Diels Alder reactions endo rule

Under the usual conditions their ratio is kinetically controlled. Alder and Stein already discerned that there usually exists a preference for formation of the endo isomer (formulated as a tendency of maximum accumulation of unsaturation, the Alder-Stein rule). Indeed, there are only very few examples of Diels-Alder reactions where the exo isomer is the major product. The interactions underlying this behaviour have been subject of intensive research. Since the reactions leadirig to endo and exo product share the same initial state, the differences between the respective transition-state energies fully account for the observed selectivity. These differences are typically in the range of 10-15 kJ per mole. ... 

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 ... 

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... 

However, Diels-Alder reactions are well known to be exceptional, with maleic anhydride reacting with cyelopentadiene by way of an endo transition structure 2.110 to give what is called the endo adduct 2.111 as the major product. The exo adduct 2.112 is a very minor product, unless the mixture is heated for a long time, when reversal of the Diels-Alder reaction and readdition establish the thermodynamic equilibrium in its favour. The endo adduct is evidently the product of kinetic control, and the preference for it is called Alder s rule. 

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... 

Cycloadditions are easier to treat than unimolecular reactions they only require an evaluation of the best FO overlap (rule 4). Let us look at the cyclodimerization of butadiene. Woodward and Hoffmann suggested that the experimentally observed endo compound is due to secondary interactions (shown by the double arrows above), which increase the stabilizing the FO s interaction.23 Cisoid configurations are often adopted by the dienophile in Diels-Alder reactions,24 as first suggested by Dewar.20 For... 

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. 

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. 

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). 

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...

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. 

Rule of endo addition (Section 16.13D) The rule that the endo product is preferred in a Diels-Alder reaction. 

Diels-Alder reactions generally proceed selectively via the TS in which the most powerful electron-withdrawing group on the dienophile is endo, i.e., sitting underneath the diene, as opposed to pointing away from it. This phenomenon is known as the endo rule. 

Stereochemistry The most electron withdrawing group on the dienophile prefers to be endo, and the out-endo-cis rule tells you that the OAc and CN groups are cis in the product. The suprafacial-suprafacial nature of the Diels-Alder reaction... 

The endo rule applies equally to inverse electron-demand Diels-Alder reactions. In these reactions, the most electron donating group on the dienophile is preferentially endo. The out-endo-cis rule applies, too. 

Another question posed in Chapter 1 was Why does the Diels-Alder reaction give endo adducts Whereas the Woodward-Hoffmann rules have been explained in several (related154) ways, the frontier orbital method is virtually the only one to have been used to account for secondary effects like this.155... 

Alder-Stein rules. Set of rules governing the stereochemistry of the Diels-Alder reaction. The most important are that (1) the stereochemical relationship of groups attached to the diene and the dienophile is maintained in the product (cis-addi-tion) and (2) the product resulting from maximum accumulation of unsaturated centers in the transition state is favored (endo rule). 

The preceding discussion is not meant to imply that stereo electronic effects alone are responsible for determining diastereoselection in the Diels-Alder reaction. Indeed, examples of reactions that do not conform to the endo rule abound, and these cases are not easily explained without invoking alternative hypotheses. For instance, it has been demonstrated that 1,1-disubstituted dien-ophiles can favor formation of the exo product with cyclopentadiene, sometimes to the complete exclusion of the electronically favored endo isomer [19]. There appears to be subtle interplay between steric and electronic factors, as simply switching the diene to cyclohexadiene or an acyclic diene results in a turnover in selectivity to favor the endo isomer. While the exact source of stereocontrol for a given cycloaddition is still a source of debate, this review will emphasize the practical ramifications of diastereoselection, namely, prototypical dienophiles such as a-methacrolein and a-bromoacrolein can be relied on to deliver exo cycloadducts preferentially with cyclopentadiene endo otherwise), while acrylate, crotonate, and cinnamate-derived dienophiles will generally favor the endo tran-... 

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