The Diels-Alder reaction in more detail

The orbital explanation for the endo rule in Diels-Alder reactions 

If we now draw the frontier orbitals in the two components as they come together for the reaction, we can see first of all that the symmetry is correct for bond formation. 

Now we shall look at that same diagram again but replace with orange dashed lines the orbitals that are overlapping to form the new o bonds so that we can see what is happening at the back of the diene. 

The symmetry of the orbitals is correct for a bonding interaction at the back of the diene too. This interaction does not lead to the formation of any new bonds but it leaves its imprint in the stereochemistry of the product. The endo product is favoured because of this favourable interaction across the space between the orbitals even though no bonds are formed. 

Another way to look at this resuft comes from recognizing the special entropy problem involved in cycloaddition reactions. A very precise orientation of the two molecules is required for two bonds to be formed at once. These reactions have large negative entropies of activation (Chapter 41)—order must be created at the transition state as the two components align with one another. The through-space attractive HOMO/LUMO interaction between the two molecules can lead to an initial association that can be compared to a squishy sandwich with 

We are going to use a diene as dienophile to explain the formation of products. The diene serves 

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Note that the stereochemistry comes out right. H s a and b are cis because they were cis in the starting quinone and the Diels-Alder reaction is stereospecific in this respect. H is also cis to and H " because the Diels-Alder reaction is stereoselectively endo. These points are described in more detail in Norman p.284-6 and explained in Ian Fleming Frontier Orbitals and Organic Chemical Reactions, Wiley 1976, p. 106-109. How would you make diene A ... 

The mechanism of the Diels-Alder cycloaddition is different from that of other reactions we ve studied because it is neither polar nor radical. Rather, the Diels-Alder reaction is a pericyclic process. Pericyclic reactions, which we ll discuss in more detail in Chapter 30, take place in a single step by a cyclic redistribution of bonding electrons. The two reactants simply join together through a cyclic transition state in which the two new carbon-carbon bonds form at the same time. 

Removal of the carbonate ring from 7 (Scheme 1) and further functional group manipulations lead to allylic alcohol 8 which can be dissected, as shown, via a retro-Shapiro reaction to give vinyl-lithium 9 and aldehyde 10 as precursors. Vinyllithium 9 can be derived from sulfonyl hydrazone 11, which in turn can be traced back to unsaturated compounds 13 and 14 via a retro-Diels-Alder reaction. In keeping with the Diels-Alder theme, the cyclohexene aldehyde 10 can be traced to compounds 16 and 17 via sequential retrosynthetic manipulations which defined compounds 12 and 15 as possible key intermediates. In both Diels-Alder reactions, the regiochemical outcome is important, and special considerations had to be taken into account for the desired outcome to. prevail. These and other regio- and stereochemical issues will be discussed in more detail in the following section. 

Further investigations showed that these accelerations in water are a general phenomenon Table 11 contains another selection from the multitude of Diels-Alder reactions in aqueous media. Note that the rate enhancements induced by water can amount to a factor of 12,800 compared to organic solvents (Table 11, entry A). A detailed study on solvent effects in an exemplary Diels-Alder reaction is presented in Table 17162. It was demonstrated that the solvent enhancements depend on the dienophile and, more strongly, on the solvent. 

An alternative is to put the alkene in another place 84 and discover a different pair of diene 86 and dienophile 85. Again the -isomers will be easier to make and this time we get the right stereochemistry 88 for a-lycorane 71. This strategy was followed in an early synthesis by Hill.9 Another synthesis using the Diels-Alder reaction is by Irie.10 More details appear in the workbook. 

The trimerization of ethylene to cyclohexane is computed to be highly exothermic, —67kcal/mol, but has a large barrier of 49kcal/mol. By comparison, the Diels—Alder reaction is much less exothermic, —44kcal/ mol, but has a much lower barrier of 22 kcal/mol. Both are computed to proceed via a concerted 6-electron/6-centered transition state, namely, both are formally allowed. Why are the barriers so different Provide a VB-based explanation for this puzzle. For more details, you may consult the original work in, A. Ioffe, S. Shaik, J. Chem. Soc. Perkin Trans. 2, 2101 (1992). 

One reason that the Diels-Alder reaction goes so well is that the transition state has six delocalized 71 electrons and thus is aromatic in character, having some of the sPec stabilization of benzene. You could look at it as a benzene ring having all its 7t bonds but missing two o bonds. This simple picture is fine as far as it goes, but it is incomplete. We shall retuf 110 a more detailed orbital analysis when we have described the reaction in more detail. 

Since the disclosures that the thermal dimerizations of acrolein and methyl vinyl ketone provide the 3,4-dihydro-2//-pyrans (1, 2) derived from 4ir and 2Tt participation of the a,3-unsaturated carbonyl compound in a Diels-Alder reaction, an extensive series of related observations have been detailed. This work has been the subject of several comprehensive reviews - - including the Desimoni and Tacco-ni extensive tabular compilation of work through 1974. Consequently, the prior reviews should be consulted for thorough treatments of the mechanism, scope, and applications of the [4 + 2] cycloaddition reactions of a,3-unsaturated carbonyl compounds. The [4 + 2] cycloaddition reactions of 1-oxa-1,3-butadienes with their 4-it participation in the Diels-Alder reaction exhibit predictable regioselectivity with the preferential or exclusive formation of 2-substituted 3,4-dihydro-2W-pyrans (equation 1). The exceptions to the predicted regioselectivity that have been observed involve the poorly matched [4 + 2] cycloaddition reaction of an electron-deficient l-oxa-l,3-butadiene with an electron-deficient dienophile, e.g. methyl crotonate or methacrolein. - Rigorous or simplified theoretical treatments of the [4 + 2] cycloaddition reaction of 1-oxa-1,3-butadienes predict the preferential formation of 2-substituted 3,4-dihy-dro-2f/-pyrans and accommodate the preferred endo approach of the reactants in which the carbon-carbon bond formation is more advanced than carbon-oxygen bond formation, i.e. a concerted but nonsynchronous [4 + 2] cycloaddition reaction. ... 

The stability of the a-dithiocarbonyl compounds follows closely their potential utility for 4ir participation in Diels-Alder reactions with typical olefinic and acetylenic dienophiles [a-dithioamide > a-dithionoester > a-dithionothioester (dimer equilibrium at 25°C) > a-dithione > a-dithioalde-hyde]. The a-dithiocarbonyl compounds are electron-deficient and consequently react rapidly with electron-rich and strained olefins in inverse electron demand (LUMOd,ene controlled) Diels-Alder reactions and more slowly with unactivated or electron-deficient dienophiles in apparent normal (HOMODiels-Alder reactions (Scheme 8-IX).36 Subtle differences in the reactivity and observed course of reactions of the various a-dithiocarbonyl compounds have been detailed.36... 

Each of the four previous reactions forms a product with two new asymmetric carbons. Thus, each product has four stereoisomers. Because only syn addition occurs, each reaction forms only two of the stereoisomers (Section 5.19). The Diels-Alder reaction is stereospecific—the configuration of the reactants is maintained during the course of the reaction— because the reaction is concerted. The stereochemistry of the reaction will be discussed in more detail in Section 29.4. 

We have tested the same range of poiphyrin hosts as for the Diels-Alder reaction, and find almost exactly tlie same spectrum of activity as for reaction 1 this is hardly surprising as both were designed for tlie same trimer. However, the flexible methylene-linked trimer is still a catalyst for this reaction, even though it is ineffective in the Diels-Alder reaction we do not yet understand this difference in behaviour but are looking in more detail into the mechanism and scope of tlie catalysis. 

In the Diels-Alder transition state, the two alkene carbons and carbons 1 and 4 of the diene rehybridize from sp to sp to form two new single bonds, while carbons 2 and 3 of the diene remain sp -hybridized to form the new double bond in the cyclohexene product. We ll study this mechanism in more detail in Section 30.5 but will concentrate for the present on learning about the characteristics and uses of the Diels-Alder reaction. 

In the forward direction, diene 5 was prepared by alkylation of metallated 1,3-dithiane 9 with allylic bromide 8. In this reaction, 9 plays the role of an acyl anion equivalent . We will talk about equivalencies in more detail in Chapter 6, but at this point it is worth noticing that the dithiane will eventually emerge as the C15 protected ketone. Dienophile 4 was prepared by an aldol-dehydration reaction between nitromethane and aldehyde 10, a reaction known as the Henry reaction. The Diels-Alder reaction between 4 and... 

Concerted reactions are commonly used to join carbons. For example, the Diels-Alder reaction is the formation of a cyclohexene from a diene and an alkene. Usually the alkene is rendered electrophilic by conjugation with a carbonyl group, and the diene may be rendered nucleophilic by electron-donating substituents. In the case shown in Equation 7.38 the alkene is further electron depleted by association with a Lewis acid [64], a common technique for accelerating Diels-Alder reactions. In some cases, the alkene is nucleophilic and the diene is electrophilic as in Equation 7.39 [65]. Examples of this sort are called reverse-electron-demand Diels-Alder reactions. It is important to point out here that the concerted reactions differ from the foregoing in that no carbanion or cation intermediate is involved, and in many cases, electrophilic and nucleophilic factors are not present, as in the very favorable dimerization of cyclopentadiene. These reactions are covered in more detail in Chapter 5. 

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