Dipolarophiles frontier orbitals

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. 

Predictions obtained by using the frontier orbital approximation213 were unsuccessful, apparently due to inadequacies in these MO calculations mostly involving the energy gap between HO of the dipole and LU of 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. 

The structural requirements of the mesomeric betaines described in Section III endow these molecules with reactive -electron systems whose orbital symmetries are suitable for participation in a variety of pericyclic reactions. In particular, many betaines undergo 1,3-dipolar cycloaddition reactions giving stable adducts. Since these reactions are moderately exothermic, the transition state can be expected to occur early in the reaction and the magnitude of the frontier orbital interactions, as 1,3-dipole and 1,3-dipolarophile approach, can be expected to influence the energy of the transition state—and therefore the reaction rate and the structure of the product. This is the essence of frontier molecular orbital (EMO) theory, several accounts of which have been published. 16.317 application of the FMO method to the pericyclic reactions of mesomeric betaines has met with considerable success. The following section describes how the reactivity, electroselectivity, and regioselectivity of these molecules have been rationalized. 

Houk has suggested that unsymmetrically substituted azomethine ylides such as munchnones will react readily with both electron-deficient and electron-rich dipolarophiles due to the narrow frontier orbital... 

A secondary orbital interaction has been used to explain other puzzling features of selectivity, but, like frontier orbital theory itself, it has not stood the test of higher levels of theoretical investigation. Although still much cited, it does not appear to be the whole story, yet it remains the only simple explanation. It works for several other cycloadditions too, with the cyclopentadiene+tropone reaction favouring the extended transition structure 2.106 because the frontier orbitals have a repulsive interaction (wavy lines) between C-3, C-4, C-5 and C-6 on the tropone and C-2 and C-3 on the diene in the compressed transition structure 3.55. Similarly, the allyl anion+alkene interaction 3.56 is a model for a 1,3-dipolar cycloaddition, which has no secondary orbital interaction between the HOMO of the anion, with a node on C-2, and the LUMO of the dipolarophile, and only has a favourable interaction between the LUMO of the anion and the HOMO of the dipolarophile 3.57, which might explain the low level or absence of endo selectivity that dipolar cycloadditions show. 

The pattern that emerges is that dipoles calculated to have HOMO are the ones that react faster (or only) with dipolarop Z-substituents, and dipoles calculated to have a low energy LI that react faster (or only) with dipolarophiles that have X-s addition, the polarization deduced for the frontier orbitals mat extent the regioselectivity observed in their reactions. The la dipoles, and the extended range created by the addition of substituents, make the subject too large to be covered any moi is enough to know that information is available if you ever nee<... 

The frontier orbital model predicts regioselectivity by determining the relative magnitudes of the coefficients in the HOMO and LUMO of the 1,3-dipole and dipolarophile.65,66 The favored cycloadduct will be that formed by the privileged union of the atoms with the largest coefficients.51,54,58 If the energy of interaction is very small for both possible orientations, addition occurs in both directions and two isomeric triazolines will be obtained.54,67... 

The molecular geometries and the frontier orbital energies of heterophospholes 28-31 were obtained from density functional theory (DFT) calculations at the B3LYP/6-311- -G, level. The 1,3-dipolar cycloaddition reactivity of these heterophospholes in reactions with diazo compounds was evaluated from frontier molecular orbital (FMO) theory. Among the different types of heterophospholes considered, the 2-acyl-l,2,3-diazaphosphole 28, 377-1,2,3,4-triazaphosphole 30, and 1,3,4-thiazaphosphole 31 were predicted to have the highest dipolarophilic reactivities. These conclusions are in qualitative agreement with available experimental results <2003JP0504>. 

As shown in the following exercise, a donor substituent raises the frontier orbital energies whereas acceptor lowers them. Consequently, introducing a substituent on the dipolarophile causes two of the frontier orbitals to become closer in energy and two to separate (see the scheme above). These frontier orbital changes mirror those discussed in relation to the Alder rule. Again, the presence of the substituent induces a faster reaction.29... 

The reactions of diazomethane with C- and X-substituted alkenes are much slower, and consequently there are fewer known examples. The slower rate of reaction is explained easily by the larger energy separation in the frontier orbitals (10 and 9.8 eV, respectively, in Fig. 6.34). The regioselectivity, however, is the same A -pyrazolines like 6.225 and 6.227 with the substituent at C-3 are obtained with both C- and X-substituted dipolarophiles. This at first sight surprising observation can be explained by the change from dipole-HO-control in the cases of the Z- and C-substituted alkenes 6.223 and 6.224 to dipole-LU-control 6.226 in the case of the X-substituted alkene ethyl vinyl ether. 

Fig. 6.35 Frontier orbitals for phenyl azide and representative dipolarophiles...

Dipolarophiles with electronegative heteroatoms such as carbonyl groups, imines and cyano groups also show an orientation in agreement with frontier orbital theory. Because heterodienophiles all have low-energy LUMOs, their reactions will usually be dipole-HO-controlled. The reaction of diazomethane with an imine giving the triazoline 6.240 and the final step in the formation of an ozonide... 

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. 

---