Diels-Alder reactions salt effects

Breslow supported this suggestion by demonstrating that the cycloaddition can be further accelerated by adding anti cliaotropic salts such as lithium chloride, whereas chaotropic salts such as guanidium chloride led to a retardation " "" ". On the basis of these experiments Breslow excluded all other possible explanations for the special effect of water on the Diels-Alder reaction " . 

Three years after the Breslow report on the large effects of water on the rate of the Diels-Alder reaction, he also demonstrated tliat the endo-exo selectivity of this reaction benefits markedly from employing aqueous media . Based on the influence of salting-in and saltirg-out agents, Breslow pinpoints hydrophobic effects as the most important contributor to the enhanced endo-exo... 

Breslow studied the dimerisation of cyclopentadiene and the reaction between substituted maleimides and 9-(hydroxymethyl)anthracene in alcohol-water mixtures. He successfully correlated the rate constant with the solubility of the starting materials for each Diels-Alder reaction. From these relations he estimated the change in solvent accessible surface between initial state and activated complex " . Again, Breslow completely neglects hydrogen bonding interactions, but since he only studied alcohol-water mixtures, the enforced hydrophobic interactions will dominate the behaviour. Recently, also Diels-Alder reactions in dilute salt solutions in aqueous ethanol have been studied and minor rate increases have been observed Lubineau has demonstrated that addition of sugars can induce an extra acceleration of the aqueous Diels-Alder reaction . Also the effect of surfactants on Diels-Alder reactions has been studied. This topic will be extensively reviewed in Chapter 4. 

Furthermore, the number of diene - dienoplrile combinations that can be expected to undergo a Lewis-acid catalysed Diels-Alder reaction is limited. Studies by Wijnen leave little doubt that the rate of typical Diels-Alder reactions, where the dienophile is activated by one or more carbonyl functionalities, does not respond to the presence of Lewis acids in aqueous solution , at least not beyond the extent that is expected for non-specific interactions (salt effects). No coordination of the Lewis acid to the dienophile was observed in these cases, which is perhaps not surprising. Water is... 

Turning the argument around reactions that do not involve proton transfer steps will only experience a significant effect of the Lewis acids if a direct interaction exists between catalyst and reactant. The conventional Diels-Alder reaction is a representative of this class of reactions. As long as monodentate reactants are used, the effects of Lewis acids on this reaction do not exceed the magnitude expected for simple salt effects, i.e. there are no indications for a direct interaction between Lewis-acid and substrate. 

Table 1.21 Effect of metal salt on enantioselectivity in the Diels-Alder reaction of cyclopentadiene and acryloyloxazolidinone [22 ...

Kobayashi et al. have reported the use of a chiral lanthanide(III) catalyst for the Diels-Alder reaction [51] (Scheme 1.63, Table 1.26). Catalyst 33 was prepared from bi-naphthol, lanthanide triflate, and ds-l,2,6-trimethylpiperidine (Scheme 1.62). When the chiral catalyst prepared from ytterbium triflate (Yb(OTf)3) and the lithium or sodium salt of binaphthol was used, less than 10% ee was obtained, so the amine exerts a great effect on the enantioselectivity. After extensive screening of amines, ds-1,2,6-... 

The first studies on cation-radical Diels-Alder reactions were undertaken by Bauld in 1981 who showed [33a] the powerful catalytic effect of aminium cation radical salts on certain Diels-Alder cycloadditions. For example, the reaction of 1,3-cyclohexadiene with trans, iraw5-2,4-hexadiene in the presence of Ar3N is complete in 1 h and gives only the endo adduct (Equation 1.14) [33]. 

Rideout and Breslow first reported [2a] the kinetic data for the accelerating effect of water, for the Diels Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile and the cycloaddition of anthracene-9-carbinol with N-ethylmaleimide, giving impetus to research in this area (Table 6.1). The reaction in water is 28 to 740 times faster than in the apolar hydrocarbon isooctane. By adding lithium chloride (salting-out agent) the reaction rate increases 2.5 times further, while the presence of guanidinium chloride decreases it. The authors suggested that this exceptional effect of water is the result of a combination of two factors the polarity of the medium and the... 

Table 6.2 Sodium and guanidinium salt effects (relative reaction rates) of Diels-Alder reaction of anthracene-9-carbinol and N-ethylmaleimide...

Kumar A. Salt Effects on Diels-Alder Reaction Kinetics Chem. Rev. 20011011 19... 

Kobayashi has found that scandium triflate, Sc(OTf)3,36 and lanthanide triflate, Ln(OTf)3, are stable and can be used as Lewis catalysts under aqueous conditions. Many other Lewis acids have also been reported to catalyze Diels-Alder reactions in aqueous media. For example, Engberts reported37 that the cyclization reaction in Eq. 12.7 in an aqueous solution containing 0.010 M Cu(N03)2 is 250,000 times faster than that in acetonitrile and about 1,000 times faster than that in water alone. Other salts, such as Co2+, Ni2+, and Zn2+, also catalyze the reaction, but not as effectively as Cu2+. However, water has no effect on the endo-exo selectivity for the Lewis-acid catalyzed reaction. 

TABLE 5-3. Solvent Effect of Amino Acid Salt-Catalyzed Diels-Alder Reaction... 

Otto et al. studied asymmetric Diels-Alder reactions in the presence of the copper salts of glycine, L-valine, L-leucine, L-phenylalanine, L-tyrosine, l-tryptophan, and /V-a-L-tryptophan (L-abrine). The copper salt of L-abrine gave the highest enantioselectivity. Table 5 3 compares the solvent effect in this reaction, and clearly water is the best solvent among the solvent systems studied. 

Desimoni and coworkers84 probed the catalytic effect of metal perchlorate salts on the rate of the Diels-Alder reactions between malonates 88 and cyclopentadiene (equation 27). They found that especially magnesium perchlorate was able to catalyze the reaction by binding two malonates in a bidentate fashion. Reaction times were shortened up to 1000 times. The endo/exo selectivity was inverted from 89/90 = 40/60 (n =4) and 17/83 (n = 5) for the thermal uncatalyzed reactions to 89/90 = 60/40 (n = 4) and 80/20 (n = 5) for the magnesium perchlorate catalyzed reactions. 

Diets-Alder catalysis.2 This cation radical enhances the reactivity of a neutral or electron-rich eis-1,3-diene in Diels-Alder reactions. Thus 1,3-cyclohexadiene undergoes Diels-Alder dimerization only at temperatures around 200°. The presence of 5-10 mole % of this salt effects dimerization even at —78°, with the usual endo/ exo selectivity (5 1). It also permits facile condensation of 1,3-cyclohexadiene with a hindered dienophile such as 2,5-dimethyl-2,4-hexadiene (equation 1) the dimer of the former diene is a minor product (20% yield). 

Diels-Alder reactivity of thiophene and benzothiophene remains poorly understood. AMI semiempirical studies examining the activation of thiophene for this thermally allowed [4+2] cycloaddition process have shown that the usual synthesis approaches (use of highly reactive dienophiles, substitution on thiophene, increased reaction pressures) have only small effects on rate enhancement. However, use of the corresponding S-methylthiophenium salts, which have little aromaticity, should provide excellent activation for Diels-Alder reactions of thiophenes even with poor dienophiles such as ethylene <95JHC483>. This AMI approach has been applied to examine Diels-Alder reactions of benzo[6] and benzo[c]thiophenes the theoretical data agree with experimental results <95JCS(P1)1217>. 

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