Endo-Rule

Alder Endo Rule In order to maximize secondary orbital interactions, the endo TS is favored in the D-A rxn. Tetrahedron 1983, 3,9, 2095... 

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. 

Known as the endo rule, it was first formulated by Alder and Stein530,532 and explained as the maximum accumulation of double bonds. Now endo selectivity is considered to be the result of stabilizing secondary orbital interactions.533 The endo rule, however, strictly applies only for cyclic dienophiles. 

As expected from Alder s endo rule, and justified by consideration of maximum accumulation of unsaturation in the transition state, secondary orbital interactions and dispersion forces, furan reacts with maleic anhydride in acetonitrile at 40 °C (78JOC518) to give initially... 

Alder s endo rule applies not only to cyclic dienes like cyclopentadiene and to disubstituted dienophiles like maleic anhydride, but also to open chain dienes and to mo no-substituted dienophiles diphenylbutadiene and acrylic acid, for example, react by way of an endo transition structure 2.113 to give largely (9 1) the adduct 2,114 with all the substituents on the cyclohexene ring cis, and equilibration again leads to the minor isomer 2.115 with the carboxyl group trans to the two phenyl groups. 

Alder s endo rule leads substituents in open-chain trans dienes to be alias on the cyclohexene ring. 

The endo rule also applies to some Diels-Alder reactions with inverse electron demand, as in the cycloaddition of butadienylsulfoxide 2.116 with the enamine 2.117, which gives only the adduct 2.118. The amino group is an... 

We shall return to frontier orbital theory to explain the much weaker elements of selectivity, like the effect of substituents on the rates and regioselectivity, and the endo rule, but we must look for something better to explain why interacting molecules conform to the rules with such dedication. 

In addition, Diels-Alder adducts are formed through two types of approaches that lead to endo or exo isomers. The endo isomer is usually favored over the exo isomer, although the exo isomer is generally the thermodynamically preferred product. This is known as the Alder, or endo, rule and can be attributed to the additional stability gained by secondary molecular orbital overlap during the cycloaddition.22 26 27 Again, the use of a Lewis acid catalyst can alter the endo/exo ratio and has even been shown to give the thermodynamic exo adduct as the major product.28... 

The influence of secondary overlap was first observed in reactions using cyclopen-tadiene to form bicyclic ring systems. In the bicyclic product (called norbornene), the electron-withdrawing substituent occupies the stereochemical position closest to the central atoms of the diene. This position is called the endo position because the substituent seems to be inside the pocket formed by the six-membered ring of norbornene. This stereochemical preference for the electron-withdrawing substituent to appear in the endo position is called the endo rule. 

The endo rule is useful for predicting the products of many types of Diels-Alder reactions, regardless of whether they use cyclopentadiene to formnorbomene systems. The following examples show the use of the endo rule with other types of Diels-Alder reactions. 

Use the endo rule to predict the product of the following cycloaddition. 

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

Indeed, it seems that intramolecular Diels-Alder reactions are governed more by normal steric considerations than by the endo rule. 

The reaction is stereospecific within each component but there is no endo rule—there is a conjugating group but no back of the diene . The least hindered transition state usually results. 

One important nitrone is a cyclic compound that has the structure below and adds to dipolarophiles (essentially any alkene ) to give two five-membered rings fused together. The stereochemistry comes from the best approach with the least steric hindrance, as shown. There is no endo rule in these cycloadditions as there is no conjugating group to interact across space at the back of the dipole or dipolarophile. The product shown here is the more stable exo product. 

Although IMDA reactions are entropically less disfavored than the intermolecular versions, they are nonetheless not as simple as might at first appear. The well-known Alder endo rule and its frontier molecular orbital theoretical interpretation involving secondary orbital interactions, together with steric considerations, serve to explain the kinetic preference for the endo-product and the thermodynamic preference for the < o-product in IMDAs. For the IMDA reaction, an additional parameter, the effect of the tether that connects the diene to the dienophile to control the conformation available to a transition state has to be considered. 

The Stereoselectivity of Diels-Alder Reactions. One of the most challenging stereochemical findings is Alder s endo rule for Diels-Alder reactions. The favoured transition structure 6.180 has the electron-withdrawing substituents in the more hindered environment, under the diene unit, giving the kinetically more favourable but thermodynamically less favourable adduct 6.181. Heating eventually equilibrates the adducts in favour of the exo adduct 6.182, by a retro-cycloaddition re-addition pathway. 

Fig. 6.30 Secondary interactions and the endo rule for the Diels-Alder reaction...

In conclusion, the standard secondary orbital interaction depicted in Fig. 6.30 is not fully accepted, yet it remains a simple and much cited explanation for the endo rule. 

Endo versus exo geometry in the Diels-Alder reaction When the Diels-Alder reaction forms bridged bicyclic adducts and an unsaturated constituent is located on this bicyclic structure, the chief product is normally the kinetically favoured endo-isomer, Alder s endo rule. 

Alder s endo rule specifies a preference for endo (C) over exo (D) addition. However, this rule appears to be strictly applicable only to the addition of cyclic dienophiles (e.g. maleic anhydride, p-qui-nones) to cyclic dienes (e.g. cyclopentadienes). 

As the focus of this chapter is on the synthetic utility of the rDA reaction, an overview of mechanism is beyond the scope of this review however, the subject has beoi reviewed previously. Structural and medium effects on the rate of the rDA reaction are of prime importance to their synthetic utility, and therefore warrant discussion here. A study of steric effects cm the rate of cycloreversicHi was the focus of early work by Bachmann and later by Vaughan. The effect of both diene and dioiophile substituticHi on Ae rate of the rDA reaction in anthracene cycloadducts has been reported in a study employing 45 different adducts. If both cycloaddition and cycloreversion processes are fast on the time scde of a given experiment, reversibility in the DA reaction is observed. Reversible cycloaddition reactions involving anthracenes, furans, fulvenes and cyclopentadienes are known. Herndon has shown that the well-known exception to the endo rule in tiie DA reaction of furan with maleic anhydride (equation 2) occurs not because exo addition is faster than endo addition (it is not), but because cycloreversion of the endo adduct is about 10 000 times faster than that of the exo adduct. ... 

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