Diels-Alder reaction secondary orbital interaction

In summary, it seems that for most Diels-Alder reactions secondary orbital interactions afford a satisfactory rationalisation of the endo-exo selectivity. However, since the endo-exo ratio is determined by small differences in transition state energies, the influence of other interactions, most often steric in origin and different for each particular reaction, is likely to be felt. The compact character of the Diels-Alder activated complex (the activation volume of the retro Diels-Alder reaction is negative) will attenuate these eflfects. The ideas of Sustmann" and Mattay ° provide an attractive alternative explanation, but, at the moment, lack the proper experimental foundation. 

Secondary orbital interaction had been proposed to explain predominant formation of endo attack prodncts in Diels Alder reaction of cyclopentadiene and dienophiles by Hoffmann and Woodward [22]. According to this rnle, the major stereoisomer in Diels-Alder reactions is that it is formed through a maximum accumulation of double bonds. In the Diels-Alder reactions, secondary orbital interaction consists of a stabilizing two-electron interaction between the atoms not involved in the formation or cleavage of o bonds (Scheme 19). 

Figure 1.2. Endo and exo pathway for the Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone. As was first noticed by Berson, the polarity of the endo activated complex exceeds that of the exo counterpart due to alignment of the dipole moments of the diene and the dienophile K The symmetry-allowed secondary orbital interaction that is only possible in the endo activated complex is usually invoked as an explanation for the preference for endo adduct exhibited by most Diels-Alder reactions.

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. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

The endo exo selectivity for the Lewis acid-catalyzed carbo-Diels-Alder reaction of butadiene and acrolein deserves a special attention. The relative stability of endo over exo in the transition state accounts for the selectivity in the Diels-Alder cycloadduct. The Lewis acid induces a strong polarization of the dienophile FMOs and change their energies (see Fig. 8.2) giving rise to better interactions with the diene, and for this reason, the role of the possible secondary-orbital interaction must be considered. Another possibility is the [4 + 3] interaction suggested by Singleton... 

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

Fig. 2 Secondary orbital interaction (SOI) in Diels-Alder reactions...

The secondary orbital interaction has been applied to explain enantioselective catalytic Diels-Alder reactions of cyclic dienes and acetylenic dienophiles [23, 24]. 

Scheme 19 Secondary orbital interaction in Diels-Alder reaction of cyclopentadiene with maleic anhydride...

In the case of the reverse-electron-demand Diels-Alder reactions, the secondary orbital interaction between the Jt-HOMO of dienophile and the LUMO of 114 or the effect of the orbital phase enviromnents (Chapter Orbital Phase Enviromnents and Stereoselectivities by Ohwada in this volume) cannot be ruled out as the factor controlling the selectivity (Scheme 55). 

Concerted cycloaddition reactions provide the most powerful way to stereospecific creations of new chiral centers in organic molecules. In a manner similar to the Diels-Alder reaction, a pair of diastereoisomers, the endo and exo isomers, can be formed (Eq. 8.45). The endo selectivity in the Diels-Alder arises from secondary 7I-orbital interactions, but this interaction is small in 1,3-dipolar cycloaddition. If alkenes, or 1,3-dipoles, contain a chiral center(s), the approach toward one of the faces of the alkene or the 1,3-dipole can be discriminated. Such selectivity is defined as diastereomeric excess (de). 

The reaction of nitrostyrene with cyclopentadiene gives the normal Diels-Alder adduct. However, the Lewis acid-catalyzed cycloaddition affords two isomeric nitronates, syn and anti in an 80-to-20 ratio. The major isomer is derived from an endo transition state. The preference of yy/i-fused cycloadducts can be understood by considering secondary orbital interactions (Eq. 8.95).152... 

According to recent quantum mechanical calculations, die importance of secondary orbital interactions, which have also been frequently used to explain die endo diastereoselectivity of Diels-Alder reactions, seems to be questionable and to be reserved for special cases like the addition of cyclopropene to various dienes. T. Karcher, W. Sicking, J. Sauer and R. Sustmann, Tetrahedron Lett., 33, 8027 (1992) R. Sustmann and W. Sicking, Tetrahedron, 48, 10293 (1992) Y. Apeloig and E. Matzner,./. Am. Chem. Soc., 117, 5375 (1995). 

The endo selectivity in many Diels-Alder reactions has been attributed to attractive secondary orbital interactions. In addition to the primary stabilizing HOMO-LUMO interactions, additional stabilizing interactions between the remaining parts of the diene and the dienophile are possible in the endo transition state (Figure 3). This secondary orbital interaction was originally proposed for substituents having jr orbitals, e.g. CN and CHO, but was later extended to substituents with tt(CH2) type of orbitals, as encountered in cyclopropene57. 

The reasons for the ewrfo-selectivity of Diels-Alder reactions are only useful for the reactions of dienophiles bearing substituents with lone pairs without a Lewis basic site no secondary orbital interactions are possible. But even in reactions of pure hydrocarbons the ewrfo-selectivity is observed, requiring alternative explanations. For example, the ewrfo-preference of the reactions of cyclopropene with substituted butadienes have been rationalized on the basis of a special type of secondary orbital interactions70. Apart from secondary orbital interactions which are probably the most important reason for the selec-tivities of Diels-Alder reactions, recent literature also advocates other interpretations. 

FIGURE 2. The Diels-Alder reaction of cyclopentadiene with methyl vinyl ketone. The selectivity leading to the endo-product (endo-selectivity of Diels-Alder reactions) is rationalized by secondary orbital interactions in the endo-transition state... 

For concerted Diels-Alder reactions, as discussed above, both AV and AF are negative and Owl. In some unhindered Diels-Alder reactions, such as those involving maleic anhydride, it was observed [275] that AV > AF. This means that the transition state has an additional volume contraction with respect to the products. Since Diels-Alder cycloadditions are essentially solvent-insensitive and thus have negligible or small environmental contribution to the activation volume, this contraction seems to be of intramolecular origin, and it was suggested [284] that it could be due to secondary orbital interactions in the transition state. This contribution to AjF has been indicated as A, V. ... 

Cyclobutadienes represent very reactive alkenes that undergo both [2 + 2] as well as [4 + 2] cycloadditions. Both the cyclodimerizations, mixed [2 + 2] cycloadditions and Diels-Alder reactions of these reactive species have been reviewed (see Houben-Weyl, Vols. 4/4, p 231 and E 17 f, Section 10B). In most instances the initially formed cyclodimer is tricyclo[4.2.0.02-5]octa-3,7-diene (36) and has the all cis-syn configuration. This is attributed to the concerted [4n -I- 2n] cycloaddition mechanism in which stereochemical control is affected by secondary orbital interactions. 

Density functional theory computational studies have been used to determine die importance of secondary orbital interactions for the stability of transition-state structures for die 4 + 2-cycloaddition of furan with cyclopropene.175 Kinetic studies of die 2 + 4-cycloaddition of 2-cyclopropylidene acetates with furan and dimethylful-vene suggest a mechanism involving diradicals or zwitterions as intermediates.176 Cyclopropene, produced by die reaction of allyl chloride with sodium bis(bimediyl-silyl)amide, reacts with 1,3-diphenylisobenzofuran to produce both endo- and exo-Diels-Alder cycloadducts isolated for the first tune.177... 

Recall that the endo transition state of the Diels-Alder reaction is stabilized by favourable secondary orbital interactions between the n systems of the diene and the dienophile. 

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