Hydrophobic interactions, enforced

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. 

The relative extents to which enforced hydrophobic interactions and hydrogen bonding influence the rate of the Diels-Alder reaction depends on the particular reaction under study". 

Appreciating the beneficial influences of water and Lewis acids on the Diels-Alder reaction and understanding their origin, one may ask what would be the result of a combination of these two effects. If they would be additive, huge accelerations can be envisaged. But may one really expect this How does water influence the Lewis-acid catalysed reaction, and what is the influence of the Lewis acid on the enforced hydrophobic interaction and the hydrogen bonding effect These are the questions that are addressed in this chapter. 

Throughout this thesis reference has been made to hydrophobic effects. Enforced hydrophobic interactions are an important contributor to the acceleration of uncatalysed and also of the Lewis-acid catalysed Diels-Alder reactions which are described in this thesis. Moreover, they are likely to be involved in the beneficial effect of water on the enantioselectivity of the Lewis-acid catalysed Diels-Alder reaction, as described in Chapter 3. Because arguments related to hydrophobic effects are spread over nearly all chapters, and ideas have developed simultaneously, we summarise our insights at the end of this thesis. 

Also the arene-arene interactions, as encountered in Chapter 3, are partly due to hydrophobic effects, which can be ranked among enforced hydrophobic interactions. Simultaneous coordination of an aromatic oc amino acid ligand and the dienophile to the central copper(II) ion offers the possibility of a reduction of the number of water molecules involved in hydrophobic hydration, leading to a strengthening of the arene-arene interaction. Hence, hydrophobic effects can have a beneficial influence on the enantioselectivity of organic reactions. This effect is anticipated to extend well beyond the Diels-Alder reaction. 

The type of enforced hydrophobic effect that is operative in the retro Diels-Alder reaction cannot be referred to an enforced hydrophobic interaction, since there is no coming together, but rather a separation of nonpolar molecules during the reaction. It is better to refer to this process as an enforced hydrophobic effect. 

The rate of the Lewis-acid catalysed Diels-Alder reaction in water has been compared to that in other solvents. The results demonstrate that the expected beneficial effect of water on the Lewis-acid catalysed reaction is indeed present. However, the water-induced acceleration of the Lewis-add catalysed reaction is not as pronounced as the corresponding effect on the uncatalysed reaction. The two effects that underlie the beneficial influence of water on the uncatalysed Diels-Alder reaction, enforced hydrophobic interactions and enhanced hydrogen bonding of water to the carbonyl moiety of 1 in the activated complex, are likely to be diminished in the Lewis-acid catalysed process. Upon coordination of the Lewis-acid catalyst to the carbonyl group of the dienophile, the catalyst takes over from the hydrogen bonds an important part of the activating influence. Also the influence of enforced hydrophobic interactions is expected to be significantly reduced in the Lewis-acid catalysed Diels-Alder reaction. Obviously, the presence of the hydrophilic Lewis-acid diminished the nonpolar character of 1 in the initial state. 

Water has physical hemical properties that are very different from those of other solvents [1] and its role in enhancing the reactivity and selectivity of some organic reactions is still a debated question. Recent experimental studies [3e, 9] and computer simulations [10] seem to indicate, at least with respect to the rate enhancement of aqueous Diels Alder reactions, that the main effects are due to the enforced hydrophobic interactions and hydrogen bond interactions. 

Density functional theory study of aqueous-phase rate acceleration and endo/exo selectivity of the butadiene and acrolein Diels-Alder reaction72 shows that approximately 50% of the rate acceleration and endo/exo selectivity is attributed to hydrogen bonding and the remainder to bulk-phase effects, including enforced hydrophobic interactions and cosolvent effects. This appears to be supported by the experimental results of Engberts where a pseudothermodynamic analysis of the rate acceleration in water relative to 1-propanol and 1-propanol-water mixtures indicates that hydrogen-bond stabilization of the polarized activated complex and the decrease of the hydrophobic surface area of the reactants during the activation process are the two main causes of the rate enhancement in water.13... 

The pseudothermodynamic analysis of solvent elfects in 1-PrOH-water mixtures over the whole composition range (shown in Figure 7.3) depicts a combination of thermodynamic transfer parameters for diene and dienophile with isobaric activation parameters that allows for a distinction between solvent elfects on reactants (initial state) and on the activated complex. The results clearly indicate that the aqueous rate accelerations are heavily dominated by initial-state solvation effects. It can be concluded that for Diels-Alder reactions in water the causes of the acceleration involve stabilization of the activated complex by enforced hydrophobic interactions and by hydrogen bonding to water (Table 7.1, Figure 7.4). °... 

Diels-Alder reactions (and other cycloadditions) are accelerated in water due to a combination of enforced hydrophobic interactions and hydrogen bonding, their relative contributions depending on the nature of the diene and dienophile. Subsequent work has shown that a large variety of other organic reactions show comparable favorable characteristics in aqueous media. 

Engberts, J. B. R N. Diels-Alder reactions in water Enforced hydrophobic interaction and hydrogen bonding, PureAppl. Chem. 1995, 67, 823-828. 

The Diels-Alder reaction in water has been used as a key step in the synthesis of ( )-l 1-ketotestosterone (Scheme 5.8) by De Clcrcq. The rate enhancement in water medium is due to the enforced hydrophobic interaction between diene and dienophile. The H-bonding properties of H2O molecules to the activated complex play a major role in selectivity. 

According to Table 10.23, there is an additional term AAV of about 4 cm mol when the reaction is run in the presence of PNB. This result is ascribed to enhanced hydrogen bonding and not to any change in magnitude of the enforced hydrophobic interactions due to the presence of PNB. The increase of AV in the... 

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