Pericyclic reactions secondary effects

Wiest O, Houk KN, Black KA, Thomas B. IV. Secondary kinetic isotope effects of diastereotopic protons in pericyclic reactions a new mechanistic probe. J Am Chem Soc 1995 117 8594-8599. 

The longest standing model to rationalize this effect emphasizes so-called secondary orbital interactions. These are molecular orbital interactions other than those primarily used to define whether the reaction is allowed or forbidden, and that are frequently invoked to describe additional features of pericyclic reactions. Consider the LUMO of the CH2=CHA fragment in Figure 15.12 C (orbital n). The p orbital associated with A is in-phase with the adjacent carbon. Now consider the HOMO of a diene. C2 and C3 are similarly in-phase with Cl and C4, respectively. Thus, if we tuck the substituent A under the diene in the transition state, an additional interaction between the HOMO and LUMO can occur, and this must be stabilizing (see margin). 

This model has provided a sensible rationalization of the cndo-effect. However, recent studies suggest that additional factors such as steric and electrostatic effects also play an important role. This has led some to conclude that secondary orbital interactions do not play a determining role in the Diels-Alder reaction nor in other pericyclic reactions. 

Experimental and computational studies of the pericyclic Meisenheimer rearrangement and a competitive rearrangement of A-propargyl morphol i nc N-oxide revealed a novel inverse secondary kinetic isotope effect (kn/kD 0.8) for the rate-determining cyclization step, probably occurring because of a C(sp) to C(sp2) change in hybridization at the reaction center (Scheme 3).5... 

We have used inter- and intramolecular kinetic isotope effects to examine the mechanism of these Lewis acid catalyzed ene reactions. The Lewis acid catalyzed ene reaction has traditionally been though to proceed through either a concerted pericyclic mechanism or a stepwise reaction with a zwitterionic intermediate. We found that the intermolecular isotope effect in the Me2AlQ catalyzed ene reaction of formaldehyde is 1.3 with methylenecyclohexane and methylenecyclohex-ane-2,2,6,6- 4 and 1.4 with 2,3-dimethyl-2-butene and 2,3-dimethyl-2-butene- /i2. Since secondary iotope effects could be responsible for these results, these values are consistent with either a stepwise or concerted mechanism. Intramolecular isotope effects were determined to be 2.9 and 2.7 with 2 and 3, respectively. These substantial intramolecular isotope effects coupled with the small intermolecular isotope effects indicate that the reaction is stepwise with proton transfer following the rate determining step. In an intramolecular competition such as the ene reactions of formaldehyde with 2 and 3 an isotope effect will still be observed if the hydrogen transfer occurs... 

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