Cyclodextrins reactions

Table 2 Telomerization of butadiene with ethylene glycol with addition of cyclodextrins. Reaction conditions 0.06 mol % Pd(acac)2/0.3 mol % TPPTS based on ethylene glycol Pd/P =1 5 butadiene/ethylene glycol = 2.5 1, si = ethylene glycol water 2 1, 80°C 4h 1200 rpm...

Since the time of Schardinger, one of the most important reasons for studying the cyclodextrins was for the information they might yield on the structure of starch and of the well known blue iodine-starch complex. In fact, the similarity between the iodine-starch reaction and the iodine-alpha cyclodextrin reaction was first noted by Schardinger in 1911, in his final paper on the cyclodextrins. 

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. 

Iwakura et al. have reported (15) that the secondary hydroxyls of cyclodextrin can be sulfonated selectively by carrying out reactions in aqueous solution so as to take advantage of the binding of toluenesul-fonyl chloride into the cavity, but we cannot confirm this for at least /3-cyclodextrin. Reaction of j3-cyclodextrin with toluenesulfonyl chloride under the conditions described (14) leads to a very bad mixture of products, in which one of the components is certainly the simple primary tosylate. Perhaps this situation is different for a-cyclodextrin. Accordingly, we have adopted a more mundane approach. 

Fig. 8. Relations between the acceleration by cyclodextrins and the activation terms in the cyclodextrin-accelerated cleavages of phenyl acetates at 2S°C AAH and AAS are the differences between the values for the cyclodextrin reactions and those for the corresponding alkaline hydrolyses the round points refer to a-cyclodextrin and the square points refer to 8-cyclodextrin. From Komiyama, M. and Bender, M.L. (1978) J. Am. Chem. Soc. 100, 4576. Reproduced by permission of the American Chemical Society, copyright owners.

In a later study on the optimization of metallocene substrates for such cyclodextrin reactions we saw that the two different enantiomers (6) of a fused ring system - in which there was no substrate flexibility - was 62-fold faster for one enantiomer than the other and showed a rate 150 million times as fast for acylation as was the rate of hydrolysis in water at the same pH. We then addressed this with molecular modeling calculations, and saw that quantitative theory accounted well for these tindings. ... 

SYNTHESIS OF 4-HYDROXYBENZOIC ACID USING IMMOBILIZED CYCLODEXTRIN reaction with the catalysis by the 3 CyD residue is conclusive. 

Water-soluble cyclodextrin complexes of water-insoluble monomers were achieved by stirring a slight excess of cyclodextrin derivatives, in most cases RAMEB, and different monomers in water. Several methods were applied to the characterizations of the host- fuest complexes. The most important behavior of the complexes is that the hydrophobic guest monomers become water-soluble by being included into cyclodextrin. Reaction control by thin-layer chromatography (TLC) with methanol as mobile phase, followed by UV detection and iodine development, shows complete conversion to the corresponding cyclodextrin complexes. The Rf values of the complexes are significantly different from the value of imcomplexed monomers and cyclodextrin (Table 1). 

Breslow, R., Trainor, G. and Ueno, A., Optimization of metallocene substrates for cyclodextrin reactions,... 

The reaction is much slower than with RNase (17-fold) but the selectivity is in accordance with an in-line mechanism without pseudo-rotation as is observed with the enzyme (refer to Section 3.3 for details). As in the case of para-chlorination of anisole (p. 291), this example of cyclodextrin reaction gives only one of two possible products. 

Being formed of D-glucose units, cyclodextrins are chiral and chiral induction on substrates have been observed with cyclodextrin reactions (173). 

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). 

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). 

The main supramolecular self-assembled species involved in analytical chemistry are micelles (direct and reversed), microemulsions (oil/water and water/oil), liposomes, and vesicles, Langmuir-Blodgett films composed of diphilic surfactant molecules or ions. They can form in aqueous, nonaqueous liquid media and on the surface. The other species involved in supramolecular analytical chemistry are molecules-receptors such as calixarenes, cyclodextrins, cyclophanes, cyclopeptides, crown ethers etc. Furthermore, new supramolecular host-guest systems arise due to analytical reaction or process. 

Professor Ronald Breslow of Columbia University has carried out a number of organic reactions in the presence of cyclodextrins to study the effect of a molecule s environment on its chemical reactivity. 

As a final example we consider noncovalent molecular complex formation with the macrocyclic ligand a-cyclodextrin, a natural product consisting of six a-D-glucose units linked 1-4 to form a torus whose cavity is capable of including molecules the size of an aromatic ring. Table 4-3 gives some rate constants for this reaction, where L represents the cyclodextrin and S is the substrate ... 

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

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

Water plays a crucial role in the inclusion process. Although cyclodextrin does form inclusion complexes in such nonaqueous solvents as dimethyl sulfoxide, the binding is very weak compared with that in water 13 Recently, it has been shown that the thermodynamic stabilities of some inclusion complexes in aqueous solutions decrease markedly with the addition of dimethyl sulfoxide to the solutions 14,15>. Kinetic parameters determined for inclusion reactions also revealed that the rate-determining step of the reactions is the breakdown of the water structure around a substrate molecule and/or within the cyclodextrin cavity 16,17). 

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. 

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... 

Cycloalkenyl sulphones, reactions of 646 Cycloalkyl aryl sulphones, lithiated 641 Cyclodextrins 59, 72 in asymmetric synthesis of sulphoxides 292... 

The transition state of concerted Diels-Alder reactions has stringent regio- and stereochemical requirements and can assume settled configurations if the reaction is carried out in a molecular cavity. Cyclodextrins, porphyrin derivatives and cyclophanes are the supramolecular systems that have been most investigated. 

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 kinetic effects of water and of cyclodextrins on Diels-Alder reactions. Host-guest chemistry, part 18 [65c]... 

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