Nitrile oxides frontier orbitals

Two dipoles especially important in organic synthesis are nitrile oxides and nitrones. The frontier orbital picture for a simple nitrile oxide is shown in Fig. 6.37, where we can see that the easy reactions ought to be decisively dipole-LU-controlled, and fast with C- and X-substituted alkenes. This matches well with the reactions of benzonitrile oxide with styrene, terminal alkenes, enol ethers and enamines which all give only the 5-substituted isoxazolines 6.235. 

In the reactions with Z-substituted alkenes, however, the frontier orbitals are not strongly in favour of either of the pairings, and the polarisation gives opposite predictions, with dipole-LU-control marginally in favour of the isoxazoline 6.236 and dipole-HO-control strongly in favour of the isoxazoline 6.237. In practice, the regiochemistry with Z-substituted alkenes is delicately balanced, and it may be that the decisive factor is simply steric, since the two ends of the nitrile oxide are very different in their steric demands. 

Fig. 6.37 Frontier orbitals for a nitrile oxide and representative dipolarophiles...

Of the 18 systems, some of which are unstable and must be generated in the reaction has been accomplished for at least 15, but not in all cases with a carbon-carbon double bond (the reaction also can be carried out with other double bonds ). Not all aUcenes undergo 1,3-dipolar addition equally well. The reaction is most successful for those that are good dienophUes in the Diels-Alder reaction (15-60). The addition is stereospecific and syn, and the mechanism is probably a one-step concerted process, as illustrated above, " largely controlled by Frontier Molecular Orbital considerations. " In-plane aromaticity has been invoked for these dipolar cycloadditions. " As expected for this type of mechanism, the rates do not vary much with changes in solvent, " although rate acceleration has been observed in ionic liquids. " Nitrile oxide cycloadditions have also been done in supercritical carbon dioxide. There are no simple rules... 

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>. 

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