Diels-Alder reaction conformational factors

The barrier to converting the s-trans conformation to the s-cis conformation contributes to the overall activation barrier for Diels-Alder reactions. Structural factors that increase the proportion of diene in its s-cis conformation increase the rate of the Diels-Alder reaction, and factors that increase the proportion of diene in its s-trans conformation decrease the rate of the reaction. Cyclopentadiene is one of the best dienes for the Diels-Alder reaction partly because it cannot rotate out of its s-cis conformation. In fact, cyclopentadiene undergoes [4 + 2] cycloaddition to itself so readily that it lasts only a few hours at 0 °C. o-Xylylenes are especially good dienes both because of their enforced s-cis geometry and because a nonaromatic starting material is transformed into an aromatic product. By contrast, dienes in which one of the double bonds is cis are poor substrates for Diels-Alder reactions because steric interactions between the in substituents in the s-cis conformation are particularly severe, and dienes whose s-trans conformation is enforced do not ever undergo the Diels-Alder reaction. 

Steric factors have also been studied in several cases. It has been found that dienes which easily adopt the. v-cis confirmation undergo Diels-Alder reaction readily. The cyclic dienes undergo the reaction if they have cis conformation. If they are frozen into a trans-conformation, the reaction does not occur. This explains why e and / undergo the reaction easily but g fails to react. 

Grieco has used his aqueous imnicmium Diels-Alder procedure to effect a number of intramolecular reactions. In one case, diene aldehyde (83) was treated with ammonium chloride to afford a 2.2 1 mixture of isomeric Diels-Alder adducts (87) and (85) (Scheme 10). Since intermediate immonium ions (84)/(86) cannot participate in secondary orbital effects as is the case with A-acyl imines (c/. 80), these results are probably due to steric factors. It was suggested that adduct (85) derives from conformation (84) and adduct (87) comes from (86). Conformer (84) is favored since there is a severe eclipsing of Ha b in (86). A more detailed account of the stereochemical aspects of intramolecular Diels-Alder reactions can be found in Chapter 4.4. 

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-... 

In general, cycloadditions catalyzed by Lewis acids proceed at significantly lower temperatures and with higher selectivities than their uncatalyzed counterparts. Factors that contribute to the increased selectivity of the catalyzed reactions include lower temperatures and more organized transition states. For enthalpy-controlled reactions, lowering temperatures increases selectivity (recall Section 1.4, equation 1.5). Coordination of a Lewis acid to the enone carbonyl not only activates the enone by electron withdrawal, it also restricts conformational motion and thereby reduces the number of competing transition states. Figure 6.12 illustrates several chiral auxiliaries for dienophile modification that have been used in the Diels-Alder reaction. 

Reactivities in Diels-Alder Reactions Rates of Diels-Alder reactions are affected by steric as well as electronic factors. For Diels-Alder reaction to proceed dienes must have double bonds on the same side of central-single bond, i.e. there must be c/s-conformation because this is high energy conformation. 

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