Cyclodextrin complexation

NMR studies of cyclodextrin and cyclodextrin complexes 98CRV1755. Organic reactions mediated by cydodextrins 98CRV2013. 

It is known that several intermolecular interactions are responsible for cyclodextrin complexation, acting simultaneously. These interactions are separable from one another by quantitative structure-reactivity analysis. Furthermore, correlations obtained by the analysis can be discussed in direct connection with actual interactions already elucidated experimentally for the action site of cyclodextrin. Thus, the results must serve to make the background of the correlation analysis more concrete. 

The present review is concerned with the applications of the quantitative structure-reactivity analysis to cyclodextrin complexation and cyclodextrin catalysis, mostly from our laboratories, as well as the experimental and theoretical backgrounds of these approaches. 

Ihb = 1, whereas Ihb = 0 when it is inert to hydrogen bonding. Since —AG,° is proportional to log 1/Kd, where Kd is the dissociation constant of a cyclodextrin complex with a guest molecule, we can derive a quantitative structure-reactivity relationship as shown, for example, in Eq. 4 ... 

Quantitative Structure-Reactivity Analyses of the Inclusion Processes of Cyclodextrin Complexes... 

Matsui and Mochida24) have determined the thermodynamic stabilities (log 1 /Kd) for a- and P-cyclodextrin complexes with a variety of alcohols (Table 2) and analyzed the results in connection with the physicochemical properties of the guest molecules by the multivariate technique. The log 1/Kd values were plotted against log Pe, where Pe is the partition coefficient of alcohol in a diethyl ether-water system. The plots for the a- and P-cyclodextrin complexes with eight 1-alkanols gave approximately straight lines with slopes of around one. 

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 values of Kd(H) were determined by the extrapolation to n = 0 of the virtually linear plots of log 1/Kd vs. n obtained for cyclodextrin complexes with methyl-,... 

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 ... 

The importance of the proximity effect in cyclodextrin catalysis has been discussed on the basis of the structural data. Harata et al. 31,35> have determined the crystal structures of a-cyclodextrin complexes with m- and p-nitrophenols by the X-ray method. Upon the assumption that m- and p-nitrophenyl acetates form inclusion complexes in the same manner as the corresponding nitrophenols, they estimated the distances between the carbonyl carbon atoms of the acetates and the adjacent second-... 

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...

As shown above, quantitative structure-reactivity analysis is very useful in elucidating the mechanisms of cyclodextrin complexation and cyclodextrin catalysis. This method enables us to separate several intermolecular interactions, acting simultaneously,... 

Tpnnesen, H.H, Masson, M., and Loftsson, T., Studies on curcumin and curcuminoids. XXVII. Cyclodextrin complexation solubility, chemical an photochemical stability, Int. J. Pharm., 244, 127, 2002. 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

In this study, complexation of A9-THC and cannabidiol (prepared by freeze drying) with randomly methylated b-cyclodextrin and hydroxypropyl-b-cyclodextrin (HP-fi-CD) was studied by the phase-solubiHty method. The aqueous solubility of CBD and THC increased as a function of CD concentration, and the dissolution increased for THC and CBD cyclodextrin complexes significantly in contrast to plain THC and CBD. These results demonstrate that cyclodextrins increased both the aqueous solubility and dissolution rate... 

It has been claimed that complexes of P-cyclodextrin with anionic surfactants, notably higher fatty alcohol ethoxylates, improve scouring efficiency on cotton and wool in laboratory-scale processing [34]. Residual surfactants carried over from preparation can have undesirable effects in subsequent processing. When cyclodextrins complex with surfactants, their surface activity is reduced. Hence cyclodextrins are potentially useful for the removal of residual amounts of surfactants from substrates [35]. The use of a- and P-cyclodextrins has been studied in this context with one cationic, one anionic and four... 

Lopez-Nicolas JM, Nunez-Delicado E, Perez-Lopez AJ, Carbonell A and Cuadra-Crespo P. 2006. Determination of stoichiometric coefficients and apparent formation constants for (3-cyclodextrin complexes of trans-resveratrol using reversed-phase liquid chromatography. J Chromatogr A 1135 158—165. 

The magnitude of association between a drag compound and various cyclodextrins depends critically on the details of the fit of the substrate into the cyclodextrin cavity. As shown in Table 6, the experimental compound RS-82856 forms the strongest complexes with /3-cyclodextrin, while maximal solubility is reached with y-cyclodextrin [62], Formation of the /8-cyclodextrin complex dramatically increased the dissolution rate of the compound as well. For RS-82856 itself, 20% dissolved within 20 minutes, while more than 80% of the drug-/3-cyclodextrin complex was found to be dissolved at the same time point. 

Table 6 Formation Constants, K, and Maximum Solubilities for the Various Cyclodextrin Complexes with the Experimental Compound RS-82856...

Convergence properties of free energy calculations Alpha-cyclodextrin complexes as a case study. J. Am. Chem. Soc. 116 6293 (1994). 

Moritz ED, Sahyun MRV (2005) Spectroscopic studies of P-cyclodextrin-complexed cyanine dyes. J Photochem Photobiol A Chem 169 211-220... 

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