). 

With capillary electrophoresis (CE), another modern primarily analytically oriented separation methodology has recently found its way into routine and research laboratories of the pharmaceutical industries. As the most beneficial characteristics over HPLC separations the extremely high efficiency leading to enhanced peak capacities and often better detectability of minor impurities, complementary selectivity profiles to HPLC due to a different separation mechanism as well as the capability to perform separations faster than by HPLC are frequently encountered as the most prominent advantages. On the negative side, there have to be mentioned detection sensitivity limitations due to the short path length of on-capillary UV detection, less robust methods, and occasionally problems with run-to-run repeatability. Nevertheless, CE assays have now been adopted by industrial labs as well and this holds in particular for enantiomer separations of chiral pharmaceuticals. While native cyclodextrins and their derivatives, respectively, are commonly employed as chiral additives to the BGEs to create mobility differences for the distinct enantiomers in the electric field, it could be demonstrated that cinchona alkaloids [128-130] and in particular their derivatives are applicable selectors for CE enantiomer separation of chiral acids [19,66,119,131-136]. 

Yamamoto and coworkers used two-dimensional, nuclear Over-hauser effect experiments (NOESY) to determine the proximity of particular protons situated on an included p-nitrophenolate ion to particular protons of a host alpha cyclodextrin molecule. The experiments showed cross-peaks connecting the H-3 resonance of alpha cyclodextrin to both meta and ortho proton resonances of the p-nitrophenolate ion, whereas H-5 of the alpha cyclodextrin gave a cross-peak only with the resonance of the meta proton thereof. As a consequence, it was unequivocally confirmed that the p-nitrophenolate ion is, in solution, preferentially included with its nitro group oriented to the narrow end of the alpha cyclodextrin... 

Both of these modes have been achieved by oriented membranes of long alkyl chain derivatives of cyclodextrin. ... 

Fig. 3. Computer projections of p-cyclodextrin inclusion complexes of (a) (R)-propranolol and (b) (5)-propranolol from x-ray crystallographic data. Dotted lines represent potential hydrogen bonds (see text). The configurations shown represent the optimal orientation of each isomer on the basis of the highest...

Solid inclusion complexes of photoreactive ketones with cyclodextrins as hosts (Figure 6) provide interesting examples of how a fairly stiff, somewhat heterogeneous (in terms of polarity, size, and guest orientation) reaction... 

The incorporation of such compounds into mixed Langmuir-Blodgett films built from a fatty acid (see 97) [8.92] or from an amphiphilic cyclodextrin [8.93] produces oriented arrangfements presenting marked NLO features. 

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