Lowest unoccupied molecular orbital regioselectivity

Theoretical calculations have been an important means of rationalizing the electronic course of hetero-Diels-Alder and related pericylic reactions for the formation of 1,2-thiazines 25 and 26. MOP AC 93 PM3 calculations have been used to deduce the regioselectivity of [4-1-2] cycloaddition reactions involving thiazinylium perchlorate 27 (Scheme 1) <1999TL1505>. Due to the higher lowest unoccupied molecular orbital (LUMO) coefficient at C-6 compared to N-2, the C-6 and S-1 behave preferentially as the dienophile double bond in cycloaddition reactions of this substrate with butadienes 28. 

Regioselectivity is quite predictable, and consistent in a simple way with typical electrophilic activation of an alkene (Markovnikov s rule). Just as in bromination of an nnsymmetrical alkene, initial coordination of an electrophile (M+, Br+) activates the alkene toward nncleophilic addition of a nncleophile, the addition is preferred at the end of the alkene that best stabilizes a cation. Electronic effects dominate over steric effects. An molecnlar orbital (MO) analysis has been pnt forward ( the slip mechanism ) to rationalize the activating effect of the metal and, in a secondary way, the regioselectivity. It focnses on the reactants and prodncts, and notes that the metal moves dnring the reaction from the approximate midpoint of the alkene to one end. As that slip occurs toward one end of the alkene, the lowest unoccupied molecular orbital (LUMO) for the complex changes and a large coefficient develops at the other end. 

Application of the FMO theory allows the reactivity and regioselectivity of a particular diene/dienophile pair in a cycloaddition reaction to be reliably predicted. Cycloadditions involving electron-rich dienes and electron-deficient dienophiles are called normal electron demand cycloadditions. In this case the primary interactions in the transition structure are between the highest occupied molecular orbital (HOMO) of the diene and the lowest unoccupied molecular orbital (LUMO) of the dienophile. Reactions between electron-poor dienes and electron-rich dienophiles are called inverse electron demand cycloadditions, and the major interactions are between the LUMO of the diene and the HOMO of the dienophile. The regioselectivity can often be rationalized or predicted by matching the larger FMO coefficients in the corresponding FMO s of both reaction components. 

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