Catalysis, Diels-Alder reactions

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. 

This thesis contributes to the knowledge of catalysis in water, us it describes an explorative journey in the, at the start of the research, unh odded field of catalysis of Diels-Alder reactions in aqueous media. The discussion will touch on organic chemistry, coordination chemistry and colloid chemistry, largely depending upon the physical-organic approach of structural variation for the elucidation of the underlying mechanisms and principles of the observed phenomena. 

Lewis-acid catalysis of Diels-Alder reactions... 

The regioselectivity benefits from the increased polarisation of the alkene moiety, reflected in the increased difference in the orbital coefficients on carbon 1 and 2. The increase in endo-exo selectivity is a result of an increased secondary orbital interaction that can be attributed to the increased orbital coefficient on the carbonyl carbon ". Also increased dipolar interactions, as a result of an increased polarisation, will contribute. Interestingly, Yamamoto has demonstrated that by usirg a very bulky catalyst the endo-pathway can be blocked and an excess of exo product can be obtained The increased di as tereo facial selectivity has been attributed to a more compact transition state for the catalysed reaction as a result of more efficient primary and secondary orbital interactions as well as conformational changes in the complexed dienophile" . Calculations show that, with the polarisation of the dienophile, the extent of asynchronicity in the activated complex increases . Some authors even report a zwitteriorric character of the activated complex of the Lewis-acid catalysed reaction " . Currently, Lewis-acid catalysis of Diels-Alder reactions is everyday practice in synthetic organic chemistry. 

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. 

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). 

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 scope of Lewis-acid catalysis of Diels-Alder reactions in water An approach of extending the scope by making use of a temporary secondary coordination site is described in Chapter 4. 

What is the effect of micelles on the aqueous Diels-Alder reaction Can micellar catalysis be combined with Lewis-acid catalysis In Chapter 5 these aspects will discussed. 

In order to be able to provide answers to these questions, a Diels-Alder reaction is required that is subject to Lewis-acid catalysis in aqueous media. Finding such a reaction was not an easy task. Fortunately the literature on other Lewis-acid catalysed organic reactions in water was helpful to some extent... 

First, the use of water limits the choice of Lewis-acid catalysts. The most active Lewis acids such as BFj, TiQ4 and AlClj react violently with water and cannot be used However, bivalent transition metal ions and trivalent lanthanide ions have proven to be active catalysts in aqueous solution for other organic reactions and are anticipated to be good candidates for the catalysis of aqueous Diels-Alder reactions. 

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. 

In the previous section efficient catalysis of the Diels-Alder reaction by copper(II)nitrate was encountered. Likewise, other bivalent metal ions that share the same row in the periodic system show catalytic activity. The effects of cobalt(II)nitrate, nickel(II)nitrate, copper(II)nitrate and zinc(ll)nitrate... 

Copper is clearly the most selective metal-ion catalyst. Interestingly, proton catalysis also leads to high selectivities. This is a strong indication that selectivity in this catalysed Diels-Alder reaction does not result from steric interactions. 

In summary, the effects of a number of important parameters on the catalysed reaction between 2.4 and 2.5 have been examined, representing the first detailed study of Lewis-acid catalysis of a Diels-Alder reaction in water. Crucial for the success of Lewis-acid catalysis of this reaction is the bidentate character of 2.4. In Chapter 4 attempts to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water beyond the restriction to bidentate substrates will be presented. 

The first example of enantioselective catalysis of a Diels-Alder reaction was reported in 1979 . Since then, an extensive set of successful chiral Lewis-acid catalysts has been prepared. Some selected examples will be presented here together with their mechanistic interpretation. For a more complete... 

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. 

In contrast, investigation of the effect of ligands on the endo-exo selectivity of the Diels-Alder reaction of 3.8c with 3.9 demonstrated that this selectivity is not significantly influenced by the presence of ligands. The effects of ethylenediamine, 2,2 -bipyridine, 1,10-phenanthroline, glycine, L-tryptophan and L-abrine have been studied. The endo-exo ratio observed for the copper(II)-catalysed reaction in the presence of these ligands never deviated more than 2% from the endo-exo ratio of 93-7 obtained for catalysis by copper aquo ion. 

Likewise, the influence of the ligand catalyst ratio has been investigated. Increase of this ratio up to 1.75 1 resulted in a slight improvement of the enantioselectivity of the copper(L-tryptophan)-catalysed Diels-Alder reaction. Interestingly, reducing the ligand catalyst ratio from 1 1 to 0.5 1 resulted in a drop of the enantiomeric excess from 25 to 18 % instead of the expected 12.5 %. Hence, as anticipated, ligand accelerated catalysis is operative. 

The merits of (enantioselective) Lewis-acid catalysis of Diels-Alder reactions in aqueous solution have been highlighted in Chapters 2 and 3. Both chapters focused on the Diels-Alder reaction of substituted 3-phenyl-1-(2-pyr idyl)-2-prop ene-1-one dienophiles. In this chapter the scope of Lewis-acid catalysis of Diels-Alder reactions in water is investigated. Some literature claims in this area are critically examined and requirements for ejfective Lewis-acid catalysis are formulated. Finally an attempt is made to extend the scope of Lewis-acid catalysis in water by making use of a strongly coordinating auxiliary. 

In summary, the groups of Espenson and Loh observe catalysis of Diels-Alder reactions involving monodentate reactants by Lewis acids in water. If their observations reflect Lewis-acid catalysis, involvirg coordination and concomitant activation of the dienophile, we would conclude that Lewis-acid catalysis in water need not suffer from a limitation to chelating reactants. This conclusion contradicts our observations which have invariably stressed the importance of a chelating potential of the dienophile. Hence it was decided to investigate the effect of indium trichloride and methylrhenium trioxide under homogeneous conditions. 

Consequently, in initial attempts to extend the scope, we aimed to identify catalysis of Diels-Alder reactions of other bidentate dienophiles in water. This task turned out to be more difficult than expected Scheme 4.5 provides a collection of potentially chelating dienophiles that all failed to... 

Scheme 4.6. Schematic representation of the use of a coordinating auxiliary for Lewis-acid catalysis of a Diels-Alder reaction.

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

As anticipated from the complexation experiments, reaction of 4.42 with cyclopentadiene in the presence of copper(II)nitrate or ytterbium triflate was extremely slow and comparable to the rate of the reaction in the absence of Lewis-acid catalyst. Apparently, Lewis-acid catalysis of Diels-Alder reactions of p-amino ketone dienophiles is not practicable. 

Note that for 4.42, in which no intramolecular base catalysis is possible, the elimination side reaction is not observed. This result supports the mechanism suggested in Scheme 4.13. Moreover, at pH 2, where both amine groups of 4.44 are protonated, UV-vis measurements indicate that the elimination reaction is significantly retarded as compared to neutral conditions, where protonation is less extensive. Interestingy, addition of copper(II)nitrate also suppresses the elimination reaction to a significant extent. Unfortunately, elimination is still faster than the Diels-Alder reaction on the internal double bond of 4.44. 

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