Cyclodextrin phenyl acetate

Table 5. The log 1/K,(X) values for cyclodextrin-phenyl acetate systems...

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 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 ... 

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. 

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

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... 

Fig. 5 Correlation of constants for transition state stabilization (p ts) and substrate binding (pKs) for the cleavage of we/o-substituted phenyl acetates by a-cyclodextrin.

Table A5.1 Basic cleavage of m- and p-X-phenyl acetates by cyclodextrin."...

The hydrolysis of substituted phenyl acetates has been studied in the presence of cyclodextrins (Van Etten et al, 1967a, b). No correlation was found between the rate constants for hydrolysis and a for the substituent group. Specificity was directed towards meta-substituents. m-t-Butylphenyl acetate hydrolyses 240 times faster in the presence of 0-01 M cyclohepta-amylose. Comparison of spectral shifts upon inclusion of p-t-butyl and m-t-butylphenol indicated that benzene rings of p-substituted phenols are included within the cavity of cyclodextrins [45], but that the benzene ring of the meta-isomer... 

Quantum yields determinations lead to analogous conclusions, although differences in the ortho-to-para ratio are found probably because of experimental reasons. However, the ortho selectivity seems to be well established. Phenyl acetate irradiated in water gives the following quantum yields of product formation 0.16 (ortho), 0.067 (para), and 0.048 (phenol) in the presence of an excess of (3-cyclodextrin, they change to 0.23 (ortho), 0.053 (para), and 0.27 (phenol) [260]. As can be seen, the ortho product is favored in the hydrophobic microenvironment of the cyclodextrin. Phenol quantum yield is enhanced with respect to the irradiation without cyclodextrin, which has been interpreted in terms of H abstraction from the inner walls of the host oligosaccharide. 

We have recently studied this point by examining the steric effect of metasubstituents of phenyl acetate on the reactivity with a- and P-cyclodextrins (CD) as enzyme model35). Cyclodextrins form an inclusion complex with phenyl acetates (PA) and then catalyze the cleavage of the ester linkage36) as shown in Eq. 37. 

Experiments were also carried out at 80 and lOO C. According to our observations at these high temperatures, solid- phase chemical transformations may take place between certain flavor constituents and cyclodextrin hydroxyls/monoterpene alcohols and phenolic compounds appear as a result of a solid-phase transacetylation of terpeneaoetates and phenyl-acetates with the simultaneous formation of cyclodextrin-acetates/. Long term heat treatments of cyclpdextrin-flavor complexes should not be run above 6o°C in order to avoid such phenomena. 

The same author has reported chiral recognition of a-amino acids by native, anionic, and cationic a- and (3-cyclodextrins [17]. Both carboxylates and amines (monosubstituted as well as hexa- and heptasubstituted) were included in this study. The best results obtained were those from a combination of (S)- and (P)-AcTrp complexed by per-NH -[3-cyclodextrin with K=2,310 and 1,420 (1/mol). In the detailed study of chiral recognition of substituted phenyl-acetic acid derivatives by aminated cyclodextrins, these were found to be again only modest with respect to the enantioselection attained [18]. 

Cyclodextrins form inclusion compounds in aqueous solution with various molecules which may then exhibit modified reactivity (see reference 185 above). It was reported in 1975 that the presence of p-cyclodextrin modified the ortho para ratio of hydroxyacetophenones formed photochemically from phenyl acetate,and the photoinduced rearrangements of acetanilide, ben-zanilide, and ethyl phenyl carbonate under similar conditions are now reported. In each case the para rearrangement isomer is favoured, and this is rationalized in terms of the aromatic nucleus being bonded into the cyclodextrin cavity such that the ortho and weta positions are shielded whDe the para position is accessible. This proposal is supported by observations that para but not ortho disubstituted arenes are well bonded into p-cyclodextrin cavities. The by-product formation of aniline from the amides and of phenol from the carbonate is also markedly reduced for reactions in the presence of the cyclodextrin. 

The rearrangement is almost exclusively intramolecular and proceeds within a solvent cage (Adam et al., 1973). In the case of phenyl acetate (X = O. R = CHj), the o p ratio increases from I in the absence of /3-cyclodextrine to 6.2 in its presence the macrocycle provides a cage for the radical pair (Ohara and Watanabe, 1975). However, these reactions are singlet reactions and should be classified as dissociations of the benzylic C—X bond rather than a-cleavage reactions (Grimme and Dreeskamp, 1992), as mentioned above. 

The cause of the scatter is the non-systematic influence of the substituent on the microscopic environment of the transition structure. The linear free energy relationship between product state XpyH (Equation 22) and the transition structure (Xpy. .. PO32 . . . isq) will be modulated by second-order non-systematic variation because the microscopic environment of the reaction centre in the standard (XpyH ) differs slightly from that (Xpy-PO ) in the reaction under investigation giving rise to specific substituent effects. These effects are mostly small. An unusually dramatic intervention of the microscopic medium effect may be found in Myron Bender s extremely scattered Hammett dependence of the reaction of cyclodextrins with substituted phenyl acetates.22 The cyclodextrin reagent complexes the substrate and interacts... 

The photo-Fries rearrangement of phenyl acetate in aqueous solution in the presence and absence of B-cyclodextrin has been reexamined. In aqueous solution a mixture of phenol and the ortho and para isomers of hydroxyacetophenone is produced. When 3-cyclodextrin is present the quantum efficiency of formation of phenol and of the ortho product is increased. It is suggested that the enhanced photochemical yield of the ortho product reflects the less polar environment of the cyclodextrin cavity while the increased quantum yield of phenol formation reflects the availability of abstractable hydrogen within the cyclodextrin cavity. 

Fig. 3 depicts the time-averaged position of phenyl acetates in the cavity of a-cyclodextrin, determined by the above method. In these time-averaged conformations, the centers of the aromatic rings of p-nitrophenyl acetate, phenyl acetate, and nj-nitrophenyl acetate, respectively, are at the heights of 2.2, 1.9 and 1.7 A with respect to the plane comprised of the 6 H-3 atoms of a-cyclodextrin. As shown in Table 1, the calculated values of the anisotropic shielding effects of the aromatic rings of the phenyl acetates on both the H-3 and H-5 atoms agree fairly well with the observed values. 

Fig. 3. Time-averaged conformations of the inclusion complexes of -cyclodextrin with p-nitrophenyl acetate (A), phenyl acetate (B), and m-nitrophenyl acetate (C) in a 1 1 (v/v) mixture of 1 N deuterium...

Observed and calculated values of the [ H]NMR chemical shift changes on the complex formation of a-cyclodextrin with phenyl acetates ... 

The most striking specificity by cyclodextrins with respect to the substrate is found in the hydrolyses of phenyl acetates. As shown in Table 4, the magnitudes of the acceleration by a-cyclodextrin for weto-substituted compounds are 29-,... 

Catalytic rate constants and acceleration in the a-cyclodextrin-catalyzed hydrolyses of phenyl acetates ... 

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