HOMO-dipole/LUMO-dipolarophile interactions

The terms endo and exo have long been used to represent the stereochemical pathway of the HOMO(dipole)-LUMO (dipolarophile) interaction-controlled cycloadditions. However, on the basis of the stereochemical analysis of the cycloadducts alone, the approach (endo or exo) cannot be specified. There are two geometries possible for each of the anti- and syn-... 

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. 

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. 

The energy levels of all MO s of both reagents are, of course, dependent on their structure. The reactivity of the case depicted in Figure 6-1 is influenced more by the HOMO(dipole) - LUMO(dipolarophile) energy difference A n than by the interaction HOMO(dipolarophile) - LUMO(dipole), i.e., AE n>A i. The reverse case (AEi > A.E11) and extremes like AEu > AEi 0 are also feasible. This clearly ex-... 

Recently, Huisgen and coworkers have reported on the first unequivocal example of a nonconcerted 1,3-dipolar cycloaddition.27 Sustmann s FMO model of concerted cycloadditions envisions two cases in which the stepwise mechanism might compete with the concerted one.21 Two similar HOMO-LUMO interaction energies correspond to a minimum of rate and a diradical mechanism is possible, especially if stabilizing substituents are present. A second case is when the HOMO (l,3-dipole)-LUMO (dipolarophile) is strongly dominant in the transition state. The higher the difference in rr-MO energies of reac-... 

The diazo compound (181a), prepared from the nitrosamine, cyclized to a pyrrolopyrazoline in 80% yield.98 The diazo compound (181b), prepared from diethyl diazomalonate and allylamine, cyclized similarly but at a much more rapid rate. This is consistent with the lowered LUMO of the dipole of (181b), substituted with an ester group here the dipole LUMO-dipolarophile HOMO is the likely dominant interaction. The N—N double bond of the pyrrolopyrazoline products was readily isomerized to afford A2-isomers. 

With electron-deficient dipolarophiles and phenyl azide, the situation is again delicately balanced. The reaction is only just a dipole-HO-controlled one (9-5 eV against 10-7 eV). For the dipole-HO-controlled reaction, we should expect to get adducts orientated as shown on the left of Fig. 4-65. However, a phenyl group reduces the coefficient at the neighbouring atom both for the HOMO and for the LUMO, and this will reduce the polarization of the HOMO. Conversely, it will increase the polarization for the LUMO and hence increase the effectiveness of the dipole LUMO s interaction with... 

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. 

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. 

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