Acceleration, of the Diels-Alder reaction

Comparison of the water-induced acceleration of the reaction of 2.4a with the corresponding effect on 2.4g is interesting, since 2.4g contains an ionic group remote from the reaction centre. The question arises whether this group has an influence on the acceleration of the Diels-Alder reaction by water. Comparison of the data in Table 2.1 demonstrates that this is not the case. The acceleration upon going from ethanol to water amounts a factor 105 ( 10) for 2.4a versus 110 ( 11) for 2.4g. Apparently, the introduction of a hydrophilic group remote from the reaction centre has no effect on the aqueous acceleration of the Diels-Alder reaction. 

In organic solvents Lewis-acid catalysis also leads to large accelerations of the Diels-Alder reaction. Table 2.2 shows the rate constants for the Cu -catalysed Diels-Alder reaction between 2.4a and 2.5 in different solvents. 

Acceleration of the Diels-Alder reaction by clays suspended in organic solvents [7]... 

The Diels-Alder reaction is one of the most important methods used to form cyclic structures and is one of the earliest examples of carbon-carbon bond formation reactions in aqueous media.21 Diels-Alder reactions in aqueous media were in fact first carried out in the 1930s, when the reaction was discovered,22 but no particular attention was paid to this fact until 1980, when Breslow23 made the dramatic observation that the reaction of cyclopentadiene with butenone in water (Eq. 12.1) was more than 700 times faster than the same reaction in isooctane, whereas the reaction rate in methanol is comparable to that in a hydrocarbon solvent. Such an unusual acceleration of the Diels-Alder reaction by water was attributed to the hydrophobic effect, 24 in which the hydrophobic interactions brought together the two nonpolar groups in the transition state. 

TABLE 1. Pressure-induced rate acceleration of the Diels-Alder reaction of isoprene with acrylonitrile at 21 °C (AV = -35.4 cm3 mol-1, AV = -37.0 cm3 mol-1)28... 

TABLE 1. Pressure-induced rate acceleration of the Diels-Alder reaction of isoprene with acryloni-... 

Yates P, Eaton P (1960) Acceleration of the Diels-Alder Reaction by Aluminum Chloride. J Am Chem Soc 82 4436... 

Yates, P., and P. Eaton Acceleration of the Diels-Alder Reaction by Aluminium Chloride. J. Amer. Chem. Soc. 82, 4436 (1960). 

Another interesting coupled system between Lewis acid and micellar catalysis was developed by Engberts et al. with a million-fold acceleration of the Diels-Alder reaction. It was shown that if in the absence of Lewis acids, the reaction is retarded by micelles of CTAB or SDS—because of the different binding locations between the diene and the dienophile—the addition of copper dodecylsulfate leads to dramatic rate accelerations due to the complexation of the dienophile to the catalytically active copper ions, and to the high local concentration of both species at the micellar surface. ... 

Studies of the Diels-Alder reaction of the ionic dienophile 2.4g have demonstrated that the acpieous acceleration of the uncatalysed reaction as well as the catalysed reaction is not significantly affected by the presence of the ionic group at a site remote from the reaction centre. 

In Chapter 2 the Diels-Alder reaction between substituted 3-phenyl-l-(2-pyridyl)-2-propene-l-ones (3.8a-g) and cyclopentadiene (3.9) was described. It was demonstrated that Lewis-acid catalysis of this reaction can lead to impressive accelerations, particularly in aqueous media. In this chapter the effects of ligands attached to the catalyst are described. Ligand effects on the kinetics of the Diels-Alder reaction can be separated into influences on the equilibrium constant for binding of the dienoplule to the catalyst (K ) as well as influences on the rate constant for reaction of the complex with cyclopentadiene (kc-ad (Scheme 3.5). Also the influence of ligands on the endo-exo selectivity are examined. Finally, and perhaps most interestingly, studies aimed at enantioselective catalysis are presented, resulting in the first example of enantioselective Lewis-acid catalysis of an organic transformation in water. 

From 1928 when Otto Diels and Kurt Alder [1] made their extraordinary discovery until 1960 when Yates and Eaton [2] reported the acceleration of the Diels-Alder cycloadditions by Lewis acid catalysts, these reactions were essentially carried out under thermal conditions owing to the simplicity of the accomplishing thermal process. Since then a variety of methods have been developed to accelerate the reactions. The reaction between 1,3-butadiene and ethylene (Equation 2.1) is a typical example of a thermal Diels-Alder cycloaddition. 

As an approach to biomimetic catalysis, Sanders and colleagues [67] synthesized a series of 1,1,2-linked cyclic porphyrin trimers that allow the stereo- and regiochemistry of the Diels-Alder reaction of 84 and 85 within the molecular cavity to be controlled, thereby producing prevalently or exclusively the endo 86 or the exo 87 adduct. Two examples are illustrated in Scheme 4.18. At 30 °C and in the absence of 88, the reaction furnishes a mixture of diastereoisomers, while the addition of one equivalent of trimer 88 accelerates the reaction 1000-fold and the thermodynamically more stable exo adduct 87 is the sole detectable product. 

Whereas maleic anhydride can react with furan (139a) at ambient pressure, citraconic anhydride (140) reacts only at high pressures due to the strong deactivating effect of the methyl group (Schemes 5.21 and 5.22). The two-step synthesis [53] of the palasonin (141), in an overall yield of 96 %, is a good example of the acceleration of the Diels-Alder by high pressure (Scheme 5.21). Previous synthesis [54] based on the thermal Diels-Alder reaction of furan with methoxy carbonyl maleic anhydride required 12 steps. 

Ijljl-trifluoroethanol (TFE), a solvent with a strong hydrogen-bond donor capacity. This supports the idea that hydrogen-bonding interactions also contribute noticeably to the acceleration of aqueous Diels-Alder reactions. 

After the discovery of the remarkable acceleration of some Diels Alder reactions performed in water, a number of polar non-aqueous solvents and their salty solutions were investigated as reaction medium. This revolutionized the concept that the Diels-Alder reaction is quite insensitive to the effect of the medium and emphasized that a careful choice of the solvent is crucial for the success of the reaction. The polarity of the reaction medium is an important variable which also provides some insights into the mechanism of the reaction. If the reaction rate increases by using a polar medium, this means that the transition state probably has polar character, while the absence of a solvent effect is generally related to an uncharged transition state. 

The powerful pressure-induced acceleration of most Diels-Alder reactions due to their highly negative volumes of activation has been exploited for synthetic purposes. Reviews... 

Despite the fact that Diels and Alder carried out a cycloaddition in water [2], it was not until 1980 that it was reported that large accelerations in the rates of the Diels-Alder reaction could be achieved in water [3], In addition, selectivity towards the endo product was also increased [4], For example, a 700-fold acceleration in the rate of reaction between cyclopentadiene and 3-buten-2-one (Scheme 7.3) was found in water as compared to reaction in 2,2,4-trimethylpentane. The addition of lithium chloride as a salting-out reagent... 

Another example is the influence of ultrasonic sound treatment. In chlorinated or bromi-nated solvents it leads to extreme rate accelerations and higher selectivities (Table 6)84. This observation was explained by the formation of hydrogen halide from the sonolysis of the solvent molecules, followed by protonation of the dienophiles and ordinary acid catalysis. Nevertheless, although there are quite a few aspects of the Diels-Alder reaction which are not totally understood, the general mechanisms leading to selectivities and catalysis are clear. 

The first kinetic study of acceleration of some Diels-Alder reactions in water by Breslow et al. has set the stage for worldwide interest in organic... 

Figure 7.4 The cause of the rate acceleration of (most) Diels-Alder reactions in water.

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