Cyclodextrins substitutions

Silipo and Hansch 77) have developed correlation equations for the formation of a-cyclodextrin-substituted phenyl acetate complexes (Eq. 13), a-cyclodextrin-RCOO complexes (Eq. 14), and P-cyclodextrin-substituted phenylcyanoacetic acid anion complexes (Eq. 15). 

Table 3. The log 1 /Kd(X) values for cyclodextrin-substituted phenol systems at pH 7.0 and 25 °C and the parameters of substituents...

Cyclodextrin-substituted molecular channel approaches have now been extended to include acyl substituents through a covalent bond formation. Stearoyl and methyl cholate-substituted cyclodextrins 10 and 11, respectively, have been synthesized. It may be worthwhile commenting on the molecular design of methyl cholate-substituted a-cyclodextrin. All of the ether groupings are convergent at the inner side of the steroidal backbone of a bent structure to make the molecule amphiphilic. Once the cyclodextrin derivative is incorporated into the membrane phase, it may easily be expected that the ether parts are assembled inside the channel in the sea of hydrophobic lipid molecules and the hydrophobic steroidal skeletons cover its outside to stabilize the inner hydrophilic pore (Figure 13). 

Yano, H., Hirayama, F., Arima, H., Uekama, K. Preparation of prednisolone-appended a-, 3- and i-cyclodextrins substitution at secondary hydroxyl groups and in vitro hydrolysis behavior. J. Pharm. Sci. 2001, 90, 493-503. 

One of the most successful derivatives in a number of separation modes has been the P-hydroxypropylated version derived by the reaction of both chiral and racemic propylene oxide with the native cyclodextrin. Substitution level has been a critical issue in the preparation of this derivative. Full derivatization of all 21 hydroxyl groups of the P-CD has led to less overall selectivity in the same manner as too little. Advanced Separation Technologies, Inc. (Astec) after much experimentation determined that a substitution level of 7 was ideal for both the bonded -CSP for HPLC and CEC and as an additive for CE. A suitable profile of derivatization is controlled by temperature, rate of addition, and concentration. In studying the chiral R form of the propylene oxide it was observed that a strong internal hydrogen bond occurred and little selectivity resulted. The 5 version did show excellent selectivity but the improvement in peak efficiency and resolution over the racemic propylene oxide was insufficient to warrant the cost differential. As a result of these observations the racemic mixture (CB-RSP) was chosen for economic reasons. 

David O, Maisoimeuve S, Xie J (2007) Generation of new fluOTophore by click chemistry synthesis and properties of P-cyclodextrin substituted by 2-pyridyl triazole. Tetrahedron Lett 48 6527-6530... 

Rao et al. showed that P-cyclodextrine substituted with an imidazole in position 2 (25) is 70 times more effective in the hydrolysis of p-nitrophenylacetate compared to a P-cyclodextrine substituted at position 6 (Scheme 7.5) [23]. 

Calixarenes (from the Latin ca/ x) may be understood as artificial receptor analogues of the natural cyclodextrins (96,97). In its prototypical form they feature a macrocycHc metacyclophane framework bearing protonizable hydroxy groups made from condensation of -substituted phenols with formaldehyde (Fig. 15b). Dependent on the ring size, benzene derivatives are the substrates most commonly included into the calix cavity (98), but other interesting substrates such as C q have also been accommodated (Fig. 8c) (45). 

Optical properties of cyanines can be usefiil for both chiral substituents/environments and also third-order nonlinear optical properties in polymer films. Methine-chain substituted die arbo cyanines have been prepared from a chiral dialdehyde (S)-(+)-2-j -butylmalonaldehyde [127473-57-8] (79), where the chiral properties are introduced via the chiral j -butyl group on the central methine carbon of the pentamethine (die arbo cyanine) chromophore. For a nonchiral oxadicarbocyanine, the dimeric aggregate form of the dye shows circular dichroism when trapped in y-cyclodextrin (80). Attempts to prepare polymers with carbocyanine repeat units (linked by flexible chains) gave oligomers with only two or three repeat units (81). However, these materials... 

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...

Upon formulating these relationships, phenols with branched alkyl substituents were not included in the data of a-cyclodextrin systems, though they were included in (3-cyclodextrin systems. In all the above equations, the n term was statistically significant at the 99.5 % level of confidence, indicating that the hydrophobic interaction plays a decisive role in the complexation of cyclodextrin with phenols. The Ibrnch term was statistically significant at the 99.5% level of confidence for (3-cyclo-dextrin complexes with m- and p-substituted phenols. The stability of the complexes increases with an increasing number of branches in substituents. This was ascribed to the attractive van der Waals interaction due to the close fitness of the branched substituents to the (3-cyclodextrin cavity. The steric effect of substituents was also observed for a-cyclodextrin complexes with p-substituted phenols (Eq. 22). In this case, the B parameter was used in place of Ibmch, since no phenol with a branched... 

The results were simple and clear-cut Only the two terms ofa° and Emin were involved for the a-cyclodextrin systems, and the two terms of k and Emin, for (S-cyclodextrin systems. This means that the stabilities of the inclusion complexes are mainly governed by the electronic and steric interactions in a-cyclodextrin systems and by the hydro-phobic and steric interactions in (i-cyclodextrin systems, regardless of the position of the substituents in the phenols. These observations agree well with those by Harata23), who showed that there is no appreciable difference in thermodynamic parameters between cyclodextrin complexes of m- and p-di substituted benzenes and that the contribution of the enthalpy term to the complexation is more significant in a-cyclodextrin systems than in P-cyclodextrin systems, where the inhibitory effect... 

Nishioka and Fujita78) have also determined the Kd values fora- and (S-cyclodextrin complexes with p- and/or m-substituted phenyl acetates through kinetic investigations on the alkaline hydrolysis of the complexes. The Kd values obtained were analyzed in the same manner as those for cyclodextrin-phenol complexes to give the Kd(X) values (Table 5). The quantitative structure-activity relationships were formulated as Eqs. 30 to 32 ... 

Only the hydrophobic and steric terms were involved in these equations. There are a few differences between these equations and the corresponding equations for cyclo-dextrin-substituted phenol systems. However, it is not necessarily required that the mechanism for complexation between cyclodextrin and phenyl acetates be the same as that for cyclodextrin-phenol systems. The kinetically determined Kj values are concerned only with productive forms of inclusion complexes. The productive forms may be similar in structure to the tetrahedral intermediates of the reactions. To attain such geometry, the penetration of substituents of phenyl acetates into the cyclodextrin cavity must be shallow, compared with the cases of the corresponding phenol systems, so that the hydrogen bonding between the substituents of phenyl acetates and the C-6 hydroxyl groups of cyclodextrin may be impossible. 

Fig. 7. Plots of log k2/k vs. Dc 0 determined by the calculation of van der Waals energies for cyclodextrin complexes with Bland p-substituted phenyl acetates...

Quantitative structure-reactivity analysis is one of the most powerful tools for elucidating the mechanisms of organic reactions. In the earliest study, Van Etten et al. 71) analyzed the pseudo-first-order rate constants for the alkaline hydrolysis of a variety of substituted phenyl acetates in the absence and in the presence of cyclodextrin. The... 

Nishioka and Fujita 68 78) have, independently of Van Etten et al.71), determined and analyzed the rate constants, k2, for the cyclodextrin-catalyzed cleavage of m-and p-substituted phenyl acetates (Table 6). They have derived Eqs. 37 to 40 ... 

A few examples have been reported in which no steric parameter is involved in the correlation analysis of cyclodextrin catalysis. Straub and Bender 108) showed that the maximal catalytic rate constant, k2, for the (5-cyclodextrin-catalyzed decarboxylation of substituted phenylcyanoacetic acid anions (J) is correlated simply by the Hammett a parameter. 

Fig. 8. Parabolic relationship between reactivity with cyclodextrin and substituent diameter of m-substituted phenyl acetates...

The rate acceleration imposed by 0-cyclodextrin was explained in terms of a microsolvent effect 6> The inclusion of the substrate within the hydrophobic cavity of cyclodextrin simulates the changes in solvation which accompany the transfer of the substrate from water to an organic solvent. Uekama et al.109) have analyzed the substituent effect on the alkaline hydrolysis of 7-substituted coumarins (4) in the... 

It has been shown that it is possible to compel regiospecific para substitution by enclosing the substrate molecules in a cavity from which only the para position projects. Anisole was chlorinated in solutions containing a cyclodextrin, a molecule in which the anisole is almost entirely enclosed (see Fig. 3.4). With a high enough concentration of cyclodextrin, it was possible to achieve a para/ortho ratio of 21.6 (in the absence of the cyclodextrin the ratio was only 1.48). This behavior is a model for the regioselectivity found in the action of enzymes. 

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