1,3-dipolar cycloaddition reactions HOMO—LUMO interactions

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 typical 1,3-dipolar cycloaddition reaction of nitrones with alkenes involves a dominant interaction of HOMO (nitrone) and LUMO (alkenes). The inverse-electron demand of the... 

The 1,3-dipolar cycloaddition of organic azides with nitriles could give rise to two regioisomers. Since organic azides are Type II 1,3-dipoles on the Sustmann classification (approximately equal HOMO-LUMO gaps between the interacting frontier orbital pairs) the reactions could be dipole HOMO or LUMO controled and the regioselectivity should be determined by the orbital coefficients for the dominant HOMO-LUMO interaction. Such systems show U-shaped kinetic curves in their... 

Such cycloadditions involve the addition of a 2tt- electron system (alkene) to a 4ir- electron system (ylide) and have been predicted to occur in a concerted manner according to the Woodward-Hoffmann rules. The two most important factors involved in the cycloaddition reactions are (i) the energy and symmetry of the reacting orbitals and (ii) the thermodynamic stability of the cycloadduct. The reactivity of 1,3-dipolar systems has been successfully accounted for in terms of HOMO-LUMO interactions using frontier MO theory (71TL2717). This approach has been extended to explain the 1,3 reactivities of the nonclassical A,B-diheteropentalenes <77HC(30)317). 

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. 

In behaviour that is typical of a 1,3-dipolar cycloaddition reaction, OSO4 reacts almost as well with electron-poor as with electron-rich alkenes. OSO4 simply chooses to attack the alk-ene HOMO or its LUMO, depending on which gives the best interaction. This is quite different from the electrophilic addition of m-CPBA or Br2 to alkenes. 

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. 

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 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>. 

Pyrazol-3-one derivatives have taken part in both 1,3-dipolar cycloaddition and Diels-Alder reactions. The 1,3-dipolar cycloaddition between (Z)-pyrazol-3-ones 694a g with an excess of ethyl vinyl ether gave the pyrazol-3-one-4-spiro-3-isoxazolidines 695a-g, in nearly quantitative yield (82G483) (Scheme 203). The kinetics of this reaction was studied by quantitative spectroscopic analysis. The rate of reaction increases with the electron-withdrawing character of the substituent on the aromatic ring and a linear relationship is obtained between logk and op constants. The LUMO nitrone-HOMO vinyl ether is taken as the dominant interaction. 

The most widely applied interpretation of substituent effects on relative reactivity is based on FMO theory. According to FMO theory, interacting orbitals are most stabilized when they are closest in energy. Substituent effects on dipolar cycloadditions can be interpreted in terms of matching of HOMO and LUMO orbitals of the two reactants.This is the same concept used in applying FMO theory to D-A reactions (see p. 844-848). In the D-A reaction, it is fairly clear which reactant is electrophilic and which is nucleophilic, and the interpretation of substituent effects follows directly. This choice is not always so obvious for 1,3-DPCA reactions. In fact, for several of the 1,3-dipoles both EWGs and ERGs in the dipolarophile enhance reactivity. These 1,3-dipoles are called ambiphilic. Let us look carefully to see why they have this property. 

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