Diels solvents

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. 

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. 

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... 

Firestone at al. " demonstrated the importance of solvent density in the special case of intramolecular Diels-Alder reaction in highly viscous media. Efficient packing of the hydrocarbon solvent was... 

In summary, solvents can influence Diels-Alder reactions through a multitude of different interactions, of which the contributions to fire overall rate uniquely depend on the particular solvent-diene-dienophile combination. Scientists usually feel uncomfortable about such a situation and try to extract generalities. When limited to the most extensively studied type A Diels-Alder reactions this approach seems feasible. These Diels-Alder reactions are dominated by hydrogen bonding interactions in combination with solvophobic interactions. This observation predicts a very special role of water as a solvent for type A Diels-Alder reactions, which is described in Section 1.4. 

In 1961 Berson et al. were the first to study systematically the effect of the solvent on the endo-exo selectivity of the Diels-Alder reaction . They interpreted the solvent dependence of the endo-exo ratio by consideririg the different polarities of the individual activated complexes involved. The endo activated complex is of higher polarity than the exo activated complex, because in the former the dipole moments of diene and dienophile are aligned, whereas in the latter they are pointing in... 

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. 

For a long time water was not a popular solvent for the Diels-Alder reaction. Before 1980 its use had been reported only incidentally. Diels and Alder themselves performed the reaction between... 

The extreme influence water can exert on the Diels-Alder reaction was rediscovered by Breslow in 1980, much by coincidence . Whale studying the effect of p-cyclodextrin on the rate of a Diels-Alder reaction in water, accidentally, the addition of the cyclodextrin was omitted, but still rate constants were observed that were one to two orders of magnitude larger than those obtained in organic solvents. The investigations that followed this remarkable observation showed that the acceleration of Diels-Alder reactions by water is a general phenomenon. Table 1.2 contains a selection from the multitude of Diels-Alder reactions in aqueous media that have been studied Note that the rate enhancements induced by water can amount up to a factor 12,800 compared to organic solvents (entry 1 in Table 1.2). 

Alternatively, authors have repeatedly invoked the internal pressure of water as an explanation of the rate enhancements of Diels-Alder reactions in this solvent ". They were probably inspired by the well known large effects of the external pressure " on rates of cycloadditions. However, the internal pressure of water is very low and offers no valid explanation for its effect on the Diels-Alder reaction. The internal pressure is defined as the energy required to bring about an infinitesimal change in the volume of the solvents at constant temperature pi = (r)E / Due to the open and... 

Table 1.2. Relative rate constants of some selected Diels-Alder reactions in water compared to organic solvents of different hydrogen bond donor capacities.

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. 

Studies on solvent effects on the endo-exo selectivity of Diels-Alder reactions have revealed the importance of hydrogen bonding interactions besides the already mentioned solvophobic interactions and polarity effects. Further evidence of the significance of the former interactions comes from computer simulations" and the analogy with Lewis-acid catalysis which is known to enhance dramatically the endo-exo selectivity (Section 1.2.4). 

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. 

In a Lewis-acid catalysed Diels-Alder reaction, the first step is coordination of the catalyst to a Lewis-basic site of the reactant. In a typical catalysed Diels-Alder reaction, the carbonyl oxygen of the dienophile coordinates to the Lewis acid. The most common solvents for these processes are inert apolar liquids such as dichloromethane or benzene. Protic solvents, and water in particular, are avoided because of their strong interactions wifti the catalyst and the reacting system. Interestingly, for other catalysed reactions such as hydroformylations the same solvents do not give problems. This paradox is a result of the difference in hardness of the reactants and the catalyst involved... 

The most effective Lewis-acid catalysts for the Diels-Alder reaction are hard cations. Not surprisingly, they coordinate to hard nuclei on the reacting system, typically oxygen atoms. Consequently, hard solvents are likely to affect these interactions significantly. Table 1.4 shows a selection of some solvents ranked according to their softness. Note that water is one of the hardest... 

In summary, water is clearly an extremely bad solvent for coordination of a hard Lewis acid to a hard Lewis base. Hence, catalysis of Diels-Alder reactions in water is expected to be difficult due to the relative inefficiency of the interactions between the Diels-Alder reactants and the Lewis-acid catalyst in this medium. 

A combination of the promoting effects of Lewis acids and water is a logical next step. However, to say the least, water has not been a very popular medium for Lewis-acid catalysed Diels-Alder reactions, which is not surprising since water molecules interact strongly with Lewis-acidic and the Lewis-basic atoms of the reacting system. In 1994, when the research described in this thesis was initiated, only one example of Lewis-acid catalysis of a Diels-Alder reaction in water was published Lubineau and co-workers employed lanthanide triflates as a catalyst for the Diels-Alder reaction of glyoxylate to a relatively unreactive diene . No comparison was made between the process in water and in organic solvents. 

What is the effect of water on the rate and selectivity of the Lewis-acid catalysed Diels-Alder reaction, when compared to oiganic solvents Do hydrogen bonding and hydrophobic interactions also influence the Lewis-acid catalysed process Answers to these questions will be provided in Chapter 2. 

What is the influence of ligands on the Lewis acid on the rate and selectivity of the Diels-Alder reaction If enantioselectivity can be induced in water, how does it compare to other solvents Chapter 3 deals with these topics. 

The Diels-Alder reaction is often quoted as an example of a reaction that is little influenced by the solvent. However, this is not fully justified, since particularly water can have a pronounced effect on the rate of this reaction. This was first noticed by E elte et al." in 1973 and rediscovered in 1980 by Breslow In the years that followed this intriguing discovery, it turned out that acceleration of Diels-Alder reactions by water is a general phenomenon that can ultimately result in up to 12,800 fold accelerations". Synthetic applications followed rapidly". ... 

Table 2,1, Second-order rate constants (k2) for the nncatalysed Diels-Alder reaction of 2,4a and2.4g with 2,5 in different solvents at 25 - C.

The solvents listed in Table 2.1 were chosen to cover a broad range in solvent properties. In fact hexane was initially also among them, but unfortunately the rate of the reaction in this solvent is extremely low. It turned out that in this solvent spontaneous decomposition of 2.4a competes with the Diels-Alder reaction. 

It is obvious that the reaction is accelerated markedly by water. However, for the first time, the Diels-Alder reaction is not fastest in water, but in 2,2,2-trifiuoroethanol (TFE). This might well be a result of the high Bronsted acidity of this solvent. Indirect evidence comes from the pH-dependence of the rate of reaction in water (Figure 2.1). Protonation of the pyridyl nitrogen obviously accelerates the reaction. 

The rate of the uncatalysed reaction in all four solvents is rather slow. (The half-life at [2.5] = 1.00 mM is at least 28 hours). However, upon complexation of Cu ion to 2.4a-g the rate of the Diels-Alder reaction between these compounds and 2.5 increases dramatically. Figure 2.2 shows the apparent rate of the Diels-Alder reaction of 2.4a with 2.5 in water as a lunction of the concentration of copper(II)nitrate. At higher catalyst concentrations the rate of the reaction clearly levels off, most likely due to complete binding of the dienophile to the catalyst. Note that in the kinetic experiments... 

---