LUMO-dipole/HOMO-dipolarophile reaction

The transition state of the concerted 1,3-dipolar cycloaddition reaction is controlled by the frontier molecular orbitals of the substrates. Hence, the reaction of dipoles with dipolarophiles involves either a LUMO-dipole/ HOMO-dipolarophile reaction or a HOMO-dipole/LUMO-dipolarophile interaction, depending on the nature of the dipole and the dipolarophile. 

Due to the increased reactivity of the reaction in the presence of a Lewis acid, the reaction scope was extended to singly activated alkenes. Previous results had shown either no reaction or extremely poor yields. However, under the Lewis acid catalyzed conditions, acrylonitrile furnished a 1 1, endo/exo mixture of products. The addition of the catalyst gave unexpected regiochemistry in the reaction, which is analogous with results described in Grigg s metal catalyzed reactions. These observations in the reversal of regio- and stereocontrol of the reactions were rationalized by a reversal of the dominant, interacting frontier orbitals to a LUMO dipole-HOMO dipolarophile combination due to the ylide-catalyst complex. This complex resulted in a further withdrawal of electrons from the azomethine ylide. 

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

Diazoamides of type 300 rapidly cyclize to form aziridines 302 (342) (Scheme 8.73). It is conceivable that this reaction proceeds through a 1,2,3-triazoline intermediate 301, which is the consequence of a LUMO(dipole)— HOMO(dipolarophile) controlled intramolecular [3 + 2] cycloaddition. Some remarkable steric effects were encountered for this cyclization. While the piperidine derivative [300, = ( 112)4] readily cyclized by diazo group transfer at... 

Whereas 260 does not react with electron-rich dipolarophiles, the more delocalized isomiinchnone 261 does react with both electron-rich and -deficient dipolarophiles (154). A detailed FMO analysis is consistent with these observations and with the regiochemistry exhibited by diethyl ketene acetal and methyl vinyl ketone as shown in Scheme 10.36. The reaction of 261 with the ketene acetal to give 262 is LUMO-dipole HOMO-dipolarophile controlled (so-called lype III process). In contrast, the reaction of 261 with methyl vinyl ketone to give 263 is HOMO-dipole LUMO-dipolarophile controlled (so-called lype I process). In competition experiments using a mixture of A-phenylmaleimide and ketene acetal only a cycloadduct from the former was isolated. This result is consistent with a smaller energy gap for... 

The enhanced reactivity of oxazoline AAoxide 10 compared to nitrone 11 could be explained in terms of FMO theory. The data of HOMO energies indicate that 10 has a higher HOMO and a lower LUMO than 11. In reactions controlled by the HOMO dipole-LUMO dipolarophile interaction, as in Figure 15.3, as well as in processes controlled by the LUMO dipole-HOMO dipolarophile interaction (Fig. 15.4), oxazoline iV-oxide 10 will provide a smaller energy gap than nitrone 11 when reacting wifli a dipolarophile. 

Incorporation of perfluoroalkyl groups into 1,3-dipoles usually increases reactivity, i.a. by lowering the energies of the frontier orbitals and reducing the LUMO 1,3-dipole/HOMO dipolarophile energy gap. On the other hand, when perfluoroalkyl and partially fluorinated substituents are directly bonded to the dipolarophile skeleton, cycloaddition reactions occur preferentially under HOMO 1,3-dipole/LUMO dipolarophile control. Furthermore, perfluoroalkyl groups often stabilize the newly formed ring systems. 

In the presence of a catalyst consisting of Ni(C104)2-6H20 and the chiral binaphthyldiimine (BDSflM) ligand 141, the first chiral Lewis acid-catalyzed dipole-HOMO/dipolarophile-LUMO-controlled asymmetric 1,3-DC reactions of azomethine imines 138 and 3-acryloyl-2-oxazolidinone 139 were achieved by Suga and... 

When both the 1,3-dipoIe and the dipolarophile are unsymmetrical, there are two possible orientations for addition. Both steric and electronic factors play a role in determining the regioselectivity of the addition. The most generally satisfactory interpretation of the regiochemistry of dipolar cycloadditions is based on frontier orbital concepts. As with the Diels-Alder reaction, the most favorable orientation is that which involves complementary interaction between the frontier orbitals of the 1,3-dipole and the dipolarophile. Although most dipolar cycloadditions are of the type in which the LUMO of the dipolarophile interacts with the HOMO of the 1,3-dipole, there are a significant number of systems in which the relationship is reversed. There are also some in which the two possible HOMO-LUMO interactions are of comparable magnitude. 

The mechanism of the reaction has generally been discussed in terms of a thermally allowed concerted 1,3-dipoIar cycloaddition process, in which control is realized by interaction between the highest occupied molecular orbital (HOMO) of the dipole (diazoalkane) and the lowest unoccupied molecular orbital (LUMO) of the dipolarophile (alkyne).76 In some cases unequal bond formation has been indicated in the transition state, giving a degree of charge separation. Compelling evidence has also been presented for a two-step diradical mechanism for the cycloaddition77 but this issue has yet to be resolved. 

Azomethine ylides are not typically isolable but must be used in situ. They undergo cycloaddition reactions that produce highly functionalized pyrrolidines, dihydropyiroles and pyrroles. The success of these reactions often depends on a judicious choice of dipole and dipolarophile. Azomethine ylides are reluctant to cycloadd to nonactivated alkenes, in large part owing to electronic considerations. The LUMO of most azomethine ylides is high in energy and there is a large gap with the HOMO of a nonactivated alkene. 

A condition for such a reaction to take place is a certain similarity of the interacting HOMO and LUMO orbitals, depending on the relative orbital energies of both the dipolarophile and the dipole. Electron-withdrawing groups on the dipolarophile normally favour an interaction of the LUMO of the dipolarophile with the HOMO of the dipole that leads to the formation of the new bonds, whereas electron donating groups on the dipolarophile normally... 

The regioselectivity of the 1,3-dipolar cycloadditions of azides to alkenes is usually difficult to predict due to the similar energies for the transition states which involve either the HOMO (dipole) or the LUMO (dipole). The results of a study which utilized 5-alkoxy-3-pyrrolin-2-ones as dipolar-ophiles in reactions with a variety of aryl azides seemed to reflect this problem the results suggested that the low regioselectivity observed was due to the frontier molecular orbital interactions between dipole and dipolarophile, and not any steric hindrance offered by the 5-alkoxy function <84H(22)2363>. 

This reaction is therefore dipole-HO-controlled, and we can turn to the coefficients , the (eft)2 values, for the HOMO of the dipole from Table 6.1 and the coefficients of the LUMO of the dipolarophile from Fig. 6.22. Regioselectivity follows in the usual way from the large-large/small-small interaction 6.223, which has the carbon end of the dipole bonding to the ft carbon of the Z-substituted alkene, as observed. 

With Z-substituted dipolarophiles and phenyl azide, the situation is again delicately balanced and only just dipole-HO-controlled (9.5 eV against 10.7 eV). For the dipole-HO-controlled reaction, we should expect to get adducts oriented as in Fig. 6.36a. However, a phenyl group reduces the coefficient at the neighbouring atom both for the HOMO and for the LUMO, and this will reduce the polarisation of the HOMO. Conversely, it will increase the polarisation for the LUMO and hence increase the effectiveness of the interaction of the LUMO of the dipole with the HOMO of the dipolarophile, as in Fig. 6.36b. The difference in... 

Dipolar cycloaddition reactions are generally classified into three types, dipole HO controlled, dipole LU controlled or HO,LU controlled, depending upon the relative energies of the dipole and dipolarophile frontier molecular orbitals. If the energy gap separating the dipole HOMO from the dipolarophile LUMO is smaller than that between the dipole LUMO and the dipolarophile HOMO, then the reaction is said to be dipole HO controlled. If the dipole LUMO-dipolarophile HOMO energy gap is smaller, then dipole LU control prevails. If the energy difference between the dipole HOMO and the dipolarophile LUMO is about the same as that between the dipole LUMO and the dipolarophile HOMO, dien neither interaction dominates and HO,LU control is operable. 

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