Diels-Alder reaction symmetry control

According to frontier molecular orbital theory (FMO), the reactivity, regio-chemistry and stereochemistry of the Diels-Alder reaction are controlled by the suprafacial in phase interaction of the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied molecular orbital (LUMO) of the other. [17e, 41-43, 64] These orbitals are the closest in energy Scheme 1.14 illustrates the two dominant orbital interactions of a symmetry-allowed Diels-Alder cycloaddition. 

The chemical reactions through cyclic transition states are controlled by the symmetry of the frontier orbitals [11]. At the symmetrical (Cs) six-membered ring transition state of Diels-Alder reaction between butadiene and ethylene, the HOMO of butadiene and the LUMO of ethylene (Scheme 18) are antisymmetric with respect to the reflection in the mirror plane (Scheme 24). The symmetry allows the frontier orbitals to have the same signs of the overlap integrals between the p-or-bital components at both reaction sites. The simultaneous interactions at the both sites promotes the frontier orbital interaction more than the interaction at one site of an acyclic transition state. This is also the case with interaction between the HOMO of ethylene and the LUMO of butadiene. The Diels-Alder reactions occur through the cyclic transition states in a concerted and stereospecific manner with retention of configuration of the reactants. 

Additional evidence for a stepwise pathway is provided by the fact that a two-step Diels-Alder reaction is observed, in which a formal [2 + 2] reaction gives a vinylcyclobutane (64) which then rearranges to the formal [4 + 2] product (Scheme 41, An = P-CH3OC6H4)118. It has been shown that orbital symmetry control does not operate in these reactions Symmetry-allowed and symmetry-forbidden reactions may take place with equal facility depending upon the conditions119. It has also been shown that the obtention of formally [4 + 2] or [2 + 2] products depends on many factors, including solvent and whether it is the diene or the dienophile which is ionized120. 

The Diels-Alder reaction between furan and maleic anhydride is reversible and gives the more stable exo-adduct 100 (also commercially available). This compound contains the bicyclic ring system of ifetroban but is achiral and the key problem is to disrupt symmetry of the adduct 100 in a controlled way. The original synthesis used to make the drug17 converted the adduct 100 into the menthyl acetal 101 as a single enantiomer in four steps and then into the carboxylic acid 102 in another six steps. This strategy amounts to a resolution as each menthol adduct could be isolated by crystallisation of a diastereoisomeric mixture in only about 30% yield. 

The Diels-Alder reaction is an example of a pericyclic reaction (see Special Topic H in WileyPLUS). Pericyclic reactions are concerted reactions that take place in one step through a cyclic transition state in which symmetry characteristics of molecular orhitals control the course of the reaction. 

Cycloaddition reactions are also orbital symmetry-controlled, pericyclic reactions. We have seen one example already, the Diels-v lder reaction, and we will use it as our prototype. We found the Diels-Alder cycloaddition to be a thermal process that takes place in a concerted (one-step) fashion, passing over a cyclic transition state. Several stereochemical labeling experiments were described in Chapter 12 (p. 549), all of which showed that the reaction involved neither diradical nor polar intermediates. This stereospecificity is important because orbital symmetry considerations apply only to concerted reactions. Of course, all reactions can be subdivided into series of single-step, single-barrier processes, and each of these steps could be... 

Although most of this section will deal with rearrangements of neutral species, we may see a few anions and cations—the key common feature of this group of reactions is that, like Diels Alder and other cycloaddition processes, they are controlled by orbital symmetry. 

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