Stereoelectronic Considerations

For the cleavage to take place it is essential that the electron density is added to, or removed from, the space between the atoms forming the scissile bond [89], In a radical ions the unpaired electron is already localized within the scissile bond. A similar situation exists in dissociative electron transfer cases, where the stretching bond accepts (or loses) an electron. In contrast, within n radical ions the unpaired electron has to be transferred from (or to) the n system into (or from) the scissile bond. Two extreme situations may be visualized [72a, 89, 90] one is termed a n-n fragmentation, the other a n--a fragmentation. 

These effects are minimized for n-o fragmentations, especially those where the intramolecular electron transfer takes place between spatially adjacent orbitals. Somewhat related stereoelectronic considerations apply to nucleophile or base assisted fragmentations where certain three-dimensional dispositions of existing bonds may favor the assistance, in a way related to, for example, the anti stereochemistry of elimination reactions (Sect. 5.2). 

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A pathway (Scheme I) (8.9) for the hydrolysis of oligoglycosides by lysozyme that differs from the previously accepted mechanism (Scheme II) (3,10-12) is described in this section. The alternative pathway, suggested by results of a 55-ps MD simulation of the lysozyme (GlcNAc)e complex (1), is consistent with the available experimental data and with stereoelectronic considerations. Experimental data have demonstrated that Glu 35 and Asp 52 are essential, as shown by recent site-directed mutagenesis results (13.) which corroborate chemical modification studies (3.14 and references cited therein), and that the reaction proceeds with retention of configuration at Ci Q and references cited therein). A fundamental feature of the alternative pathway is that an endocyclic bond is broken in the initial step, in contrast to the exocyclic bond cleavage in the accepted mechanism. 

C. B. Post and M. Karplus, Does lysozyme follow die lysozyme pathway An alternative based on dynamics, structural, and stereoelectronic considerations, J. Am. Chem. Soc., 108 (1986) 1317—1319. 

SCHEME 5.2 Stereoelectronic considerations for the reaction of interconverting conformers of a sialyl oxocarbenium ion. 

For ring closures involving ketone enolates, Baldwin and Lusch modified the original rules as shown below. Again, these empirical rales are based on stereoelectronic considerations. 

The vast majority of stereoselective reactions in organic chemistry, especially in asymmetric synthesis, involve diastereofacial differentiation of a trigonal, sp -atom. The stereoelectronic considerations outlined in the introduction to this chapter afford a rare opportunity in stereoselective synthesis the preparation of a chiral organometallic in which the carbon bearing the metal is stereogenic. As a result of the... 

The reaction of cyclohexene oxide with MeMgX was reexamined in 1969, in work which clearly established the importance of the halide. Standard conditions (1 h at 80 C) were employed with 1.4 equiv. of the organometallic, to give the yields listed under equation (83). Only minor amounts of the normal displacement product (200) are formed from the chloride and bromide, and none from the iodide. The iodide and bromide give extensive rearrangement, with the bromide being more selective in the sense that product (198) is expected on the basis of stereoelectronic considerations (backside displacement of halide) from the rra/is-halohydrin. The unusual product from this perspective is (199). It must arise either from the c/s-halohydrin or a process which is not subject to the same stereoelectronic controls, e.g. via a carbenium ion. 

Post, C. B. and Karplus, M. (1986) Does Lysozyme Follow the Lysozyme Pathway An Alternative Based on Dynamic, Structural, and Stereoelectronic Considerations, J. Am. Chem. Soc. 108, 1317-1319. 

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. 

These terms, introduced by Baldwin in his analysis of the facility of cyclising processes according to stereoelectronic considerations, are well described in Stereoelectronic effects in organic chemistry , Deslongchamps, P., Pergamon Press, 1983. 

The enhanced rate of solvolysis of the exo-isomer (350-fold) as compared to endo isomer is, according to Winstein, due to an intramolecular attack by cj-electrons of the C —C bond on in the transition state of the C —O bond heterolysis. In the endo epimer, since the stereoelectronic considerations require a backside attack, the participation of the C —C bond is impossible. The a-participation of the C —C bond is stereoelectronically feasible and would yield ion 24. This ion could only be attacked by a nucleophile from the endo-side but no such products have been isolated. Seemingly, the participation of the bond would bring about so high an... 

These stereoelectronic considerations and calculations are in full agreement with the experimental results, because only the C4-01 bond cleavage is observed and it is a fast process. This latter observation can also be rationaUzed in terms of stereoelectronic effects, because once protonated at position 01, both lone pairs f and d (which are already partially responsible for the large basicity of the 01 oxygen) immediately provoke C4—01 bond breaking without further backbcaie motion. 

Analysis below will focus on the first order effects of a-lone pair on both kinetics and thermodynamics instead of the second order effects such as the deviations from the Bronsted plots. We will illustrate how basic stereoelectronic considerations can explain why both basicity and nucleophilicity are significantly different in the HOO-/HO-, t-BuOO-/t-BuO-, EifiJRf), NH3/N3H pairs. 

Other examples of this type of stereoelectronic consideration exist, in line with standard mterpretapons of such effects in polar organic reactions. But complications can arise in which the paradigm seems to break down, as in the example shown in Scheme 7.11. In this case, it was proposed that neighboring group participation resulted in a stereochemically labile species (35), leading to loss of stereochemical control.It is thus likely that rapid isomerization interfered with an otherwise mechanistically well-defined process. 

Another promising system involves the concerted acid/base catalysis of enolization of ketones. Stereoelectronic considerations [25] indicate that an optimal catalyst for this reaction requires that acid and base components converge from perpendicular directions on the ketone (Scheme 12). The structure 27 (a glycine derivative of Kemp s triacid) exhibits considerable activity in the enolization of phenylacetone. It should be possible to engineer additional points of contact between ketone (substrate) and diacid (catalyst) to enhance the enolization process, and we are working toward this goal. 

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