Cycloadditions rates

In this context, note that the cycloaddition rate of a crown ether-annulated diazo(diphenyl)methane such as 1 with maleic anhydride is ion-selectively retarded in the presence of alkali perchlorates (21). This observation was attributed to a lowering of the HOMO (dipole) level, due to the electron-withdrawing electrostatic effect of the complexed cation. A parallel to the negative Hammett p values for cycloadditions of ring-substituted diazo(diphenyl)methanes with TONE (22) (p = —2.67) and chloranil (23) (p = —1.67) was drawn. 

The entropically enhanced cycloaddition rate of an intramolecular cycloaddition permits alkenyl nitrile oxides to cyclize in the presence of free amino groups, in contrast to intermolecular reactions. Since nitrile oxides have a wide spectrum of possible intermolecular reactions, they also react well in macro-cyclic cyclizations. 

OnBu f. .OnBu ortho meta cycloaddition rate = 2.7 1 12,108, 120... 

This rule states that cycloaddition rates rise as a diene becomes more electron rich and the dienophile more electron poor. Cycloadditions are also accelerated in cases of inverse electron demand, when an electron-poor diene reacts with an electron-rich dienophile. 

Cycloaddition rates range over several orders of magnitude and to predict the likely success of a reaction, when alternative reaction pathways such as nitrile oxide dimerization are possible, it is necessary to understand the reactivity of the system. 

In comparison with alkjmes, cycloaddition of azides to alkenes proceeds at a much slower rate. Ring strain and substitution of the double bond with electron-withdrawing groups have been found to lead to enhancement of the cycloaddition rate <68x349. 2757). Double bonds which are part of strained bicyclic s) tems are particularly reactive. Thus, the addition of phenyl azide to norbornene leads in a very fast reaction to the triazoline (256), the... 

The addition of a C-2 (equation 1 R = H > alkyl, aryl > OMe NR2), C-3, or C-4 electron-donating substituent to a 1 -oxa-1,3-butadiene electronically decreases its rate of 4ir participation in a LUMOdiene-controlled Diels-Alder reaction (c/. Table 5). Nonetheless, a useful set of C-3 substituted l-oxa-l,3-buta-dienes have proven to be effective dienes ° and have been employed in the preparation of carbohydrates (Table 6). The productive use of such dienes may be attributed to the relative increased stability of the cisoid versus transoid diene conformation that in turn may be responsible for the Diels-Alder reactivity of the dienes. Clear demonstrations of the anticipated [4 + 2] cycloaddition rate deceleration of 1-oxa-1,3-butadienes bearing a C-4 electron-donating substituent have been detailed (Table 6 entry 4). >> "3 In selected instances, the addition of a strong electron-donating substituent (OR, NR2) to the C-4 position provides sufficient nucleophilic character to the 1-oxa-1,3-butadiene to permit the observation of [4 + 2] cycloaddition reactions with reactive, electrophilic alkenes including ketenes and sul-fenes, often in competition with [2 + 2] cycloaddition reactions. ... 

The coupling of the ion pair to form the cycloadduct is a very fast process as judged by the ultrashort lifetimes found for various arene ion radicals (t a 20 ps, see inset in Figure 10). However, the low quantum efficiencies (3>c < 0.01) [114, 161] of the cycloadditions indicate that the predominant decay pathway of the ion radical pair in Eq. 34 is not the coupling step kc), but back electron transfer (k-Ex) to restore the original EDA complex. Quantitative evaluation of kinetics and quantum efficiencies yields the relatively fast cycloaddition rate constants of kc 10 s characteristic for highly exergonic bond formation. 

These results, including the fact that the cycloaddition rates are independent of solvent polarity, are consistent with a concerted LUMO-diene controlled process. This assumption is also supported by calculations [79]. Interestingly, the... 

Studies on the mechanism and regioselectivity of the Diels-Alder reaction with inverse electron demand have been published by Sauer and co-workers 381 383,384 it was found that the cycloaddition rate of cyclooctyne to a number of 1,2,4-triazines can be correlated with the reduction potential of these dienes provided steric substitution effects are approximately equal. 

Perhaps the most successful approach for promoting the 47r participation of 1-oxabutadiene systems in intermolecular Diels-Alder reactions employs a,/8-unsaturated carbonyl compounds substituted with an additional C-3 (a) electron-withdrawing group. The addition of the C-3 electron-withdrawing substituent increases the electron-deficient character of the oxabutadiene system, decreases the LUM0oxabutadiene, and as expected, enhances the observed [4 + 2] cycloaddition rate and regioselec-... 

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. 

Fig. 10.13. Hammett plots of cycloaddition rates of substituted aryl azides with nucleophiUc, electrophilic, and unsubstituted alkenes showing the ambiphilic character of the azide cycloaddition. Reaction with maleic anhydride (electrophilic) is favored by donor substituents. Reaction with pyrroUdinocy-clohexene (nucleophilic) is favored by acceptor substituents.

Most applications of this chemistry have utilized more highly substituted and functionalized systems, for which intramolecular cycloaddition rates and yields are significantly better than in the original prototypical examples. Only substitution at the olefinic C-atoms is generally detrimental to the success of the reaction. For example, while 1,6-heptenyne cyclizes to give only 31% of bicyclo[3.3.0]oct-l-en-3-one after four days at 95°C, substrates with C4 disubstitution typically proceed to product in much less time with yields at least twice as high ( gm-dialkyl effect ). Using either dry-state conditions or amine oxide promoters, 55-95% yields are routinely obtained after hours or in some cases even minutes. 

The formation of tetrazoles can generally occur intermolecularly as well as intramolecularly, whereas the latter show enhanced cycloaddition rates and less heating is required. 

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