The retro Diels-Alder reaction

Cyclopentadiene is a popular moiety to release in a retro Diels-Alder reaction, as the cyclohexene portion of the bicyclo[2.2.1]heptene is locked in a boat conformation, as required in the transition state for the retro (and indeed forward Diels-Alder) reaction. Other bridged bicyclic systems are also more prone to undergo retro Diels-Alder reaction. The bridged adduct from fiiran and maleic anhydride readily undergoes the retro reaction and, although the endo isomer is formed at a much faster rate, the reversible nature of the reaction leads to the accumulation of the more stable exo isomer. 

---

In summary, it seems that for most Diels-Alder reactions secondary orbital interactions afford a satisfactory rationalisation of the endo-exo selectivity. However, since the endo-exo ratio is determined by small differences in transition state energies, the influence of other interactions, most often steric in origin and different for each particular reaction, is likely to be felt. The compact character of the Diels-Alder activated complex (the activation volume of the retro Diels-Alder reaction is negative) will attenuate these eflfects. The ideas of Sustmann" and Mattay ° provide an attractive alternative explanation, but, at the moment, lack the proper experimental foundation. 

The observation that in the activated complex the reaction centre has lost its hydrophobic character, can have important consequences. The retro Diels-Alder reaction, for instance, will also benefit from the breakdown of the hydrophobic hydration shell during the activation process. The initial state of this reaction has a nonpolar character. Due to the principle of microscopic reversibility, the activated complex of the retro Diels-Alder reaction is identical to that of the bimoleciilar Diels-Alder reaction which means this complex has a negligible nonpolar character near the reaction centre. O nsequently, also in the activation process of the retro Diels-Alder reaction a significant breakdown of hydrophobic hydration takes placed Note that for this process the volume of activation is small, which implies that the number of water molecules involved in hydration of the reacting system does not change significantly in the activation process. 

We conclude that the beneficial effects of water are not necessarily limited to reactions that are characterised by a negative volume of activation. We infer that, apart from the retro Diels-Alder reaction also other reactions, in which no significant reduction or perhaps even an increase of solvent accessible surface area takes place, can be accelerated by water. A reduction of the nonpolar nature during the activation process is a prerequisite in these cases. 

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 type of enforced hydrophobic effect that is operative in the retro Diels-Alder reaction cannot be referred to an enforced hydrophobic interaction, since there is no coming together, but rather a separation of nonpolar molecules during the reaction. It is better to refer to this process as an enforced hydrophobic effect. 

The reaction of o-iodophenol, norbornadiene and CO proceeds via alkene and CO insertions to afford the lactone 562, which is converted into coumarin (563) by the retro-Diels-Alder reaction. In this coumarin synthesis, norbona-diene behaves as a masked acetylene[4)3],... 

The Diels-Alder reaction is of wide scope. Not all the atoms involved in ring formation have to be carbon atoms the hetero-Diels-Alder reaction involving one or more heteroatom centers can be used for the synthesis of six-membered heterocycles. The reverse of the Diels-Alder reaction—the retro-Diels-Alder reaction —also is of interest as a synthetic method. Moreover and most importantly the usefulness of the Diels-Alder reaction is based on its 5y -stereospecifi-city, with respect to the dienophile as well as the diene, and its predictable regio-and c ifo-selectivities. °... 

The combination of the Diels-Alder reaction of fi-sulfonylnitroethylene and the Barton-Zard reaction provides a new synthesis of pyrroles fused with polycyclic skeletons fEq 10 31 Pyrroles fused with bicycle [3 3 3 Qctodiene are important precursors for synthesis of isoindoles via the retro Diels-Alder reaction fEq 10 33 ... 

Based on the facile formation and reactivity of323, and the retro Diels-Alder reaction of 325306,310, a simple procedure has been developed for the stereoselective synthesis of functionalized conjugated dienes as well as vinylallenes311 (see equation 119). 

The retro Diels-Alder reaction usually requires high temperatures in order to surmount the high activation barrier of the cycloreversion. Moreover, the strategy of retro Diels-Alder reaction is used in organic synthesis to mask a diene fragment or to protect a double bond [47]. Some examples are illustrated in Scheme 1.11. 

The retro Diels-Alder reaction is strongly accelerated when an oxide anion substituent is incorporated at positions 1 and 2 of the six-membered ring which has to be cycloreversed, namely at one terminus carbon of the original diene or at one sp carbon of the dienophile [51] (Equation 1.22). 

Rickborn B. The Retro-Diels-Alder Reaction. Part II. Dienoplules with One or More Heteroatoms Org. React. (N. Y.) 1998 53 223-629... 

Similarly, /V-sulfonyl-protected vinylimidazole 597 reacts with PTAD to provide the cycloaddition reaction product 598 which easily undergoes the retro-Diels-Alder reaction upon heating or with acid treatment. The primary product is easily isomerized using a base to the aromatized condensed imidazole 599 (Scheme 95) <1998TL4561>. 

A somewhat milder route which appears to be devoid of the complications of isomerization is the retro-Diels-Alder reaction of bicyclo [2.2.2] octadienes, frequently substituted with aryl groups (5,30,53,65), [Eq. (2)], and recently Wiberg (88,90) described a very mild route involving both [2 + 2] and [2 + 4] cycloreversions which occur at 60°C to generate Me2Si=C(SiMe3)2. However, the generality of this latter source of silenes has not been established yet [Eq. (3)]. 

To avoid the retro-Diels-Alder reaction, 56 was dihydroxylated prior to the introduction of the bromine atom (57). Removal of the acetonide group followed by cleavage of the diol afforded a bis-hemiacetal. Selective reduction of the less-hindered hemiacetal group gave 58. The remaining hemiacetal was protected, and the ketone was converted to an enol triflate, thus concluding the synthesis of the electrophilic coupling component 51. 

The secondary deuterium KIEs for the retro-Diels-Alder reaction of ethanoanthracene has been investigated also207 (equation 87)206. 

The term Diels-Alder reaction in a general sense refers to the reaction between a diene and a dienophile. Retro Diels-Alder reaction is a process that, under certain conditions, produces diene and olefin or a compound containing a C=C bond. The application of flash vacuum pyrolysis to effect the retro Diels-Alder reaction, as shown in Schemes 5-46 and 5-47, has become the standard procedure since the introduction of the method by Stork et al.74 in the 1970s. Therefore, alkenes that are difficult to access by conventional methods may be obtained via retro Diels-Alder reactions.75 In particular, this reaction allows the preparation of thermodynamically less stable compounds such as 4,5-dialkyl cyclopenta-2-en-one. In this case, the alkene functional group can be regarded as being protected by cyclopentadiene (as shown in 154 or 157), which, after subsequent reaction, can easily be removed through quick pyrolysis. 

Hetero Diels-Alder reactions are very useful for constructing heterocyclic compounds, and many important chiral molecules have thus been synthesized. Although the retro Diels-Alder reaction does not itself involve the asymmetric formation of chiral centers, this reaction can still be used as an important tool in organic synthesis, especially in the synthesis of some thermodynamically less stable compounds. The temporarily formed Diels-Alder adduct can be considered as a protected active olefin moiety. Cyclopentadiene dimer was initially used, but it proved difficult to carry out the pyrrolytic process. Pentamethyl cyclopentadiene was then used, and it was found that a retro Diels-Alder reaction could easily be carried out under mild conditions. 

In general, C-acyl nitroso compounds-9,10-dimethylanthracene cycloadducts derived from hydroxamic acids (-R = alkyl, aryl, ti/2 = 4.1 h for -R = -Ph at 60°C) decompose more slowly than those derived from N-hydroxycarbamates or N-hydroxyureas [11, 13, 14]. Further addition of alkyl groups to the N atom of N-hydroxyurea-derived cycloadducts produces a further increase in the rate of the retro-Diels-Alder reaction of these cycloadducts [36]. These general trends suggest the possibility of the development of acyl nitroso compound-9, 10-dimethylanthracene cycloadducts as a general class of HNO or NO donors with varied release profiles. 

The reverse reaction, the retro-Diels-Alder reaction is a clean first order reaction, both in the gaseous and condensed phase. 

The analogous transformation of 125, also realized by flash vacuum pyrolysis, gave rise to allenic oximes 126 [165], which are not directly accessible by the classical route starting from allenyl ketones and hydroxylamine (see Section 7.3.2) [122], Because compounds 125 are prepared from allenyl ketones and furan by [4 + 2]-cycloaddition followed by treatment with hydroxylamine, the retro-Diels-Alder reaction 125 —> 126 is in principle the removal of a protecting group (see also Scheme 7.46). 

Limonene, one of the most prominent natural monoterpenes (cf Section VII), represents a particular derivative of 4-vinylcyclohexene since it has been studied with respect to the pronounced energy dependence of its fragmentation behaviour (Scheme 7). Counterintuitively, and in contrast to 4-vinylcyclohexene, the radical cations of limonene (27) do not undergo the retro-Diels-Alder reaction if the internal energy of the ions is low. As... 

As with the McLafferty rearrangement and the retro-Diels-Alder reaction before, the occurrence of the ortho elimination is not restricted to molecular ions. It may equally well proceed in even-electron species. 

Problems. CCXXXIII. Stereochemical Dep dence of the Retro-Diels-Alder Reaction. J. Am. Chem. Soc. 1973, 95, 5806-5807. 

The retro-Diels-Alder reaction has been reviewed.A fully concerted cyclic transition state has been proposed for conrotatory opening of cyclobutenes, in order to account for the low activation entropy and unexpected activation volume of ca —2 to —3cm mol . ... 

The energy gained in producing the aromatic triazole system facilitates the retro-Diels-Alder reaction of suitably substituted triazolines. The reaction is potentially useful as a method of synthesis of highly reactive species (e.g.. Scheme 18) rather than as a preparative procedure for triazoles. 

An even more pronounced retro-Diels-Alder reaction occurs by using 1,3-di-phenylisobenzofuran (DPIF), 9-methylanthracene or 9,10-dimethylanthracene as dienes [8, 10-12]. The monoadduct of DPIF cannot be isolated from the reaction mixture, while the monoadduct of the 9-methyl- or 9,10-dimethyl- derivatives of anthracene can be isolated at temperatures lower than room temperature [10]. Both anthracene derivatives decompose at room temperature, the adduct with one methyl group within hours, the adduct with two methyl groups within minutes. For DPIF and the anthracene compounds the retro-Diels-Alder reaction seems to be facilitated by steric repulsion due to the bulky groups. However, as shown by Wudl and coworkers [13], the cycloadduct of with isobenzofuran (Scheme 4.2), which was generated in situ from l,4-dihydro-l,4-epoxy-3-phenylisoquinoline, is stable in the solid state as well as in solution and shows no tendency to undergo cycloreversion. 

These examples already prove that the potential of such reactions for the synthesis of stable fuUerene derivatives is restricted due to the facile cycloreversion to the starting materials. Nevertheless, cycloreversion can also be useful. Reversibility of dimefhylanthracene addition was utilized for the selective synthesis of Ti -symme-trical hexakisadducts (see Chapter 10) [12]. In another example, a dendritic polyamidoamine-addend was reversibly attached to via an anthracene anchor (Figure 4.1) [14, 15]. The dendrofullerene, which is soluble in polar solvents, can be obtained in 70% yield and the retro-Diels-Alder reaction at 45 °C proceeds with a conversion rate of more than 90%. 

A -sulfinylacetamide 297 in greater than 90% yield when a catalytic amount of methyltrioxorhenium is employed. Futhermore, the hetero-Diels-Alder adduct is highly soluble in both chlorinated and ethereal solvents. A detailed investigation of the retro-Diels-Alder reaction of 298 by thermogravimetric analysis revealed an onset temperature of 120 °C and complete conversion of bicycle 298 to pentacene 296 at 160 °C, which are temperatures compatible with the polymer supports typically used in electronics applications. The electronic properties of these newly prepared OTFTs are similar to those prepared by traditional methods. Later improvements to this chemistry included the use of A -sulfinyl-/< r/-butylcarbamate 299 as the dienophile <2004JA12740>. The retro-Diels-Alder reaction of substrate 300 proceeds at much lower temperatures (130 °C, 5 min with FlTcatalyst 150 °C, Ih with no catalyst). 

---