Dienophiles substituent effects

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 are probably several factors which contribute to determining the endo exo ratio in any specific case. These include steric effects, dipole-dipole interactions, and London dispersion forces. MO interpretations emphasize secondary orbital interactions between the It orbitals on the dienophile substituent(s) and the developing 7t bond between C-2 and C-3 of the diene. There are quite a few exceptions to the Alder rule, and in most cases the preference for the endo isomer is relatively modest. For example, whereas cyclopentadiene reacts with methyl acrylate in decalin solution to give mainly the endo adduct (75%), the ratio is solvent-sensitive and ranges up to 90% endo in methanol. When a methyl substituent is added to the dienophile (methyl methacrylate), the exo product predominates. ... 

It has long been known that the Diels-Alder reaction is particularly efficient and rapid when the dienophile contains one or more electron-attracting groups. These substituent effects are illustrated by the data in Table 11.3. In the case of the diene, reactivity is increased by electron-releasing substituents. Some illustrative data are given in Table 11.4. 

Both the reactivity data in Tables 11.3 and 11.4 and the regiochemical relationships in Scheme 11.3 ean be understood on the basis of frontier orbital theory. In reactions of types A and B illustrated in Seheme 11.3, the frontier orbitals will be the diene HOMO and the dienophile LUMO. This is illustrated in Fig. 11.12. This will be the strongest interaction because the donor substituent on the diene will raise the diene orbitals in energy whereas the acceptor substituent will lower the dienophile orbitals. The strongest interaction will be between j/2 and jc. In reactions of types C and D, the pairing of diene LUMO and dienophile HOMO will be expected to be the strongest interaction because of the substituent effects, as illustrated in Fig. 11.12. 

More complete interpretations of Diels-Alder regioselectivity have been developed. MO results can be analyzed from an electrostatic perspective by calculating potentials at the various atoms in the diene and dienophile. These results give a more quantitatively accurate estimate of the substituent effects. Diels-Alder regioselectivity can also be accounted for in terms of HSAB theory (see Section 1.2.3). The expectation would be that the most polarizable (softest) atoms would lead to bond formation and that regioselectivity would reflect the best mateh between the diene and dienophile termini. These ideas have been applied using 3-2IG computations. The results are in agreement with the ortho rule for normal-electron-demand Diels-Alder reactions. ... 

Equation 1.5) [13], Diels Alder reactions which are insensitive to the substituent effects in the diene and/or dienophile are classified as neutral (Equation 1.6) [14]. 

The influence of the solvent on the regioselectivity is perfectly described by FMO theory142. As mentioned above, the regioselectivity is determined by orbital coefficients on the terminal carbons of the diene and dienophile which, in turn, are determined by the electronic substituent effects. These can be modified by electron donation or electron withdrawal by the solvent or additives like Lewis acids. 

The characteristics of the vinylboranes as dienophiles can be rationalized in terms of a strong interaction of the diene with the empty n orbital at boron. Molecular orbital calculations show a strong interaction between B and C-l in the transition state, and the transition state shows little charge separation, accounting for the relative insensitivity to substituent effects. As for regiochemistry, the para-like selectivity would also be expected to be reduced because the LUMO of the dienophile is nearly equally distributed between B and C-2.36... 

Despite the concerted nature of most Diels-Alder reactions, substituent effects are evident. Electronic compatibility of the reaction partners is of paramount importance, therefore while a normal Diels-Alder reaction is characterized by the union of an electron-rich diene and an electron-poor dienophile, the Diels-Alder reaction with inverse electron demand features an electron-poor diene and electron-rich dienophile. 

DFT calculations on the intramolecular Diels-Alder reaction of penta-l,3-dienyl acrylates predict stereoselectivities that are in good agreement with the experimen- (g) tal results.85 Another DFT study at the B3LYP/6-31G(d) level of the intramolecular Diels-Alder cycloaddition of 5-vinylcyclohexa-1,3-dienes has been reported. Reaction rates are influenced by dienophile twisting and substituent effects.86 The intramolecular dehydro-Diels-Alder reactions of ynamides (79) provides a new synthesis of benzo[fc]-, tetrahydrobenzo[fc]-, naphtho[l,2-/j -, and dibenzo[a,c]carbazoles... 

The first term of Equation 15.3 is responsible for most of the transition state stabilization of a Diels-Alder reaction with normal electron demand. In this case, the first term is larger than the second term because the denominator is smaller. The denominator of the first term is smaller because the HOMO of an electron-rich diene is closer to the LUMO of an electron-poor dienophile than is the LUMO of the same electron-rich diene with respect to the HOMO of the same electron-poor dienophile (Figure 15.24, column 2). Acceptors lower the energy of all 7F-type MOs irrespective of whether these MOs are bonding or antibonding. This is all the more true the stronger the substituent effects and the more substituents are present. 

Fig. 15.25. Regioselective Diels-Alder reactions with a 2-substituted 1,3-diene I comparison of the effects exerted by one or two dienophile substituents.

Asymmetric Diels-Alder Reaction of Unsaturated Aldehydes . The boron atom of acyloxyborane is activated by the electron-withdrawing acyloxy groups, and consequently acyloxyborane derivatives are sufficiently Lewis acidic to catalyze certain reactions. Thus, asymmetric Diels-Alder reactions of a,p-enals with dienes using (1) as a Lewis acid catalyst have been developed. For example, the reaction of cyclopentadiene and methacrolein gives the adduct in 85% yield (endo exo= 11 89) and 96% ee (major exo isomer) (eq 3). Some additional examples are listed in Figure 1. The a-substituent on the dienophile increases the enantioselectivity, while p-substitution dramatically decreases the selectivity. In the case of a substrate having substituents in both a- and p-positions, high enantioselectivity is observed thus the a-substituent effect overcomes that of the p-substituent. 

A question of regioselectivity arises when both the diene (VI) and the dienophile (Vll) are nonsymme-trically substituted as this can give a mixture of two regioisomers (VIII) + ). Their relative proportions depend on the individual nature of, and on the interplay between, substituent effects (Scheme 2). 

This hierarchy of substituent effects can be exploited to obtain adducts with predictable and high regioselectivity through the use of dienes and dienophiles containing temporary substituents which control the regiochemisby of the addition and are removed thereafter. Sulfide (diene) and nitro (dienophile) groups can serve in this manner as powerful regiocontrol elements (Sections 4.1.3.3 and 4.1.2.1). 

It is well established that 3-alkyl pyridines are selectively reduced at N1-C2, to produce 3-alkyl-l,2-DHPs [58,59,60], 5-Alkyl-l,2-DHPs, which result from hydride addition at C-6, are potentially valuable synthetic intermediates [61]. Substituent effects on the regiochemistry of the reduction of A-carbalkoxypyridinium salts have been studied in detail by Sundberg [62]. These DHPs have served as useful dienes for the synthesis of ISQs. Methyl 2-[l-phenylsulfonyl-lH-indol-2-yl]-2-propenoate (62) served as dienophile in most of these reactions [61,62,63,64,65,66,67,68]. Palladium-catalyzed radical cyclization [63], photocyclization [64] or thermal cyclization [61,65,66,67,68] reactions have all been employed to furnish the Diels-Alder adducts (e.g., 63). 

There is a strong electronic substituent effect on the D-A cycloaddition. It has long been known that the reaction is particularly efficient and rapid when the dienophile contains one or more EWG and is favored still more if the diene also contains an ERG. Thus, among the most reactive dienophiles are quinones, maleic anhydride, and nitroalkenes. a,6-Unsaturated esters, ketones, and nitriles are also effective dienophiles. The D-A reaction between unfunctionalized alkenes and dienes is quite slow. Eor example, the reaction of cyclopentadiene and ethene occurs at around 200°C. These substituent effects are illustrated by the data in Table 10.1. In the case of the diene, reactivity is increased by ERG substituents. Data for some dienes are given in Table 10.2. Note that ERG substituents at C(l) have a larger effect than those at C(2). Scheme 10.2 gives some representative examples of dienophiles activated by EWG substitution. 

Fig. 10.6. Schematic diagram illustrating substituent effect on reactivity in terms of FMO theory. HOMO-LUMO gap narrows, transition state is stabihzed, and reactivity is increased in normal electron-demand Diels-Alder reaction as the nucleophilicity of diene and the electrophihcity of dienophile increase.

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