Cyclodextrins reaction media

Others have investigated the influence of the presence of (i-cyclodextrin in the reaction medium on the electrochemical carboxylation of a-bromoethylbenzene and l-(4-isobutylphenyl)ethyl chloride [41], It has been reported that the preparative electrocarboxylahon of the inclusion complex (i-cyclodextrin-l-(4-isobutylphenyl) ethylchloride afforded the S-form of 2-(4-isobutylphenyl) propionic acid (S-ibuprofen) in a high enantiomeric excess (97%). 

The other point that was discovered was that some reaction rates were accelerated by operating in a mixed solvent rather than in pure water. The one that was examined most carefully was the acetyl transfer from bound ra-f-butylphenyl acetate to /3-cyclodextrin with buffers that in water give a pH of 9.5. It was observed that the reaction was almost 50-fold accelerated in a 60% DMS0-H20 solvent compared with the reaction rate in pure water. Part of this acceleration came from an increase in the apparent basicity of the medium, since relative pK s are solvent dependent part of it was also a solvent effect on the reaction rate of the cyclodextrin anion with the substrate. Thus, in 60% DMSO-H20 the /3-cyclodextrin reaction with this substrate was 13,000-fold faster than was the rate of hydrolysis of the substrate in an aqueous buffer of the same composition. Of this approximately 50-fold acceleration over cyclodextrin in water, about 10-fold was caused by changes in the pK s in the system and about 5-fold was caused by a change in the reaction rate of the cyclodextrin. 

The reason for interest in the details is that the acceleration with I was very large compared with that which had been observed previously with cyclodextrin reactions. In fact, in a system with 60% DMSO-40% H20 and hydroxide supplied by a buffer that in H20 would have a pH of 6.8, the Vmax was 0.18 sec-1. This represented an acceleration 750,000-fold compared with hydrolysis by the hydroxide ion alone in this same buffered medium in the absence of cyclodextrin. The product of this reaction was the ferrocinnamate ester of cyclodextrin, which then hydrolyzed slowly in a second step to the salt of the free acid. 

Kinetic experiments Either PMHS or HMS-301 reacted in toluene at 60 °C with peracetylated monoaUyl P-cyclodextrin in stoichiometric amounts with respect to Si-H. The concentration of P-cyclodextrin and Si-H was 0.032mol/L. The concentration of Karstedt catalyst was 20ppm of platinum content. Ahquots of the reaction medium were coUected at different times and the solutions were directly analyzed by IR spectroscopy in a hquid cell. The absorbance of the Si-H band at 2160cm was normalized to the absorbance of the C=0 stretching band of the ester at 1740cm . The decrease of the Si-H band was plotted as a function of time. The conversion is the complement to 100%. 

Water is the usual reaction medium for enzymes however, organic solvents or cyclodextrins can be added to increase the solubility of poorly soluble compoimds. While multienzyme donor recycling systems can be used for in situ donor production [12,19], the following examples utilize stoichiometric donors. 

Intramolecular versions of the aqueous Diels-Alder reactions have also been investigated, though not to the same extent as with their bimolecular counterparts. However, since intramolecular reactions often exhibit considerable rate enhancements due to lowering of the entropy of activation, and the unique conformational aspects of the (necessarily cyclic) transition state can result in enhanced selectivities, it is not always clear what effect water has on a particular intramolecular Diels-Alder process. The situation is often complicated by the routine addition of p-cyclodextrin to the reaction medium. Blokzijl and Engberts have reported quantitative data on the intramolecular cycloadditions of substrates 6.1 in water and various solvents as a function of substituent R [71]. 

Micellar medium has received great attention because it solubilizes, concentrates and orientates the reactants within the micelle core and in this way accelerates the reaction and favors the regio- and stereoselectivity of the process [68], In addition the micellar medium is cheap, can be reused, is more versatile than cyclodextrins and more robust than enzymes. With regard to Diels Alder reactions, we may distinguish between (i) those in which one or both reagents are surfactants which make up the micellar medium, and (ii) those that are carried out in a micellar medium prepared by a suitable surfactant. 

The Diels-Alder reaction of nonyl acrylate with cyclopentadiene was used to investigate the effect of homochiral surfactant 114 (Figure 4.5) on the enantioselectivity of the reaction [77]. Performing the reaction at room temperature in aqueous medium at pH 3 and in the presence of lithium chloride, a 2.2 1 mixture of endo/exo adducts was obtained with 75% yield. Only 15% of ee was observed, which compares well with the results quoted for Diels-Alder reactions in cyclodextrins [65d]. Only the endo addition was enantioselective and the R enantiomer was prevalent. This is the first reported aqueous chiral micellar catalysis of a Diels-Alder reaction. 

The same authors studied the CL of 4,4,-[oxalylbis(trifluoromethylsulfo-nyl)imino]to[4-methylmorphilinium trifluoromethane sulfonate] (METQ) with hydrogen peroxide and a fluorophor in the presence of a, p, y, and heptakis 2,6-di-O-methyl P-cyclodextrin [66], The fluorophors studied were rhodamine B (RH B), 8-aniline-l-naphthalene sulfonic acid (ANS), potassium 2-p-toluidinylnaph-thalene-6-sulfonate (TNS), and fluorescein. It was found that TNS, ANS, and fluorescein show CL intensity enhancement in all cyclodextrins, while the CL of rhodamine B is enhanced in a- and y-cyclodextrin and reduced in P-cyclodextrin medium. The enhancement factors were found in the range of 1.4 for rhodamine B in a-cyclodextrin and 300 for TNS in heptakis 2,6-di-O-methyl P-cyclodextrin. The authors conclude that this enhancement could be attributed to increases in reaction rate, excitation efficiency, and fluorescence efficiency of the emitting species. Inclusion of a reaction intermediate and fluorophore in the cyclodextrin cavity is proposed as one possible mechanism for the observed enhancement. 

Provided due attention is paid to the potential deprotonation of the substrate, and of the cyclodextrins (VanEtten et al., 1967a,b Gelb et al., 1980, 1982 Tee and Takasaki, 1985), the value of Ks should not be pH dependent. However, for many reactions, such as the widely studied ester cleavage, ku, kc, and k2 are all dependent on the pH of the medium. This makes direct comparisons between the observed constants for different CD-mediated reactions either difficult or problematical. However, in general, the ratios kc/ku and k2/ku are independent of pH and so are more useful for comparative purposes. 

D. Reaction Cavities with Strong External Medium Influences Cyclodextrin Complexes and Their Aqueous Solutions... 

Photolyses of the solid cyclodextrin complexes 1 were carried out with a Hano-via 450-W medium-pressure Hg lamp for 3 h at room temperature in a quartz vessel under vacuum. The photolysis vessel was tumbled continuously during the irradiation to ensure homogeneous photolysis of the sample. Conversions were limited to less than 20%. After photolysis, the solid complexes were dissolved in excess water and extracted with diethyl ether and chromatographed with hexane-ethyl acetate (5 1) to isolate the products in pure form. Irradiation of solid / -cy-clodextrin complexes of benzaldehyde resulted in an intramolecular reaction to give benzoin (/ )-(-)-2 and 4-benzoylbenzaldehyde 3 (7 3, 80%). 

The ESIPT of 2-(2 -hydroxyphenyl)-4-methyloxazole (HPMO) (27) has been explored by Douhal and co-workers [166] for its probe characteristics in a variety of organized media which include cyclodextrin, calixarene, micelle, and HSA. The incorporation of HPMO into hydrophobic cavities in an aqueous medium involves the rupture of its intermolecular hydrogen bond to water and formation of an intramolecular hydrogen bond in the sequestered molecule. Upon excitation (280-330 nm) of this entity, a fast intramolecular proton-transfer reaction of the excited state produces a phototautomer (28), the fluorescence of which (Xm = 450 170 nm) shows a largely Stokes-shifted band. Because of the existence of a twisting motion around the C2—C bond of this phototautomer, the absorption and emission properties of the probe depend on the size of the host cav-... 

Mechanisms have been suggested for the N-bromosuccinimide (NBS) oxidation of cyclopentanol and cyclohexanol, catalysed by iridium(III) chloride,120 of ethanolamine, diethanolamine, and triethanolamine in alkaline medium,121 and for ruthenium(III)-catalysed and uncatalysed oxidation of ethylamine and benzylamine.122 A suitable mechanism has been suggested to explain the break in the Hammett plot observed in the oxidation of substituted acetophenone oximes by NBS in acidic solution.123 Oxidation of substituted benhydrols with NBS showed a C-H/C-D primary kinetic isotope effect and a linear correlation with er+ values with p = —0.69. A cyclic transition state in the absence of mineral acid and a non-cyclic transition state in the presence of the acid are proposed.124 Sulfides are selectively oxidized to sulfoxides with NBS, catalysed by ft-cyclodextrin, in water. This reaction proceeds without over-oxidation to sulfones under mild conditions.125... 

Unlike isotropic media, where molecules have equal mobility and conformational flexibility in all dimensions, in an organized medium their mobility and flexibility are restricted or constrained in at least one dimension. For example, the reaction cavities of a micelle and cyclodextrins are made up of a hydrophobic core and a hydrophilic exterior (Fig. 11). A highly polar boundary separates the hydrophobic core from the aqueous exterior. Such a boundary provides unique features to these media that are absent in isotropic solution. Translational motion of a guest present within the reaction cavity is hindered by the well-defined boundary. 

A good example of this is the classic work by Bender (6) on the reaction ofra-f-butylphenyl acetate. This substrate binds well into the cavity, and the substrate then undergoes an acetyl transfer reaction in which a cyclodextrin hydroxyl group is acetylated. The reaction can be compared with the first step in the action of a serine esterase, or a serine protease acting on an ester substrate. However, the acceleration of this acetyl transfer, compared with simple hydrolysis by the medium, was only 250-fold. 

Before we could take up this study in general, we had to solve one of the more bothersome aspects of cyclodextrin chemistry. It was believed strongly that cyclodextrin would bind substrates only in pure water solution, and this was a serious defect. First of all, it severely restricted the range of substrates that could be examined, since many interesting molecules have low water solubility. As a second point, it made it difficult to examine another feature of enzyme-catalyzed reactions. One of the roles that can be ascribed to the large protein mass, which contains the functional groups of an enzyme, is the function of water exclusion. That is, enzyme reactions can be considered to be operating in a nonaqueous or only partially aqueous medium. 

The p-cyclodextrin-catalyzed reaction of phenols and carbon tetrachloride in an alkaline medium in the presence of copper powder also results in almost exclusive attack at the para-position to give 4-hydroxybenzoic acids. 2-Methylphenol also undergoes almost exclusive para-carboxylation. P-Cyclodextrin has only a negligible effect on the carbox-ylation of 3-methylphenol.-... 

Catalytic reactions in aqueous solution can be modified by changes in the supramolecular state of the medium in which they are conducted. One approach to using medium changes to influence catalytic reactions is to introduce host molecules, such as cyclodextrins, into the reaction mixtures. Cyclodextrins have inner lipophilic cavities enclosed by hydrophilic surfaces. A cyclodextrin can bind a hydrophilic terminal alkene into its... 

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... 

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