Diels-Alder reactions cyclodextrins

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). 

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]... 

The Diels-Alder reactions of alkyl-substituted benzoquinones with penta-1,3-diene and isoprene were also studied in aqueous cyclodextrin solutions. Highly enhanced ortho- and mefa-regioselectivities were observed (Eq. 12.11).48... 

In recent years, supramolecular chemistry has produced a number of systems which have been shown to be able to effectively catalyze a Diels-Alder reaction. Most systems selectively afforded only one diastereomer because of a pre-organized orientation of the reactants. These systems include cyclodextrines, of which applications in Diels-Alder chemistry have recently been reviewed89. Some other kinds of non-Lewis acid catalyzed Diels-Alder reactions, including catalysis by proteins and ultrasound, have been discussed by Pindur and colleagues90. 

TABLE 27. Rate constants (M 1 s ) for Diels-Alder reactions of cyclopentadiene with several dienophiles in methanol, water and a, 6-cyclodextrin 12 water solution 125... 

Another successful example of such guest design is the Diels-Alder reaction markedly accelerated by the cyclodextrin inclusion. As shown in Table XXIV, /J-cyclodextrin accelerates the addition of a small dienophile to cyclopentadiene, but inhibits that of N-ethylmaleimide to anthracene-9-carbinol (117). Thus, the guest design is a really helpful concept for the remarkable catalysis. However, there seems to be some limitation in the choice of reactions, if cyclodextrins have no special functional group for the... 

Diels-Alder catalysis. Water can accelerate the Diels-Alder reaction of cyclopentad iene with methyl vinyl ketone or acrylonitrile by a hydrophobic interaction. / -Cyclodextrin can increase this effect, possibly because the components can fit into the hydrophobic cavity.1... 

SchneidCT, H.-J. Sangwan, N. K. Changes of stereoselectivity in Diels-Alder reactions by hydrophobic solvent effects and by p-cyclodextrin, Angew. Chem. Int. Ed. Engl 1987,26, 896-897. 

Kim SP, Leach AG, Honk KN. The origins of noncovalent catalysis of intermolecular Diels-Alder reactions by cyclodextrins, self-assembling capsules, antibodies, and RNAses. J. Org. Chem. 105. 2002 67(12) 4250-4260. 

On the basis of the pronounced non-polar character of the majority of Diels-Alder reactants, efficient micellar catalysis of their reaction might be anticipated. The first time a micellar catalysed Diels-Alder reaction was mentioned, not the micelle itself, but some type of micellar catalysis, resulting in mutual binding of reactants was suggested to be responsible for the observed rate accelerations . Further investigations on the catalytic activity of micelles showed that several species which are able to form micelles in aqueous solution lead to higher yields in intramolecular Diels-Alder reactions . In detailed studies of the effects of /3-cyclodexlrin 12 on the rates of Diels-Alder reactions " it became clear that the infiuence of cyclodextrin micelles can lead either to inhibition or to acceleration (Table 27). 

In this pioneering work [la], Breslow studied the kinetics of the cycloaddition between cyclopentadiene and methyl vinyl ketone (Eq. (1) and Table 1). The implication of the hydrophobic effect in Diels-Alder reactions was extensively supported by the effect of cyclodextrins [26] and additives, such as lithium chloride (salting-out agent) or guanidinium chloride (salting-in agent), which respectively increases or decreases the rate of the reaction [27]. 

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