Regioselectivity of 1,3-dipolar cycloadditions

The regioselectivity of 1,3-dipolar cycloadditions can also be analyzed by MO calculations on transition-state models. For example, there are two possible regioisomers from the reaction of diazomethane and methyl vinyl ether, but only the 3-methoxy isomer is formed. 

Fig. 6.12. Prediction of regioselectivity of 1,3-dipolar cycloaddition on the basis of FMO theory. The energies of the HOMO and LUMO of the reactants (in eV) are indicated in parentheses.

The reactivity and regioselectivity of 1,3-dipolar cycloadditions have been discussed in terms of the frontier orbitals [271]. Most of the features may be understood on the basis of simple Hfickel MO theory. The HOMO and LUMO n orbitals and n orbital energies for all 18 combinations of the parent dipoles are shown in Figure 12.8. The frontier orbitals of many of the 1,3-dipoles have previously been derived by CNDO/2 and extended Hfickel theory [272]. The first six structures, all of 16-electron type, are shown in greater detail ... 

In the beginning, Ken created a frontier molecular orbital (FMO) theory of regioselectivity in cycloadditions. In particular, his classic series of papers showed how FMO theory could be used to understand and predict the regioselectivity of 1,3-dipolar cycloadditions. Ken s generalizations about the shapes and energies of frontier molecular orbitals of alkenes, dienes, and 1,3-dipoles, are in common use today and they appear in many texts and research articles. 

Theoretical studies are also done to interpret the synthesis reactions and mechanism of reactions. The regioselectivity of 1,3-dipolar cycloaddition reaction between substituted trimethylstannyl-ethynes and nitrile oxides yielding isoxazoles, was interpreted by the application of frontier electron theory <93CPB478>. By the combination of experimental and molecular orbital (ab initio) studies, a multistep mechanism is proposed for unimolecular radical chemistry of isoxazoles in the gas phase <920MS(27)317>. 

Occasionally, the reverse orientation is obtained. The reaction of a trans-disubstituted nitrone, a-phenyl-W-methylnitrone (10a), with nitroethylene gives the 4-substituted isoxazolidine (II).23 With N-t-butylnitrone (11a), however, the same olefin gives the 5-substituted isomer (I).23 Each reaction is regiospecific in that, of the two possible orientations, only one is produced in the reaction. The reaction of phenyl vinyl sulfone with nitrones is one of the rare examples where regiospecificity is lost. Thus, both nitrones 10a and 11a give a mixture of adducts I and II (31 68), and (70 30), respectively.23 Recently, the regioselectivity of 1,3-dipolar cycloadditions have been interpreted by... 

Although from the conceptual point of view such a simple qualitative picture is completely clear, the practical discrimination between the individual alternative reaction paths can be, in a given case, quite complicated. The best that can be done in these cases is to calculate the energies of the molecular oibitals by some quantum chemical method. The typical example where such subtle effects of the quantitative nature play the role is the regioselectivity of 1,3 dipolar cycloadditions [44,45], which is the cycloaddition of substituted alkenes, called in this coimection dipolarophiles, with the so-called 1,3 dipoles as, e.g., azides, diazoalkanes, nitriloxides, nitrones and some other, usually rather unstable species. 

Prediction of regioselectivity of 1,3-dipolar cycloaddition HOMO-LUMO interactions in the [2 + 2] cycloaddition of an alkene and a ketene... 

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