Lewis acid organic

As metals easily form Lewis acids, organic catalysts are more prone to form heteroatom-centered Lewis bases. Among these catalysts, the N- and P-based... 

By far the most effective method, however, is catalysis by Lewis-acids. In organic solvents. 

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. 

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. 

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... 

Lewis-acid catalysis of organic reactions in aqueous solutions ... 

Scheme 2.1. Lewis-acid catalysed organic reactions that are promoted by small amounts ofwater in organic solvents.

Bcamples of metal-ion catalysed organic reactions in water where the catalyst acts exclusively as Lewis acid are the hromination of diketones" " and the decarboxylation of oxaloacetate. The latter reaction has been studied in detail. In 1941 it was demonstrated that magnesium(II) ions catalyse this reaction" Later also catalysis by other multivalent metal ions, such as Zn(II), Mn(II), Cu(II), Cd(ir), Fe(II), Pb(II), Fe(III)... 

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. 

To our knowledge, the results presented in this chapter provide the first example of enantioselective Lewis-acid catalysis of an organic reaction in water. This discovery opens the possibility of employing the knowledge and techniques from aqueous coordination chemistry in enantioselective catalysis. This work represents an interface of two disciplines hitherto not strongly connected. 

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. 

To the best of our knowledge the data in Table 3.2 constitute the first example of enantio selectivity in a chiral Lewis-acid catalysed organic transformation in aqueous solution. Note that for the majority of enantioselective Lewis-acid catalysed reactions, all traces of water have to be removed from the... 

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. 

The use of dienophile 5.1 also allows study of the effect of micelles on the Lewis-acid catalysed reaction. These studies are described in Section 5.2.2. and represent the first in-depth study of Lewis-acid catalysis in conjunction with micellar catalysis , a combination that has very recently also found application in synthetic organic chemistry . ... 

Interestingly, at very low concentrations of micellised Qi(DS)2, the rate of the reaction of 5.1a with 5.2 was observed to be zero-order in 5.1 a and only depending on the concentration of Cu(DS)2 and 5.2. This is akin to the turn-over and saturation kinetics exhibited by enzymes. The acceleration relative to the reaction in organic media in the absence of catalyst, also approaches enzyme-like magnitudes compared to the process in acetonitrile (Chapter 2), Cu(DS)2 micelles accelerate the Diels-Alder reaction between 5.1a and 5.2 by a factor of 1.8710 . This extremely high catalytic efficiency shows how a combination of a beneficial aqueous solvent effect, Lewis-acid catalysis and micellar catalysis can lead to tremendous accelerations. 

The thiazolium ring, as most heterocycloammoniums, is a Lewis acid conferring to the carbon atom in the 2-position the carbocationic property of adding the free pair of a base either organic or mineral that may be the molecule of solvent as ROH (Scheme 11). For many nuclei of suitable acidity, these equilibria can be observed in dilute solution by means of absorption spectra when species A and C possess different characteristics (24). For example, benzothiazolium and benzoxazolium in methanol and ethanol give at 10 mole liter 8 and 54% of the alkoxy derivatives for the former and 29 and 90% for the latter respectively. 

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