Of a-cyclodextrins

Fig. 15. Prototype examples of (a) cyclodextrins and (b) calixarenes, showing conformational stmctures and dimensions.

Figure 5-9. Free energy reaction coordinate diagram for System 2 of Table 4-3, the formation of a cyclodextrin inclusion complex.

Fig. 1. Chemical structure of a-cyclodextrin. Six glucopyranose units are numbered G1 to G6. The numbers on the G1 glucopyranose refer to those of the carbon atoms...

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. 

Fig. 2. Geometries calculated (solid lines) and observed (bold dashed lines) for 1-propanol in its a-cyclodextrin adduct. G3 and G6 denote the numbers of glucopyranose units of a-cyclodextrin. H3 and H5 refer to the hydrogen atoms located inside of the cyclodextrin cavity. The hydrogen atoms for the observed geometry of 1-propanol are not shown, since their atomic coordinates have not been determined. The observed 1-propanol is twofold disordered, with site a occupied 80%, site b 20%. Interatomic distances are shown in bold italics on fine dashed lines (nm). Reproduced with permission from the Chemical Society of Japan...

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 ... 

Fig. 4. Plots of log 1 /Kd vs. log Pe for complexes of a-cyclodextrin with branched alkanols (O) and cycloalkanols ( ). The solid line was given by the plots for an a-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...

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). 

In these equations, MR3 4, MR, and MR4 are the molar refractivities of 3- and 4-substituents, of R-, and of 4-substituents, respectively. All the equations exhibited positive coefficients of the MR terms. This suggests that the dispersion forces of substituents are actually responsible for the binding of ligands to cyclodextrin. Eq. 14 shows that the stability of a-cyclodextrin-RCOO complexes increases linearly up to MR = 4.0 and then falls off linearly. 

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 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-... 

In these equations, Dmax is the larger of the summed values of STERIMOL parameters, Bj, for the opposite pair 68). It expresses the maximum total width of substituents. The coefficients of the ct° terms in Eqs. 37 to 39 were virtually equal to that in Eq. 40. This means that the a° terms essentially represent the hydrolytic reactivity of an ester itself and are virtually independent of cyclodextrin catalysis. The catalytic effect of cyclodextrin is only involved in the Dmax term. Interestingly, the coefficient of Draax was negative in Eq. 37 and positive in Eq. 38. This fact indicates that bulky substituents at the meta position are favorable, while those at the para position unfavorable, for the rate acceleration in the (S-cyclodextrin catalysis. Similar results have been obtained for a-cyclodextrin catalysis, but not for (S-cyclodextrin catalysis, by Silipo and Hansch described above. Equation 39 suggests the existence of an optimum diameter for the proper fit of m-substituents in the cavity of a-cyclodextrin. The optimum Dmax value was estimated from Eq. 39 as 4.4 A, which is approximately equivalent to the diameter of the a-cyclodextrin cavity. The situation is shown in Fig. 8. A similar parabolic relationship would be obtained for (5-cyclodextrin catalysis, too, if the correlation analysis involved phenyl acetates with such bulky substituents that they cannot be included within the (5-cyclodextrin cavity. 

On the other hand, the use of a-cyclodextrin decreased the rate of the reaction. This inhibition was explained by the fact that the relatively smaller cavity can only accommodate the binding of cyclopentadiene, leaving no room for the dienophile. Similar results were observed between the reaction of cyclopentadiene and acrylonitrile. The reaction between hydroxymethylanthracene and N-ethylmaleimide in water at 45°C has a second-order rate constant over 200 times larger than in acetonitrile (Eq. 12.2). In this case, the P-cyclodextrin became an inhibitor rather than an activator due to the even larger transition state, which cannot fit into its cavity. A slight deactivation was also observed with a salting-in salt solution (e.g., quanidinium chloride aqueous solution). 

Figure 4.15 Selective adsorption synthesis of a-cyclodextrin from starch applying a hatch process using a sequence of stirred-tank reactor, heat exchanger modules and adsorption step...

An additional example is the observed moderate acceleration in the cleavage of particular phenyl esters in the presence of a cyclodextrin. In such cases, the bound ester is attacked by an hydroxyl group on the cyclodextrin to yield a new ester. There was found to be a significant enhancement of phenol release from meta-substituted phenyl acetate on interaction with cyclodextrin (relative to other esters which do not fit the cavity so well) (Van Etten, Clowes, Sebastian Bender, 1967). During the reaction, the acyl moiety transfers to an hydroxyl group on the... 

Almost no influence of the methylated /i-cyclodextrin on the yield can be observed if no additional organic solvent (except for butadiene or the product) is used as the non-polar phase. With hydroxypropyl-jd-cyclodextrin a decreased yield is obtained and the phase separation is more difficult. If cyclohexane or n-octane is added as the non-polar solvent the conversion and the yield increase with increasing cyclodextrin concentration up to a concentration of about 2 mol % cyclodextrin based on butadiene. Because of the high viscosity of the solution no further improvement can be achieved using higher cyclodextrin concentrations. Lower yields are obtained by use of a-cyclodextrin as compared with the methylated j8-cyclodextrin. 

Reaction of the m-nitrophenyl ester of pyridine-2,5-dicarboxylic acid with cyclodextrin (see Section 3) gives a picolinate ester [52] of a cyclodextrin secondary hydroxyl group (Breslow, 1971 Breslow and Overman, 1970) which will bind metal ions or a metal ion-pyridine carboxaldoxime complex. Such a complex will catalyse hydrolysis of p-nitrophenyl acetate bound within the cyclodextrin cavity leading to a rate constant approximately 2000-fold greater at... 

In an oligonucleotide-drug hydrate complex, the appearance of a clathrate hydrate-like water structure prompt a molecular dynamics simulation (40). Again the results were only partially successful, prompting the statement, "The predictive value of simulation for use in analysis and interpretation of crystal hydrates remains to be established." However, recent molecular dynamics calculations have been more successful in simulating the water structure in Ae host lattice of a-cyclodextrin and P-cyclodextrin in the crystal structures of these hydrates (41.42). 

A linear tube consisting of a -cyclodextrins cross-linked with l-chloro-2,3-epoxypropane. 

In situ STM has been applied [326] to study the potential-induced self-organi-zation of a-cyclodextrin on Au(lll) surfaces in NaCl04 solutions. The adsorbed molecules formed an ordered array of a cylindrical structure in the potential range 0.20 to —0.15 V (versus SCE), while they were desorbed at potentials lower than -0.40 V. 

Figure 18. Cyclic voltammograms of 1,4-benzoquinone (p-quinone) as permeability marker. Curve A in the absence of a cyclodextrin monolayer on a buffer solution containing no guest (p.1 M CH3C02Na-CH3C00H, pH 6.0). Curve B in the presence of the condensed monolayer of p-cyclodextrin derivative 41 on a buffer solution containing no guest. Curve C-E in the presence of the condensed monolayer of 41 on a buffer solution containing guest 59 at concentrations of 5.0 x 10", 1.0 x 10 , and 2.0 x 10 M, respectively (reprinted with permission from Anal. Chem. 1993, 65, 930. Copyright 1993 American Chemical Society).

Chemical compositions of a-cyclodextrin (a-CD) = C36H60O30, /J-CD = C42H70O35, and y-CD = C48H80O40. b Uncomplexed-hydrated cyclodextrins. c Guest molecules are largely disordered. 

Since the first X-ray analysis of the complex of a-cyclodextrin with potassium acetate was reported by Hyble et al. (8), the various types of cyclodextrin complexes have been studied by X-ray crystallography as shown in Table I. In contrast with cyclodextrin, only two examples of X-ray analyses of cyclo-phanes as inclusion hosts are known, which are also shown in Table I. 

FtG. 5. The crystallographic structure of the inclusion complex of a-cyclodextrin with iodine (15). 

Release of two water molecules from the cavity of a-cyclodextrin (form I) (19) is accompanied not only by the loss of van der Waals interaction (/fj jdw) and hydrogen bonding ( —2 A/fH.bond), but also by the gain of motional freedoms of two water molecules as to translation (2S ans) and three-dimensional rotation (2S ,I(3 D)). At the same time, a change in conformational energy of a-cyclodextrin is involved which is estimated by the use of Allinger s method (49). 

The results reveal many important aspects of the inclusion process of a-cyclodextrin. 

The units of enthalpy change are kcal mol 25"C. h The conformation of a-cyclodextrin was taken from Refs. 22 and 27. 

Another type of the crystalline form of a-cyclodextrin (form II) is known, though the full description of this crystal is not yet published, see (10). The similar polymorphism of /i-cyclodextrin is also observed. Jogun, K. H., and Stezowski, J. J., Nature (London) 278, 667(1979). 

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