Solvent effects on Diels-Alder reactions

Solvents exert their influence on organic reactions through a complicated mixture of all possible types of noncovalent interactions. Chemists have tried to unravel this entanglement and, ideally, want to assess the relative importance of all interactions separately. In a typical approach, a property of a reaction (e.g. its rate or selectivity) is measured in a laige number of different solvents. All these solvents have unique characteristics, quantified by their physical properties (i.e. refractive index, dielectric constant) or empirical parameters (e.g. ET(30)-value, AN). Linear correlations between a reaction property and one or more of these solvent properties (Linear Free Energy Relationships - LFER) reveal which noncovalent interactions are of major importance. The major drawback of this approach lies in the fact that the solvent parameters are often not independent. Alternatively, theoretical models and computer simulations can provide valuable information. Both methods have been applied successfully in studies of the solvent effects on Diels-Alder reactions. 

3a Solvent effects on the rate of Diels-Alder reactions 

Desimoni et al. initially advocated the Acceptor Number (AN) as the dominant solvent parameter The AN describes the ease with which a solvent can act as an electron pair acceptor (Lewis acid) and 

Studies by the group directed by Mayoral have been limited to Diels-Alder reactions of type A. When water was not included, the rate constants correlate with the solvent hydrogen-bond-donating capacity Upon inclusion of water the solvophobidty parameter, Sp, contributed significantly in 

Recently the solvent effect on the [4+2] cycloaddition of singlet oxygen to cyclic dienes has been subjected to a multiparameter analysis. A pre-equilibrium with charge-transfer character is involved, which is affected by the solvent through dipolarity-polarisability (n ) and solvophobic interactions ( Sjf and Another multiparameter analysis has been published by Gajewski, demonstrating the 

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In this chapter we wish to review the collected evidence for the astonishing effects of water on reactivities and selectivities as exemplified by the Diels-Alder reactions of dienes. Examples of Lewis acid and micellar catalysis in aqueous media are also presented. Finally, the newest computational investigations including solvent effects on Diels-Alder reactions are put forward in order to rationalize some of the remarkable observations. 

In summary, the interactions responsible for the typical solvent effects on Diels-Alder reactions are comparable to those of Lewis acids. The rate acceleration, the increase of regioselectivity and the higher endo/exo selectivity on changing the solvent may be explained by the FMO theory. 

Diels-Alder reactions. This tenn describes how much energy is needed for evaporation of the solvent per unit of volume and represents a measure of the internal water-water interactions. In contrast to the internal pressure, the ced of water is extremely high due to the large number of hydrogen bonds per unit volume. Since solvation and cavity formation lead to the rupture of solvent-solvent interactions, the ced essentially quantifies solvophobicity and hydrophobicity, and has been used successfully for describing solvent effects on Diels-Alder reactions. These studies stress the importance of hydrophobic interactions. The significance of these and the relative unimportance of internal pressure is further supported by the observation that Diels-Alder reactions in water are less accelerated by pressure than those in organic solvents, which is in line with the notion that pressure diminishes hydrophobic interactions. 

Bini, R., Chiappe, C., Mestre, VL., Pomelli, C.S. and Welton, T., A theoretical study of the solvent effect on Diels-Alder reaction in room temperature ionic liquids using a supermolecular approach, Theor. Chem. Acc. 123, 347-352 (2009). 

This chapter introduces the experimental work described in the following chapters. Some mechanistic aspects of the Diels-Alder reaction and Lewis-acid catalysis thereof are discussed. This chapter presents a critical survey of the literature on solvent ejfects on Diels-Alder reactions, with particular emphasis on the intriguing properties of water in connection with their effect on rate and selectivity. Similarly, the ejfects of water on Lewis acid - Lewis base interactions are discussed. Finally the aims of this thesis are outlined. 

Blokzijl, W., and Engberts, J.B.F.N.J. (1992) Initial-state and transition-state effects on Diels-Alder reactions in water and mixed aqueous solvents./. Am. Chem. Soc. 114, 5440-5442. 

In further studies of the remarkable water effects on Diels-Alder reactions, we examined the exo-endo selectivity of the processes. We saw that butenone added with a 95.7% preference for endo addition in water, but only an 80% endo preference in cyclopentadiene as solvent. Thus the endo addition is favored not only by secondary orbital overlap , it is even more strikingly favored by the hydrophobic effect. In the transition state for the addition reaction, the endo geometry diminishes the amount of water/hydrocarbon interface more than does the exo geometry. The high energy of a hydrocarbon/water interface is the cause of hydrophobicity, the tendency of nonpolar materials and segments to cluster in water so as to diminish the interface with water. 

As additional evidence for hydrophobic effects in the Diels-Alder reaction, there was a great inaease in the preference for an endo geometry in the Diels-Alder reactions in water [11], as expected if the transition state becomes more compact to minimize exposure of hydrocarbon segments to the water solvent. This endo preference was also inaeased to some extent when LiCl was added, and decreased when GnCl was the additive. Other evidence has also been cited for a hydrophobic effect on Diels-Alder reactions [12], and the water effect on geometric selectivity has been used in synthetic applications [13]. 

Tire importance of hydrophobic interactions in the aqueous acceleration is further demonstrated by a qualitative study described by Jenner on the effect of pressure on Diels-Alder reactions in water and a number of organic solvents. Invariably, the reactions in water were less accelerated by pressure than those in organic solvents, which is in line with the notion that pressure diminishes hydrophobic interactions. 

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. 

First of all, given the well recognised promoting effects of Lewis-acids and of aqueous solvents on Diels-Alder reactions, we wanted to know if these two effects could be combined. If this would be possible, dramatic improvements of rate and endo-exo selectivity were envisaged Studies on the Diels-Alder reaction of a dienophile, specifically designed for this purpose are described in Chapter 2. It is demonstrated that Lewis-acid catalysis in an aqueous medium is indeed feasible and, as anticipated, can result in impressive enhancements of both rate and endo-exo selectivity. However, the influences of the Lewis-acid catalyst and the aqueous medium are not fully additive. It seems as if water diminishes the catalytic potential of Lewis acids just as coordination of a Lewis acid diminishes the beneficial effects of water. Still, overall, the rate of the catalysed reaction... 

Further examples of Diels-Alder cycloaddition reactions with small or negligible rate solvent effects can be found in the literature [531-535], The thermolysis of 7-oxabicyclo[2.2.1]hept-5-ene derivatives is an example of a solvent-independent retro-Diels-Alder reaction [537]. For some theoretical treatments of the solvent influence on Diels-Alder cycloaddition reactions, which, in general, confirm their small solvent-dependence, see references [536, 797-799]. 

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