Diels-Alder reversed polarity

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%. 

In order to form the activated complex required for the formation of product D, rotational changes of the less dipolar anti-form A to the more dipolar s jn-conformer B are necessary, to give an activated complex C with more parallel bond dipoles, which is thus more dipolar and better solvated than the reactant molecule. In agreement with this explanation is the observation that the reverse refro-Diels-Alder reaction exhibits no large solvent effect, since the activated complex C is quite similar to the reactant D [807], A very subtle solvent effect has been observed in the Diels-Alder addition of methyl acrylate to cyclopentadiene [124], The polarity of the solvent determines the ratio of endo to exo product in this kinetically controlled cycloaddition reaction, as shown in Eq. (5-43). The more polar solvents favour endo addition. 

Until recently, the reaction of a,/3-unsaturated esters with electron-rich olefins has been reported to afford cyclobutane [2 + 2] cycloaddition products. Amice and Conia first proposed the intermediacy of [4 + 2] cycloadducts in the reaction of ketene acetals with methyl acrylate,108 and the first documented example of the 4v participation of an a,/3-unsatu-rated ester in a Diels-Alder reaction appears to be the report of Snider and co-workers of the reversible, intramolecular cycloaddition of 1-allylic-2,2-dimethyl ethylenetricarboxylates.142 Subsequent efforts have recognized that substitution of the a,/3-unsaturated ester with a C-3 electron withdrawing substituent permits the 4w participation of such oxabutadiene systems in inverse electron demand Diels-Alder reactions with electron-rich olefins. In the instances studied, the rate of the [4 + 2] cycloaddition showed little dependence on solvent polarity [ aeetomtnie/ cycio-hexane — 3, Eq. (15) j acctomtnic toiuene 10, Eq. (20)], and reactions generally... 

The potential of reversing the diene/dienophile polarity of the normal Diels-Alder reaction was first discussed in the course of the early work on the [4 + 2] cycloaddition reaction Bachmann, W. E., and Deno, N. C. (1949). J. Am. Chem. Soc. 71, 3062. The first experimental demonstration of the inverse electron demand Diels-Alder reaction employed electron-deficient perfluoroalkyl-l,2,4,5-tetrazines Carboni, R. A., and Lindsey, R. V., Jr. (1959). J. Am. Chem. Soc. 81,4342. A subsequent study confirmed the [4 + 2] cycloaddition rate acceleration accompanying the complementary inverse electron demand diene/dienophile substituent effects Sauer, J., and Wiest, H. (1962). Angew. Chem. Int. Ed. Engl. 1, 269. 

There is a well-established electronic substituent effect in the Diels-Alder addition. The most favorable alkenes for reaction with most dienes are those bearing electron-attracting groups. Thus, among the most reactive dienophiles are quinones, maleic anhydride, and nitroalkenes. a,jS-Unsaturated esters, ketones, and nitriles are also effective dienophiles. It is significant that if a relatively electron-deficient diene is utilized, the polarity of the transition state is apparently reversed, and electron-rich dienophiles are then preferred. For example, in the reaction of... 

The activation entropy values are found to be zero or positive for the extrusion of nitrogen from the azo-compound (212), to give cycloheptatriene, in various solvents. The rate of nitrogen loss decreases with increasing solvent polarity and internal pressure of the solvent an inverse solvent dependence, of the same order of magnitude, is evident from previous studies on the bimolecular reverse (Diels-Alder) reaction. These and other considerations lend support to the continuity of mechanisms in these cases, and no distinction between concerted or radical pathways can be made from the sign of Another remarkable example has appeared that further... 

The reaction of an electron poor diene with an electron rich dienophile is referred to as an inverse electron demand Diels-Alder (iEDDA) reaction. The first experimental evidence that the normal electron polarity of the diene/dienophile pair can be reversed dates back to 1959 [79]. Although a number of azadienes can participate in iEDDA reaction [80], the highly electron deficient nature of 1,2,4,5-tetrazines made these dienes versatile building blocks in bioconjugation applications. 

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