Diels-Alder reactions secondary orbital overlap

In most Diels-Alder reactions, there is secondary overlap between the p orbitals of the electron-withdrawing group and one of the central carbon atoms of the diene. Secondary overlap stabilizes the transition state, and it favors products having the electron-withdrawing groups in endo positions. 

Intramolecular Diels-Alder reactions can give endo or exo products. We should first discover which this is. Drawing the transition state for the endo product, we find that the endo product is indeed formed. So electronic factors dominate, perhaps because the dienophile has such a low-energy LUMO and has two carbonyl groups for secondary orbital overlap with the back of the diene. 

Dendrobium Alkaloids.—8-Epidendrobine (14) has been synthesized employing a route involving a diene isomerization in a Diels-Alder reaction (Scheme 3). To account for the unexpected stereochemical result of the latter addition [(12)->(13) and epimeride] it is proposed that ester (15) assumes a very hindered conformation in the transition state, involving no secondary orbital overlap between diene and ester groups. However isomerization of the trisubstituted double bond to give (16) leads... 

The two products are called the exo and endo products respectively. The endo product is favoured over the exo product under all normal conditions. It has been suggested that the reason why the endo product is preferred is that in the transition state it is possible for there to be a favourable overlap of secondary orbitals, i.e. orbitals that are not primarily involved in the carbon/carbon bonds that are being made or broken. Notice that the result of adopting such a geometry during the transition state is that the addition to both the diene and the dienophile is syn, and that the stereochemistry of four adjacent carbon atoms is thereby controlled. This control over the stereochemistry of four carbon centres is one of the reasons why the Diels-Alder reaction is so important in synthetic chemistry. 

Molecules like 1,3-butadiene may exist in the cisoid or transoid conformers, as a result of the small barrier to free rotation that exists due to the fact that the central single bond has some double bond characteristics. Only the cisoid conformer undergoes the Diels-Alder reaction. Usually, the rate of the Diels-Alder reaction is increased by electron donating substituents on the diene, and by electron withdrawing groups on the alkene, or dienophile. Thus, the diene acts as the nucleophile, while the dienophile acts as the electrophile. Under all normal conditions, the endo adduct is preferred due to favourable overlap of secondary orbitals. This results in syn-addition of an R-R unit. 

Endo addition In the Diels-Alder reaction, if part of the dieneophile is under the diene such that the hydrogens on the dieneophile adopt the equatorial position in the product, then the addition is endo. This allows for maximum overlap of secondary orbitals, and is thus favoured hence this is the kinetic product. The opposite of exo addition. 

Fig. 4-19 Secondary overlap of the frontier orbitals of Diels-Alder reactions. The dotted lines show the bonding overlap which stabilizes the lendo transition...

The high endo selectivity of aromatic aldehydes is also a result of their capability to participate in secondary orbital interactions. The mixing of the LUMO of benzaldehyde with the HOMO of the diene can form secondary orbital overlap which lowers the energy of the endo transition state. The electron-withdrawing effect of the catalyst [e.g. Eu(fod)3] on the aldehyde further enhances secondary orbital overlap with aromatic aldehydes by an additional reduction of the LUMO energy (Figure 2). Similar arguments have been made to rationalize the increase in endo selectivity of homo Diels-Alder reactions when Lewis acids are used as catalysts.Secondary orbital interactions are, however, absent when the dienophile is an aliphatic aldehyde in such reactions the cis (endo) stereoselectivity is based solely on steric interactions. 

Wiberg reported the Diels-Alder reaction of butadiene and cyclopropene [53] and Baldwin estimated from the reaction between cyclopropene and 1-deuteriobutadiene at 0°C that 99.4% of the formed cycloadduct was the endo isomer [54], There are many suggestions which attempt to explain endo selectivity in Diels-Alder reactions (Alder s rule [55]), but none are firmly established. According to Woodward and Hoffmann [56], the preference is the result of favorable Secondary Orbital Interactions (SOI) or secondary orbital overlap [57-59] between the diene and dienophile in the corresponding transition state structure. One can also find an explanation for the reaction preference in the difference between primary overlap [60], volumes of activation [61], and the polarity of the transition states [62]. Secondary orbital overlap between the diene and the dienophile does not lead to bonds in the adduct, but primary orbital overlaps do. 

There is a second type of stereoselectivity that is characteristic of the Diels-Alder reaction. The addition of a dienophile such as maleic anhydride to a cyclic diene like 1,3-cyclopentadiene could provide two products, the endo-adduct 2 and the exoadduct 3 (Eq. 12.5). However, only the e do-cycloadduct 2, in which the two boldfaced hydrogens are syn to the one-carbon bridge, is observed experimentally, and its preferential formation follows what is now commonly termed the Alder rule. The basis for this result is believed to be stabilization of the transition state 4 by secondary orbital interactions that occur through space between the p-orbitals on the internal carbons of the diene and the carbonyl carbon atoms of the dienophile, as shown by the dashed lines in 4. Analogous stabilization is not possible in transition state 5. Structure 4 is thus characterized as the one being stabilized by maximum orbital overlap. It should be noted that not all Diels-Alder reactions are as stereoselective as the one between l,3maleic anhydride mixtures of endo-and cxo-products are sometimes obtained. 

Extended Hiickel Theory has been used to calculate an approximate energy surface for the [1,3] sigmatropic rearrangement connecting (171) to (172). The calculated relative ease of the various reaction paths is correlated with both the experimental data and the predictions of orbital symmetry theory. A non-coplanar transition state in the Diels-Alder reaction of cyclopentadiene with maleic anhydride, or with other five-membered cyclic dienophiles of C2 symmetry, is suggested by the relationship between the primary and secondary overlap integrals in the Salem-type analysis of the reaction path. ... 

In further studies of the remarkable water effects on Diels-Alder reactions, we examined the exo-endo selectivity of the processes. We saw that butenone added with a 95.7% preference for endo addition in water, but only an 80% endo preference in cyclopentadiene as solvent. Thus the endo addition is favored not only by secondary orbital overlap , it is even more strikingly favored by the hydrophobic effect. In the transition state for the addition reaction, the endo geometry diminishes the amount of water/hydrocarbon interface more than does the exo geometry. The high energy of a hydrocarbon/water interface is the cause of hydrophobicity, the tendency of nonpolar materials and segments to cluster in water so as to diminish the interface with water. 

Figure 13.13 Diels-Alder reaction of cyclopentadiene and maleic anhydride, (a) When the highest occupied molecular orbital (HOMO) of the diene (cyclopentadiene) interacts with the lowest unoccupied molecular orbital (LUMO) of the dienophile (maleic anhydride), favorable secondary orbital interactions occur involving orbitals of the dienophile. (b) This interaction is indicated by the purple plane. Favorable overlap of secondary orbitals (indicated by the green plane) leads to a preference for the endo transition state shown.

When conventional Diels-Alder reaction conditions were employed (entries 1 and 2), a chromatographically inseparable mixture of stereoisomers 3.20/3.21 (R = Et) was obtained. Unfortunately, only 3.20 could be used for their proposed synthesis of glaucarubinone. This posed an interesting stereocontrol problem since the formation of both products involved secondary orbital (endo) overlap of the diene with an activating group - the former with the ketone and the latter with the aldehyde. 

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. 

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