Diels additions

Aldrin is obtained from the Diels-Alder addition product of cyclopentadiene and vinyl chloride by dehydrochlorination followed by condensation with hexachlorocyclopenta-diene. 

Diels-Alder reaction is the 1,4-addition of an alkene or alkyne (dienophile) across a conjugated diene. An example is the addition of pro-penal to buta-l,3-diene to give A -tetrahy-... 

Chemists usually learn about reactions according to fiinctional groups for example, How can I make an aldehyde and what reactions are known for aldehydes " This is clearly not a very good starting point for classifying reactions. The poor state of affairs in the definition of reaction types is further quite vividly illustrated by the fact that many chemical reactions are identified by being named after their inventor Diels-Alder reaction, Michael addition, Lobry-de Bruyn-van Ekenstein rear-... 

W C, A Tempcz)rrk, R C Hawley and T Hendrickson 1990. Semianalytical Treatment of Solvation for Molecular Mechanics and Dynamics. Journal of the American Chemical Society 112 6127-6129. ensson M, S Humbel, R D J Froese, T Matsubara, S Sieber and K Morokuma 1996. ONIOM A Multilayered Integrated MO + MM Method for Geometry Optimisations and Single Point Energy Predictions. A Test for Diels-Alder Reactions and Pt(P(t-Bu)3)2 + H2 Oxidative Addition. Journal of Physical Chemistry 100 19357-19363. 

Compounds containing a double or triple bond, usually activated by additional unsaturation (carbonyl, cyano, nitro, phenyl, etc.) In the ap position, add to the I 4-positions of a conjugated (buta-1 3-diene) system with the formation of a ax-membered ring. The ethylenic or acetylenic compound is known as the dieTwphile and the second reactant as the diene the product is the adduct. The addition is generally termed the Diels-Alder reaction or the diene synthesis. The product in the case of an ethylenic dienophile is a cyctohexene and in that of an acetylenic dienophile is a cyctohexa-1 4-diene. The active unsaturated portion of the dienophile, or that of the diene, or those in both, may be involved in rings the adduct is then polycyclic. 

Diels-Alder reactions can be divided into normal electron demand and inverse electron demand additions. This distinction is based on the way the rate of the reaction responds to the introduction of electron withdrawing and electron donating substituents. Normal electron demand Diels-Alder reactions are promoted by electron donating substituents on the diene and electron withdrawii substituents on the dienophile. In contrast, inverse electron demand reactions are accelerated by electron withdrawing substituents on the diene and electron donating ones on the dienophile. There also exists an intermediate class, the neutral Diels-Alder reaction, that is accelerated by both electron withdrawing and donating substituents. 

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). 

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. 

The effect of additives on the selectivity of the Diels-Alder reaction in water has not received much... 

Appreciating the beneficial influences of water and Lewis acids on the Diels-Alder reaction and understanding their origin, one may ask what would be the result of a combination of these two effects. If they would be additive, huge accelerations can be envisaged. But may one really expect this How does water influence the Lewis-acid catalysed reaction, and what is the influence of the Lewis acid on the enforced hydrophobic interaction and the hydrogen bonding effect These are the questions that are addressed in this chapter. 

Recently Desimoni et used the same bis(oxazoline) ligand in the magnesium(II) catalysed Diels-Alder reaction of the N-acyloxazolidinone depicted in Scheme 3.4. In dichloromethane a modest preference was observed for the formation of the S-enantiomer. Interestingly, upon addition of two equivalents of water, the R-enantiomer was obtained in excess. This remarkable observation was interpreted in terms of a change from tetrahedral to octahedral coordination upon the introduction of the strongly coordinating water molecules. 

Finally the influence of the temperature and addition of ethanol on the enantioselectivity of the Diels-Alder reaction was studied. Table 3.3 summarises the results for different aqueous media. Apparently, changes in temperature as well as the presence of varying amounts of ethanol have only a modest influence on the selectivity of the Cu(tryptophan)-catalysed Diels-Alder reaction in aqueous solution. However, reaction times tend to increase significantly at lower temperatures. Also increasing the alcohol content induces an increase of the reaction times. 

This goal might well be achieved by introducing an auxiliary that aids the coordination to the catalyst. After completion of the Diels-Alder reaction and removal of the auxiliary the desired adduct is obtained. This approach is summarised in Scheme 4.6. Some examples in which a temporary additional coordination site has been introduced to aid a catalytic reaction have been reported in the literature and are described in Section 4.2.1. Section 4.2.2 relates an attempt to use (2-pyridyl)hydrazone as coordinating auxiliary for the Lewis-acid catalysed 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. 

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. 

Fortunately, in the presence of excess copper(II)nitrate, the elimination reaction is an order of magnitude slower than the desired Diels-Alder reaction with cyclopentadiene, so that upon addition of an excess of cyclopentadiene and copper(II)nitrate, 4.51 is converted smoothly into copper complex 4.53. Removal of the copper ions by treatment with an aqueous EDTA solution afforded in 71% yield crude Diels-Alder adduct 4.54. Catalysis of the Diels-Alder reaction by nickel(II)nitrate is also... 

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... 

Dramatic rate accelerations of [4 + 2]cycloadditions were observed in an inert, extremely polar solvent, namely in5 M solutions oflithium perchlorate in diethyl ether(s 532 g LiC104 per litre ). Diels-Alder additions requiring several days, 10—20 kbar of pressure, and/ or elevated temperatures in apolar solvents are achieved in high yields in some hours at ambient pressure and temperature in this solvent (P.A. Grieco, 1990). Also several other reactions, e.g, allylic rearrangements and Michael additions, can be drastically accelerated by this magic solvent. The diastereoselectivities of the reactions in apolar solvents and in LiClO EtjO are often different or even complementary and become thus steerable. 

Classical syntheses of steroids consist of the stepwise formation of the four rings with or without angular alkyl groups and the final construction of the C-17 side-chain. The most common reactions have been described in chapter 1, e.g. Diels-AIder (p. 85) and Michael additions (p. 

A particular kind of conjugate addition reaction earned the Nobel Prize in chemistry for Otto Diels and Kurt Alder of the University of Kiel (Germany) m 1950 The Diels-Alder reaction is the conjugate addition of an alkene to a diene Using 1 3 buta diene as a typical diene the Diels-Alder reaction may be represented by the general equation... 

The product of a Diels-Alder cycloaddition always contains one more ring than was present m the reactants The dienophile maleic anhydride contains one ring so the product of Its addition to a diene contains two... 

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