Diels-Alder reaction entropy effects

Unfortunately, the number of mechanistic studies in this field stands in no proportion to its versatility" . Thermodynamic analysis revealed that the beneficial effect of Lewis-acids on the rate of the Diels-Alder reaction can be primarily ascribed to a reduction of the enthalpy of activation ( AAH = 30-50 kJ/mole) leaving the activation entropy essentially unchanged (TAAS = 0-10 kJ/mol)" . Solvent effects on Lewis-acid catalysed Diels-Alder reactions have received very little attention. A change in solvent affects mainly the coordination step rather than the actual Diels-Alder reaction. Donating solvents severely impede catalysis . This observation justifies the widespread use of inert solvents such as dichloromethane and chloroform for synthetic applications of Lewis-acid catalysed Diels-Alder reactions. 

Most Diels-Alder reactions, particularly the thermal ones and those involving apolar dienes and dienophiles, are described by a concerted mechanism [17]. The reaction between 1,3-butadiene and ethene is a prototype of concerted synchronous reactions that have been investigated both experimentally and theoretically [18]. A concerted unsymmetrical transition state has been invoked to justify the stereochemistry of AICI3-catalyzed cycloadditions of alkylcyclohexenones with methyl-butadienes [12]. The high syn stereospecificity of the reaction, the low solvent effect on the reaction rate, and the large negative values of both activation entropy and activation volume comprise the chemical evidence usually given in favor of a pericyclic Diels-Alder reaction. 

By measuring activation parameters (Eq. (2) and Table 2), it has been shown that the cceleration arises from a favorable change of activation entropy, which is an indication of the implication of the hydrophobic effect [32], Concentrated aqueous carbohydrate solutions (glucose and saccharose for instance) have been shown to accelerate the Diels-Alder reaction. The acceleration is even greater than that observed with saturated fi-cyclodextrin solution (Eq. (3) and Table 3) [32],... 

The influence of the hydrophobic effect on the aqueous pericychc reactions can be compared with the effect of catalytic antibodies. Antibodies have been found to catalyze Diels-Alder reactions, hetero-Diels-Alder reactions, and Claisen and oxy-Cope rearrangements. It is suggested that antibodies catalyze these reactions by acting as an entropy trap, primarily through binding and orienting the substrates in the cyclic conformations. 

Figure 11.19 Diels-Alder reaction catalyzed by entropy trap antibody Hexachloronorbonrnene that mimics the expected transition state is used as hapten (shown under the transition state) to elicit the antibody which effectively catalyzes the bimolecular...

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]. 

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