Alder rule

Another stereochemical feature of the Diels-Alder reaction is addressed by the Alder rule. The empirical observation is that if two isomeric adducts are possible, the one that has an unsaturated substituent(s) on the alkene oriented toward the newly formed cyclohexene double bond is the preferred product. The two alternative transition states are referred to as the endo and exo transition states ... 

In general, stereochemical predictions based on the Alder rule can be made by aligning the diene and dienophile in such a way that the unsaturated substituent on the dienophile overlaps the diene n system. The stereoselectivity predicted by the Alder rule is independent of the requirement for suprafacial-suprafacial cycloaddition, since both the endo and exo transition states meet this requirement. 

There are probably several factors which contribute to determining the endo exo ratio in any specific case. These include steric effects, dipole-dipole interactions, and London dispersion forces. MO interpretations emphasize secondary orbital interactions between the It orbitals on the dienophile substituent(s) and the developing 7t bond between C-2 and C-3 of the diene. There are quite a few exceptions to the Alder rule, and in most cases the preference for the endo isomer is relatively modest. For example, whereas cyclopentadiene reacts with methyl acrylate in decalin solution to give mainly the endo adduct (75%), the ratio is solvent-sensitive and ranges up to 90% endo in methanol. When a methyl substituent is added to the dienophile (methyl methacrylate), the exo product predominates. ... 

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. 

Theoretical considerations in the same fashion enable predication of the possible configuration of the transition state. Eq. (3.25 b) for the multicentre interaction is utilized. Hoffmann and Woodward 136> used such methods to explain the endo-exo selectivity of the Diels-Alder reaction (Fig. 7.28). The maximum overlapping criteria of the Alder rule is in this case valid. The prevalence of the endo-addition is experimentally known 137>. 

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... 

As shown in the following exercise, a donor substituent raises the frontier orbital energies whereas acceptor lowers them. Consequently, introducing a substituent on the dipolarophile causes two of the frontier orbitals to become closer in energy and two to separate (see the scheme above). These frontier orbital changes mirror those discussed in relation to the Alder rule. Again, the presence of the substituent induces a faster reaction.29... 

Very often, one of the reaction partners contains a carbonyl or cyano function which can form a complex with the Lewis acid. This complexation lowers the energy of the LUMO (cf. the discussion of electrophilic assistance, p. 60), and facilitates the reaction. It is the same phenomenon as that governing the Alder rule.30... 

Generalizing the Alder rule. After considering Alder s rule, we can naturally ask the following questions ... 

A comparison of the relevant transition states of the intramolecular Diels-Alder reaction can explain the observed configuration of the products 76 and 77. In the case of 76 (n = 0), the diene moiety is more likely to approach from underneath the enal face in an "endo manner (the Alder rule) because of a steric interaction with the phenyl group. The other structures 77 that contain a longer side chain (n = 1) allow the approach from both beneath and above the enal face, but NOE analyses of the isolated products 77 revealed that the diene approaches the dienophile from the top. Thus, in both systems, the trans-fused endo-configuration is preferred because of steric interactions with the phenyl substituents and the nitro group (Enders et al. 2007b). 

Stereochemical predictions based on the Alder rule are made by aligning the diene and dienophile in such a way that the unsaturated substituent on the dienophile overlaps the diene tt system. 

Since its discovery over sixty years ago [1] the Diels-Alder reaction has lost none of its attraction. [2, 3] It enables, in a one-step inter- or intramolecular reaction, the rapid preparation of cyclic compounds having a six-membered ring. During the course of the [4 -I- 2] cycloaddition four new stereocenters can be introduced directly, and their stereo-control is a topic of major interest in modem synthetic chemistry. [4-6] In addition, in intermolecular reactions, the relative positions of the reaction partners (regiochemistry) must be taken into account. If a concerted reaction is assumed, both a cis addition (suprafacial mode) and a preferred endo orientation (Alder rules) can be expected. But how can the absolute configuration of the desired product be controlled There are three basic possibilities the use of a chirally modified diene, a chirally modified dienophile, or a chiral catalyst. Although the first successes resulted from the attractive, hut difficult, catalytic route, [4b, 7] the majority of the investigators are concerned with the stoichiometric... 

Similar observations have been made many times in Diels-Alder reactions and are the basis of the Alder rule, or the rule of maximum accumulation of unsaturation In a Diels-Alder reaction, the major stereoisomer is derived from the transition state in which unsaturated groups in the dienophile are endo with respect to the diene. 

Figure 10.10 illustrates the application of the Alder rule to the Diels-Alder reaction just described. In the arrangement that leads to the endo diastereomer, the diene unit lies closer to the carbonyl groups of the dienophile than in the arrangement that leads to the... 

The Alder rule is not perfect. It correctly predicts the major product from the Diels-Alder reaction of 1,3-cyclopentadiene with methyl acrylate, but is incorrect in the case of methyl methacrylate. On the basis of these facts, give the structure of the major product isolated in each case. 

The preference for endo cycloadducts is known as the Alder rule. 

The transition-state geometries that lead to the formation of the endo- and -adducts, respectively, can be approximated by A and B. In A, the rr-electron systems of the carbonyl group and diene interact more strongly than in B. The physical basis for the Alder rule is not well understood it could arise from a variety of electronic, steric, dipole, or London forces, and must be applied with caution, since there are known exceptions. It has been found, for example, that in decalin solution at 56°C, methyl acrylate adds to cyclopentadiene to yield predominantly (76%) the enrfo-adduct, while methyl methacrylate affords the exo-adduct (67%). In addition, the stereoselectivity is sensitive to the polarity of the solvent. ... 

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