Stereoelectronic Effects and Reactivity

This book will be particularly valuable to all investigators working with complex organic molecules, whether they be synthetic, medicinal or bioorganic chemists, since it will provide a timely view of stereoelectronic effects and how they may be applied, both to rationalise and to predict organic chemical reactivity. 

Together, these effects are called stereoelectronic effects, because they depend on the shape and orientation of orbitals. Most of the examples we have presented you with have been stereoelectronic effects on reactivity, but the next section will deal with how stereoelectronic effects affect conformation. 

The optimized geometry of the biphenol MOM ether-SnCU was obtained from a partial PM3 calculation of the MOM units on the basis of a B3LYP/LANL2DZ-opti-mized geometry for a biphenol-SnCU complex (Fig. 5). It is noteworthy that the C5-04 bond is almost perpendicular to the C1-C3 axis, presumably because of the steric repulsive interactions with apical and equatorial chlorines. Also of interest is the observation that the C5-06 bond is shorter than the 04-C5 bond. This indicates that the C5-06 bond has a partial double-bond character because of the stereoelectronic effect and its most stable conformer would be the reactive oxonium intermediate. 

Two of the factors that determine the reactivity of tethered ir-nucleophiles in Mannich-type cycliza-tions have been emphasized stereoelectronic effects and reaction medium effects. The stereoelectronics of orbital overlaps between the ir-nucleophile and the iminium electrophile are best evaluated by considerations such as antiperiplanar addition trajectories and Baldwin s rules for ring formation. The critical importance of the reaction medium has received serious attention only recently. However, it already appears clear that Tr-nucleophiles that would lead, upon cyclization, to relatively unstable carbocations can have their reactivity markedly increased by carrying out the cyclization in the presence of a nucleophilic solvent or additive which, by nucleophilic participation, can obviate the formation of high energy cyclic carbenium ion intermediates. 

Figure 735 Stereoelectronic effects on reactivity of N-containing multiple bonds are analogous to those seen in alkenes and alkynes.

In summary, this chapter has discussed stereoelectronic effects on reactivity and stability which benefit from the rigid preorganization and closer spatial orbital proximity imposed by the presence of a double bond between the donor and acceptor orbitals. 

The incorporation of heteroatoms can result in stereoelectronic effects that have a pronounced effect on conformation and, ultimately, on reactivity. It is known from numerous examples in carbohydrate chemistry that pyranose sugars substituted with an electron-withdrawing group such as halogen or alkoxy at C-1 are often more stable when the substituent has an axial, rather than an equatorial, orientation. This tendency is not limited to carbohydrates but carries over to simpler ring systems such as 2-substituted tetrahydropyrans. The phenomenon is known as the anomeric ect, because it involves a substituent at the anomeric position in carbohydrate pyranose rings. Scheme 3.1 lists... 

The most direct evidence that stereoelectronic effects are also important in these reactions follows from the specificity observed in hydrogen atom abstraction from conformationally constrained compounds,18 60 C-H bonds adjacent to oxygen113"118 or nitrogen110 and which subtend a small dihedral angle with a lone pair orbital (<30°) are considerably activated in relation to those where the dihedral angle is or approaches 90°. Thus, the equatorial H in 20 is reported to be 12 times more reactive towards /-butoxy radicals than the axial 11 in 21.115... 

The interpretation of the basis for this stereoselectivity can be made in terms of the steric, torsional, and stereoelectronic effects discussed in connection with reduction by hydrides. It has been found that crown ethers enhance stereoselectivity in the reaction of both Grignard reagents and alkyllithium compounds.119 This effect was attributed to decreased electrophilicity of the metal cations in the presence of the crown ether. The attenuated reactivity leads to greater selectivity. 

A further test of the stereoelectronic theory of reactivity of phosphate esters has been attempted using measurements of the rates of displacement of 4-nitrophenate from the esters (23) and (24), their phosphorus epimers, and also (25), in aqueous methanol the introduction of the 4a-Me group into the system would, it was hoped, reduce the the flexibility of the bicyclic structures and so possibly eliminate the participation of twist-boat conformations. The presence of the 4a-Me group has no effect of the rate of displacement of the axial ArO group... 

Taira, K. and Gorenstein, D.C., Experimental tests of the stereoelectronic effect at phosphorus Michaelis-Arbuzov reactivity of phosphite esters, Tetrahedron, 40, 3215, 1984. 

Stereoelectronic effects in chemical reactivity The bond-lengthening and -weakening influence of an antiperiplanar lone pair leads to strong stereoelectronic effects on chemical reactivity.97 In molecule 28a with lone-pair-bearing atom D adjacent to an A—B bond, a vicinal nD—s-cab hyperconjugative interaction can be associated (cf. Example 1.4 and Section 3.3.1) with a partial admixture of the alternative resonance structure 28b,... 

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