P-Cyclodextrine

The extreme influence water can exert on the Diels-Alder reaction was rediscovered by Breslow in 1980, much by coincidence . Whale studying the effect of p-cyclodextrin on the rate of a Diels-Alder reaction in water, accidentally, the addition of the cyclodextrin was omitted, but still rate constants were observed that were one to two orders of magnitude larger than those obtained in organic solvents. The investigations that followed this remarkable observation showed that the acceleration of Diels-Alder reactions by water is a general phenomenon. Table 1.2 contains a selection from the multitude of Diels-Alder reactions in aqueous media that have been studied Note that the rate enhancements induced by water can amount up to a factor 12,800 compared to organic solvents (entry 1 in Table 1.2). 

Fig. 7. A tethered cyclodextrin and the structure of P-cyclodextrin, the most common cyclodextrin used as a bonded ligand in Hquid chromatography.

Fig. 1. Stmctural diagram of (a) P-cyclodextrin and (b) two of the glucopyranose units illustrating details of the a-(l,4) glycosidic linkage, C-1 (d) chair...

Several procedures are used to control the ratios of cyclodextrins produced. One is addition of a substance to the reaction mixture that can gready affect the formation of one specific cyclodextrin over another. For example, in the presence of 1-decanol and 1-nonanol, a-cyclodextrin is produced almost exclusively whereas hexane or toluene promote the production of P-cyclodextrin. Conversely both cyclodextrins are produced simultaneously in the presence of 1-heptanol (2,4). 

Immobilization. The abiUty of cyclodextrins to form inclusion complexes selectively with a wide variety of guest molecules or ions is well known (1,2) (see INCLUSION COMPOUNDS). Cyclodextrins immobilized on appropriate supports are used in high performance Hquid chromatography (hplc) to separate optical isomers. Immobilization of cyclodextrin on a soHd support offers several advantages over use as a mobile-phase modifier. For example, as a mobile-phase additive, P-cyclodextrin has a relatively low solubiUty. The cost of y- or a-cyclodextrin is high. Furthermore, when employed in thin-layer chromatography (tic) and hplc, cyclodextrin mobile phases usually produce relatively poor efficiencies. 

Appllca.tlons. The first widely appHcable Ic separation of enantiomeric metallocene compounds was demonstrated on P-CD bonded-phase columns. Thirteen enantiomeric derivatives of ferrocene, mthenocene, and osmocene were resolved (7). Retention data for several of these compounds are listed in Table 2, and Figure 2a shows the Ic separation of three metallocene enantiomeric pairs. P-Cyclodextrin bonded phases were used to resolve several racemic and diastereomeric 2,2-binaphthyldiyl crown ethers (9). These compounds do not contain a chiral carbon but stiU exist as enantiomers because of the staggered position of adjacent naphthyl rings, and a high degree of chiral recognition was attained for most of these compounds (9). 

Fig. 2. Chromatogram showing (a) the Ic separation of A, (+) (T)-(l-ferrocenyl-ethyl)thioethanol B, (+) 1-ferrocenyl-l-methoxyethane and C, (+) 1-mthenocenylethanol, on a 25-cm P-cyclodextrin column (see Table 2), and (b) the potential use of a P-cyclodextrin column to determine optical purity...

Table 2. Retention Data for Racemic Compounds Separated on a p-Cyclodextrin Stationary Phase ...

Catechin and epicatechin are two flavanols of the catechin family. They are enantiomers. The capillary zone electrophoresis (CE) methods with UV-detection were developed for quantitative determination of this flavanols in green tea extracts. For this purpose following conditions were varied mnning buffers, pH and concentration of chiral additive (P-cyclodextrin was chosen as a chiral selector). Borate buffers improve selectivity of separation because borate can make complexes with ortho-dihydroxy groups on the flavanoid nucleus. 

Electrophoretic condition 60 cm (effective length of 50 cm)x75 p.m I.D. fused capillary column, run buffer borate buffer pH 9,0, P-cyclodextrin, electrophoresis voltage 20 kV, detection at 254 nm. 

Purification of C q from a C(,q/C-,q mixture was achieved by dissolving in an aqueous soln of y (but not p) cyclodextrin (0.02M) upon refluxing. The rate of dissolution (as can be followed by UV spectra) is quite slow and constant up to lO M of C o- The highest concn of C o in H2O obtained was 8 x 10 M and a 2 y-cyclodextrin C q clathrate is obtained. C ) is extracted from this aqueous soln by toluene and C oof >99 purity is obtained by evaporation. With excess of y-cyclodextrin more C g dissolves and the complex precipitates. The ppte is insol in cold H2O but sol in boiling H2O to give a yellow soln. [J Chem Soc, Chem Commun 604 7922.]... 

On the other hand, the values of AH° and AS° for a-cyclodextrin-l-alkanol systems are significantly more negative than those for the corresponding P-cyclOdextrin systems. 1-Alkanols must fit closely into the cavity of a-cyclodextrin, so that the com-plexation is governed by van der Waals interaction rather than by hydrophobic interaction. 

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. 

Figures 4 and 5 show the plots of log 1/Kd vs. log Pe for branched or cyclic alcohol-cyclodextrin systems. Both of the plots showed considerable scatter in contrast to the plots for 1-alkanol systems (solid lines). However, a remarkable trend was found by comparing both plots. Most of the plots for an a-cyclodextrin system (Fig. 4) are located below the straight line due to Eq. 5, whereas those for a P-cyclodextrin system (Fig. 5) are located above the straight line given by Eq. 6. This shows that it is general for a bulky alcohol to associate with a-cyclodextrin less strongly and with P-cyclodextrin more strongly than a rod-like 1-alkanol if the log Pe values are the...

Fig. 5. Plots of log 1/K.d vs. log Pe for complexes of P-cyclodextrin with branched alkanols (O) and cycloalkanols ( ). The solid line was given by the plots for a p-cyclodextrin- 1-alkanol system. Numbers shown refer to the numbers in the first column of Table 2. Reproduced with permission from the Chemical Society of Japan...

These equations show that hydrophobic and steric (van der Waals) interactions are of prime importance in the inclusion processes of cyclodextrin-alcohol systems. The coefficient of Es was positive in sign for an a-cyclodextrin system and negative for a P-cyclodextrin system. These clear-cut differences in sign reflect the fact that a bulky alcohol is subject to van der Waals repulsion by the a-cyclodextrin cavity and to van der Waals attraction by the p-cyclodextrin cavity. 

Matsui75) has computed energies (Emin) which correspond to the minimal values of Evdw in Eq. 1 for cyclodextrin-alcohol systems (Table 2). Besides normal and branched alkanols, some diols, cellosolves, and haloalkanols were involved in the calculations. The Emi values obtained were adopted as a parameter representing the London dispersion force in place of Es. Regression analysis gave Eqs. 9 and 10 for a- and P-cyclodextrin systems respectively. 

Regression analysis of the results gave Eqs. 11 and 12 fora- and P-cyclodextrin systems respectively. 

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). 

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) ... 

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... 

---