Stereoelectronic hypothesis

The efTect is simply referred to as "the stereoelectronic effect" (Gorenstein, 1987). The use of a specific acronym is necessary for brevity and to distinguish this very specific stereoelectronic hypothesis from the various other stereoelectronic effects that have been postulated in phosphorus chemistry. 

The ground-state conformations of six-membered phosphorus compounds containing endocyclic heteroatoms adjacent to phosphorus are strongly influenced by the generalized anomeric effect (Kirby, 1983). Exocyclic electronegative phosphorus substituents prefer an axial position, whereas electropositive (i.e. pyridinium) and carbon substituents prefer equatorial. Stereoelectronic effects have also been postulated for transition-state six-membered TBP phosphorus species, based upon a proposed stereoelectronic hypothesis (PAPH, see p. 178). 

Much effort has been expanded in drawing mechanistic inferences from the observation that cofacial bismetalloporphyrins containing a non-redox-active metal ion are fairly selective catalysts (e.g., (DPA)CoM, where M = Lu, Sc, Al, Ag, Pd, 2H, i.e., monometallic porphyrins Fig. 18.15). At least two hypotheses have been proposed (i) polarization of the 0-0 bond in catalytic intermediates by the second ion (on an N-H moiety) acting as a Lewis acid [CoUman et al., 1987, 1994] and (ii) spatial positioning of H+ donors especially favorable for proton transfer to the terminal O atoms of coordinated O2 [Ni et al., 1987 Rosenthal and Nocera, 2007]. To the best of my knowledge, neither hypothesis has yet been convincingly proven nor resulted in improved ORR catalysts. When seeking stereoelectronic rational of the observed av values, it is useful to be mindful that a fair number of simple Co porphyrins are also relatively selective ORR catalysts (Section 18.4.2). 

The elimination reactions discussed above for diethyl ether are suggested to proceed via a transition state with a periplanar geometry. This hypothesis has been tested by studying the stereoelectronic control in the base-induced elimination reactions of cis- and /ra s-4-t-butylmethoxycyclohexane (de Koning and Nibbering, 1987). Both compounds give free and water-solvated methoxide by reaction with OTP, as summarized in (39a) and (39b). 

The stereoselectivity of the second and key Michael-type conjugate addition reaction can be rationalized as follows. The conformation of 63 will be restricted to 63-A due to A(l 3) strain between the N-methoxycarbonyl and w-propyl groups in 63-B. Attack of the vinyl anion from the stereoelectronically favored a-axial direction provides the adduct 64 exclusively. It is noteworthy that the stereochemical course of the above reaction is controlled by the stereoelectronic effect in spite of severe 1,3-diaxial steric repulsion between the axial ethyl group at the 5-position and the incoming vinyl anion. This remarkable stereoselectivity can be also explained by Cieplak s hypothesis[31]. On the preferred conformation 63-A, the developing a of the transition state is stabilized by the antiperiplanar donor Gc-h at the C-4 position. 

The photochemical rearrangement of a -epoxyketones to / -diketones has been studied further. Results with 3-oxo-4,5-oxido-steroids indicate P — a alkyl shifts to be subject to stereoelectronic control, providing selectivity of the migrating group and stereospecificity of the rearrangement. The selective isomerizations of the epoxy-enone (48a)—> (49) at —65 °C and of (48b)— (50) plus (51) at 20 °C support such a hypothesis. Indeed, at higher temperatures even (48a) can be converted into (51), presumably via an additional radical intermediary step. ... 

Figure 3.10 Ideas behind the theory of stereoelectronic control or antiperiplanar lone pair hypothesis (ALPH) Antiperiplanar (sp ) lone pairs are shown shaded.

Taschner and coworkers proposed a similar model based on two other fla-voenzymes the human and E. coli glutathione reductase. The FAD binding domain of glutathione reductase and p-hydroxybenzoate hydroxylase have been shown to resemble each other closely via comparison of their respective X-ray crystal structures. Extrapolating this information to CHMO leads to the proposal that the hydroperoxide is attached to the re-face of the isoalloxazine ring and that the ketone substrates approach the hydroperoxide from the direction of the dimethylbenzene moiety[97). Further stereochemical and stereoelectronic considerations lead to a hypothesis explaining the observed stereoselectivities. 

Many examples of stereoelectronic effects have been proposed in numerous areas of organic chemistry. The textbook example is perhaps the requirement for the anti conformation of the electrons of the scissile C—H bond with the leaving group in the E2 elimination reaction. However, over the past decade, the term stereoelectronic effect has become synonymous with an effect otherwise termed the kinetic anomeric effect or the antiperiplanar lone-pair hypothesis. While it is quite erroneous to label this hypothesis as the stereoelectronic effect , the fact that this situation has come about does serve to emphasize the ascendency of this hypothesis in the minds of many organic chemists. 

If it is assumed that effects on the ground state are amplified in the transition state, this purely empirical thermodynamic anomeric effect is transformed into a predictive kinetic anomeric effect (Kirby, 1983). In the transition state for breakdown of a tetrahedral species containing the X—C—X—C fragment, breakdown of the isomer with the scissile bond antiperiplanar to a heteroatom lone pair will proceed more rapidly, under stereoelectronic acceleration (Scheme 17). The theory has obvious utility in predicting product distribution when a single species may break down by a number of possible pathways (Deslongchamps, 1983). However, the hypothesis has not been without its detractors. Some of the experimental work used... 

Sinnott (1988) discusses ALPH and the generalized anomeric effect in the context of epiphenomena, that is, secondary symptoms, mere concomitants of something else not regarded as its cause or result. It is therefore important in our review to discuss the hypothesized stereoelectronic effect in phosphorus chemistry, but it is essential to describe the theoretical calculations, the interpretation of which has been used to formulate this hypothesis. 

PAPH may be summarized as follows. The effect of an app interaction of sp -hybrid nonbonding electrons on equatorial oxygen with an apical P—O bond, in a phosphorus TBP transition state, is to weaken that apical bond and lower the energy of that pentacoordinate structure relative to other conformers. The hypothesis predicts that (1) a reaction involving such an app interaction will occur faster than a similar reaction where no similar stereoelectronic interaction exists, and (2) a phosphorus TBP will breakdown preferentially via cleavage of an apical P—O bond involved in an app interaction. PAPH may be extrapolated to situations in which heteroatoms other than oxygen are attached to phosphorus. 

Woerpel and Smith [101] assumed that the sulfur substituents might not participate in the chelated transition structure but would instead influence the conformational preference of the oxocarbenium ion intermediate. According to that hypothesis and the stereoelectronic model [101, 102], contrasteric 1,4-c/s product 84 would arise from inside attack of the nucleophile to the lower energy diequatorial oxocarbenium ion 85 (Fig. 4.30). This reaction pathway would provide a lower energy transition structure relative to inside attack of the nucleophile on the diaxial conformer 86 (vide infra) [84, 107] (Figs. 4.30 and 4.31). 

In summary, this mechanistic hypothesis has a number of stereoelectronic features that are tightly coordinated to create an efficient enzymatic process. Formation of H MPT via removal of the axial C-H is favored by the combined stereoelectronic assistance of the lone pairs of the three nitrogen atoms. However, the fnU power of snch assistance in an enzyme would be counterproductive because it would overstabilize the cationic part of the catalytic cycle. Instead, the enzyme imposes a non-planar conformation where excessive stereoelectronic stabilization is avoided. This system illnstrates an interesting connection between geometry, reactivity and enzymatic fnnction. 

Working on the hypothesis that the stereochemical course of squalene biocycliza-tion may be controlled, in part, by stereoelectronic factors rather than by enzymatic conformational influences, a strong asymmetric induction has been achieved in the cyclization of the dienic acetal (97) with SnCl in benzene. The epimeric mixture (98) was oxidized to the octalones (99a and b) which were then separated and their absolute configurations determined. The (stereoselective) yields resulting from the cyclization reaction were 8 and 92 % for (99a) and (99b) respectively. 

This section is devoted to this question through the presentation of a relatively new concept in organic chemistry, stereoelectronic control, exploited by P. Deslongchamps from the University of Sherbrooke (114,115). It uses the properties of proper orbital orientation in the breakdown of tetrahedral intermediates in hydrolytic reactions. This concept is quite different from Koshland s orbital steering hypothesis where proper orbital alignment is invoked for the formation of a tetrahedral intermediate. Here we are interested by the process that follows the cleavage of the tetrahedral intermediate in the hydrolysis of esters and amides. 

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