Diels-Alder reaction thermodynamic control

Stereochemistry of Diels-Alder Reactions. Thermodynamic vs. Kinetic Control... 

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. 

As an approach to biomimetic catalysis, Sanders and colleagues [67] synthesized a series of 1,1,2-linked cyclic porphyrin trimers that allow the stereo- and regiochemistry of the Diels-Alder reaction of 84 and 85 within the molecular cavity to be controlled, thereby producing prevalently or exclusively the endo 86 or the exo 87 adduct. Two examples are illustrated in Scheme 4.18. At 30 °C and in the absence of 88, the reaction furnishes a mixture of diastereoisomers, while the addition of one equivalent of trimer 88 accelerates the reaction 1000-fold and the thermodynamically more stable exo adduct 87 is the sole detectable product. 

The different ratios of 52/53 produced by cycloadditions performed at atmospheric and high pressure, and the forma tion of the unusual trans adducts 53, have been explained by the facts that (i) Diels-Alder reactions under atmospheric pressure are thermodynamically controlled, and (ii) the anti-endo adducts 52 are converted into the short-lived syn-endo adducts 54 which tautomerize (via a dienol or its aluminum complexes) to 53. The formation of trans compounds 53 by induced post-cycloaddition isomerization makes the method more flexible and therefore more useful in organic synthesis. 

Lubineau and coworkers [18] have shown that glyoxal 8 (Ri = R2 = H), glyoxylic acid 8 (Ri = H, R2 = OH), pyruvic acid 8 (Ri = Me, R2 = OH) and pyruvaldehyde 8 (Ri = H, R2 = Me) give Diels-Alder reactions in water with poor reactive dienes, although these dienophiles are, for the most part, in the hydrated form. Scheme 6.6 illustrates the reactions with (E)-1,3-dimethyl-butadiene. The reaction yields are generally good and the ratio of adducts 9 and 10 reflects the thermodynamic control of the reaction. In organic solvent, the reaction is kinetically controlled and the diastereoselectivity is reversed. 

Despite the fact that the exo adduct is likely to be the more stable of the two thermodynamically, it is often (though not universally) found in Diels-Alder reactions that the endo adduct is the major, if not the sole, product. To explain this, it has been suggested that in endo addition stabilisation of the T.S. can occur (and the rate of reaction thereby speeds up) through secondary interaction of those lobes of the HOMO in, e.g. (32) and of the LUMO in (33) that are not themselves involved directly in bond-formation, provided these are of the same phase. Such interaction would not, of course, be possible in the T.S. for exo addition because the relevant sets of centres in (32) and (33) will now be too far apart from each other the endo adduct is thus the kinetically controlled product. It is significant in this connection that the relative proportion of exo... 

Domingo and coworkers [11] have contributed an important theoretical input for the understanding of domino reactions. An interesting example is the domino Diels-Alder reaction of 4-33 and 4-34, in which the products 4-37 and 4-38 could be formed via 4-35 and 4-36, respectively (Scheme 4.7). Visnick and Battiste [12] had shown that, at room temperature, only cycloadduct 4-37 is formed, whereas with heat 4-38 is obtained quantitatively. This is in line with the calculations showing that TS5 is higher in energy than TS4 (74.5 and 55.3 kj mol"1, respectively) on the other hand, cycloadduct 4-38 is more stable (-92.9 kj mol"1) than cycloadduct 4-37 (-78.7 kj mol"1), which explains the formation of 4-38 under thermodynamic control. Calculations have also been performed for the bisfuran system 4-28a [13]. 

Actually one orientation predominates (called high regioselectivity) and only one diastereoisomer is produced (called high stereoselectivity). The Diels-Alder reaction is reversible and may be carried out under thermodynamic or kinetic controlled conditions. 

Marchand and coworkers102 reported a difference in site selectivity between the thermodynamically and kinetically controlled Diels-Alder reactions of cyclopentadiene with 2,3-dicyano-p-benzoquinone (126) (equation 37). Under kinetic conditions, the more reactive double bond of 126 reacted with cyclopentadiene affording 127, whereas the less substituted double bond reacted under thermodynamic conditions affording 128. Both reactions proceeded with complete endo selectivity. These findings were in agreement with ab initio HF/3-21G calculations. 

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. 

We have expanded our collection of stereoselective reactions even more in the making of alkenes by the Wittig reaction (chapter 15), from acetylenes (chapter 16), by thermodynamic control in enone synthesis (chapters 18 and 19) and in sigmatropic rearrangements (chapter 35). We have seen that such E- or Z-alkenes can be transformed into three-dimensional stereochemistry by the Diels-Alder reaction (chapter 17), by electrophilic addition (chapters 23 and 30), by carbene insertion (chapter 30) and by cycloadditions to make four-membered rings (chapters 32 and 33). 

Here we are primarily concerned with the fact that this ortho -adduct may occur in the form of two diastereomers. The diastereomers are formed as a 57 43 cis/trans-mixtme in the absence of A1C13, but a 95 5 cis/trans-mixture is obtained in the presence of A1C13. In the latter case, thus, one is dealing with a Diels-Alder reaction that exhibits a substantial simple diastereoselectivity (see Section 11.1.3 for a definition of the term). Here, the simple diastereoselectivity is due to kinetic rather than thermodynamic control, since the preferentially formed ds-disubstituted cyclohexene is less stable than its irans-isomer. 

This section has been strong on thermodynamic control but weak on the more common kinetic control. This will be remedied in Chapter 35 where you will meet the most important cydization reaction of all—the Diels-Alder reaction. It is under kinetic control and there is a great deal of stereochemistry associated with it. 

The product is, in fact, the endo compound. This is impressive not only because only one diastereoisomer is formed but also because it is the less stable one. How do we know this Well, if the Diels-Alder reaction is reversible and therefore under thermodynamic control, the exo product is formed instead. The best known example results from the replacement of cyclopentadiene with furan in reaction with the same dienophile. 

If pyrrole would do a similar thermodynamically controlled exo Diels-Alder reaction with a vinyl pyridine, a short route to the interesting analgesic epibatidine could be imagined, with just a simple reduction of the remaining alkene left to do. The reaction looks promising as the pyridine makes the dienophile electron-deficient and pyrrole is an electron-rich diene . 

The isolation of 61, as well as the expected syn/endo-Hlsyn/endo-H isomer 59 (Scheme 13), illustrates, for the first time, evidence for the existence of a second reaction pathway operating during these repetitive Diels-Alder reactions. HPLC analysis of the reaction mixture, isolated after a high pressure reaction between 38 and 57, revealed the product ratio of 59 61 to be 18 1. The question of whether 61 owes its origin to the existence of a second, less favorable reaction pathway in a kinetically-controlled process, or is, in fact, the outcome of a degree of thermodynamic control, involving a retro Diels-Alder reaction, followed by recombination, will be discussed in Section 3.2. 

Kinetic Versus Thermodynamic Control Within the Repetitive Diels-Alder Reaction Regime... 

Scheme 18. If the repetitive Diels-Alder reaction adducts reported were being formed under thermodynamic control, heating the hexadecadeutero 2 1 adduct 68 under reflux in toluene in the presence of a 10 molar equivalent of the bisdiene 37 should give rise to a mixture of compounds comprised of 68, 69, and 41. A retro Diels-Alder reaction of 68, followed by scrambling of the labeled bisdiene 66 with the excess of the bisdiene 37 should favor preferential cycloaddition with 37 to afford 69. The excess of 37 should ultimately drive the equilibration process toward the unlabeled 2 1 adduct 41. No evidence for such an equilibration process has been found... 

Whereas cyclic secondary enaminones and nitroolefins mainly yield indoles in which the enamine nitrogen is incorporated into the heterocyclus (equation 242), linear tertiary a-ketoenamines are shown to react with nitroolefines at low temperature under kinetic control to give 1,2-oxazine N-oxides as [4 + 2]-cycloadducts, followed by retro-Diels-Alder reaction or rearrangement under thermodynamic control which leads diastereo-selectively to aminocyclopentenes. The reaction is called [3 + 2]-carbocyclization, apparently because the ketoenamine is reacting as a 1,3-dipole. The products are hydrolysable to polysubstituted nitrocyclopentanones with retained configuration325 (equation 243). 

Intermolecular [4 + 2] cycloadditions exhibit strongly negative activation volumes and reaction volumes. High pressure, therefore, can be applied to accelerate Diels-Alder reactions and to shift the reaction equilibrium towards the cycloadducts. These effects are of particular advantage to (1) promote odierwise slow [4 + 2] cycloadditions involving heat or Lewis acid sensitive educts or products (2) suppress cycloreversion processes which are eidier thermodynamically favored or would interfere with a kinetically controlled stereochemistry. In view of a recent review (1985) only a few examples are presented here. 

There has obviously been a cycloaddition between the furan as diene and maleic anhydride and an esterification of the free OH group by the anhydride. Whichever we do first, the stereochemistry is t xo. This is because furans are aromatic and the Diels-Alder reaction is reversible and under thermodynamic control. We ll do that first. 

Marchand and coworkers reported a difference in site selectivity between the thermodynamically and kinetically controlled Diels-Alder reactions of cyclopentadiene with... 

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