Highest occupied molecular orbital cycloadditions

According to frontier molecular orbital theory (FMO), the reactivity, regio-chemistry and stereochemistry of the Diels-Alder reaction are controlled by the suprafacial in phase interaction of the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied molecular orbital (LUMO) of the other. [17e, 41-43, 64] These orbitals are the closest in energy Scheme 1.14 illustrates the two dominant orbital interactions of a symmetry-allowed Diels-Alder cycloaddition. 

In the course of investigation of reactivity of the mesoionic compound 44 (Scheme 2) the question arose if this bicyclic system participates in Diels-Alder reactions as an electron-rich or an electron-poor component <1999T13703>. The energy level of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals were calculated by PM3 method. Comparison of these values with those of two different dienophiles (dimethyl acetylenedicarboxylate (DMAD) and 1,1-diethylamino-l-propyne) suggested that a faster cycloaddition can be expected with the electron-rich ynamine, that is, the Diels-Alder reaction of inverse electron demand is preferred. The experimental results seemed to support this assumption. 

In accordance with theoretical predictions (90), the concerted pathway for 1,3-dipolar cycloaddition is replaced by a two-step mechanism when two requirements are satisfied. One of the criteria involves an extremely large difference in the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energies of the reaction partners. The other factor involves a pronounced steric hindrance at one termini of the 1,3-dipole (190). The first case of a stepwise... 

AMI calculations were performed using SPARTAN software, and these FMO predictions are consistent with the fact that the observed cycloaddition regiochemistry is generally /t -FMO . The HOMO/LUMO energies are listed in Table 9, and Figure 10 depicts the coefficients for the favored HOMO(miinchnone) - - LUMO(nitroindole) interaction (HOMO = highest, occupied molecular orbital LUMO = lowest unoccupied molecular orbital). 

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. 

Few reactions of the parent oxazole with the usual alkenic and alkynic dienophiles have been reported. Most oxazoles which yield Diels-Alder adducts contain electron-releasing substituents, the order of reactivity being alkoxy> alkyl 4-phenyl > acetyl > ethoxycarbonyl. This sequence suggests that the oxazole functions as the electron-rich component and that the reaction is governed by interaction of the highest occupied molecular orbital of the oxazole and the lowest unoccupied orbital of the dienophile. Cycloadditions with inverse electron demand of electron-deficient oxazoles with electron-rich dienophiles can be envisaged. 

Theoretical analysis of this [4% + 27r]-cycloaddition reaction by consideration of frontier-orbital interactions between the electron-rich olefin (highest occupied molecular orbital, HOMO) and the electron-poor 5-nitropyrimidine (LUMO) has shown that the FMO perturbation theory correctly predicts an exclusive regiospecific addition of the enamine to N-l and C-4 of the pyrimidine ring (86JOC4070). 

The easiest explanation is based on the frontier orbitals—the highest occupied molecular orbital (HOMO) of one component and the lowest unoccupied orbital (LUMO) of the other. Thus if we compare a [2 + 2] cycloaddition 6.133 with a [4 + 2] cycloaddition 6.134 and 6.135, we see that the former has frontier orbitals that do not match in sign at both ends, whereas the latter do, whichever way round, 6.134 or 6.135, we take the frontier orbitals. In the [2 + 2] reaction 6.133, the lobes on C-2 and C-2 are opposite in sign and represent a repulsion—an antibonding interaction. There is no barrier to formation of the bond between C-l and C-l, making stepwise reactions possible the barrier is only there if both bonds are trying to form at the same time. The [4 + 4] and [6 + 6] cycloadditions have the same problem, but the [4 + 2], [8 + 2] and [6 + 4] do not. Frontier orbitals also explain why the rules change so completely for photochemical reactions, as we shall see in Chapter 8. 

---