Diels-Alder reaction orientation effects

In the case of the retro Diels-Alder reaction, the nature of the activated complex plays a key role. In the activation process of this transformation, the reaction centre undergoes changes, mainly in the electron distributions, that cause a lowering of the chemical potential of the surrounding water molecules. Most likely, the latter is a consequence of an increased interaction between the reaction centre and the water molecules. Since the enforced hydrophobic effect is entropic in origin, this implies that the orientational constraints of the water molecules in the hydrophobic hydration shell are relieved in the activation process. Hence, it almost seems as if in the activated complex, the hydrocarbon part of the reaction centre is involved in hydrogen bonding interactions. Note that the... 

The substituents at C-2, C-3 within diene 97 and those at C-1, C-2 within dienophiles 98-100 are electronically and/or sterically equivalent with respect to diene and dienophile reaction centers, respectively, and therefore cycloaddition should not display regiochemical bias in the absence of orientational effects. The Diels-Alder reactions of 97 prepared in situ with 98-100 gave an excess of 101 (Scheme 4.19) [70b], which are the expected regioisomers if the reagents react in their preferred orientations within a mixed micelle with an ammonium head group at the aggregate-water interface and the remainder in the micelle interior. 

Parallel studies on the cycloadditions of non-surfactant dienes 106 and 107 and the dienophile 108 (Figure 4.4), analogs of 97,103 and 98-100, respectively, show that the regioisomer adducts were, in this case, obtained in equal amounts, supporting the idea that orientational effects in micelles promote the regioselectivity of a Diels-Alder reaction of a surfactant diene and a surfactant dienophile. 

In recent years, supramolecular chemistry has produced a number of systems which have been shown to be able to effectively catalyze a Diels-Alder reaction. Most systems selectively afforded only one diastereomer because of a pre-organized orientation of the reactants. These systems include cyclodextrines, of which applications in Diels-Alder chemistry have recently been reviewed89. Some other kinds of non-Lewis acid catalyzed Diels-Alder reactions, including catalysis by proteins and ultrasound, have been discussed by Pindur and colleagues90. 

Fig. 12.24. Orientation-selective Diels-Alder reactions with a 2-substituted 1,3-diene I comparison of the effects exerted by one or two dienophile substituents.

The increase in orientation selectivity of Diels-Alder reactions upon addition of Lewis acid has a second cause aside from the one which was just mentioned.The reaction conditions described in Figure 12.27 indicate that A1C13 increases the rate of cycloaddition. The same effect also was seen in the cycloaddition depicted in Figure 12.20. In both instances, the effect is the consequence of the lowering of the LUMO level of the dienophile. According to Equation 12.2, this means that the magnitude of the denominator of the first term decreases and the first term therefore becomes larger than the second term. II) in addition, the numerators of these terms differ by a certain amount for the para and meta transition states (as determined by the combinations of the LCAO coefficients), the effect is further enhanced. This also increases the para selectivity. 

Acetylallene (1) behaves as an excellent dienophile in Diels-Alder reactions and induces peculiar orienting effects, allowing reactions with high regio- and stereoselectivities.2 Retro Diels-Alder reactions of modified adducts of furan and 1 afford a general method of synthesis of cc-functionalized ailenes.3... 

The influence of the hydrophobic effect on the aqueous pericychc reactions can be compared with the effect of catalytic antibodies. Antibodies have been found to catalyze Diels-Alder reactions, hetero-Diels-Alder reactions, and Claisen and oxy-Cope rearrangements. It is suggested that antibodies catalyze these reactions by acting as an entropy trap, primarily through binding and orienting the substrates in the cyclic conformations. 

The factors that determine the steric course of these cycloaddition reactions are still not completely clear. It appears that a number of forces operate in the transition state and the precise composition of the product depends on the balance among these. The preference for the endo adduct, in which the dienophile substituents are oriented over the residual unsaturation of the diene in the transition state, has been rationalized by Woodward and Hoffmann in terms of secondary orbital interactions. In this explanation, the atomic orbital at C-2 (and/or C-3) in the HOMO of the diene interacts with the atomic orbital of the activating group in the LUMO of the dienophile. However, there is no evidence for this secondary orbital interaction and the stereoselectivities in the Diels-Alder reaction can be explained in terms of steric interactions, solvent effects, hydrogen-bonding, electrostatic and other forces (3.70). ... 

Regioselectivity An increase in the regioselectivity in the catalyzed reactions can also be explained on the basis of FMO interactions. More effective overlap of the orbitals in the transition state of a Diels—Alder reaction takes place when the reacting compounds are oriented in such a way that the atom with the largest coefficient in the dienophile interacts preferentially with the... 

Reactive Enophile in [4 + 2] Cycloadditions. Vinylketenes are not effective as dienes in Diels-Alder reactions because they undergo only [2 + 2] cycloaddition with alkenes, as predicted by frontier molecular orbital theory. However, silylketenes exhibit dramatically different properties from those found for most ketenes. (Trimethylsilyl)vinylketene (1) is a relatively stable isolable compound which does not enter into typical [2 + 2] cy do additions with electron-rich alkenes. Instead, (1) participates in Diels-Alder reactions with a variety of alkenic and alkynic dienophiles. The directing effect of the carhonyl group dominates in controlling the regiochemical course of cycloadditions using this diene. For example, reaction of (1) with methyl propiolate produced methyl 3-(trimethylsilyl)sahcylate with the expected regiochemical orientation. ProtodesUylation of this adduct with trifluoroacetic acid in chloroform (25 °C, 24 h) afforded methyl salicylate in 78% yield (eq 2). 

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