This Thesis

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. 

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 summary, the following questions will be addressed in this thesis ... 

Most of the work described in this thesis has been published... 

Fortunately, azachalcone derivatives (2.4a-g, Scheme 2.4) turned out to be extremely suitable dienophiles for Lewis-add catalysed Diels-Alder reactions with cyclopentadiene (2.5). This reaction is outlined in Scheme 2.4 and a large part of this thesis will be devoted to the mechanistic details of this process. The presence of a chromophore in 2.4 allows kinetic studies as well as complexation studies by means of UV-vis spectroscopy. Furthermore, the reactivity of 2.4 is such that also the... 

Literature claims of Lewis-acid catalysis of Diels-Alder reactions in water At the time of the printing of this thesis eight reports describe Lewis-acid catalysis of Diels-Alder reactions in water. This small number indicates that Lewis-add catalysis in aqueous media suffers not only from unpopularity, but also from an intrinsic disadvantage. Three of these reports originate... 

In the final chapter ofi this thesis, the work described in the preceding chapters is evaluated. Furthermore, two pivotal themes ofi this work, Lewis acid - Lewis base interactions in water and hydrophobic fiects, are reviewed. Finally, the prospects ofi Lewis-acid catalysis in aqueous solution are discussed. 

Finally, Section 6.5 will close this thesis by suggesting lines for continuation of the research. 

Of all the work described in this thesis, this discovery is probably the most significant. Given the fact that the arene - arene interactions underlying the observed enantioselectivity of ftie Diels-Alder reactions described in Chapter 3 are also encountered in other organic reactions, we infer that, in the near future, the beneficial influence of water on enantioselectivity can also be extended to these transformations. Moreover, the fact that water can now be used as a solvent for enantioselective Lewis-add catalysed reactions facilitates mechanistic studies of these processes, because the number of equilibria that need to be considered is reduced Furthermore, knowledge and techniques from aqueous coordination chemistry can now be used directly in enantioselective catalysis. 

In summary, the work in this thesis provides an overview of what can be achieved with Lewis-acid and micellar catalysis for Diels-Alder reactions in water as exemplified by the reaction of3-phenyl-l-(2-pyridyl)-2-propene-l-ones with cyclopentadiene. Extension of the observed beneficial effect of water on rates and particularly enantioselectivities to other systems is envisaged. 

This thesis has been completely devoted to catalysis by relatively hard catalysts. When aiming at the catalysis of Diels-Alder reactions, soft catalysts are not an option. Soft catalysts tend to coordinate directly to the carbon - carbon double bonds of diene and dienophile, leading to an activation towards nucleophilic attack rather than to a Diels-Alder reaction . This is unfortunate, since in water, catalysis by hard catalysts suffers from a number of intrinsic disadvantages, which are absent for soft catalysts. 

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. 

Developments along these three lines can be expected to greatly extend the yet limited utility of catalysis by hard Lewis acids in aqueous media. The work described in this thesis has demonstrated drat these efforts can be rewarded by increased in rate and most importantly, enantioselectivity. 

We would like to conclude this thesis with the expression of the hope drat in its course, we have taken away... 

This thesis describes a study of catalysis of Diels-Alder reactions in water. No studies in this field had been reported at the start of the research, despite the well known beneficial effects of acpieous solvents as well as of Lewis-add catalysts on rate and endo-exo selectivity of Diels-Alder reactions in organic solvents. We envisaged that a combination of these two effects might well result in extremely large rate enhancements and improvements of the endo-exo selectivity. 

Finally, we summarise our insight into hydrophobic effects that have developed during the work described in this thesis. The discussion focuses on the influence of hydrophobic effects on organic reactivity. 

The research for this thesis was carried out in connection with NIOK, the Netherlands Institute for Catalysis Research and supported by the Department of Economic Affairs. 

I owe a lot to Federica Bertondn and Giovanni Boccaletti. During their stay as Erasmus students in Groningen they brought a little bit of Italy with them (I remember some very good meals). Also from a chemical point of view their stays were successful. The compounds prepared and purified by Federica are at the basis of the work described in this thesis. The work of Giovanni has paved the way to enantioselective Lewis-acid catalysis in water, which is perhaps the most significant result of this thesis. 

In this thesis we suggest a model of the formation of elements, which allows us to make the connection between the spread of elements and their nuclear char ge. We ve got a function of distribution for the state close to the final period of active formation of elements and for the state, corresponding to the period of forming of condensed bodies [2, 3]. 

On the basis of this analysis, it may be anticipated that the extent of aldehyde diastereofa-cial selectivity will depend on the difference in size of the R3 aldehyde substituent relative to that of the methyl group. The examples summarized in Table 2 are generally supportive of this thesis, particularly the reactions of (F)-2-butenylboronntc. The data cited for reactions of 3-methoxymethoxy-2-methylbutanal with (Z)-2-butenylboronate and 2-propenylboronate, however, also show that diastereoselectivity depends on the stereochemistry at C-3 of the chiral aldehydes. These data imply that simple diastereoselectivity depends not simply on reduced mass considerations, but rather on the stereochemistry and conformation of the R3 substituent in the family of potentially competing transition states21,60. The dependence of aldehyde diastcrcofacial selectivity on the stereochemistry of remote positions of chiral aldehydes has also been documented for reactions involving the ( )-2-butenylchromium reagent62. 

A possible example of this thesis is the crystalline insect toxin found in Bacillus thuringiensis spores and discussed here by Dr. Anderson. Although neither the bacillus nor its spores exhibit useful antibiotic activity against other microorganisms, the very specific toxicity to insects has become of major commercial interest. The enormous number and variety of fungal species available for further examination must lead inevitably to one or more which produces pesticidal metabolites. 

As shown by Garnett and Patience (1993), the exponent p is inversely proportional to the number of scaled dimensions of the production-rate-limiting activity. As such, it should vary from 1/3 to 1/1. Indeed, factors given in Table 7.3-3 do. support this thesis. One would expect... 

The preparation of this thesis would not have been possible without the advice and help I got from many people. 

Redgrove further honed this thesis in his 1920 volume, Magic and Mysticism. 

Of course, this thesis remains to be tested and probably can be confirmed or rejected through study of a series of close derivatives of HPNPP where the aryloxy group is varied which is currently underway in our laboratories.100... 

Jizomoto and Hirano [3.41 ] tried to increase the amount of drug inclusions in liposomes by inserting Ca2+ ions in dipalmitoylphosphatidylcholine (DPPC) liposomes. The included volume (mL) per g of liposomes is called Vcap, and this can be increased as a function of the Ca2+ concentration up to ten fold of the minimum Vcap The increase in Vcap is attributed to the electrostatic repulsion between the Ca ions, which reduces the number of lamella and increases the diameter of the liposomes to a certain extent, but increases substantially. A calculated simulation of this thesis is in reasonable agreement with the measurements... 

In this thesis an Inherent Safety Index for conceptual chemical process design is presented. This is required, since inherent safety should be considered in the early phases of design when the major decisions on the chemical process are made. The presented methodology allows such a consideration since the index is based on the knowledge available in the preliminary process design stage. 

Last but not least, I wish to express my gratitude to my family and friends for their support and understanding during the past few years. Without their encouragement this thesis would never have come to fruition. 

In practice the main purpose of the process plant design is to minimize the total process risk for the limitation of effects. Here risk is the product of the probability of an incident to happen and the possible consequences of that incident. In this thesis the limitation of effects by the means of inherent safety principles is evaluated. 

In this thesis an index based method was selected since inherent safety in formed of many subfactors which are interrelated. Therefore it is more straightforward to represent these factors as subindices which are weighted by score means as discussed later in Chapter 9. 

In this thesis an inherent safety index for evaluating inherent safety in preliminary process design was presented. The inherent safety of a process is affected by both chemical and process engineering aspects. These have been dealt separately, since the index was divided into the Chemical Inherent Safety Index and the Process Inherent Safety Index. These two indices consist of several subindices which further depict specific safety aspects. The Chemical Inherent Safety Index describes the inherent safety of chemicals in the process. The affecting factors are the heat of the main reaction and the maximum heat of possible side reactions, flammability, explosiveness, toxicity, corrosiveness and the interaction of substances present in the process. The Process Inherent Safety Index expresses safety of the process itself. The subindices describe maximum inventory, maximum process temperature and pressure, safety of equipment and the safety of process structure. 

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