The Diels-Alder Reaction General Features

Wasserman, Diels-Alder Reactions, Elsevier, New York, 1965 R. Huisgen, R. Grashey, and J. Sauer, in 

Chemistry of Alkenes, S. Patai, ed., John Wiley Sons, New York, 1964, pp. 878-928. 

A question of regioselectivity arises when both the diene and the alkene are unsymmetrically substituted. Generally, there is a preference for the ortho and para orientations, respectively, as in the examples shown.2 

For an unsymmetrical dienophile, there are two possible stereochemical orientations with respect to the diene. The two possible orientations are called endo and exo, as illustrated in Fig. 6.3. In the endo transition state, the reference substituent on the dienophile is oriented toward the % orbitals of the diene. In the exo transition state, the substituent is oriented away from the % system. For many substituted butadiene derivatives, the two transition states lead to two different stereoisomeric products. The endo mode of addition is usually preferred when an electron-attracting substituent such as a carbonyl group is present on the dienophile. The empirical statement which describes this preference is called the Alder rule. Frequently, a mixture of both stereoisomers is formed, and sometimes the exo product predominates, but the Alder rule is a useful initial guide to prediction of the stereochemistry of a Diels-Alder reaction. The endo product is often the more sterically congested. The preference for the endo transition state 

Diels-Alder cycloadditions are sensitive to steric effects of two major types. Bulky substituents on the dienophile or on the termini of the diene can hinder approach of the two components to each other and decrease the rate of reaction. This effect can be seen in the relative reactivity of 1-substituted butadienes toward maleic anhydride.5 

The cycloaddition of alkenes and dienes is a very useful method for forming substituted cyclohexenes. This reaction is known as the Diels-Alder reaction The concerted nature of the mechanism was generally accepted and the stereospecificity of the reaction was firmly established before the importance of orbtial symmetry was recognized. In the terminology of orbital symmetry classification, the Diels-Alder reaction is a [AUg + lUg] cycloaddition, an allowed process. The transition state for a concerted reaction requires that the diene adopt the s-cis conformation. The diene and substituted alkene (which is called the dienophile) approach each other in approximately parallel planes. The symmetry properties of the n orbitals permit stabilizing interations between C-1 and C-4 of the diene and the dienophile. Usually, the strongest interaction is between the highest occupied molecular orbital (HOMO) of the diene and the lowest unoccupied molecular orbital (LUMO) of the dienophile. The interaction between the frontier orbitals is depicted in Fig. 6.1. 

Butz and A. W. Rytina, Org. React. 5 136 (1949) M. C. Kloetzel, Org. React. 4 1 (1948) A. Wasserman, Diels-Alder Reactionsy Elsevier, New York, 1965 R. Huisgen, R. Grashey, and J. Sauer, in Chemistry of Alkenes y S. Patai, ed., John Wiley Sons, New York, 1964, pp. 878-928. 

For an unsymmetrical dienophile, there are two possible stereochemical orientations with respect to the diene. The two possible orientations, called endo and exo, are illustrated in Fig. 6.2. In the endo transition state, the reference substituent on the dienophile is oriented toward the tt orbitals of the diene. In the exo transition state, the substituent is oriented away from the tt system. 

Whether the products of endo and exo addition will be different depends on the substitution pattern in the diene. Except for symmetrically substituted butadiene derivatives, the two transition states will lead to two different stereoisomeric products. The endo mode of addition is usually preferred when an unsaturated substituent, such as a carbonyl group, is present on the dienophile. The empirical statement 

Cycloaddition reactions result in the formation of a new ring from two reactants. A concerted mechanism requires that a single transition state, and therefore no intermediate, lie on the reaction path between reactants and adduct. The most important example of cycloaddition is the Diels-Alder (D-A) reaction. The cycloaddition of alkenes and dienes is a very useful method for forming substituted cyclohexenes.1 

---

This theory proves to be remarkably useful in rationalizing the whole set of general rules and mechanistic aspects described in the previous section as characteristic features of the Diels-Alder reaction. The application of perturbation molecular orbital theory as an approximate quantum mechanical method forms the theoretical basis of Fukui s FMO theory. Perturbation theory predicts a net stabilization for the intermolecular interaction between a diene and a dienophile as a consequence of the interaction of an occupied molecular orbital of one reaction partner with an unoccupied molecular orbital of the other reaction partner. 

Synthetically, the Diels-Alder reaction is the most important cycloaddition and arguably the most important pericyclic reaction. Because of this, we will consider several additional features of this reaction here. It is a [ 4 +, 2 ] cycloaddition, and it best illustrates a key feature of pericyclic reactions that we have yet to touch on. Since, by definition, pericyclic reactions involve a well controlled array of a toms/orbitals in the transition state, well-defined stereochemistry is a hallmark of pericyclic reactions. In general, a high degree of control of stereochemistry is associated with pericyclic reactions, and this is one of their most valuablefeatures. Eq. 15.6 illustrates this aspect of the Diels-Alder reaction. As many as four new stereocenters are created, and the control is often complete. 

Another common feature of Diels-Alder stereochemistry is the so-called endo effect. Phenomenologically, this is a stereochemical effect whereby an acceptor substituent on the dienophile ends up in the endo position of the product, as shown in Eqs. 15.9 and 15.10. This is a useful and fairly general feature of the Diels-Alder reaction. 

Full accounts have been given of the Diels-Alder reactions of 1-acylamino-dienes (156), salient features of which are their wide application (even with reluctant dienophiles such as cyclohexenone), their generally good endo-selec-tivity, and their high regioselectivity with unsymmetrical dienophiles. Full details have also been given of the Diels-Alder reactions of the silyl-dienes (157), which are useful precursors of cyclic allyl silanes. ... 

The theoretical principles of cycloaddition reactions are well understood and there have been many computational studies (see Pericyclic Reactions The Diels-Alder Reaction). Often the hetero-cycloaddition reaction shows similar characteristics to the carbocyclic analog, but a number of special features have been noted. In heterocyclic chemistry the cycloaddition reactions are often dipolar computational studies show that a concerted mechanism is followed in the gas phase. However, a number of studies have noted that these dipolar cycloaddition reactions become stepwise when solvent effects are included (via the reaction field method), with a consequent loss of stereospecificity." Other characteristics of hetero-cycloaddition reactions which have been studied include the endo/exo selectivity" and the regiose-lectivity (for example, [2-1-2] vs. [2-1-4])." High levels of electron correlation are generally required in order to establish these selectivities. 

Simple stereoinduction in the Diels-Alder reaction typically follows a number of general guidelines. Two of these are well known to the student of organic chemistry, namely the notable preference for endo selectivity, as a consequence of secondary orbital overlap, and regioselectivity consistent with the optimal interactions of the frontier molecular orbitals [38]. Additional stereochemical preferences may also be observed for chiral reacting partners. In a study by Overman with cyclic dienes such as 30, cycloaddition was observed to occur on the olefin face anti to the allylic substituent in 30 (Scheme 17.7) [39]. The superimposition of the basic stereochemical features of the Diels-Alder reaction (i.e., endo selectivity cf 32) on the steric differentiation of the olefin faces leads to the preferential formation of 33-35 with increasing diastereoselectivity as a function of the size of the substituent X. 

This reviews contends that, throughout the known examples of facial selections, from classical to recently discovered ones, a key role is played by the unsymmetri-zation of the orbital phase environments of n reaction centers arising from first-order perturbation, that is, the unsymmetrization of the orbital phase environment of the relevant n orbitals. This asymmetry of the n orbitals, if it occurs along the trajectory of addition, is proposed to be generally involved in facial selection in sterically unbiased systems. Experimentally, carbonyl and related olefin compounds, which bear a similar structural motif, exhibit the same facial preference in most cases, particularly in the cases of adamantanes. This feature seems to be compatible with the Cieplak model. However, this is not always the case for other types of molecules, or in reactions such as Diels-Alder cycloaddition. In contrast, unsymmetrization of orbital phase environment, including SOI in Diels-Alder reactions, is a general concept as a contributor to facial selectivity. Other interpretations of facial selectivities have also been reviewed [174-180]. 

Diels-Alder reactions provide one of the few general methods of forming two carbon-carbon bonds simultaneously. The main features of these reactions are described in Box 1.3. The reaction finds widespread industrial use for example hardeners for epoxy resins are made by reaction of maleic anhydride with dienes such as 2-methyl-1,4-butadiene. 

The use of porphyrinic ligands in polymeric systems allows their unique physio-chemical features to be integrated into two (2D)- or three-dimensional (3D) structures. As such, porphyrin or pc macrocycles have been extensively used to prepare polymers, usually via a radical polymerization reaction (85,86) and more recently via iterative Diels-Alder reactions (87-89). The resulting polymers have interesting materials and biological applications. For example, certain pc-based polymers have higher intrinsic conductivities and better catalytic activity than their parent monomers (90-92). The first example of a /jz-based polymer was reported in 1999 by Montalban et al. (36). These polymers were prepared by a ROMP of a norbor-nadiene substituted pz (Scheme 7, 34). This pz was the first example of polymerization of a porphyrinic macrocycle by a ROMP reaction, and it represents a new general route for the synthesis of polymeric porphyrinic-type macrocycles. 

In this structure type the cleavage of the labile bonds in ring C by a retro Diels-Alder reaction is dominant, generating two fragments one, the most characteristic, represents the pyrrolidine ring (plus substituents in position 2), and the other (a less abundant fragment) encompasses the aromatic lactone or hemilactone moiety (Fig. 14). A further general and noteworthy feature is the low abundance of the molecular ion in all compounds with a double bond (211). 

It should be noted, however, that there are a number of Diels-Alder reactions for which the above generalization does not hold, in which reaction takes place between an electron-rich dienophile and an electron-deficient diene. The essential feature is that the two components should have complementary electronic character. These Diels-Alder reactions with inverse electron demand, as they are called, also have their uses in synthesis, but the vast majority of reactions involve an electron-rich diene and an electron-deficient dienophile. 

---