LUMO-dipole/HOMO-dipolarophile

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... 

HOMO, dipole LUMO, dipolarophile HOMO, dipolarophile LUMO, dipole... 

HOMO,dipole LUMO,dipolarophile HOMO,dipolar ophile LUMO,dipole... 

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 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-... 

Those reactions with unsubstituted ethene and with its derivatives containing a conjugated (e.g., CH2 = CH- in butadiene) or an electron-withdrawing substituent are controlled by the HOMO(dipole) - LUMO(dipolarophile) overlap, those with electron-rich dipolarophiles (e. g., ethoxyethene) are predicted to follow clearly the reverse overlap, and in alkyl-substituted ethenes both modes are approximately equally important. 

Gowravaram and Gallop adapted the rhodium-catalyzed generation of isomunchnones from diazo imides to the solid-phase synthesis of furans, following a 1,3-dipolar cycloaddition reaction with alkynes. A variety of furans 492 were prepared in this fashion (Fig. 4.150). With unsymmetrical electron-deficient alkynes (e.g., methyl propiolate), the anticipated regiochemistry is observed, e.g., HOMO-dipole LUMO-dipolarophile, as seen previously. 

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. 

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. 

Azide cycloaddition to electron-deficient dipolarophiles is normally HOMO-dipole LUMO-dipolaro-phile controlled, whereas the reverse is true for electron-rich dipolarophiles. Products with an electron-deficient group at the 5-position or an election-rich group at the 4-position are favored electronically in intramolecular cycloadditions, steric constraints can be expected to outweigh these considerations. 

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. 

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. 

It has been established that [3+2] eyeloadditions with nitronates are HOMO nitro-nate (dipole)-LUMO dipolarophile eontrolled and show a elear preferenee for the exo approach of the dipolarophile (versus the endo mode). 

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